28 Mayıs 2012 Pazartesi

İLAÇLARDA TEST VE DENEY VERİLERİNİN KORUNMASI:


İLAÇLARDA
TEST VE DENEY VERİLERİNİN
KORUNMASI:
AVRUPA BİRLİĞİ’NDE YENİ SİSTEM
İKTİSADİ SEKTÖRLER VE KOORDİNASYON GENEL MÜDÜRLÜĞÜ
ANKARA 2005
İLAÇLARDA TEST VE DENEY
VERİLERİNİN KORUNMASI:
AVRUPA BİRLİĞİ’NDE YENİ SİSTEM
HASİBE IŞIKLI
İKTİSADİ SEKTÖRLER VE KOORDİNASYON GENEL MÜDÜRLÜĞÜ
HUKUKİ TEDBİRLER VE KURUMSAL DÜZENLEMELER DAİRESİ
ANKARA, 2005
ISBN 975 – 19 – 3750-7 (basılı nüsha)
Bu Çalışma Devlet Planlama Teşkilatının görüşlerini yansıtmaz.
Sorumluluğu yazarına aittir. Yayın ve referans olarak kullanılması
Devlet Planlama Teşkilatının iznini gerektirmez;
Bu yayın500 adet basılmıştır. Elektronik olarak, 1 adet pdf dosyası üretilmiştir
http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
İÇİNDEKİLER

Sayfa
ÖNSÖZ ................................................................................................................................ 1
BÖLÜM I. İLAÇLARDA TEST VE DENEY VERİLERİNİN KORUNMASI.............. 5
1. GİRİŞ.......................................................................................................................... 5
2. İLAÇ SANAYİİNDE AR-GE SÜRECİ................................................................... 6
2.1. Klinik Öncesi Deneyler.............................................................................................. 7
2.2. Klinik Deneyler.......................................................................................................... 7
3. VERİ KORUMASI/MÜNHASIRIYETİ.............................................................. 8
3.1. Tanım...................................................................................................................... 9
4. PATENT VE VERİ KORUMASI..................................................................... 10
BÖLÜM II. AVRUPA BİRLİĞİ’NDE OLUŞTURULAN YENİ SİSTEM............... 13
1. AB’DE İLAÇLARA YÖNELİK MEVZUATIN GÖZDEN GEÇİRİLMESİ
SÜRECİ (REVIEW 2001).................................................................................... 14
1.1. Reform İhtiyacının Nedenleri................................................................................. 15
1.2. Reform Süreci........................................................................................................ 16
1.3. Mevcut Sistemin ve Komisyon Önerilerinin Değerlendirilmesi............................ 19
1.3.1. Merkezi Ruhsatlandırma Prosedürü................................................................. 20
1.3.2. EMEA-Avrupa İlaç Değerlendirme Ajansı....................................................... 22
1.3.3. Karşılıklı Tanıma Prosedürü............................................................................. 23
2. VERİ KORUMASI DÜZENLEMELERİ.......................................................... 25
2.1. Veri Korumasında Temel İlkeler........................................................................... 28
2.2. Global Ruhsat......................................................................................................... 31
2.3. Bilinen/Tanınmış İlaçların Yeni Endikasyonlarına Veri Koruması....................... 32
2.4. Reçetesiz İlaç (OTC) Sınıfına Değiştirme Durumunda Veri Koruması................ 32
2.5. Bolar İlkesi Uygulaması........................................................................................ 33
2.6. Referans İlaç Tanımı.............................................................................................. 34
2.7. Jenerik İlaç Tanımı................................................................................................ 34
2.8. Biyo-benzerlik İçin Kısaltılmış Prosedürün Uygulanması.................................... 35
2.9. Avrupa Referans İlaç Ürünü.................................................................................. 36
2.10.Ürün Özelliklerinin Özeti (SmPC) ve Patentin Kullanımı ................................... 36
i http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
Sayfa
2.11. Merkezi Ruhsatlandırma Prosedürünce Onaylanmış Referans İlaçların
Jeneriklerinin Ruhsatlandırılması........................................................................ 37
2.12. Merkezi Ruhsatlandırma Prosedürünün Zorunluluk Kapsamı............................. 38
2.13. Ruhsatların Sona Erme Durumu.......................................................................... 38
2.14. Ruhsatların Yenilenmesi...................................................................................... 38
3. AB’NE YENİ KATILAN ÜLKELERDE VERİ KORUMASINA İLİŞKİN
DÜZENLEMELER……………………………………………………………… 39
4. AB’NE ADAY ÜLKELERDE VERİ KORUMASI............................................ 44
BÖLÜM III. TÜRKİYE’DE VERİ KORUMASI.......................................................... 47
1. AB İLE İLİŞKİLER KAPSAMINDA YÜKÜMLÜLÜKLER........................... 47
2. YASAL DÜZENLEMELER................................................................................. 49
2.1. Patent Haklarının Korunması Hakkında 551 Sayılı Kanun Hükmünde Kararname 49
2.2. Tıbbi Farmasötik Ürünler Ruhsatlandırma Yönetmeliği (2.3.1995)....................... 50
2.3. Beşeri Tıbbi Ürünler Ruhsatlandırma Yönetmeliği (19.1.2005)............................. 51
GENEL DEĞERLENDİRME VE SONUÇ..................................................................... 55
KAYNAKÇA....................................................................................................................... 57
EKLER
EK:1. AB’DE İLAÇ MEVZUATININ YASALAŞMA SÜRECİ................................... 61
EK:2. AB ÜLKELERİNDE VERİ KORUMASINA İLİŞKİN MEVZUAT.................. 63
EK:3. BEŞERİ TIBBİ ÜRÜNLER RUHSATLANDIRMA YÖNETMELİĞİ.............. 65
EK:4. 2001/83/EC SAYILI DİREKTİF............................................................................. 81
ii http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
ÖNSÖZ
İlaç sanayii, ürünleri itibariyle diğer sanayii dallarından ayrı ve özel bir önem taşıyan;
sadece üretim boyutuyla değil, sağlık ve sosyal güvenlik boyutuyla da toplumsal düzeyde
önemli etkilere sahip bulunan bir sanayiidir. Ürünlerinin doğrudan insan sağlığı için
kullanılıyor olması, bu sektörde yer alan tüm faaliyetlerin resmi makamlarca sürekli biçimde
kontrole, denetime ve incelemeye tabii tutulmasını gerektiren en önemli faktör olmaktadır.
İlaç sanayiinde diğer sanayiilerde olduğu gibi ürün kalitesi sıralaması yoktur, ikinci ya da
üçüncü kalite bir ilaç üretilmesi mümkün değildir, ilaç her zaman birinci kalite ürün
olmalıdır. Üretim standartları hassasiyetle oluşturulmuş, ilaç üretimi belli koşullara
bağlanmıştır. Ürün pazarlaması, reklamı, satışı serbest değildir; devletin bu faaliyetlere ilişkin
olarak çeşitli denetim mekanizmaları vardır.
İlaç sanayiinde mevcut olan bu özel durum, bu alana yapılacak yatırımların ve
araştırma-geliştirme (Ar-Ge) çalışmalarının değerlendirilmesinde de ortaya çıkmaktadır.
Yüksek standartlarda üretim teknikleri, ileri teknoloji araştırma yöntemleri gibi maliyet
artırıcı faktörler, bu alana yönelik yatırım faaliyetlerinde karar vermeyi zorlaştırıcı olarak
değerlendirilmektedir.
İlaç sanayiinde Ar-Ge özel bir önem ve ayrıcalık taşımaktadır. Bu alandaki Ar-Ge
faaliyetleri doğrudan insan sağlığını iyileştirmeye, hastalıkları tedavi etmeye ve yeni tedavi
yöntemlerini geliştirmeye yönelik olduğundan ülkelerin hükümetlerince desteklenmekte ve
yakından takip edilmektedir. Bu alana yapılan harcamalar ve Ar-Ge maliyetleri de dönemsel
olarak artış göstermektedir. Herhangi bir molekülün ilaç etkin maddesi olarak bulunması ve
ilaç biçiminde piyasaya sunulması için gerekli harcama 1970’lerde 57 milyon $ iken
günümüzde 500 milyon $ düzeyine ulaşmıştır. Yeni ilaçların ve yeni tedavi yöntemlerinin
kullanılmasıyla; hastalar daha uzun yaşamakta, hastanelerde kalma süresi ve doktor
meşguliyetinin azalmasıyla birlikte hasta bakım masrafları da azalmakta, toplamda ülkelerin
sağlık harcamalarında önemli düşüşler kaydedilmektedir. Yeni ilaçların ülke ekonomilerine
1 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
sağladığı çok yönlü katkılar, bu alana yapılan harcamaların desteklenmesi için çeşitli araçlar
geliştirilmesine de yol açmıştır. Bu araçlar arasında “fikri haklar sistemi” oldukça önemli bir
yer tutmaktadır.
Fikri haklar sistemi içerisinde “patent koruması” ve “veri koruması/veri
münhasiriyeti” ilaç sanayiinde Ar-Ge maliyetlerinin karşılanması için alternatif yöntemler
sunmaktadır. Uzun süren araştırmalar ve yüksek harcamalar sonucu bulunan kimyasal
maddeye sağlanan patent koruması ile, bu araştırmaları yapanlar ortalama 20-25 yıllık bir
süre için rakiplerinden korunarak ödüllendirilmektedir. Benzer şekilde, ilaç haline gelen
molekülün etkinlik, kalite ve etkililik test ve deneylerine yapılan harcamalar da, bu verilerin
5-10 yıllık bir süre için veriyi üreten dışında başka firmalara kullandırılmamasıyla
desteklenmektedir. Böylelikle, bir taraftan yeni araştırmaların yapılması ve toplumun yeni
ilaçlardan yararlanması sağlanmakta, diğer taraftan da yüksek maliyetleri göze alarak bu
araştırmaları yapanlar teşvik edilmiş olmaktadır.
Bu çalışmada, “veri koruması” olarak tanımlanan, ilaçların piyasaya sunulmasından
önce yapılması gerekli test ve deneylerin sonucunda elde edilen ve ilacın ruhsatlandırılması
için resmi makamlara sunulması gereken verilerin korunması konusu ele alınmaktadır.
Çalışmanın kapsamı Avrupa Birliği’nde veri koruma düzenlemeleri ile sınırlandırılmıştır.
Avrupa Birliği’nde yirmi yıldan fazla bir süredir var olan veri koruması uygulaması özellikle
son yıllarda yoğun tartışmalara yol açmış; bir taraftan halk sağlığının daha da iyileştirilmesi
amaçlanırken diğer taraftan da Avrupalı ilaç üreticilerinin dünya ölçeğinde rekabet
edebilirliklerinin artırılması hedeflenerek yeni bir sistem yaratılmıştır. Yeni sistem 2005 yılı
sonlarında uygulamaya geçecek olup Avrupa Birliği’ne yeni katılan ve aday statüsünde olan
ülkeler açısından da önemli değişiklikler getirmektedir.
Çalışma üç ana bölümde yapılandırılmıştır. İlk bölümde ilaç sanayiinde Ar-Ge süreci
ve veri korumasına ilişkin genel bir bilgi verilmekte, veri korumasının ilkelerine ve bu
koruma biçiminin patent koruması ile bağlantısına değinilmektedir. İkinci bölümde, Avrupa
2 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
Birliği bünyesinde ilaç sanayiinin durumu, mevcut olan ve getirilen yeni sistemin temel
ilkeleri, veri korumasına ilişkin son yasal değişiklikler ve yeni üye olan ülkeler ile aday
ülkelerdeki veri koruma düzenlemeleri incelenmektedir. Son bölümde ise, Türkiye’nin AB ile
ilişkiler bağlamında veri korumasına ilişkin yükümlülükleri ve bu kapsamdaki yasal
düzenlemeler değerlendirilmektedir.
Bu çalışmanın gerçekleştirilmesinde sırasında, başlangıç aşamasından itibaren
yönlendirici ve destekleyici yorumlarıyla son derece değerli katkılar sunan ve raporun
şekillenmesinde büyük emeği olan Sayın Hülya ÇAYLI’ya; raporu okuyarak üzerinde gerekli
düzeltmelerin yapılmasına yardımcı olan Sayın Osman YILMAZ ve Sayın Derya
FIRATOĞLU’na; metnin biçimsel düzenlemesinde yardımlarını esirgemeyen Sayın Uğur
EMEK’e teşekkür ederim. Bu faydalı katkı ve yardımlara rağmen, çalışmada olabilecek hata
ve eksikliklerin sorumluluğu hiç kuşkusuz ki tamamiyle şahsıma aittir.
3 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
4 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
BÖLÜM I. İLAÇLARDA TEST VE DENEY VERİLERİNİN KORUNMASI
1. GİRİŞ1
Yeni bir ilaç bileşiminin ya da aşının keşfedilmiş olması, onun hastalar tarafından
kullanılabilecek düzeyde etkili ve güvenli bir ürün olduğunu göstermemekte; tam tersine, bu
yeni ürünün toplum tarafından kullanılabilir bir ilaç ya da aşı haline gelmesi için, yetkili
kurumlara ilacın güvenliğini, kalitesini ve etkinliğini gösteren ve yoğun çaba gerektiren bir
dizi klinik deneylerin yapılması gerekmektedir.
Yeni bir ilacın maliyeti, klinik öncesi ve klinik deneme fazlarıyla birlikte
değerlendirildiğinde ortalama 500 milyon $ gerektirmekte ve 15 yıla kadar uzayan bir
zamana yayılmaktadır. ABD’de araştırma üzerine kurulmuş ilaç şirketleri, Ar-Ge’ye 1998
yılında 21,8 milyar $ yatırım yapmışlardır. Bu Ar-Ge harcamalarının % 70’i yasal ruhsat
alma prosedürü için ( % 40 oranında klinik öncesi işlemler, % 30 oranında Faz I, II ve III’ün
yer aldığı klinik deneyler) harcanmıştır. Tek bir tedavi için, klinik deneme evresindeki ilaca
ilişkin tüm testler 150 milyon $ ya da daha fazla maliyete neden olmaktadır. Diğer taraftan,
bu tür yüksek oranda harcamaların yapıldığı ilacı piyasaya sunmak isteyen bir jenerik
üreticinin, eğer kendisinden ruhsat için kendi verisini üretmesi istenmiyorsa,
biyoeşdeğerliğini göstermesi şartıyla sadece 1 milyon $ yatırım yapması yeterli olmaktadır.
Bu durumda jenerik üretici, gerekli tüm test ve deneyler için herhangi bir yatırım yapmadan
orijinal ilaç sahibinin verilerini kullanarak kendisine önemli ölçüde ticari avantaj
yaratmaktadır. Böyle bir durum, ilacın orijinal sahibinin sonuçlarını rakiplerine sıfır maliyetle
anında erişilebilir kıldığından, güçlü ve etkili bir patent korumasına sahip ülkelerde bile
varolan yatırım potansiyelini azaltmaktadır.
1 Bu bölümde “Encouragement of New Clinical Drug Development: The Role of Data Exclusivity”,
International Federation of Pharmaceutical Manufacturers Associations, s:1, 2000, Switzerland, dokumanından
yararlanılmıştır.
5 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
İlaç sanayiinde deney verilerinin korunması, fikri haklar sisteminin hukuki ve
ekonomik anlamda önemli bir bileşenidir. İlacın ruhsatının alınabilmesi için gerekli verinin
üretilmesi hiç şüphesiz ki önemli ölçüde zaman, uzmanlık, kaynak ve paraya yatırımı
gerektirmektedir. Fikri haklar sistemindeki diğer uygulamalara benzer şekilde, ilacı ortaya
çıkaran kişiye bir teşvik unsuru olarak bu maliyetleri geri alabileceği bir ortam yaratılması
gerekli olmakta, bu da rakiplerinin bu veriyi kullanarak jenerik alternatiflerinin ruhsatını
almalarından önce piyasada belli bir süre tek başına yer almalarıyla sağlanmaktadır.
Bu özel koruma biçimi uluslararası platformda yoğun tartışmalara konu olmuştur.
Tartışmalar halen günümüzde de çeşitli boyutlarda devam etmekte, bu alanda ülkeler kendi
koşullarına uygun koruma sistemini oluşturmaktadır. ABD’de genellikle “data exclusivity”,
AB’de ise “data protection” ya da “regulatory data protection” olarak tanımlanan ve bu
çalışmada “veri koruması” olarak adlandırılan bu hak türü bağımsız bir fikri mülkiyet
hakkıdır ve diğer haklarla, özellikle patentle sağlanan koruma ile karıştırılmamalıdır. Bu hak,
sahibi tarafından üretilen verinin bir başka kişi ya da şirket tarafından belirli bir süre için
kullanılamayacağını ya da referans olarak gösterilemeyeceğini ifade eder. Ancak, bir başka
şirketin aynı veriyi üretmesine de engel olmaz. Dolayısıyla ilk bakışta çok sınırlı bir hak
olarak gözükmekteyse de, ülkeler buna büyük önem vermekte ve ihtiyaç duyulan verinin
üretilmesini tıbbi ürünlerin ruhsat (pazarlama izni) sürecine dahil ederek şirketlere gereken
teşvikleri sağlamaktadır.
2. İLAÇ SANAYİİNDE AR-GE SÜRECİ2
İlaç sanayiinde Ar-Ge süreci klinik deneyler öncesi çalışmalar ve klinik deneyler
olarak iki ana bölüme ayrılmakta; her bölümün de alt fazları bulunmaktadır.
2 8.Beş Yıllık Kalkınma Planı İlaç Sanayi ÖİK Raporu için Hülya Çaylı ve Hasibe Işıklı tarafından hazırlanan
rapordan alınmıştır.
6 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
2.1. Klinik öncesi deneyler
• Kimyasal (aktif maddenin araştırması),
• Farmakolojik (toksikoloji, çeşitli hayvan türleri üzerindeki etkilerin incelenmesi),
• Yeni İlacın Denenmesi (yeni ilacın insanlar üzerinde denenmesi süreci için resmi
makamlardan izin alınması),
aşamalarını kapsamaktadır. Bu dönem içerisinde kimyasal ve farmakolojik araştırmalar 2-4
yıl arasında, ilacın denenmesi için izin alınması süreci ise 2-6 ay arasında değişmektedir.
2.2. Klinik deneyler
• Faz I, sağlıklı insanlar üzerindeki etkinin değerlendirilmesi(50-100 kişi)
• Faz II, sınırlı sayıda hasta üzerinde klinik çalışmalar (100-200 kişi)
• Faz III, çok sayıda hasta üzerinde karşılaştırmalı çalışmalar (500-5000 kişi)
• Yeni İlacın Uygulanması (yeni ilacın pazarlanması için resmi makamlardan izin
süreci)
• Faz IV, karşılaştırmalı çalışmaların sürdürülmesi, ruhsatlandırma, piyasaya
sunma,
aşamalarını kapsamaktadır. Bu dönemde süre, ilk üç faz 3-6 yıl arasında, pazarlama izni
süreci 1-3 yıl arasında ve son fazda ise belli bir zaman kısıtı olmaksızın toplam 6-10 yıl
arasında değişmektedir.
Yukarıda belirtildiği üzere, bir kimyasal maddenin buluş aşamasından piyasaya
sunulacak bir ilaç haline gelmesi için minimum 10-15 yıl arasında değişen uzun ve maliyetli
bir “Araştırma Prosesi” gerekmektedir. 1970’li yıllarda bir ilacın Ar-Ge maliyeti 57 milyon $
iken, bu rakam 1990 başlarında 230 milyon $ ve günümüzde ise 500 milyon $ civarına
yükselmiştir.
7 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
3. VERİ KORUMASI/MÜNHASIRIYETİ
Bir ilacın amaçlanan tedavi yöntemi için etkin ve güvenli olduğunun gösterilmesi
için, ilacın buluşçusu tarafından klinik öncesi ve klinik deneyler olmak üzere hayvanlar ve
insanlar üzerinde yoğun testlerin ve aynı zamanda ilacın toksikolojisi, üretim fizibilitesi ve
diğer bilimsel çalışmalarının yapılması gerekmektedir3. Bu testlerin ve çalışmaların sonuçları,
ilacın piyasaya sunulması için hükümet otoritelerine verilecek olan ruhsatlandırma dosyasının
içinde yer alır.
Üretilen veri, yetkili makamlara güvenilerek verilir ve üçüncü kişilerin referans olarak
kullanmaları istenmez. Eğer bu veri, üçüncü kişiler için anında ulaşılabilir olursa, o zaman
firma açısından bu verinin ilk önce kendisi tarafından üretilmesinin anlamı kalmaz. Genel
olarak ilaç ürünleri patent korumasından yararlanmaktadır, ancak herhangi bir nedenle patent
korumasından yararlanmayan birçok bileşik de geliştirilmekte ve bu durumda sadece veri
koruması uygulanabilir bir fikri hak olarak gözükmektedir. Bu verinin gizliliğinin haksız
kullanımlara ya da açıklamalara karşı korunması, daha ileri ilaç Ar-Ge çalışmaları için
ekonomik bir destek sağlaması ve bilim adamlarının çabalarının korunması açısından çok
önemli olmaktadır.
Diğer taraftan, hayvanlar ve insanlar üzerinde yapılan test ve deneylerin tekrarından
kaçınmak üzere, buluşçunun mülkiyet hakkına belli bir sınır getirilmiştir. Bu sınırlı süre sona
erdiği zaman verinin jenerik firmalarca referans olarak kullanımı mümkün hale gelmekte;
böylece, buluşu yapanın yatırımı korunurken aynı zamanda test ve deneylerin gereksiz tekrarı
da önlenmiş olmaktadır.
3 “Encouragement of New Clinical Drug Development: The Role of Data Exclusivity”, International Federation
of Pharmaceutical Manufacturers Associations, s:2, 2000, Switzerland.
8 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
3.1.Tanım4
Veri koruması, bir kuruluşun bir ürünü için ruhsat almak amacıyla devletin ruhsat
otoritesine sunduğu test ve klinik verilerine atıfta bulunarak veya kullanarak, bir başka
kuruluşun ruhsat almak için başvuramadığı bir süreyi ifade eder. Diğer bir anlatımla, ilaçta
veri koruması bir devletin ilaçlara ilişkin ruhsat verileri için sağlaması gereken “ifşa
edilemezlik” ve “isnat edilemezlik” süresidir.
Veri koruması, ruhsatlandırma için başvuruda bulunulan bir ürün hakkındaki bilimsel
bilgilerin, ürün pazarlama izni aldıktan sonra ilgili otorite tarafından belli bir süre ile orijinal
firma lehine münhasıran korunmasını ifade etmektedir. İdari otoritenin bu konudaki
sorumluluğu, orijinal ürün verilerini referans gösteren herhangi bir jenerik ürün başvurusunu,
belirlenen süre içerisinde kabul etmemek/değerlendirmemektir. Farklı bir klinik araştırma
dosyası sunmaları durumunda veya orijinal ilaç şirketinden izin alınması yoluyla bu süre
içinde de jenerik ilaçların piyasaya sürülmesi mümkündür.
Bir ilacın piyasaya sunulması; birincisi yeni bir molekülün/farmasötik bileşiğin
bulunması için gösterilen çalışmalar, ikincisi ise söz konusu molekülün/farmasötik bileşiğin
emniyetli, kaliteli ve etkili bir ilaç olduğunun yetkili otoritelere kanıtlanması için gerekli
deney ve testlerin yapılmasını içeren iki aşamayı gerektirir. Burada birinci aşama çalışmaları
genellikle patent korumasından yararlanmakta, ikinci aşama çalışmaları ise veri koruması
kapsamına girmektedir.
Veri korumasının konusu ilacın bileşiminde yer alan “yeni kimyasal” dır. ABD Gıda
ve Sağlık Kurumu (FDA-Food and Drug Administration) ile Avrupa ruhsat otoriteleri “yeni
kimyasal” kavramını, “daha önceden ilaç olarak ruhsat almamış, tüm geliştirme aşama ve
4 Bu bölüm “İlaçta Veri Korumasının Mali Yansımaları” Baykara T. Prof.Dr., Çaylı H., Çelik H. Uz., Tokat M.
Prof Dr., Ünalan T. Doç.Dr., Bilimsel Çalışma Grubu, Haziran 2003, Ankara, dokumanından alınmıştır.
9 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
testlerinden geçmiş, etkili ve emniyetli olduğu kanıtlanmış yeni bir bileşiktir” şeklinde
açıklamaktadır (65/65 EEC, 87/21/EEC).
AB konuya ilişkin yasal düzenlemelerinde, veri korumasına konu yeni
kimyasal terimi için “Yeni Etkin Madde (New Active Substance)” terimini kullanmış ve
kapsamını aşağıdaki gibi belirlemiştir5.
“Yeni bir kimyasal, biyolojik veya radyofarmasötik etken madde;
• AB’de daha önce tıbbi ürün olarak izin almamış bir kimyasal, biyolojik veya
radyofarmasötik maddeyi içerir.
• AB’de daha önce tıbbi ürün olarak izin almış bir kimyasal maddenin izomeri,
izomerler karışımı, kompleksi veya derivesi veya tuzunu içerir; ancak bu
maddenin emniyet ve etkinlik özellikleri bir önce izin almış olan kimyasal
maddeninkinden farklı olmalıdır.
• AB’de daha önce tıbbi ürün olarak izin almış olan bir biyolojik maddeyi
içerir; ancak molekül yapısı, kaynak materyalin cinsi ve üretim prosesi farklı
olmalıdır.
AB’de daha önce tıbbi ürün olarak izin almamış radyonükloid veya ligand olan
bir radyofarmasötik maddeyi içerir; veya molekül ve radyonükloidi bir arada
tutan bağlanma mekanizması daha önce AB’de onay almamış olmalıdır.”
4. PATENT VE VERİ KORUMASI
Patent ile veri koruması fikri haklar sistemi içerisinde yer alan, birbirine benzemeyen
ancak çeşitli durumlarda birbirine karıştırılan iki ayrı hak türüdür. Bu hakların tek temel
benzerliği, uygulamada hak sahibine bazı münhasır yetkiler vermesidir.
5 “Notice to Applicants, Volume 2A Procedures for Marketing Authorisation, Chapter 1 Marketing
Authorisation” , Final-Revision 1, European Commission, Enterprise Directorate-General, ENTR/F2/BL
D(2002), Brussels, November 2002.
10 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
Yeni bir molekülün ya da ilaç bileşiminin bulunması, buluşla ilgili patent
başvur
Veri korumasından yararlanacak ürünler ise sadece “yeni bir kimyasal madde”
olmalıd
Patent ile veri koruması arasında “hakkın kapsamı” yönünden de fark vardır. Patent
hakkı,
usunun yapılmasına yol açmaktadır. Buluşların patent konusu olabilmeleri için üç
temel kriter vardır: yenilik, tekniğin bilinen durumunun aşılması ve sanayiye uygulanabilirlik.
Burada yenilikten kastedilen tüm dünyada yeniliktir, yani bulunan molekül o ana kadar
dünyanın hiç bir yerinde açıklanmamış ve kamunun bilgisine sunulmamış olmalıdır. Tekniğin
bilinen durumunun aşılması kriteri ise, bulunan yeni molekülün alanın uzmanları tarafından
mevcut teknik yöntemlerin kullanılmasıyla açıkça ve kolayca bulunamaması anlamına
gelmektedir. Son olarak ise, buluşun sanayii üretimine konu olması gerekmektedir; üretim
imkanı bulunmayan bir buluşun patentlenebilmesi mümkün değildir. Dolayısıyla yeni bir
molekülün patent konusu olabilmesi için tüm bu koşulları sağlaması ve patentlendirme
sürecini tamamlaması gerekmektedir.
ır. Buradaki yenilik, patentlenebilirlik kriterlerindeki yenilik ile aynı değildir.
Yukarıdaki bölümde de bahsedildiği gibi; bir ülkede ruhsatlandırma için daha önce başvuruda
bulunulmamış, ilaç olarak geliştirilmesine yönelik gereken tüm testleri yapılmış, güvenli ve
emniyetli olduğu deneylerle kanıtlanmış yeni bir molekül anlamına gelmektedir. Dolayısıyla
bir başka ülkede piyasaya sunulmuş olsa bile, korumanın sağlandığı ülke sınırları içerisinde
ruhsat başvuru yapılmamış bir ürün “yeni” olarak değerlendirilmektedir.
buluşu yapana buluşla ilgili ürününü üretme, satma, satış için teklifte bulunma ve ithal
etme için 20 yıllık bir tekel hakkı verir. Bir başkası patent sahibinin izni olmadan buluşla
ilgili hiçbir tasarrufta bulunamaz. Veri koruması ise, veriyi üretenin ruhsat otoritelerine
sunduğu test verilerini kullanarak bir başkasının ruhsat başvurusunda bulunmasını 5-10 yıllık
bir süre ile engeller ve böylece hak sahibine pazarda tek başına bulunma hakkı verir; ancak,
herhangi bir jenerik ilaç üreticisinin kendi test verilerini üreterek başka bir başvuruda
bulunmasına da engel olmaz.
11 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
Patent ve veri koruması birbirine bağlı koruma biçimleri değildir, nitekim ilacı
oluştur
Her iki hak türü arasında sahip olunan bilginin açıklanması yönünden de önemli bir
fark bu
acak yeni bir molekül patent konusu olmasa dahi veri koruma konusu olabilmektedir.
Ayrıca, patentten doğan hakkın kullanılması doğrudan hak sahibinin talebine bağlıdır, talep
yapıldığı zaman hak tesis edilmektedir. Veri korumasında ise, bu hakkın tesisi ve korunması
görevi tamamiyle devletin yükümlülüğündedir, hak sahibinin talebine bağlı olarak ortaya
çıkan bir hak değildir. Devlet hukuken hakkın korunmasını düzenler, hak sahibi de bu
düzenlemeden yararlanır.
lunmaktadır. Patent başvuruları patent ile sonuçlandığı zaman, buluşa yönelik bilgi
kamunun istifadesine sunulur. Böylece geliştirilmiş olan teknik bilgi, diğer bilimsel
çalışmalara baz teşkil eder. Veri korumasında ise, ruhsatlandırma sürecinin sonunda ilaç
piyasaya çıktığı zaman, bu ilacın geliştirilmesine yönelik bilgi saklı tutulur, ancak koruma
süresi sonunda başkaları tarafından kullanılır hale gelir.
12 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
BÖLÜM II. AVRUPA BİRLİĞİ’NDE OLUŞTURULAN YENİ SİSTEM
Avrupa Birliği’nde (AB) ilaçlara yönelik ilk düzenleme 1960’ların başlarında yaşanan
“thalidomide felaketi”ne bir tepki olan 65/65/EEC sayılı Direktif’tir. Bu direktifin amacı,
kamu sağlığının yüksek düzeyde korunmasını sağlamak ve sürdürmek olarak belirlenmiştir.
Bundan on yıl sonra getirilen iki direktif (75/318/EEC ve 75/319/EEC) ise bu sektörde bir
dönüm noktası olmuş; üye ülkelerin ruhsatlandırmaya ilişkin yetkili makamlarının karşılıklı
tanınmasını sağlamıştır. 1985 yılından itibaren ise, ilaçlarda Avrupa çapında tek pazarın
oluşturulmasına yönelik bir dizi düzenleme kabul edilmiştir.
1992 yılında yine bir dizi mevzuat oluşturulmuş, ilaç ürünlerinde toptan dağıtım,
sınıflandırma, etiketleme ve paketleme ile reklama ilişkin direktifler Konsey tarafından kabul
edilmiştir. Bu dönemde ayrıca, ilaçların zararlı etkilerine ilişkin bilginin toplanması ve
değerlendirilmesi için ulusal sistemlerin kurulmasını gerekli kılan farmakovijilans (ilacın
yaşam süresi boyunca güvenliğinin izlenmesi) ilkesi de getirilmiştir.
İlaçların ruhsatlandırılması için yeni bir sistem yaratan düzenleme seti de (2309/906
sayılı Tüzük, 93/41/EEC sayılı Direktif) 1 Ocak 1995 tarihinde yürürlüğe girmiş; iki farklı
ruhsatlandırma prosedürü getirmiştir. Bunlardan birisi Avrupa İlaç Değerlendirme Ajansı
(European Medicines Evaluation Agency-EMEA) tarafından yürütülen “merkezi
ruhsatlandırma prosedürü (centralised procedure)”, diğeri ise başvuran tarafından seçilen
ülkelerde karşılıklı olarak birbirini tanıyan yetkili makamlar aracılığıyla gerçekleştirilen
“karşılıklı tanıma prosedürü (mutual recognition or decentralised procedure)”dür.
Bu düzenlemelerin ardından 2000 yılında yapılan çeşitli değerlendirmelerin
sonucunda mevzuatın yeniden gözden geçirilmesine (Review 2001) karar verilmiş ve dört yıl
kadar süren bir hazırlık, danışma ve yasama sürecinden sonra 2004 yılında AB’de ilaçlara
yönelik yeni bir sistem getirilmiştir. Bu sistem, her yönüyle çeşitli değişiklikler getirirken,
13 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
ilaçlarda test verilerinin korunmasına yönelik olarak da tam anlamıyla “yeni” bir sistem
yaratmıştır.
1. AB’DE İLAÇLARA YÖNELİK MEVZUATIN GÖZDEN GEÇİRİLMESİ
SÜRECİ (REVIEW 2001)
Avrupa Birliği’nde ilaçlara yönelik mevzuatın yenilenmesi süreci (“Review 2001” adı
verilir) 2001 yılının Temmuz ayında Komisyonca hazırlanan bir dizi yasa önerisi ile başlamış
ve 2004 Mart ayında söz konusu düzenlemelerin yasalaşması ile sona ermiştir. Kamu
sağlığının ileri düzeyde korunması ve iç pazarın tamamlanması, bu reform çalışmalarında ele
alınan iki temel amaç olmuş ve düzenlemeler bu temel amaçlar çerçevesinde oluşturulmuş ve
yönlendirilmiştir. Reform ya da gözden geçirme süreci, ruhsatlandırma prosedürleri,
hastaların bilgilendirilmesi, test verilerinin korunması ve farmakovijilans gibi oldukça
tartışmalı konuları ele almış ve AB’de bu alanda yeni bir sistem yaratmıştır.
Bu gözden geçirme sürecindeki çalışmalar, Komisyon tarafından aynı süre içinde
oluşturulan ve “G10 Medicines”6 adı verilen ve ulusal hükümetlerin yetkilileri, sanayiciler,
hastalar ve sağlık sigorta kuruluşlarının (mutualities) üst düzey temsilcilerinden oluşturulmuş
bir grup tarafından da desteklenmiştir. Grubun amacı, bir taraftan halk sağlığının yüksek
düzeyde korunmasının temin edilmesi, diğer taraftan da sanayinin rekabet gücünün
artırılması için Avrupa çapında bir girişim başlatmak olmuştur. Gözden geçirme süreciyle
aynı amaçlara sahip olan bu grubun oluşturulmasındaki temel neden, endüstrinin karşılaştığı
sorunların tek başına mevzuat ile çözülemeyeceğinin anlaşılması ve bunun ulusal eylemlerle
de desteklenmesi ihtiyacıdır. Grubun hem ulusal düzeyde hem de Avrupa düzeyinde, yetkili
tüm taraflar arasında bir köprü görevini üstlenmesi hedeflenmiştir.
6 “A Stronger European-based Pharmaceutical Industry for the Benefit of the Patient (G10 Medicines), Speech
for Mr. Erkki Liikanen (Commissioner for Enterprise and Information Society), 25 February 2004, Alliance
UniChem Seminar.
14 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
1.1. Reform İhtiyacının Nedenleri
Avrupa ilaç sanayi, Avrupa’nın en iyi performansa sahip yüksek teknoloji
sektörlerinden biridir. Üretim, katma değer, yüksek nitelikli istihdam, Ar-Ge ve ticaret fazlası
gibi standart göstergelerde oldukça başarılı olan bir sanayi dalıdır. AB ticaret dengesine
önemli bir pozitif katkı sağlamakta, mevcut yüksek nitelikli işgücü ise Avrupa bilimsel
tabanının sürekliliğini sağlayan önemli bir kaynak olarak görülmektedir7. Ayrıca, sanayinin
ürettiği etkili ve güvenli ilaçlar ile hastalara sağladığı büyük faydanın da hepsinden daha
önemli bir unsur olduğu ifade edilmektedir.
Avrupa kökenli ilaç sanayi 1990’lı yıllara kadar dünyada en güçlü sanayi dalı olmuş,
ilaçlarda Ar-Ge ve yenilikte dünya lideri konuma gelmiştir. Ancak, sanayiinin bu öncü
pozisyonu özellikle 1990’ların ikinci yarısından sonra gerilemeye başlamış ve 1997 yılında
ABD ilaç sanayi ilk kez, Avrupalı rakiplerinin yerini almıştır. Günümüzde yeni kimyasallar
ve biyolojik maddelerin keşfinde ABD önde gitmektedir. 1999-2003 döneminde geliştirilen
171 yeni kimyasal ve biyolojik maddenin 73 adedi ABD (% 43), 62 adedi Avrupa (% 36)
kökenlidir8. Bu durum, 1990 yılından itibaren ABD’de ilaç araştırmalarına yapılan
harcamanın, Avrupa’da yapılan harcamanın iki katına ulaşmasının bir sonucu olarak
görülmektedir. 1990-2003 döneminde Ar-Ge yatırımları Avrupa’da 2,6 kat artarken ABD’de
4 kat artış göstermiştir.
Avrupa ilaç sanayiinde Ar-Ge alanında görülen bu gerileme, geliştirilen yeni ilaçların
dünya pazarlarındaki payları açısından daha çarpıcı sonuçlar vermektedir. Bu alandaki
gerileme daha fazla olmuş, ABD kökenli firmalar dünyada en çok satılan yeni ilaçlardaki
paylarını önemli ölçüde artırmışlardır. 1998-2002 döneminde dünya piyasalarında satılan
yeni ilaçların % 70’i ABD’de, % 18’i de Avrupa’da üretilmiştir.
7 A.g.e., p:4.
8 “The Pharmaceutical Industry in Figures 2004”, EFPIA, Brussels.
15 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
2002 yılındaki Ar-Ge harcamaları açısından en büyük 40 firma arasında ABD ile
başabaş giden Avrupa’nın (14 ABD, 14 Avrupa, 12 Japon firması) hem yeni kimyasalların
keşfinde hem de dünya pazarlarındaki payının bu şekilde gerilemesindeki nedenlerin
araştırılması ve sanayiinin rekabet gücünün yeniden artırılmasına yönelik yeni girişim
gerekliliği böylece ortaya çıkmıştır.
1.2. Reform Süreci
Avrupa ilaç sanayinin ABD’li firmalar karşısında rekabet gücünü kaybetmesinin
nedenleri araştırılırken mevcut sistem yeniden ele alınmıştır. Mevcut sistem, ilaç sanayiinde
ortaya çıkan bu sorunları gidermeyi amaçlayan ve 1995 yılında yürürlüğe giren yeni
ruhsatlandırma (merkezi ruhsatlandırma ve karşılıklı tanıma) ve izleme prosedürlerini9
içermektedir. Bu sistemin ana düzenlemesi 2309/93 sayılı Tüzük’tür ve Tüzük kapsamında
Komisyona bir görev yüklenmiştir. Buna göre Komisyon, uygulamanın başlamasından
itibaren altı yıl içerisinde, sistemi izleyecek ve amaçlara ne kadar ulaşıldığını gösteren bir
raporu hazırlayacaktır. Bunun yanısıra, bilimsel ilerlemenin son derece hızlı olması ve sürekli
biçimde yeni tedavilerin geliştirilmesi de Komisyonca ortaya konmuş olan; ilaçların serbest
dolaşımının sağlanması, kamu sağlığının yüksek seviyede korunması ve yeni jenerasyon
ilaçların üretilmesi hedeflerinin halen geçerliliğini korumakta olduğunu göstermiştir10.
Dolayısıyla zaten Tüzük’ten kaynaklanan yasal bir gereklilik olan sistemin gözden
geçirilmesi, sorunların devam etmesi nedeniyle daha sistematik bir şekilde ele alınmıştır.
Mevcut yasal düzenlemelerin AB ülkelerinde uyumlaştırılması ve geleceğin pazarlarında yer
alacak ilaçların ruhsatlandırılması için daha basit bir yöntem geliştirilmesi gibi düşünceler
daha sık ifade edilir olmuş ve Komisyonun başlattığı girişimi güçlendirmiştir.
Komisyon bu amaçlarla, ilk olarak bu alanda sektörün tüm yönleriyle analizini
öngören bir çalışma başlatmıştır. Çalışmanın ilk sonucu 2000 yılında Cameron McKenna ve
9 93/39/EEC, 93/40/EEC, 93/41/EEC Direktifleri ve 2309/93 sayılı Tüzük.
10 “Review of Pharmaceutical Legislation”, Discussion Document (Final Version), European Commission,
Enterprise Directorate-General, 22 January 2001, Brussels.
16 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
Andersen Danışmanlık Şirketi’nin raporunun11 yayınlanması olmuştur. Rapordan da
esinlenerek Komisyon, ilaçlara ilişkin yasal düzenlemelerin gözden geçirilmesinde 7 temel
hedef belirlemiştir12:
1. Avrupa vatandaşlarına olabildiğince güvenli ve yeni ürünler aracılığıyla yüksek
sağlık koruması garantisini vermek,
2. Farmakovijilans sürecinin güçlendirilmesiyle piyasanın daha sıkı izlenmesini
sağlamak,
3. Veteriner ilaçlarında ilaç sayısının artırılmasıyla hayvan sağlığının daha iyi
korunmasını sağlamak,
4. Küreselleşmenin de dikkate alınmasıyla ilaçlarda tek pazarın tamamlanmasını
sağlamak,
5. Avrupa ilaç sanayiinin rekabet edebilirliğini teşvik edici yasal bir çerçeve
oluşturmak,
6. AB genişlemesinin yaratacağı zorlukların üstesinden gelmek,
7. Sistemi modernleştirme ve mümkünse basitleştirme (“daha iyi düzenleme”)
fırsatını değerlendirmek; böylelikle sistemin tutarlılığını, profilini ve karar alma
sürecinin şeffaflığını geliştirmek.
Belirlenen bu hedefler çerçevesinde Komisyon bir düzenleme seti tasarısı hazırlamış
ve bu düzenleme seti 8 Temmuz 2001 tarihinde görüşülerek kabul edilmiştir13. Komisyonun
teklifi 3 temel düzenlemeyi içermiştir: ruhsatlandırmaya ve Avrupa İlaç Değerlendirme
Ajansı’nın (European Medicines Evaluation Agency-EMEA) fonksiyonlarına ilişkin bir taslak
tüzük, beşeri ilaçlar için bir taslak direktif ve veteriner ilaçları için bir taslak direktif.
11 “Evaluation of the Operation of Community Procedures for the Authorization of Medicinal Products”, CMC
Cameron McKenna and Andersen Consulting, carried out on behalf of the European Commission Directorate-
General Enterprise Pharmaceuticals and Cosmetics, 17 November 2000.
12 Bu hedefler Komisyon çalışmaları sonuçlanıncaya kadar değişmemiş ancak, ilk 3 hedefin tek bir başlıkta
toplanması ve 4 ile 5 inci hedeflerin de birleştirilmesiyle sonraki Komisyon yayınlarında 4 temel hedefe
indirgenmiştir.
13 “Commission Proposes Comprehensive Reform of EU Pharmaceutical Legislation”, IP/01/1027, European
Commission, Brussels, 18 July 2001.
17 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
Mevcut sistemi uyumlaştıran, modernleştiren ve basitleştiren önemli bir girişim olan bu
düzenlemeler, karar alma yöntemi ve sürecinde daha çok şeffaflığı getirirken, mevcut
ruhsatlandırma prosedürlerinin temel ilkelerinde herhangi bir değişiklik yaratmamıştır.
Bu düzenlemelerin temel hedeflerinden biri, 1995 yılında merkezi ruhsatlandırma
prosedürünün uygulanmasıyla ilaçların tüm üye ülkelerde aynı anda piyasaya sunulmaları
amacıyla kurulmuş olan EMEA’nın sadece biyoteknoloji ürünü ilaçlarda değil, daha geniş bir
yelpazede yer alan yeni ilaçlara uygulanabilmesi ve yeni uzmanlar ve çalışma gruplarının
eklenmesiyle EMEA’nın bilim komitelerininin güçlendirilmesidir. Ayrıca, EMEA’nın ilaçları
ilgilendiren tüm bilimsel konularda; uluslararası faaliyetlerdeki etkinliği artırılmış ve
ruhsatlandırma için gerekli tüm deney ve testlere başlamadan önce şirketlere bilimsel öneriler
sunma alanındaki rolü de güçlendirilmiştir.
Taslak düzenlemelerle, kaliteli, etkili ve güvenli yeni ilaçların Avrupa pazarına bir an
önce girmeleri ve her an bulunabilir olmalarını artırmak hedeflenmiştir. Belirli tedavi
gruplarındaki ilaçlar için “hızlı (fast-track)” ruhsatlandırma süreci getirilmiş; böylelikle bu
ürünlerin ABD’de uygulanan ruhsat verme süreciyle eş anlı olarak Avrupa’da da hızlı bir
şekilde incelenip ruhsatlandırılmaları öngörülmüştür. Bu süreç ile inceleme süresi iki ay
kısaltılmış, böylelikle ABD’de de öncelikli inceleme sistemine göre 30 gün daha erken sonuç
alınması öngörülmüştür14. Buna ek olarak, bir yıllık bir süre için “şartlı ruhsatlandırılma
(conditional marketing authurisation)” yöntemi getirilmiştir. Bu yöntem, “şefkatli
(compassionate) kullanım” durumunda önem kazanan bir uygulama olacaktır. “Şefkatli
kullanım” hükmü de yeni bir uygulama biçimi olup, kronik ya da ciddi bir şekilde kuvvetten
düşüren hastalığı olan ya da yaşamı tehdit edici hastalığı bulunan ve ruhsatlı bir ilaçla iyi bir
şekilde tedavi edilemeyen hastalarda, geliştirilen yeni ilacın ruhsatlandırma öncesi
kullanımına izin veren bir hükümdür. Böylelikle, hasta sağlığı için önemli yarar sağlayacağı
düşünülen ilaçlarda, şirketin de ek klinik çalışmalar ve izleme yapmayı kabul etmesi halinde,
şartlı ruhsat verilecek ve 1 yıl sonunda bu ruhsat gözden geçirilerek ya normal ruhsat
14 “EU Surprises Itself by Agreeing to Pharma Rules” O’Donnell, P., Applied Clinical Trials, Feb 1, 2004.
18 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
başvurusuna konu olacak ya da klinik deneylerin sürdürülmesi mecbur tutulacaktır. Bu
yöntemin hastaların sağlığına önemli derecede yarar sağlayacağı ve şirketlerin süre sonunda
yeniden gözden geçirilecek olan ek bir izleme ve klinik çalışma yapmayı üstlenecekleri
düşünülmüştür. Bunların yanısıra getirilen bu yeni tedbir ile, “şefkatli kullanım” için
“ruhsatlandırma öncesinde” ilaçların Avrupa çapında bulunabilir olması da sağlanmaktadır.
Liikanen’e15 göre bu uygulama ile; belli bir şirket tarafından belli bir hasta grubunda
sürdürülen klinik deneylerin, yer farkı gözetilmeksizin diğer hastaların da kullanımına
açılması sağlanacaktır. Ayrıca bu uygulama, ruhsatlandırmanın incelenmesi esnasında
tedavinin de sürdürülmesini gerektirdiğinden, klinik deneylerde hastaların daha güvenli ve
başarılı bir şekilde tedavi edilmelerini sağlayacaktır.
Komisyon teklifi ayrıca, hem yenilikçi hem de jenerik ilaç sanayiin rekabet
edebilirliğini geliştirecek mekanizmaları da ortaya koymuştur. İlaçların ruhsatlandırılmasında
sunulan verinin korunmasını içeren ulusal idari koruma süreleri 10 yıl olarak
uyumlaştırılmakta; böylece yenilikçi ilaç sanayiine, jenerik ürünlerin
ruhsatlandırılmalarından önce kendi yatırımlarını telafi etmek için daha uzun zaman
tanınmaktadır. Jenerik ilaç sanayi için ise, Avrupa’da uygulanacak jenerik ilaç ruhsatları için
gereken testlerin fikri hak koruma süresi bitmeden önce başlatılabileceği hükmü
getirilmektedir.
1.3. Mevcut Sistemin ve Komisyon Önerilerinin Değerlendirilmesi16
AB Komisyonu’nun 2001 yılında hazırladığı yasa teklifi yasama süreci dahilinde
çeşitli aşamalardan geçerek 2 Haziran 2003 tarihinde Sağlık Bakanları Konseyi’nde
görüşülmüştür. Burada bazı değişikliklere uğramış, son olarak da 18 Aralık 2003 tarihinde
Avrupa Parlamentosu’nda görüşülerek nihai metne dönüşmüştür. Avrupa Parlamentosu’nun
15 A.g.e.
16 “Reform of EU Pharmaceutical Legislation”, MEMO/01/267, European Commission, Brussels, 18 July 2001
ve “Reform of EU Pharmaceutical Legislation”, MEMO/03/262, European Commission, Brussels, 18 December
2003 dokumanlarından yararlanılmıştır.
19 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
önerdiği değişiklikler Konsey tarafından da kabul edilmiş ve düzenleme seti 30 Nisan 2004
tarihinde Topluluk Resmi Gazetesi’nde yayımlanarak yürürlüğe girmiştir. Sistemde getirilen
değişiklikler bu bölümde daha detaylı ele alınacaktır.
1.3.1. Merkezi Ruhsatlandırma Prosedürü
Avrupa Birliği’nde merkezi ruhsatlandırma prosedürü, yüksek teknoloji gerektiren
yenilikçi ilaç ürünlerinde ve özellikle biyoteknolojik ürünlerde zorunlu olarak
kullanılmaktadır. Bunun yanısıra, yeni geliştirilen ilaçların üye ülkelerin tümünde
ruhsatlandırılması istendiğinde de kullanılan bir yöntemdir. Merkezi ruhsatlandırma
prosedürü EMEA tarafından uygulanır. Yeni düzenleme ile bu sistem daha geniş bir ürün
yelpazesine yayılmış, son dönemde piyasanın gereklerini ve özellikle belli hastalık
alanlarında tek, yani tüm üye ülkelerde geçerli bir bilimsel değerlendirmeye duyulan ihtiyacı
karşılamayı da amaçlamıştır. Bu sistemde getirilen değişikler aşağıda verilmektedir:
1. Komisyon, merkezi ruhsatlandırma prosedürünün zorunlu olarak uygulanacağı
ilaç ürünlerinin bütün yeni aktif maddelere genişletilmesini, yani herhangi bir üye
ülkede ilaç olarak onay almamış tüm maddelerin bu prosedüre dahil edilmesini
teklif etmiştir. Ancak, görüşmeler sonunda bu hüküm daraltılmış ve sadece
“herhangi bir ülkede onaylanmış bir ilacın parçası olmayan, AIDS, kanser, şeker
ve sinir bozukluğu hastalıklarının tedavisinde etki gösteren tüm maddeler” olarak
kapsam belirlenmiştir. Nadir hastalıklara tahsis edilen ilaçlar da zorunlu olarak
merkezi ruhsatlandırma prosedürüne tabi tutulacaktır. Bu prosedür yeni mevzuatın
yürürlüğe girmesinden 4 yıl sonra, antiviral ve bağışıklık sistemi hastalıklarının
tedavisinde etkili iki yeni ilaç kategorisine genişletilecektir. Sistemde ayrıca bir
“gözden geçirme hükmü” de öngörülmektedir.
2. Merkezi ruhsatlandırma prosedürü,
• Başvuruyu yapan tarafından önemli bir yenilik getirdiği ortaya konan ya da
hastalar ya da hayvanlar için bir Topluluk kararı olan herhangi bir ürüne,
20 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
• Topluluğun hastalıklardan koruyucu ilkelerine tabi imunolojik veteriner
ilaçlarına,
• Merkezi ruhsat almış ilaçların jeneriklerine,
istenildiği zaman uygulanabilir olacaktır.
3. Ruhsatlandırma prosedürünün uygulama basamakları, hem insan hem de veteriner
ilaçları için temelde aynı kalmıştır.
4. Ruhsatlandırma prosedürü, farklı aşamalardaki nihai tarihlerin bazılarının
kısaltılması aracılığıyla hızlandırılmıştır.
5. Kamu sağlığı ve teropatik yenilik açısından büyük ölçüde yarar görülen ilaçlarda
hızlandırılmış değerlendirme prosedürleri (fast-track procedures) öngörülmüştür.
6. Olağanüstü durumlarda şartlı ruhsat (conditional marketing authorisation) alma
imkanı getirilmiştir.
7. İnsanlarda ilaçların “şefkatli kulanımı (compassionate use)” yönünden EMEA,
bunun başvurulacağı ülkelerde uygulama koşullarını belirleyerek tavsiyelerde
bulunabilecektir.
8. Ruhsatların geçerliliğine yönelik süre limitinin kaldırılması ve ruhsatlara sınırsız
geçerlilik sağlanması Komisyonca önerilmiş; ancak bu hüküm daha sonra
“ruhsatın verilmesinden sonraki ilk beş yıllık yenilemeden sonra, farmakovijilans
nedenlerine bağlı küçük değişiklikler getirilmediği sürece ruhsatlar sınırsız geçerli
olacaklardır” şeklinde düzeltilmiştir.
9. Ruhsat sahibi ürününü gerçek anlamda belirli bir süre piyasada bulunduracak, aksi
halde olağanüstü durumlar ve kamu sağlığı nedenleri dışında ruhsatların
geçerliliği sona erecektir. Ayrıca, ilacın üye ülke piyasalarında gerçekten var
olduğu sürelerin ya da ürünün piyasada satılmasına son verilmesi halinde bu
durumun EMEA’ya bildirilmesi zorunluluğu bulunmaktadır.
10. Farmakovijilansın da yer aldığı güvenlik raporları düzenli olarak hazırlanacak ve
mevcut sistemde olduğundan daha sık bir şekilde gözden geçirilecektir.
21 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
1.3.2. EMEA-Avrupa İlaç Değerlendirme Ajansı
Komisyon, EMEA’nın bilimsel komitelerinin ve Yönetim Kurulunun oluşumu ve
yapısının AB’nin geleceğe yönelik genişlemesi dikkate alınarak gözden geçirilmesini teklif
etmiştir. Buna gerekçe olarak, EMEA’nın faaliyet alanının sadece ilaçlara ruhsat verme
sürecindeki değerlendirme ile sınırlı kalmadığını, bilimsel danışmanlık rolünün giderek
arttığını; EMEA’nın şirketlere özellikle küçük ve orta büyüklükteki işletmelere
biyoteknolojik ya da yenilikçi ürünleri geliştirmeleri için bilimsel tavsiyeler vermeye yetkili
kılındığını; dünyada bazı ülkelerde piyasaya sunulması istenen belli ilaçların
değerlendirilmesi için Dünya Sağlık Örgütü (World Health Organisation-WHO) ile yakın
işbirliğinin vazgeçilmez olduğunu göstermektedir.
Komisyon ayrıca, ruhsat sahiplerinin sahip oldukları ruhsatlarla bağlantılı belirli
zorunlulukları gözlemlemeleri hususunda başarısız olmaları durumunda, ruhsat sahiplerine
doğrudan mali müeyyideler yükleme imkanının verilerek EMEA’nın gözetici fonksiyonunun
kuvvetlendirilmesi gerektiğini de savunmaktadır.
Bu kapsamda getirilen yeni sistem aşağıdaki gibidir:
1. EMEA’nın yapısı, zaten var olan “Nadir İlaçlar Komitesi (Committee Orphan
Medicinal Products)” ve yeni bir yasa ile oluşturulacak olan “Bitkisel İlaçlar
Komitesi (Committee of Herbal Medicinal Products)” gibi belirli Komitelerin
eklenmesiyle tamamlanmıştır.
2. Komisyon ulusal otoritelerin temsilcilerinden oluşan ve ruhsatlandırma
prosedürlerinde istişari görev yapacak bir Danışma Kurulu oluşturulmasını
önermiş ancak bu hüküm kabul görmemiştir.
3. Farklı alanlarda uzmanlık grupları, çalışma grupları, bilimsel komitelerin
oluşturulması ve bunlara farklı görevlendirme yapılabilmesi hususlarında daha
22 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
fazla esneklik getirilmiştir. Ayrıca, gerektiği zaman AB dışından uzmanlardan
yararlanma imkanı da sağlanmıştır.
4. Yönetim Kurulu’nun yapısı, AB’nin gelecekteki genişlemesi ve sivil toplum
kuruluşlarının temsil edilmesi gözönünde bulundurularak yeniden gözden
geçirilmiştir.
5. EMEA, uluslararası uyum arayışlarının çerçevesinin belirlenmesinde daha aktif
bir şekilde katkıda bulunacaktır.
6. EMEA, merkezi ruhsatlandırma prosedürü altında izin verilen paralel dağıtım
durumuna uyan ruhsatlandırma işinde ve ilaçlarla ilgili Topluluk mevzuatında yer
alan şartların yerine getirilmesini sağlamak ile görevlendirilmiştir.
7. EMEA’nın komiteleri oluşturmakla görevli bölümü, EMEA’nın Yöneticisine ve
talep edildiği durumda Komisyona, ilaçları ilgilendiren bilimsel konularda görüş
hazırlamak için yardımcı olacaktır.
8. EMEA’ya mali müeyyide uygulama yetkisi verilmiştir.
1.3.3. Karşılıklı Tanıma Prosedürü
Karşılıklı tanıma prosedürü AB bünyesinde az sayıda ülkede uygulanmakta ve
Avrupa pazarının sadece sınırlı bir bölümü için düşünülen ilaçlarda, özellikle veteriner
ilaçlarında, önemli bir kolaylık/esneklik sunmaktadır. Bu prosedür ile ilgili olarak yapılan en
önemli eleştiri, sürenin çok uzun olduğu ve uygulamada üye ülkelerin bir diğer ülkede
alınmış ruhsatı ve bilimsel değerlendirmeyi tanımadığı şeklindedir. Sistemin işlerlik
kazanması için gayri resmi olarak çalışma grupları (MRFG: Mutual Recognition Facilitation
Group, VMRFG: Veterinary Mutual Recognition Facilitation Group) oluşturulmuş ve büyük
başarı sağlanmış olup, bu grupların yasal bir zemine oturtulmaları yönünde de eğilim
bulunmaktadır.
Komisyon ayrıca, farmakovijilans önlemlerinin izlenmesi için yasal bir çerçeve
geliştirilmesi gerektiğini düşünmüştür. Mevcut kurallara göre, acil durumlarda üye ülkeler
23 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
kendi bölgelerindeki bir ruhsatı, Topluluk düzeyinde gerekli izleme sonuçları
tamamlanmadan yürürlükten kaldırabilmektedir.
Bunun yanısıra Komisyon, gen tedavisi ve hücre tedavisine yönelik tıbbi tedavilerin
yeni ya da gelecekteki biçimlerini kapsayacak ve yenilikçi ilaçlar ile jenerik ilaçlar arasında
optimal bir denge sağlayacak yeni bir düzenleyici çerçeveye ihtiyaç olduğunu da tespit
etmiştir. Komisyon ayrıca, ulusal ruhsatlı ilaçlar için sağlanan veri koruma (data protection)
süreleri ve patent koruması ile bağlantılı veri koruması uygulamalarının uyumlaştırılmasına
dikkati çekmiştir.
Bu çerçevede gerçekleştirilen değişiklikler şu şekildedir:
1. Ulusal ruhsatlandırma prosedüründeki sürenin 210 günden 150 güne indirilmesi
önerilmiş, ancak bu hüküm kabul görmemiştir.
2. Karşılıklı tanıma prosedürü;
• bir üye ülkede önceden ruhsat almış bir ilaç olup olmadığına bağlı olarak
farklı uygulama şekillerinin getirilmesiyle,
• kamu sağlığı riski kavramının daha kesin bir şekilde tanımlanmasıyla,
• mevcut MRFG ve VMRFG’ya yasal ve resmi bir statü verilmesiyle,
• kamu sağlığı için ciddi risk konusundaki itirazların düzgün bir şekilde
değerlendirilmesi ve gerekli izleme tedbirlerinin alınmasını sağlamak ve ayrıca
değerlendirme prosedüründeki süreleri kısaltmak amacıyla arabuluculuk evresinin
iyileştirilmesi,
gibi önlemlerle kolaylaştırılmaktadır.
3. Bir üye ülkede alınan acil bir önlem Avrupa düzeyinde değerlendirilecek ve
gerekiyorsa bütün üyelerde de uygun tedbirler alınacaktır.
4. İlaçlarda başlatıcı maddeler olan aktif maddelerin üretimine ve kullanımına ilişkin
rehber ilkelerin belirlenmesi için Komisyon yetkilendirilmiştir.
5. İlaç ürünlerinin tanımı, yeni tedavileri de içerecek şekilde değiştirilmiştir.
24 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
6. Veri koruma süresi, merkezi ruhsatlandırma prosedüründeki süre ile
uyumlaştırılmıştır. Normal bir veri koruma süresine sahip olan ilaçla ilgili olarak,
hastalara önemli bir yarar sağlayacak yeni bir tedavi endikasyonu geliştirilirse bir
yıllık bir ek koruma süresine daha izin verilecektir.
7. Jenerik ilaç terimi ve biyo-benzer ilaç terimi getirilmiş ve mevzuatta
tanımlanmıştır.
8. Referans ilaca verilen ek koruma sertifikasının geçerliliği esnasında jenerik bir
müracaatın hazırlanması ve yapılabilmesi imkanı getirilmiştir.
9. Belirli homeopatik ilaçlar için basitleştirilmiş tescil prosedürünün oluşturulması
seçeneğinin bir zorunluluk haline getirilmesi önerilmiş ancak kabul görmemiştir.
10. Veteriner ilaçlarında veri koruması süresine yönelik özel tedbirler getirilmiş, 10
yıllık veri koruma süresi, firmanın alacağı ruhsatın kaç hayvan türü için olduğuna
bağlı olarak genişletilmiştir.
Böylelikle Temmuz 2001’de başlayan uzun bir gözden geçirme sürecinden sonra,
Avrupa Komisyonu, Avrupa Parlamentosu ve Avrupa Konseyi, Aralık 2003 tarihinde
Parlamento tarafından kabul edilen ve Mart 2004 tarihinde de Konsey tarafından resmi olarak
uzlaşılan ortak tutum üzerinde fikir birliğine varmıştır. Düzenlemelerin 10 yeni üye ülkenin
AB’ne katılım tarihi olan 1 Mayıs 2004 tarihinden önce yasalaşması AB yönetimi için bir tür
zorunluluk olarak görülmüş ve çalışmalar bu takvime göre sonuçlandırılmıştır. Ek.1’de yer
alan tabloda AB’nde yasama sürecinin aşamaları özetlenmektedir. Bu yasama sürecinde
Ortak Karar usulü (Co-decision procedure) uygulanmıştır.
2. VERİ KORUMASI DÜZENLEMELERİ
AB Komisyonu tarafından başlatılan 2001 gözden geçirmesine temel teşkil eden
Cameron McKenna&Andersen Danışmanlık Şirketi’nin raporunda, ilaçlarda test verilerinin
korunmasına ilişkin koruma sürelerinin ve Birlik içerisinde farklılık arzeden ruhsatlandırma
sistemlerinin üye ülkelerde uyumlaştırılması hususunda genel bir fikir birliği olduğu ve
25 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
65/65/EEC sayılı Direktifin 4/8(a)(iii)17 maddesinin mevcut halinden daha açık bir tanıma
ihtiyaç bulunduğuna ilişkin genel bir bakış açısı bulunduğu ifade edilmektedir18.
Benzer şekilde “G10 Medicines19” grubunun çalışmalarında, fikri haklar ve veri
korumasının sanayinin rekabet gücünün artırılmasında ve yenilikçi ürünler ortaya
çıkarılmasında önemli rolü bulunduğu, mevcut ürünlerin yeni tedaviler için geliştirilmesine
imkan tanınması ve jenerik ilaçların mevcudiyetinin sağlanması için uygun bir koruma
düzeyinin olması gerektiği tespiti yapılmıştır. Bu çalışmaların sonucunda ortaya çıkan 26
Şubat 200220 tarihli raporda da öneriler arasında; yenilikçi ilaçlar için yeterli fikri hak
korumasının sağlanması ile jenerik ürünlerin piyasaya girişini kolaylaştıran Bolar ilkesinin
getirilmesi arasında uygun bir denge oluşturulmasına yönelik bir yöntem geliştirilmesi yer
almaktadır.
Avrupa Birliği’nde veri koruması ilk olarak 65/65/EEC sayılı Direktifin 4/8(a)(iii)
maddesi ile düzenlenmiş ve daha sonra 1987 yılında 87/21/EEC sayılı Direktif ile
değiştirilmiştir. Değişiklik ile amaçlanan, insanlar ve hayvanlar üzerinde yapılan testlerin
gereksiz yere tekrarının önüne geçmek ve yenilikçi ilaç endüstrisini de koruyucu önlem
getirmek olmuştur21. Bu nedenle jenerik ilaç üreticileri için, yeniden kendi çalışmalarını
yapmak/tekrar etmek yerine yenilikçi firma tarafından yapılan önceki çalışmalara
(yenilikçinin başvuru dosyasında yer alan) atıf yapılması imkanı getirilmiştir. Bu kısaltılmış
prosedürü kullanmak için aşağıdaki şartlar gerekmektedir:
17 Bu madde 2001 yılında yapılan düzenleme ile 2001/83/EC Direktif’te Madde 10/1/(a)(iii) olmuştur.
18 “Evaluation of the Operation of Community Procedures for the Authorization of Medicinal Products”, CMC
Cameron McKenna and Andersen Consulting, carried out on behalf of the European Commission Directorate-
General Enterprise Pharmaceuticals and Cosmetics, 17 November 2000, p: 41-42.
19 “G10 Medicines, High Level Group on Innovation and Provision of Medicines”, Consultation Paper,
European Commission, Enterprise Directorate-General, Brussels, 27 September 2001, p: 14.
20 “G10 Medicines, High Level Group on Innovation and Provision of Medicines”, Report, European
Commission, Enterprise Directorate-General, Brussels, 26 February 2002, p: 8.
21 “Data Exclusivity and the 2001 Review”, EGA Discussion Paper, July 2001.
26 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
􀀹 6 ya da 10 yıllık veri koruma süresinin sona ermesi,
􀀹 İkinci -jenerik- başvuruyu yapanın ürününün yenilikçi firmanın ürününe “önemli
ölçüde benzer (essentially similar)” olması,
􀀹 Yenilikçi firmanın ürününün başvurunun yapıldığı ülkede “pazarda” olması.
Bu süreçte veri koruması açısından üzerinde durulması gereken en önemli husus, 6 ya
da 10 yıllık veri koruma süresinin sonunda firmanın dosyasında bulunan bilginin kamuya
açıklanır hale gelmemesi, sadece jenerik müracaatçının dosyasını değerlendirirken yetkili
makamlara bu bilgiyi kullanma izninin verilmiş olmasıdır.
Kamu sağlığının korunması, hastaların yeni ilaçlara anında ulaşabilmesi ve yeni
tedavi yöntemlerinin geliştirilmesinin, aynı zamanda etkin bir jenerik ürün piyasasanın
gelişimiyle paralel bir şekilde sağlanabileceğinin farkında olan AB yetkilileri, 2001 gözden
geçirmesinde özellikle bu alanda özel bir hassasiyet göstermişler ve yenilikçi ürünlerin
özendirilmesine yönelik tedbirler getirirken jenerik sanayiinin ihtiyaçlarını da gözönünde
bulundurmuşlardır.
Avrupa Birliği’nde ilaçlara yönelik yeni mevzuat 31 Mart 2004 tarihinde kabul
edilmiş ve 30 Nisan 2004 tarihinde Topluluk Resmi Gazetesi’nde yayımlanmıştır. Söz
konusu mevzuat ile “veri koruması”na ilişkin bir takım düzenlemeler getirilmiştir. Bir Tüzük
(Regulasyon) ve 3 tane Direktifi22 içeren düzenleme seti ile oluşturulan yeni mevzuatta
konuyla bağlantılı hükümler aşağıda verilmektedir.
22 *Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down
Community procedures for the authorization and supervision of medicinal products for human and veterinary
use and establishing a European Medicines Agency.
*Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive
2001/83/EC on the Community code relating to medicinal products for human use.
*Directive 2004/28/EC of the European Parliament and of the Council of 31 March 2004 amending Directive
2001/82/EC on the Community code relating to veterinary medicinal products.
*Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as
regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to
medicinal products for human use.
27 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
2.1. Veri Korumasında Temel İlkeler 23
1. 8+2+1 (8 yıl veri koruma+ 2 yıl pazar koruması+ 1 yıl yeni tedavi yöntemleri)
bütün prosedürler için:
􀂾 726/2004 sayılı Tüzük;
“Madde 14(11): Sınai ve ticari mülkiyet haklarının korunmasını sağlayan
mevzuat hükümlerine bir zarara vermemek kaydıyla, bu Tüzük hükümlerine
göre ruhsatlandırılmış bir ilaç ürünü için 8 yıllık veri koruması ve 10 yıllık
pazar koruması sağlanacak; bu 10 yıllık sürenin ilk 8 yılı içerisinde ruhsat
sahibi tarafından, ilacın mevcut tedavi yöntemleri dışında önemli bir klinik
fayda sağlayacak yeni bir ya da birden çok tedavi biçimi için (new
therapeutic indications) ruhsat alınması durumunda ki bu durum ruhsat
verilmeden önceki bilimsel değerlendirme aşamasında ortaya çıkarsa, pazar
koruma süresi 11 yıla uzatılabilecektir.”
Bu madde ile AB’de yenilikçi ilaç endüstrisinin ruhsatlandırma sürecinin gereği
olarak sundukları test verileri koruması 6 yıldan 10 yıla çıkarılmıştır. Ayrıca, bu 10 yıllık
sürenin ilk 8 yılı içerisinde aynı ilacın başka bir tedavi yöntemi için de kullanılabilirliği
anlaşıldığında bu 10 yıllık süre ek 1 yıl ile 11 yıla uzatılmaktadır. Burada, yeni ilaçların 10
yıl süre ile piyasada jenerik rekabetinden korunmaları sağlanmakta ancak, bu sürenin ilk 8
yılında pazar korumasına eş anlı veri koruması getirilmektedir. Son 2 yıl içerisinde jenerik
firmaların başvuru yapabilmelerine imkan sağlamak için (bkz. Direktif Madde 10(1)) bu
verilerin kullanılma imkanı getirilmiştir.
23 “Main Outcomes of the Pharma Review-after the Compromise between the Council and the European
Parliament”, The European Generic Medicines Association, December 2003 dokumanından yararlanılmıştır.
28 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 10(1): Madde 8(3)(i)’de yapılan değişiklikle ve sınai ve ticari
mülkiyet haklarının korunmasını sağlayan mevzuat hükümlerine bir zarar
vermemek kaydıyla, Madde 6 hükümlerine göre bir üye ülkede ya da
Toplulukta 8 yıldan daha az olmamak üzere ruhsatlı bir referans ilacın
jeneriği olan ilaç başvurularında klinik öncesi ve klinik test sonuçlarının
verilmesi istenmeyecektir.”
Bu hüküm ile AB ilaç sanayiinde jenerik üreticiler lehine bir uygulama
başlatılmaktadır. Orijinal ilacın 10 yıllık veri koruma süresinin bitmesinden 2 yıl önce jenerik
ürün ruhsat başvurusu yapılabilmesine imkan tanınmıştır. Bu nedenle, 10 yıllık koruma
süresinin ilk 8 yılı için “veri koruması”, son 2 yılı için ise “pazar koruması” terimleri
kullanılmaktadır. Böylelikle, Tüzük Madde 14(11) ile birlikte değerlendirildiğinde AB ilaç
pazarında orijinal-jenerik dengesinin gözetilmesine çalışıldığı ortaya çıkmaktadır.
2. +2 yıllık Pazar koruması esnasında üretim kısıtlamasının olmaması:
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 10(1): Bu hükme göre ruhsatlandırılmış bir jenerik ilaç ürünü,
referans ilaç için mevcut ruhsatın başlangıcından 10 yıl geçmeden piyasaya
sunulamayacaktır.”
Yukarıdaki hüküm ile birlikte düşünüldüğünde, bu düzenleme hem yenilikçi
firmaların piyasa hakimiyetini korumakta, hem de orijinal ilacın veri koruma süresi bitmeden
jenerik ilacın üretiminin yapılabilmesine ve süre biter bitmez anında piyasaya çıkarılmasına
fırsat yaratmaktadır.
29 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
3. Yeni endikasyonlar için sadece bir kez +1 yıllık veri koruması:
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 10(1): Bu paragrafta geçen 10 yıllık veri koruma süresi; bu 10 yılın
ilk 8 yılı içerisinde ruhsat sahibi tarafından, ilacın mevcut tedavi yöntemleri
dışında önemli bir klinik fayda sağlayacak yeni bir ya da birden çok tedavi
biçimi için (new therapeutic indications)ruhsat alınması durumunda ki bu
durum ruhsat verilmeden önceki bilimsel değerlendirme aşamasında ortaya
çıkarsa, maksimum 11 yıla uzatılacaktır.”
Tüzük Madde 14(11)’de de yer alan bu hüküm ile AB ilaç sanayiinde yenilikçi
firmalar lehine önemli bir avantaj sağlanmıştır. ABD yasalarıyla karşılaştırıldığında, yeni
endikasyonlara sağlanan ek 1 yıllık korumanın orijinal ürünün koruma süresine eklenmesi
önemli bir farklılık olarak ortaya çıkmaktadır. ABD’de yenilikçi firma veri korumasını
orijinal üründen bağımsız olarak sadece yeni endikasyon için alabilmektedir24. Böylelikle,
AB ilaç sanayiinin ABD ilaç sanayii karşısında avantajlı duruma getirilmesi amaçlanmıştır.
4. Geleceğe yönelik uygulama:
􀂾 726/2004 sayılı Tüzük;
“Madde 89: Madde 90(2)’de bahsi geçen tarihlerden (veri koruma süreleri
için 20 Kasım 2005 ve bağışıklık sistemi hastalıkları ile viral enfeksiyonlar
için 20 Mayıs 2008) önce ruhsat başvurusu yapılan referans ilaç ürünlerine,
Madde 14(11)(beşeri ilaçlar için veri koruma) ve 39(10)(veteriner ilaçları
için veri koruma) da öngörülen koruma süreleri uygulanmayacaktır.”
Tüzük, yayım tarihinden 20 gün sonra yani 20 Mayıs 2004 tarihinde yürürlüğe
girmiştir. Direktifler de aynı tarihte yayımlanmış ancak, üye ülkelerdeki
24 “European revisions offer new freedoms for generics”, Generics Bulletin, 16 January 2004, p:20.
30 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
uyumlaştırmanın bitiminden sonra (30 Ekim 2005) yürürlüğe gireceklerdir. Bu madde ile
bu düzenlemelerin tamamlanması sürecinde bir derogasyon tanınmakta, piyasada mevcut
ürünlerin etkilenmemesi sağlanmaktadır. 20 Kasım 2005 tarihinden itibaren
biyoteknolojik ürünler ile AIDS, kanser, şeker, sinir bozukluğu hastalıkları için olan yeni
kimyasallar; 20 Mayıs 2008 tarihinden itibaren ise viral enfeksiyonlar ile bağışıklık
sistemi hastalıkları için olan yeni kimyasallar merkezi ruhsatlandırma prosedürüne tabi
olacaklardır.
2.2. Global Ruhsat (“line extention”25 için veri korumasının olmaması)
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 6(1): Bir ilaç ürünü ilk kez ruhsatlandırıldıktan sonra; aynı ilacın
değişik varyasyonları veya formlarında da olduğu gibi, ilacın bünyesindeki
maddenin daha sonraki değişik kombinasyonları (any additional strengths26),
farmasötik formları (pharmaceutical forms27), ilacın veriliş yolları
(administration routes28), sunum biçimleri de (presantations) ayrıca ruhsat
alabilir ya da bu ilk ruhsat bünyesine dahil edilir. Tüm bu ruhsatların Madde
10(1)’in uygulaması anlamında aynı global ruhsata ait olduğu kabul edilir.”
Bu hükmün, genel olarak “line extension” adı verilen ve orijinal bir ilacın başka bir
hastalığın tedavisindeki kullanımı, kullanım yolunun değiştirilmesi, kullanım dozunun
değişimi, bünyesindeki etken madde miktarının değişimi, farmasötik formunun değişimi gibi
25 “line extension”; orijinal bir ilacın, başka bir hastalık tedavisi için kullanımı, insanlardaki kullanım yolunda
değişim (ağızdan, enjeksiyon şeklinde vb.), dozundaki değişim (4 saatte 1, 12 saatte 1 gibi günlük kullanım
dozları,), etkinliğinde (birim hacimde ya da ağırlıktaki etken madde oranının değişimi), ya da farmasotik
formundaki değişim (tablet, kapsül, serum, vb.) sonucunda ortaya çıkan yeni ilaç ürünü anlamına gelir.
26 “any additional strength”; ilacın bünyesindeki maddenin konsantrasyonunu (örneğin, ağırlık/ağırlık,
ağırlık/hacim ya da birim doz/hacim) ve/veya etkisini yani, ilacın uygun laboratuvar testleriyle ya da kontrollü
klinik deneylerle kanıtlanan tedaviye yönelik etkinliğini ifade eder.
27 “pharmaceutical forms”; ilacın tablet, kapsül, şurup, enjeksiyon, serum, krem, vb. biçimlerini ifade eder.
28 “administration routes”; ilacın ağızdan, enjeksiyonla, yüzeye tatbik edilerek, vb. kullanım yollarını ifade eder.
31 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
yeni kullanım biçimleriyle veri koruması talep eden ve böylelikle jenerik rekabeti ile
mücadele etmeye çalışan orijinator firmaları durduracağı yorumu yapılmaktadır29.
2.3. Bilinen/Tanınmış (well-established) İlaçların Yeni Endikasyonlarına Veri
Koruması
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 10(5): Madde 10(1)’de yer alan hükümlere ek olarak, iyi bilinen bir
maddenin yeni bir tedavi biçimi için yapılan bir müracaat olduğu durumda,
bu yeni endikasyona ait klinik ve klinik öncesi testlerin yapılmış olması
halinde, sadece 1 yıllık bir veri (toplama ait olmayan) koruması
sağlanacaktır.”
Bu madde ile mevcut veri koruma süresi uzatılmamakta, bütün ürüne değil sadece
yeni endikasyona uygulanmakta ve bunun için ayrı bir yıllık bir koruma getirilmektedir.
Bilinen bir ilaç hammaddesinin yapılan araştırmalar sonucu bir başka hastalığın tedavisinde
kullanılabilirliğinin ortaya çıkması durumunda uygulanacak olup, bu tür çalışmaların teşvik
edilmesini amaçlamaktadır. Bu koruma tüm firmalar tarafından kullanılabilecek bir koruma
biçimidir. Sadece ilk ruhsatlı ürüne değil, jenerikler de dahil olmak üzere bilinen herhangi bir
ilaca uygulanabilecektir30.
2.4. Reçetesiz İlaç (OTC) Sınıfına Değiştirme Durumunda Veri Koruması
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 74a: Klinik ve klinik öncesi testleri temel alınarak ruhsatlandırılmış
bir ilacın kategorisinin değişimi durumunda; yetkili makamlar, ilk
değişikliğin onaylanmasından sonra 1 yıl süresince aynı maddenin sınıfının
29 “European revisions offer new freedoms for generics”, Generics Bulletin, 16 January 2004, p:20.
30 A.g.e., p:21.
32 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
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değiştirilmesi için ruhsat sahibinin ya da bir başkasının başvurusunu
incelerken bu testlerin ya da deneylerin sonuçlarını referans olarak
kullanamayacaklardır .”
Yeni sistem ile, reçetesiz ilaçlar iki durumda ruhsat alabilecektir31; birincisi “Topluluk
düzeyinde hastaların tedavisi” için reçetesiz ilaç ruhsatının alınması, ikincisi, merkezi ruhsat
almış bir ilacın ruhsatının reçetesiz ilaç sınıfına değiştirilmesi durumunda olacaktır. Bu
durumda, ilacın kategorisinin reçetesiz ilaç kategorisine alınması amacıyla sunulan gerekli
klinik öncesi test ve klinik deney sonuçları için de 1 yıllık bir veri koruması öngörülmektedir.
2.5. Bolar İlkesi Uygulaması
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 10(6): Bu maddenin veri korumasına ilişkin 1, 2, 3, ve 4 nolu
paragraflarının uygulanması ve sonrasındaki pratik talepler nedeniyle ihtiyaç
duyulan çalışmaların ve denemelerin yapılması, ilaçlarda patent hakkının ya
da ek koruma belgesinin ihlali anlamına gelmeyecektir.”
AB’de daha önce mevcut olmayan ve “Bolar ilkesi” adı verilen bu yeni düzenleme ile
jenerik ilaç üretiminde önemli bir yenilik getirilmiştir. Bolar ilkesinin bulunmaması
nedeniyle, AB’de patent konusu ilaçların jeneriklerinin üretimi ve satışa sunulabilir hale
gelmesi, ancak patent süresi sonunda mümkün olabilmekte, bu ise en az 2 yıllık bir süreyi
gerektirmektedir. AB’de jenerik ilaç için yapılamayan bu tür geliştirme çalışmaları ve
ilaçların ilk üretimleri, Bolar ilkesinin mevcut olduğu AB dışı ülkelerde yapılmakta ve patent
süresi sonunda da hemen AB’ne ithal edilmektedir. Avrupa Jenerik İlaçlar Birliği (European
Generic Medicines Association-EGA) tarafından, AB jenerik ilaç sanayiinin dünya jenerik
sanayiiyle rekabet avantajını bu yüzden kaybettiği ve AB’nin yıllık 1 milyar EURO civarında
31 “The Right Treatment?”, Britton I., Gavey M., Linklaters 2004.
33 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
ekonomik kaybı olduğu ifade edilmektedir32. Getirilen bu yeni düzenleme ile AB’nde jenerik
ilaç ruhsatlandırmasında ortaya çıkan bu tür kayıpların giderilmesi amaçlanmaktadır.
2.6. Referans İlaç Tanımı
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 10(2)(a): Referans ilaç, Madde 8’de yer alan hükümlere bağlı
olarak Madde 6 hükümlerine göre ruhsatlandırılmış ilaçtır.”
Yeni düzenleme ile “referans ilaç” tanımı yapılmıştır. Direktifte Madde 8’de ruhsat
başvurusunun yapılma biçimi ile içereceği bilgi ve dokumanlar sıralanmakta; madde 6’da ise
ruhsatın kapsamı belirlenmektedir.
2.7. Jenerik İlaç Tanımı
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 10(2)(b): Jenerik ilaç, referans ilaç ile aynı farmasötik formda ve
aktif maddeleri nitelik ve nicelik olarak aynı bileşimde olan ve referans ilaç
ile biyoeşdeğerliliği uygun biyoeşdeğerlik çalışmalarıyla ispatlanmış ilaçtır.
Aktif maddenin farklı tuzları, esterleri, eterleri, izomerleri, izomerlerinin
karışımı, kompleksleri ve türevleri; güvenlik ve/veya etkililik açısından
özellikleri önemli ölçüde farklılık göstermediği sürece aynı aktif madde
olarak kabul edilecektir. Eğer bu özelliklerde farklılık varsa o zaman, ruhsatlı
aktif maddenin muhtelif tuzları, esterleri veya türevlerinin güvenlik ve/veya
etkililiğinin ispatını gösteren ek bilginin başvuran tarafından sunulması
zorunlu olacaktır. Oral farmasötik formdaki ilaçların vücutta farklı
salıverilme biçimleri, tek ve aynı farmasötik form olarak kabul edilecektir.
32 EurActive.com Portal-Links Dossier- Generic Medicines, 26 March 2004, http://www.euractive.com
34 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
Başvuruyu yapan, jenerik ilaç ürününün ayrıntılı rehber ilkelerde tanımlanan
ilgili kriterlere sahip olduğunu gösterebiliyorsa o zaman biyoeşdeğerlilik
çalışmaları istenmeyecektir.”
Görüldüğü gibi, “jenerik ilaç” tanımı oldukça detaylı ve kapsamlı bir şekilde
yapılarak Direktife yerleştirilmiş ve uygulamalar yasal bir netliğe kavuşturulmuştur.
2.8. Biyo-benzerlik İçin Kısaltılmış Prosedürün Uygulanması
􀂾 2004/27/EC
“Giriş 14: Referans ilaca benzer olan biyolojik ilaç ürünü, daha çok üretim
prosesi özellikleri, kullanılan hammaddeler, moleküler özellikler ve etki
gösterdiği tedavi biçimi açısından jenerik ilaç olarak kabul edilebilecek
bütün şartları genelde karşılamaz. Biyolojik ilaç ürünü jenerik ilaç olarak
kabul edilebilecek bütün şartları karşılamadığı zaman, bu durumda güvenliği
(klinik öncesi testler) ya da etkililiği (klinik testler) ya da her ikisini
ilgilendiren gerekli testlerin sonuçları verilecektir.”
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 10(4): Referans biyolojik ürüne benzer olan biyolojik ilaç; özellikle,
biyolojik ilacın ve referans biyolojik ilacın hammaddeleri ya da üretim
proseslerindeki farklılıklar nedeniyle jenerik ilaç tanımındaki şartları
karşılamıyorsa, bu şartların gerektirdiği klinik öncesi testler ya da klinik
deneylerin sonuçları verilmek zorundadır. Bu ek verinin niceliği ve çeşidi, EK
1’de ve ayrıntılı rehber ilkelerde yer alan kriterlere uygun olmak zorundadır.
Referans ilaç ürününün dosyasındaki diğer test ve deney sonuçlarının
verilmesine gerek yoktur.”
35 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
2.9. Avrupa Referans İlaç Ürünü
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 10(1): (Bu maddenin 3. paragrafı)
Referans ilaç ürünü, jenerik ilaç başvurusunun yapıldığı üye ülkede
ruhsatlanmamışsa da bu maddenin 1. paragrafı uygulanır. Bu durumda,
başvuru sahibi, başvuru formunda referans ilaç ürününün ruhsatlı olduğu
ülkenin adını belirtir. Başvurunun yapıldığı ülkenin yetkili makamının talebi
üzerine, diğer ülkenin yetkili makamı bir aylık bir süre içinde, referans ilaç
ürününün tüm kompozisyonuyla ve gerekiyorsa diğer ilgili dökumanlarıyla
birlikte ruhsatlı olup olmadığının teyitini iletir.”
Bu düzenleme jenerik ilaçlara yönelik bir hükümdür. Eğer orijinal ilacın sahibi bir
ülkede, ticari nedenlerle kendi ilacını piyasaya sürmemişse ya da piyasadan çekmişse, bu
ilacın jenerikleri “Avrupa Referans İlacı” ve buna bağlı tek bir “Avrupa Ruhsatı”
uygulamasının sonucu olarak o ülkede satışa sunulabilecektir33.
2.10. Ürün Özelliklerinin Özeti (SmPC) ve Patentin Kullanımı
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 30(2): Toplulukta ruhsatlı ilaç ürünlerinin ruhsatlandırılmasının
uyumlaştırılması için, üye ülkeler, her yıl, koordinasyon grubuna, ürün
özelliklerinin uyumlaştırılmış özetinin yer aldığı ilaç listelerini
göndereceklerdir.”
33 “MEPs Recommended to Accept EU Pharmaceutical Compromise”, EGA Press Release, 16 December 2003,
http://www.egagenerics.com/pr-2003-12-16.htm
36 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
􀂾 726/2004 sayılı Tüzük;
“Madde 3(3)(b): Ürün karakteristiklerinin özeti, jenerik ilaç piyasaya
sunulduğu anda hala patent hukukuyla korunan endikasyon ve dozaj
formlarına atıf yapan ürün karakteristiklerinin özet bölümleri hariç olmak
üzere, Toplulukça ruhsatlandırılmış bir ilaçla her yönden tutarlılık arzeder.”
Bu düzenleme ile, tüm ülkelerde ilaçların özelliklerinin yer aldığı ürün bilgisinin
uyumlaştırılması amaçlanmaktadır. Bu madde kapsamında, jenerik ilaç üreticilerinin patentli
tedavi biçimleri ve dozaj formları ile ilgili bilgiyi, patent yasalarının ihlaline meydan
vermemek amacıyla, ürün özelliklerinin kapsamından çıkarmaları imkanı sunulmaktadır34.
2.11. Merkezi Ruhsatlandırma Prosedürünce Onaylanmış Referans İlaçların
Jeneriklerinin Ruhsatlandırılması
􀂾 726/2004 sayılı Tüzük;
“Madde 3(3): Toplulukta ruhsat almış bir referans ilacın jeneriğine, üye
ülkelerin yetkili makamlarınca 2001/83/EC ve 2001/82/EC sayılı Direktifler
kapsamında aşağıdaki şartlar altında ruhsat verilebilir:
(a) ruhsatlandırma başvurusu, 2001/83/EC sayılı Direktifin 10.
maddesi ve 2001/82/EC sayılı Direktifin 13. maddesi gereğince yapılır;
(b) ürün karakteristiklerinin özeti, jenerik ilaç piyasaya sunulduğu
anda hala patent hukukuyla korunan endikasyon ve dozaj formlarına
atıf yapan ürün karakteristiklerinin özet bölümleri hariç olmak üzere,
Toplulukça ruhsatlandırılmış bir ilaçla her yönden tutarlılık arzeder; ve
(c) jenerik ilaç ürünü başvurunun yapıldığı bütün üye ülkelerde
aynı isim altında ruhsatlandırılır. Bu amaçla, INN’in (international
non-proprietary name) tüm dillerdeki karşılığının aynı isim olduğu
kabul edilir.”
34 A.g.e.
37 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
2.12. Merkezi Ruhsatlandırma Prosedürünün Zorunluluk Kapsamı
􀂾 726/2004 sayılı Tüzük;
“Ek:-biyoteknolojik ürünler;
-AIDS, kanser, şeker, sinir bozukluğu hastalıkları, bağışıklık sistemi
hastalıkları ve bozuklukları, viral hastalıklar için olan yeni kimyasallar;
-nadir (orphan) bulunan ilaçlar.”
Merkezi ruhsatlandırma prosedürü bütün “yeni kimyasal madde”ler için zorunlu
değildir. Sadece yukarıda belirtilen gruplardaki ilaçlara uygulanacaktır. Bu gruplardan
bağışıklık sistemi ve viral enfeksiyonlar için geliştirilen ilaçlar bu kapsama 20 Mayıs 2008
tarihinden itibaren dahil olacaktır.
2.13. Ruhsatların Sona Erme Durumu
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 24(4): Ruhsatın alınmasından sonraki 3 yıl içerisinde ruhsatlı
ürünün ruhsatı veren üye ülke piyasasında gerçek anlamda yer almaması
halinde ruhsat geçerliliğini kaybeder.”
“Madde 24(5): Ruhsatın verildiği üye ülke piyasasında önceden yer aldığı
halde, birbirini izleyen 3 yıl piyasada gerçek anlamda bulunmamışsa, o ürüne
ait ruhsat geçerliliğini kaybeder.”
2.14. Ruhsatların Yenilenmesi
􀂾 2001/83/EC sayılı Direktif (2004/27/EC ile değiştirilmiş)
“Madde 24(1): Bu maddenin 4 ve 5 nolu paragraf hükümlerine zarar
vermeksizin bir ruhsatın geçerliliği 5 yıldır.”
38 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
“Madde 24(2): Ruhsatlar, üye ülkenin yetkili makamlarınca kar-zarar
dengesinin gözden geçirilmesiyle 5 yıl sonra yenilenebilir.
Bu durumda ruhsat sahibi, yetkili makamlara, kalite, güvenlik ve etkililik
açısından ruhsatın verildiği tarihten itibaren getirilen bütün değişiklikleri de
içeren birleştirilmiş dosyayı, ruhsatın paragraf 1’e göre bitiş tarihinden en az
6 ay önce verecektir.”
“Madde 24(3): Yetkili makamların farmakovijilansa dayalı haklı gerekçelerle
Paragraf 2’deki ek 5 yıl yenilemeye karar vermemeleri haricinde, ruhsatlar
bir defa yenilendikten sonra sınırsız geçerli olacaktır.”
Bu bölümde, AB’nde 1 Kasım 2005 tarihinden itibaren geçerli olacak yeni sistemi
getiren düzenlemelerin veri korumasına doğrudan ya da dolaylı olarak etki eden hükümleri
kısaca incelenmiştir. Komisyon tarafından önerilen bu düzenlemelerin bir amacının da
Avrupa ilaç sanayiinin dünya ölçeğinde yitirdiği rekabet avantajına yeniden kavuşması
olduğu bir çok ortamda ifade edilmiştir. Yeni düzenleme ile getirilen bazı hükümlerle, AB
ilaç sanayii dünyadaki bir çok ülkedeki rakiplerinden daha avantajlı bir duruma gelmektedir.
3. AB’NE YENİ KATILAN ÜLKELERDE VERİ KORUMASINA İLİŞKİN
DÜZENLEMELER
AB’nin üye sayısı 1 Mayıs 2004 tarihinden itibaren katılan 10 yeni ülke ile beraber 25
üyeye ulaşmıştır. Yeni katılan bu ülkeler; Çek Cumhuriyeti, Estonya, Macaristan, Letonya,
Slovak Cumhuriyeti, Kıbrıs Rum Kesimi, Litvanya, Malta, Polonya ve Slovenya’dır.
Bulgaristan ve Romanya 2007’de üye olacak olup, Türkiye ise aday ülke konumundadır.
Veri korumasına ilişkin olarak, yeni üye olan tüm ülkelerde 2001/83/EC sayılı
direktifte yapılan son değişiklikler öncesinde öngörülen koruma süreleri uygulanmaktadır.
Yeni mevzuata uyum için ise bir geçiş süresi olabileceği yönünde yaklaşımlar bulunmaktadır.
Yeni üye ülkeler, halihazırda 6 yıl olan veri koruma süresinin 4 yıl daha uzatılmasının ulusal
39 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
sağlık bütçelerine zarar vereceği yönünde fikir birliğine varmıştır. Nitekim, 5 Eylül 2003
tarihinde 10 yeni üye ülkenin yayınladıkları bildiri35 (Milan Declaration) ve 26 Kasım 2003
tarihinde bu ülkelerden 94 gözlemci tarafından Avrupa Parlamentosuna gönderilen
dilekçede36; yeni düzenlemenin taslak çalışmaları esnasında henüz üye olmadıkları için aktif
bir katılım sağlayamadıklarından, özellikle veri korumasına getirilen ek koruma sürelerinin
zaten hassas olan ilaç sanayilerini olumsuz etkileyeceği, ulusal sağlık sigorta sistemlerine
daha fazla yük getireceği, toplumun ilacı temin etme ve bedelini ödemede sorunlarla
karşılaşacağından bahisle veri koruma süresinin yeni üyeler için 6 yıl olarak muhafaza
edilmesi talep edilmektedir. Bu belgelerde ayrıca, bu ülkelerde jenerik ilaçların tüm reçeteli
ilaçlar içerisindeki oranının hacimsel olarak % 70 olduğu ancak, ilaç harcamalarının ise
sadece % 30’una karşı geldiği belirtilmektedir. Güçlü bir jenerik sektörün yeniliği uyarıcı
olduğu, yeni geliştirilen ilaçların satın alınması için bütçelerde imkan yarattığı, jenerik
ilaçların sağlık harcamalarını azaltıcı politikalarda hayati önem taşıdığı ve ulusal geri ödeme
sistemlerinin temelini oluşturduğu ifade edilmektedir.
AB Komisyonu, yeni üye ülkelere Katılım Antlaşmaları’nda yer alan hükümler
çerçevesinde, yeni düzenlemelere uyum için bir geçiş süresi talebi yapma imkanı vermiş
bulunmaktadır. Bu kapsamda ilk olarak Nisan 2004’te Polonya hükümeti37, AB’nin ilaçlara
ilişkin yeni düzenlemesinde yer alan veri korumasına ilişkin hükümlerinin uygulanması için
15 yıllık bir geçiş süresi talebinde bulunmuştur. Diğer ülkelerden Malta 15 yıl, Macaristan 10
yıl, Slovenya ve Slovakya ise 4 yıl olmak üzere geçiş süreleri talep etmiştir38.
AB ülkelerinden Avusturya, Danimarka, Finlandiya, Yunanistan, İrlanda, Portekiz ve
İspanya’da 6 yıl; Belçika, Almanya, Fransa, İtalya, Lüksemburg, Hollanda, İsveç ve
35 “The Acceding Countries Declaration”, 5 September 2003.
36 “Petition to the European Parliament”, 26 November 2003.
37 “Pharmaceuticals; Poland is the first to request transition period on data protection”, Health & Pharma,
Euractiv.com Portal-news nr 1507517, 8 April 2004, http://www.euractiv.com
“Government seeks 15-year transition period on EU pharmaceutical law”, Warsaw Business Journal, 7 April
2004, http://www.wbj.pl/?command=article&id=22008&
38 “What the EU Pharmaceutical Review Legislation Means for the New Member States”, Hogan&Hartson,
http://www.hhlaw.com/articles/1815_EU%20Accession%20Guide%20-
%20EU%20Pharmaceutical%20Review%20Legislation%20April%202005.pdf
40 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
İngiltere’de 10 yıl olarak veri koruma süreleri mevcuttur39. Yunanistan, Portekiz ve
İspanya’daki veri koruması patent koruma süresinin sonuna kadar uygulanmaktadır40. Yeni
düzenleme ile bütün ülkeler mevzuatlarını uygulamanın başlayacağı tarih olan 1 Kasım
2005’e kadar değiştirmek durumundadır. Sadece yeni katılan 10 ülkenin durumu netlik
kazanmamıştır. Yukarıda anlatılanlar çerçevesinde bu ülkelere son düzenlemedeki veri
koruma süreleri için bir geçiş süresi tanınıp tanınmayacağı hususunda belirsizlik
bulunmaktadır. AB Komisyonunca yapılacak değerlendirmenin Eylül 2005’ten önce
sonuçlanması beklenmemektedir.
Yeni katılan 10 ülkede veri korumasına ilişkin düzenlemeler katılım öncesi süreçte
gerçekleştirilmiştir. Üyelik öncesinde tüm ülkelerde 6 ile 10 yıllık koruma süreleri getirilmiş,
sadece Polonya bu süreyi 3 yıl olarak devam ettirmiştir. Macaristan, Litvanya, Polonya,
Slovenya’da patentle bağlantılı veri koruması vardır. Yapılan düzenlemeler ülke bazında
aşağıda verilmektedir.
Çek Cumhuriyeti’nde, 1997 tarihli İlaç Yasası (Article 32 of Law No. 79/1997 Col.
on Pharmaceuticals41) ile, 1 Ocak 1998 tarihinden itibaren 6 yıllık veri koruması getirilmiştir.
Çek Cumhuriyeti’nin bu alanda AB’ne yükümlülüğü 65/65/EEC sayılı Direktifle uyumlu veri
korumasını 1 Ocak 1997 tarihinden itibaren sağlamaktır. Yapılan düzenleme ile, AB’ndeki
sisteme göre merkezi ruhsatlandırmaya tabi yüksek teknoloji ürünü ilaçlara 10 yıl, diğer
ürünlere ise 6 yıllık bir veri koruma süresi uygulaması başlatılmıştır42.
Macaristan’da veri korumasına ilişkin düzenleme AB mevzuatı (65/65/EEC sayılı
Direktif) ile uyumlu bir şekilde, 12/2001 sayılı Sağlık Bakanlığı Kararı’nda yer almıştır43. 12
39 Data Exclusivity and Market Protection, http://www.egagenerics.com/gen-dataex.htm
40 “The Impact of the EU-Enlargement on the Pharmaceutical Industry”, Alexa von Uexküll, Vossius and
Partner, 4 May 2004, http://www.voissiusandpartner.com/eng/publication/impact_eu-enlargement.html
41 Review of Legislation, Czech Republic, TRIPS Council, IP/Q3/CZE/1, 17 December 1997.
42 http://www.cptech.org/ip/health/phrma/nte-99/czech.html
43 “Striking New Balances: The Protection of Pharmaceuticals and the Future of the Industrial Property System
in Europe, A Central and Eastern European Perspective”, Fiscor, M.Z., Vice-President, Hungarian Patent
41 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
Nisan 2001 tarihinde yayımlanan ve 12 Haziran 2001 tarihinde yürürlüğe giren bu Karar’a
göre veri koruması fiili olarak 1 Ocak 2003 tarihinde başlayacak ve bu tarihten sonra
başlatılan ruhsatlandırma prosedürlerine uygulanacaktır. Ancak, geriye dönük bir uygulama
olarak Karar’ın yayımlandığı 12 Nisan 2001 tarihinden sonra ruhsat başvurusu yapılan tüm
ürünlere uygulanması hükmü getirilmiş, ancak bu uygulama başarılı olamamıştır. AB’nde
olduğu gibi merkezi ruhsatlandırma prosedürünün uygulanacağı yüksek teknoloji ürünlerinde
10 yıl olan veri koruması, diğer ürünlerde 6 yıl olarak belirlenmiş ve patent süresi ile sınırlı
tutulmuştur.
Polonya’da 15 Aralık 1993 tarihli düzenlemeyle ilaçlarda 3 yıllık bir veri koruma
süresi uygulanmaktadır44. AB mevzuatına uyum kapsamında tüm ilaç mevzuatı 6 Eylül 2001
tarihli yasa (Art.3 of the Act of 6th September 2001 introducing the Pharmaceutical Law, Act
on Medical Devices and Act on the Office for Registration of Medicinal Products, Medical
Devices and Biocides45) ile değiştirilmiştir. Söz konusu yasa 1 Nisan 2002 tarihinde
yürürlüğe girmiş ve veri koruması alanında Polonya tam üye oluncaya kadar 3 yıllık koruma
süresinde herhangi bir değişiklik getirmemiştir. Veri koruma süresi, ilacın dünyanın herhangi
bir ülkesinde ilk ruhsat aldığı tarihten başlatılmaktadır ve bunun gerçekte 3 yıldan daha az bir
koruma süresine karşı geldiği şeklinde yorumlanmaktadır46. Tam üyelik ile AB
mevzuatındaki 6-10 yıllık koruma süreleri AB’de ilk ruhsatlandığı tarih itibariyle ürünün
patent süresiyle bağlantılı olarak uygulanmaya başlamıştır.
Slovenya’da yeni Tıbbi Ürünler Yasası’nda (Slovenian Medicinal Law) veri
korumasına ilişkin hükümler getirilmiştir. Gizli verilerin korunması 6 yıl ile ve patent koruma
Office, International Conference on Intellectual Property, The Internet, Electronic Commerce and Traditional
Knowledge, WIPO/ECTK/SOF/01/2.2, May 2001.
44 “Preparing for Enlargement by Revising the Rules: An Opportunity for Self-Medication”, AESGP Members’
Meeting, Warsaw, 30-31 January 2002, http://www.aesgp.be/Warsaw2002/WarsawJan2002.pdf
45 “Parliamentary Legislative Procedures”, Request No 084 “Pharmaceutical Law-Treaty of Accession”, August
2003, http://www1.ukie.gov.pl/HLP/files.nsf/ 0/e16a25fd53e9f64ac1256e840036da42?OpenDocument
46 http://www.ustr.gov/assets/World_Regions/Europe_Mediterranean/European_Union/asset_uploadfile21_
4196.pdf
42 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
süresiyle sınırlandırılmıştır47. Veri korumasına ilişkin düzenleme 2000 yılında yapılmış
olmasına rağmen, fiili olarak Mart 2002 tarihinde uygulamaya geçilmiştir. Veri korumasının
başlangıcı olarak, Slovenya’da ya da AB ülkelerinden herhangi birindeki (hangisi daha
erkense) ruhsatlandırma tarihi esas alınmıştır48.
Estonya’da veri korumasına ilişkin düzenleme, 1996 tarihli ruhsatlandırmaya ilişkin
yönetmeliği değiştiren 26 Şubat 2001 tarih ve 25 sayılı Yönetmelik ile yapılmış ve AB
mevzuatına uyumlu 6 ve 10 yıllık veri koruma süreleri getirilmiştir49 (Regulation No. 25 of
the Minister of Social Affairs of 26 February 2001, amending the Regulation No. 13 of the
Minister of Social Affairs of 29 March 1996 on the Procedure for Registration of Medicinal
Products and Approval of Variations to the Terms of Registered Medicinal Products).
Slovak Cumhuriyeti’nde, 1998 tarihli İlaçlar ve Tıbbi Cihazlar Yasası’nda (Act No.
140/1998 Coll. on Medicines and Medical Devices) 2000 yılında yapılan değişiklikle (Act
No. 119/2000 Coll.) 6 yıl süreli veri koruması getirilmiştir50. Aynı yasada daha sonra yeniden
yapılan değişiklik Aralık 2001’de yürürlüğe girmiş ve yüksek teknoloji ürünü ilaçlar için 10
yıl veri koruması getirmiştir51. Bu yasadaki son değişiklik 1 Ağustos 2003 tarihinde yapılmış
ve AB mevzuatına tam uyum sağlanmıştır52.
Litvanya-AB Ortaklık Anlaşması (Association Agreement) 65/65/EEC Direktifin
uygulamasını da içermekte olup 10 yıllık veri koruması 1 Ocak 2000 tarihine kadar yürürlüğe
47 http://www.cptech.org/ip/health/phrma/nte-99/slovenia.html
48 PhRMA “Special 301” Submission, 2004, p:127.
49 Review of Legislation, Estonia, TRIPS Council, IP/Q/EST/1, IP/Q2/EST/1, IP/Q3/EST/1, IP/Q4/EST/1, 29
March 2001.
50 http://www.foreign.gov.sk/En/files/add.php3?text=Slovakia%20and%20EU&file=eu_poz1e.html
51 “2002 Regular Report on Slovakia’s Progress towards Accession- Chapter 1:Free Movement of Goods”,
http://www.fifoost.org/slowakei/EU_Slovakia_2002/node36.php
52 http://www.safs.sk/En/presscenter_06.html
43 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
girecektir53. Ancak bu tarih realize edilememiştir. 22 Aralık 2001 tarih ve 669 sayılı Karar ile
AB mevzuatına uyumlu veri koruma uygulaması 1 Mart 2003 tarihi itibariyle başlatılmıştır54.
Letonya’da 20 Ocak 1998 tarih ve 24 sayılı İlaç ve Tıbbi Ürünler Tesciline İlişkin Genel
İlkeler’inde yer alan veri korumasına 2000 yılında yapılan düzenleme ile açıklık getirilmiş ve
AB mevzuatına uyumlu 6-10 yıl süreli veri koruması sağlanmıştır55.
4.
AB’NE ADAY ÜLKELERDE VERİ KORUMASI
Romanya’da ilaçlara ilişkin olarak AB üyeliği gözetilerek 1999 yılında başlatılan
yeni düzenlemeler, ruhsatlandırma işlemlerinden ilaçların gözetimine, kalite değerlendirme
ve veri korumasına yönelik bir dizi tedbiri içermektedir (Government Emergency Ordinance
No 152/1999) 56. Veri korumasına ilişkin düzenleme ise ilk olarak 2.3.2001 tarihli ve 3 sayılı
Karar ile, daha sonra da bu Kararı değiştiren 17.5.2002 tarih ve 12 sayılı Karar ile yapılmış
ve AB mevzuatına uyumlu veri koruması getirilmiştir (Decision No. 3/02.03.2001 regarding
the approval of Regulations on data exclusivity for medicinal products for human use-
Modified by Decision No. 12/17.05.2002). Ancak, veri koruması uygulamasına 14 Nisan
2004 tarihinde, 152 sayılı Karar’ın yeni 23.1 maddesiyle beraber (Ordinance No 152 of
October, 1999) başlanılmıştır57. Bu kapsamda, 6 yıllık veri koruması (yüksek teknoloji
ürünler için 10 yıl), orijinal ilaç ürününün AB’de ya da üretildiği ülkede alınan ruhsat
tarihinden itibaren başlamaktadır.
53 http://strategis.ic.gc.ca/epic/internet/inimr-ri.nsf/en/gr-84232e.html
54 Medford-Rosow T., Williams C.A., “A Review of Existing Data Exclusivity Legislation in Selected
Countries”, Third Revised Version, January 2004, Intellectual Property Institute, London.
55 Review of Legislation, Latvia, TRIPS Council, IP/Q/LVA/1/Add.1, IP/Q2/LVA/1/Add.1,
IP/Q3/LVA/1/Add.1, IP/Q4/LVA/1/Add.1, 26 May 2000.
56 “Romania’s Position Paper”, Conference on Accession to the European Union, CONF-RO 52/01, Brussels, 14
December 2001, p:16-21, http://www.mie.ro/Negocieri/English/position_doc/CAP01-DP%20eng.doc
57 “A Guide to Patent Infringement Legislation”, Oproiu M., Vasilescu R., Managing Intellectual Property,
Supplement-IP at the border 2005.
http://www.managingip.com/includes/supplements/PRINT.asp?SID=495086&ISS=14231&PUBID=199
44 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
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Bulgaristan’da veri korumasına ilişkin düzenleme 2002 yılında yapılmış ve 1 Ocak
2003 tarihinden itibaren de yürürlüğe girmiştir58. 1995 tarihli Bulgaristan İlaç ve Eczaneler
Yasası59, Şubat 2000 ve Aralık 2002 tarihlerinde değişikliğe uğramış ve son değişiklikte,
geçerli bir patentle bağlantılı 6 yıllık veri koruması ile patent süresinin bitiminden 2 yıl once
yapılan klinik deney ve uygulamaları kapsayan Bolar hükmü getirilmiştir60.
Hırvatistan’da AB mevzuatına uyumlu bir veri koruma uygulaması
bulunmamaktadır.
58 Bulgaria Country Commercial Guide FY 2004: Invest Climate
http://strategis.ic.gc.ca/epic/internet/inimr-ri.nsf/en/gr121087e.html
59 Bulgarian Law of Medicines and Pharmacies in Human Medicine, generally referred to as Drug Act, State
Gazette No. 36/1995.
60 “Economic and Legal Framework for Non-Prescription Medicines”, Country Profiles, Bulgaria, The
Association of the European Self-Medication Industry, June 2004,
http://www.aesgp.be/CountryProfiles/Bulgaria2004.pdf
45 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
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46 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
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BÖLÜM III. TÜRKİYE’DE VERİ KORUMASI
1. AB İLE İLİŞKİLER KAPSAMINDA YÜKÜMLÜLÜKLER
1. Türkiye-AB Gümrük Birliği Anlaşması
Türkiye ile Avrupa Birliği (AB) arasında Gümrük Birliği kurulmasını düzenleyen 22
Aralık 1995 tarih ve 1/95 sayılı Ortaklık Konseyi Kararı, 1 Ocak 1996 tarihinde yürürlüğe
girmiştir. 1/95 sayılı Kararın KISIM I, BÖLÜM II’si miktar kısıtlamalarının ve eş etkili
tedbirlerin kaldırılması ile ilgili hükümleri kapsamaktadır. Bu bölümde Madde 8 paragraf 1
ile, Kararın yürürlüğe girmesinden itibaren beş yıl içerisinde Türkiye’nin, ticarette teknik
engellerin kaldırılması konusundaki Topluluk araçlarını kendi iç yasal düzenlemelerine dahil
edeceği; paragraf 2 ile de, bu araçların listesi ve bunların Türkiye tarafından uygulanma
koşul ve kurallarının Kararın yürürlüğe girmesinden itibaren bir yıl içerisinde Ortaklık
Konseyi Kararı ile belirleneceği ifade edilmektedir.
Bu çerçevede Türkiye tarafından uyumlaştırılacak söz konusu teknik mevzuatı
uyumlaştıracak kamu kurum ve kuruluşlarını belirleyen 97/9196 sayılı Bakanlar Kurulu
Kararı 29 Nisan 1997 tarihli Resmi gazetede yayımlanmıştır. Bu kararın eki listede 13.
maddede Tıbbi Ürünler altında “a)Beşeri İlaçlar” alanındaki teknik mevzuatın Sağlık
Bakanlığı tarafından uyumlaştıracağı belirtilmektedir. Diğer taraftan mevzuatın ayrıntılı
listesi ise, 21 Mayıs 1997 tarih ve 2/97 sayılı Ortaklık Konseyi Kararı (EK II) ile
belirlenmiştir. Buna göre, test verilerinin korunmasına ilişkin mevzuatı belirleyen 65/65
sayılı Direktif listenin ilk sırasında yer almaktadır.
Böylelikle, veri korumasına ilişkin AB’ndeki sisteme uyumlu düzenleme yapma
yükümlülüğümüz teknik mevzuat uyumu kapsamında 1 Ocak 2001 tarihi itibariyle başlamış
bulunmaktadır.
47 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
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2. 2003 Türkiye Ulusal Programı
2003 yılında gözden geçirilerek yeniden oluşturulan Türkiye Ulusal
Programı’nda test verilerinin korunmasına yönelik olarak yer alan hüküm şu
şekildedir:
ÖNCELİK 5.3 Sınai Mülkiyet Hakları
“İlaveten, ilaçlardaki test verilerinin korunması (veri imtiyazı) konusunda Mart
2003 tarihinde Avrupa Komisyonuna bir eylem planı verilmiştir. Buna göre,
ülkemizin yol haritasının belirlenmesinde ilk adımı teşkil edecek olan ve bu
yükümlüğünün getireceği mali yükün boyutlarını ortaya koymayı hedefleyen
sektör raporu tamamlanmıştır. Sektör raporu, Avrupa Komisyonu uzmanları ile
değerlendirilecek ve bu çerçevede mevzuat yönünden ihtiyaç duyulan değişiklik
çalışmaları başlatılacaktır. Bu çalışmaların 2003-2004 yasama döneminde
tamamlanması öngörülmektedir.”
3. 2003 Katılım Ortaklığı Belgesi
Katılım Ortaklığı Belgesi’nde kısa vadede veri korumasına ilişkin aşağıdaki hüküm
yer almaktadır:
KISA VADE:
“Eczacılık ürünleri konusundaki fikri mülkiyet hakları mevzuatı dahil olmak
üzere, fikri ve sınai mülkiyet hakları alanındaki müktesabata uyumun
tamamlanması ve korsanlık ve sahtecilik ile mücadelenin güçlendirilmesi.”
48 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
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2. YASAL DÜZENLEMELER
2.1. Patent Haklarının Korunması Hakkında 551 sayılı Kanun Hükmünde
Kararname
Türkiye’de 1 Ocak 2005 tarihinden önce, veri koruması ile ilgili tek özel düzenleme
1995 tarihli Patent Haklarının Korunması Hakkında 551 sayılı Kanun Hükmünde Kararname
(KHK) olmuştur. KHK’nın “Patent Başvurusu veya Patentten Doğan Koruma Kapsamı ve
İstem veya İstemlerin Yorumlanması” başlıklı 83. Maddesinin 3. paragrafında yer alan
hüküm aşağıdaki şekildedir:
“Patent başvurusu yapılmış olan beşeri, veteriner ve zirai ilaçların imalat ve
satış ruhsatlarının tasdiki için ilgili makamlarca talep edilen ve yaratılmaları ve
birikimleri önemli bir gayret ve masraf gerektiren ve sahipleri tarafından umuma
açıklanmamış olan bilgi ve test sonuçları talep sahibi makam tarafından gizli
tutulur. Bilgi ve test sonuçlarını talep eden makam bunların haksız kullanımının
önlenmesi için gerekli önlemleri alır.”.
Görüleceği üzere mevzuatımızda veri korumasına ilişkin hüküm AB’nde olduğu gibi
ruhsatlandırma sürecinde değil, patentlendirme sürecinde ele alınmış ve sedece patent
koruması ile bağlantılı ilaç ürünleri için düzenlenmiştir. Veri koruma sisteminde uygulayıcı
kurum Türk Patent Enstitüsü (TPE) değil Sağlık Bakanlığı olduğundan ve bu maddeye
aykırılık halinde herhangi bir yaptırım getirilmediğinden, bir yasa maddesi olmanın ötesine
geçememiştir. Ayrıca, bu düzenleme ile herhangi bir süre tespiti de yapılmamış olduğundan
uygulanabilirliği mümkün olmamış; diğer taraftan patent başvurusu bulunmayan ilaçlar için
açıklayıcı bir hüküm içermediğinden sistemin bütünlüğünü sağlayamamıştır.
49 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
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2.2. Tıbbi Farmasötik Ürünler Ruhsatlandırma Yönetmeliği (2 Mart 1995)
Sağlık Bakanlığı tarafından yürütülen “Tıbbi Farmasötik Ürünler Ruhsatlandırma
Yönetmeliği” 2 Mart 1995 tarihli ve 22218 sayılı Resmi Gazete’de yayımlanmış ve 19 Ocak
2005 tarihli “Beşeri Tıbbi Ürünler Ruhsatlandırma Yönetmeliği” nin yayımlanmasıyla 1
Ocak 2005 tarihinden itibaren yürürlükten kalkmıştır. İlaçların ruhsatlandırılması sürecine
yönelik bir düzenleme olan bu Yönetmelikte, veri korumasına ilişkin özel bir hüküm
bulunmamakla birlikte “kısaltılmış başvurular” başlıklı 9. maddede, ilaçların ruhsat
başvuruları ekinde istenmeyecek durumlar sayılmakta ve böylelikle test verilerine atıfta
bulunulmaktadır. Madde hükmü şu şekildedir:
“Kısaltılmış Başvurular
Madde 9- Aşağıda belirtilen durumların yeterince belgelenmesi ve desteklenmesi
halinde, tıbbi farmasötik ürüne ait farmakolojik ve toksikolojik test sonuçlarının
veya klinik çalışmaların başvuru ekinde sunulması gerekmeyebilir.
a) Ürünün, Bakanlıkça daha önce ruhsatlandırılmış bir diğer ürünle tamamen
aynı (etkin maddeler açısından aynı kalitatif ve kantitatif terkibe sahip, aynı
farmasötik formda, aynı yoldan kullanılan ve gerektiğinde ilgili yönetmeliğe göre
biyoeşdeğerliği kanıtlanmış) olması,
b) Yayınlanmış literatüre referans yapılmak suretiyle etkin madde/maddelerin
bilinen bir etkinliğe, kabul edilebilir bir emniyete ve yerleşmiş bir tıbbi kullanıma
sahip olduğunun ispatlanması,
Bu durumlarda, başvuru sahibi, ürünün etkinlik emniyetine ilişkin yayınlanmış
literatür bilgilerini başvuru ekinde sunmak zorundadır.”
Söz konusu hüküm, uygulamada orijinal ilaç geliştirenlerin test verilerinin jenerik
üreticilerce kullanılmasına, belirlenen koşullar dahilinde herhangi bir engel getirmemekte,
söz konusu verilerin AB’nde mevcut sistemde olduğu gibi korunmasını sağlamamaktadır.
50 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
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2.3. Beşeri Tıbbi Ürünler Ruhsatlandırma Yönetmeliği (19 Ocak 2005)
2 Mart 1995 tarihli Tıbbi Farmasötik Ürünler Ruhsatlandırma Yönetmeliği, 19 Ocak
2005 tarihli ve 25705 sayılı Resmi Gazete’de yayımlanan “Beşeri Tıbbi Ürünler
Ruhsatlandırma Yönetmeliği” ile yürürlükten kaldırılmıştır. Yönetmeliğin veri koruması
hükümlerini içeren 9. maddesi 1 Ocak 2005 tarihi itibariyle, diğer maddeleri ise 30 Haziran
2005 tarihi itibariyle yürürlüğe girmiştir. Söz konusu madde “Kısaltılmış Başvuru” başlığıyla
aşağıda verilmektedir.
“Kısaltılmış Başvuru
Madde 9- 24/6/1995 tarihli ve 551 sayılı Patent Haklarının Korunması
Hakkında Kanun Hükmünde Kararname hükümleri saklı kalmak kaydıyla;
a) Yapılacak kısaltılmış başvurularda başvuru sahibi, aşağıdaki
hususlardan birinin kanıtlanması şartıyla, toksikolojik ve farmakolojik testlerin
ve klinik araştırmaların sonuçlarını sunmak zorunda değildir:
1) Tıbbi ürünün esas itibarıyla Türkiye’de daha önce ruhsatlandırılmış bir
tıbbi ürüne büyük ölçüde benzer olması ve orijinal tıbbi ürüne ilişkin pazarlama
ruhsatı sahibinin, söz konusu başvurunun incelenmesi amacıyla orijinal tıbbi
ürün dosyasında bulunan toksikolojik, farmakolojik ve/veya klinik referansların
kullanılmasına rıza göstermesi,
2) Tıbbi ürünün bileşen veya bileşenlerinin, detaylı bilimsel bibliyografi
yoluyla tespit edilen, makul düzeyde etkinlik ve kabul edilebilir güvenilirlikle
yerleşmiş bir tıbbi kullanımının olması,
3) Tıbbi ürünün, yürürlükteki mevzuat hükümleri uyarınca ruhsatlandırılmış
ve veri imtiyazı süresini doldurmuş bir tıbbi ürüne temelde benzer olması. Bu
alt bent ile hükme bağlanan veri imtiyazı süresi, Gümrük Birliği Alanında yer
alan ülkelerden birinde 1/1/2001 tarihinden sonra ilk defa ruhsatlandırılmış
orijinal ürünlerden 1/1/2005 tarihine kadar Türkiye’de herhangi bir jenerik
ruhsat başvurusu yapılmamış olanlar ile Gümrük Birliği Alanında yer alan
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ülkelerden birinde 1/1/2005 tarihinden sonra ilk defa ruhsatlandırılacak
orijinal ürünler açısından geçerli olup, Gümrük Birliği Alanında ilk defa
ruhsatlandırıldığı tarihten başlayarak molekülün Türkiye'deki patent süresi ile
sınırlı olmak üzere 6 (altı) yıldır.
Bununla birlikte, piyasaya sürülmüş tıbbi ürünlerden farklı terapötik
endikasyon, farklı kullanım yolu, farklı doz uygulanmasının öngörülmesi
halinde, buna yönelik yapılmış klinik araştırmaların sonuçları ve eğer gerekli
ise toksikolojik, farmakolojik çalışmaların sonuçlarının sağlanması zorunludur.
b) Bilinen bileşenleri içeren, ancak henüz terapötik amaçlarla, kombine
olarak kullanılmamış, yeni tıbbi ürünlerin, bu kombinasyonla ilgili toksikolojik
ve farmakolojik testler ve klinik araştırmalarının sonuçlarının sağlanması
zorunludur. Ancak her bir bileşene ilişkin referansların sağlanması gerekli
değildir.
Bu maddenin birinci fıkrasının (a) bendinin (2) numaralı alt bendine uygun
olarak, yayımlanmış verilere dayanan bibliyografik referansların sunulması
durumunda, başvurular Ek-1’e uygun şekilde yapılır.
Bakanlık, kamu sağlığını ciddi olarak tehdit eden istisnai durumlarda bu
maddedeki hükümlerden bağımsız olarak literatürde yayımlanan toksikolojik,
farmakolojik ve klinik verilere dair bilgilere dayanarak yapılan jenerik ürün
ruhsat başvurularını, bilimsel veriler ve uygulamalar doğrultusunda dikkate
alabilir. “
Maddenin incelenmesinden görüleceği üzere, Türkiye’de 1 Ocak 2005 tarihinden
itibaren başlayan veri koruması uygulaması yeni bir takım düzenlemeler getirmektedir.
Yönetmeliğin “Dayanak” başlıklı 3. maddesinde, AB’nin beşeri tıbbi ürünler ile ilgili
mevzuatına uyum sağlanması amacıyla, 2001/83 sayılı Direktifine paralel olarak hazırlandığı
belirtilmektedir. Dolayısıyla, veri koruması yönünden bakıldığında, söz konusu Direktif’in
10. maddesinde yer alan düzenlemelere esas itibariyle uyumlu bir değişiklik yapılmış ve
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ayrıca yeni bazı hükümler getirilmiştir. Yeni sistemde veri korumasının ilkeleri (başlangıcı,
kapsamı, yöntemi ve süresi) şu şekilde belirlenmiştir:
􀂾 Veri koruma süresi 6 yıldır.
􀂾 Veri koruma süresi, Gümrük Birliği alanında yer alan ülkelerden birinde 1 Ocak
2005 tarihinden sonra ilk defa ruhsatlandırılacak orijinal ürünler için geçerli
olacaktır.
􀂾 Veri koruma süresi, orijinal ürünün Gümrük Birliği alanında ilk defa
ruhsatlandırıldığı tarihten başlayacaktır.
􀂾 Veri koruması, orijinal tıbbi ürünün (molekülün) Türkiye’deki patent süresi ile
sınırlı olacaktır.
Getirilen bu yeni sistem ile Türkiye’de veri koruması, geriye dönük olarak 1 Ocak
2001 tarihinden itibaren başlatılmış; ancak, Gümrük Birliği Alanında yer alan ülkelerden
birinde 1 Ocak 2001 tarihinden sonra ilk defa ruhsatlandırılmış orijinal ürünlerden 1 Ocak
2005 tarihine kadar Türkiye’de herhangi bir jenerik ruhsat başvurusu yapılmamış olanlar
kapsam dahiline alınmıştır.
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GENEL DEĞERLENDİRME VE SONUÇ
Bu çalışmada ilaç sanayiinde, kapsamı ve uygulama yöntemi yönünden oldukça
tartışmalı bir konu olan test ve deney verilerinin korunması konusu değerlendirilmeye
alınmıştır. Dünyada halen bir çok ülkede tartışmalar devam etmekte, ülkeler kendi yapılarına
en uygun koruma sistemini getirmeye çalışmaktadır. Ülkemizin Avrupa Birliği ile ilişkileri
çerçevesinde son dönemde ortaya çıkan gelişmeler gözönüne alınarak, bu çalışmada konuya
sadece Avrupa Birliği bakış açısıyla yaklaşılmış, AB’nde ortaya çıkan değişim ve yakın
gelecekte oluşturulacak sistem incelenmeye çalışılmıştır.
AB’nde ilaç sanayiinde yeniden yapılanmaya ve özelde veri korumasına yönelik
olarak gerçekleştirilen düzenlemelerin etkilerinin ne olacağı fiili olarak 2005 yılı sonundan
itibaren uygulama ile birlikte ortaya çıkacaktır. Sanayiinin rekabet gücünün artırılması, Ar-
Ge faaliyetlerinin daha ileri düzeye getirilmesi ve ileri düzey sağlık hizmetlerinin sağlanması
hedeflerine ne ölçüde ulaşılacağı Avrupa yetkililerinin yakından izleyecekleri temel
faktörlerdir. Veri koruma sisteminde yeni yaklaşım ile orijinal ve jenerik ilaçlar arasında
“kazan-kazan” ilkesi ile yaratılmaya çalışılan dengenin olumlu sonuçlar vermesi
beklenmekte, ancak yasal düzenlemelerin tek başına yeterli olmadığı, sahip olunan anlayış ve
uygulama yöntemlerinin daha etkili olduğu üzerinde önemle durulmaktadır.
AB’nde yaşanan bu değişimin yanısıra, ülkemizde de veri koruması alanında yeni bir
sistem oluşturulmuş bulunmaktadır. Bu yeni düzenleme ile, test ve deney verilerinin
korunabilirliği sağlanmış, AB ile uyum sürecinde önemli bir adım atılmış olmaktadır. İlaçlara
yönelik mevzuatımızın AB ile üyelik müzakereleri çerçevesinde yeniden gözden geçirileceği
ve bazı değişikliklere uğrayacağı bilinmektedir. Bu kapsamda; AB’nde olduğu gibi
ülkemizde de, ilaç sanayiinde bir gözden geçirme sürecinin başlatılması ve sistemi etkileyen
unsurların (sanayii, sağlık ve fiyatlandırma politikaları, ödeme sistemleri, vb.) bir bütünlük
içerisinde ele alınmasında sonsuz yarar vardır. Böylelikle ülkemiz, insan sağlığının
iyileştirilmesi temel hedefini benimseyen, Ar-Ge faaliyetlerine önem veren, fikri haklar
55 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
sistemininin tüm imkanlarından yararlanan güçlü bir ilaç sanayii sayesinde sahip olduğu
potansiyeli daha fazla değerlendirebilecektir.
56 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
KAYNAKÇA
1. “A Guide to Patent Infringement Legislation”, Oproiu M., Vasilescu R., Managing
Intellectual Property, Supplement-IP at the border 2005.
http://www.managingip.com/includes/supplements/PRINT.asp?SID=495086&ISS=14
231&PUBID=199
2. “A Review of Existing Data Exclusivity Legislation in Selected Countries”,
Medford-Rosow T., Williams C.A., Third Revised Version, Intellectual Property
Institute, London, January 2004.
3. “A Stronger European-based Pharmaceutical Industry for the Benefit of the Patient
(G10 Medicines), Speech for Mr. Erkki Liikanen (Commissioner for Enterprise and
Information Society), 25 February 2004, Alliance UniChem Seminar.
4. “Bulgaria Country Commercial Guide FY 2004: Invest Climate”
http://strategis.ic.gc.ca/epic/internet/inimr-ri.nsf/en/gr121087e.html
5. “Commission Proposes Comprehensive Reform of EU Pharmaceutical Legislation”,
IP/01/1027, European Commission, Brussels, 18 July 2001.
6. “Data Exclusivity and the 2001 Review”, EGA Discussion Paper, July 2001.
7. “Data Exclusivity and Market Protection”
http://www.egagenerics.com/gen-dataex.htm
8. “Developments in Intellectual Property Protection 2002-2003”, Office of the United
State Trade Represantative, May 1, 2003,
http://www.ustr.gov/reports/2003/developments.pdf
9. “Economic and Legal Framework for Non-Prescription Medicines”, Country Profiles,
Bulgaria, The Association of the European Self-Medication Industry, June 2004,
http://www.aesgp.be/CountryProfiles/Bulgaria2004.pdf
10. “Encouragement of New Clinical Drug Development: The Role of Data Exclusivity”,
International Federation of Pharmaceutical Manufacturers Associations, 2000,
Switzerland.
11. “Encouragement of New Clinical Drug Development: The Role of Data Exclusivity”,
International Federation of Pharmaceutical Manufacturers Associations, Fourth
Revised Version, January 2005, Switzerland.
http://www.ifpma.org/site_search.asp?FileNumPosition=10&search=data+exclusivity
&mode=allwords
57 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
12. “EU Surprises Itself by Agreeing to Pharma Rules” O’Donnell, P., Applied Clinical
Trials, Feb 1, 2004.
13. “EurActive.com Portal-Links Dossier- Generic Medicines”, 26 March 2004,
http://www.euractive.com
14. “European revisions offer new freedoms for generics”, Generics Bulletin, 16 January 2004.
15. “Evaluation of the Operation of Community Procedures for the Authorization of
Medicinal Products”, CMC Cameron McKenna and Andersen Consulting, carried out
on behalf of the European Commission Directorate-General Enterprise
Pharmaceuticals and Cosmetics, 17 November 2000.
16. “Fixing the Safety Net, Data Protection and Related Measures under the New
European Pharmaceutical Legislation”, Campolini M., Patent World, No. 162, May
2004. http://www.ipworldonline.com
17. “G10 Medicines, High Level Group on Innovation and Provision of Medicines”,
Consultation Paper, European Commission, Enterprise Directorate-General, Brussels,
27 September 2001.
18. “G10 Medicines, High Level Group on Innovation and Provision of Medicines”,
Report, European Commission, Enterprise Directorate-General, Brussels, 26 February
2002.
19. “Global Competitiveness in Pharmaceuticals A European Perspective”, Gambardella
A., Orsenigo L., Pammolli F., Enterprise Papers, No.1-2001, European Commission,
November 2000.
20. “Globalization, TRIPs and Access to Paharmaceuticals”, WHO Policy Perspectives
on Medicines, No.3, March 2001, World Health Organization, WHO/EDM/2001.2,
Geneva.
21. “Government seeks 15-year transition period on EU pharmaceutical law”, Warsaw
Business Journal, 7 April 2004, http://www.wbj.pl/?command=article&id=22008&
22. “İlaçta Veri Korumasının Mali Yansımaları” Baykara T. Prof.Dr., Çaylı H., Çelik H.
Uz., Tokat M. Prof Dr., Ünalan T. Doç.Dr., Bilimsel Çalışma Grubu, Haziran 2003, Ankara.
23. “MEPs Recommended to Accept EU Pharmaceutical Compromise”, EGA Press
Release, 16 December 2003, http://www.egagenerics.com/pr-2003-12-16.htm
24. “Main Outcomes of the Pharma Review-after the Compromise between the Council
and the European Parliament”, The European Generic Medicines Association,
December 2003.
58 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
25. “Notice to Applicants, Volume 2A Procedures for Marketing Authorisation, Chapter
1 Marketing Authorisation” , Final-Revision 1, European Commission, Enterprise
Directorate-General, ENTR/F2/BL D(2002), Brussels, November 2002.
26. “Parliamentary Legislative Procedures”, Request No. 084 “Pharmaceutical Law-
Treaty of Accession”, August 2003, http://www1.ukie.gov.pl/HLP/files.nsf/
0/e16a25fd53e9f64ac1256e840036da42?OpenDocument
27. “Petition to the European Parliament”, 26 November 2003.
28. PhRMA “Special 301” Submission, 2003.
29. PhRMA “Special 301” Submission, 2004.
30. “Pharmaceuticals; Poland is the first to request transition period on data protection”,
Health & Pharma, Euractiv.com Portal-news nr 1507517, 8 April 2004,
http://www.euractiv.com
31. “Preparing for Enlargement by Revising the Rules: An Opportunity for Self-
Medication”, AESGP Members’ Meeting, Warsaw, 30-31 January 2002
http://www.aesgp.be/Warsaw2002/WarsawJan2002.pdf
32. “Reform of EU Pharmaceutical Legislation”, MEMO/01/267, European Commission,
Brussels, 18 July 2001.
33. “Reform of EU Pharmaceutical Legislation”, MEMO/03/262, European Commission,
Brussels, 18 December 2003.
34. “Review of Legislation, Czech Republic”, TRIPS Council, IP/Q3/CZE/1, 17
December 1997.
35. “Review of Legislation, Estonia”, TRIPS Council, IP/Q/EST/1, IP/Q2/EST/1,
IP/Q3/EST/1, IP/Q4/EST/1, 29 March 2001.
36. “Review of Legislation, Latvia”, TRIPS Council, IP/Q/LVA/1/Add.1,
IP/Q2/LVA/1/Add.1, IP/Q3/LVA/1/Add.1, IP/Q4/LVA/1/Add.1, 26 May 2000.
37. “Review of Pharmaceutical Legislation”, Discussion Document (Final Version),
European Commission, Enterprise Directorate-General, 22 January 2001, Brussels.
38. “Romania’s Position Paper”, Conference on Accession to the European Union,
CONF-RO 52/01, Brussels, 14 December 2001
http://www.mie.ro/Negocieri/English/position_doc/CAP01-DP%20eng.doc
59 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
39. “Striking New Balances: The Protection of Pharmaceuticals and the Future of the
Industrial Property System in Europe, A Central and Eastern European Perspective”,
Fiscor, M.Z., Vice-President, Hungarian Patent Office, International Conference on
Intellectual Property, The Internet, Electronic Commerce and Traditional Knowledge,
WIPO/ECTK/SOF/01/2.2, May 2001.
40. “The Acceding Countries Declaration”, 5 September 2003.
41. “The Impact of the EU-Enlargement on the Pharmaceutical Industry”, Alexa von
Uexküll, Vossius and Partner, 4 May 2004.
http://www.voissiusandpartner.com/eng/publication/impact_eu-enlargement.html
42. “The Making of New Medicines, Manufacturing, the Environment and the
Pharmaceutical Industry”, European Federation of Pharmaceutical Industries and
Associations- EFPIA, Brussels, June 2001.
43. “The Pharmaceutical Industry in Figures 2004”, EFPIA, Brussels.
44. “2002 Regular Report on Slovakia’s Progress towards Accession- Chapter 1:Free
Movement of Goods”,
http://www.fifoost.org/slowakei/EU_Slovakia_2002/node36.php
45. “The Right Treatment?”, Britton I., Gavey M., Linklaters 2004.
46. “What the EU Pharmaceutical Review Legislation Means for the New Member
States”, Hogan&Hartson,
http://www.hhlaw.com/articles/1815_EU%20Accession%20Guide%20-
%20EU%20Pharmaceutical%20Review%20Legislation%20April%202005.pdf
60 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
EK:1. AB’DE İLAÇ MEVZUATININ YASALAŞMA SÜRECİ
TARİH YASAMA SÜRECİ
8 Temmuz 2001 Avrupa Komisyonu gözden geçirme tekliflerini iletmiştir.
26 Kasım 2001 Komisyon teklifleri kabul etmiştir.
23 Ekim 2002 Arupa Parlamentosunda İlk Görüşme(First Reading)
tamamlanmıştır.
10 Aralık 2002 Komisyon Tüzük taslağındaki değişiklik önerilerini kabul
etmiştir.
3 Nisan 2003 Komisyon Direktif taslaklarındaki değişiklik önerilerini kabul
etmiştir.
29 Eylül 2003 Konsey ortak bir tutum (Common Position) belirlemiştir.
27 Kasım 2003 Parlamento Komitesi İkinci Görüşmedeki (Second Reading)
değişiklik önerilerini kabul etmiştir.
11 Aralık 2003 Bütün ikinci görüşme değişiklik önerilerinin son tarihidir. Konsey
ve Parlamento arasında fikir birliğine varılan değişiklik paketi
üzerinde uzlaşma sağlanmıştır.
17 Aralık 2003 Parlamento oylama oturumunda ikinci görüşmedeki uzlaşma
paketine destek vermiştir.
31 Mart 2004
1 Kasım 2005
Tüzük ve Direktifler yasalaşmıştır.
Direktifler ulusal yasalara aktarılacaktır.
Kaynak: “European revisions offer new freedoms for generics”, Generics Bulletin, 16 January 2004.
61 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
http://ekutup.dpt.gov. 62 tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
EK:2. AB ÜLKELERİ VE ADAY ÜLKELERDE VERİ KORUMASINA İLİŞKİN
MEVZUAT
ÜLKE SÜRE YASAL DAYANAK
BELÇİKA 10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
DANİMARKA 6-10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
FİNLANDİYA 6-10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
FRANSA 10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
ALMANYA 10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
YUNANİSTAN 6-10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
İRLANDA 6-10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
İTALYA 10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
LÜKSEMBURG 10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
HOLLANDA 10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
PORTEKİZ 6-10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
İSPANYA 6-10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
1993 TARİHLİ YASA
İSVEÇ 10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
İNGİLTERE 10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III)
ÇEK CUMHURİYETİ 6-10 YIL 79/1997 SAYILI İLAÇ YASASI, MD.(32) (1998’de
başladı)
147/1996 SAYILI BİTKİSEL TIBBİ TEDAVİ
YASASI, MD.20
ESTONYA 6-10 YIL RUHSATLANDIRMA YÖNETMELİĞİ, MD.2
MACARİSTAN 6-10 YIL 12/2001 SAYILI TIBBİ ÜRÜNLERİN TESCİLİ VE
RUHSATLANDIRILMASI KARARI (1 Ocak 2003’te
başladı)
LETONYA 6-10 YIL 20 OCAK 1998 TARİH ve 24 SAYILI İLAÇ ve TIBBİ
ÜRÜNLERİN TESCİLİNE İLİŞKİN GENEL
İLKELER, MD.17
POLONYA 6-10 YIL DİREKTİF 2001/83, MD.10(1)(a)(III) ve 2001
TARİHLİ İLAÇ YASASI (Üye oluncaya kadar veri
koruması 3 yıl olarak uygulanmıştır)
SLOVAK CUMHURİYETİ 6-10 YIL 140/1998 SAYILI İLAÇ KARARNAMESİ
SLOVENYA 6-10 YIL TIBBİ ÜRÜNLER YASASI, MD.15
LİTVANYA 6-10 YIL 22/12/2001 TARİH VE 669 SAYILI KARAR (1 Mart
2003’te başladı)
HIRVATİSTAN Süre
belirtilmemiş
İLAÇ VE TIBBİ ÜRÜNLER YASASI, MD.15
ROMANYA 6-10 YIL 2/3/2001 TARİH VE 3 SAYILI KARAR (14 Nisan
2004’te başladı)
BULGARİSTAN 6-10 YIL İLAÇ VE ECZANELER YASASI, MD.18 (1 Ocak
2003’te başladı)
Kaynak: -Medford-Rosow T., Williams C.A., “A Review of Existing Data Exclusivity Legislation in
Selected Countries”, Third Revised Version, January 2004, Intellectual Property Institute, London.
-“Developments in Intellectual Property Protection 2002-2003”, Office of the United State Trade
Represantative, May 1, 2003, http://www.ustr.gov/reports/2003/developments.pdf.
- Review of Legislation, Latvia, TRIPS Council, IP/Q/LVA/1/Add.1, IP/Q2/LVA/1/Add.1,
IP/Q3/LVA/1/Add.1, IP/Q4/LVA/1/Add.1, 26 May 2000.
- Review of Legislation, Czech Republic, TRIPS Council, IP/Q3/CZE/1, 17 December 1997.
63 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
64 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
EK:3. BEŞERİ TIBBİ ÜRÜNLER RUHSATLANDIRMA YÖNETMELİĞİ
Resmi Gazete
Tarih: 19.1.2005; Sayı: 25705
BİRİNCİ BÖLÜM
Amaç, Kapsam, Dayanak ve Tanımlar
Amaç
Madde 1- Bu Yönetmeliğin amacı; beşeri tıbbi ürünlerin istenen etkinlik ve güvenilirliğe,
gereken kaliteye sahip olmalarını sağlamak üzere, ruhsatlandırma işlemlerinde uygulanacak
usul ve esaslar ile ruhsatlandırılmış beşeri tıbbi ürünlere ilişkin uygulamaları belirlemektir.
Kapsam
Madde 2- Bu Yönetmelik, beşeri kullanım için endüstriyel olarak üretilen veya ithal
edilen beşeri tıbbi ürünler ile bunlar için ruhsat başvurusunda bulunan ve/veya ruhsat
verilmiş olan gerçek ve tüzel kişileri kapsar.
Ancak;
a) Sadece bir hasta için reçeteye göre eczanede hazırlanan ve yaygın olarak majistral
formül ismiyle anılan her türlü ürün,
b) Bir farmakopenin formüllerine uygun olarak eczane tarafından doğrudan sunulmak
amacıyla hazırlanan ve yaygın olarak ofisinal formül adıyla anılan her türlü ürün,
c) 29/1/1993 tarihli ve 21480 sayılı Resmi Gazete’de yayımlanan İlaç Araştırmaları
Hakkında Yönetmelik hükümleri saklı kalmak kaydıyla araştırma ve geliştirme
çalışmalarında kullanılması amaçlanan tıbbi ürünler,
d) Yetkili üretici tarafından ileri işlemlerde kullanılması amaçlanan yarı mamul ürünler,
e) Kapalı kaynak halinde hazırlanan her türlü radyonüklidler,
f) İnsan kaynaklı tam kan, plazma veya kan fraksiyonları,
bu Yönetmeliğin kapsamı dışındadır.
Dayanak
Madde 3- Bu Yönetmelik; 14/5/1928 tarihli ve 1262 sayılı İspençiyari ve Tıbbi
Müstahzarlar Kanununa, 7/5/1987 tarihli ve 3359 sayılı Sağlık Hizmetleri Temel Kanunun
3/k maddesine, 23/6/1983 tarihli ve 2857 sayılı Kan ve Kan Ürünleri Kanununun 8 inci
maddesine ve 13/12/1983 tarihli ve 181 sayılı Sağlık Bakanlığının Teşkilat ve Görevleri
Hakkında Kanun Hükmünde Kararnamenin 43 üncü maddesine dayanılarak;
Avrupa Birliği’nin beşeri tıbbi ürünler ile ilgili mevzuatına uyum sağlanması amacıyla,
2001/83/EC sayılı beşeri tıbbi ürünler hakkındaki direktifine paralel olarak hazırlanmıştır.
65 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
Tanımlar
Madde 4- Bu Yönetmelikte geçen;
a) Bakanlık: Sağlık Bakanlığını,
b) Kanun: 1262 sayılı İspençiyari ve Tıbbi Müstahzarlar Kanununu,
c) Beşeri Tıbbi Ürün/Ürün : Hastalığı tedavi etmek ve/veya önlemek, bir teşhis yapmak
veya bir fizyolojik fonksiyonu düzeltmek, düzenlemek veya değiştirmek amacıyla, insana
uygulanan doğal ve/veya sentetik kaynaklı etkin madde veya maddeler kombinasyonunu,
d) Ruhsatlı Beşeri Tıbbi Ürün: Bakanlıkça onaylanmış, kullanıma hazır şekilde, özel bir
ambalajda ve belirli bir isim ile pazara sunulan beşeri tıbbi ürünü,
e) Madde: Kaynağı insan (insan kanı ve insan kanından elde edilen ürünler), hayvan
(mikroorganizmalar, bütün hayvanlar, organ parçaları, hayvan salgıları, toksinler, özler, kan
ürünleri), bitki (mikroorganizmalar, bitkiler, bitkilerin bölümleri, bitki salgıları, bitki özleri),
kimyasal (elementler, doğal olarak oluşan kimyasal materyaller, kimyasal değişiklik ya da
sentez yoluyla elde edilen kimyasal ürünler) olabilen her türlü maddeyi,
f) İmmünolojik Ürün: Kolera, BCG, polio ve çiçek aşıları gibi aktif bağışıklık sağlayan
ajanlar; tüberkülin ve tüberkülin PPD, brusella, Schick ve Dick testleri dahil bağışıklık
durumunu teşhis etmek için kullanılan ajanlar ve difteri antitoksini, anti-çiçek globulini,
antilenfotik globulin gibi pasif bağışıklık sağlamak için kullanılan ajanları içeren tüm aşılar,
toksinler ve serumlar ile allerjen bir ajana karşı kazanılan spesifik immünolojik cevabı
değiştirmek veya tanımlamak niyeti ile kullanılan allerjen ürünlerden oluşan beşeri tıbbi
ürünleri,
g) Radyofarmasötik: Tıbbi amaçla kullanılmak üzere hazırlanılan ve kullanıma hazır
olduğunda, yapısında bir veya birden fazla radyonüklid içeren ürünü,
h) Radyonüklid: Çekirdeği kendiliğinden bozunmaya uğrayarak, bir veya birden çok
iyonlaştırıcı radyasyon yayınlayan radyoaktif nitelikli atomu,
ı) Radyoaktif Madde: Bir veya birden çok iyonlaştırıcı radyasyon yayınlayarak
çekirdekleri kendiliğinden bozunmaya uğrayan alaşım, karışım, çözelti veya bileşik formunda
radyonüklid içeren maddeleri,
i) Radyonüklid Jeneratör: Yavru bir radyonüklidden elüsyon yoluyla veya diğer bir
yöntemle elde edilen radyofarmasötik ürünü, radyofarmasotiklerde kullanılan sabit bir ana
radyonüklidle birleştiren her türlü sistemi,
j) Radyonüklid Kit: Bitmiş radyofarmasötik, genellikle kullanımdan önce radyonüklidle
birleşmiş veya yeniden oluşturulmuş her türlü preparatı,
k) Radyonüklid Prekürsör: Uygulamadan önce bir başka maddenin radyoaktif
işaretlenmesi için üretilen herhangi başka bir radyonüklidi,
l) Kan Ürünü: İnsan kanı veya plazmasından endüstriyel yöntemlerle kamu ya da özel
kurumlar tarafından elde edilen ve özellikle albumin, immünoglobulin ve koagülasyon
faktörleri gibi ürünleri içeren kan bileşenlerine dayalı tıbbi ürünleri,
m) Etkin Madde: Beşeri tıbbi ürünlerde kullanılan farmakolojik aktif maddeleri,
n) Yardımcı Madde: Bir ürünün terkibinde yer alan, etkin madde ve maddeler dışında
kalan maddeleri,
o) Başlangıç Maddeleri: Bir ürünün üretiminde kullanılan, ambalaj malzemeleri dışındaki
her türlü maddeleri,
ö) Bitmiş Ürün: Bütün üretim aşamalarından geçmiş, son ambalajı içinde kullanıma hazır
ürünü,
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p) Ruhsatlandırma: Bir ürünün, pazara sunulabilmesi için Bakanlıkça yapılan inceleme ve
onay işlemlerini,
r) Ruhsat: Bir ürünün belirli bir formül ile belirli bir farmasötik form ve dozda, kabul
edilen ürün bilgilerine uygun olarak üretilip pazara sunulabileceğini gösteren, Bakanlıkça
düzenlenen belgeyi,
s) Plazma: Kanın hücrelerinden ayrıldığı ve içinde sadece kan proteinleri bulunan sıvı
kısmını,
ş) Seri: Bir ürünün üretim sırasında tek bir üretim döngüsünde elde edilen ve homojenliğin
sağlandığı miktarı,
t) TAEK : Türkiye Atom Enerjisi Kurumunu,
u) Spesifik Aktivite : Bir radyoaktif maddenin birim kütlesinin Curie veya Becquerel
cinsinden ifade edilen aktivite yoğunluğunu,
ü) Gümrük Birliği Alanı: Türkiye ile Avrupa Birliği arasında Gümrük Birliğini tesis eden
1/95 sayılı Ortaklık Konseyi Kararının 3 üncü maddesinin 3 üncü bendinde tanımlanan
Gümrük Birliği Gümrük Alanını,
v) Orijinal Tıbbi Ürün: Etkin madde/maddeler açısından bilimsel olarak kabul edilebilir
etkinlik, kalite ve güvenliğe sahip olduğu kanıtlanarak, dünyada pazara ilk defa sunulmak
üzere ruhsatlandırılmış/izin verilmiş ürünü,
y) Jenerik Tıbbi Ürün: Etkin maddeler açısından orijinal tıbbi ürün ile aynı kalitatif ve
kantitatif terkibe ve aynı farmasötik forma sahip olan ve orijinal tıbbi ürün ile
biyoeşdeğerliliği, uygun biyoyararlanım çalışmaları ile kanıtlanmış tıbbi ürünü,
ifade eder.
İKİNCİ BÖLÜM
Ruhsat Başvurusu
Ruhsat
Madde 5- Bu Yönetmelik hükümlerine göre Bakanlık tarafından ruhsatlandırılarak satış
izni verilmeyen hiçbir beşeri tıbbi ürün pazara sunulamaz.
Ruhsatlandırma işlemi; radyonüklid jeneratörler, radyonüklid kitler, radyonüklid
prekürsörler, radyofarmasötikler ve endüstriyel olarak hazırlanmış radyofarmasötikler için de
geçerlidir.
Ulusal mevzuat hükümleri uyarınca, radyofarmasötik tıbbi ürünleri kullanmaya yetkili bir
sağlık kuruluşunda, bu kuruluş veya yetkili kişi tarafından kullanımları sırasında üretim
talimatlarına göre, özellikle ruhsatlı radyonüklid jeneratörler, radyonüklid kitler ve
radyonüklid prekürsörlerden hazırlanan radyofarmasötikler için pazarlama ruhsatı aranmaz.
Başvuru
Madde 6- Türkiye sınırları dahilinde yerleşik bulunan gerçek veya tüzel kişiler, bir ürünü
pazara sunmak amacıyla ruhsat alabilmek için gereken ve bu Yönetmeliğin Ek-1’inde
belirtilen tıbbi ürün ruhsat başvurusunda sunulması gereken bilgi ve belgeleri, her bir
farmasötik form için bu Yönetmelikte öngörüldüğü şekilde hazırlayarak Bakanlığa sunar.
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Ruhsat Başvurusunda Bulunabilecek Kişiler
Madde 7- Kanunun 5 inci maddesi gereğince, ürünü pazara sunmak üzere ruhsat almak
isteyen;
a) Gerçek kişilerin; eczacılık, tıp veya kimya bilim dallarında eğitim veren okullardan
birisinden mezun olmaları ve Türkiye’de mesleğini icra etme yetkisine sahip olmaları,
b) Tüzel kişilerin; (a) bendinde belirtilen vasıfları taşıyan ve başvuruya konu ürün veya
ürünler hakkında bilgi birikimi ve deneyimi olan birini “yetkili kişi” sıfatıyla istihdam
etmeleri,
şarttır.
Diş hekimliği mesleğine mensup ve Türkiye’de mesleğini icra etme yetkisine sahip gerçek
kişiler de, diş hekimliğinde kullanılan ürünler için ruhsat başvurusu yapma hakkına
sahiptirler.
Başvuruda Sunulması Gereken Bilgi ve Belgeler
Madde 8- Bir ürüne ruhsat almak isteyen gerçek veya tüzel kişiler, bu Yönetmeliğin Ek-
1'ine uygun olarak hazırlanmış bilgiler ve aşağıda sayılan hususların gerçekleştirildiğine dair
belgeler ile birlikte Bakanlığa başvuruda bulunur:
a) Başvuru sahibinin bu Yönetmeliğin 7 nci maddesinde belirtilen mesleklerden birine
mensup olduğunu gösteren diplomasının noter onaylı örneği,
b) Başvuru sahibinin başvuruyu yapmaya yetkili olduğunu gösteren onaylı belge,
c) Başvuru sahibinin tüzel kişi olması durumunda, şirketin kuruluş amaçlarını, ortaklarını
ve sorumlu kişilerin görev ve unvanlarını belirten ticaret sicil gazetesinin aslı veya sureti,
d) Başvuru sahibinin adı veya firma adı, daimi adresi, elektronik posta adresi, telefon ve
faks numarası,
e) Üreticinin adı, daimi adresi, telefon ve faks numarası,
f) Ürünün adı,
g) Ampirik kimyasal formülün dışında, ürünün bileşenlerinin günlük terminolojideki
kantitatif ve kalitatif özellikleri, şayet varsa Dünya Sağlık Örgütü tarafından önerilen
uluslararası mülkiyeti haiz olmayan ismi (INN),
h) Üretim metodunun tanımı,
ı) Terapötik endikasyonlar, kontrendikasyonlar ve advers etkileri,
i) Dozu, farmasötik formu, uygulama metodu ve yolu, raf ömrü, ambalaj miktarı,
j) Ürünün saklama koşulları, hastalara uygulanması, söz konusu ürünün çevre için
yarattığı potansiyel riskler de göz önünde bulundurularak atık ürünün imha şeklinin
belirtilmesi,
k) Üretici tarafından kullanılan kontrol metotlarının tanımı (bileşenlerin ve bitmiş ürünün
kantitatif ve kalitatif olarak analizi, sterilite testleri, pirojen maddeler, ağır metallerin bulunup
bulunmadığına dair testler gibi özel testler, stabilite testleri, biyolojik ve toksisite testleri,
üretim işleminin ara aşamasında yürütülen kontroller),
l) Fiziko-kimyasal, biyolojik veya mikrobiyolojik testlerin sonuçları,
m) Toksikolojik ve farmakolojik testlerin ve klinik araştırmaların sonuçları,
n) Ürünün ithali/lisanslı üretimi durumunda orijin firma tarafından düzenlenen ve
geçerlilik süresini de gösteren ürüne ait orijinal kısa ürün bilgileri (KÜB), kullanma talimatı
ve ambalaj örnekleri,
o) Ürünün ithali durumunda, ithalatı yapan gerçek veya tüzel kişinin söz konusu ürünün
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Türkiye’ye ithali, ruhsatlandırılması ve satışı konusunda yetkili tek temsilci olduğunu veya
eğer varsa ortak pazarlama yetkisini gösteren orijin firma tarafından düzenlenmiş belge ve
Türkçe tercümesi,
ö) Ürünün lisans altında üretilmesi durumunda, üretimi yapan gerçek veya tüzel kişinin,
söz konusu ürünü Türkiye’de üreterek satabilecek yetkili tek temsilci olduğunu veya eğer
varsa ortak pazarlama yetkisini gösteren orijin firma tarafından düzenlenmiş belge ve Türkçe
tercümesi,
p) Üreticinin, Bakanlık yahut ilgili ülkenin yetkili otoritesi tarafınca onaylanmış İyi
Üretim Uygulamaları çerçevesinde üretim yapabileceğini gösterir GMP belgesi,
r) Başvuru sahibinin üretici olmaması durumunda, 23/10/2003 tarihli ve 25268 sayılı
Resmi Gazete’de yayımlanan Beşeri Tıbbi Ürünler İmalathaneleri Yönetmeliğinde belirtilen
şartlara sahip bir üretici ile yaptığı noter onaylı fason üretim sözleşmesi,
s) Başvurusu yapılan ürün için, ruhsat başvurusu yapılmış diğer ülkelerin listesi ile birlikte
ürünün pazara sunulduğu diğer ülke veya ülkelerin yetkili otoritelerince verilmiş onaylı
Farmasötik Ürün Sertifikaları,
t) 24/7/1985 tarihli ve 85/9727 sayılı Bakanlar Kurulu Kararı ile yürürlüğe konulan
Radyasyon Güvenliği Tüzüğü, 10/9/1997 tarihli ve 23106 sayılı Resmi Gazete’de yayımlanan
Radyoaktif Maddenin Güvenli Taşınması Yönetmeliği, 24/3/2000 tarihli ve 23999 sayılı
Resmi Gazete’de yayımlanan Radyasyon Güvenliği Yönetmeliği ile 2/9/2004 tarihli ve
25571 sayılı Resmi Gazete’de yayımlanan Radyoaktif Madde Kullanımında Oluşan Atıklara
İlişkin Yönetmelik hükümleri de dikkate alınarak uygulanabilir halde tıbbi ürünün çevre
açısından oluşturabileceği risklerin tanımı,
u) Bir radyonüklid jeneratörün ruhsatlandırma başvurusunda yukarıda belirtilenlere ek
olarak, elüe edilecek nüklit preparatın kalitesini ve bileşimini etkileyebileceği için sistemin
ve sistemi oluşturan bileşenlerin detaylı tanımının ve elüat veya süblimenin kantitatif ve
kalitatif özelliklerinin bildirilmesi,
ü) Ambalaj ve etiketlemeye ilişkin mevzuatta belirtilen kısa ürün bilgileri ve bu
doğrultuda hazırlanmış kullanma talimatı ve ürüne ait pazara sunulacak boyut ve dizaynda içdış
ambalaj taslak örnekleri ile ithal/lisanslı üretilen ürünlerde bunların diğer ülke yetkili
otoriteleri tarafından onaylanmış orijinal kısa ürün bilgileri, kullanma talimatı ve ambalaj
örnekleri,
v) Başvurusu yapılan ürün diğer ülkelerin yetkili otoritesi tarafından reddedilmiş, geri
çekilmiş, askıya alınmış ise veya başvuru sahibi tarafından geri çekilmiş ise, bu ülkelerin
listesinin, ürünün söz konusu ülkede ruhsatlandırılmış adı, yapılan işlemlerin tarihi ve
gerekçesi ile birlikte belirtilmesi.
Bu maddede yer alan bilgilerden güncellenenlerin Bakanlığa bildirilmesi zorunludur.
Kısaltılmış Başvuru
Madde 9- 24/6/1995 tarihli ve 551 sayılı Patent Haklarının Korunması Hakkında Kanun
Hükmünde Kararname hükümleri saklı kalmak kaydıyla;
a) Yapılacak kısaltılmış başvurularda başvuru sahibi, aşağıdaki hususlardan birinin
kanıtlanması şartıyla, toksikolojik ve farmakolojik testlerin ve klinik araştırmaların
sonuçlarını sunmak zorunda değildir:
1) Tıbbi ürünün esas itibarıyla Türkiye’de daha önce ruhsatlandırılmış bir tıbbi ürüne
büyük ölçüde benzer olması ve orijinal tıbbi ürüne ilişkin pazarlama ruhsatı sahibinin, söz
69 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
konusu başvurunun incelenmesi amacıyla orijinal tıbbi ürün dosyasında bulunan toksikolojik,
farmakolojik ve/veya klinik referansların kullanılmasına rıza göstermesi,
2) Tıbbi ürünün bileşen veya bileşenlerinin, detaylı bilimsel bibliyografi yoluyla tespit
edilen, makul düzeyde etkinlik ve kabul edilebilir güvenilirlikle yerleşmiş bir tıbbi
kullanımının olması,
3) Tıbbi ürünün, yürürlükteki mevzuat hükümleri uyarınca ruhsatlandırılmış ve veri
imtiyazı süresini doldurmuş bir tıbbi ürüne temelde benzer olması. Bu alt bent ile hükme
bağlanan veri imtiyazı süresi, Gümrük Birliği Alanında yer alan ülkelerden birinde 1/1/2001
tarihinden sonra ilk defa ruhsatlandırılmış orijinal ürünlerden 1/1/2005 tarihine kadar
Türkiye’de herhangi bir jenerik ruhsat başvurusu yapılmamış olanlar ile Gümrük Birliği
Alanında yer alan ülkelerden birinde 1/1/2005 tarihinden sonra ilk defa ruhsatlandırılacak
orijinal ürünler açısından geçerli olup, Gümrük Birliği Alanında ilk defa ruhsatlandırıldığı
tarihten başlayarak molekülün Türkiye'deki patent süresi ile sınırlı olmak üzere 6 (altı) yıldır.
Bununla birlikte, piyasaya sürülmüş tıbbi ürünlerden farklı terapötik endikasyon, farklı
kullanım yolu, farklı doz uygulanmasının öngörülmesi halinde, buna yönelik yapılmış klinik
araştırmaların sonuçları ve eğer gerekli ise toksikolojik, farmakolojik çalışmaların
sonuçlarının sağlanması zorunludur.
b) Bilinen bileşenleri içeren, ancak henüz terapötik amaçlarla, kombine olarak
kullanılmamış, yeni tıbbi ürünlerin, bu kombinasyonla ilgili toksikolojik ve farmakolojik
testler ve klinik araştırmalarının sonuçlarının sağlanması zorunludur. Ancak her bir bileşene
ilişkin referansların sağlanması gerekli değildir.
Bu maddenin birinci fıkrasının (a) bendinin (2) numaralı alt bendine uygun olarak,
yayımlanmış verilere dayanan bibliyografik referansların sunulması durumunda, başvurular
Ek-1’e uygun şekilde yapılır.
Bakanlık, kamu sağlığını ciddi olarak tehdit eden istisnai durumlarda bu maddedeki
hükümlerden bağımsız olarak literatürde yayımlanan toksikolojik, farmakolojik ve klinik
verilere dair bilgilere dayanarak yapılan jenerik ürün ruhsat başvurularını, bilimsel veriler ve
uygulamalar doğrultusunda dikkate alabilir.
Özel Durumlarda Ruhsatlandırma
Madde 10- Aşağıda sıralanan özel durumlarda ruhsatın verilmesini takiben daha ileri
çalışmaların yürütülmesi ve tıbbi ürünle ilgili advers etkilerin bildirilmesi koşuluyla
Bakanlığın kararı çerçevesinde ruhsat verilebilir:
a) Söz konusu ürünün terapötik endikasyonlarının, başvuru sahibinin ayrıntılı kanıt
sağlayamayacağı kadar az olması,
b) Mevcut bilimsel verilerin ışığı altında ayrıntılı bilginin sağlanamaması,
c) Bu tür bilgileri toplamanın kabul gören etik ilkelere aykırı olması.
Özel durumlarda ruhsatlandırma halinde ürünün ambalaj ve kullanma talimatı, ürünle
ilgili mevcut duruma ve ürünün belli açılardan halen yetersiz olduğuna dikkati çekecek
biçimde olmalıdır.
Kısa Ürün Bilgileri
Madde 11 - Kısa Ürün Bilgileri;
a) Ürünün adını,
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b)Ürünün etkin madde/maddeler ve yardımcı maddeler bakımından kantitatif ve kalitatif
kompozisyonunu, uygulama yolu için gerekli bilgileri, yaygın ismini veya kimyasal tanımını,
c) Farmasötik formunu,
d) Farmakolojik özelliklerini ve terapötik amaç kapsamında faydalı olabildiği ölçüde
farmakokinetik özelliklerini,
e) Klinik özellikleri;
1) Terapötik endikasyonlarını,
2) Kontrendikasyonlarını,
3) Görülme sıklığı ve ciddiyeti de belirtilecek şekilde advers etkilerini,
4) Özel kullanım önlemleri; immünolojik tıbbi ürünlerin olması durumunda, bu ürünlerle
çalışan ve bunları hastalara uygulayan kişiler tarafından alınacak her türlü önlemlerle hasta
tarafından alınacak her türlü önlemi,
5) Gebelik ve laktasyon döneminde kullanımını,
6) Diğer ilaçlarla etkileşme ve diğer etkileşme şekillerini,
7) Pozoloji, yetişkinler ve gerektiğinde çocuklar için uygulama yolunu,
8) Doz aşımı durumunda semptomlar, uygulanacak acil işlemler ve gerekli antidotları,
9) Özel uyarıları,
10) Araba ve diğer makine çeşitlerini kullanma yeteneği üzerindeki etkilerini,
f) Farmasötik özellikleri;
1) Başlıca geçimsizlikleri,
2) Tıbbi ürünün raf ömrü, gerektiğinde rekonstitüsyondan sonraki veya iç ambalajın ilk
kez açıldığı tarih de belirtilerek raf ömrünü,
3) Saklama için özel önlemleri,
4) İç ambalajın özellikleri ve içeriğini,
5) Gerektiğinde kullanılmamış ürünlerin veya bu tür ürünlerden türetilmiş materyallerin
atılması için gerekli önlemleri,
g) Ruhsat sahibinin adı, adresi, telefon ve faks numarasını,
h) Radyofarmasötikler için dahili radyasyon dozimetresinin tüm ayrıntılarını,
ı) Radyofarmasötikler için detaylı kullanım kılavuzu, hazırlama ve kalite kontrolüne
yönelik bilgiler, gerekli olduğu yerlerde maksimum saklama süresi, elüat veya kullanıma
hazır ürünün spesifikasyonlarına uygun maksimum saklama süresini,
içermelidir.
Uzman Raporları
Madde 12- Ruhsat sahibi, Bakanlığa başvuruda bulunurken ruhsat dosyasının kimyasal,
farmakolojik, biyolojik, toksikolojik ve klinik kısımlarının her biri için ilgili uzmanlarca
imzalanmış uzman raporlarını sunar.
Raporları hazırlayacak olan uzmanların niteliklerine göre görevleri şunlardır:
a) Kendi disiplinleri içindeki (analiz, farmakoloji ve benzer deneysel bilimler, klinik
araştırmalar) görevleri yerine getirmek ve elde edilen kalitatif ve kantitatif sonuçları nesnel
olarak tanımlamak,
b) Gözlemlerini Ek-1'e göre tanımlamak ve özellikle aşağıdaki hususları belirtmek;
1) Analiz uzmanları için, tıbbi ürünün beyan edilen kompozisyonuna uygun olup
olmadığının, üretici tarafından kullanılan kontrol yöntemleriyle saptanması,
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2) Tıbbi ürünün toksisitesinin ve farmakolojik özelliklerinin gözlenmesi,
3) Klinisyenler söz konusu ise, bu Yönetmeliğin hükümlerine göre başvuru sahibi
tarafından Bakanlığa sunulan bilgi ve belgelerin söz konusu ürünle tedavi edilen hastalar
üzerindeki etkisinden emin olunup olunmadığı, hastanın ürünü iyi tolere edip etmediği,
klinisyenin pozoloji, kontrendikasyonlar ve advers etki ile ilgili tavsiyesi.
Uzmanın özgeçmişi ve başvuru sahibi ile profesyonel ilişkisinin beyanı ve gerektiğinde
bibliyografik başvuru için kullanılan bilgi ve belgelerin gerekçesi belirtilmelidir.
Uzmanların ayrıntılı raporları, başvuru sahibinin Bakanlığa sunduğu başvurunun
ilişiğindeki bilgi ve belgelerin bir parçasını oluşturur.
ÜÇÜNCÜ BÖLÜM
Ruhsat Başvurusunun Değerlendirilmesi ve Ruhsatlandırma
Ön İnceleme
Madde 13- Beşeri tıbbi ürün için ruhsat almak üzere Bakanlığa sunulan başvuru
dosyasının, başvurunun niteliğine göre sunulması gereken bilgi ve belgeler açısından eksiksiz
ve tam bir başvuru olup olmadığı hususu, Bakanlık tarafından ön incelemeye tabi tutularak
değerlendirilir. Başvuru dosyasının Bakanlığa ulaşmasından itibaren 30 (otuz) gün içinde
gerekli değerlendirme yapılarak durum başvuru sahibine bildirilir. Başvurunun eksik
bulunması halinde başvuru sahibi eksikliklerini 30 (otuz) gün içinde tamamlar. Eksikliklerin
tamamlanarak Bakanlığa sunulmasından sonra yapılacak ikinci ön inceleme de 30 (otuz) gün
içinde sonuçlandırılır.
Başvurunun İadesi
Madde 14- Bakanlık tarafından bu Yönetmeliğin 13 üncü maddesi kapsamında yapılan ön
incelemede, aşağıdaki durumların tesbiti halinde, başvuru usulden reddedilerek sahibine iade
edilir:
a) Başvuru sahibinin Kanun ve bu Yönetmeliğin 7 nci maddesinde belirtilen niteliklere
sahip olmaması,
b) İkinci ön incelemeye tabi tutulan ve eksikliği tamamlanmamış olan başvuru olması.
Ruhsatlandırma Süresi
Madde 15- Bakanlık, ön incelemesi tamamlanmış eksiksiz bir ruhsat başvurusunu,
ruhsatlandırma koşullarının yerine getirilip getirilmediğini inceleyerek, bu başvurunun kabul
edilmesini takiben 210 (ikiyüzon) gün içinde sonuçlandırır. Ancak, Bakanlığın başvuru
sahibinden talep ettiği hususların temin edilmesi için gereken süre, olağanüstü haller ile
Bakanlık dışı kuruluşların değerlendirmeleri bu süreye dahil edilmez.
Ayrıca aşağıdaki hallerde 210 (ikiyüzon) günlük süre durdurulur:
a) Üretici tarafından ürün üretiminde kullanılan ve bu Yönetmeliğin 8 inci maddesinin
birinci fıkrasının (m) bendi uyarınca başvuru beraberinde sunulan bilgi ve belgelerde
tanımlanan kontrol yöntemlerinin beyan edilen doğruluğunun saptanması için Bakanlık,
ürünün başlangıç materyallerinin ve ihtiyaç olması halinde ara ürünlerin ve diğer bileşen
maddelerinin ulusal bir laboratuvarda veya Bakanlık tarafından bu amaçla kabul edilmiş bir
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laboratuvarda test edilmek üzere sunulması talep edildiği durumlarda eksiklikler
tamamlanıncaya kadar,
b) Bakanlıkça ruhsatlandırma süreci sırasında gerektiği durumlarda bu Yönetmeliğin 8, 9,
10 ve 11 inci maddeleri kapsamında başvuru sahibinden ek bilgi ve belge talep edildiği
durumlarda ilgili bilgi ve belgeler temin edilene kadar,
c) Bakanlığın başvuru sahibinden sözlü veya yazılı açıklamada bulunmasını talep ettiği
durumlarda gerekli yazılı veya sözlü açıklama yapılana kadar.
Ruhsatlandırma Kriterleri
Madde 16- Beşeri tıbbi ürüne ruhsat verilirken, ürünle ilgili olarak Bakanlıkça dikkate
alınacak kriterler şunlardır:
a) Öngörülen kullanım şartlarındaki etkinliğinin kanıtlanmış olması,
b) Güvenilirliğin kanıtlanmış olması,
c) Mevcut tedavilere katkısının olması,
d) Uygun teknik ve farmasötik özelliklere sahip olması.
Başvuruların Değerlendirilmesi
Madde 17- Başvurular değerlendirilirken asgari olarak aşağıdaki hususlar gözetilir:
a) Bir ürünün etkinlik, güvenilirlik ve kalitesini kanıtlayan bilgi ve belgelerin bilimsel ve
teknolojik açıdan incelenmesi,
b) Ürüne ait formülasyonun doğruluğu ve imalatçı tarafından ürünün kontrolünde
kullanılan yöntemlerin uygulanabilirliğinin tesbiti için ulusal bir laboratuvarda veya Bakanlık
tarafından bu amaçla kabul edilmiş bir laboratuvarda test edilmiş olması,
c) Kan ürünlerinde viral kontaminasyon olup olmadığını belirlemek için yapılmış olan
kontrol testlerinin ürünün güvenilir olduğunu kanıtlaması ve bu ürünlerin hazırlanmasında
kullanılan plazmanın temin edildiği kaynağın bildirilmesi,
d) Radyofarmasötikler/kitler formülasyonlarında hayvansal kaynaklı maddeler içeriyorsa
BSE virüsü olmadığına dair resmi otoriteden yazı, kan ve plazma ürünleri içeriyorsa viral
kontaminasyon, AIDS, hepatit ve benzeri testlerin istenilmesi.
Ruhsat Talebinin Reddi
Madde 18- Bir ürünün ruhsatlandırılması için Bakanlığa yapılan başvurunun
değerlendirilmesi sürecinde ürünün;
a) Normal kullanma şartlarında, potansiyel riskin tedavi etkisinden fazla olduğunun,
b) Terapötik etkisinin yetersiz olduğu veya bunun yeterli şekilde kanıtlanamadığının,
c) Gerekli görülen ürünlerde biyoyararlanımının yeterli olmadığının,
d) Mevcut tedavilere katkısının olmadığının,
e)Kalitatif ve kantitatif formülünün, başvuruda bildirilene uygun olmadığı veya bildirilen
kontrol yöntemleri uygulandığında sonuç alınamadığı veya beyan edilen spesifikasyonlarının
kabul edilebilir limitlerin dışında bulunduğu hususunda başvuru sahibi ikaz edilmesine
rağmen ikinci kez yapılan kontrollerde de uygunsuzluğun devam ettiğinin,
tespit edilmesi durumlarında başvuru reddedilir.
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Bildirim ve İtiraz
Madde 19- Ruhsat başvurusunun reddi halinde karar gerekçeli olarak başvuru sahibine
bildirilir. Başvuru sahibinin karara 30 (otuz) gün içinde yazılı olarak itiraz etme hakkı vardır.
30 (otuz) gün içinde itiraz edilmediği takdirde, başvuru belgeleri sahibine iade edilir.
Yapılan itiraz 90 (doksan) gün içinde Bakanlık tarafından değerlendirilerek sonuç başvuru
sahibine bildirilir. İtirazın değerlendirilmesi sırasında, gerekli görülür ise, başvuru sahibine
sözlü açıklama ve savunma hakkı verilir. İtirazın değerlendirilmesi sonucunda çıkan karar
kesindir ve bu karara itiraz edilemez.
Ruhsatın Verilmesi
Madde 20- Başvuru sahibi tarafından Bakanlığa sunulan bilgi ve belgelerin incelenmesi
ve değerlendirilmesi sonucunda, bu Yönetmelikte öngörülen hususlara uygun olduğu tespit
edilen ürüne ruhsat düzenlenir ve başvuru sahibi bilgilendirilir.
Bakanlıkça ruhsatlandırılan aynı formül ve farmasötik şekildeki ürün için aynı gerçek
veya tüzel kişiye, farklı bir ticari isimle de olsa ikinci bir yerli veya ithal ruhsatı verilemez.
Bakanlıkça ruhsat verilen ürünlerin isimleri, ruhsat sahibinin adı soyadı ve ruhsat
numarası ile birlikte Resmi Gazete’de ilan edilir.
Ruhsatın Geçerlilik Süresi
Madde 21- Ruhsatlar 5 (beş) yıl süreyle geçerlidir. Ruhsat sahibi, ruhsatın geçerlilik
süresi sona ermeden en az 3 (üç) ay öncesinde, gerekli farmakovijilans verileri ile birlikte
ruhsatın verildiği tarihten itibaren tüm değişiklikleri kapsayacak biçimde kalite, güvenilirlik
ve etkinliğine ilişkin bilgileri ruhsatın yenilenmesi için Bakanlığa sunar.
Ruhsatın Askıya Alınması
Madde 22- Ruhsatlı bir ürün ile ilgili olarak aşağıdaki durumlardan birinin tespiti halinde,
ürüne ait ruhsat Bakanlık tarafından askıya alınır:
a) Normal kullanım şartlarında zararlı etkilerinin ortaya çıkması,
b) Terapötik etkisinin olmadığının tesbiti veya yetersiz olduğunun tesbiti,
c) Ruhsata esas olan formülasyondan farklı bir formülasyon ile üretilmesi,
d) Ruhsata esas formül, doz, farmasötik form, ambalaj ve kısa ürün bilgilerinde
Bakanlığın bilgisi ve/veya onayı dışında değişiklik yapılması,
e) Ruhsat sahibi tarafından üretim ve kontrol yöntemleri bakımından bilimsel ve teknik
ilerlemelerin dikkate alınmaması ve tıbbi ürünün genel kabul gören bilimsel yöntemlerle
üretilmesini ve kontrol edilmesini sağlamak amacıyla gerekli her türlü değişikliğin
yapılmaması ve bu değişikliğin Bakanlığın onayına sunulmaması,
f) Yapılan piyasa kontrolleri sonucunda hatalı olduğu tespit edilen ürünler için yapılan
uyarının dikkate alınmaması ve hatalı üretime devam edilmesi,
g) Ambalaj ve etiketleme ile ilgili mevzuat hükümlerine uyulmaması ve ruhsat sahibine
yapılan uyarının etkisiz kalması,
h) Ruhsat sahibi tarafından, ürünle ilgili olarak Bakanlık talimatlarına ve uyarılarına cevap
verilmemesi,
i) Bu Yönetmeliğin hükümlerine göre bir ürünün ruhsatlandırılması için sunulan bilgi ve
belgelerde yanlışlık olduğunun tespit edilmesi,
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j) Ruhsat verilmiş bir tıbbi ürünün ruhsatlandırıldıktan sonra 3 (üç) yıl içinde fiili olarak
pazara sunulmaması,
k) Ruhsatın geçerlik süresinin dolmuş olmasına rağmen bu Yönetmeliğin 21 inci maddesi
uyarınca yenileme başvurusunun yapılmamış olması,
l) Farmakovijilans uygulamaları çerçevesinde ulaşan bildirimlerin Bakanlık tarafından
yapılan risk/yarar değerlendirilmesi sonucunda ruhsatın askıya alınmasına karar verilmesi.
Ruhsatı askıya alınan bir ürünün üretimi durdurulur. Dağıtımda ve satışta olan ürünler
hakkındaki karar, ruhsatın askıya alınma gerekçesi dikkate alınarak, Bakanlıkça verilir.
Ruhsatın İptali
Madde 23- Aşağıda belirtilen durumlardan birinin mevcudiyeti halinde ürün için verilmiş
olan ruhsat iptal edilir:
a) Bu Yönetmeliğin 22 nci maddesinde sayılan hallerden biri veya birkaçı sebebiyle
ruhsatı askıya alınan ürünler hakkında ruhsat sahibi tarafından en geç 6 (altı) ay içinde askıya
alınma gerekçesinin aksini ispatlayan bilgi ve belgelerin sunulmaması,
b) Ruhsat sahibinin talebi ve Bakanlığın uygun görmesi durumunda üretimden
vazgeçilmesi.
Ruhsatı iptal edilen bir ürünün üretimi durdurulur. Dağıtımda ve satışta olan ürünler
hakkındaki karar, ruhsatın iptal gerekçesi dikkate alınarak Bakanlıkça verilir.
Bakanlıkça ruhsatları iptal edilen ürünlerin isimleri, ruhsat sahibinin adı, soyadı ve ruhsat
numaraları ile birlikte Resmi Gazete’de ilan edilir.
Ruhsat Sahibinin Sorumluluğu
Madde 24- Ruhsat sahibi, ruhsatına sahip olduğu ürünle ilgili olarak aşağıdaki hususlarda
Bakanlığa karşı sorumludur:
a) Ürünün, başvuru ekinde verilen ve Bakanlıkça kabul edilen spesifikasyonlara uygun
olarak üretilmesi,
b) Üretim ve kontrol yöntemleri bakımından bilimsel ve teknik ilerlemelerin dikkate
alınması ve tıbbi ürünün genel kabul gören bilimsel yöntemlerle üretilmesini ve kontrol
edilmesini sağlamak amacıyla gerekli her türlü değişikliği yapmak üzere Bakanlığın onayına
sunulması,
c) Ürünün doğru ve güvenli kullanımını sağlamak için gerektiği durumlarda kısa ürün
bilgilerinin ve kullanma talimatının güncelleştirilmesi,
d) Ürünle ilgili herhangi bir değişiklik olduğunda, ilgili kılavuz hükümleri çerçevesinde
değişikliğin Bakanlığa bildirilmesi,
e) Ürün hakkında Bakanlıkça talep edilen hususlara cevap verilmesi,
f) Ürünün piyasaya verilmesini takiben farmakovijilans uygulamaları çerçevesinde gerekli
yükümlülüklerin yerine getirilmesi,
g) Ürünün biyolojik bir ürün olması durumunda bulaşabilecek enfeksiyonların önlenmesi
için tedbirlerin alınmasının sağlanması,
h) Ruhsatına sahip olduğu ürünün piyasada bulanabilirliğinin sağlanması,
ı) Ürünün etkinliği veya halk sağlığının korunması gerekçesiyle ruhsatının askıya alınması
veya pazardan çekilmesi ile ilgili alınan her türlü tedbirin tüm gerekçeleriyle birlikte derhal
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Bakanlığa bildirilmesi,
i) Ürün ile ilgili olarak mevzuatın gereklerinin yerine getirilmesi,
j) Ürünlerle ilgili belirlenmiş harçların ve ücretlerin ödenmesi.
Ruhsat Sahibi Değişikliği
Madde 25- Bakanlık tarafından ruhsatlandırılmış bir ürününün ruhsat sahibi değişikliği
yapılabilir. Ruhsat sahibi değişikliği işlemleri için aşağıdaki bilgi ve belgeler Bakanlığa
sunulur:
a) Mahkeme/icra dairesince ruhsat sahibi değişikliğine dair verilmiş karar veya noter
huzurunda düzenlenmiş ve aşağıdaki hususları içeren sözleşme,
1) Ruhsat sahibi değişikliği işlemine konu olan ürünün ismi, ruhsat tarihi ve sayısı,
2) Ruhsat sahibi değişikliği ile ruhsatı verecek ve ruhsatı alacak olan gerçek veya tüzel
kişilerin isim ve adresleri,
3) Bakanlıkça onaylanmış, tam ve güncellenmiş olan mevcut ürün dosyasının eksiksiz bir
biçimde devralan kişiye teslim edildiğine dair tutanak,
b) Ruhsat sahibi değişikliği ile ruhsatı alan kişi, ruhsat sahibinden beklenen tüm
sorumlulukları yerine getirme kapasitesine sahip olduğunu gösteren aşağıdaki bilgi ve
belgeleri Bakanlığa sunar;
1) Bu Yönetmeliğin 7 nci maddesinde ruhsat başvurusunda bulunabilecek kişiler için
belirtilen mesleklerden birine mensup olduğunu gösteren noter onaylı diploma örneği,
2) Tüzel kişi olması durumunda, şirketin kuruluş amaçlarını, ortaklarını ve sorumlu
kişilerin görev ve unvanlarını belirten ticaret sicil gazetesinin aslı veya sureti,
3) Farmakovijilans uygulamaları kapsamında ürün güvenliği sorumlusunun özgeçmişi,
adresi, telefon ve faks numarası ve bu kişinin görevini tanımlayan belge,
4) 23/10/2003 tarihli ve 25268 sayılı Resmi Gazete’de yayımlanan Beşeri Tıbbi Ürünlerin
Tanıtım Faaliyetleri Hakkında Yönetmelik kapsamında bilim servisini tanımlayan belge ve
bu servisin adresi, telefon ve faks numarası,
c) Ruhsat sahibi değişikliği ile ruhsatı alan kişinin adı, soyadı, adresi, telefon ve faks
numaralarıyla birlikte, ürünün kısa ürün bilgileri, kullanma talimatı, iç ve dış ambalajın birer
örneği ve noter aracılığıyla yapılan devirlerde, söz konusu ürün için evvelce verilmiş olan
ruhsatın aslı.
Ürünün ithal bir ürün olması durumunda, yukarıda belirtilen bilgi ve belgelere ek olarak,
orijin firmanın söz konusu ürünün Türkiye’de ruhsatlandırılması ve satışına ilişkin
yetkilendirdiği gerçek veya tüzel kişiyi değiştirdiğine dair orijinal belge ve noter onaylı
Türkçe tercümesi ile birlikte Bakanlığa başvuruda bulunulur.
Orijin firmanın söz konusu ürünün Türkiye’de ruhsatlandırılması ve satışına ilişkin
yetkilendirdiği gerçek veya tüzel kişiyi tek taraflı değiştirmesi durumunda, orijin firmanın
ürünün Türkiye’de ruhsatlandırılmasına ve satışına ilişkin verdiği yetkiyi gösterir, yeni tarihli
orijinal belge, noter onaylı Türkçe tercümesi ve bu maddenin birinci fıkrasının (a) bendi
hariç, Bakanlıkça onaylanmış tam ve güncellenmiş mevcut ürün dosyası ile birlikte bu
maddedeki tüm gerekliliklerin yerine getirilmesi zorunludur.
Ürünlere ilişkin yapılacak olan tüm değişiklikler için ilgili kılavuz hükümlerine göre
Bakanlığa ayrı bir başvuruda bulunulur. Değişikliğe ilişkin yapılmış olan başvuru, ürünün
ruhsat sahibi değişiklik işlemleri tamamlandıktan sonra Bakanlık tarafından değerlendirmeye
alınır.
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Bakanlık, eksiksiz bilgi ve belgelerle yapılan ruhsat sahibi değişikliği başvurusunu 60
(altmış) gün içinde sonuçlandırır.
Satış İzni Alınması
Madde 26- Ruhsat sahibi, ruhsatını aldığı beşeri tıbbi bir ürünü ilk kez pazara sunmadan
önce, satışa sunulacak son şekliyle iki adet numuneyi satış izni almak üzere Bakanlığa sunar.
Bakanlık, satış izni vereceği ürünün numunelerini, kullanma talimatının, ambalaj ve etiket
bilgilerinin doğruluğu ve fiyatının uygunluğu açısından inceler. Ürünün ruhsata esas ambalaj
ve etiket bilgilerinin ve/veya özelliklerinin değişmesine yol açan işlemler için yeniden satış
izni alınması zorunludur.
Ruhsatı alınan ürün, kan ürünü veya kan ürünü içeren beşeri tıbbi ürün ise, ruhsat sahibi
bu ürünü piyasaya arz etmeden önce birinci fıkrada yer alan hususlara ek olarak ürünün her
serisi için satış izni almak üzere Bakanlığa başvurur. Bu seriye ait ürüne göre yapılacak
analizler ulusal bir laboratuvarda veya Bakanlık tarafından bu amaçla atanmış bir
laboratuvarda test edilmesini müteakiben verilir.
Kan ürünleri veya kan ürünü içeren beşeri tıbbi ürünlere satış izni alınabilmesi için satışa
sunulması talep edilen miktar bildirilerek aşağıda belirtilen belge ve bilgiler Bakanlığa
sunulur:
a) Ürünün adı ve içeriği,
b) Her seri için akredite edilmiş ulusal veya uluslararası laboratuvar tarafından verilen
Ulusal Sağlık Otoritesi tasdikli seri serbest bırakma sertifikası,
c) Her seri için üretim merkezinin teknik müdürü tarafından onaylanmış analiz sertifikası
aslı,
d) Her serinin ruhsatlandırıldığı/üretildiği ülke ile hangi ülkelerde satıldığını gösteren
orijin firma tarafından düzenlenmiş belge aslı (apostil onaylı),
e) Plazma bağışında esas alınan kurallar, plazmanın toplanma tarihi ve donör tipi (gönüllü,
paralı) ve gerekli durumlarda donörlerin listesi,
f) Her donörün Hepatit B, Hepatit C ve HIV ½ yönünden test edildiği ve plazma
havuzunda HCV RNA testinin uygulandığını ve neticelerini belirten yukarıda belirtilen
laboratuvar tarafından verilen belge,
g) Her seri için donörlerin Creutzfeld-Jacob (CJ) hastalığı ile ilgili olarak hastalık veya
hastalık şüphesi yönünden güvenli olduğuna ve donörler arasında CJ hastalığı tanısı
olmadığına dair üretici firma tarafından verilecek orijinal belge (apostil onaylı).
Ruhsatı alınan ürün immünolojik ürün ise; ruhsat sahibi, bu ürünü piyasaya arz etmeden
önce birinci fıkrada yer alan hususlara ek olarak ürünün her serisi için satış izni almak üzere
Bakanlığa başvurur.
İmmünolojik ürünlere satış izni alınabilmesi için satışa sunulması talep edilen miktar
bildirilerek aşağıda belirtilen belge ve bilgiler Bakanlığa sunulur:
a) Her seri için akredite edilmiş ulusal laboratuvar veya uluslararası laboratuvar tarafından
verilen Ulusal Sağlık Otoritesi tasdikli Batch / Lot Release Sertifikası,
b) Her seri için üretim merkezinin teknik müdürü tarafından onaylanmış analiz
sertifikasının aslı.
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Ruhsata İlişkin Değişiklikler
Madde 27- Bir ruhsat verildikten sonra ürüne ilişkin tüm değişiklikler, ilgili kılavuz
hükümlerine göre ruhsat sahibi tarafından Bakanlığa sunulur.
DÖRDÜNCÜ BÖLÜM
Çeşitli ve Son Hükümler
Gizlilik
Madde 28- Bir ürüne ruhsat almak üzere başvuru sahibi tarafından Bakanlığa sunulan
bilgiler gizlidir. Bu gizlilik Bakanlıkça korunur.
Cezai Hükümler
Madde 29- Bu Yönetmelik hükümlerine uymayanlar hakkında 1/3/1926 tarihli ve 765
sayılı Türk Ceza Kanunu ve ilgili diğer mevzuat hükümleri uygulanır.
Yürürlükten Kaldırılan Mevzuat
Madde 30- 23/12/1993 tarihli ve 21797 sayılı Resmi Gazete’de yayımlanan
Radyofarmasötik Yönetmeliği, 2/3/1995 tarihli ve 22218 sayılı Resmi Gazete’de yayımlanan
Tıbbi Farmasötik Ürünler Ruhsatlandırma Yönetmeliği ile 20/5/2002 tarihli ve 24760 sayılı
Resmi Gazete’de yayımlanan Kan Ürünlerinin Ruhsatlandırılmasına Dair Yönetmelik
yürürlükten kaldırılmıştır.
Geçici Madde 1- Bu Yönetmelik yürürlüğe girmeden önce yapılan ruhsat/izin
başvuruları, başvurunun yapıldığı tarihte yürürlükte olan mevzuat hükümlerine göre
değerlendirilir.
Bu Yönetmeliğin 9 uncu maddesi haricindeki diğer hükümlerinin yürürlüğe gireceği
30/6/2005 tarihine kadar bu Yönetmeliğin 9 uncu maddesine uygun olarak yapılan kısaltılmış
başvurular için, yürürlükteki Yönetmelikte yer alan başvuru formatına göre yapılan
başvurular kabul edilir.
Geçici Madde 2- Tıbbi farmasötik ürün benzeri ürünlerin izinlerine ilişkin usul ve
esasların belirlendiği yönetmelik ile ruhsatlandırılmış veya ruhsatlandırma başvurusu
yapılmış beşeri tıbbi ürünlerdeki yapılacak değişiklik başvurularına uygulanacak esasların
belirlendiği yönetmelik yürürlüğe girinceye kadar ilgili kılavuzlar mevcut şekliyle
uygulanmaya devam edilir.
Geçici Madde 3- Bu Yönetmeliğin yürürlüğe girdiği tarihten önce ithalat izni ile piyasaya
arz edilen aşı, antiserum ve allerjen içeren biyolojik ürünlerle ilgili gerekli değerlendirmeler
yapılmak üzere ithalat izni sahibi kişiler, bu Yönetmeliğin yürürlüğe girdiği tarihten itibaren
1 (bir) yıl içerisinde Bakanlıkça istenilen belgeler ile ruhsat müracaatında bulunurlar. Bu süre
zarfında ruhsat başvurusu yapılmayan ürünlerin ithalat izni geçersiz olur.
Geçici Madde 4- Bu Yönetmeliğin yürürlüğe girdiği tarihten önce 23/12/1993 tarihli ve
21797 sayılı Resmi Gazete’de yayımlanan Radyofarmasötik Yönetmeliğine göre
78 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
tescillendirilmiş ürünlerle ilgili gerekli değerlendirmeler yapılmak üzere tescil belgesine
sahip ilgili kişiler, bu Yönetmeliğin yürürlüğe girdiği tarihten itibaren 1 (bir) yıl içerisinde
Bakanlıkça istenilen belgeler ile ruhsat müracaatında bulunurlar. Bu süre zarfında ruhsat
müracaatında bulunulmayan ürünlerin tescil belgeleri geçersiz olur.
Yürürlük
Madde 31- Bu Yönetmeliğin 9 uncu maddesi ile Geçici 1 inci maddesinin ikinci fıkrası
1/1/2005 tarihinden geçerli olmak üzere yayımı tarihinde, diğer hükümleri ise 30/6/2005
tarihinde yürürlüğe girer.
Yürütme
Madde 32- Bu Yönetmelik hükümlerini Sağlık Bakanı yürütür.
(EKLERİ ALINMAMIŞTIR)
79 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
Işıklı Ilaçlarda Test ve Deney Verilerinin Korunması: Avrupa Birlği’nde Yeni Sistem
80 http://ekutup.dpt.gov.tr/hukuk/saglik/isiklih/veri.pdf
EN
Consolidated TEXT
produced by the CONSLEG system
of the Office for Official Publications of the European Communities
CONSLEG: 2001L0083 — 30/04/2004
Number of pages: 117
Office for Official Publications of the European Communities <
2001L0083 — EN — 30.04.2004 — 003.001 — 1
This document is meant purely as a documentation tool and the institutions do not assume any liability for its contents
►B DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
of 6 November 2001
on the Community code relating to medicinal products for human use
(OJ L 311, 28.11.2001, p. 67)
Amended by:
Official Journal
No page date
►M1 Directive 2002/98/EC of the European Parliament and of the Council of
27 January 2003
L 33 30 8.2.2003
►M2 Commission directive 2003/63/EC of 25 June 2003 L 159 46 27.6.2003
►M3 Directive 2004/24/EC of the European Parliament and of the Council of
31 March 2004
L 136 85 30.4.2004
►M4 Directive 2004/27/EC of the European Parliament and of the Council of
31 March 2004
L 136 34 30.4.2004
▼B
DIRECTIVE 2001/83/EC OF THE EUROPEAN PARLIAMENT
AND OF THE COUNCIL
of 6 November 2001
on the Community code relating to medicinal products for human
use
THE EUROPEAN PARLIAMENT AND THE COUNCIL OF THE
EUROPEAN UNION,
Having regard to the Treaty establishing the European Community, and
in particular Article 95 thereof,
Having regard to the proposal from the Commission;
Having regard to the opinion of the Economic and Social
Committee (1),
Acting in accordance with the procedure laid down in Article 251 of
the Treaty (2),
Whereas:
(1) Council Directive 65/65/EEC of 26 January 1965 on the approximation
of provisions laid down by law, regulation or
administrative action relating to medicinal products (3), Council
Directive 75/318/EEC of 20 May 1975 on the approximation of
the laws of Member States relating to analytical, pharmaco-toxicological
and clinical standards and protocols in respect of the
testing of proprietary medicinal products (4), Council Directive
75/319/EEC of 20 May 1975 on the approximation of provisions
laid down by law, regulation or administrative action relating to
proprietary medicinal products (5), Council Directive 89/342/
EEC of 3 May 1989 extending the scope of Directives 65/65/
EEC and 75/319/EEC and laying down additional provisions for
immunological medicinal products consisting of vaccines, toxins
or serums and allergens (6), Council Directive 89/343/EEC of 3
May 1989 extending the scope of Directives 65/65/EEC and 75/
319/EEC and laying down additional provisions for radiopharmaceuticals
(7), Council Directive 89/381/EEC of 14 June 1989
extending the scope of Directives 65/65/EEC and 75/319/EEC
on the approximation of provisions laid down by law, regulation
or administrative action relating to medicinal products and
laying down special provisions for proprietary medicinal
products derived from human blood or human plasma (8),
Council Directive 92/25/EEC of 31 March 1992 on the wholesale
distribution of medicinal products for human use (9),
Council Directive 92/26/EEC of 31 March 1992 concerning the
classification for the supply of medicinal products for human
use (10), Council Directive 92/27/EEC of 31 March 1992 on the
labelling of medicinal products for human use and on package
leaflets (11), Council Directive 92/28/EEC of 31 March 1992 on
the advertising of medicinal products for human use (12), Council
Directive 92/73/EEC of 22 September 1992 widening the scope
2001L0083 — EN — 30.04.2004 — 003.001 — 2
(1) OJ C 368, 20.12.1999, p. 3.
(2) Opinion of the European Parliament of 3 July 2001 (not yet published in the
Official Journal) and Council Decision of 27 September 2001.
(3) OJ 22, 9.2.1965, p. 369/65. Directive as last amended by Directive 93/39/
EEC (OJ L 214, 24.8.1993, p. 22).
(4) OJ L 147, 9.6.1975, p. 1. Directive as last amended by Commission Directive
1999/83/EC (OJ L 243, 15.9.1999, p. 9).
(5) OJ L 147, 9.6.1975, p. 13. Directive as last amended by Commission Directive
2000/38/EC (OJ L 139, 10.6.2000, p. 28).
(6) OJ L 142, 25.5.1989, p. 14.
(7) OJ L 142, 25.5.1989, p. 16.
(8) OJ L 181, 28.6.1989, p. 44.
(9) OJ L 113, 30.4.1992, p. 1.
(10) OJ L 113, 30.4.1992, p. 5.
(11) OJ L 113, 30.4.1992, p. 8.
(12) OJ L 113, 30.4.1992, p. 13.
▼B
of Directives 65/65/EEC and 75/319/EEC on the approximation
of provisions laid down by law, regulation or administrative
action relating to medicinal products and laying down additional
provisions on homeopathic medicinal products (1) have been
frequently and substantially amended. In the interests of clarity
and rationality, the said Directives should therefore be codified
by assembling them in a single text.
(2) The essential aim of any rules governing the production, distribution
and use of medicinal products must be to safeguard
public health.
(3) However, this objective must be attained by means which will
not hinder the development of the pharmaceutical industry or
trade in medicinal products within the Community.
(4) Trade in medicinal products within the Community is hindered
by disparities between certain national provisions, in particular
between provisions relating to medicinal products (excluding
substances or combinations of substances which are foods,
animal feeding-stuffs or toilet preparations), and such disparities
directly affect the functioning of the internal market.
(5) Such hindrances must accordingly be removed; whereas this
entails approximation of the relevant provisions.
(6) In order to reduce the disparities which remain, rules should be
laid down on the control of medicinal products and the duties
incumbent upon the Member States' competent authorities should
be specified with a view to ensuring compliance with legal
requirements.
(7) The concepts of harmfulness and therapeutic efficacy can only
be examined in relation to each other and have only a relative
significance depending on the progress of scientific knowledge
and the use for which the medicinal product is intended. The
particulars and documents which must accompany an application
for marketing authorization for a medicinal product demonstrate
that potential risks are outweighed by the therapeutic efficacy of
the product.
(8) Standards and protocols for the performance of tests and trials
on medicinal products are an effective means of control of these
products and hence of protecting public health and can facilitate
the movement of these products by laying down uniform rules
applicable to tests and trials, the compilation of dossiers and
the examination of applications.
(9) Experience has shown that it is advisable to stipulate more
precisely the cases in which the results of toxicological and
pharmacological tests or clinical trials do not have to be
provided with a view to obtaining authorization for a medicinal
product which is essentially similar to an authorized product,
while ensuring that innovative firms are not placed at a disadvantage.
(10) However, there are reasons of public policy for not conducting
repetitive tests on humans or animals without over-riding cause.
(11) The adoption of the same standards and protocols by all the
Member States will enable the competent authorities to arrive at
their decisions on the basis of uniform tests and by reference to
uniform criteria and will therefore help to avoid differences in
evaluation.
(12) With the exception of those medicinal products which are
subject to the centralized Community authorization procedure
established by Council Regulation (EEC) No 2309/93 of 22
July 1993 laying down Community procedures for the authorization
and supervision of medicinal products for human and
veterinary use and establishing a European Agency for the
2001L0083 — EN — 30.04.2004 — 003.001 — 3
(1) OJ L 297, 13.10.1992, p. 8.
▼B
Evaluation of Medicinal Products (1) a marketing authorization
for a medicinal product granted by a competent authority in one
Member State ought to be recognized by the competent authorities
of the other Member States unless there are serious grounds
for supposing that the authorization of the medicinal product
concerned may present a risk to public health. In the event of a
disagreement between Member States about the quality, the
safety or the efficacy of a medicinal product, a scientific evaluation
of the matter should be undertaken according to a
Community standard, leading to a single decision on the area of
disagreement binding on the Member States concerned. Whereas
this decision should be adopted by a rapid procedure ensuring
close cooperation between the Commission and the Member
States.
(13) For this purpose, a Committee for Proprietary Medicinal
Products should be set up attached to the European Agency for
the Evaluation of Medicinal Products established in the abovementioned
Regulation (EEC) No 2309/93.
(14) This Directive represents an important step towards achievement
of the objective of the free movement of medicinal products.
Further measures may abolish any remaining barriers to the free
movement of proprietary medicinal products will be necessary in
the light of experience gained, particularly in the abovementioned
Committee for Proprietary Medicinal Products.
(15) In order better to protect public health and avoid any unnecessary
duplication of effort during the examination of application
for a marketing authorization for medicinal products, Member
States should systematically prepare assessment reports in
respect of each medicinal product which is authorized by them,
and exchange the reports upon request. Furthermore, a Member
State should be able to suspend the examination of an application
for authorization to place a medicinal product on the
market which is currently under active consideration in another
Member State with a view to recognizing the decision reached
by the latter Member State.
(16) Following the establishment of the internal market, specific
controls to guarantee the quality of medicinal products imported
from third countries can be waived only if appropriate arrangements
have been made by the Community to ensure that the
necessary controls are carried out in the exporting country.
(17) It is necessary to adopt specific provisions for immunological
medicinal products, homeopathic medicinal products, radiopharmaceuticals,
and medicinal products based on human blood or
human plasma.
(18) Any rules governing radiopharmaceuticals must take into
account the provisions of Council Directive 84/466/Euratom of
3 September 1984 laying down basic measures for the radiation
protection of persons undergoing medical examination or treatment
(2). Account should also be taken of Council Directive 80/
836/Euratom of 15 July 1980 amending the Directives laying
down the basic safety standards for the health protection of the
general public and workers against the dangers of ionizing radiation
(3), the objective of which is to prevent the exposure of
workers or patients to excessive or unnecessarily high levels of
ionizing radiation, and in particular of Article 5c thereof, which
requires prior authorization for the addition of radioactive
2001L0083 — EN — 30.04.2004 — 003.001 — 4
(1) OJ L 214, 24.8.1993, p. 1. Regulation as amended by Commission Regulation
(EC) No 649/98 (OJ L 88, 24.3.1998, p. 7).
(2) OJ L 265, 5.10.1984, p. 1. Directive repealed with effect from 13 May 2000
by Directive 97/43/Euratom (OJ L 180, 9.7.1997, p. 22).
(3) OJ L 246, 17.9.1980, p. 1. Directive as amended by Directive 84/467/
Euratom (OJ L 265, 5.10.1984, p. 4), repealed with effect from 13 May
2000 by Directive 96/29/Euratom (OJ L 314, 4.12.1996, p. 20).
▼B
substances to medicinal products as well as for the importation
of such medicinal products.
(19) The Community entirely supports the efforts of the Council of
Europe to promote voluntary unpaid blood and plasma donation
to attain self-sufficiency throughout the Community in the
supply of blood products, and to ensure respect for ethical principles
in trade in therapeutic substances of human origin.
(20) The rules designed to guarantee the quality, safety and efficacy
of medicinal products derived from human blood or human
plasma must be applied in the same manner to both public and
private establishments, and to blood and plasma imported from
third countries.
(21) Having regard to the particular characteristics of these homeopathic
medicinal products, such as the very low level of active
principles they contain and the difficulty of applying to them
the conventional statistical methods relating to clinical trials, it
is desirable to provide a special, simplified registration procedure
for those homeopathic medicinal products which are
placed on the market without therapeutic indications in a pharmaceutical
form and dosage which do not present a risk for the
patient.
(22) The anthroposophic medicinal products described in an official
pharmacopoeia and prepared by a homeopathic method are to
be treated, as regards registration and marketing authorization,
in the same way as homeopathic medicinal products.
(23) It is desirable in the first instance to provide users of these
homeopathic medicinal products with a very clear indication of
their homeopathic character and with sufficient guarantees of
their quality and safety.
(24) The rules relating to the manufacture, control and inspection of
homeopathic medicinal products must be harmonized to permit
the circulation throughout the Community of medicinal products
which are safe and of good quality.
(25) The usual rules governing the authorization to market medicinal
products should be applied to homeopathic medicinal products
placed on the market with therapeutic indications or in a form
which may present risks which must be balanced against the
desired therapeutic effect. In particular, those Member States
which have a homeopathic tradition should be able to apply
particular rules for the evaluation of the results of tests and trials
intended to establish the safety and efficacy of these medicinal
products provided that they notify them to the Commission.
(26) In order to facilitate the movement of medicinal products and to
prevent the controls carried out in one Member State from being
repeated in another, minimum requirements should be laid down
for manufacture and imports coming from third countries and for
the grant of the authorization relating thereto.
(27) It should be ensured that, in the Member States, the supervision
and control of the manufacture of medicinal products is carried
out by a person who fulfils minimum conditions of qualification.
(28) Before an authorization to market an immunological medicinal
product or derived from human blood or human plasma can be
granted, the manufacturer must demonstrate his ability to attain
batch-to-batch consistency. Before an authorization to market a
medicinal product derived from human blood or human plasma
can be granted, the manufacturer must also demonstrate the
absence of specific viral contamination, to the extent that the
state of technology permits.
(29) The conditions governing the supply of medicinal products to the
public should be harmonized.
(30) In this connection persons moving around within the Community
have the right to carry a reasonable quantity of medicinal
products lawfully obtained for their personal use. It must also
2001L0083 — EN — 30.04.2004 — 003.001 — 5
▼B
be possible for a person established in one Member State to
receive from another Member State a reasonable quantity of
medicinal products intended for his personal use.
(31) In addition, by virtue of Regulation (EC) No 2309/93, certain
medicinal products are the subject of a Community marketing
authorization. In this context, the classification for the supply of
medicinal products covered by a Community marketing authorization
needs to be established. It is therefore important to set the
criteria on the basis of which Community decisions will be
taken.
(32) It is therefore appropriate, as an initial step, to harmonize the
basic principles applicable to the classification for the supply of
medicinal products in the Community or in the Member State
concerned, while taking as a starting point the principles already
established on this subject by the Council of Europe as well as
the work of harmonization completed within the framework of
the United Nations, concerning narcotic and psychotropic
substances.
(33) The provisions dealing with the classification of medicinal
products for the purpose of supply do not infringe the national
social security arrangements for reimbursement or payment for
medicinal products on prescription.
(34) Many operations involving the wholesale distribution of medicinal
products for human use may cover several Member States
simultaneously.
(35) It is necessary to exercise control over the entire chain of distribution
of medicinal products, from their manufacture or import
into the Community through to supply to the public, so as to
guarantee that such products are stored, transported and handled
in suitable conditions. The requirements which must be adopted
for this purpose will considerably facilitate the withdrawal of
defective products from the market and allow more effective
efforts against counterfeit products.
(36) Any person involved in the wholesale distribution of medicinal
products should be in possession of a special authorization. Pharmacists
and persons authorized to supply medicinal products to
the public, and who confine themselves to this activity, should
be exempt from obtaining this authorization. It is however necessary,
in order to control the complete chain of distribution of
medicinal products, that pharmacists and persons authorized to
supply medicinal products to the public keep records showing
transactions in products received.
(37) Authorization must be subject to certain essential conditions and
it is the responsibility of the Member State concerned to ensure
that such conditions are met; whereas each Member State must
recognize authorizations granted by other Member States.
(38) Certain Member States impose on wholesalers who supply
medicinal products to pharmacists and on persons authorized to
supply medicinal products to the public certain public service
obligations. Those Member States must be able to continue to
impose those obligations on wholesalers established within their
territory. They must also be able to impose them on wholesalers
in other Member States on condition that they do not impose any
obligation more stringent than those which they impose on their
own wholesalers and provided that such obligations may be
regarded as warranted on grounds of public health protection
and are proportionate in relation to the objective of such protection.
(39) Rules should be laid down as to how the labelling and package
leaflets are to be presented.
(40) The provisions governing the information supplied to users
should provide a high degree of consumer protection, in order
that medicinal products may be used correctly on the basis of
full and comprehensible information.
2001L0083 — EN — 30.04.2004 — 003.001 — 6
▼B
(41) The marketing of medicinal products whose labelling and
package leaflets comply with this Directive should not be
prohibited or impeded on grounds connected with the labelling
or package leaflet.
(42) This Directive is without prejudice to the application of
measures adopted pursuant to Council Directive 84/450/EEC of
10 September 1984 relating to the approximation of the laws,
regulations and administrative provisions of the Member States
concerning misleading advertising (1).
(43) All Member States have adopted further specific measures
concerning the advertising of medicinal products. There are
disparities between these measures. These disparities are likely
to have an impact on the functioning of the internal market,
since advertising disseminated in one Member State is likely to
have effects in other Member States.
(44) Council Directive 89/552/EEC of 3 October 1989 on the coordination
of certain provisions laid down by law, regulation or
administrative action in Member States concerning the pursuit
of television broadcasting activities (2) prohibits the television
advertising of medicinal products which are available only on
medical prescription in the Member State within whose jurisdiction
the television broadcaster is located. This principle should
be made of general application by extending it to other media.
(45) Advertising to the general public, even of non-prescription
medicinal products, could affect public health, were it to be
excessive and ill-considered. Advertising of medicinal products
to the general public, where it is permitted, ought therefore to
satisfy certain essential criteria which ought to be defined.
(46) Furthermore, distribution of samples free of charge to the
general public for promotional ends must be prohibited.
(47) The advertising of medicinal products to persons qualified to
prescribe or supply them contributes to the information available
to such persons. Nevertheless, this advertising should be subject
to strict conditions and effective monitoring, referring in particular
to the work carried out within the framework of the
Council of Europe.
(48) Advertising of medicinal products should be subject to effective,
adequate monitoring. Reference in this regard should be made to
the monitoring mechanisms set up by Directive 84/450/EEC.
(49) Medical sales representatives have an important role in the
promotion of medicinal products. Therefore, certain obligations
should be imposed upon them, in particular the obligation to
supply the person visited with a summary of product characteristics.
(50) Persons qualified to prescribe medicinal products must be able to
carry out these functions objectively without being influenced by
direct or indirect financial inducements.
(51) It should be possible within certain restrictive conditions to
provide samples of medicinal products free of charge to persons
qualified to prescribe or supply them so that they can familiarize
themselves with new products and acquire experience in dealing
with them.
(52) Persons qualified to prescribe or supply medicinal products must
have access to a neutral, objective source of information about
products available on the market. Whereas it is nevertheless for
the Member States to take all measures necessary to this end, in
the light of their own particular situation.
2001L0083 — EN — 30.04.2004 — 003.001 — 7
(1) OJ L 250, 19.9.1984, p. 17. Directive as amended by Directive 97/55/EC
(OJ L 290, 23.10.1997, p. 18).
(2) OJ L 298, 17.10.1989, p. 23. Directive as amended by Directive 97/36/EC
(OJ L 202, 30.7.1997, p. 60).
▼B
(53) Each undertaking which manufactures or imports medicinal
products should set up a mechanism to ensure that all information
supplied about a medicinal product conforms with the
approved conditions of use.
(54) In order to ensure the continued safety of medicinal products in
use, it is necessary to ensure that pharmacovigilance systems in
the Community are continually adapted to take account of scientific
and technical progress.
(55) It is necessary to take account of changes arising as a result of
international harmonisation of definitions, terminology and technological
developments in the field of pharmacovigilance.
(56) The increasing use of electronic networks for communication of
information on adverse reactions to medicinal products marketed
in the Community is intended to allow competent authorities to
share the information at the same time.
(57) It is the interest of the Community to ensure that the pharmacovigilance
systems for centrally authorised medicinal products and
those authorised by other procedures are consistent.
(58) Holders of marketing authorisations should be proactively
responsible for on-going pharmacovigilance of the medicinal
products they place on the market.
(59) The measures necessary for the implementation of this Directive
should be adopted in accordance with Council Decision 1999/
468/EC of 28 June 1999 laying down the procedures for the
exercise of implementing powers conferred on the Commission
(1).
(60) The Commission should be empowered to adopt any necessary
changes to Annex I in order to take into account scientific and
technical progress.
(61) This Directive should be without prejudice to the obligations of
the Member States concerning the time-limits for transposition
of the Directives set out in Annex II, Part B.
HAVE ADOPTED THIS DIRECTIVE:
TITLE I
DEFINITIONS
Article 1
For the purposes of this Directive, the following terms shall bear the
following meanings:
2. Medicinal product:
(a) Any substance or combination of substances presented as
having properties for treating or preventing disease in
human beings; or
(b) Any substance or combination of substances which may be
used in or administered to human beings either with a view
to restoring, correcting or modifying physiological functions
by exerting a pharmacological, immunological or metabolic
action, or to making a medical diagnosis.
2001L0083 — EN — 30.04.2004 — 003.001 — 8
(1) OJ L 184, 17.7.1999, p. 23.
▼M4
▼B
3. Substance:
Any matter irrespective of origin which may be:
— human, e.g.
human blood and human blood products;
— animal, e.g.
micro-organisms, whole animals, parts of organs, animal
secretions, toxins, extracts, blood products;
— vegetable, e.g.
micro-organisms, plants, parts of plants, vegetable secretions,
extracts;
— chemical, e.g.
elements, naturally occurring chemical materials and
chemical products obtained by chemical change or synthesis.
4. Immunological medicinal product:
Any medicinal product consisting of vaccines, toxins, serums or
allergen products:
(a) vaccines, toxins and serums shall cover in particular:
(i) agents used to produce active immunity, such as
cholera vaccine, BCG, polio vaccines, smallpox
vaccine;
(ii) agents used to diagnose the state of immunity,
including in particular tuberculin and tuberculin PPD,
toxins for the Schick and Dick Tests, brucellin;
(iii) agents used to produce passive immunity, such as
diphtheria antitoxin, anti-smallpox globulin, antilymphocytic
globulin;
(b) ‘allergen product’ shall mean any medicinal product which
is intended to identify or induce a specific acquired alteration
in the immunological response to an allergizing agent.
5. Homeopathic medicinal product:
Any medicinal product prepared from substances called homeopathic
stocks in accordance with a homeopathic manufacturing
procedure described by the European Pharmacopoeia or, in the
absence thereof, by the pharmacopoeias currently used officially
in the Member States. A homeopathic medicinal product
may contain a number of principles.
6. Radiopharmaceutical:
Any medicinal product which, when ready for use, contains one
or more radionuclides (radioactive isotopes) included for a
medicinal purpose.
7. Radionuclide generator:
Any system incorporating a fixed parent radionuclide from
which is produced a daughter radionuclide which is to be
obtained by elution or by any other method and used in a radiopharmaceutical.
8. ►M4 Kit ◄:
Any preparation to be reconsitituted or combined with radionuclides
in the final radiopharmaceutical, usually prior to its
administration.
9. Radionuclide precursor:
Any other radionuclide produced for the radio-labelling of
another substance prior to administration.
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10. Medicinal products derived from human blood or human
plasma:
Medicinal products based on blood constitutents which are
prepared industrially by public or private establishments, such
medicinal products including, in particular, albumin, coagulating
factors and immunoglobulins of human origin.
11. Adverse reaction:
A response to a medicinal product which is noxious and unintended
and which occurs at doses normally used in man for the
prophylaxis, diagnosis or therapy of disease or for the restoration,
correction or modification of physiological function.
12. Serious adverse reaction:
An adverse reaction which results in death, is life-threatening,
requires inpatient hospitalisation or prolongation of existing
hospitalisation, results in persistent or significant disability or
incapacity, or is a congenital anomaly/birth defect.
13. Unexpected adverse reaction:
An adverse reaction, the nature, severity or outcome of which is
not consistent with the summary of product characteristics.
14. Periodic safety update reports:
The periodical reports containing the records referred to in
Article 104.
15. Post-authorisation safety study:
A pharmacoepidemiological study or a clinical trial carried out
in accordance with the terms of the marketing authorisation,
conducted with the aim of identifying or quantifying a safety
hazard relating to an authorised medicinal product.
16. Abuse of medicinal products:
Persistent or sporadic, intentional excessive use of medicinal
products which is accompanied by harmful physical or psychological
effets.
17. Wholesale distribution of medicinal products:
All activities consisting of procuring, holding, supplying or
exporting medicinal products, apart from supplying medicinal
products to the public. Such activities are carried out with
manufacturers or their depositories, importers, other wholesale
distributors or with pharmacists and persons authorized or
entitled to supply medicinal products to the public in the
Member State concerned.
18. Public service obligation:
The obligation placed on wholesalers to guarantee permanently
an adequate range of medicinal products to meet the requirements
of a specific geographical area and to deliver the
supplies requested within a very short time over the whole of
the area in question.
18a Representative of the marketing authorisation holder:
The person, commonly known as local representative, designated
by the marketing authorisation holder to represent him
in the Member State concerned.
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19. Medicinal Prescription:
Any medicinal prescription issued by a professional person
qualified to do so.
20. Name of the medicinal product:
The name, which may be either an invented name not liable to
confusion with the common name, or a common or scientific
name accompanied by a trade mark or the name of the
marketing authorisation holder.
21. Common name:
The international non-proprietary name recommended by the
World Health Organization, or, if one does not exist, the usual
common name.
22. Strength of the medicinal product:
The content of the active substances expressed quantitatively
per dosage unit, per unit of volume or weight according to the
dosage form.
23. Immediate packaging:
The container or other form of packaging immediately in
contact with the medicinal product.
24. Outer packaging:
The packaging into which is placed the immediate packaging.
25. Labelling:
Information on the immediate or outer packaging.
26. Package leaflet:
A leaflet containing information for the user which accompanies
the medicinal product.
27. Agency:
The European Medicines Agency established by Regulation
(EC) No 726/2004 (1).
28. Risks related to use of the medicinal product:
— any risk relating to the quality, safety or efficacy of the
medicinal product as regards patients' health or public
health;
— any risk of undesirable effects on the environment.
28a. Risk-benefit balance:
An evaluation of the positive therapeutic effects of the medicinal
product in relation to the risks as defined in point 28, first
indent.
29. Traditional herbal medicinal product:
A herbal medicinal product that fulfils the conditions laid down
in Article 16a(1).
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30. Herbal medicinal product:
Any medicinal product, exclusively containing as active ingredients
one or more herbal substances or one or more herbal
preparations, or one or more such herbal substances in combination
with one or more such herbal preparations.
31. Herbal substances:
All mainly whole, fragmented or cut plants, plant parts, algae,
fungi, lichen in an unprocessed, usually dried, form, but sometimes
fresh. Certain exudates that have not been subjected to a
specific treatment are also considered to be herbal substances.
Herbal substances are precisely defined by the plant part used
and the botanical name according to the binomial system
(genus, species, variety and author).
32. Herbal preparations:
Preparations obtained by subjecting herbal substances to treatments
such as extraction, distillation, expression, fractionation,
purification, concentration or fermentation. These include
comminuted or powdered herbal substances, tinctures, extracts,
essential oils, expressed juices and processed exudates.
TITLE II
SCOPE
Article 2
1. This Directive shall apply to medicinal products for human use
intended to be placed on the market in Member States and either
prepared industrially or manufactured by a method involving an industrial
process.
2. In cases of doubt, where, taking into account all its characteristics,
a product may fall within the definition of a ‘medicinal product’
and within the definition of a product covered by other Community
legislation the provisions of this Directive shall apply.
3. Notwithstanding paragraph 1 and Article 3(4), Title IV of this
Directive shall apply to medicinal products intended only for export
and to intermediate products.
Article 3
This Directive shall not apply to:
1. Any medicinal product prepared in a pharmacy in accordance with a
medical prescription for an individual patient (commonly known as
the magistral formula).
2. Any medicinal product which is prepared in a pharmacy in accordance
with the prescriptions of a pharmacopoeia and is intended to
be supplied directly to the patients served by the pharmacy in question
(commonly known as the officinal formula).
3. Medicinal products intended for research and development trials, but
without prejudice to the provisions of Directive 2001/20/EC of the
European Parliament and of the Council of 4 April 2001 on the
approximation of the laws, regulations and administrative provisions
of the Member States relating to the implementation of good clinical
practice in the conduct of clinical trials on medicinal products for
human use (1).
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4. Intermediate products intended for further processing by an authorized
manufacturer.
5. Any radionuclides in the form of sealed sources.
6. Whole blood, plasma or blood cells of human origin, except for
plasma which is prepared by a method involving an industrial
process.
Article 4
1. Nothing in this Directive shall in any way derogate from the
Community rules for the radiation protection of persons undergoing
medical examination or treatment, or from the Community rules laying
down the basic safety standards for the health protection of the general
public and workers against the dangers of ionizing radiation.
2. This Directive shall be without prejudice to Council Decision 86/
346/EEC of 25 June 1986 accepting on behalf of the Community the
European Agreement on the Exchange of Therapeutic Substances of
Human Origin (1).
3. The provisions of this Directive shall not affect the powers of the
Member States' authorities either as regards the setting of prices for
medicinal products or their inclusion in the scope of national health
insurance schemes, on the basis of health, economic and social conditions.
4. This Directive shall not affect the application of national legislation
prohibiting or restricting the sale, supply or use of medicinal
products as contraceptives or abortifacients. The Member States shall
communicate the national legislation concerned to the Commission.
Article 5
1. A Member State may, in accordance with legislation in force and
to fulfil special needs, exclude from the provisions of this Directive
medicinal products supplied in response to a bona fide unsolicited
order, formulated in accordance with the specifications of an authorised
health-care professional and for use by an individual patient under his
direct personal responsibility.
2. Member States may temporarily authorise the distribution of an
unauthorised medicinal product in response to the suspected or
confirmed spread of pathogenic agents, toxins, chemical agents or
nuclear radiation any of which could cause harm.
3. Without prejudice to paragraph 1, Member States shall lay down
provisions in order to ensure that marketing authorisation holders,
manufacturers and health professionals are not subject to civil or
administrative liability for any consequences resulting from the use of
a medicinal product otherwise than for the authorised indications or
from the use of an unauthorised medicinal product, when such use is
recommended or required by a competent authority in response to the
suspected or confirmed spread of pathogenic agents, toxins, chemical
agents or nuclear radiation any of which could cause harm. Such provisions
shall apply whether or not national or Community authorisation
has been granted.
4. Liability for defective products, as provided for by Council Directive
85/374/EEC of 25 July 1985 on the approximation of the laws,
regulations and administrative provisions of the Member States,
concerning liability for defective products (2), shall not be affected by
paragraph 3.
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(1) OJ L 207, 30.7.1986, p. 1.
(2) OJ L 210, 7.8.1985, p. 29. Directive as last amended by Directive 1999/34/
EC of the European Parliament and of the Council (OJ L 141, 4.6.1999,
p. 20).
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TITLE III
PLACING ON THE MARKET
CHAPTER 1
Marketing authorization
Article 6
1. No medicinal product may be placed on the market of a Member
State unless a marketing authorization has been issued by the competent
authorities of that Member State in accordance with this Directive
or an authorization has been granted in accordance with Regulation
(EEC) No 2309/93.
When a medicinal product has been granted an initial marketing
authorisation in accordance with the first subparagraph, any additional
strengths, pharmaceutical forms, administration routes, presentations, as
well as any variations and extensions shall also be granted an authorisation
in accordance with the first subparagraph or be included in the
initial marketing authorisation. All these marketing authorisations shall
be considered as belonging to the same global marketing authorisation,
in particular for the purpose of the application of Article 10(1).
1a The marketing authorisation holder shall be responsible for
marketing the medicinal product. The designation of a representative
shall not relieve the marketing authorisation holder of his legal responsibility.
2. The authorisation referred to in paragraph 1 shall also be required
for radionuclide generators, ►M4 kits ◄, radionuclide precursor
radiopharmaceuticals and industrially prepared radiopharmaceuticals.
Article 7
A marketing authorization shall not be required for a radiopharmaceutical
prepared at the time of use by a person or by an establishment
authorized, according to national legislation, to use such medicinal
products in an approved health care establishment exclusively from
authorized radionuclide generators, ►M4 kits ◄ or radionuclide
precursors in accordance with the manufacturer's instructions.
Article 8
1. In order to obtain an authorization to place a medicinal product
on the market regardless of the procedure established by Regulation
(EEC) No 2309/93, an application shall be made to the competent
authority of the Member State concerned.
2. A marketing authorization may only be granted to an applicant
established in the Community.
3. The application shall be accompanied by the following particulars
and documents, submitted in accordance with Annex I:
(a) Name or corporate name and permanent address of the applicant
and, where applicable, of the manufacturer.
(b) Name of the medicinal product.
(c) Qualitative and quantitative particulars of all the constituents of
the medicinal product, including the reference to its international
non-proprietary name (INN) recommended by the WHO, where
an INN for the medicinal product exists, or a reference to the
relevant chemical name.
(ca) Evaluation of the potential environmental risks posed by the
medicinal product. This impact shall be assessed and, on a
case-by-case basis, specific arrangements to limit it shall be
envisaged.
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(d) Description of the manufacturing method.
(e) Therapeutic indications, contra-indications and adverse reactions.
(f) Posology, pharmaceutical form, method and route of administration
and expected shelf life.
(g) Reasons for any precautionary and safety measures to be taken
for the storage of the medicinal product, its administration to
patients and for the disposal of waste products, together with an
indication of potential risks presented by the medicinal product
for the environment.
(h) Description of the control methods employed by the manufacturer.
(i) Results of:
— pharmaceutical (physico-chemical, biological or microbiological)
tests,
— pre-clinical (toxicological and pharmacological) tests,
— clinical trials.
(ia) A detailed description of the pharmacovigilance and, where
appropriate, of the risk-management system which the applicant
will introduce.
(ib) A statement to the effect that clinical trials carried out outside
the European Union meet the ethical requirements of Directive
2001/20/EC.
(j) A summary, in accordance with Article 11, of the product characteristics,
a mock-up of the outer packaging, containing the
details provided for in Article 54, and of the immediate packaging
of the medicinal product, containing the details provided
for in Article 55, together with a package leaflet in accordance
with Article 59.
(k) A document showing that the manufacturer is authorised in his
own country to produce medicinal products.
(l) Copies of any authorisation obtained in another Member State or
in a third country to place the medicinal product on the market,
together with a list of those Member States in which an application
for authorisation submitted in accordance with this Directive
is under examination. Copies of the summary of the product
characteristics proposed by the applicant in accordance with
Article 11 or approved by the competent authorities of the
Member State in accordance with Article 21. Copies of the
package leaflet proposed in accordance with Article 59 or
approved by the competent authorities of the Member State in
accordance with Article 61. Details of any decision to refuse
authorization, whether in the Community or in a third country,
and the reasons for such a decision.
This information shall be updated on a regular basis.
(m) A copy of any designation of the medicinal product as an orphan
medicinal product under Regulation (EC) No 141/2000 of the
European Parliament and of the Council of 16 December 1999
on orphan medicinal products (1), accompanied by a copy of the
relevant Agency opinion.
(n) Proof that the applicant has the services of a qualified person
responsible for pharmacovigilance and has the necessary means
for the notification of any adverse reaction suspected of occurring
either in the Community or in a third country.
The documents and information concerning the results of the pharmaceutical
and pre-clinical tests and the clinical trials referred to in point
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(i) of the first subparagraph shall be accompanied by detailed summaries
in accordance with Article 12.
Article 9
In addition to the requirements set out in Articles 8 and 10(1), an application
for authorization to market a radionuclide generator shall also
contain the following information and particulars:
— a general description of the system together with a detailed
description of the components of the system which may affect
the composition or quality of the daughter nucleid preparation,
— qualitative and quantitative particulars of the eluate or the sublimate.
Article 10
1. By way of derogation from Article 8(3)(i), and without prejudice
to the law relating to the protection of industrial and commercial property,
the applicant shall not be required to provide the results of preclinical
tests and of clinical trials if he can demonstrate that the medicinal
product is a generic of a reference medicinal product which is or
has been authorised under Article 6 for not less than eight years in a
Member State or in the Community.
A generic medicinal product authorised pursuant to this provision shall
not be placed on the market until ten years have elapsed from the
initial authorisation of the reference product.
The first subparagraph shall also apply if the reference medicinal
product was not authorised in the Member State in which the application
for the generic medicinal product is submitted. In this case, the
applicant shall indicate in the application form the name of the
Member State in which the reference medicinal product is or has been
authorised. At the request of the competent authority of the Member
State in which the application is submitted, the competent authority of
the other Member State shall transmit within a period of one month, a
confirmation that the reference medicinal product is or has been
authorised together with the full composition of the reference product
and if necessary other relevant documentation.
The ten-year period referred to in the second subparagraph shall be
extended to a maximum of eleven years if, during the first eight years
of those ten years, the marketing authorisation holder obtains an
authorisation for one or more new therapeutic indications which, during
the scientific evaluation prior to their authorisation, are held to bring a
significant clinical benefit in comparison with existing therapies.
2. For the purposes of this Article:
(a) ‘reference medicinal product’ shall mean a medicinal product
authorised under Article 6, in accordance with the provisions of
Article 8;
(b) ‘generic medicinal product’ shall mean a medicinal product which
has the same qualitative and quantitative composition in active
substances and the same pharmaceutical form as the reference
medicinal product, and whose bioequivalence with the reference
medicinal product has been demonstrated by appropriate bioavailability
studies. The different salts, esters, ethers, isomers, mixtures
of isomers, complexes or derivatives of an active substance shall be
considered to be the same active substance, unless they differ
significantly in properties with regard to safety and/or efficacy. In
such cases, additional information providing proof of the safety
and/or efficacy of the various salts, esters or derivatives of an
authorised active substance must be supplied by the applicant. The
various immediate-release oral pharmaceutical forms shall be
considered to be one and the same pharmaceutical form. Bioavailability
studies need not be required of the applicant if he can
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demonstrate that the generic medicinal product meets the relevant
criteria as defined in the appropriate detailed guidelines.
3. In cases where the medicinal product does not fall within the
definition of a generic medicinal product as provided in paragraph
2(b) or where the bioequivalence cannot be demonstrated through bioavailability
studies or in case of changes in the active substance(s),
therapeutic indications, strength, pharmaceutical form or route of
administration, vis-à-vis the reference medicinal product, the results of
the appropriate pre-clinical tests or clinical trials shall be provided.
4. Where a biological medicinal product which is similar to a reference
biological product does not meet the conditions in the definition
of generic medicinal products, owing to, in particular, differences
relating to raw materials or differences in manufacturing processes of
the biological medicinal product and the reference biological medicinal
product, the results of appropriate pre-clinical tests or clinical trials
relating to these conditions must be provided. The type and quantity
of supplementary data to be provided must comply with the relevant
criteria stated in Annex I and the related detailed guidelines. The
results of other tests and trials from the reference medicinal product's
dossier shall not be provided.
5. In addition to the provisions laid down in paragraph 1, where an
application is made for a new indication for a well-established
substance, a non-cumulative period of one year of data exclusivity shall
be granted, provided that significant pre-clinical or clinical studies
were carried out in relation to the new indication.
6. Conducting the necessary studies and trials with a view to the
application of paragraphs 1, 2, 3 and 4 and the consequential practical
requirements shall not be regarded as contrary to patent rights or to
supplementary protection certificates for medicinal products.
Article 10a
By way of derogation from Article 8(3)(i), and without prejudice to the
law relating to the protection of industrial and commercial property, the
applicant shall not be required to provide the results of pre-clinical
tests or clinical trials if he can demonstrate that the active substances
of the medicinal product have been in well-established medicinal use
within the Community for at least ten years, with recognised efficacy
and an acceptable level of safety in terms of the conditions set out in
Annex I. In that event, the test and trial results shall be replaced by
appropriate scientific literature.
Article 10b
In the case of medicinal products containing active substances used in
the composition of authorised medicinal products but not hitherto used
in combination for therapeutic purposes, the results of new pre-clinical
tests or new clinical trials relating to that combination shall be
provided in accordance with Article 8(3)(i), but it shall not be necessary
to provide scientific references relating to each individual active
substance.
Article 10c
Following the granting of a marketing authorisation, the authorisation
holder may allow use to be made of the pharmaceutical, pre-clinical
and clinical documentation contained in the file on the medicinal
product, with a view to examining subsequent applications relating to
other medicinal products possessing the same qualitative and quantitative
composition in terms of active substances and the same
pharmaceutical form.
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Article 11
The summary of the product characteristics shall contain, in the order
indicated below, the following information:
1. name of the medicinal product followed by the strength and the
pharmaceutical form.
2. qualitative and quantitative composition in terms of the active
substances and constituents of the excipient, knowledge of which
is essential for proper administration of the medicinal product.
The usual common name or chemical description shall be used.
3. pharmaceutical form.
4. clinical particulars:
4.1. therapeutic indications,
4.2. posology and method of administration for adults and,
where necessary for children,
4.3. contra-indications,
4.4. special warnings and precautions for use and, in the case
of immunological medicinal products, any special precautions
to be taken by persons handling such products and
administering them to patients, together with any precautions
to be taken by the patient,
4.5. interaction with other medicinal products and other forms
of interactions,
4.6. use during pregnancy and lactation,
4.7. effects on ability to drive and to use machines,
4.8. undesirable effects,
4.9. overdose (symptoms, emergency procedures, antidotes).
5. pharmacological properties:
5.1. pharmacodynamic properties,
5.2. pharmacokinetic properties,
5.3. preclinical safety data.
6. pharmaceutical particulars:
6.1. list of excipients,
6.2. major incompatibilities,
6.3. shelf life, when necessary after reconstitution of the medicinal
product or when the immediate packaging is opened
for the first time,
6.4. special precautions for storage,
6.5. nature and contents of container,
6.6. special precautions for disposal of a used medicinal
product or waste materials derived from such medicinal
product, if appropriate.
7. marketing authorisation holder.
8. marketing authorisation number(s).
9. date of the first authorisation or renewal of the authorisation.
10. date of revision of the text.
11. for radiopharmaceuticals, full details of internal radiation dosimetry.
12. for radiopharmaceuticals, additional detailed instructions for
extemporaneous preparation and quality control of such preparation
and, where appropriate, maximum storage time during which
any intermediate preparation such as an eluate or the ready-to-use
pharmaceutical will conform with its specifications.
For authorisations under Article 10, those parts of the summary of
product characteristics of the reference medicinal product referring to
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indications or dosage forms which were still covered by patent law at
the time when a generic medicine was marketed need not be included.
Article 12
1. The applicant shall ensure that, before the detailed summaries
referred to in the last subparagraph of Article 8(3) are submitted to
the competent authorities, they have been drawn up and signed by
experts with the necessary technical or professional qualifications,
which shall be set out in a brief curriculum vitae.
2. Persons having the technical and professional qualifications
referred to in paragraph 1 shall justify any use made of scientific literature
under Article 10a in accordance with the conditions set out in
Annex I.
3. The detailed summaries shall form part of the file which the
applicant submits to the competent authorities.
CHAPTER 2
Specific provisions applicable to homeopathic medicinal products
Article 13
1. Member States shall ensure that homeopathic medicinal products
manufactured and placed on the market within the Community are
registered or authorised in accordance with Articles 14, 15 and 16,
except where such medicinal products are covered by a registration or
authorisation granted in accordance with national legislation on or
before 31 December 1993. In case of registrations, Article 28 and
Article 29(1) to (3) shall apply.
2. Member States shall establish a special simplified registration
procedure for the homeopathic medicinal products referred to in Article
14.
Article 14
1. Only homeopathic medicinal products which satisfy all of the
following conditions may be subject to a special, simplified registration
procedure:
— they are administered orally or externally,
— no specific therapeutic indication appears on the labelling of the
medicinal product or in any information relating thereto,
— there is a sufficient degree of dilution to guarantee the safety of the
medicinal product; in particular, the medicinal product may not
contain either more than one part per 10 000 of the mother tincture
or more than 1/100th of the smallest dose used in allopathy with
regard to active substances whose presence in an allopathic medicinal
product results in the obligation to submit a doctor's
prescription.
If new scientific evidence so warrants, the Commission may amend the
third indent of the first subparagraph by the procedure referred to in
Article 121(2).
At the time of registration, Member States shall determine the classification
for the dispensing of the medicinal product.
2. The criteria and rules of procedure provided for in Article 4(4),
Article 17(1) and Articles 22 to 26, 112, 116 and 125 shall apply by
analogy to the special, simplified registration procedure for homeopathic
medicinal products, with the exception of the proof of
therapeutic efficacy.
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Article 15
An application for special, simplified registration may cover a series of
medicinal products derived from the same homeopathic stock or stocks.
The following documents shall be included with the application in
order to demonstrate, in particular, the pharmaceutical quality and the
batch-to-batch homogeneity of the products concerned:
— scientific name or other name given in a pharmacopoeia of the
homeopathic stock or stocks, together with a statement of the
various routes of administration, pharmaceutical forms and degree
of dilution to be registered,
— dossier describing how the homeopathic stock or stocks is/are
obtained and controlled, and justifying its/their homeopathic use,
on the basis of an adequate bibliography,
— manufacturing and control file for each pharmaceutical form and a
description of the method of dilution and potentization,
— manufacturing authorization for the medicinal product concerned,
— copies of any registrations or authorizations obtained for the same
medicinal product in other Member States,
— one or more mock-ups of the outer packaging and the immediate
packaging of the medicinal products to be registered,
— data concerning the stability of the medicinal product.
Article 16
1. Homeopathic medicinal products other than those referred to in
Article 14(1) shall be authorized and labelled in accordance with
►M4 Articles 8, 10, 10a, 10b, 10c and 11 ◄.
2. A Member State may introduce or retain in its territory specific
rules for the ►M4 pre-clinical tests ◄ and clinical trials of homeopathic
medicinal products other than those referred to in Article 14(1)
in accordance with the principles and characteristics of homeopathy as
practised in that Member State.
In this case, the Member State concerned shall notify the Commission
of the specific rules in force.
3. Title IX shall apply to homeopathic medicinal products, with the
exception of those referred to in Article 14(1).
CHAPTER 2a
Specific provisions applicable to traditional herbal medicinal
products
Article 16a
1. A simplified registration procedure (hereinafter ‘traditional-use
registration’) is hereby established for herbal medicinal products which
fulfil all of the following criteria:
(a) they have indications exclusively appropriate to traditional herbal
medicinal products which, by virtue of their composition and
purpose, are intended and designed for use without the supervision
of a medical practitioner for diagnostic purposes or for prescription
or monitoring of treatment;
(b) they are exclusively for administration in accordance with a specified
strength and posology;
(c) they are an oral, external and/or inhalation preparation;
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(d) the period of traditional use as laid down in Article 16c(1)(c) has
elapsed;
(e) the data on the traditional use of the medicinal product are sufficient;
in particular the product proves not to be harmful in the
specified conditions of use and the pharmacological effects or efficacy
of the medicinal product are plausible on the basis of longstanding
use and experience.
2. Notwithstanding Article 1(30), the presence in the herbal medicinal
product of vitamins or minerals for the safety of which there is
well-documented evidence shall not prevent the product from being
eligible for registration in accordance with paragraph 1, provided that
the action of the vitamins or minerals is ancillary to that of the herbal
active ingredients regarding the specified claimed indication(s).
3. However, in cases where the competent authorities judge that a
traditional herbal medicinal product fulfils the criteria for authorisation
in accordance with Article 6 or registration pursuant to Article 14, the
provisions of this chapter shall not apply.
Article 16b
1. The applicant and registration holder shall be established in the
Community.
2. In order to obtain traditional-use registration, the applicant shall
submit an application to the competent authority of the Member State
concerned.
Article 16c
1. The application shall be accompanied by:
(a) the particulars and documents:
(i) referred to in Article 8(3)(a) to (h), (j) and (k);
(ii) the results of the pharmaceutical tests referred to in the
second indent of Article 8(3)(i);
(iii) the summary of product characteristics, without the data
specified in Article 11(4);
(iv) in case of combinations, as referred to in Article 1(30) or
Article 16a(2), the information referred to in Article
16a(1)(e) relating to the combination as such; if the individual
active ingredients are not sufficiently known, the data
shall also relate to the individual active ingredients;
(b) any authorisation or registration obtained by the applicant in
another Member State, or in a third country, to place the medicinal
product on the market, and details of any decision to refuse
to grant an authorisation or registration, whether in the Community
or a third country, and the reasons for any such decision;
(c) bibliographical or expert evidence to the effect that the medicinal
product in question, or a corresponding product has been in
medicinal use throughout a period of at least 30 years preceding
the date of the application, including at least 15 years within the
Community. At the request of the Member State where the application
for traditional-use registration has been submitted, the
Committee for Herbal Medicinal Products shall draw up an
opinion on the adequacy of the evidence of the long-standing use
of the product, or of the corresponding product. The Member State
shall submit relevant documentation supporting the referral;
(d) a bibliographic review of safety data together with an expert
report, and where required by the competent authority, upon additional
request, data necessary for assessing the safety of the
medicinal product.
Annex I shall apply by analogy to the particulars and documents specified
in point (a).
2. A corresponding product, as referred to in paragraph 1(c), is characterised
by having the same active ingredients, irrespective of the
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excipients used, the same or similar intended purpose, equivalent
strength and posology and the same or similar route of administration
as the medicinal product applied for.
3. The requirement to show medicinal use throughout the period of
30 years, referred to in paragraph 1(c), is satisfied even where the
marketing of the product has not been based on a specific authorisation.
It is likewise satisfied if the number or quantity of ingredients of
the medicinal product has been reduced during that period.
4. Where the product has been used in the Community for less than
15 years, but is otherwise eligible for simplified registration, the
Member State where the application for traditional-use registration has
been submitted shall refer the product to the Committee for Herbal
Medicinal Products. The Member State shall submit relevant documentation
supporting the referral.
The Committee shall consider whether the other criteria for a simplified
registration as referred to in Article 16a are fully complied with.
If the Committee considers it possible, it shall establish a Community
herbal monograph as referred to in Article 16h(3) which shall be taken
into account by the Member State when taking its final decision.
Article 16d
1. Without prejudice to Article 16h(1), Chapter 4 of Title III shall
apply by analogy to registrations granted in accordance with Article
16a, provided that:
(a) a Community herbal monograph has been established in accordance
with Article 16h(3), or
(b) the herbal medicinal product consists of herbal substances,
preparations or combinations thereof contained in the list referred
to in Article 16f.
2. For other herbal medicinal products as referred to in Article 16a,
each Member State shall, when evaluating an application for traditional-
use registration, take due account of registrations granted by
another Member State in accordance with this chapter.
Article 16e
1. Traditional-use registration shall be refused if the application does
not comply with Articles 16a, 16b or 16c or if at least one of the
following conditions is fulfilled:
(a) the qualitative and/or quantitative composition is not as declared;
(b) the indications do not comply with the conditions laid down in
Article 16a;
(c) the product could be harmful under normal conditions of use;
(d) the data on traditional use are insufficient, especially if pharmacological
effects or efficacy are not plausible on the basis of longstanding
use and experience;
(e) the pharmaceutical quality is not satisfactorily demonstrated.
2. The competent authorities of the Member States shall notify the
applicant, the Commission and any competent authority that requests
it, of any decision they take to refuse traditional-use registration and
the reasons for the refusal.
Article 16f
1. A list of herbal substances, preparations and combinations thereof
for use in traditional herbal medicinal products shall be established in
accordance with the procedure referred to in Article 121(2). The list
shall contain, with regard to each herbal substance, the indication, the
specified strength and the posology, the route of administration and any
other information necessary for the safe use of the herbal substance as
a traditional medicinal product.
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2. If an application for traditional-use registration relates to a herbal
substance, preparation or a combination thereof contained in the list
referred to in paragraph 1, the data specified in Article 16c(1)(b)(c)
and (d) do not need to be provided. Article 16e(1)(c) and (d) shall not
apply.
3. If a herbal substance, preparation or a combination thereof ceases
to be included in the list referred to in paragraph 1, registrations
pursuant to paragraph 2 for herbal medicinal products containing this
substance shall be revoked unless the particulars and documents
referred to in Article 16c(1) are submitted within three months.
Article 16g
1. Articles 3(1) and (2), 4(4), 6(1), 12, 17(1), 19, 20, 23, 24, 25, 40
to 52, 70 to 85, 101 to 108, 111(1) and (3), 112, 116 to 118, 122, 123,
125, 126, second subparagraph, and 127 of this Directive as well as
Commission Directive 91/356/EEC (1) shall apply, by analogy, to traditional-
use registration granted under this chapter.
2. In addition to the requirements of Articles 54 to 65, any labelling
and user package leaflet shall contain a statement to the effect that:
(a) the product is a traditional herbal medicinal product for use in
specified indication(s) exclusively based upon long-standing use;
and
(b) the user should consult a doctor or a qualified health care practitioner
if the symptoms persist during the use of the medicinal
product or if adverse effects not mentioned in the package leaflet
occur.
A Member State may require that the labelling and the user package
leaflet shall also state the nature of the tradition in question.
3. In addition to the requirements of Articles 86 to 99, any advertisement
for a medicinal product registered under this chapter shall
contain the following statement: Traditional herbal medicinal product
for use in specified indication(s) exclusively based upon long-standing
use.
Article 16h
1. A Committee for Herbal Medicinal Products is hereby established.
That Committee shall be part of the Agency and shall have the
following competence:
(a) as regards simplified registrations, to:
— perform the tasks arising from Article 16c(1) and (4),
— perform the tasks arising from Article 16d,
— prepare a draft list of herbal substances, preparations and
combinations thereof, as referred to in Article 16f(1), and
— establish Community monographs for traditional herbal medicinal
products, as referred to in paragraph 3 of this Article;
(b) as regards authorisations of herbal medicinal products, to establish
Community herbal monographs for herbal medicinal products, as
referred to in paragraph 3 of this Article;
(c) as regards referrals to the Agency under Chapter 4 of Title III, in
relation to herbal medicinal products as referred to in Article 16a,
to perform the tasks set out in Article 32;
(d) where other medicinal products containing herbal substances are
referred to the Agency under Chapter 4 of Title III, to give an
opinion on the herbal substance where appropriate.
Finally, the Committee for Herbal Medicinal Products shall perform
any other task conferred upon it by Community law.
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The appropriate coordination with the Committee for Human Medicinal
Products shall be ensured by a procedure to be determined by the
Executive Director of the Agency in accordance with Article 57(2) of
Regulation (EEC) No 2309/93.
2. Each Member State shall appoint, for a three-year term which
may be renewed, one member and one alternate to the Committee for
Herbal Medicinal Products.
The alternates shall represent and vote for the members in their
absence. Members and alternates shall be chosen for their role and
experience in the evaluation of herbal medicinal products and shall
represent the competent national authorities.
The said Committee may coopt a maximum of five additional members
chosen on the basis of their specific scientific competence. These
members shall be appointed for a term of three years, which may be
renewed, and shall not have alternates.
With a view to the coopting of such members, the said Committee shall
identify the specific complementary scientific competence of the additional
member(s). Coopted members shall be chosen among experts
nominated by Member States or the Agency.
The members of the said Committee may be accompanied by experts
in specific scientific or technical fields.
3. The Committee for Herbal Medicinal Products shall establish
Community herbal monographs for herbal medicinal products with
regard to the application of Article 10(1)(a)(ii) as well as traditional
herbal medicinal products. The said Committee shall fulfil further
responsibilities conferred upon it by provisions of this chapter and
other Community law.
When Community herbal monographs within the meaning of this paragraph
have been established, they shall be taken into account by the
Member States when examining an application. Where no such
Community herbal monograph has yet been established, other appropriate
monographs, publications or data may be referred to.
When new Community herbal monographs are established, the registration
holder shall consider whether it is necessary to modify the
registration dossier accordingly. The registration holder shall notify
any such modification to the competent authority of the Member State
concerned.
The herbal monographs shall be published.
4. The general provisions of Regulation (EEC) No 2309/93 relating
to the Committee for Human Medicinal Products shall apply by
analogy to the Committee for Herbal Medicinal Products.
Article 16i
Before 30 April 2007, the Commission shall submit a report to the
European Parliament and to the Council concerning the application of
the provisions of this chapter.
The report shall include an assessment on the possible extension of
traditional-use registration to other categories of medicinal products.
CHAPTER 3
Procedures relevant to the marketing authorization
Article 17
1. Member States shall take all appropriate measures to ensure that
the procedure for granting a marketing authorisation for medicinal
products is completed within a maximum of 210 days after the submission
of a valid application.
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Applications for marketing authorisations in two or more Member
States in respect of the same medicinal product shall be submitted in
accordance with Articles 27 to 39.
2. Where a Member State notes that another marketing authorisation
application for the same medicinal product is being examined in
another Member State, the Member State concerned shall decline to
assess the application and shall advise the applicant that Articles 27 to
39 apply.
Article 18
Where a Member State is informed in accordance with Article 8(3)(1)
that another Member State has authorised a medicinal product which is
the subject of a marketing authorisation application in the Member
State concerned, it shall reject the application unless it was submitted
in compliance with Articles 27 to 39.
Article 19
In order to examine the application submitted in accordance with
►M4 Articles 8, 10, 10a, 10b and 10c ◄, the competent authority
of the Member State:
1. must verify whether the particulars submitted in support of the
application comply with the said ►M4 Articles 8, 10, 10a, 10b
and 10c ◄ and examine whether the conditions for issuing an
authorization to place medicinal products on the market
(marketing authorization) are complied with.
2. may submit the medicinal product, its starting materials and, if
need be, its intermediate products or other constituent materials,
for testing by ►M4 an Official Medicines Control Laboratory
or a laboratory that a Member State has designated for that
purpose ◄ in order to ensure that the control methods employed
by the manufacturer and described in the particulars accompanying
the application in accordance with Article 8(3)(h) are
satisfactory.
3. may, where appropriate, require the applicant to supplement the
particulars accompanying the application in respect of the items
listed in the ►M4 Articles 8(3), 10, 10a, 10b and 10c ◄. Where
the competent authority avails itself of this option, the time limits
laid down in Article 17 shall be suspended until such time as the
supplementary information required has been provided. Likewise,
these time limits shall be suspended for the time allowed the
applicant, where appropriate, for giving oral or written explanation.
Article 20
Member States shall take all appropriate measures to ensure that:
(a) the competent authorities verify that manufacturers and importers
of medicinal products coming from third countries are able to
carry out manufacture in compliance with the particulars supplied
pursuant to Article 8(3)(d), and/or to carry out controls according
to the methods described in the particulars accompanying the
application in accordance with Article 8(3)(h);
(b) the competent authorities may allow manufacturers and importers
of medicinal products coming from third countries, ►M4 in
justifiable cases ◄, to have certain stages of manufacture and/or
certain of the controls referred to in (a) carried out by third
parties; in such cases, the verifications by the competent authorities
shall also be made in the establishment designated.
Article 21
1. When the marketing authorization is issued, the holder shall be
informed, by the competent authorities of the Member State concerned,
of the summary of the product characteristics as approved by it.
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2. The competent authorities shall take all necessary measures to
ensure that the information given in the summary is in conformity
with that accepted when the marketing authorization is issued or subsequently.
3. The competent authorities shall make publicly available without
delay the marketing authorisation together with the summary of the
product characteristics for each medicinal product which they have
authorised.
4. The competent authorities shall draw up an assessment report and
comments on the file as regards the results of the pharmaceutical and
pre-clinical tests and the clinical trials of the medicinal product
concerned. The assessment report shall be updated whenever new
information becomes available which is of importance for the evaluation
of the quality, safety or efficacy of the medicinal product
concerned.
The competent authorities shall make publicly accessible without delay
the assessment report, together with the reasons for their opinion, after
deletion of any information of a commercially confidential nature. The
justification shall be provided separately for each indication applied
for.
Article 22
In exceptional circumstances and following consultation with the applicant,
the authorisation may be granted subject to a requirement for the
applicant to meet certain conditions, in particular concerning the safety
of the medicinal product, notification to the competent authorities of
any incident relating to its use, and action to be taken. This authorisation
may be granted only for objective, verifiable reasons and must be
based on one of the grounds set out in Annex I. Continuation of the
authorisation shall be linked to the annual reassessment of these conditions.
The list of these conditions shall be made publicly accessible
without delay, together with deadlines and dates of fulfilment.
Article 23
After an authorization has been issued, the authorization holder must,
in respect of the methods of manufacture and control provided for in
Article 8(3)(d) and (h), take account of scientific and technical progress
and introduce any changes that may be required to enable the medicinal
product to be manufactured and checked by means of generally
accepted scientific methods.
These changes shall be subject to the approval of the competent
authority of the Member State concerned.
The authorisation holder shall forthwith supply to the competent
authority any new information which might entail the amendment of
the particulars or documents referred to in Articles 8(3), 10, 10a, 10b
and 11, or 32(5), or Annex I.
In particular, he shall forthwith inform the competent authority of any
prohibition or restriction imposed by the competent authorities of any
country in which the medicinal product for human use is marketed
and of any other new information which might influence the evaluation
of the benefits and risks of the medicinal product for human use
concerned.
In order that the risk-benefit balance may be continuously assessed, the
competent authority may at any time ask the holder of the marketing
authorisation to forward data demonstrating that the risk-benefit
balance remains favourable.
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Article 23a
After a marketing authorisation has been granted, the holder of the
authorisation shall inform the competent authority of the authorising
Member State of the date of actual marketing of the medicinal product
for human use in that Member State, taking into account the various
presentations authorised.
The holder shall also notify the competent authority if the product
ceases to be placed on the market of the Member State, either temporarily
or permanently. Such notification shall, otherwise than in
exceptional circumstances, be made no less than 2 months before the
interruption in the placing on the market of the product.
Upon request by the competent authority, particularly in the context of
pharmacovigilance, the marketing authorisation holder shall provide the
competent authority with all data relating to the volume of sales of the
medicinal product, and any data in his possession relating to the
volume of prescriptions.
Article 24
1. Without prejudice to paragraphs 4 and 5, a marketing authorisation
shall be valid for five years.
2. The marketing authorisation may be renewed after five years on
the basis of a re-evaluation of the risk-benefit balance by the competent
authority of the authorising Member State.
To this end, the marketing authorisation holder shall provide the
competent authority with a consolidated version of the file in respect
of quality, safety and efficacy, including all variations introduced since
the marketing authorisation was granted, at least six months before the
marketing authorisation ceases to be valid in accordance with paragraph
1.
3. Once renewed, the marketing authorisation shall be valid for an
unlimited period, unless the competent authority decides, on justified
grounds relating to pharmacovigilance, to proceed with one additional
five-year renewal in accordance with paragraph 2.
4. Any authorisation which within three years of its granting is not
followed by the actual placing on the market of the authorised product
in the authorising Member State shall cease to be valid.
5. When an authorised product previously placed on the market in
the authorising Member State is no longer actually present on the
market for a period of three consecutive years, the authorisation for
that product shall cease to be valid.
6. The competent authority may, in exceptional circumstances and
on public health grounds grant exemptions from paragraphs 4 and 5.
Such exemptions must be duly justified.
Article 25
Authorization shall not affect the civil and criminal liability of the
manufacturer and, where applicable, of the marketing authorization
holder.
Article 26
1. The marketing authorisation shall be refused if, after verification
of the particulars and documents listed in Articles 8, 10, 10a, 10b and
10c, it is clear that:
(a) the risk-benefit balance is not considered to be favourable; or
(b) its therapeutic efficacy is insufficiently substantiated by the applicant;
or
(c) its qualitative and quantitative composition is not as declared.
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2. Authorisation shall likewise be refused if any particulars or documents
submitted in support of the application do not comply with
Articles 8, 10, 10a, 10b and 10c.
3. The applicant or the holder of a marketing authorisation shall be
responsible for the accuracy of the documents and the data submitted.
CHAPTER 4
Mutual recognition procedure and decentralised procedure
Article 27
1. A coordination group shall be set up for the examination of any
question relating to marketing authorisation of a medicinal product in
two or more Member States in accordance with the procedures laid
down in this Chapter. The Agency shall provide the secretariat of this
coordination group.
2. The coordination group shall be composed of one representative
per Member State appointed for a renewable period of three years.
Members of the coordination group may arrange to be accompanied
by experts.
3. The coordination group shall draw up its own Rules of Procedure,
which shall enter into force after a favourable opinion has been given
by the Commission. These Rules of Procedure shall be made public.
Article 28
1. With a view to the granting of a marketing authorisation for a
medicinal product in more than one Member State, an applicant shall
submit an application based on an identical dossier in these Member
States. The dossier shall contain the information and documents
referred to in Articles 8, 10, 10a, 10b, 10c and 11. The documents
submitted shall include a list of Member States concerned by the application.
The applicant shall request one Member State to act as ‘reference
Member State’ and to prepare an assessment report on the medicinal
product in accordance with paragraphs 2 or 3.
2. Where the medicinal product has already received a marketing
authorisation at the time of application, the concerned Member States
shall recognise the marketing authorisation granted by the reference
Member State. To this end, the marketing authorisation holder shall
request the reference Member State either to prepare an assessment
report on the medicinal product or, if necessary, to update any existing
assessment report. The reference Member State shall prepare or update
the assessment report within 90 days of receipt of a valid application.
The assessment report together with the approved summary of product
characteristics, labelling and package leaflet shall be sent to the
concerned Member States and to the applicant.
3. In cases where the medicinal product has not received a
marketing authorisation at the time of application, the applicant shall
request the reference Member State to prepare a draft assessment
report, a draft summary of product characteristics and a draft of the
labelling and package leaflet. The reference Member State shall
prepare these draft documents within 120 days after receipt of a valid
application and shall send them to the concerned Member States and to
the applicant.
4. Within 90 days of receipt of the documents referred to in paragraphs
2 and 3, the Member States concerned shall approve the
assessment report, the summary of product characteristics and the
labelling and package leaflet and shall inform the reference Member
State accordingly. The reference Member State shall record the agreement
of all parties, close the procedure and inform the applicant
accordingly.
5. Each Member State in which an application has been submitted in
accordance with paragraph 1 shall adopt a decision in conformity with
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the approved assessment report, the summary of product characteristics
and the labelling and package leaflet as approved, within 30 days after
acknowledgement of the agreement.
Article 29
1. If, within the period laid down in Article 28(4), a Member State
cannot approve the assessment report, the summary of product characteristics,
the labelling and the package leaflet on the grounds of
potential serious risk to public health, it shall give a detailed exposition
of the reasons for its position to the reference Member State, to the
other Member States concerned and to the applicant. The points of
disagreement shall be forthwith referred to the coordination group.
2. Guidelines to be adopted by the Commission shall define a potential
serious risk to public health.
3. Within the coordination group, all Member States referred to in
paragraph 1 shall use their best endeavours to reach agreement on the
action to be taken. They shall allow the applicant the opportunity to
make his point of view known orally or in writing. If, within 60 days
of the communication of the points of disagreement, the Member States
reach an agreement, the reference Member State shall record the agreement,
close the procedure and inform the applicant accordingly. Article
28(5) shall apply.
4. If the Member States fail to reach an agreement within the 60-day
period laid down in paragraph 3, the Agency shall be immediately
informed, with a view to the application of the procedure under Articles
32, 33 and 34. The Agency shall be provided with a detailed
statement of the matters on which the Member States have been unable
to reach agreement and the reasons for their disagreement. A copy shall
be forwarded to the applicant.
5. As soon as the applicant is informed that the matter has been
referred to the Agency, he shall forthwith forward to the Agency a
copy of the information and documents referred to in the first subparagraph
of Article 28(1).
6. In the circumstances referred to in paragraph 4, Member States
that have approved the assessment report, the draft summary of product
characteristics and the labelling and package leaflet of the reference
Member State may, at the request of the applicant, authorise the medicinal
product without waiting for the outcome of the procedure laid
down in Article 32. In that event, the authorisation granted shall be
without prejudice to the outcome of that procedure.
Article 30
1. If two or more applications submitted in accordance with Articles
8, 10, 10a, 10b, 10c and 11 have been made for marketing authorisation
for a particular medicinal product, and if Member States have
adopted divergent decisions concerning the authorisation of the medicinal
product or its suspension or revocation, a Member State, the
Commission or the applicant or the marketing authorisation holder
may refer the matter to the Committee for Medicinal Products for
Human Use, hereinafter referred to as ‘the Committee’, for the application
of the procedure laid down in Articles 32, 33 and 34.
2. In order to promote harmonisation of authorisations for medicinal
products authorised in the Community, Member States shall, each year,
forward to the coordination group a list of medicinal products for
which a harmonised summary of product characteristics should be
drawn up.
The coordination group shall lay down a list taking into account the
proposals from all Member States and shall forward this list to the
Commission.
The Commission or a Member State, in agreement with the Agency
and taking into account the views of interested parties, may refer these
products to the Committee in accordance with paragraph 1.
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Article 31
1. The Member States or the Commission or the applicant or the
marketing authorisation holder shall, in specific cases where the interests
of the Community are involved, refer the matter to the Committee
for application of the procedure laid down in Articles 32, 33 and 34
before any decision is reached on a request for a marketing authorisation
or on the suspension or revocation of an authorisation, or on any
other variation to the terms of a marketing authorisation which appears
necessary, in particular to take account of the information collected in
accordance with Title IX.
The Member State concerned or the Commission shall clearly identify
the question which is referred to the Committee for consideration and
shall inform the applicant or the marketing authorisation holder.
The Member States and the applicant or the marketing authorisation
holder shall supply the Committee with all available information
relating to the matter in question.
2. Where the referral to the Committee concerns a range of medicinal
products or a therapeutic class, the Agency may limit the
procedure to certain specific parts of the authorisation.
In that event, Article 35 shall apply to those medicinal products only if
they were covered by the authorisation procedures referred to in this
Chapter.
Article 32
1. When reference is made to the procedure laid down in this
Article, the Committee shall consider the matter concerned and shall
issue a reasoned opinion within 60 days of the date on which the
matter was referred to it.
However, in cases submitted to the Committee in accordance with Articles
30 and 31, this period may be extended by the Committee for a
further period of up to 90 days, taking into account the views of the
applicants or the marketing authorisation holders concerned.
In an emergency, and on a proposal from its Chairman, the Committee
may agree to a shorter deadline.
2. In order to consider the matter, the Committee shall appoint one
of its members to act as rapporteur. The Committee may also appoint
individual experts to advise it on specific questions. When appointing
experts, the Committee shall define their tasks and specify the timelimit
for the completion of these tasks.
3. Before issuing its opinion, the Committee shall provide the applicant
or the marketing authorisation holder with an opportunity to
present written or oral explanations within a time limit which it shall
specify.
The opinion of the Committee shall be accompanied by a draft
summary of product characteristics for the product and a draft text of
the labelling and package leaflet.
If necessary, the Committee may call upon any other person to provide
information relating to the matter before it.
The Committee may suspend the time-limits referred to in paragraph 1
in order to allow the applicant or the marketing authorisation holder to
prepare explanations.
4. The Agency shall forthwith inform the applicant or the marketing
authorisation holder where the opinion of the Committee is that:
(a) the application does not satisfy the criteria for authorisation; or
(b) the summary of the product characteristics proposed by the applicant
or the marketing authorisation holder in accordance with
Article 11 should be amended; or
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(c) the authorisation should be granted subject to certain conditions,
in view of conditions considered essential for the safe and effective
use of the medicinal product including pharmacovigilance; or
(d) a marketing authorisation should be suspended, varied or revoked.
Within 15 days after receipt of the opinion, the applicant or the
marketing authorisation holder may notify the Agency in writing of
his intention to request a re-examination of the opinion. In that case,
he shall forward to the Agency the detailed grounds for the request
within 60 days after receipt of the opinion.
Within 60 days following receipt of the grounds for the request, the
Committee shall re-examine its opinion in accordance with the fourth
subparagraph of Article 62(1) of Regulation (EC) No 726/2004. The
reasons for the conclusion reached shall be annexed to the assessment
report referred to in paragraph 5 of this Article.
5. Within 15 days after its adoption, the Agency shall forward the
final opinion of the Committee to the Member States, to the Commission
and to the applicant or the marketing authorisation holder, together
with a report describing the assessment of the medicinal product and
stating the reasons for its conclusions.
In the event of an opinion in favour of granting or maintaining an
authorisation to place the medicinal product concerned on the market,
the following documents shall be annexed to the opinion:
(a) a draft summary of the product characteristics, as referred to in
Article 11;
(b) any conditions affecting the authorisation within the meaning of
paragraph 4(c);
(c) details of any recommended conditions or restrictions with regard
to the safe and effective use of the medicinal product;
(d) the proposed text of the labelling and leaflet.
Article 33
Within ►M4 15 days ◄ of the receipt of the opinion, the Commission
shall prepare a draft of the decision to be taken in respect of the
application, taking into account Community law.
In the event of a draft decision which envisages the granting of
marketing authorization, the documents referred to in ►M4 Article
32(5), second subparagraph ◄ shall be annexed.
Where, exceptionally, the draft decision is not in accordance with the
opinion of the Agency, the Commission shall also annex a detailed
explanation of the reasons for the differences.
The draft decision shall be forwarded to the Member States and the
applicant ►M4 or the marketing authorisation holder ◄.
Article 34
1. The Commission shall take a final decision in accordance with,
and within 15 days after the end of, the procedure referred to in Article
121(3).
2. The rules of procedure of the Standing Committee established by
Article 121(1) shall be adjusted to take account of the tasks incumbent
upon it under this Chapter.
Those adjustments shall entail the following provisions:
(a) except in cases referred to in the third paragraph of Article 33, the
opinion of the Standing Committee shall be given in writing;
(b) Member States shall have 22 days to forward their written observations
on the draft decision to the Commission. However, if a
decision has to be taken urgently, a shorter time-limit may be set
by the Chairman according to the degree of urgency involved.
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This time-limit shall not, otherwise than in exceptional circumstances,
be shorter than 5 days;
(c) Member States shall have the option of submitting a written request
that the draft Decision be discussed in a plenary meeting of the
Standing Committee.
Where, in the opinion of the Commission, the written observations of a
Member State raise important new questions of a scientific or technical
nature which have not been addressed in the opinion delivered by the
Agency, the Chairman shall suspend the procedure and refer the application
back to the Agency for further consideration.
The provisions necessary for the implementation of this paragraph shall
be adopted by the Commission in accordance with the procedure
referred to in Article 121(2).
3. The decision as referred to in paragraph 1 shall be addressed to
all Member States and reported for information to the marketing
authorisation holder or applicant. The concerned Member States and
the reference Member State shall either grant or revoke the marketing
authorisation, or vary its terms as necessary to comply with the decision
within 30 days following its notification, and they shall refer to
it. They shall inform the Commission and the Agency accordingly.
Article 35
1. Any application by the marketing authorization holder to vary a
marketing authorization which has been granted in accordance with
the provisions of this Chapter shall be submitted to all the Member
States which have previously authorized the medicinal product
concerned.
The Commission shall, in consultation with the Agency, adopt appropriate
arrangements for the examination of variations to the terms of a
marketing authorization.
These arrangements shall be adopted by the Commission in the form of
an implementing Regulation in accordance with the procedure referred
to in Article 121(2).
2. In case of arbitration submitted to the Commission, the procedure
laid down in Articles 32, 33 and 34 shall apply by analogy to variations
made to marketing authorizations.
Article 36
1. Where a Member State considers that the variation of a marketing
authorization which has been granted in accordance with the provisions
of this Chapter or its suspension or withdrawal is necessary for the
protection of public health, the Member State concerned shall forthwith
refer the matter to the Agency for the application of the procedures laid
down in Articles 32, 33 and 34.
2. Without prejudice to the provisions of Article 31, in exceptional
cases, where urgent action is essential to protect public health, until a
definitive decision is adopted a Member State may suspend the
marketing and the use of the medicinal product concerned on its territory.
It shall inform the Commission and the other Member States no
later than the following working day of the reasons for its action.
Article 37
Articles 35 and 36 shall apply by analogy to medicinal products authorized
by Member States following an opinion of the Committee given in
accordance with Article 4 of Directive 87/22/EEC before 1 January
1995.
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Article 38
1. The Agency shall publish an annual report on the operation of the
procedures laid down in this Chapter and shall forward that report to
the European Parliament and the Council for information.
2. At least every ten years the Commission shall publish a report on
the experience acquired on the basis of the procedures described in this
Chapter and shall propose any amendments which may be necessary to
improve those procedures. The Commission shall submit this report to
the European Parliament and to the Council.
Article 39
Article 29(4), (5) and (6) and Articles 30 to 34 shall not apply to the
homeopathic medicinal products referred to in Article 14.
Articles 28 to 34 shall not apply to the homeopathic medicinal products
referred to in Article 16(2).
TITLE IV
MANUFACTURE AND IMPORTATION
Article 40
1. Member States shall take all appropriate measures to ensure that
the manufacture of the medicinal products within their territory is
subject to the holding of an authorization. This manufacturing authorization
shall be required nothwithstanding that the medicinal products
manufactured are intended for export.
2. The authorization referred to in paragraph 1 shall be required for
both total and partial manufacture, and for the various processes of
dividing up, packaging or presentation.
However, such authorization shall not be required for preparation,
dividing up, changes in packaging or presentation where these
processes are carried out, solely for retail supply, by pharmacists in
dispensing pharmacies or by persons legally authorized in the Member
States to carry out such processes.
3. Authorization referred to in paragraph 1 shall also be required for
imports coming from third countries into a Member State; this Title
and Article 118 shall have corresponding application to such imports
as they have to manufacture.
4. The Member States shall forward to the Agency a copy of the
authorisation referred to in paragraph 1. The Agency shall enter that
information on the Community database referred to in Article 111(6).
Article 41
In order to obtain the manufacturing authorization, the applicant shall
meet at least the following requirements:
(a) specify the medicinal products and pharmaceutical forms which are
to be manufactured or imported and also the place where they are
to be manufactured and/or controlled;
(b) have at his disposal, for the manufacture or import of the above,
suitable and sufficient premises, technical equipment and control
facilities complying with the legal requirements which the Member
State concerned lays down as regards both manufacture and control
and the storage of medicinal products, in accordance with Article
20;
(c) have at his disposal the services of at least one qualified person
within the meaning of Article 48.
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The applicant shall provide particulars in support of the above in his
application.
Article 42
1. The competent authority of the Member State shall issue the
manufacturing authorization only after having made sure of the accuracy
of the particulars supplied pursuant to Article 41, by means of an
inquiry carried out by its agents.
2. In order to ensure that the requirements referred to in Article 41
are complied with, authorization may be made conditional on the
carrying out of certain obligations imposed either when authorization
is granted or at a later date.
3. The authorization shall apply only to the premises specified in the
application and to the medicinal products and pharmaceutical forms
specified in that same application.
Article 43
The Member States shall take all appropriate measures to ensure that
the time taken for the procedure for granting the manufacturing authorization
does not exceed 90 days from the day on which the competent
authority receives the application.
Article 44
If the holder of the manufacturing authorization requests a change in
any of the particulars referred to in points (a) and (b) of the first paragraph
of Article 41, the time taken for the procedure relating to this
request shall not exceed 30 days. In exceptional cases this period of
time may be extended to 90 days.
Article 45
The competent authority of the Member State may require from the
applicant further information concerning the particulars supplied
pursuant to Article 41 and concerning the qualified person referred to
in Article 48; where the competent authority concerned exercises this
right, application of the time-limits referred to in Article 43 and 44
shall be suspended until the additional data required have been
supplied.
Article 46
The holder of a manufacturing authorization shall at least be obliged:
(a) to have at his disposal the services of staff who comply with the
legal requirements existing in the Member State concerned both as
regards manufacture and controls;
(b) to dispose of the authorized medicinal products only in accordance
with the legislation of the Member States concerned;
(c) to give prior notice to the competent authority of any changes he
may wish to make to any of the particulars supplied pursuant to
Article 41; the competent authority shall, in any event, be immediately
informed if the qualified person referred to in Article 48 is
replaced unexpectedly;
(d) to allow the agents of the competent authority of the Member State
concerned access to his premises at any time;
(e) to enable the qualified person referred to in Article 48 to carry out
his duties, for example by placing at his disposal all the necessary
facilities;
(f) to comply with the principles and guidelines of good manufacturing
practice for medicinal products and to use as starting
materials only active substances, which have been manufactured
in accordance with the detailed guidelines on good manufacturing
practice for starting materials.
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This point shall also be applicable to certain excipients, the list of
which as well as the specific conditions of application shall be
established by a Directive adopted by the Commission in accordance
with the procedure referred to in Article 121(2).
Article 46a
1. For the purposes of this Directive, manufacture of active
substances used as starting materials shall include both total and partial
manufacture or import of an active substance used as a starting material
as defined in Part I, point 3.2.1.1 (b) Annex I, and the various
processes of dividing up, packaging or presentation prior to its incorporation
into a medicinal product, including repackaging or relabelling,
such as are carried out by a distributor of starting materials.
2. Any amendments necessary to adapt paragraph 1 to new scientific
and technical developments shall be laid down in accordance with the
procedure referred to in Article 121(2).
Article 47
The principles and guidelines of good manufacturing practices for
medicinal products referred to in Article 46(f) shall be adopted in the
form of a directive, in accordance with the procedure referred to in
Article 121(2).
Detailed guidelines in line with those principles will be published by
the Commission and revised necessary to take account of technical
and scientific progress.
The principles of good manufacturing practice for active substances
used as starting materials referred to in point (f) of Article 46 shall be
adopted in the form of detailed guidelines.
The Commission shall also publish guidelines on the form and content
of the authorisation referred to in Article 40(1), on the reports referred
to in Article 111(3) and on the form and content of the certificate of
good manufacturing practice referred to in Article 111(5).
Article 48
1. Member States shall take all appropriate measures to ensure that
the holder of the manufacturing authorization has permanently and
continuously at his disposal the services of at least one qualified
person, in accordance with the conditions laid down in Article 49,
responsible in particular for carrying out the duties specified in Article
51.
2. If he personally fulfils the conditions laid down in Article 49, the
holder of the authorization may himself assume the responsibility
referred to in paragraph 1.
Article 49
1. Member States shall ensure that the qualified person referred to in
Article 48 fulfils the ►M4 ◄ conditions of qualification
set out in paragraphs 2 and 3.
2. A qualified person shall be in possession of a diploma, certificate
or other evidence of formal qualifications awarded on completion of a
university course of study, or a course recognized as equivalent by the
Member State concerned, extending over a period of at least four years
of theoretical and practical study in one of the following scientific
disciplines: pharmacy, medicine, veterinary medicine, chemistry, pharmaceutical
chemistry and technology, biology.
However, the minimum duration of the university course may be three
and a half years where the course is followed by a period of theoretical
and practical training of a minimum duration of one year and including
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a training period of at least six months in a pharmacy open to the
public, corroborated by an examination at university level.
Where two university courses or two courses recognized by the State as
equivalent co-exist in a Member State and where one of these extends
over four years and the other over three years, the three-year course
leading to a diploma, certificate or other evidence of formal qualifications
awarded on completion of a university course or its recognized
equivalent shall be considered to fulfil the condition of duration
referred to in the second subparagraph in so far as the diplomas, certificates
or other evidence of formal qualifications awarded on
completion of both courses are recognized as equivalent by the State
in question.
The course shall include theoretical and practical study bearing upon at
least the following basic subjects:
— ►M4 Experimental physics ◄
— General and inorganic chemistry
— Organic chemistry
— Analytical chemistry
— Pharmaceutical chemistry, including analysis of medicinal products
— General and applied biochemistry (medical)
— Physiology
— Microbiology
— Pharmacology
— Pharmaceutical technology
— Toxicology
— Pharmacognosy (study of the composition and effects of the natural
active substances of plant and animal origin).
Studies in these subjects should be so balanced as to enable the person
concerned to fulfil the obligations specified in Article 51.
In so far as certain diplomas, certificates or other evidence of formal
qualifications mentioned in the first subparagraph do not fulfil the
criteria laid down in this paragraph, the competent authority of the
Member State shall ensure that the person concerned provides evidence
of adequate knowledge of the subjects involved.
3. The qualified person shall have acquired practical experience over
at least two years, in one or more undertakings which are authorized to
manufacture medicinal products, in the activities of qualitative analysis
of medicinal products, of quantitative analysis of active substances and
of the testing and checking necessary to ensure the quality of medicinal
products.
The duration of practical experience may be reduced by one year
where a university course lasts for at least five years and by a year
and a half where the course lasts for at least six years.
Article 50
1. A person engaging in the activities of the person referred to in
Article 48 from the time of the application of Directive 75/319/EEC,
in a Member State without complying with the provisions of Article
49 shall be eligible to continue to engage in those activities
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2. The holder of a diploma, certificate or other evidence of formal
qualifications awarded on completion of a university course — or a
course recognized as equivalent by the Member State concerned — in
a scientific discipline allowing him to engage in the activities of the
person referred to in Article 48 in accordance with the laws of that
State may — if he began his course prior to 21 May 1975 — be
considered as qualified to carry out in that State the duties of the
person referred to in Article 48 provided that he has previously
engaged in the following activities for at least two years before 21
May 1985 following notification of this directive in one or more undertakings
authorized to manufacture: production supervision and/or
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qualitative and quantitative analysis of active substances, and the
necessary testing and checking under the direct authority of the person
referred to in Article 48 to ensure the quality of the medicinal products.
If the person concerned has acquired the practical experience referred
to in the first subparagraph before 21 May 1965, a further one year's
practical experience in accordance with the conditions referred to in
the first subparagraph will be required to be completed immediately
before he engages in such activities.
Article 51
1. Member States shall take all appropriate measures to ensure that
the qualified person referred to in Article 48, without prejudice to his
relationship with the holder of the manufacturing authorization, is
responsible, in the context of the procedures referred to in Article 52,
for securing:
(a) in the case of medicinal products manufactured within the Member
States concerned, that each batch of medicinal products has been
manufactured and checked in compliance with the laws in force in
that Member State and in accordance with the requirements of the
marketing authorization;
(b) in the case of medicinal products coming from third countries, irrespective
of whether the product has been manufactured in the
Community, that each production batch has undergone in a
Member State a full qualitative analysis, a quantitative analysis of
at least all the active substances and all the other tests or checks
necessary to ensure the quality of medicinal products in accordance
with the requirements of the marketing authorisation.
The batches of medicinal products which have undergone such controls
in a Member State shall be exempt from the controls if they are
marketed in another Member State, accompanied by the control reports
signed by the qualified person.
2. In the case of medicinal products imported from a third country,
where appropriate arrangements have been made by the Community
with the exporting country to ensure that the manufacturer of the
medicinal product applies standards of good manufacturing practice at
least equivalent to those laid down by the Community, and to ensure
that the controls referred to under point (b) of the first subparagraph
of paragraph 1 have been carried out in the exporting country, the
qualified person may be relieved of responsibility for carrying out
those controls.
3. In all cases and particularly where the medicinal products are
released for sale, the qualified person must certify in a register or
equivalent document provided for that purpose, that each production
batch satisfies the provisions of this Article; the said register or equivalent
document must be kept up to date as operations are carried out and
must remain at the disposal of the agents of the competent authority for
the period specified in the provisions of the Member State concerned
and in any event for at least five years.
Article 52
Member States shall ensure that the duties of qualified persons referred
to in Article 48 are fulfilled, either by means of appropriate administrative
measures or by making such persons subject to a professional code
of conduct.
Member States may provide for the temporary suspension of such a
person upon the commencement of administrative or disciplinary
procedures against him for failure to fulfil his obligations.
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Article 53
The provisions of this Title shall also apply to homeopathic medicinal
products.
TITLE V
LABELLING AND PACKAGE LEAFLET
Article 54
The following particulars shall appear on the outer packaging of medicinal
products or, where there is no outer packaging, on the immediate
packaging:
(a) the name of the medicinal product followed by its strength and
pharmaceutical form, and, if appropriate, whether it is intended
for babies, children or adults; where the product contains up to
three active substances, the international non-proprietary name
(INN) shall be included, or, if one does not exist, the common
name;
(b) a statement of the active substances expressed qualitatively and
quantitatively per dosage unit or according to the form of administration
for a given volume or weight, using their common names;
(c) the pharmaceutical form and the contents by weight, by volume or
by number of doses of the product;
(d) a list of those excipients known to have a recognized action or
effect and included in the ►M4 detailed guidance ◄ published
pursuant to Article 65. However, if the product is injectable, or a
topical or eye preparation, all excipients must be stated;
(e) the method of administration and, if necessary, the route of administration.
Space shall be provided for the prescribed dose to be
indicated;
(f) a special warning that the medicinal product must be stored out of
the reach and sight of children;
(g) a special warning, if this is necessary for the medicinal product;
(h) the expiry date in clear terms (month/year);
(i) special storage precautions, if any;
(j) specific precautions relating to the disposal of unused medicinal
products or waste derived from medicinal products, where appropriate,
as well as reference to any appropriate collection system in
place;
(k) the name and address of the marketing authorisation holder and,
where applicable, the name of the representative appointed by the
holder to represent him;
(l) the number of the authorization for placing the medicinal product
on the market;
(m) the manufacturer's batch number;
(n) in the case of non-prescription medicinal products, instructions for
use.
Article 55
1. The particulars laid down ►M4 in Article 54 ◄ shall appear on
immediate packagings other than those referred to in paragraphs 2 and
3.
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2. The following particulars at least shall appear on immediate
packagings which take the form of blister packs and are placed in an
outer packaging that complies with the requirements laid down in Articles
54 and 62.
— the name of the medicinal product as laid down in point (a) of
Article 54,
— the name of the holder of the authorization for placing the product
on the market,
— the expiry date,
— the batch number.
3. The following particulars at least shall appear on small immediate
packaging units on which the particulars laid down in Articles 54 and
62 cannot be displayed:
— the name of the medicinal product as laid down in point (a) of
Article 54 and, if necessary, the route of administration,
— the method of administration,
— the expiry date,
— the batch number,
— the contents by weight, by volume or by unit.
Article 56
The particulars referred to in Articles 54, 55 and 62 shall be easily
legible, clearly comprehensible and indelible.
Article 56a
The name of the medicinal product, as referred to in Article 54, point
(a) must also be expressed in Braille format on the packaging. The
marketing authorisation holder shall ensure that the package information
leaflet is made available on request from patients' organisations
in formats appropriate for the blind and partially-sighted.
Article 57
Notwithstanding Article 60, Member States may require the use of
certain forms of labelling of the medicinal product making it possible
to ascertain:
— the price of the medicinal product,
— the reimbursement conditions of social security organizations,
— the legal status for supply to the patient, in accordance with Title
VI,
— identification and authenticity.
For medicinal products authorised under Regulation (EC) No 726/2004,
Member States shall, when applying this Article, observe the detailed
guidance referred to in Article 65 of this Directive.
Article 58
The inclusion in the packaging of all medicinal products of a package
leaflet shall be obligatory unless all the information required by Articles
59 and 62 is directly conveyed on the outer packaging or on the
immediate packaging.
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Article 59
1. The package leaflet shall be drawn up in accordance with the
summary of the product characteristics; it shall include, in the
following order:
(a) for the identification of the medicinal product:
(i) the name of the medicinal product followed by its strength and
pharmaceutical form, and, if appropriate, whether it is intended
for babies, children or adults. The common name shall be
included where the product contains only one active substance
and if its name is an invented name;
(ii) the pharmaco-therapeutic group or type of activity in terms
easily comprehensible for the patient;
(b) the therapeutic indications;
(c) a list of information which is necessary before the medicinal
product is taken:
(i) contra-indications;
(ii) appropriate precautions for use;
(iii) forms of interaction with other medicinal products and other
forms of interaction (e.g. alcohol, tobacco, foodstuffs) which
may affect the action of the medicinal product;
(iv) special warnings;
(d) the necessary and usual instructions for proper use, and in particular:
(i) the dosage,
(ii) the method and, if necessary, route of administration;
(iii) the frequency of administration, specifying if necessary the
appropriate time at which the medicinal product may or must
be administered;
and, as appropriate, depending on the nature of the product:
(iv) the duration of treatment, where it should be limited;
(v) the action to be taken in case of an overdose (such as symptoms,
emergency procedures);
(vi) what to do when one or more doses have not been taken;
(vii) indication, if necessary, of the risk of withdrawal effects;
(viii) a specific recommendation to consult the doctor or the pharmacist,
as appropriate, for any clarification on the use of the
product;
(e) a description of the adverse reactions which may occur under
normal use of the medicinal product and, if necessary, the action
to be taken in such a case; the patient should be expressly asked
to communicate any adverse reaction which is not mentioned in
the package leaflet to his doctor or pharmacist;
(f) a reference to the expiry date indicated on the label, with:
(i) a warning against using the product after that date;
(ii) where appropriate, special storage precautions;
(iii) if necessary, a warning concerning certain visible signs of
deterioration;
(iv) the full qualitative composition (in active substances and excipients)
and the quantitative composition in active substances,
using common names, for each presentation of the medicinal
product;
(v) for each presentation of the product, the pharmaceutical form
and content in weight, volume or units of dosage;
(vi) the name and address of the marketing authorisation holder
and, where applicable, the name of his appointed representatives
in the Member States;
(vii) the name and address of the manufacturer;
(g) where the medicinal product is authorised in accordance with Articles
28 to 39 under different names in the Member States
concerned, a list of the names authorised in each Member State;
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(h) the date on which the package leaflet was last revised.
2. The list set out in point (c) of paragraph 1 shall:
(a) take into account the particular condition of certain categories of
users (children, pregnant or breastfeeding women, the elderly,
persons with specific pathological conditions);
(b) mention, if appropriate, possible effects on the ability to drive vehicles
or to operate machinery;
(c) list those excipients knowledge of which is important for the safe
and effective use of the medicinal product and which are included
in the detailed guidance published pursuant to Article 65.
3. The package leaflet shall reflect the results of consultations with
target patient groups to ensure that it is legible, clear and easy to use.
Article 60
Member States may not prohibit or impede the placing on the market
of medicinal products within their territory on grounds connected with
labelling or the package leaflet where these comply with the requirements
of this Title.
Article 61
1. One or more mock-ups of the outer packaging and the immediate
packaging of a medicinal product, together with the draft package
leaflet, shall be submitted to the authorities competent for authorising
marketing when the marketing authorisation is requested. The results
of assessments carried out in cooperation with target patient groups
shall also be provided to the competent authority.
2. The competent authority shall refuse the marketing authorization
if the labelling or the package leaflet do not comply with the provisions
of this Title or if they are not in accordance with the particulars listed
in the summary of product characteristics.
3. All proposed changes to an aspect of the labelling or the package
leaflet covered by this Title and not connected with the summary of
product characteristics shall be submitted to the authorities competent
for authorizing marketing. If the competent authorities have not
opposed a proposed change within 90 days following the introduction
of the request, the applicant may put the change into effect.
4. The fact that the competent authority do not refuse a marketing
authorization pursuant to paragraph 2 or a change to the labelling or
the package leaflet pursuant to paragraph 3 does not alter the general
legal liability of the manufacturer ►M4 and ◄ the marketing authorization
holder.
Article 62
The outer packaging and the package leaflet may include symbols or
pictograms designed to clarify certain information mentioned in Articles
54 and 59(1) and other information compatible with the summary
of the product characteristics which is useful ►M4 for the patient ◄,
to the exclusion of any element of a promotional nature.
Article 63
1. The particulars for labelling listed in Articles 54, 59 and 62 shall
appear in the official language or languages of the Member State where
the product is placed on the market.
The first subparagraph shall not prevent these particulars from being
indicated in several languages, provided that the same particulars
appear in all the languages used.
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In the case of certain orphan medicinal products, the particulars listed
in Article 54 may, on reasoned request, appear in only one of the official
languages of the Community.
2. The package leaflet must be written and designed to be clear and
understandable, enabling the users to act appropriately, when necessary
with the help of health professionals. The package leaflet must be
clearly legible in the official language or languages of the Member
State in which the medicinal product is placed on the market.
The first subparagraph shall not prevent the package leaflet from being
printed in several languages, provided that the same information is
given in all the languages used.
3. When the product is not intended to be delivered directly to the
patient, the competent authorities may grant an exemption to the obligation
that certain particulars should appear on the labelling and in the
package leaflet and that the leaflet must be in the official language or
languages of the Member State in which the product is placed on the
market.
Article 64
Where the provisions of this Title are not complied with, and a notice
served on the person concerned has remained without effect, the
competent authorities of the Member States may suspend the marketing
authorization, until the labelling and the package leaflet of the medicinal
product in question have been made to comply with the
requirements of this Title.
Article 65
In consultation with the Member States and the parties concerned, the
Commission shall draw up and publish detailed guidance concerning in
particular:
(a) the wording of certain special warnings for certain categories of
medicinal products;
(b) the particular information needs relating to non-prescription medicinal
products;
(c) the legibility of particulars on the labelling and package leaflet;
(d) the methods for the identification and authentication of medicinal
products;
(e) the list of excipients which must feature on the labelling of medicinal
products and the way in which these excipients must be
indicated;
(f) harmonised provisions for the implementation of Article 57.
Article 66
1. The outer carton and the container of medicinal products
containing radionuclides shall be labelled in accordance with the regulations
for the safe transport of radioactive materials laid down by the
International Atomic Energy Agency. Moreover, the labelling shall
comply with the provisions set out in paragraphs 2 and 3.
2. The label on the shielding shall include the particulars mentioned
in Article 54. In addition, the labelling on the shielding shall explain in
full, the codings used on the vial and shall indicate, where necessary,
for a given time and date, the amount of radioactivity per dose or per
vial and the number of capsules, or, for liquids, the number of millilitres
in the container.
3. The vial shall be labelled with the following information:
— the name or code of the medicinal product, including the name or
chemical symbol of the radionuclide,
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— the batch identification and expiry date,
— the international symbol for radioactivity,
— the name and address of the manufacturer,
— the amount of radioactivity as specified in paragraph 2.
Article 67
The competent authority shall ensure that a detailed instruction leaflet
is enclosed with the packaging of radiopharmaceuticals, radionuclide
generators, radionuclide kits or radionuclide precursors. The text of
this leaflet shall be established in accordance with the provisions of
Article 59. In addition, the leaflet shall include any precautions to be
taken by the user and the patient during the preparation and administration
of the medicinal product and special precautions for the disposal
of the packaging and its unused contents.
Article 68
Without prejudice to the provisions of Article 69, homeopathic medicinal
products shall be labelled in accordance with the provisions of this
title and shall be identified by a reference on their labels, in clear and
legible form, to their homeopathic nature.
Article 69
1. In addition to the clear mention of the words ‘homeopathic
medicinal product’, the labelling and, where appropriate, the package
insert for the medicinal products referred to in Article 14(1) shall bear
the following, and no other, information:
— the scientific name of the stock or stocks followed by the degree of
dilution, making use of the symbols of the pharmacopoeia used in
accordance with Article 1(5); if the homeopathic medicinal product
is composed of two or more stocks, the scientific names of the
stocks on the labelling may be supplemented by an invented name,
— name and address of the registration holder and, where appropriate,
of the manufacturer,
— method of administration and, if necessary, route,
— expiry date, in clear terms (month, year),
— pharmaceutical form,
— contents of the sales presentation,
— special storage precautions, if any,
— a special warning if necessary for the medicinal product,
— manufacturer's batch number,
— registration number,
— ‘homeopathic medicinal product without approved therapeutic indications’,
— a warning advising the user to consult a doctor if the symptoms
persist.
2. Notwithstanding paragraph 1, Member States may require the use
of certain types of labelling in order to show:
— the price of the medicinal product,
— the conditions for refunds by social security bodies.
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TITLE VI
CLASSIFICATION OF MEDICINAL PRODUCTS
Article 70
1. When a marketing authorization is granted, the competent authorities
shall specify the classification of the medicinal product into:
— a medicinal product subject to medical prescription,
— a medicinal product not subject to medical prescription.
To this end, the criteria laid down in Article 71(1) shall apply.
2. The competent authorities may fix sub-categories for medicinal
products which are available on medical prescription only. In that
case, they shall refer to the following classification:
(a) medicinal products on medical prescription for renewable or nonrenewable
delivery;
(b) medicinal products subject to special medical prescription;
(c) medicinal products on ‘restricted’ medical prescription, reserved for
use in certain specialised areas.
Article 71
1. Medicinal products shall be subject to medical prescription where
they:
— are likely to present a danger either directly or indirectly, even
when used correctly, if utilized without medical supervision, or
— are frequently and to a very wide extent used incorrectly, and as a
result are likely to present a direct or indirect danger to human
health, or
— contain substances or preparations thereof, the activity and/or
adverse reactions of which require further investigation, or
— are normally prescribed by a doctor to be administered parenterally.
2. Where Member States provide for the sub-category of medicinal
products subject to special medical prescription, they shall take account
of the following factors:
— the medicinal product contains, in a non-exempt quantity, a
substance classified as a narcotic or a psychotropic substance within
the meaning of the international conventions in force, such as the
United Nations Conventions of 1961 and 1971, or
— the medicinal product is likely, if incorrectly used, to present a
substantial risk of medicinal abuse, to lead to addiction or be
misused for illegal purposes, or
— the medicinal product contains a substance which, by reason of its
novelty or properties, could be considered as belonging to the group
envisaged in the second indent as a precautionary measure.
3. Where Member States provide for the sub-category of medicinal
products subject to restricted prescription, they shall take account of
the following factors:
— the medicinal product, because of its pharmaceutical characteristics
or novelty or in the interests of public health, is reserved for treatments
which can only be followed in a hospital environment,
— the medicinal product is used in the treatment of conditions which
must be diagnosed in a hospital environment or in institutions with
adequate diagnostic facilities, although administration and followup
may be carried out elsewhere, or
— the medicinal product is intended for outpatients but its use may
produce very serious adverse reactions requiring a prescription
drawn up as required by a specialist and special supervision
throughout the treatment.
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4. A competent authority may waive application of paragraphs 1, 2
and 3 having regard to:
(a) the maximum single dose, the maximum daily dose, the strength,
the pharmaceutical form, certain types of packaging; and/or
(b) other circumstances of use which it has specified.
5. If a competent authority does not designate medicinal products
into sub-categories referred to in Article 70(2), it shall nevertheless
take into account the criteria referred to in paragraphs 2 and 3 of this
Article in determining whether any medicinal product shall be classified
as a prescription-only medicine.
Article 72
Medicinal products not subject to prescription shall be those which do
not meet the criteria listed in Article 71.
Article 73
The competent authorities shall draw up a list of the medicinal
products subject, on their territory, to medical prescription, specifying,
if necessary, the category of classification. They shall update this list
annually.
Article 74
When new facts are brought to their attention, the competent authorities
shall examine and, as appropriate, amend the classification of a
medicinal product by applying the criteria listed in Article 71.
Article 74a
Where a change of classification of a medicinal product has been
authorised on the basis of significant pre-clinical tests or clinical trials,
the competent authority shall not refer to the results of those tests or
trials when examining an application by another applicant for or holder
of marketing authorisation for a change of classification of the same
substance for one year after the initial change was authorised.
Article 75
Each year, Member States shall communicate to the Commission and
to the other Member States, the changes that have been made to the
list referred to in Article 73.
TITLE VII
WHOLESALE DISTRIBUTION OF MEDICINAL PRODUCTS
Article 76
►M4 1. ◄ Without prejudice to Article 6, Member States shall
take all appropriate action to ensure that only medicinal products in
respect of which a marketing authorization has been granted in accordance
with Community law are distributed on their territory.
2. In the case of wholesale distribution and storage, medicinal
products shall be covered by a marketing authorisation granted
pursuant to Regulation (EC) No 726/2004 or by the competent authorities
of a Member State in accordance with this Directive.
3. Any distributor, not being the marketing authorisation holder,
who imports a product from another Member State shall notify the
marketing authorisation holder and the competent authority in the
Member State to which the product will be imported of his intention
to import it. In the case of products which have not been granted an
authorisation pursuant to Regulation (EC) No 726/2004, the notification
to the competent authority shall be without prejudice to
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additional procedures provided for in the legislation of that Member
State.
Article 77
1. Member States shall take all appropriate measures to ensure that
the wholesale distribution of medicinal products is subject to the
possession of an authorization to engage in activity as a wholesaler in
medicinal products, stating the place for which it is valid.
2. Where persons authorized or entitled to supply medicinal
products to the public may also, under national law, engage in wholesale
business, such persons shall be subject to the authorization
provided for in paragraph 1.
3. Possession of a manufacturing authorization shall include authorization
to distribute by wholesale the medicinal products covered by
that authorization. Possession of an authorization to engage in activity
as a wholesaler in medicinal products shall not give dispensation from
the obligation to possess a manufacturing authorization and to comply
with the conditions set out in that respect, even where the manufacturing
or import business is secondary.
4. At the request of the Commission or any Member State, Member
States shall supply all appropriate information concerning the individual
authorizations which they have granted under paragraph 1.
5. Checks on the persons authorized to engage in the activity of
wholesaler in medicinal products and the inspection of their premises,
shall be carried out under the responsibility of the Member State which
granted the authorization.
6. The Member State which granted the authorization referred to in
paragraph 1 shall suspend or revoke that authorization if the conditions
of authorization cease to be met. It shall forthwith inform the other
Member States and the Commission thereof.
7. Should a Member State consider that, in respect of a person
holding an authorization granted by another Member State under the
terms of paragraph 1, the conditions of authorization are not, or are
no longer met, it shall forthwith inform the Commission and the other
Member State involved. The latter shall take the measures necessary
and shall inform the Commission and the first Member State of the
decisions taken and the reasons for those decisions.
Article 78
Member States shall ensure that the time taken for the procedure for
examining the application for the distribution authorization does not
exceed 90 days from the day on which the competent authority of the
Member State concerned receives the application.
The competent authority may, if need be, require the applicant to
supply all necessary information concerning the conditions of authorization.
Where the authority exercises this option, the period laid down
in the first paragraph shall be suspended until the requisite additional
data have been supplied.
Article 79
In order to obtain the distribution authorization, applicants must fulfil
the following minimum requirements:
(a) they must have suitable and adequate premises, installations and
equipment, so as to ensure proper conservation and distribution of
the medicinal products;
(b) they must have staff, and in particular, a qualified person designated
as responsible, meeting the conditions provided for by the
legislation of the Member State concerned;
(c) they must undertake to fulfil the obligations incumbent on them
under the terms of Article 80.
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Article 80
Holders of the distribution authorization must fulfil the following
minimum requirements:
(a) they must make the premises, installations and equipment referred
to in Article 79(a) accessible at all times to the persons responsible
for inspecting them;
(b) they must obtain their supplies of medicinal products only from
persons who are themselves in possession of the distribution
authorization or who are exempt from obtaining such authorization
under the terms of Article 77(3);
(c) they must supply medicinal products only to persons who are themselves
in possession of the distribution authorization or who are
authorized or entitled to supply medicinal products to the public
in the Member State concerned;
(d) they must have an emergency plan which ensures effective implementation
of any recall from the market ordered by the competent
authorities or carried out in cooperation with the manufacturer or
marketing authorization holder for the medicinal product
concerned;
(e) they must keep records either in the form of purchase/sales
invoices, or on computer, or in any other form, giving for any
transaction in medicinal products received or dispatched at least
the following information:
— date,
— name of the medicinal product,
— quantity received or supplied,
— name and address of the supplier or consignee, as appropriate;
(f) they must keep the records referred to under (e) available to the
competent authorities, for inspection purposes, for a period of five
years;
(g) they must comply with the principles and guidelines of good distribution
practice for medicinal products as laid down in Article 84.
Article 81
With regard to the supply of medicinal products to pharmacists and
persons authorised or entitled to supply medicinal products to the
public, Member States shall not impose upon the holder of a distribution
authorisation which has been granted by another Member State
any obligation, in particular public service obligations, more stringent
than those they impose on persons whom they have themselves
authorised to engage in equivalent activities.
The holder of a marketing authorisation for a medicinal product and
the distributors of the said medicinal product actually placed on the
market in a Member State shall, within the limits of their responsibilities,
ensure appropriate and continued supplies of that medicinal
product to pharmacies and persons authorised to supply medicinal
products so that the needs of patients in the Member State in question
are covered.
The arrangements for implementing this Article should, moreover, be
justified on grounds of public health protection and be proportionate
in relation to the objective of such protection, in compliance with the
Treaty rules, particularly those concerning the free movement of goods
and competition.
Article 82
For all supplies of medicinal products to a person authorized or entitled
to supply medicinal products to the public in the Member State
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concerned, the authorized wholesaler must enclose a document that
makes it possible to ascertain:
— the date,
— the name and pharmaceutical form of the medicinal product,
— the quantity supplied,
— the name and address of the supplier and consignor.
Member States shall take all appropriate measures to ensure that
persons authorized or entitled to supply medicinal products to the
public are able to provide information that makes it possible to trace
the distribution path of every medicinal product.
Article 83
The provisions of this Title shall not prevent the application of more
stringent requirements laid down by Member States in respect of the
wholesale distribution of:
— narcotic or psychotropic substances within their territory,
— medicinal products derived from blood,
— immunological medicinal products,
— radiopharmaceuticals.
Article 84
The Commission shall publish guidelines on good distribution practice.
To this end, it shall consult the Committee for Medicinal Products for
Human Use and the Pharmaceutical Committee established by Council
Decision 75/320/EEC (1).
Article 85
This Title shall apply to homeopathic medicinal products.
TITLE VIII
ADVERTISING
Article 86
1. For the purposes of this Title, ‘advertising of medicinal products’
shall include any form of door-to-door information, canvassing activity
or inducement designed to promote the prescription, supply, sale or
consumption of medicinal products; it shall include in particular:
— the advertising of medicinal products to the general public,
— advertising of medicinal products to persons qualified to prescribe
or supply them,
— visits by medical sales representatives to persons qualified to
prescribe medicinal products,
— the supply of samples,
— the provision of inducements to prescribe or supply medicinal
products by the gift, offer or promise of any benefit or bonus,
whether in money or in kind, except when their intrinsic value is
minimal,
— sponsorship of promotional meetings attended by persons qualified
to prescribe or supply medicinal products,
— sponsorship of scientific congresses attended by persons qualified to
prescribe or supply medicinal products and in particular payment of
their travelling and accommodation expenses in connection therewith.
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2. The following are not covered by this Title:
— the labelling and the accompanying package leaflets, which are
subject to the provisions of Title V,
— correspondence, possibly accompanied by material of a non-promotional
nature, needed to answer a specific question about a
particular medicinal product,
— factual, informative announcements and reference material relating,
for example, to pack changes, adverse-reaction warnings as part of
general drug precautions, trade catalogues and price lists, provided
they include no product claims,
— information relating to human health or diseases, provided that
there is no reference, even indirect, to medicinal products.
Article 87
1. Member States shall prohibit any advertising of a medicinal
product in respect of which a marketing authorization has not been
granted in accordance with Community law.
2. All parts of the advertising of a medicinal product must comply
with the particulars listed in the summary of product characteristics.
3. The advertising of a medicinal product:
— shall encourage the rational use of the medicinal product, by
presenting it objectively and without exaggerating its properties,
— shall not be misleading.
Article 88
1. Member States shall prohibit the advertising to the general public
of medicinal products which:
(a) are available on medical prescription only, in accordance with Title
VI;
(b) contain substances defined as psychotropic or narcotic by international
convention, such as the United Nations Conventions of
1961 and 1971.
2. Medicinal products may be advertised to the general public
which, by virtue of their composition and purpose, are intended and
designed for use without the intervention of a medical practitioner for
diagnostic purposes or for the prescription or monitoring of treatment,
with the advice of the pharmacist, if necessary.
3. Member States shall be entitled to ban, on their territory, advertising
to the general public of medicinal products the cost of which
may be reimbursed.
4. The prohibition contained in paragraph 1 shall not apply to vaccination
campaigns carried out by the industry and approved by the
competent authorities of the Member States.
5. The prohibition referred to in paragraph 1 shall apply without
prejudice to Article 14 of Directive 89/552/EEC.
6. Member States shall prohibit the direct distribution of medicinal
products to the public by the industry for promotional purposes.
TITLE VIIIa
INFORMATION AND ADVERTISING
Article 88a
Within three years of the entry into force of Directive 2004/726/EC,
the Commission shall, following consultations with patients' and consumers'
organisations, doctors' and pharmacists' organisations, Member
States and other interested parties, present to the European Parliament
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and the Council a report on current practice with regard to information
provision — particularly on the Internet — and its risks and benefits
for patients.
Following analysis of the above data, the Commission shall, if appropriate,
put forward proposals setting out an information strategy to
ensure good-quality, objective, reliable and non-promotional information
on medicinal products and other treatments and shall address the
question of the information source's liability.
Article 89
1. Without prejudice to Article 88, all advertising to the general
public of a medicinal product shall:
(a) be set out in such a way that it is clear that the message is an
advertisement and that the product is clearly identified as a medicinal
product;
(b) include the following minimum information:
— the name of the medicinal product, as well as the common
name if the medicinal product contains only one active
substance,
— the information necessary for correct use of the medicinal
product,
— an express, legible invitation to read carefully the instructions
on the package leaflet or on the outer packaging, as the case
may be.
2. Member States may decide that the advertising of a medicinal
product to the general public may, notwithstanding paragraph 1,
include only the name of the medicinal product or its international
non-proprietary name, where this exists, or the trademark if it is
intended solely as a reminder.
Article 90
The advertising of a medicinal product to the general public shall not
contain any material which:
(a) gives the impression that a medical consultation or surgical operation
is unnecessary, in particular by offering a diagnosis or by
suggesting treatment by mail;
(b) suggests that the effects of taking the medicine are guaranteed, are
unaccompanied by adverse reactions or are better than, or equivalent
to, those of another treatment or medicinal product;
(c) suggests that the health of the subject can be enhanced by taking
the medicine;
(d) suggests that the health of the subject could be affected by not
taking the medicine; this prohibition shall not apply to the vaccination
campaigns referred to in Article 88(4);
(e) is directed exclusively or principally at children;
(f) refers to a recommendation by scientists, health professionals or
persons who are neither of the foregoing but who, because of their
celebrity, could encourage the consumption of medicinal products;
(g) suggests that the medicinal product is a foodstuff, cosmetic or other
consumer product;
(h) suggests that the safety or efficacy of the medicinal product is due
to the fact that it is natural;
(i) could, by a description or detailed representation of a case history,
lead to erroneous self-diagnosis;
(j) refers, in improper, alarming or misleading terms, to claims of
recovery;
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(k) uses, in improper, alarming or misleading terms, pictorial representations
of changes in the human body caused by disease or injury,
or of the action of a medicinal product on the human body or parts
thereof.
Article 91
1. Any advertising of a medicinal product to persons qualified to
prescribe or supply such products shall include:
— essential information compatible with the summary of product characteristics;
— the supply classification of the medicinal product.
Member States may also require such advertising to include the selling
price or indicative price of the various presentations and the conditions
for reimbursement by social security bodies.
2. Member States may decide that the advertising of a medicinal
product to persons qualified to prescribe or supply such products may,
notwithstanding paragraph 1, include only the name of the medicinal
product, or its international non-proprietary name, where this exists, or
the trademark, if it is intended solely as a reminder.
Article 92
1. Any documentation relating to a medicinal product which is
transmitted as part of the promotion of that product to persons qualified
to prescribe or supply it shall include, as a minimum, the particulars
listed in Article 91(1) and shall state the date on which it was drawn
up or last revised.
2. All the information contained in the documentation referred to in
paragraph 1 shall be accurate, up-to-date, verifiable and sufficiently
complete to enable the recipient to form his or her own opinion of the
therapeutic value of the medicinal product concerned.
3. Quotations as well as tables and other illustrative matter taken
from medical journals or other scientific works for use in the documentation
referred to in paragraph 1 shall be faithfully reproduced and the
precise sources indicated.
Article 93
1. Medical sales representatives shall be given adequate training by
the firm which employs them and shall have sufficient scientific
knowledge to be able to provide information which is precise and as
complete as possible about the medicinal products which they promote.
2. During each visit, medical sales representatives shall give the
persons visited, or have available for them, summaries of the product
characteristics of each medicinal product they present together, if the
legislation of the Member State so permits, with details of the price
and conditions for reimbursement referred to in Article 91(1).
3. Medical sales representatives shall transmit to the scientific
service referred to in Article 98(1) any information about the use of
the medicinal products they advertise, with particular reference to any
adverse reactions reported to them by the persons they visit.
Article 94
1. Where medicinal products are being promoted to persons qualified
to prescribe or supply them, no gifts, pecuniary advantages or
benefits in kind may be supplied, offered or promised to such persons
unless they are inexpensive and relevant to the practice of medicine or
pharmacy.
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2. Hospitality at sales promotion events shall always be strictly
limited to their main purpose and must not be extended to persons
other than health-care professionals.
3. Persons qualified to prescribe or supply medicinal products shall
not solicit or accept any inducement prohibited under paragraph 1 or
contrary to paragraph 2.
4. Existing measures or trade practices in Member States relating to
prices, margins and discounts shall not be affected by paragraphs 1, 2
and 3.
Article 95
The provisions of Article 94(1) shall not prevent hospitality being
offered, directly or indirectly, at events for purely professional and
scientific purposes; such hospitality shall always be strictly limited to
the main scientific objective of the event; it must not be extended to
persons other than health-care professionals.
Article 96
1. Free samples shall be provided on an exceptional basis only to
persons qualified to prescribe them and on the following conditions:
(a) the number of samples for each medicinal product each year on
prescription shall be limited;
(b) any supply of samples shall be in response to a written request,
signed and dated, from the prescribing agent;
(c) those supplying samples shall maintain an adequate system of
control and accountability;
(d) each sample shall be no larger than the smallest presentation on the
market;
(e) each sample shall be marked ‘free medical sample — not for sale’
or shall show some other wording having the same meaning;
(f) each sample shall be accompanied by a copy of the summary of
product characteristics;
(g) no samples of medicinal products containing psychotropic or
narcotic substances within the meaning of international conventions,
such as the United Nations Conventions of 1961 and 1971,
may be supplied.
2. Member States may also place further restrictions on the distribution
of samples of certain medicinal products.
Article 97
1. Member States shall ensure that there are adequate and effective
methods to monitor the advertising of medicinal products. Such
methods, which may be based on a system of prior vetting, shall in
any event include legal provisions under which persons or organizations
regarded under national law as having a legitimate interest in
prohibiting any advertisement inconsistent with this Title, may take
legal action against such advertisement, or bring such advertisement
before an administrative authority competent either to decide on
complaints or to initiate appropriate legal proceedings.
2. Under the legal provisions referred to in paragraph 1, Member
States shall confer upon the courts or administrative authorities powers
enabling them, in cases where they deem such measures to be necessary,
taking into account all the interests involved, and in particular
the public interest:
— to order the cessation of, or to institute appropriate legal proceedings
for an order for the cessation of, misleading advertising, or
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— if misleading advertising has not yet been published but publication
is imminent, to order the prohibition of, or to institute appropriate
legal proceedings for an order for the prohibition of, such publication,
even without proof of actual loss or damage or of intention or negligence
on the part of the advertiser.
3. Member States shall make provision for the measures referred to
in the second subparagraph to be taken under an accelerated procedure,
either with interim effect or with definitive effect.
It shall be for each Member State to decide which of the two options
set out in the first subparagraph to select.
4. Member States may confer upon the courts or administrative
authorities powers enabling them, with a view to eliminating the continuing
effects of misleading advertising the cessation of which has been
ordered by a final decision:
— to require publication of that decision in full or in part and in such
form as they deem adequate,
— to require in addition the publication of a corrective statement.
5. Paragraphs 1 to 4 shall not exclude the voluntary control of
advertising of medicinal products by self-regulatory bodies and
recourse to such bodies, if proceedings before such bodies are possible
in addition to the judicial or administrative proceedings referred to in
paragraph 1.
Article 98
1. The marketing authorization holder shall establish, within his
undertaking, a scientific service in charge of information about the
medicinal products which he places on the market.
2. The marketing authorization holder shall:
— keep available for, or communicate to, the authorities or bodies
responsible for monitoring advertising of medicinal products, a
sample of all advertisements emanating from his undertaking
together with a statement indicating the persons to whom it is
addressed, the method of dissemination and the date of first dissemination,
— ensure that advertising of medicinal products by his undertaking
conforms to the requirements of this Title,
— verify that medical sales representatives employed by his undertaking
have been adequately trained and fulfill the obligations
imposed upon them by Article 93(2) and (3),
— supply the authorities or bodies responsible for monitoring advertising
of medicinal products with the information and assistance
they require to carry out their responsibilities,
— ensure that the decisions taken by the authorities or bodies responsible
for monitoring advertising of medicinal products are
immediately and fully complied with.
3. The Member States shall not prohibit the co-promotion of a
medicinal product by the holder of the marketing authorisation and
one or more companies nominated by him.
Article 99
Member States shall take the appropriate measures to ensure that the
provisions of this Title are applied and shall determine in particular
what penalties shall be imposed should the provisions adopted in the
execution of Title be infringed.
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Article 100
Advertising of the homeopathic medicinal products referred to in
Article 14(1) shall be subject to the provisions of this Title with the
exception of Article 87(1).
However, only the information specified in Article 69(1) may be used
in the advertising of such medicinal products.
TITLE IX
PHARMACOVIGILANCE
Article 101
The Member States shall take all appropriate measures to encourage
doctors and other health care professionals to report suspected adverse
reactions to the competent authorities.
The Member States may impose specific requirements on doctors and
other health-care professionals in respect of the reporting of suspected
serious or unexpected adverse reactions.
Article 102
In order to ensure the adoption of appropriate and harmonised regulatory
decisions concerning the medicinal products authorised within the
Community, having regard to information obtained about adverse reactions
to medicinal products under normal conditions of use, the
Member States shall operate a pharmacovigilance system. This system
shall be used to collect information useful in the surveillance of medicinal
products, with particular reference to adverse reactions in human
beings, and to evaluate such information scientifically.
Member States shall ensure that suitable information collected within
this system is communicated to the other Member States and the
Agency. The information shall be recorded in the database referred to
in point (l) of the second subparagraph of Article 57(1) of Regulation
(EC) No 726/2004 and shall be permanently accessible to all Member
States and without delay to the public.
This system shall also take into account any available information on
misuse and abuse of medicinal products which may have an impact
on the evaluation of their benefits and risks.
Article 102a
The management of funds intended for activities connected with pharmacovigilance,
the operation of communication networks and market
surveillance shall be under the permanent control of the competent
authorities in order to guarantee their independence.
Article 103
The marketing authorization holder shall have permanently and
continuously at his disposal an appropriately qualified person responsible
for pharmacovigilance.
That qualified person shall reside in the Community and shall be
responsible for the following:
(a) the establishment and maintenance of a system which ensures that
information about all suspected adverse reactions which are
reported to the personnel of the company, and to medical representatives,
is collected and collated in order to be accessible at least at
one point within the Community;
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(b) the preparation for the competent authorities of the reports referred
to in Article 104, in such form as may be laid down by those
authorities, in accordance with the guidance referred to in Article
106(1);
(c) ensuring that any request from the competent authorities for the
provision of additional information necessary for the evaluation of
the benefits and risks afforded by a medicinal product is answered
fully and promptly, including the provision of information about
the volume of sales or prescriptions of the medicinal product
concerned;
(d) the provision to the competent authorities, of any other information
relevant to the evaluation of the benefits and risks afforded by a
medicinal product, including appropriate information on postauthorization
safety studies.
Article 104
1. The marketing authorisation holder shall be required to maintain
detailed records of all suspected adverse reactions occurring either in
the Community or in a third country.
Save in exceptional circumstances, these reactions shall be communicated
electronically in the form of a report in accordance with the
guidelines referred to in Article 106(1).
2. The marketing authorisation holder shall be required to record all
suspected serious adverse reactions which are brought to his attention
by a health-care professional and to report them promptly to the
competent authority of the Member State on whose territory the incident
occurred, and no later than 15 days following the receipt of the
information.
3. The marketing authorisation holder shall be required to record
and report all other suspected serious adverse reactions which meet
the notification criteria in accordance with the guidelines referred to
in Article 106(1), of which he can reasonably be expected to have
knowledge, promptly to the competent authority of the Member State
in whose territory the incident occurred, and no later than 15 days
following the receipt of the information.
4. The marketing authorisation holder shall ensure that all suspected
serious unexpected adverse reactions and any suspected transmission
via a medicinal product of any infectious agent occurring in the territory
of a third country are reported promptly in accordance with the
guidelines referred to in Article 106(1), so that the Agency and the
competent authorities of the Member States in which the medicinal
product is authorised are informed of them, and no later than 15 days
following the receipt of the information.
5. By way of derogation from paragraphs 2, 3 and 4, in the case of
medicinal products which are covered by Directive 87/22/EEC or
which have qualified for the procedures laid down in Articles 28 and
29 of this Directive or which have been the subject of the procedures
under Articles 32, 33 and 34 of this Directive, the marketing authorisation
holder shall also ensure that all suspected serious adverse reactions
occurring in the Community are reported in such a way as to be accessible
to the reference Member State or to any competent authority
acting as reference Member State. The reference Member State shall
assume the responsibility of analysing and monitoring such adverse
reactions.
6. Unless other requirements have been laid down as a condition for
the granting of the marketing authorisation, or subsequently as indicated
in the guidelines referred to in Article 106(1), reports of all
adverse reactions shall be submitted to the competent authorities in
the form of a periodic safety update report, immediately upon request
or at least every six months after authorisation and until the placing on
the market. Periodic safety update reports shall also be submitted
immediately upon request or at least every six months during the first
two years following the initial placing on the market and once a year
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for the following two years. Thereafter, the reports shall be submitted
at three-yearly intervals, or immediately upon request.
The periodic safety update reports shall include a scientific evaluation
of the risk-benefit balance of the medicinal product.
7. The Commission may lay down provisions to amend paragraph 6
in view of experience gained through its operation. The Commission
shall adopt the provisions in accordance with the procedure referred to
in Article 121(2).
8. Following the granting of a marketing authorisation, the
marketing authorisation holder may request the amendment of the
periods referred to in paragraph 6 in accordance with the procedure
laid down by Commission Regulation (EC) No 1084/2003 (1).
9. The holder of a marketing authorisation may not communicate
information relating to pharmacovigilance concerns to the general
public in relation to its authorised medicinal product without giving
prior or simultaneous notification to the competent authority.
In any case, the marketing authorisation holder shall ensure that such
information is presented objectively and is not misleading.
Member States shall take the necessary measures to ensure that a
marketing authorisation holder who fails to discharge these obligations
is subject to effective, proportionate and dissuasive penalties.
Article 105
1. The Agency, in collaboration with the Member States and the
Commission, shall set up a data-processing network to facilitate the
exchange of pharmacovigilance information regarding medicinal
products marketed in the Community in order to allow all competent
authorities to share the information at the same time.
2. Making use of the network referred to in paragraph 1, Member
States shall ensure that reports of suspected serious adverse reactions
that have taken place on their territory are promptly made available to
the Agency and the other Member States, and in any case within 15
days after their notification at the latest.
3. The Member States shall ensure that reports of suspected serious
adverse reactions that have taken place on their territory are promptly
made available to the marketing authorisation holder, and in any case
within 15 days after their notification at the latest.
Article 106
1. In order to facilitate the exchange of information on pharmacovigilance
within the Community, the Commission, after consulting the
Agency, the Member States and interested parties, shall draw up guidelines
on the collection, verification and presentation of adverse reaction
reports, including technical requirements for electronic exchange of
pharmacovigilance information in accordance with internationally
agreed formats, and shall publish a reference to an internationally
agreed medical terminology.
Acting in accordance with the guidelines, marketing authorisation
holders shall use internationally agreed medical terminology for the
reporting of adverse reactions.
These guidelines shall be published in Volume 9 of The Rules
governing Medicinal Products in the European Community and shall
take account of international harmonisation work carried out in the
field of pharmacovigilance.
2. For the interpretation of the definitions referred to in points (11)
to (16) of Article 1 and of the principles outlined in this Title, the
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marketing authorisation holder and the competent authorities shall
follow the guidelines referred to in paragraph 1.
Article 107
1. Where, as a result of the evaluation of pharmacovigilance data, a
Member State considers that a marketing authorisation should be
suspended, revoked or varied in accordance with the guidelines referred
to in Article 106(1), it shall forthwith inform the Agency, the other
Member States and the marketing authorisation holder.
2. Where urgent action to protect public health is necessary, the
Member State concerned may suspend the marketing authorisation of
a medicinal product, provided that the Agency, the Commission and
the other Member States are informed no later than the following
working day.
When the Agency is informed in accordance with paragraph 1 in relation
to suspensions and revocation, or the first subparagraph of this
paragraph, the Committee shall prepare an opinion within a time-frame
to be determined depending on the urgency of the matter. In relation to
variations, the Committee may upon request from a Member State
prepare an opinion.
Acting on the basis of this opinion, the Commission may request all
Member States in which the product is being marketed to take
temporary measures immediately.
The final measures shall be adopted in accordance with the procedure
referred to in Article 121(3).
Article 108
Any amendments which may be necessary to update provisions of Articles
101 to 107 to take account of scientific and technical progress
shall be adopted in accordance with the procedure referred to in Article
121(2).
TITLE X
SPECIAL PROVISIONS ON MEDICINAL PRODUCTS DERIVED FROM
HUMAN BLOOD AND PLASMA
Article 109
For the collection and testing of human blood and human plasma,
Directive 2002/98/EC of the European Parliament and of the Council
of 27 January 2003 setting standards of quality and safety for the
collection, testing, processing, storage and distribution of human blood
and blood components and amending Directive 2001/83/EC (1) shall
apply.
Article 110
Member States shall take the necessary measures to promote Community
self-sufficiency in human blood or human plasma. For this
purpose, they shall encourage the voluntary unpaid donation of blood
and plasma and shall take the necessary measures to develop the
production and use of products derived from human blood or human
plasma coming from voluntary unpaid donations. They shall notify the
Commission of such measures.
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TITLE XI
SUPERVISION AND SANCTIONS
Article 111
1. The competent authority of the Member State concerned shall
ensure, by means of repeated inspections, and if necessary unannounced
inspections, and, where appropriate, by asking an Official
Medicines Control Laboratory or a laboratory designated for that
purpose to carry out tests on samples, that the legal requirements
governing medicinal products are complied with.
The competent authority may also carry out unannounced inspections
at the premises of manufacturers of active substances used as starting
materials, or at the premises of marketing authorisation holders whenever
it considers that there are grounds for suspecting non-compliance
with the principles and guidelines of good manufacturing practice
referred to in Article 47. These inspections may also be carried out at
the request of a Member State, the Commission or the Agency.
In order to verify whether the data submitted in order to obtain a
conformity certificate comply with the monographs of the European
Pharmacopoeia, the standardisation body of the nomenclatures and the
quality norms within the meaning of the Convention relating to the
elaboration of the European Pharmacopoeia (1) (European Directorate
for the quality of Medicinal Products) may ask the Commission or the
Agency to request such an inspection when the starting material
concerned is the subject of a European Pharmacopoeia monograph.
The competent authority of the Member State concerned may carry out
inspections of starting material manufacturers at the specific request of
the manufacturer himself.
Such inspections shall be carried out by officials representing the
competent authority who shall be empowered to:
(a) inspect the manufacturing or commercial establishments of manufacturers
of medicinal products or of active substances used as
starting materials, and any laboratories employed by the holder of
the manufacturing authorisation to carry out checks pursuant to
Article 20;
(b) take samples including with a view to independent tests being
carried out by an Official Medicines Control Laboratory or a
laboratory designated for that purpose by a Member State;
(c) examine any documents relating to the object of the inspection,
subject to the provisions in force in the Member States on 21 May
1975 placing restrictions on these powers with regard to the
description of the manufacturing method;
(d) inspect the premises, records and documents of marketing authorisation
holders or any firms employed by the marketing
authorisation holder to perform the activities described in Title IX,
and in particular Articles 103 and 104.
2. Member States shall take all appropriate steps to ensure that the
manufacturing processes used in the manufacture of immunological
products are properly validated and attain batch-to-batch consistency.
3. After every inspection as referred to in paragraph 1, the officials
representing the competent authority shall report on whether the manufacturer
complies with the principles and guidelines of good
manufacturing practice laid down in Article 47 or, where appropriate,
with the requirements laid down in Articles 101 to 108. The content
of such reports shall be communicated to the manufacturer or
marketing authorisation holder who has undergone the inspection.
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4. Without prejudice to any arrangements which may have been
concluded between the Community and third countries, a Member
State, the Commission or the Agency may require a manufacturer
established in a third country to submit to an inspection as referred to
in paragraph 1.
5. Within 90 days of an inspection as referred to in paragraph 1, a
certificate of good manufacturing practice shall be issued to a manufacturer
if the outcome of the inspection shows that the manufacturer
complies with the principles and guidelines of good manufacturing
practice as provided for by Community legislation.
If inspections are performed as part of the certification procedure for
the monographs of the European Pharmacopoeia, a certificate shall be
drawn up.
6. Member States shall enter the certificates of good manufacturing
practice which they issue in a Community database managed by the
Agency on behalf of the Community.
7. If the outcome of the inspection as referred to in paragraph 1 is
that the manufacturer does not comply with the principles and guidelines
of good manufacturing practice as provided for by Community
legislation, the information shall be entered in the Community database
as referred to in paragraph 6.
Article 112
Member States shall take all appropriate measures to ensure that the
holder of the marketing authorization for a medicinal product and,
where appropriate, the holder of the manufacturing authorization,
furnish proof of the controls carried out on the medicinal product and/
or the ingredients and of the controls carried out at an intermediate
stage of the manufacturing process, in accordance with the methods
laid down in Article 8(3)(h).
Article 113
For the purpose of implementing Article 112, Member States may
require manufacturers of immunological products to submit to a
competent authority copies of all the control reports signed by the
qualified person in accordance with Article 51.
Article 114
1. Where it considers it necessary in the interests of public health, a
Member State may require the holder of an authorization for
marketing:
— live vaccines,
— immunological medicinal products used in the primary immunization
of infants or of other groups at risk,
— immunological medicinal products used in public health immunization
programmes,
— new immunological medicinal products or immunological medicinal
products manufactured using new or altered kinds of technology or
new for a particular manufacturer, during a transitional period
normally specified in the marketing authorization,
to submit samples from each batch of the bulk and/or the medicinal
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Laboratory or a laboratory that a Member State has designated for
that purpose ◄ before release on to the market unless, in the case of
a batch manufactured in another Member State, the competent
authority of that Member State has previously examined the batch in
question and declared it to be in conformity with the approved specifications.
Member States shall ensure that any such examination is
completed within 60 days of the receipt of the samples.
2. Where, in the interests of public health, the laws of a Member
State so provide, the competent authorities may require the marketing
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authorization holder for medicinal products derived from human blood
or human plasma to submit samples from each batch of the bulk and/or
the medicinal product for testing ►M4 by an Official Medicines
Control Laboratory or a laboratory that a Member State has designated
for that purpose ◄ before being released into free circulation, unless
the competent authorities of another Member State have previously
examined the batch in question and declared it to be in conformity
with the approved specifications. Member States shall ensure that any
such examination is completed within 60 days of the receipt of the
samples.
Article 115
Member States shall take all necessary measures to ensure that the
manufacturing and purifying processes used in the preparation of
medicinal products derived from human blood or human plasma are
properly validated, attain batch-to-batch consistency and guarantee,
insofar as the state of technology permits, the absence of specific viral
contamination. To this end manufacturers shall notify the competent
authorities of the method used to reduce or eliminate pathogenic
viruses liable to be transmitted by medicinal products derived from
human blood or human plasma. The competent authority may submit
samples of the bulk and/or the medicinal product for testing by a State
laboratory or a laboratory designated for that purpose, either during the
examination of the application pursuant to Article 19, or after a
marketing authorization has been granted.
Article 116
The competent authorities shall suspend, revoke, withdraw or vary a
marketing authorisation if the view is taken that the product is harmful
under normal conditions of use, or that it lacks therapeutic efficacy, or
that the risk-benefit balance is not positive under the normal conditions
of use, or that its qualitative and quantitative composition is not as
declared. Therapeutic efficacy is lacking when it is concluded that therapeutic
results cannot be obtained from the medicinal product.
An authorisation shall also be suspended, revoked, withdrawn or varied
where the particulars supporting the application as provided for in
Article 8 or Articles 10, 10a, 10b, 10c and 11 are incorrect or have
not been amended in accordance with Article 23, or where the controls
referred to in Article 112 have not been carried out.
Article 117
1. Without prejudice to the measures provided for in Article 116,
Member States shall take all appropriate steps to ensure that the supply
of the medicinal product is prohibited and the medicinal product withdrawn
from the market, if the view is taken that:
(a) the medicinal product is harmful under normal conditions of use; or
(b) it lacks therapeutic efficacy; or
(c) the risk-benefit balance is not favourable under the authorised
conditions of use; or
(d) its qualitative and quantitative composition is not as declared; or
(e) the controls on the medicinal product and/or on the ingredients and
the controls at an intermediate stage of the manufacturing process
have not been carried out or if some other requirement or obligation
relating to the grant of the manufacturing authorisation has
not been fulfilled.
2. The competent authority may limit the prohibition to supply the
product, or its withdrawal from the market, to those batches which are
the subject of dispute.
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Article 118
1. The competent authority shall suspend or revoke the marketing
authorization for a category of preparations or all preparations where
any one of the requirements laid down in Article 41 is no longer met.
2. In addition to the measures specified in Article 117, the competent
authority may suspend manufacture or imports of medicinal
products coming from third countries, or suspend or revoke the manufacturing
authorization for a category of preparations or all preparations
where Articles 42, 46, 51 and 112 are not complied with.
Article 119
The provisions of this Title shall apply to homeopathic medicinal
products.
TITLE XII
STANDING COMMITTEE
Article 120
Any changes which are necessary in order to adapt Annex I to take
account of scientific and technical progress shall be adopted in accordance
with the procedure referred to in Article 121(2).
Article 121
1. The Commission shall be assisted by the Standing Committee on
Medicinal Products for Human Use, hereinafter called ‘the Standing
Committee’, in the task of adapting to technical progress the directives
on the removal of technical barriers to trade in the medicinal products
sector.
2. Where reference is made to this paragraph, Articles 5 and 7 of
Decision 1999/468/EC shall apply, having regard to the provisions of
Article 8 thereof.
The period laid down in Article 5(6) of Decision 1999/468/EC shall be
set at three months.
3. Where reference is made to this paragraph, Articles 4 and 7 of
Decision 1999/468/EC shall apply, having regard to the provisions of
Article 8 thereof.
The period laid down in Article 4(3) of Decision 1999/468/EC shall be
set at one month.
4. The Standing Committee shall adopt its own rules of procedure
which shall be made public.
TITLE XIII
GENERAL PROVISIONS
Article 122
1. Member States shall take all appropriate measures to ensure that
the competent authorities concerned communicate to each other such
information as is appropriate to guarantee that the requirements placed
on the authorisations referred to in Articles 40 and 77, on the certificates
referred to in Article 111(5) or on the marketing authorisations
are fulfilled.
2. Upon reasoned request, Member States shall forthwith communicate
the reports referred to in Article 111(3) to the competent
authorities of another Member State.
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3. The conclusions reached in accordance with Article 111(1) shall
be valid throughout the Community.
However, in exceptional cases, if a Member State is unable, for reasons
relating to public health, to accept the conclusions reached following
an inspection under Article 111(1), that Member State shall forthwith
inform the Commission and the Agency. The Agency shall inform the
Member States concerned.
When the Commission is informed of these divergences of opinion, it
may, after consulting the Member States concerned, ask the inspector
who performed the original inspection to perform a new inspection;
the inspector may be accompanied by two other inspectors from
Member States which are not parties to the disagreement.
Article 123
1. Each Member State shall take all the appropriate measures to
ensure that decisions authorizing marketing, refusing or revoking a
marketing authorization, cancelling a decision refusing or revoking a
marketing authorization, prohibiting supply, or withdrawing a product
from the market, together with the reasons on which such decisions
are based, are brought to the attention of the Agency forthwith.
2. The marketing authorization holder shall be obliged to notify the
Member States concerned forthwith of any action taken by him to
suspend the marketing of a medicinal product or to withdraw a medicinal
product from the market, together with the reasons for such action
if the latter concerns the efficacy of the medicinal product or the
protection of public health. Member States shall ensure that this information
is brought to the attention of the Agency.
3. Member States shall ensure that appropriate information about
action taken pursuant to paragraphs 1 and 2 which may affect the
protection of public health in third countries is forthwith brought to
the attention of the World Health Organization, with a copy to the
Agency.
4. The Commission shall publish annually a list of the medicinal
products which are prohibited in the Community.
Article 124
Member States shall communicate to each other all the information
necessary to guarantee the quality and safety of homeopathic medicinal
products manufactured and marketed within the Community, and in
particular the information referred to in Articles 122 and 123.
Article 125
Every decision referred to in this Directive which is taken by the
competent authority of a Member State shall state in detail the reasons
on which it is based.
Such decision shall be notified to the party concerned, together with
information as to the redress available to him under the laws in force
and of the time-limit allowed for access to such redress.
Decisions to grant or revoke a marketing authorisation shall be made
publicly available.
Article 126
An authorization to market a medicinal product shall not be refused,
suspended or revoked except on the grounds set out in this Directive.
No decision concerning suspension of manufacture or of importation of
medicinal products coming from third countries, prohibition of supply
or withdrawal from the market of a medicinal product may be taken
except on the grounds set out in Articles 117 and 118.
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Article 126a
1. In the absence of a marketing authorisation or of a pending application
for a medicinal product authorised in another Member State in
accordance with this Directive, a Member State may for justified public
health reasons authorise the placing on the market of the said medicinal
product.
2. When a Member State avails itself of this possibility, it shall
adopt the necessary measures in order to ensure that the requirements
of this Directive are complied with, in particular those referred to in
Titles V, VI, VIII, IX and XI.
3. Before granting such an authorisation a Member State shall:
(a) notify the marketing authorisation holder, in the Member State in
which the medicinal product concerned is authorised, of the
proposal to grant an authorisation under this Article in respect of
the product concerned; and
(b) request the competent authority in that State to furnish a copy of
the assessment report referred to in Article 21(4) and of the
marketing authorisation in force in respect of the said medicinal
product.
4. The Commission shall set up a publicly accessible register of
medicinal products authorised under paragraph 1. Member States shall
notify the Commission if any medicinal product is authorised, or ceases
to be authorised, under paragraph 1, including the name or corporate
name and permanent address of the authorisation holder. The Commission
shall amend the register of medicinal products accordingly and
make this register available on their website.
5. No later than 30 April 2008, the Commission shall present a
report to the European Parliament and the Council concerning the
application of this provision with a view to proposing any necessary
amendments.
Article 126b
In order to guarantee independence and transparency, the Member
States shall ensure that members of staff of the competent authority
responsible for granting authorisations, rapporteurs and experts
concerned with the authorisation and surveillance of medicinal products
have no financial or other interests in the pharmaceutical industry
which could affect their impartiality. These persons shall make an
annual declaration of their financial interests.
In addition, the Member States shall ensure that the competent
authority makes publicly accessible its rules of procedure and those of
its committees, agendas for its meetings and records of its meetings,
accompanied by decisions taken, details of votes and explanations of
votes, including minority opinions.
Article 127
1. At the request of the manufacturer, the exporter or the authorities
of an importing third country, Member States shall certify that a manufacturer
of medicinal products is in possession of the manufacturing
authorization. When issuing such certificates Member States shall
comply with the following conditions:
(a) they shall have regard to the prevailing administrative arrangements
of the World Health Organization;
(b) for medicinal products intended for export which are already
authorized on their territory, they shall supply the summary of the
product characteristics as approved in accordance with Article 21.
2. When the manufacturer is not in possession of a marketing
authorization he shall provide the authorities responsible for establishing
the certificate referred to in paragraph 1, with a declaration
explaining why no marketing authorization is available.
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Article 127a
When a medicinal product is to be authorised in accordance with Regulation
(EC) No 726/2004 and the Scientific Committee in its opinion
refers to recommended conditions or restrictions with regard to the
safe and effective use of the medicinal product as provided for in
Article 9(4)(c) of that Regulation, a decision addressed to the Member
States shall be adopted in accordance with the procedure provided for
in Articles 33 and 34 of this Directive, for the implementation of those
conditions or restrictions.
Article 127b
Member States shall ensure that appropriate collection systems are in
place for medicinal products that are unused or have expired.
TITLE XIV
FINAL PROVISIONS
Article 128
Directives 65/65/EEC, 75/318/EEC, 75/319/EEC, 89/342/EEC, 89/343/
EEC, 89/381/EEC, 92/25/EEC, 92/26/EEC, 92/27/EEC, 92/28/EEC and
92/73/EEC, amended by the Directives referred to in Annex II, Part A,
are repealed, without prejudice to the obligations of the Member States
concerning the time-limits for implementation set out in Annex II, Part
B.
References to the repealed Directives shall be construed as references
to this Directive and shall be read in accordance with the correlation
table in Annex III.
Article 129
This Directive shall enter into force on the twentieth day following that
of its publication in the Official Journal of the European Communities.
Article 130
This Directive is addressed to the Member States.
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ANNEX I
ANALYTICAL, PHARMACOTOXICOLOGICAL AND CLINICAL STANDARDS AND
PROTOCOLS IN RESPECT OF THE TESTING OF MEDICINAL PRODUCTS
TABLE OF CONTENTS
Introduction and general principles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Part I: Standardised marketing authorisation dossier requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Module 1: Administrative information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Table of contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2. Application form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3. Summary of product characteristics, labelling and package leaflet . . . . . . . . . . . . . . . . .
1.3.1. Summary of product characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.2. Labelling and package leaflet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.3. Mock-ups and specimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.3.4. Summaries of product characteristics already approved in the Member States . . . . . . . .
1.4. Information about the experts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.5. Specific requirements for different types of applications . . . . . . . . . . . . . . . . . . . . . . . . .
1.6. Environmental risk assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Module 2: Summaries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Overall table of contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. Quality overall summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4. Non-clinical overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5. Clinical overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6. Non-clinical summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7. Clinical Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Module 3: Chemical, pharmaceutical and biological information for medicinal products
containing chemical and/or biological active substances . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Format and presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Content: basic principles and requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1. Active substance(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.1. General information and information related to the starting and raw materials . . . . . . .
3.2.1.2. Manufacturing process of the active substance(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.3. Characterisation of the active substance(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.4. Control of active substance(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.5. Reference standards or materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.6. Container and closure system of the active substance . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.1.7. Stability of the active substance(s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2. Finished medicinal product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.1. Description and composition of the finished medicinal product . . . . . . . . . . . . . . . . . . . .
3.2.2.2. Pharmaceutical development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.3. Manufacturing process of the finished medicinal product . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.4. Control of excipients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.5. Control of the finished medicinal product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.6. Reference standards or materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.7. Container and closure of the finished medicinal product . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2.8. Stability of the finished medicinal product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Module 4: Non-clinical reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1. Format and Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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4.2. Content: basic principles and requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.2. Pharmaco-kinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.3. Toxicology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Module 5: Clinical study reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1. Format and Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2. Content: basic principles and requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.1. Reports of bio-pharmaceutics studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.2. Reports of studies pertinent to pharmaco-kinetics using human bio-materials . . . . . . . .
5.2.3. Reports of human pharmaco-kinetic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.4. Reports of human pharmaco-dynamic studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.5. Reports of efficacy and safety studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.5.1. Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication . . . . .
5.2.5.2. Study reports of uncontrolled clinical studies reports of analyses of data from more than
one study and other clinical study reports . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.6. Reports of post-marketing experience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.7. Case reports forms and individual patient listings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Part II: Specific marketing authorisation dossiers and requirements . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Well-established medicinal use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Essentially similar medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3. Additional data required in specific situations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Similar biological medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Fixed combination medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6. Documentation for applications in exceptional circumstances . . . . . . . . . . . . . . . . . . . . .
7. Mixed marketing authorisation applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Part III: Particular medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Biological medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.1. Plasma-derived medicinal product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2. Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Radio-pharmaceuticals and precursors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. Radio-pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. Radio-pharmaceutical precursors for radio-labelling purposes . . . . . . . . . . . . . . . . . . . . .
3. Homeopathic medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Herbal medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5. Orphan Medicinal Products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Part IV: Advanced therapy medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Gene therapy medicinal products (human and xenogeneic) . . . . . . . . . . . . . . . . . . . . . . .
1.1. Diversity of gene therapy medicinal products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1.2. Specific requirements regarding Module 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Somatic cell therapy medicinal products (human and xenogeneic) . . . . . . . . . . . . . . . . .
3. Specific requirements for gene therapy and somatic cell therapy (human and xenogeneic)
medicinal products regarding Modules 4 and 5 . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1. Module 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2. Module 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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3.2.1. Human pharmacology and efficacy studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.2. Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Specific Statement on Xeno-transplantation Medicinal Products . . . . . . . . . . . . . . . . . . .
2001L0083 — EN — 30.04.2004 — 003.001 — 67
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Introduction and general principles
(1) The particulars and documents accompanying an application for
marketing authorisation pursuant to Articles 8 and 10 (1) shall be
presented in accordance with the requirements set out in this Annex
and shall follow the guidance published by the Commission in The
rules governing medicinal products in the European Community,
Volume 2 B, Notice to applicants, Medicinal products for human use,
Presentation and content of the dossier, Common Technical Document
(CTD).
(2) The particulars and documents shall be presented as five modules:
Module 1 provides European Community specific administrative data;
Module 2 provides quality, non-clinical and clinical summaries,
Module 3 provides chemical, pharmaceutical and biological information,
Module 4 provides non-clinical reports and Module 5 provides
clinical study reports. This presentation implements a common format
for all ICH (1) regions (European Community, United States of
America, Japan). These five Modules shall be presented in strict accordance
with the format, content and numbering system delineated in
details in Volume 2 B of the Notice to Applicants referred to above.
(3) The European Community-CTD-presentation is applicable for all types
of marketing authorisation applications irrespective of the procedure to
be applied (i.e. centralised, mutual recognition or national) and of
whether they are based on a full or abridged application. It is also
applicable for all types of products including new chemical entities
(NCE), radio-pharmaceuticals, plasma derivatives, vaccines, herbal
medicinal products, etc.
(4) In assembling the dossier for application for marketing authorisation,
applicants shall also take into account the scientific guidelines relating
to the quality, safety and efficacy of medicinal products for human use
as adopted by the Committee for Proprietary Medicinal Products
(CPMP) and published by the European Medicine Evaluation Agency
(EMEA) and the other pharmaceutical Community guidelines published
by the Commission in the different volumes of The rules governing
medicinal products in the European Community.
(5) With respect to the quality part (chemical, pharmaceutical and biological)
of the dossier, all monographs including general monographs
and general chapters of the European Pharmacopoeia are applicable.
(6) The manufacturing process shall comply with the requirements of
Commission Directive 91/356/EEC laying down the principles and
guidelines of Good Manufacturing Practice (GMP) for medicinal
products for human use (2) and with the principles and guidelines on
GMP, published by the Commission in The rules governing medicinal
products in the European Community, Volume 4.
(7) All information, which is relevant to the evaluation of the medicinal
product concerned, shall be included in the application, whether favourable
or unfavourable to the product. In particular, all relevant details
shall be given of any incomplete or abandoned pharmaco-toxicological
or clinical test or trial relating to the medicinal product and/or
completed trials concerning therapeutic indications not covered by the
application.
(8) All clinical trials, conducted within the European Community, must
comply with the requirements of Directive 2001/20/EC of the European
Parliament and of the Council on the approximation of the laws, regulations
and administrative provisions of the Member States relating to the
implementation of good clinical practice in the conduct of clinical trials
on medicinal products for human use (3). To be taken into account
during the assessment of an application, clinical trials, conducted
outside the European Community, which relate to medicinal products
intended to be used in the European Community, shall be designed,
implemented and reported on what good clinical practice and ethical
principles are concerned, on the basis of principles, which are equivalent
to the provisions of Directive 2001/20/EC. They shall be carried
out in accordance with the ethical principles that are reflected, for
example, in the Declaration of Helsinki.
2001L0083 — EN — 30.04.2004 — 003.001 — 68
(1) International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use.
(2) OJ L 193, 17.7.1991, p. 30.
(3) OJ L 121, 1.5.2001, p. 34.
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(9) Non-clinical (pharmaco-toxicological) studies shall be carried out in
conformity with the provisions related to Good Laboratory Practice
laid down in Council Directives 87/18/EEC on the harmonisation of
regulations and administrative provisions relating to the application of
the principles of good laboratory practice and the verification of their
application for tests in chemical substances (1) and 88/320/EEC on the
inspection and verification of good laboratory practice (GLP) (2).
(10) Member States shall also ensure that all tests on animals are conducted
in accordance with Council Directive 86/609/EEC of 24 November
1986 on the approximation of laws, regulation and administrative provisions
of the Member States regarding the protection of animals for
experimental and other scientific purposes.
(11) In order to monitor the benefit/risk assessment, any new information
not in the original application and all pharmaco-vigilance information
shall be submitted to the competent authority. After marketing authorisation
has been granted, any change to the data in the dossier shall be
submitted to the competent authorities in accordance with the requirements
of Commission Regulations (EC) No 1084/2003 (3) and (EC) No
1085/2003 (4) of the Commission or, if relevant, in accordance with
national provisions, as well as the requirements in Volume 9 of
Commission publication The rules governing medicinal products in the
European Community.
This Annex is divided in four different parts:
— Part I describes the application format, the summary of product
characteristics, the labelling, the leaflet and presentation requirements
for standard applications (Modules 1 to 5).
— Part II provides derogation for ‘Specific applications’, i.e. wellestablished
medicinal use, essentially similar products, fixed combinations,
similar biological products, exceptional circumstances and
mixed applications (part bibliographic and part own studies).
— Part III deals with ‘Particular application requirements’ for biological
medicinal products (Plasma Master File; Vaccine Antigen
Master File), radio-pharmaceuticals, homeopathic medicinal
products, herbal medicinal products and orphan medicinal products.
— Part IV deals with ‘Advanced therapy medicinal products’ and
concerns specific requirements for gene therapy medicinal products
(using human autologous or allogeneic system, or xenogeneic
system) and cell therapy medicinal products both of human or
animal origin and xenogeneic transplantation medicinal products.
PART I
STANDARDISED MARKETING AUTHORISATION DOSSIER
REQUIREMENTS
1. MODULE 1: ADMINISTRATIVE INFORMATION
1.1. Table of contents
A comprehensive table of contents of Modules 1 to 5 of the dossier
submitted for marketing authorisation application shall be presented.
1.2. Application form
The medicinal product, which is the subject of the application, shall be
identified by name and name of the active substance(s), together with
the pharmaceutical form, the route of administration, the strength and
the final presentation, including packaging.
The name and address of the applicant shall be given, together with the
name and address of the manufacturers and the sites involved in the
different stages of the manufacture (including the manufacturer of the
finished product and the manufacturer(s) of the active substance(s)),
and where relevant the name and address of the importer.
The applicant shall identify the type of application and indicate what
samples, if any, are also provided.
2001L0083 — EN — 30.04.2004 — 003.001 — 69
(1) OJ L 15, 17.1.1987, p. 29.
(2) OJ L 145, 11.6.1988, p. 35.
(3) See p. 1 of this Official Journal.
(4) See p. 24 of this Official Journal.
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Annexed to the administrative data shall be copies of the manufacturing
authorisation as defined in Article 40, together with a list of countries
in which authorisation has been granted, copies of all the summaries of
product characteristics in accordance with Article 11 as approved by
Member States and a list of countries in which an application has been
submitted.
As outlined in the application form, the applicants shall provide, inter
alia, details of the medicinal product subject of the application, the
legal basis of the application, the proposed marketing authorisation
holder and manufacture(s), information on orphan medicinal product
status, scientific advice and paediatric development program.
1.3. Summary of product characteristics, labelling and package leaflet
1.3.1. Summary of product characteristics
The applicant shall propose a summary of the product characteristics, in
accordance with Article 11.
1.3.2. Labelling and package leaflet
A proposed labelling text for immediate and outer packaging as well as
for the package leaflet shall be provided. These shall be in accordance
with all mandatory items listed in Title V on the labelling of medicinal
products for human use (Article 63) and on package leaflet (Article 59).
1.3.3. Mock-ups and specimens
The applicant shall provide specimen and/or mock-ups of the
immediate and outer packaging, labels and package leaflets for the
medicinal product concerned.
1.3.4. Summaries of product characteristics already approved in the Member
States
Annexed to the administrative data of the application form shall be
copies of all the summaries of product characteristics in accordance
with Articles 11 and 21 as approved by Member States, where applicable
and a list of countries in which an application has been submitted.
1.4. Information about the experts
In accordance with Article 12 (2) experts must provide detailed reports
of their observations on the documents and particulars which constitute
the marketing authorisation dossier and in particular on Modules 3, 4
and 5 (chemical, pharmaceutical and biological documentation, nonclinical
documentation and clinical documentation, respectively). The
experts are required to address the critical points related to the quality
of the medicinal product and of the investigations carried out on
animals and human beings and bring out all the data relevant for
evaluation.
These requirements shall be met by providing a quality overall
summary, a non-clinical overview (data from studies carried out in
animals) and a clinical overview that shall be located in Module 2 of
the marketing authorisation application dossier. A declaration signed
by the experts together with brief information on their educational
background, training and occupational experience shall be presented in
Module 1. The experts shall have suitable technical or professional
qualifications. The professional relationship of the expert to the applicant
shall be declared.
1.5. Specific requirements for different types of applications
Specific requirements for different types of applications are addressed
in Part II of the present Annex.
1.6. Environmental risk assessment
Where applicable, applications for marketing authorisations shall
include a risk assessment overview evaluating possible risks to the
environment due to the use and/or disposal of the medicinal product
and make proposals for appropriate labelling provisions. Environmental
risk connected with the release of medicinal products containing or
consisting of GMOs (Genetically Modified Organisms) within the
meaning of Article 2 of Directive 2001/18/EC of the European
2001L0083 — EN — 30.04.2004 — 003.001 — 70
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Parliament and of the Council of 12 March 2001 on the deliberate
release into the environment of modified organisms and repealing
Council Directive 90/220/EEC (1) shall be addressed.
Information pertaining to the environmental risk shall appear as an
appendix to Module 1.
The information shall be presented in accordance with the provisions of
Directive 2001/18/EC, taking into account any guidance documents
published by the Commission in connection with the implementation
of the said Directive.
The information shall consist of:
— an introduction;
— a copy of any written consent or consents to the deliberate release
into the environment of the GMO(s) for research and development
purposes according to Part B of Directive 2001/18/EC;
— the information requested in Annexes II to IV of the Directive 2001/
18/EC, including detection and identification methods as well as
unique code of the GMO, plus any additional information on the
GMO or the product of relevance to evaluating the environmental
risk;
— an environment risk assessment (ERA) report prepared on basis of
the information specified in Annexes III and IV of Directive 2001/
18/EC and in accordance with Annex II of Directive 2001/18/EC;
— taking into account the above information and the ERA, a conclusion
which proposes an appropriate risk management strategy
which includes, as relevant to the GMO and product in question, a
post-market monitoring plan and the identification of any special
particulars which need to appear in the Summary of Product Characteristics,
labelling and package leaflet;
— appropriate measures in order to inform the public.
A dated signature of the author, information on the author's educational,
training and occupational experience, and a statement of the author's
relationship with the applicant, shall be included.
2. MODULE 2: SUMMARIES
This Module aims to summarise the chemical, pharmaceutical and
biological data, the non-clinical data and the clinical data presented in
Modules 3, 4 and 5 of the dossier for marketing authorisation, and to
provide the reports/overviews described in Article 12 of this Directive.
Critical points shall be addressed and analysed. Factual summaries
including tabular formats shall be provided. Those reports shall provide
cross-references to tabular formats or to the information contained in
the main documentation presented in Module 3 (chemical, pharmaceutical
and biological documentation), Module 4 (non-clinical
documentation) and Module 5 (clinical documentation).
Information contained in Module 2 shall be presented in accordance
with the format, content and numbering system delineated in the
Volume 2 of the Notice to Applicants. The overviews and summaries
shall comply with the basic principles and requirements as laid down
herewith:
2.1. Overall table of contents
Module 2 shall contain a table of contents for the scientific documentation
submitted in Modules 2 to 5.
2.2. Introduction
Information on the pharmacological class, mode of action and proposed
clinical use of the medicinal product for which a marketing authorisation
is requested shall be supplied.
2.3. Quality overall summary
A review of the information related to the chemical, pharmaceutical and
biological data shall be provided in a quality overall summary.
2001L0083 — EN — 30.04.2004 — 003.001 — 71
(1) OJ L 106, 17.4.2001, p. 1.
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Key critical parameters and issues related to quality aspects shall be
emphasised as well as justification in cases where the relevant guidelines
are not followed. This document shall follow the scope and
outline of the corresponding detailed data presented in Module 3.
2.4. Non-clinical overview
An integrated and critical assessment of the non-clinical evaluation of
the medicinal product in animals/in vitro shall be required. Discussion
and justification of the testing strategy and of deviation from the relevant
guidelines shall be included.
Except for biological medicinal products, an assessment of the impurities
and degradation products shall be included along with their
potential pharmacological and toxicological effects. The implications
of any differences in the chirality, chemical form, and impurity profile
between the compound used in the non-clinical studies and the product
to be marketed shall be discussed.
For biological medicinal products, comparability of material used in
non-clinical studies, clinical studies, and the medicinal product for
marketing shall be assessed.
Any novel excipient shall be the subject of a specific safety assessment.
The characteristics of the medicinal product, as demonstrated by the
non-clinical studies shall be defined and the implications of the findings
for the safety of the medicinal product for the intended clinical use in
human shall be discussed.
2.5. Clinical overview
The clinical overview is intended to provide a critical analysis of the
clinical data included in the clinical summary and Module 5. The
approach to the clinical development of the medicinal product,
including critical study design, decisions related to and performance of
the studies shall be provided.
A brief overview of the clinical findings, including important limitations
as well as an evaluation of benefits and risks based on the
conclusions of the clinical studies shall be provided. An interpretation
of the way the efficacy and safety findings support the proposed dose
and target indications and an evaluation of how the summary of product
characteristics and other approaches will optimise the benefits and
manage the risks is required.
Efficacy or safety issues encountered in development and unresolved
issues shall be explained.
2.6. Non-clinical summary
The results of pharmacology, pharmaco-kinetics and toxicology studies
carried out in animals/in vitro shall be provided as factual written and
tabulated summaries which shall be presented in the following order:
— Introduction
— Pharmacology Written Summary
— Pharmacology Tabulated Summary
— Pharmaco-kinetics Written Summary
— Pharmaco-kinetics Tabulated Summary
— Toxicology Written Summary
— Toxicology Tabulated Summary.
2.7. Clinical Summary
A detailed, factual summary of the clinical information on the medicinal
product included in Module 5 shall be provided. This shall
include the results of all bio-pharmaceutics studies, of clinical pharmacology
studies, and of clinical efficacy and safety studies. A synopsis of
the individual studies is required.
Summarised clinical information shall be presented in the following
order:
— Summary of Bio-pharmaceutics and Associated Analytical Methods
— Summary of Clinical Pharmacology Studies
— Summary of Clinical Efficacy
— Summary of Clinical Safety
2001L0083 — EN — 30.04.2004 — 003.001 — 72
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— Synopses of Individual Studies
3. MODULE 3: CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL
INFORMATION FOR MEDICINAL PRODUCTS CONTAINING
CHEMICAL AND/OR BIOLOGICAL ACTIVE SUBSTANCES
3.1. Format and presentation
The general outline of Module 3 is as follows:
— Table of contents
— Body of data
— Active substance
General Information
— Nomenclature
— Structure
— General Properties
Manufacture
— Manufacturer(s)
— Description of Manufacturing Process and Process Controls
— Control of Materials
— Controls of Critical Steps and Intermediates
— Process Validation and/or Evaluation
— Manufacturing Process Development
Characterisation
— Elucidation of Structure and other Characteristics
— Impurities
Control of Active Substance
— Specification
— Analytical Procedures
— Validation of Analytical Procedures
— Batch Analyses
— Justification of Specification
Reference Standards or Materials
Container Closure System
Stabil i ty
— Stability Summary and Conclusions
— Post-approval Stability Protocol and Stability Commitment
— Stability Data
— Finished Medicinal Product
Description and Composition of the Medicinal
Product
Pharmaceutical Development
— Components of the Medicinal Product
— Active Substance
— Excipients
— Medicinal Product
— Formulation Development
— Overages
— Physicochemical and Biological Properties
— Manufacturing Process Development
— Container Closure System
— Microbiological Attributes
— Compatibility
Manufacture
— Manufacturer(s)
— Batch Formula
— Description of Manufacturing Process and Process Controls
— Controls of Critical Steps and Intermediates
— Process Validation and/or Evaluation
2001L0083 — EN — 30.04.2004 — 003.001 — 73
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Control of Excipients
— Specifications
— Analytical Procedures
— Validation of Analytical Procedures
— Justification of Specifications
— Excipients of Human or Animal Origin
— Novel Excipients
Control of Finished Medicinal Product
— Specification(s)
— Analytical Procedures
— Validation of Analytical Procedures
— Batch Analyses
— Characterisation of Impurities
— Justification of Specification(s)
Reference Standards or Materials
Container Closure System
Stabil i ty
— Stability Summary and Conclusion
— Post-approval Stability Protocol and Stability Commitment
— Stability Data
— Appendices
— Facilities and Equipment (Biological Medicinal Products
only)
— Adventitious Agents Safety Evaluation
— Excipients
— European Community Additional Information
— Process Validation Scheme for the Medicinal Product
— Medical Device
— Certificate(s) of Suitability
— Medicinal products containing or using in the manufacturing
process materials of animal and/or human origin (TSE
procedure)
— Literature References
3.2. Content: basic principles and requirements
(1) The chemical, pharmaceutical and biological data that shall be
provided shall include for the active substance(s) and for the
finished medicinal product all of relevant information on: the
development, the manufacturing process, the characterisation and
properties, the quality control operations and requirements, the
stability as well as a description of the composition and presentation
of the finished medicinal product.
(2) Two main sets of information shall be provided, dealing with the
active substance(s) and with the finished medicinal product,
respectively.
(3) This Module shall in addition supply detailed information on the
starting and raw materials used during the manufacturing operations
of the active substance(s) and on the excipients incorporated
in the formulation of the finished medicinal product.
(4) All the procedures and methods used for manufacturing and
controlling the active substance and the finished medicinal product
shall be described in sufficient details to enable them to be
repeated in control tests, carried out at the request of the competent
authority. All test procedures shall correspond to the state of
scientific progress at the time and shall be validated. Results of
the validation studies shall be provided. In the case of test procedures
included in the European Pharmacopoeia, this description
shall be replaced by the appropriate detailed reference to the
monograph(s) and general chapter(s).
(5) The monographs of the European Pharmacopoeia shall be applicable
to all substances, preparations and pharmaceutical forms
appearing in it. In respect of other substances, each Member State
may require observance of its own national pharmacopoeia.
However, where a material in the European Pharmacopoeia or in
the pharmacopoeia of a Member State has been prepared by a
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method liable to leave impurities not controlled in the pharmacopoeia
monograph, these impurities and their maximum tolerance
limits must be declared and a suitable test procedure must be
described. In cases where a specification contained in a monograph
of the European Pharmacopoeia or in the national
pharmacopoeia of a Member State might be insufficient to ensure
the quality of the substance, the competent authorities may request
more appropriate specifications from the marketing authorisation
holder. The competent authorities shall inform the authorities
responsible for the pharmacopoeia in question. The marketing
authorisation holder shall provide the authorities of that pharmacopoeia
with the details of the alleged insufficiency and the
additional specifications applied.
In the case of analytical procedures included in the European
Pharmacopoeia, this description shall be replaced in each relevant
section by the appropriate detailed reference to the monograph(s)
and general chapter(s).
(6) In case where starting and raw materials, active substance(s) or
excipient(s) are described neither in the European Pharmacopoeia
nor in the pharmacopoeia of a Member State, compliance with the
monograph of a third country pharmacopoeia can be accepted. In
such cases, the applicant shall submit a copy of the monograph
accompanied by the validation of the analytical procedures
contained in the monograph and by a translation where appropriate.
(7) Where the active substance and/or a raw and starting material or
excipient(s) are the subject of a monograph of the European Pharmacopoeia,
the applicant can apply for a certificate of suitability
that, where granted by the European Directorate for the Quality
of Medicines, shall be presented in the relevant section of this
Module. Those certificates of suitability of the monograph of the
European Pharmacopoeia are deemed to replace the relevant data
of the corresponding sections described in this Module. The manufacturer
shall give the assurance in writing to the applicant that the
manufacturing process has not been modified since the granting of
the certificate of suitability by the European Directorate for the
Quality of Medicines.
(8) For a well-defined active substance, the active substance manufacturer
or the applicant may arrange for the
(i) detailed description of the manufacturing process,
(ii) quality control during manufacture, and
(iii) process validation
to be supplied in a separate document directly to the competent
authorities by the manufacturer of the active substance as an
Active Substance Master File.
In this case, the manufacturer shall, however, provide the applicant
with all of the data, which may be necessary for the latter to
take responsibility for the medicinal product. The manufacturer
shall confirm in writing to the applicant that he shall ensure batch
to batch consistency and not modify the manufacturing process or
specifications without informing the applicant. Documents and
particulars supporting the application for such a change shall be
supplied to the competent authorities; these documents and particulars
will be also supplied to the applicant when they concern
the open part of the active substance master file.
(9) Specific measures concerning the prevention of the transmission
of animal spongiform encephalopathies (materials from ruminant
origin): at each step of the manufacturing process, the applicant
must demonstrate the compliance of the materials used with the
Note for Guidance on Minimising the Risk of Transmitting
Animal Spongiform Encephalopathy Agents via Medicinal
Products and its updates, published by the Commission in the
Official Journal of the European Union. Demonstration of compliance
with the said Note for Guidance can be done by submitting
either, preferably a certificate of suitability to the relevant monograph
of the European Pharmacopoeia that has been granted by
the European Directorate for the Quality of Medicines or by the
supply of scientific data to substantiate this compliance.
(10) For adventitious agents, information assessing the risk with respect
to potential contamination with adventitious agents, whether they
are non-viral or viral, as laid down in relevant guidelines as well
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as in relevant general monograph and general chapter of the
European Pharmacopoeia, shall be provided.
(11) Any special apparatus and equipment, which may be used at any
stage of the manufacturing process and control operations of the
medicinal product, shall be described in adequate details.
(12) Where applicable and if needed, a CE marking which is required
by Community legislation on medical devices shall be provided.
Special attention shall be paid to the following selected elements.
3.2.1. Active substance(s)
3.2.1.1. General informat ion and informat ion related to the star t ing
and raw materials
a) Information on the nomenclature of the active substance shall be
provided, including recommended International Non-proprietary
Name (INN), European Pharmacopoeia name if relevant, chemical
name(s).
The structural formula, including relative and absolute stereo-chemistry,
the molecular formula, and the relative molecular mass shall
be provided. For biotechnological medicinal products if appropriate,
the schematic amino acid sequence and relative molecular mass
shall be provided.
A list shall be provided of physicochemical and other relevant properties
of the active substance, including biological activity for
biological medicinal products.
b) For the purposes of this Annex, starting materials shall mean all the
materials from which the active substance is manufactured or
extracted.
For biological medicinal products, starting materials shall mean any
substance of biological origin such as micro-organisms, organs and
tissues of either plant or animal origin, cells or fluids (including
blood or plasma) of human or animal origin, and biotechnological
cell constructs (cell substrates, whether they are recombinant or
not, including primary cells).
A biological medicinal product is a product, the active substance of
which is a biological substance. A biological substance is a
substance that is produced by or extracted from a biological source
and that needs for its characterisation and the determination of its
quality a combination of physico-chemical-biological testing,
together with the production process and its control. The following
shall be considered as biological medicinal products: immunological
medicinal products and medicinal products derived from human
blood and human plasma as defined, respectively in paragraphs (4)
and (10) of Article 1; medicinal products falling within the scope of
Part A of the Annex to Regulation (EEC) No 2309/93; advanced
therapy medicinal products as defined in Part IV of this Annex.
Any other substances used for manufacturing or extracting the active
substance(s) but from which this active substance is not directly
derived, such as reagents, culture media, foetal calf serum, additives,
and buffers involved in chromatography, etc. are known as raw
materials.
3.2.1.2. Manufactur ing process of the act ive substance( s)
a) The description of the active substance manufacturing process represents
the applicant's commitment for the manufacture of the active
substance. To adequately describe the manufacturing process and
process controls, appropriate information as laid down in guidelines
published by the Agency shall be provided.
b) All materials needed in order to manufacture the active substance(s)
shall be listed, identifying where each material is used in the
process. Information on the quality and control of these materials
shall be provided. Information demonstrating that materials meet
standards appropriate for their intended use shall be provided.
Raw materials shall be listed and their quality and controls shall also
be documented.
The name, address, and responsibility of each manufacturer,
including contractors, and each proposed production site or facility
involved in manufacturing and testing shall be provided.
c) For biological medicinal products, the following additional requirements
shall apply.
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The origin and history of starting materials shall be described and
documented.
Regarding the specific measures for the prevention of the Transmission
of animal Spongiform Encephalopathies, the applicant must
demonstrate that the active substance complies with the Note for
Guidance on Minimising the Risk of Transmitting Animal Spongiform
Encephalopathy Agents via Medicinal Products and its
updates, published by the Commission in the Official Journal of the
European Union.
When cell banks are used, the cell characteristics shall be shown to
have remained unchanged at the passage level used for the production
and beyond.
Seed materials, cell banks, pools of serum or plasma and other materials
of biological origin and, whenever possible, the materials from
which they are derived shall be tested for adventitious agents.
If the presence of potentially pathogenic adventitious agents is inevitable,
the corresponding material shall be used only when further
processing ensures their elimination and/or inactivation, and this
shall be validated.
Whenever possible, vaccine production shall be based on a seed lot
system and on established cell banks. For bacterial and viral
vaccines, the characteristics of the infectious agent shall be demonstrated
on the seed. In addition, for live vaccines, the stability of the
attenuation characteristics shall be demonstrated on the seed; if this
proof is not sufficient, the attenuation characteristics shall also be
demonstrated at the production stage.
For medicinal products derived from human blood or plasma, the
origin and the criteria and procedures for collection, transportation
and storage of the starting material shall be described and documented
in accordance with provisions laid down in Part III of this
Annex.
The manufacturing facilities and equipment shall be described.
d) Tests and acceptance criteria carried out at every critical step, information
on the quality and control of intermediates and process
validation and/or evaluation studies shall be provided as appropriate.
e) If the presence of potentially pathogenic adventitious agents is inevitable,
the correspondent material shall be used only when further
processing ensures their elimination and/or inactivation and this
shall be validated in the section dealing with viral safety evaluation.
f) A description and discussion of the significant changes made to the
manufacturing process during development and/or manufacturing
site of the active substance shall be provided.
3.2.1.3. Character i sat ion of the act ive substance( s)
Data highlighting the structure and other characteristics of the active
substance(s) shall be provided.
Confirmation of the structure of the active substance(s) based on any
physico-chemical and/or immuno-chemical and/or biological methods,
as well as information on impurities shall be provided.
3.2.1.4. Cont rol of act ive substance( s)
Detailed information on the specifications used for routine control of
active substance(s), justification for the choice of these specifications,
methods of analysis and their validation shall be provided.
The results of control carried out on individual batches manufactured
during development shall be presented.
3.2.1.5. Reference standards or mater ial s
Reference preparations and standards shall be identified and described
in detail. Where relevant, chemical and biological reference material
of the European Pharmacopoeia shall be used.
3.2.1.6. Container and closure system of the act ive substance
A description of the container and the closure system(s) and their specifications
shall be provided.
3.2.1.7. Stabi l i ty of the act ive substance ( s)
a) The types of studies conducted, protocols used, and the results of the
studies shall be summarised
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b) Detailed results of the stability studies, including information on the
analytical procedures used to generate the data and validation of
these procedures shall be presented in an appropriate format
c) The post authorisation stability protocol and stability commitment
shall be provided
3.2.2. Finished medicinal product
3.2.2.1. Descr ipt ion and composi t ion of the f ini shed medicinal
product
A description of the finished medicinal product and its composition
shall be provided. The information shall include the description of the
pharmaceutical form and composition with all the constituents of the
finished medicinal product, their amount on a per-unit basis, the function
of the constituents of:
— the active substance(s),
— the constituent(s) of the excipients, whatever their nature or the
quantity used, including colouring matter, preservatives, adjuvants,
stabilisers, thickeners, emulsifiers, flavouring and aromatic
substances, etc.,
— the constituents, intended to be ingested or otherwise administered
to the patient, of the outer covering of the medicinal products
(hard capsules, soft capsules, rectal capsules, coated tablets, filmscoated
tablets, etc.),
— these particulars shall be supplemented by any relevant data
concerning the type of container and, where appropriate, its manner
of closure, together with details of devices with which the medicinal
product will be used or administered and which will be delivered
with the medicinal product.
The ‘usual terminology’, to be used in describing the constituents of
medicinal products, shall mean, notwithstanding the application of the
other provisions in Article 8 (3) (c):
— in respect of substances which appear in the European Pharmacopoeia
or, failing this, in the national pharmacopoeia of one of the
Member States, the main title at the head of the monograph in question,
with reference to the pharmacopoeia concerned,
— in respect of other substances, the international non-proprietary
name (INN) recommended by the World Health Organisation, or,
failing this, the exact scientific designation; substances not having
an international non-proprietary name or an exact scientific designation
shall be described by a statement of how and from what they
were prepared, supplemented, where appropriate, by any other relevant
details,
— in respect of colouring matter, designation by the ‘E’ code assigned
to them in Council Directive 78/25/EEC of 12 December 1977 on
the approximation of the rules of the Member States concerning
the colouring matters authorised for use in medicinal products (1)
and/or European Parliament and Council Directive 94/36/EC of
30 June 1994 on colours for use in foodstuffs (2).
In order to give the ‘quantitative composition’ of the active substance(s)
of the finished medicinal products, it is necessary, depending on the
pharmaceutical form concerned, to specify the mass, or the number of
units of biological activity, either per dosage-unit or per unit of mass or
volume, of each active substance.
Active substances present in the form of compounds or derivatives shall
be designated quantitatively by their total mass, and if necessary or
relevant, by the mass of active entity or entities of the molecule.
For medicinal products containing an active substance, which is the
subject of an application for marketing authorisation in any Member
State for the first time, the quantitative statement of an active
substance, which is a salt or hydrate shall be systematically expressed
in terms of the mass of the active entity or entities in the molecule.
All subsequently authorised medicinal products in the Member States
shall have their quantitative composition stated in the same way for
the same active substance.
Units of biological activity shall be used for substances, which cannot
be defined molecularly. Where an International Unit of biological
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(1) OJ L 11, 14.1.1978, p. 18.
(2) OJ L 237, 10.9.1994, p. 13.
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activity has been defined by the World Health Organisation, this shall
be used. Where no International Unit has been defined, the units of
biological activity shall be expressed in such a way as to provide unambiguous
information on the activity of the substances by using where
applicable the European Pharmacopoeia Units.
3.2.2.2. Pharmaceut ical development
This chapter shall be devoted to information on the development studies
conducted to establish that the dosage form, the formulation, manufacturing
process, container closure system, microbiological attributes and
usage instructions are appropriate for the intended use specified in the
marketing authorisation application dossier.
The studies described in this chapter are distinct from routine control
tests conducted according to specifications. Critical parameters of the
formulation and process attributes that can influence batch reproducibility,
medicinal product performance and medicinal product quality
shall be identified and described. Additional supportive data, where
appropriate, shall be referenced to the relevant chapters of Module 4
(Non Clinical Study Reports) and Module 5 (Clinical Study Reports)
of the marketing authorisation application dossier.
a) The compatibility of the active substance with excipients as well as
key physicochemical characteristics of the active substance that can
influence the performance of the finished product or the compatibility
of different active substances with each other in the case of
combination products, shall be documented.
b) The choice of excipients, in particular relative to their respective
functions and concentration shall be documented.
c) A description of the development of the finished product shall be
provided, taking into consideration the proposed route of administration
and usage.
d) Any overages in the formulation(s) shall be warranted.
e) As far as the physiochemical and biological properties are
concerned, any parameter relevant to the performance of finished
product shall be addressed and documented.
f) The selection and optimisation of the manufacturing process as well
as differences between the manufacturing process(es) used to
produce pivotal clinical batches and the process used for manufacturing
the proposed finished medicinal product shall be provided.
g) The suitability of the container and closure system used for the
storage, shipping and use of the finished product shall be documented.
A possible interaction between medicinal product and
container may need to be considered.
h) The microbiological attributes of the dosage form in relation with
non-sterile and sterile products shall be in accordance with and
documented as prescribed in the European Pharmacopoeia.
i) In order to provide appropriate and supportive information for the
labelling the compatibility of the finished product with reconstitution
diluent(s) or dosage devices shall be documented.
3.2.2.3. Manufactur ing process of the f ini shed medicinal product
a) The description of the manufacturing method accompanying the
application for Marketing Authorisation pursuant to Article 8 (3) (d),
shall be drafted in such a way as to give an adequate synopsis of the
nature of the operations employed.
For this purpose it shall include at least:
— mention of the various stages of manufacture including process
controls and corresponding acceptance criteria, so that an assessment
can be made of whether the processes employed in
producing the pharmaceutical form might have produced an
adverse change in the constituents,
— in the case of continuous manufacture, full details concerning
precautions taken to ensure the homogeneity of the finished
product,
— experimental studies validating the manufacturing process, where
a non-standard method of manufacture is used or where it is
critical for the product,
— for sterile medicinal products, details of the sterilisation
processes and/or aseptic procedures used,
— a detailed batch formula.
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The name, address, and responsibility of each manufacturer,
including contractors, and each proposed production site or facility
involved in manufacturing and testing shall be provided.
b) Particulars relating to the product control tests that may be carried
out at an intermediate stage of the manufacturing process, with a
view to ensuring the consistency of the production process shall be
included.
These tests are essential for checking the conformity of the medicinal
product with the formula when, exceptionally, an applicant
proposes an analytical method for testing the finished product which
does not include the assay of all the active substances (or of all the
excipient constituents subject to the same requirements as the active
substances).
The same applies where the quality control of the finished product
depends on in-process control tests, particularly if the medicinal
product is essentially defined by its method of preparation.
c) Description, documentation, and results of the validation studies for
critical steps or critical assays used in the manufacturing process
shall be provided.
3.2.2.4. Cont rol of excipient s
a) All the materials needed in order to manufacture the excipient(s)
shall be listed identifying where each material is used in the process.
Information on the quality and control of these materials shall be
provided. Information demonstrating that materials meet standards
appropriate for their intended use shall be provided.
Colouring matter shall, in all cases, satisfy the requirements of
Directives 78/25/EEC and/or 94/36/EC. In addition, colouring matter
shall meet purity criteria as laid down in Directive 95/45/EC, as
amended.
b) For each excipient, the specifications and their justifications shall be
detailed. The analytical procedures shall be described and duly validated.
c) Specific attention shall be paid to excipients of human or animal
origin.
Regarding the specific measures for the prevention of the Transmission
of animal Spongiform Encephalopathies, the applicant must
demonstrate also for excipients that the medicinal product is manufactured
in accordance with the Note for Guidance on Minimising
the Risk of Transmitting Animal Spongiform Encephalopathy
Agents via Medicinal Products and its updates, published by the
Commission in the Official Journal of the European Union.
Demonstration of compliance with the aforementioned Note for
Guidance can be done by submitting either preferably a certificate
of suitability to the relevant monograph on Transmissible Spongiform
Encephalopathies of the European Pharmacopoeia, or by the
supply of scientific data to substantiate this compliance.
d) Novel excipients:
For excipient(s) used for the first time in a medicinal product or by
a new route of administration, full details of manufacture, characterisation,
and controls, with cross references to supporting safety data,
both non-clinical and clinical, shall be provided according to the
active substance format previously described.
A document containing the detailed chemical, pharmaceutical and
biological information shall be presented. This information shall be
formatted in the same order as the chapter devoted to Active
Substance(s) of Module 3.
Information on novel excipient(s) may be presented as a stand-alone
document following the format described in the former paragraphs.
Where the applicant differs from the novel excipient manufacturer
the said stand-alone document shall be made available to the applicant
for submission to the competent authority.
Additional information on toxicity studies with the novel excipient
shall be provided in Module 4 of the dossier.
Clinical studies shall be provided in Module 5.
3.2.2.5. Cont rol of the f ini shed medicinal product
For the control of the finished medicinal product, a batch of a medicinal
product is an entity which comprises all the units of a pharmaceutical
form which are made from the same initial quantity of material and
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have undergone the same series of manufacturing and/or sterilisation
operations or, in the case of a continuous production process, all the
units manufactured in a given period of time.
Unless there is appropriate justification, the maximum acceptable deviation
in the active substance content of the finished product shall not
exceed ± 5 % at the time of manufacture.
Detailed information on the specifications, (release and shelf life) justification
for their choice, methods of analysis and their validation shall
be provided.
3.2.2.6. Reference standards or mater ial s
Reference preparations and standards used for testing of the finished
medicinal product shall be identified and described in detail, if not
previously provided in the section related to the active substance.
3.2.2.7. Container and closure of the f ini shed medicinal product
A description of the container and the closure system(s) including the
identity of each immediate packaging material and their specifications
shall be provided. The specifications shall include description and identification.
Non-pharmacopoeial methods (with validation) shall be
included where appropriate.
For non-functional outer packaging materials only a brief description
shall be provided. For functional outer packaging materials additional
information shall be provided.
3.2.2.8. Stabi l i ty of the f ini shed medicinal product
a) The types of studies conducted, protocols used, and the results of the
studies shall be summarised;
b) Detailed results of the stability studies, including information on the
analytical procedures used to generate the data and validation of
these procedures shall be presented in an appropriate format; in
case of vaccines, information on cumulative stability shall be
provided where appropriate;
c) The post authorisation stability protocol and stability commitment
shall be provided.
4. MODULE 4: NON-CLINICAL REPORTS
4.1. Format and Presentation
The general outline of Module 4 is as follows:
— Table of contents
— Study reports
— Pharmacology
— Primary Pharmaco-dynamics
— Secondary Pharmaco-dynamics
— Safety Pharmacology
— Pharmaco-dynamic Interactions
— Pharmaco-kinetics
— Analytical Methods and Validation Reports
— Absorption
— Distribution
— Metabolism
— Excretion
— Pharmaco-kinetic Interactions (non-clinical)
— Other Pharmaco-kinetic Studies
— Toxicology
— Single-Dose Toxicity
— Repeat-Dose Toxicity
— Genotoxicity
— In vitro
— In vivo (including supportive toxico-kinetics evaluations)
— Carcinogenicity
— Long-term studies
— Short- or medium-term studies
— Other studies
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— Reproductive and Developmental Toxicity
— Fertility and early embryonic development
— Embryo-fetal development
— Prenatal and postnatal development
— Studies in which the offspring (juvenile animals) are
dosed and/or further evaluated
— Local Tolerance
— Other Toxicity Studies
— Antigenicity
— Immuno-toxicity
— Mechanistic studies
— Dependence
— Metabolites
— Impurities
— Other
— Literature references
4.2. Content: basic principles and requirements
Special attention shall be paid to the following selected elements.
(1) The pharmacological and toxicological tests must show:
a) the potential toxicity of the product and any dangerous or undesirable
toxic effects that may occur under the proposed
conditions of use in human beings; these should be evaluated
in relation to the pathological condition concerned;
b) the pharmacological properties of the product, in both qualitative
and quantitative relationship to the proposed use in human
beings. All results must be reliable and of general applicability.
Whenever appropriate, mathematical and statistical procedures
shall be used in designing the experimental methods and in evaluating
the results.
Additionally, it is necessary for clinicians to be given information
about the therapeutic and toxicological potential of the
product.
(2) For biological medicinal products such as immunological medicinal
products and medicinal products derived from human blood or
plasma, the requirements of this Module may have to be adapted
for individual products; therefore the testing program carried out
shall be justified by the applicant.
In establishing the testing program, the following shall be taken
into consideration:
all tests requiring repeated administration of the product shall be
designed to take account of the possible induction of, and interference
by, antibodies;
examination of reproductive function, of embryo/foetal and perinatal
toxicity, of mutagenic potential and of carcinogenic potential
shall be considered. Where constituents other than the active
substance(s) are incriminated, validation of their removal may
replace the study.
(3) The toxicology and pharmaco-kinetics of an excipient used for the
first time in the pharmaceutical field shall be investigated.
(4) Where there is a possibility of significant degradation during
storage of the medicinal product, the toxicology of degradation
products must be considered.
4.2.1. Pharmacology
Pharmacology study shall follow two distinct lines of approach.
— Firstly, the actions relating to the proposed therapeutic use shall be
adequately investigated and described. Where possible, recognised
and validated assays, both in vivo and in vitro, shall be used. Novel
experimental techniques must be described in such detail as to allow
them to be reproduced. The results shall be expressed in quantitative
terms using, for example, dose-effect curves, time-effect curves, etc.
Wherever possible, comparisons shall be made with data relating to
a substance or substances with a similar therapeutic action.
— Secondly, the applicant shall investigate the potential undesirable
pharmaco-dynamic effects of the substance on physiological functions.
These investigations shall be performed at exposures in the
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anticipated therapeutic range and above. The experimental techniques,
unless they are standard procedures, must be described in
such detail as to allow them to be reproduced, and the investigator
must establish their validity. Any suspected modification of
responses resulting from repeated administration of the substance
shall be investigated.
For the pharmaco-dynamic medicinal product interaction, tests on
combinations of active substances may be prompted either by pharmacological
premises or by indications of therapeutic effect. In the first
case, the pharmaco-dynamic study shall demonstrate those interactions,
which might make the combination of value in therapeutic use. In the
second case, where scientific justification for the combination is sought
through therapeutic experimentation, the investigation shall determine
whether the effects expected from the combination can be demonstrated
in animals, and the importance of any collateral effects shall at least be
investigated.
4.2.2. Pharmaco-kinetics
Pharmaco-kinetics means the study of the fate of the active substance,
and its metabolites, within the organism, and covers the study of the
absorption, distribution, metabolism (bio-transformation) and excretion
of these substances.
The study of these different phases may be carried mainly by means of
physical, chemical or possibly by biological methods, and by observation
of the actual pharmaco-dynamic activity of the substance itself.
Information on distribution and elimination shall be necessary in all
cases where such data are indispensable to determine the dosage for
humans, and in respect of chemo-therapeutic substances (antibiotics,
etc.) and substances whose use depends on their non-pharmaco-dynamic
effects (e.g. numerous diagnostic agents, etc.).
In vitro studies also can be carried out with the advantage of using
human material for comparison with animal material (i.e. protein
binding, metabolism, drug-drug interaction).
Pharmaco-kinetic investigation of all pharmacologically active
substances is necessary. In the case of new combinations of known
substances, which have been investigated in accordance with the provisions
of this Directive, pharmaco-kinetic studies may not be required, if
the toxicity tests and therapeutic experimentation justify their omission.
The pharmaco-kinetic program shall be design to allow comparison and
extrapolation between animal and human.
4.2.3. Toxicology
a) Single-dose toxicity
A single-dose toxicity test shall mean a qualitative and quantitative
study of the toxic reactions, which may result from a single administration
of the active substance or substances contained in the
medicinal product, in the proportions and physico-chemical state in
which they are present in the actual product.
The single-dose toxicity test must be carried out in accordance with
the relevant guidelines published by the Agency.
b) Repeat-dose toxicity
Repeated dose toxicity tests are intended to reveal any physiological
and/or anatomo-pathological changes induced by repeated administration
of the active substance or combination of active substances
under examination, and to determine how these changes are related
to dosage.
Generally, it is desirable that two tests be performed: one short term,
lasting two to four weeks, the other long-term. The duration of the
latter shall depend on the conditions of clinical use. Its purpose is to
describe potential adverse effects to which attention should be paid
in clinical studies. The duration is defined in the relevant guidelines
published by the Agency.
c) Geno-toxicity
The purposes of the study of mutagenic and clastogenic potential is
to reveal the changes which a substance may cause in the genetic
material of individuals or cells. Mutagenic substances may present
a hazard to health since exposure to a mutagen carries the risk of
inducing germ-line mutation, with the possibility of inherited disorders,
and the risk of somatic mutations including those leading to
cancer. These studies are obligatory for any new substance.
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d) Carcino-genicity
Tests to reveal carcinogenic effects shall normally be required:
1. These studies shall be performed for any medicinal product
whose expected clinical use is for a prolonged period of a
patient's life, either continuously or repeatedly in an intermittent
manner.
2. These studies are recommended for some medicinal products if
there is concern about their carcinogenic potential, e.g. from
product of the same class or similar structure, or from evidence
in repeated dose toxicity studies.
3. Studies with unequivocally geno-toxic compounds are not
needed, as they are presumed to be trans-species carcinogens,
implying a hazard to humans. If such a medicinal product is
intended to be administered chronically to humans a chronic
study may be necessary to detect early tumorigenic effects.
e) Reproductive and developmental toxicity
Investigation of possible impairment of male or female reproductive
function as well as harmful effects on progeny shall be performed
by appropriate tests.
These tests comprise studies of effect on adult male or female reproductive
function, studies of the toxic and teratogenic effects at all
stages of development from conception to sexual maturity as well
as latent effects, when the medicinal product under investigation
has been administered to the female during pregnancy.
Omission of these tests must be adequately justified.
Depending on the indicated use of the medicinal product, additional
studies addressing development when administering the medicinal
product of the offspring may be warranted.
Embryo/foetal toxicity studies shall normally be conducted on two
mammalian species, one of which shall be other than a rodent.
Peri- and postnatal studies shall be conducted in at least one species.
If the metabolism of a medicinal product in particular species is
known to be similar to that in man, it is desirable to include this
species. It is also desirable that one of the species is the same as in
the repeated dose toxicity studies.
The state of scientific knowledge at the time when the application is
lodged shall be taken into account when determining the study
design.
f) Local tolerance
The purpose of local tolerance studies is to ascertain whether medicinal
products (both active substances and excipients) are tolerated at
sites in the body, which may come into contact with the medicinal
product as a result of its administration in clinical use. The testing
strategy shall be such that any mechanical effects of administration
or purely physico-chemical actions of the product can be distinguished
from toxicological or pharmaco-dynamic ones.
Local tolerance testing shall be conducted with the preparation being
developed for human use, using the vehicle and/or excipients in
treating the control group(s). Positive controls/reference substances
shall be included where necessary.
The design of local tolerance tests (choice of species, duration,
frequency and route of administration, doses) will depend upon the
problem to be investigated and the proposed conditions of administration
in clinical use. Reversibility of local lesions shall be
performed where relevant.
Studies in animals can be substituted by validated in vitro tests
provided that the test results are of comparable quality and usefulness
for the purpose of safety evaluation.
For chemicals applied to the skin (e.g. dermal, rectal, vaginal) the
sensitising potential shall be evaluated in at least one of the test
systems currently available (the guinea pig assay or the local lymph
node assay).
5. MODULE 5: CLINICAL STUDY REPORTS
5.1. Format and Presentation
The general outline of Module 5 is as follows:
— Table of contents for clinical study reports
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— Tabular listing of all clinical studies
— Clinical study reports
— Reports of Bio-pharmaceutical Studies
— Bio-availability Study Reports
— Comparative Bio-availability and Bio-equivalence Study
Reports
— In vitro — In vivo Correlation Study Report
— Reports of Bio-analytical and Analytical Methods
— Reports of Studies Pertinent to Pharmaco-kinetics Using Human
Bio-materials
— Plasma Protein Binding Study Reports
— Reports of Hepatic Metabolism and Interaction Studies
— Reports of Studies Using Other Human Bio-materials
— Reports of Human Pharmaco-kinetic Studies
— Healthy subjects Pharmaco-kinetics and Initial Tolerability
Study Reports
— Patient Pharmaco-kinetics and Initial Tolerability Study
Reports
— Intrinsic Factor Pharmaco-kinetics Study Reports
— Extrinsic Factor Pharmaco-kinetics Study Reports
— Population Pharmaco-kinetics Study Reports
— Reports of Human Pharmaco-dynamic Studies
— Healthy Subject Pharmaco-dynamic and Pharmaco-kinetics/
Pharmaco-dynamic Study Reports
— Patient Pharmaco-dynamic and Pharmaco-kinetics/Pharmaco-
dynamic Studies Study Reports
— Reports of Efficacy and Safety Studies
— Study Reports of Controlled Clinical Studies Pertinent to the
Claimed Indication
— Study Reports of Uncontrolled Clinical Studies
— Reports of Analyses of Data from More than One Study
including any formal integrated analyses, meta-analyses and
bridging analyses
— Other Study Reports
— Reports of Post-marketing Experience
— Literature references
5.2. Content: basic principles and requirements
Special attention shall be paid to the following selected elements.
a) The clinical particulars to be provided pursuant to Articles 8 (3) (i)
and 10 (1) must enable a sufficiently well-founded and scientifically
valid opinion to be formed as to whether the medicinal product
satisfies the criteria governing the granting of a marketing authorisation.
Consequently, an essential requirement is that the results of all
clinical trials should be communicated, both favourable and unfavourable.
b) Clinical trials must always be preceded by adequate pharmacological
and toxicological tests, carried out on animals in accordance with
the requirements of Module 4 of this Annex. The investigator must
acquaint himself with the conclusions drawn from the pharmacological
and toxicological studies and hence the applicant must
provide him at least with the investigator's brochure, consisting of
all the relevant information known prior to the onset of a clinical
trial including chemical, pharmaceutical and biological data, toxicological,
pharmaco-kinetic and pharmaco-dynamic data in animals
and the results of earlier clinical trials, with adequate data to justify
the nature, scale and duration of the proposed trial; the complete
pharmacological and toxicological reports shall be provided on
request. For materials of human or animal origin, all available
means shall be employed to ensure safety from transmission of
infectious agents prior to the commencement of the trial.
c) Marketing authorisation holders must arrange for essential clinical
trial documents (including case report forms) other than subject's
medical files, to be kept by the owners of the data:
— for at least 15 years after completion or discontinuation of the
trial,
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— or for at least two years after the granting of the last marketing
authorisation in the European Community and when there are no
pending or contemplated marketing applications in the European
Community,
— or for at least two years after formal discontinuation of clinical
development of the investigational product.
Subject's medical files should be retained in accordance with applicable
legislation and in accordance with the maximum period of time
permitted by the hospital, institution or private practice.
The documents can be retained for a longer period, however, if
required by the applicable regulatory requirements or by agreement
with the sponsor. It is the responsibility of the sponsor to inform the
hospital, institution or practice as to when these documents no
longer need to be retained.
The sponsor or other owner of the data shall retain all other documentation
pertaining to the trial as long as the product is
authorised. This documentation shall include: the protocol including
the rationale, objectives and statistical design and methodology of
the trial, with conditions under which it is performed and managed,
and details of the investigational product, the reference medicinal
product and/or the placebo used; standard operating procedures; all
written opinions on the protocol and procedures; the investigator's
brochure; case report forms on each trial subject; final report; audit
certificate(s), if available. The final report shall be retained by the
sponsor or subsequent owner, for five years after the medicinal
product is no longer authorised.
In addition for trials conducted within the European Community, the
marketing authorisation holder shall make any additional arrangements
for archiving of documentation in accordance with the
provisions of Directive 2001/20/EC and implementing detailed
guidelines.
Any change of ownership of the data shall be documented.
All data and documents shall be made available if requested by relevant
authorities.
d) The particulars of each clinical trial must contain sufficient detail to
allow an objective judgement to be made:
— the protocol, including the rationale, objectives and statistical
design and methodology of the trial, with conditions under
which it is performed and managed, and details of the investigational
medicinal product used
— audit certificate(s), if available
— the list of investigator(s), and each investigator shall give his
name, address, appointments, qualifications and clinical duties,
state where the trial was carried out and assemble the information
in respect of each patient individually, including case
report forms on each trial subject
— final report signed by the investigator and for multi-centre trials,
by all the investigators or the co-ordinating (principal) investigator.
e) The particulars of clinical trials referred to above shall be forwarded
to the competent authorities. However, in agreement with the
competent authorities, the applicant may omit part of this information.
Complete documentation shall be provided forthwith upon
request.
The investigator shall, in his conclusions on the experimental
evidence, express an opinion on the safety of the product under
normal conditions of use, its tolerance, its efficacy and any useful
information relating to indications and contra-indications, dosage
and average duration of treatment as well as any special precautions
to be taken during treatment and the clinical symptoms of over
dosage. In reporting the results of a multi-centre study, the principal
investigator shall, in his conclusions, express an opinion on the
safety and efficacy of the investigational medicinal product on
behalf of all centres.
f) The clinical observations shall be summarised for each trial indicating:
1) the number and sex of subjects treated;
2) the selection and age-distribution of the groups of patients being
investigated and the comparative tests;
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3) the number of patients withdrawn prematurely from the trials and
the reasons for such withdrawal;
4) where controlled trials were carried out under the above conditions,
whether the control group:
— received no treatment
— received a placebo
— received another medicinal product of known effect
— received treatment other than therapy using medicinal
products
5) the frequency of observed adverse reactions;
6) details concerning patients who may be at increased risk, e.g.
elderly people, children, women during pregnancy or menstruation,
or whose physiological or pathological condition requires
special consideration;
7) parameters or evaluation criteria of efficacy and the results in
terms of these parameters;
8) a statistical evaluation of the results when this is called for by the
design of the trials and the variable factors involved.
g) In addition, the investigator shall always indicate his observations
on:
1) any signs of habituation, addiction or difficulty in weaning
patients from the medicinal product;
2) any interactions that have been observed with other medicinal
products administered concomitantly;
3) the criteria determining exclusion of certain patients from the
trials;
4) any deaths which occurred during the trial or within the followup
period.
h) Particulars concerning a new combination of medicinal substances
must be identical to those required for new medicinal products and
must substantiate the safety and efficacy of the combination.
i) Total or partial omission of data must be explained. Should unexpected
results occur during the course of the trials, further pre
clinical toxicological and pharmacological tests must be undertaken
and reviewed.
j) If the medicinal product is intended for long-term administration,
particulars shall be given of any modification of the pharmacological
action following repeated administration, as well as the
establishment of long-term dosage.
5.2.1. Reports of bio-pharmaceutics studies
Bio-availability study reports, comparative bio-availability, bio-equivalence
study reports, reports on in vitro and in vivo correlation study,
and bio-analytical and analytical methods shall be provided.
In addition, an assessment of bio-availability shall be undertaken where
necessary to demonstrate bio-equivalence for the medicinal products
referred to in Article 10 (1) (a).
5.2.2. Reports of studies pertinent to pharmaco-kinetics using human biomaterials
For the purposes of this Annex, human bio-materials shall mean any
proteins, cells, tissues and related materials derived from human sources
that are used in vitro or ex vivo to assess pharmaco-kinetics properties
of drug substances.
In this respect, reports of plasma protein binding study, hepatic metabolism
and active substance interaction studies and studies using other
human bio-materials shall be provided.
5.2.3. Reports of human pharmaco-kinetic studies
a) The following pharmaco-kinetic characteristics shall be described:
— absorption (rate and extent),
— distribution,
— metabolism,
— excretion.
Clinically significant features including the implication of the
kinetic data for the dosage regimen especially for patients at risk,
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and differences between man and animal species used in the pre
clinical studies, shall be described.
In addition to standard multiple-sample pharmaco-kinetics studies,
population pharmaco-kinetics analyses based on sparse sampling
during clinical studies can also address questions about the contributions
of intrinsic and extrinsic factors to the variability in the dosepharmaco-
kinetics response relationship. Reports of pharmacokinetic
and initial tolerability studies in healthy subjects and in
patients, reports of pharmaco-kinetic studies to assess effects of
intrinsic and extrinsic factors, and reports of population pharmacokinetic
studies shall be provided.
b) If the medicinal product is normally to be administered concomitantly
with other medicinal products, particulars shall be given of
joint administration tests performed to demonstrate possible modification
of the pharmacological action.
Pharmaco-kinetic interactions between the active substance and
other medicinal products or substances shall be investigated.
5.2.4. Reports of human pharmaco-dynamic studies
a) The pharmaco-dynamic action correlated to the efficacy shall be
demonstrated including:
— the dose-response relationship and its time course,
— justification for the dosage and conditions of administration,
— the mode of action, if possible.
The pharmaco-dynamic action not related to efficacy shall be
described.
The demonstration of pharmaco-dynamic effects in human beings
shall not in itself be sufficient to justify conclusions regarding any
particular potential therapeutic effect.
b) If the medicinal product is normally to be administered concomitantly
with other medicinal products, particulars shall be given of
joint administration tests performed to demonstrate possible modification
of the pharmacological action.
Pharmaco-dynamic interactions between the active substance and
other medicinal products or substances shall be investigated.
5.2.5. Reports of efficacy and safety studies
5.2.5.1. Study Repor t s of Cont rol led Cl inical Studies Per t inent to
the Claimed Indication
In general, clinical trials shall be done as ‘controlled clinical trials’ if
possible, randomised and as appropriate versus placebo and versus an
established medicinal product of proven therapeutic value; any other
design shall be justified. The treatment of the control groups will vary
from case to case and also will depend on ethical considerations and
therapeutic area; thus it may, in some instances, be more pertinent to
compare the efficacy of a new medicinal product with that of an established
medicinal product of proven therapeutic value rather than with
the effect of a placebo.
(1) As far as possible, and particularly in trials where the effect of the
product cannot be objectively measured, steps shall be taken to
avoid bias, including methods of randomisation and blinding.
(2) The protocol of the trial must include a thorough description of the
statistical methods to be employed, the number and reasons for
inclusion of patients (including calculations of the power of the
trial), the level of significance to be used and a description of the
statistical unit. Measures taken to avoid bias, particularly methods
of randomisation, shall be documented. Inclusion of a large number
of subjects in a trial must not be regarded as an adequate substitute
for a properly controlled trial.
The safety data shall be reviewed taking into account guidelines
published by the Commission, with particular attention to events
resulting in changes of dose or need for concomitant medication,
serious adverse events, events resulting in withdrawal, and deaths. Any
patients or patient groups at increased risk shall be identified and particular
attention paid to potentially vulnerable patients who may be
present in small numbers, e.g., children, pregnant women, frail elderly,
people with marked abnormalities of metabolism or excretion etc. The
implication of the safety evaluation for the possible uses of the medicinal
product shall be described.
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5.2.5.2. Study repor t s of uncont rol led cl inical studies repor t s of
analyses of data from more than one study and other cl inical
study reports
These reports shall be provided.
5.2.6. Reports of post-marketing experience
If the medicinal product is already authorised in third countries, information
shall be given in respect of adverse reactions of the medicinal
product concerned and medicinal products containing the same active
substance(s), in relation to the usage rates if possible.
5.2.7. Case reports forms and individual patient listings
When submitted in accordance with the relevant Guideline published by
the Agency, case report forms and individual patient data listings shall
be provided and presented in the same order as the clinical study
reports and indexed by study.
PART II
SPECIFIC MARKETING AUTHORISATION DOSSIERS AND
REQUIREMENTS
Some medicinal products present specific features which are such that all the
requirements of the marketing authorisation application dossier as laid down in
Part I of this Annex need to be adapted. To take account of these particular
situations, an appropriate and adapted presentation of the dossier shall be
followed by applicants.
1. WELL-ESTABLISHED MEDICINAL USE
For medicinal products the active substance(s) of which has/have a
‘well-established medicinal use’ as referred to Article 10(1)(a)(ii), with
recognised efficacy and an acceptable level of safety, the following
specific rules shall apply.
The applicant shall submit Modules 1, 2 and 3 as described in part I of
this Annex.
For Modules 4 and 5, a detailed scientific bibliography shall address
non-clinical and clinical characteristics.
The following specific rules shall apply in order to demonstrate the
well-established medicinal use:
a) Factors which have to be taken into account in order to establish a
well-established medicinal use of constituents of medicinal products
are:
— the time over which a substance has been used,
— quantitative aspects of the use of the substance,
— the degree of scientific interest in the use of the substance
(reflected in the published scientific literature) and
— the coherence of scientific assessments.
Therefore different periods of time may be necessary for establishing
well-established use of different substances. In any case,
however, the period of time required for establishing a well established
medicinal use of a constituent of a medicinal product must
not be less than one decade from the first systematic and documented
use of that substance as a medicinal product in the
Community.
b) The documentation submitted by the applicant should cover all
aspects of the safety and/or efficacy assessment and must include
or refer to a review of the relevant literature, taking into account
pre- and post-marketing studies and published scientific literature
concerning experience in the form of epidemiological studies and
in particular of comparative epidemiological studies. All documentation,
both favourable and unfavourable, must be communicated.
With respect to the provisions on ‘well-established medicinal use’
it is in particular necessary to clarify that ‘bibliographic reference’
to other sources of evidence (post marketing studies, epidemiological
studies, etc.) and not just data related to tests and trials may
serve as a valid proof of safety and efficacy of a product if an application
explains and justifies the use of these sources of information
satisfactorily.
c) Particular attention must be paid to any missing information and
justification must be given why demonstration of an acceptable level
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of safety and/or efficacy can be supported although some studies are
lacking.
d) The non-clinical and/or clinical overviews must explain the relevance
of any data submitted which concern a product different
from the product intended for marketing. A judgement must be
made whether the product studied can be considered as similar to
the product, for which application for a marketing authorisation has
been made in spite of the existing differences.
e) Post-marketing experience with other products containing the same
constituents is of particular importance and applicants should put a
special emphasis on this issue.
2. ESSENTIALLY SIMILAR MEDICINAL PRODUCTS
a) Applications based upon Article 10(1) (a) (i) (essentially similar
products) shall contain the data described in Modules 1, 2 and 3 of
Part I of this Annex provided the applicant has been granted the
consent of the holder of the original marketing authorisation to cross
refer to the content of his Modules 4 and 5.
b) Applications based upon Article 10(1) (a) (iii) (essentially similar
products i.e. generics) shall contain the data described in Modules 1,
2 and 3 of Part I of this Annex together with data showing bio-availability
and bio-equivalence with the original medicinal product
provided the latter is not a biological medicinal product (see Part II,
4 Similar biological medicinal products).
For these products the non-clinical/clinical overviews/summaries shall
particularly focus on the following elements:
— the grounds for claiming essential similarity;
— a summary of impurities present in batches of the active
substance(s) as well as those of the finished medicinal product
(and where relevant decomposition products arising during storage)
as proposed for use in the product to be marketed together with an
evaluation of these impurities;
— an evaluation of the bio-equivalence studies or a justification why
studies were not performed with respect to the guideline on ‘Investigation
of Bio-availability and Bio-equivalence’;
— an update of published literature relevant to the substance and the
present application. It may be acceptable for articles in ‘peer
review’ journals to be annotated for this purpose;
— every claim in the summary of product characteristics not known
from or inferred from the properties of the medicinal product and/
or its therapeutic group should be discussed in the non clinical/clinical
overviews/summaries and substantiated by published literature
and/or additional studies.
— if applicable, additional data in order to demonstrate evidence on
the equivalence of safety and efficacy properties of different salts,
esters or derivatives of an authorised active substance should be
provided by the applicant when he claims essential similarity.
3. ADDITIONAL DATA REQUIRED IN SPECIFIC SITUATIONS
Where the active substance of an essentially similar medicinal product
contains the same therapeutic moiety as the original authorised product
associated with a different salt/ester complex/derivative evidence that
there is no change in the pharmaco-kinetics of the moiety, pharmacodynamics
and/or in toxicity which could change the safety/efficacy
profile shall be demonstrated. Should this not be the case, this association
shall be considered as a new active substance.
Where a medicinal product is intended for a different therapeutic use or
presented in a different pharmaceutical form or to be administered by
different routes or in different doses or with a different posology, the
results of appropriate toxicological and pharmacological tests and/or of
clinical trials shall be provided.
4. SIMILAR BIOLOGICAL MEDICINAL PRODUCTS
The provisions of Article 10(1)(a) (iii) may not be sufficient in the case
of biological medicinal products. If the information required in the case
of essentially similar products (generics) does not permit the demonstration
of the similar nature of two biological medicinal products,
additional data, in particular, the toxicological and clinical profile shall
be provided.
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When a biological medicinal product as defined in Part I, paragraph 3.2
of this Annex, which refers to an original medicinal product having
been granted a marketing authorisation in the Community, is submitted
for a marketing authorisation by an independent applicant after the
expiry of data protection period, the following approach shall be
applied.
— Information to be supplied shall not be limited to Modules 1, 2 and 3
(pharmaceutical, chemical and biological data), supplemented with
bio-equivalence and bio-availability data. The type and amount of
additional data (i.e. toxicological and other non-clinical and appropriate
clinical data) shall be determined on a case by case basis in
accordance with relevant scientific guidelines.
— Due to the diversity of biological medicinal products, the need for
identified studies foreseen in Modules 4 and 5, shall be required
by the competent authority, taking into account the specific characteristic
of each individual medicinal product.
The general principles to be applied are addressed in a guideline taking
into account the characteristics of the concerned biological medicinal
product published by the Agency. In case the originally authorised
medicinal product has more than one indication, the efficacy and safety
of the medicinal product claimed to be similar has to be justified or, if
necessary, demonstrated separately for each of the claimed indications.
5. FIXED COMBINATION MEDICINAL PRODUCTS
Applications based upon Article 10 (1) (b) shall relate to new medicinal
products made of at least two active substances not previously
authorised as a fixed combination medicinal product.
For those applications a full dossier (Modules 1 to 5) shall be provided
for the fixed combination medicinal product. Where applicable, information
regarding the manufacturing sites and the adventitious agents,
safety evaluation shall be provided.
6. DOCUMENTATION FOR APPLICATIONS IN EXCEPTIONAL
CIRCUMSTANCES
When, as provided for in Article 22, the applicant can show that he is
unable to provide comprehensive data on the efficacy and safety under
normal conditions of use, because:
— the indications for which the product in question is intended are
encountered so rarely that the applicant cannot reasonably be
expected to provide comprehensive evidence, or
— in the present state of scientific knowledge, comprehensive information
cannot be provided, or
— it would be contrary to generally accepted principles of medical
ethics to collect such information,
marketing authorisation may be granted subject to certain specific obligations.
These obligations may include the following:
— the applicant shall complete an identified programme of studies
within a time period specified by the competent authority, the
results of which shall form the basis of a reassessment of the
benefit/risk profile,
— the medicinal product in question may be supplied on medical
prescription only and may in certain cases be administered only
under strict medical supervision, possibly in a hospital and in the
case of a radio-pharmaceutical, by an authorised person,
— the package leaflet and any medical information shall draw the
attention of the medical practitioner to the fact that the particulars
available concerning the medicinal product in question are as yet
inadequate in certain specified respects.
7. MIXED MARKETING AUTHORISATION APPLICATIONS
Mixed marketing-authorisation applications shall mean marketingauthorisation
application dossiers where Module 4 and/or 5 consists of
a combination of reports of limited non-clinical and/or clinical studies
carried out by the applicant and of bibliographical references. All other
Module(s) are in accordance with the structure described in Part I of
this Annex. The competent authority shall accept the proposed format
presented by the applicant on a case by case basis.
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PART III
PARTICULAR MEDICINAL PRODUCTS
This Part lays down specific requirements related to the nature of identified
medicinal products.
1. BIOLOGICAL MEDICINAL PRODUCTS
1.1. Plasma-derived medicinal product
For medicinal products derived from human blood or plasma and by
derogation from the provisions of Module 3, the dossier requirements
mentioned in ‘Information related to the starting and raw materials’,
for starting materials made of human blood/plasma may be replaced
by a Plasma Master File certified in accordance with this Part.
a) Pr inciples
For the purposes of this Annex:
— Plasma Master File shall mean a stand-alone documentation, which
is separate from the dossier for marketing authorisation which
provides all relevant detailed information on the characteristics of
the entire human plasma used as a starting material and/or a raw
material for the manufacture of sub/intermediate fractions, constituents
of the excipient and active substance(s), which are part of
medicinal products or medical devices referred to in Directive
2000/70/EC of the European Parliament and of the Council of
16 November 2000 amending Council Directive 93/42/EC as
regards medical devices incorporating stable derivatives of human
blood or human plasma (1).
— Every centre or establishment for fractionation/processing of human
plasma shall prepare and keep updated the set of detailed relevant
information referred to in the Plasma Master File.
— The Plasma Master File shall be submitted to the Agency or to the
competent authority by the applicant for a marketing authorisation
or the holder of the marketing authorisation. Where the applicant
for a marketing authorisation or the marketing authorisation holder
differs from the holder of the Plasma Master File, the Plasma
Master File shall be made available to the applicant or marketing
authorisation holder for submission to the competent authority. In
any case, the applicant or marketing authorisation holder shall take
responsibility for the medicinal product.
— The competent authority that is evaluating the marketing authorisation
shall await for the Agency to issue the certificate before
deciding on the application.
— Any marketing authorisation dossier containing a human plasmaderived
constituent shall refer to the Plasma Master File corresponding
to the plasma used as a starting/raw material.
b) Content
In accordance with the provisions of Article 109, as amended by Directive
2002/98/EC, which refers to the requirements for donors and the
testing of donations, the Plasma Master File shall include information
on the plasma used as starting/raw material, in particular:
(1) Plasma origin
(i) information on centres or establishments in which blood/
plasma collection is carried out, including inspection and
approval, and epidemiological data on blood transmissible
infections.
(ii) information on centres or establishments in which testing of
donations and plasma pools is carried out, including inspection
and approval status.
(iii) selection/exclusion criteria for blood/plasma donors.
(iv) system in place which enables the path taken by each donation
to be traced from the blood/plasma collection establishment
through to finished products and vice versa.
(2) Plasma quality and safety
(i) compliance with European Pharmacopoeia Monographs.
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(ii) testing of blood/plasma donations and pools for infectious
agents, including information on test methods and, in the case
of plasma pools, validation data on the tests used.
(iii) technical characteristics of bags for blood and plasma collection,
including information on anticoagulants solutions used.
(iv) conditions of storage and transport of plasma.
(v) procedures for any inventory hold and/or quarantine period.
(vi) characterisation of the plasma pool.
(3) System in place between the plasma-derived medicinal product
manufacturer and/or plasma fractionator/processor on the one
hand, and blood/plasma collection and testing centres or establishments
on the other hand, which defines the conditions of their
interaction and their agreed specifications.
In addition, the Plasma Master File shall provide a list of the
medicinal products for which the Plasma Master File is valid,
whether the medicinal products have been granted a marketing
authorisation or are in the process of being granted such an authorisation,
including medicinal products referred to in Article 2 of
Directive 2001/20/EC of the European Parliament and of the
Council relating to the implementation of good clinical practice in
the conduct of clinical trials on medicinal products for human use.
c) Evaluation and Certification
— For medicinal products not yet authorised, the marketing authorisation
applicant shall submit a full dossier to a competent authority,
which shall be accompanied by a separate Plasma Master File
where one does not already exist.
— The Plasma Master File is subject to a scientific and technical
evaluation carried out by the Agency. A positive evaluation shall
result in a certificate of compliance with Community legislation
for the Plasma Master File, which shall be accompanied by the
evaluation report. The certificate issued shall apply throughout the
Community.
— The Plasma Master File shall be updated and re-certified on an
annual basis.
— Changes subsequently introduced to the terms of a Plasma Master
File must follow evaluation procedure laid down by Commission
Regulation (EC) No 542/95 (1) concerning the examination of variations
to the terms of a marketing authorisation falling within the
scope of Council regulation (EEC) No 2309/93 of 22 July 1993
laying down Community procedures for the authorisation and supervision
of medicinal products for human and veterinary use and
establishing a European Agency for the Evaluation of Medicinal
Products (2). Conditions for the assessment of these changes are
laid down by Regulation (EC) No 1085/2003.
— As a second step to the provisions in the first, second, third and
fourth indents, the competent authority that will grant or has granted
the marketing authorisation shall take into account the certification,
re-certification or variation of the Plasma Master File on the
concerned medicinal product(s).
— By derogation from the provisions of the second indent of the
present point (evaluation and certification), where a Plasma Master
File corresponds only to blood/plasma-derived medicinal products
the marketing authorisation of which is restricted to a single
Member State, the scientific and technical evaluation of the said
Plasma Master File shall be carried out by the national competent
authority of that Member State.
1.2. Vaccines
For vaccines for human use and by derogation from the provisions of
Module 3 on ‘Active substance(s)’, the following requirements when
based on the use of a Vaccine Antigen Master File system shall apply.
The marketing authorisation application dossier of a vaccine other than
human influenza vaccine, shall be required to include a Vaccine
Antigen Master File for every vaccine antigen that is an active
substance of this vaccine.
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(1) OJ L 55, 11.3.1995, p. 15.
(2) OJ L 214, 24.8.1993, p. 1.
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a) Pr inciples
For the purposes of this Annex:
— Vaccine Antigen Master File shall mean a stand-alone part of the
marketing authorisation application dossier for a vaccine, which
contains all relevant information of biological, pharmaceutical and
chemical nature concerning each of the active substances, which
are part of this medicinal product. The stand-alone part may be
common to one or more monovalent and/or combined vaccines
presented by the same applicant or marketing authorisation holder.
— A vaccine may contain one or several distinct vaccine antigens.
There are as many active substance(s) as vaccine antigen(s) present
in a vaccine.
— A combined vaccine contains at least two distinct vaccine antigens
aimed at preventing a single or several infectious diseases.
— A monovalent vaccine is a vaccine, which contains one vaccine
antigen aimed at preventing a single infectious disease.
b) Content
The Vaccine Antigen Master File shall contain the following information
extracted from the relevant part (Active substance) of Module 3 on
‘Quality Data’ as delineated in Part I of this Annex:
Active Substance
1. General Information, including compliance with the relevant monograph(
s) of the European Pharmacopoeia.
2. Information on the manufacture of the active substance: this heading
must cover the manufacturing process, information on the starting
and raw materials, specific measures on TSEs and adventitious
agents safety evaluation and facilities and equipment.
3. Characterisation of the active substance
4. Quality control of the active substance
5. Reference standard and materials
6. Container and closure system of the active substance
7. Stability of the active substance.
c) Evaluation and Certification
— For novel vaccines, which contain a novel vaccine antigen, the
applicant shall submit to a competent authority a full marketingauthorisation
application dossier including all the Vaccine Antigen
Master Files corresponding to each single vaccine antigen that is
part of the novel vaccine where no master file already exists for
the single vaccine antigen. A scientific and technical evaluation of
each Vaccine Antigen Master File shall be carried out by the
Agency. A positive evaluation shall result in a certificate of compliance
to the European legislation for each Vaccine Antigen Master
File, which shall be accompanied by the evaluation report. The
certificate shall apply throughout the Community.
— The provisions of the first indent shall also apply to every vaccine,
which consists of a novel combination of vaccine antigens, irrespective
of whether or not one or more of these vaccine antigens are
part of vaccines already authorised in the Community.
— Changes to the content of a Vaccine Antigen Master File for a
vaccine authorised in the Community shall be subject to a scientific
and technical evaluation carried out by the Agency in accordance
with the procedure laid down in Commission Regulation (EC)
No 1085/2003. In the case of a positive evaluation the Agency shall
issue a certificate of compliance with Community legislation for the
Vaccine Antigen Master File. The certificate issued shall apply
throughout the Community.
— By derogation from the provisions of the first, second and third
indents of the present point (evaluation and certification), where a
Vaccine Antigen Master File corresponds only to a vaccine which
is the subject of a marketing authorisation which has not been/will
not be granted according to a Community procedure, and, provided
the authorised vaccine includes vaccine antigens which have not
been evaluated through a Community procedure, the scientific and
technical evaluation of the said Vaccine Antigen Master File and
its subsequent changes, shall be carried out by the national competent
authority that has granted the marketing authorisation.
— As a second step to the provisions in the first, second, third and
fourth indents, the competent authority that will grant or has granted
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the marketing authorisation shall take into account the certification,
re-certification or variation of the Vaccine Antigen Master File on
the concerned medicinal product(s).
2. RADIO-PHARMACEUTICALS AND PRECURSORS
2.1. Radio-pharmaceuticals
For the purposes of this chapter, applications based upon Articles 6 (2)
and 9 shall provide a full dossier in which the following specific details
shall be included:
Module 3
a) In the context of a radio-pharmaceutical kit, which is to be radiolabelled
after supply by the manufacturer, the active substance is
considered to be that part of the formulation which is intended to
carry or bind the radio-nuclide. The description of the manufacturing
method of radio-pharmaceutical kits shall include details of the
manufacture of the kit and details of its recommended final processing
to produce the radioactive medicinal product. The necessary
specifications of the radio-nuclide shall be described in accordance,
where relevant, with the general monograph or specific monographs
of the European Pharmacopoeia . In addition, any compounds essential
for the radio-labelling shall be described. The structure of the
radio-labelled compound shall also be described.
For radio-nuclides, the nuclear reactions involved shall be discussed.
In a generator, both mother and daughter radio-nuclides shall be
considered as active substances.
b) Details of the nature of the radio-nuclide, the identity of the isotope,
likely impurities, the carrier, the use and the specific activity shall
be provided.
c) Starting materials include irradiation target materials.
d) Considerations on chemical/radiochemical purity and its relationship
to bio-distribution shall be provided.
e) Radio-nuclide purity, radiochemical purity and specific activity shall
be described.
f) For generators, details on the testing for mother and daughter radionuclides
are required. For generator-eluates, tests for mother radionuclides
and for other constituents of the generator system shall be
provided.
g) The requirement to express the content of active substances in terms
of the mass of active entities shall onlyapply to radio-pharmaceutical
kits. For radio-nuclides, radioactivity shall be expressed in
Becquerels at a given date and, if necessary, time with reference to
time zone. The type of radiation shall be indicated.
h) For kits, the specifications of the finished product shall include tests
on performance of products after radio-labelling. Appropriate
controls on radiochemical and radio-nuclidic purity of the radiolabelled
compound shall be included. Any material essential for
radio-labelling shall be identified and assayed.
i) Information on stability shall be given for radio-nuclide generators,
radio-nuclide kits and radio-labelled products. The stability during
use of radio-pharmaceuticals in multi-dose vials shall be documented.
Module 4
It is appreciated that toxicity may be associated with a radiation dose.
In diagnosis, this is a consequence of the use of radio-pharmaceuticals;
in therapy, it is the property desired. The evaluation of safety and efficacy
of radio-pharmaceuticals shall, therefore, address requirements for
medicinal products and radiation dosimetry aspects. Organ/tissue exposure
to radiation shall be documented. Absorbed radiation dose
estimates shall be calculated according to a specified, internationally
recognised system by a particular route of administration.
Module 5
The results of clinical trials shall be provided where applicable otherwise
justified in the clinical overviews.
2.2. Radio-pharmaceutical precursors for radio-labelling purposes
In the specific case of a radio-pharmaceutical precursor intended solely
for radio-labelling purposes, the primary objective shall be to present
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information which would address the possible consequences of poor
radio-labeling efficiency or in vivo dissociation of the radio-labeled
conjugate, i.e. questions related to the effects produced in the patient
by free radio-nuclide. In addition, it is also necessary to present relevant
information relating to occupational hazards, i.e. radiation exposure to
hospital staff and to the environment.
In particular, the following information where applicable shall be
provided:
Module 3
The provisions of Module 3 shall apply to the registration of radiopharmaceutical
precursors as define above (indents a) to i)), where
applicable.
Module 4
Concerning single dose and repeat dose toxicity, the results of studies
carried out in conformity with the provisions related to good laboratory
practice laid down in Council Directives 87/18/EEC and 88/320/EEC
shall be provided, unless otherwise justified.
Mutagenicity studies on the radio-nuclide are not considered to be
useful in this particular case.
Information relating to the chemical toxicity and disposition of the relevant
‘cold’ nuclide shall be presented.
Module 5
Clinical information generated from clinical studies using on the
precursor itself is not considered to be relevant in the specific case of
a radio-pharmaceutical precursor intended solely for radio-labelling
purposes.
However, information demonstrating the clinical utility of the radiopharmaceutical
precursor when attached to relevant carrier molecules
shall be presented.
3. HOMEOPATHIC MEDICINAL PRODUCTS
This section sets out specific provisions on the application of Modules 3
and 4 to homeopathic medicinal products as defined in Article 1(5).
Module 3
The provisions of Module 3 shall apply to the documents submitted in
accordance with Article 15 in the simplified registration of homeopathic
medicinal products referred to in Article 14(1) as well as to the documents
for authorisation of other homeopathic medicinal products
referred to in Article 16(1) with the following modifications.
a) Terminology
The Latin name of the homeopathic stock described in the marketing
authorisation application dossier must be in accordance with the
Latin title of the European Pharmacopoeia or, in absence thereof,
by an official pharmacopoeia of a Member State. Where relevant
the traditional name(s) used in each Member State shall be provided.
b) Control of starting materials
The particulars and documents on the starting materials, i.e. all of
the materials used including raw materials and intermediates up to
the final dilution to be incorporated into the finished medicinal
product, accompanying the application shall be supplemented by
additional data on the homeopathic stock.
The general quality requirements shall apply to all of the starting
and raw materials as well as intermediate steps of the manufacturing
process up to the final dilution to be incorporated into the finished
medicinal product. If possible, an assay is required if toxic components
are present and if the quality cannot be controlled on final
dilution to be incorporated because of the high dilution degree.
Every step of the manufacturing process from the starting materials
up to the final dilution to be incorporated into the finished medicinal
product must be fully described.
In case dilutions are involved, these dilution steps should be done in
accordance with the homeopathicmanufacturing methods laid down
in the relevant monograph of the European Pharmacopoeia or, in
absence thereof, by an official pharmacopoeia of a Member State.
c) Control tests on the finished medicinal product
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The general quality requirements shall apply to the homeopathic
finished medicinal products, any exception needs to be duly justified
by the applicant.
Identification and assay of all the toxicologically relevant constituents
shall be carried out. If it can be justified that an identification
and/or an assay on all the toxicologically relevant constituents is not
possible e.g. due to their dilution in the finished medicinal product
the quality shall be demonstrated by complete validation of the
manufacturing and dilution process.
d) Stability tests
The stability of the finished medicinal product must be demonstrated.
Stability data from the homeopathic stocks are generally
transferable to dilutions/triturations obtained thereof. If no identification
or assay of the active substance is possible due to the degree of
dilution, stability data of the pharmaceutical form may be considered.
Module 4
The provisions of Module 4 shall apply to the simplified registration of
homeopathic medicinal products referred to in Article 14(1) with the
following specifications.
Any missing information must be justified, e.g., justification must be
given why demonstration of an acceptable level of safety can be
supported although some studies are lacking.
4. HERBAL MEDICINAL PRODUCTS
Applications for herbal medicinal products shall provide a full dossier
in which the following specific details shall be included.
Module 3
The provisions of Module 3, including compliance with monograph(s)
of the European Pharmacopoeia, shall apply to the authorisation of
herbal medicinal products. The state of scientific knowledge at the
time when the application is lodged shall be taken into account.
The following aspects specific to herbal medicinal products shall be
considered:
(1) Herbal substances and herbal preparations
For the purposes of this Annex the terms ‘herbal substances and
preparations’ shall be considered equivalent to the terms ‘herbal drugs
and herbal drug preparations’, as defined in the European Pharmacopoeia.
With respect to the nomencRlature of the herbal substance, the binomial
scientific name of plant (genus, species, variety and author), and
chemotype (where applicable), the parts of the plants, the definition of
the herbal substance, the other names (synonyms mentioned in other
Pharmacopoeias) and the laboratory code shall be provided.
With respect to the nomenclature of the herbal preparation, the binomial
scientific name of plant (genus, species, variety and author), and
chemotype (where applicable), the parts of the plants, the definition of
the herbal preparation, the ratio of the herbal substance to the herbal
preparation, the extraction solvent(s), the other names (synonyms
mentioned in other Pharmacopoeias) and the laboratory code shall be
provided.
To document the section of the structure for herbal substance(s) and
herbal preparation(s) where applicable, the physical form, the description
of the constituents with known therapeutic activity or markers
(molecular formula, relative molecular mass, structural formula,
including relative and absolute stereo-chemistry, the molecular formula,
and the relative molecular mass) as well as other constituent(s) shall be
provided.
To document the section on the manufacturer of the herbal substance,
the name, address, and responsibility of each supplier, including
contractors, and each proposed site or facility involved in production/
collection and testing of the herbal substance shall be provided, where
appropriate.
To document the section on the manufacturer of the herbal preparation,
the name, address, and responsibility of each manufacturer, including
contractors, and each proposed manufacturing site or facility involved
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in manufacturing and testing of the herbal preparation shall be
provided, where appropriate.
With respect to the description of manufacturing process and process
controls for the herbal substance, information shall be provided to
adequately describe the plant production and plant collection, including
the geographical source of the medicinal plant and cultivation,
harvesting, drying and storage conditions.
With respect to the description of manufacturing process and process
controls for the herbal preparation, information shall be provided to
adequately describe the manufacturing process of the herbal preparation,
including description of the processing, solvents and reagents,
purification stages and standardisation.
With respect to the manufacturing process development, a brief
summary describing the development of the herbal substance(s) and
herbal preparation(s) where applicable shall be provided, taking into
consideration the proposed route of administration and usage. Results
comparing the phyto-chemical composition of the herbal substance(s)
and herbal preparation(s) where applicable used in supporting bibliographic
data and the herbal substance(s) and herbal preparation(s),
where applicable, contained as active substance(s) in the herbal medicinal
product applied for shall be discussed, where appropriate.
With respect to the elucidation of the structure and other characteristics
of the herbal substance, information on the botanical, macroscopical,
microscopical, phyto-chemical characterisation, and biological activity
if necessary, shall be provided.
With respect to the elucidation of the structure and other characteristics
of the herbal preparation, information on the phyto- and physicochemical
characterisation, and biological activity if necessary, shall be
provided.
The specifications for the herbal substance(s) and herbal preparation(s)
where applicable shall be provided.
The analytical procedures used for testing the herbal substance(s) and
herbal preparation(s) where applicable shall be provided.
With respect to the validation of analytical procedures, analytical validation
information, including experimental data for the analytical
procedures used for testing the herbal substance(s) and herbal preparation(
s) where applicable shall be provided.
With respect to batch analyses, description of batches and results of
batch analyses for the herbal substance(s) and herbal preparation(s)
where applicable shall be provided, including those for pharmacopoeial
substances.
Justification for the specifications of the herbal substance(s) and herbal
preparation(s) where applicable shall be provided.
Information on the reference standards or reference materials used for
testing of the herbal substance(s) and herbal preparation(s) where
applicable shall be provided.
Where the herbal substance or the herbal preparation is the subject of a
monograph, the applicant can apply for a certificate of suitability that
was granted by the European Directorate for the Quality of Medicines.
(2) Herbal Medicinal Products
With respect to the formulation development, a brief summary
describing the development of the herbal medicinal product should be
provided, taking into consideration the proposed route of administration
and usage. Results comparing the phyto-chemical composition of the
products used in supporting bibliographic data and the herbal medicinal
product applied for shall be discussed, where appropriate.
5. ORPHAN MEDICINAL PRODUCTS
— In the case of an orphan medicinal product in the meaning of Regulation
(EC) No 141/2000, general provisions of Part II-6
(exceptional circumstances) can be applied. The applicant shall
then justify in the non-clinical and clinical summaries the reasons
for which it is not possible to provide the complete information
and shall provide a justification of the benefit/risk balance for the
orphan medicinal product concerned.
— When an applicant for an marketing authorisation for an orphan
medicinal product invokes the provisions of Article 10 (1)(a)(ii)
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and Part II-1 of this Annex (well-established medicinal use), the
systematic and documented use of the concerned substance can refer
— as way of derogation — to the use of that substance in accordance
with the provisions of Article 5 of this Directive.
PART IV
ADVANCED THERAPY MEDICINAL PRODUCTS
Advanced therapy medicinal products are based on manufacturing processes
focussed on various gene transfer-produced bio-molecules, and/or biologically
advanced therapeutic modified cells as active substances or part of active
substances.
For those medicinal products the presentation of the Marketing Authorisation
application dossier shall fulfil the format requirements as described in Part I of
this Annex.
Modules 1 to 5 shall apply. For Genetically Modified Organisms deliberate
release in the environment, attention shall be paid to the persistence of the
Genetically Modified Organisms in the recipient and to the possible replication
and/or modification of the Genetically Modified Organisms when released in the
environment. The information concerning the environmental risk should appear
in the Annex to Module 1.
1. GENE THERAPY MEDICINAL PRODUCTS (HUMAN AND XENOGENEIC)
For the purposes of this Annex, gene therapy medicinal product shall
mean a product obtained through a set of manufacturing processes
aimed at the transfer, to be performed either in vivo or ex vivo, of a
prophylactic, diagnostic or therapeutic gene (i.e. a piece of nucleic
acid), to human/animal cells and its subsequent expression in vivo.
The gene transfer involves an expression system contained in a delivery
system known as a vector, which can be of viral, as well as non-viral
origin. The vector can also be included in a human or animal cell.
1.1. Diversity of gene therapy medicinal products
a) Gene therapy medicinal products based on allogeneic or xenogeneic
cells
The vector is ready-prepared and stored before its transfer into the
host cells.
The cells have been obtained previously and may be processed as a
cell bank (bank collection or bank established from procurement of
primary cells) with a limited viability.
The cells genetically modified by the vector represent an active
substance.
Additional steps may be carried out in order to obtain the finished
product. By essence, such a medicinal product is intended to be
administered to a certain number of patients.
b) Gene therapy medicinal products using autologous human cells
The active substance is a batch of ready-prepared vector stored
before its transfer into the autologous cells.
Additional steps may be carried out in order to obtain the finished
medicinal product.
Those products are prepared from cells obtained from an individual
patient. The cells are then genetically modified using a readyprepared
vector containing the appropriate gene that has been
prepared in advance and that constitutes the active substance. The
preparation is re-injected into the patient and is by definition
intended to a single patient. The whole manufacturing process from
the collection of the cells from the patient up to the re-injection to
the patient shall be considered as one intervention.
c) Administration of ready-prepared vectors with inserted (prophylactic,
diagnostic or therapeutic) genetic material
The active substance is a batch of ready-prepared vector.
Additional steps may be carried out in order to obtain the finished
medicinal product. This type of medicinal product is intended to be
administered to several patients.
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Transfer of genetic material may be carried out by direct injection of
the ready-prepared vector to the recipients.
1.2. Specific requirements regarding Module 3
Gene therapy medicinal products include:
— naked nucleic acid
— complex nucleic acid or non viral vectors
— viral vectors
— genetically modified cells
As for other medicinal products, one can identify the three main
elements of the manufacturing process, i.e.:
— starting materials: materials from which the active substance is
manufactured such as, gene of interest, expression plasmids, cell
banks and virus stocks or non viral vector;
— active substance: recombinant vector, virus, naked or complex plasmids,
virus producing cells, in vitro genetically modified cells;
— finished medicinal product: active substance formulated in its final
immediate container for the intended medical use. Depending on the
type of gene therapy medicinal product, the route of administration
and conditions of use may necessitate an ex vivo treatment of the
cells of the patient (see 1.1.b).
A special attention shall be paid to the following items:
a) Information shall be provided on the relevant characteristics of the
gene therapy medicinal product including its expression in the target
cell population. Information concerning the source, construction,
characterisation and verification of the encoding gene sequence
including its integrity and stability shall be provided. Apart from
therapeutic gene, the complete sequence of other genes, regulatory
elements and the vector backbone shall be provided.
b) Information concerning the characterisation of the vector used to
transfer and deliver the gene shall be provided. This must include
its physico-chemical characterisation and/or biological/immunological
characterisation.
For medicinal products that utilise a micro-organism such as bacteria
or viruses to facilitate gene transfer (biological gene transfer), data
on the pathogenesis of the parental strain and on its tropism for
specific tissues and cell types as well as the cell cycle-dependence
of the interaction shall be provided.
For medicinal products that utilise non-biological means to facilitate
gene transfer, the physico-chemical properties of the constituents
individually and in combination shall be provided.
c) The principles for cell banking or seed lot establishment and characterisation
shall apply to gene transfer medicinal products as
appropriate.
d) The source of the cells hosting the recombinant vector shall be
provided.
The characteristics of the human source such as age, sex, results of
microbiological and viral testing, exclusion criteria and country of
origin shall be documented.
For cells of animal origin, detailed information related to the
following items shall be provided:
— Sourcing of the animals
— Animal husbandry and care
— Transgenic animals (methods of creation, characterisation of
transgenic cells, nature of the inserted gene)
— Measures to prevent and monitor infections in the source/donor
animals
— Testing for infectious agents
— Facilities
— Control of starting and raw materials.
Description of cell collection methodology including location, type
of tissue, operating process, transportation, storage and traceability
as well as controls carried out during the collection process shall
be documented.
e) The evaluation of the viral safety as well as the traceability of the
products from the donor to the finished medicinal product, are an
essential part of the documentation to be supplied. E.g., the presence
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of replication competent virus in stocks of non-replication competent
viral vectors must be excluded.
2. SOMATIC CELL THERAPY MEDICINAL PRODUCTS (HUMAN
AND XENOGENEIC)
For the purposes of this Annex, somatic cell therapy medicinal products
shall mean the use in humans of autologous (emanating from the patient
himself), allogeneic (coming from another human being) or xenogeneic
(coming from animals) somatic living cells, the biological characteristics
of which have been substantially altered as a result of their
manipulation to obtain a therapeutic, diagnostic or preventive effect
through metabolic, pharmacological and immunological means. This
manipulation includes the expansion or activation of autologous cell
populations ex vivo (e.g., adoptive immuno-therapy), the use of allogeneic
and xenogeneic cells associated with medical devices used ex
vivo or in vivo (e.g., micro-capsules, intrinsic matrix scaffolds, biodegradable
or not).
Specific requirements for cell therapy medicinal products regarding
Module 3
Somatic cell therapy medicinal products include:
— Cells manipulated to modify their immunological, metabolic or
other functional properties in qualitative or quantitative aspects;
— Cells sorted, selected and manipulated and subsequently undergoing
a manufacturing process in order to obtain the finished medicinal
product;
— Cells manipulated and combined with non-cellular components (e.g.
biological or inert matrixes or medical devices) and exerting the
principle intended action in the finished product;
— Autologous cell derivatives expressed in vitro under specific culture
conditions;
— Cells genetically modified or otherwise manipulated to express
previously unexpressed homologous or non-homologous functional
properties.
The whole manufacturing process from the collection of the cells from
the patient (autologous situation) up to the re-injection to the patient
shall be considered as one single intervention.
As for other medicinal products, the three elements of the manufacturing
process are identified:
— starting materials: materials from which the active substance is
manufactured, i.e., organs, tissues, body fluids or cells;
— active substance: manipulated cells, cell lysates, proliferating cells
and cells used in conjunction with inert matrixes and medical
devices;
— finished medicinal products: active substance formulated in its final
immediate container for the intended medical use.
a) General information on active substance(s)
The active substances of cell therapy medicinal products consist of
cells which as a consequence of in vitro processing display prophylactic,
diagnostic or therapeutic properties different from the original
physiological and biological one.
This section shall describe the type of cells and culture concerned.
Tissues, organs or biological fluids from which cells are derived as
well as the autologous, allogeneic, or xenogeneic nature of the donation
and its geographical origin shall be documented. Collection of
the cells, sampling and storage prior further processing shall be
detailed. For allogeneic cells, special attention shall be paid to the
very first step of the process, which covers selection of donors. The
type of manipulation carried out and the physiological function of
the cells that are used as active substance shall be provided.
b) Information related to the starting materials of active substance(s)
1. Human somatic cel ls
Human somatic cell therapy medicinal products are made of a
defined number (pool) of viable cells, which are derived from a
manufacturing process starting either at the level of organs or tissues
retrieved from a human being, or, at the level of a well defined cell
bank system where the pool of cells relies on continuous cell lines.
For the purposes of this chapter, active substance shall mean the
seed pool of human cells and finished medicinal product shall
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mean seed pool of human cells formulated for the intended medical
use.
Starting materials and each step of the manufacturing process shall
be fully documented including viral safety aspects.
(1) Organs, tissues, body fluids and cells of human origin
The characteristics of the human source such as age, sex, microbiological
status, exclusion criteria and country of origin shall be
documented.
Description of sampling including site, type, operating process,
pooling, transportation, storage and traceability as well as controls
carried out on sampling shall be documented.
(2) Cell banking systems
Relevant requirements depicted in part I shall apply for the preparation
and quality control of cell banking systems. This may
essentially be the case for allogeneic or xenogeneic cells.
(3) Ancillary materials or ancillary medical devices
Information shall be provided on the use of any raw materials (e.g.,
cytokines, growth factors, culture media) or of possible ancillary
products and medical devices e.g., cell sorting devices, biocompatible
polymers, matrix, fibres, beads in terms of bio-compatibility,
functionality as well as the risk of infectious agents.
2. Animal somat ic cells (xenogeneic)
Detailed information related to the following items shall be
provided:
— Sourcing of the animals
— Animal husbandry and care
— Genetically modified animals (methods of creation, characterisation
of transgenic cells, nature of the inserted or excised (knock
out) gene)
— Measures to prevent and monitor infections in the source/donor
animals
— Testing for infectious agents including vertically transmitted
micro-organisms (also endogenous retro viruses)
— Facilities
— Cell banking systems
— Control of starting and raw materials.
a) Information on the manufacturing process of the active
substance(s) and the finished product
The different steps of the manufacturing process such as organ/tissue
dissociation, selection of the cell population of interest, in vitro cell
culture, cell transformation either by physico-chemical agents or
gene transfer shall be documented.
b) Characterisation of active substance(s)
All of the relevant information on the characterisation of the cell
population of interest in terms of identity (species of origin, banding
cytogenetics, morphological analysis), purity (adventitious microbial
agents and cellular contaminants), potency (defined biological
activity), and suitability (karyology and tumorigenicity tests) for the
intended medicinal use shall be provided.
c) Pharmaceutical development of finished medicinal product
Apart from the specific method of administration used (intravenous
infusion, site-injection, transplantation surgery), information shall
also be provided on the use of possible ancillary medical devices
(bio-compatible polymers, matrix, fibres, beads) in terms of biocompatibility
and durability.
d) Traceability
A detailed flow chart shall be provided insuring the traceability of
the products from the donor to the finished medicinal product.
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▼M2
3. SPECIFIC REQUIREMENTS FOR GENE THERAPY AND
SOMATIC CELL THERAPY (HUMAN AND XENOGENEIC)
MEDICINAL PRODUCTS REGARDING MODULES 4 AND 5
3.1. Module 4
For gene and somatic cell therapy medicinal products, it is recognised
that conventional requirements as laid down in Module 4 for non-clinical
testing of medicinal products may not always be appropriate due to
unique and diverse structural and biological properties of the products
in question, including high degree of species specificity, subject specificity,
immunological barriers and differences in pleiotropic responses.
The rationale underpinning the non-clinical development and the
criteria used to choose relevant species and models shall be properly
captioned in Module 2.
It may be necessary to identify or develop new animal models in order
to assist in the extrapolation of specific findings on functional endpoints
and toxicity to in vivo activity of the products in human beings. The
scientific justification for the use of these animal models of disease to
support safety and proof of concept for efficacy shall be provided.
3.2. Module 5
The efficacy of advanced therapy medicinal products must be demonstrated
as described in Module 5. For some products and for some
therapeutic indications, however, it may not be possible to perform
conventional clinical trials. Any deviation from the existing guidelines
shall be justified in Module 2.
The clinical development of advanced therapy medicinal products will
have some special features owing to the complex and labile nature of
the active substances. It requires additional considerations because of
issues related to viability, proliferation, migration and differentiation
of cells (somatic cell therapy), because of the special clinical circumstances
where the products are used or because of the special mode of
action through gene expression (somatic gene therapy).
Special risks associated with such products arising from potential
contamination with infectious agents must be addressed in the application
for marketing authorisation for advanced therapy medicinal
products. Special emphasis should be put on both the early stages of
development in one hand, including the choice of donors in the case
of cell therapy medicinal products, and on the therapeutic intervention
as a whole, including the proper handling and administration of the
product on the other hand.
Furthermore, Module 5 of the application should contain, as relevant,
data on the measures to surveying and control of the functions and
development of living cells in the recipient, to prevent transmission of
infectious agents to the recipient and to minimise any potential risks to
public health.
3.2.1. Human pharmacology and efficacy studies
Human pharmacology studies should provide information on the
expected mode of action, expected efficacy based on justified endpoints,
bio-distribution, adequate dose, schedule, and methods of
administration or modality of use desirable for efficacy studies.
Conventional pharmaco-kinetic studies may not be relevant for some
advanced therapy products. Sometimes studies in healthy volunteers
are not feasible and the establishment of dose and kinetics will be difficult
to determine in clinical trials. It is necessary, however, to study the
distribution and in vivo behaviour of the product including cell proliferation
and long-term function as well as the extent, distribution of the
gene product and duration of the desired gene expression. Appropriate
tests shall be used and, if necessary, developed for the tracing of the
cell product or cell expressing the desired gene in the human body and
for the monitoring of the function of the cells that were administered or
transfected.
The assessment of the efficacy and safety of an advanced therapy
medicinal product must include the careful description and evaluation
of the therapeutic procedure as a whole, including special ways of
administration, (such as transfection of cells ex vivo, in vitro manipulation,
or use of interventional techniques), and testing of the possible
associated regimens (including immuno-suppressive, antiviral, cytotoxic
treatment).
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▼M2
The whole procedure must be tested in clinical trials and described in
the product information.
3.2.2. Safety
Safety issues arising from immune response to the medicinal products
or to the expressed proteins, immune rejection, immuno-suppression,
and breakdown of immuno-isolation devices shall be considered.
Certain advanced gene therapy and somatic cell therapy medicinal
products (e.g. xenogeneic cell therapy and certain gene transfer
products) may contain replication-competent particles and/or infectious
agents. The patient may have to be monitored for the development of
possible infections and/or their pathological sequelae during pre- and/
or post-authorisation phases; this surveillance may have to be extended
to close contacts of the patient including health-care workers.
The risk of contamination with potentially transmissible agents cannot
be totally eliminated in the use of certain somatic cell therapy medicinal
products and certain gene transfer medicinal products. The risk
can be minimised, however, by appropriate measures as described in
Module 3.
The measures included in the production process must be complemented
with accompanied testing methods, quality control processes
and by appropriate surveillance methods that must be described in
Module 5.
The use of certain advanced somatic cell therapy medicinal products
may have to be limited, temporarily or permanently, to establishments
that have documented expertise and facilities for assuring a specific
follow up of the safety of the patients. A similar approach may be relevant
for certain gene therapy medicinal products that are associated
with a potential risk of replication-competent infectious agents.
The long term monitoring aspects for the development of late complications
shall also be considered and addressed in the submission, where
relevant.
Where appropriate, the applicant has to submit a detailed risk management
plan covering clinical and laboratory data of the patient, emerging
epidemiological data, and, if relevant, data from archives of tissue
samples from the donor and the recipient. Such a system is needed to
ensure the traceability of the medicinal product and the rapid response
to suspicious patterns of adverse events.
4. SPECIFIC STATEMENT ON XENO-TRANSPLANTATION MEDICINAL
PRODUCTS
For the purposes of this Annex, xeno-transplantation shall mean any
procedure that involves the transplantation, implantation, or infusion
into a human recipient of either live tissues or organs retrieved from
animals, or, human body fluids, cells, tissues or organs that have undergone
ex vivo contact with live non-human animal cells, tissues or
organs.
Specific emphasis shall be paid to the starting materials.
In this respect, detailed information related to the following items shall
be provided according to specific guidelines:
— Sourcing of the animals
— Animal husbandry and care
— Genetically modified animals (methods of creation, characterisation
of transgenic cells, nature of the inserted or excised (knock out)
gene)
— Measures to prevent and monitor infections in the source/donor
animals
— Testing for infectious agents
— Facilities
— Control of starting and raw materials
— Traceability.
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▼B
ANNEX II
PART A
Repealed Directives, with their successive amendments (referred to by
Article 128)
Council Directive 65/65/EEC (OJ 22, 9. 2. 1965, p. 369/65)
Council Directive 66/454/EEC (OJ 144, 5. 8. 1966, p. 2658/66)
Council Directive 75/319/EEC (OJ L 147, 9. 6. 1975, p. 13)
Council Directive 83/570/EEC (OJ L 332, 28. 11. 1983, p. 1)
Council Directive 87/21/EEC (OJ L 15, 17. 1. 1987, p. 36)
Council Directive 89/341/EEC (OJ L 142, 25. 5. 1989, p. 11)
Council Directive 92/27/EEC (OJ L 113, 30. 4. 1992, p. 8)
Council Directive 93/39/EEC (OJ L 214, 24. 8. 1993, p. 22)
Council Directive 75/318/EEC (OJ L 147, 9. 6. 1975, p. 1)
Council Directive 83/570/EEC
Council Directive 87/19/EEC (OJ L 15, 17. 1. 1987, p. 31)
Council Directive 89/341/EEC
Commission Directive 91/507/EEC (OJ L 270, 26. 9. 1991, p. 32)
Council Directive 93/39/EEC
Commission Directive 1999/82/EC (OJ L 243, 15. 9. 1999, p. 7)
Commission Directive 1999/83/EC (OJ L 243, 15. 9. 1999, p. 9)
Council Directive 75/319/EEC
Council Directive 78/420/EEC (OJ L 123, 11. 5. 1978, p. 26)
Council Directive 83/570/EEC
Council Directive 89/341/EEC
Council Directive 92/27/EEC
Council Directive 93/39/EEC
Commission Directive 2000/38/EC (OJ L 139, 10. 6. 2000, p. 28)
Council Directive 89/342/EEC (OJ L 142, 25. 5. 1989, p. 14)
Council Directive 89/343/EEC (OJ L 142, 25. 5. 1989, p. 16)
Council Directive 89/381/EEC (OJ L 181, 28. 6. 1989, p. 44)
Council Directive 92/25/EEC (OJ L 113, 30. 4. 1992, p. 1)
Council Directive 92/26/EEC (OJ L 113, 30. 4. 1992, p. 5)
Council Directive 92/27/EEC
Council Directive 92/28/EEC (OJ L 113, 30. 4. 1992, p. 13)
Council Directive 92/73/EEC (OJ L 297, 13. 10. 1992, p. 8)
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▼B
PART B
Time-limits for transposition into national law (referred to by Article 128)
Directive Deadline for transposition
Directive 65/65/EEC 31 December 1966
Directive 66/454/EEC —
Directive 75/318/EEC 21 November 1976
Directive 75/319/EEC 21 November 1976
Directive 78/420/EEC —
Directive 83/570/EEC 31 October 1985
Directive 87/19/EEC 1 July 1987
Directive 87/21/EEC 1 July 1987
1 January 1992 (1)
Directive 89/341/EEC 1 January 1992
Directive 89/342/EEC 1 January 1992
Directive 89/343/EEC 1 January 1992
Directive 89/381/EEC 1 January 1992
Directive 91/507/EEC 1 January 1992 (2)
1 January 1995 (3)
Directive 92/25/EEC 1 January 1993
Directive 92/26/EEC 1 January 1993
Directive 92/27/EEC 1 January 1993
Directive 92/28/EEC 1 January 1993
Directive 92/73/EEC 31 December 1993
Directive 93/39/EEC 1 January 1995 (4)
1 January 1998 (5)
Directive 1999/82/EC 1 January 2000
Directive 1999/83/EC 1 March 2000
Directive 2000/38/EC 5 December 2001
(1) Deadline for transposition applicable to Greece, Spain and Portugal.
(2) Except Section A, point 3.3 in Part II of the Annex.
(3) Deadline for transposition applicable to Section A, point 3.3 in Part II of the Annex.
(4) Except with regard to Article 1(6).
(5) Deadline for transposition applicable to Article 1(7).
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ANNEX III
CORRELATION TABLE
This Dir. 65/65/EEC 75/318/EEC 75/319/EEC 89/342/EEC 89/343/EEC 89/381/EEC 92/25/EEC 92/26/EEC 92/27/EEC 92/28/EEC 92/73/EEC
Art. 1(1) to (3) Art. 1(1) to
(3)
Art. 1(4) Annex Art. 1(1) and
(2)
Art. 1(5) Art. 1
Art. 1(6) to (9) Art. 1(2)
Art. 1(10) Art. 1(1)
Art. 1(11) to
(16)
Art. 29b, 1st
paragraph
Art. 1(17) and
(18)
Art. 1(2)
Art. 1(19) Art. 1(2), 2nd
sentence
Art. 1(20) to
(26)
Art. 1(2)
Art. 1(27) Art. 8(1)
Art. 1(28) Art. 10(1)
Art. 2 Art. 2(1)
Art. 3(1) and
(2)
Art. 1(4) and
(5)
Art 2(3), 1st
indent
▼B
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Art. 3(3) and
(4)
Art.2(3), 2nd
and 3rd
indents
Art. 3(5) Art. 1(1)
Art. 3(6) Art. 1(2)
Art. 4(1) Art. 1(3)
Art. 4(2) Art. 1(3)
Art. 4(3) Art. 3, 2nd
subparagraph
Art. 4(4) Art. 6
Art. 5 Art. 2(4)
Art. 6(1) Art. 3(1)
Art. 6(2) Art. 2, 1st
sentence
Art. 7 Art. 2, 2nd
sentence
Art. 8(1) and
(2)
Art. 4(1) and
(2)
Art. 8(3)(a) to
(e)
Art. 4, 3rd
para., points 1
to 5
Art. 1, 1st
paragraph
Art. 8(3)(f) to
(i)
Art. 4, 3rd
para., points 6
to 8.1
Art. 8(3)(j) to
(l)
Art. 4, 3rd
para., points 9
to 11
▼B
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Art. 9 Art. 3
Art. 10(1) Art. 4, 3rd
paragraph,
point 8.2
Art. 10(2) Art. 1, 2nd
paragraph
Art. 11, points
1 to 5.3
Art. 4a, points
1 to 5.3
Art. 11, point
5.4
Art. 4a, point
5.4
Art. 3
Art. 11, points
5.5 to 6.4
Art. 4a, points
5.5 to 6.4
Art. 11, point
6.5
Art. 4a, point
6.6
Art. 11, point 7 Art. 4a, point
6.5
Art. 11, points
8 to 9
Art. 4
Art. 12(1) Art. 1
Art. 12(2) and
(3)
Art. 2
Art. 13 Art. 6(1) and
(2)
Art. 14(1) and
(2)
Art. 7(1) and
(4)
Art. 14(3) Art. 4, 2nd
paragraph
▼B
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Art. 15 Art. 8
Art. 16 Art. 9
Art. 17 Art. 7
Art. 18 Art. 7a
Art. 19 Art. 4
Art. 20 Art. 5
Art. 21 Art. 4b
Art. 22 Art. 10(2)
Art. 23 Art. 9a
Art. 24 Art. 10(1)
Art. 25 Art. 9
Art. 26 Art. 5
Art. 27 Art. 8
Art. 28(1) Art. 9(3)
Art. 28(2) Art. 9(1)
Art. 28(3) Art. 9(2)
Art. 28(4) Art. 9(4)
Art. 29 Art. 10
Art. 30 Art. 11
Art. 31 Art. 12
▼B
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Art. 32 Art. 13
Art. 33 Art. 14(1)
Art. 34 Art. 14(2) to
(4)
Art. 35 Art. 15
Art. 36 Art. 15a
Art. 37 Art. 15b
Art. 38 Art. 15c
Art. 39 Art. 14(5)
Art. 40 Art. 16
Art. 41 Art. 17
Art. 42 Art. 18
Art. 43 Art. 20(1)
Art. 44 Art. 20(2)
Art. 45 Art. 20(3)
Art. 46 Art. 19
Art. 47 Art. 19a
Art. 48 Art. 21
Art. 49 Art. 23
Art. 50 Art. 24
▼B
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Art. 51(1) and
(2)
Art. 22(1)
Art. 51(3) Art. 22(2)
Art. 52 Art. 25
Art. 53 Art. 3
Art. 54 Art. 2(1)
Art. 55 Art. 3
Art. 56 Art. 4(1)
Art. 57 Art. 5(2)
Art. 58 Art. 6
Art. 59 Art. 7(1) and
(2)
Art. 60 Art. 5(1) and
Art. 9
Art. 61 Art. 10(1) to
(4)
Art. 62 Art. 2(2) and
Art. 7(3)
Art. 63(1) Art. 4(2)
Art. 63(2) Art. 8
Art. 63(3) Art. 10(5)
Art. 64 Art. 11(1)
▼B
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Art. 65 Art. 12
Art. 66 Art. 5
Art. 67 Art. 6(1)
Art. 68 Art. 2(2)
Art. 69 Art. 7(2) and
(3)
Art. 70 Art. 2
Art. 71 Art. 3
Art. 72 Art. 4
Art. 73 Art. 5(1)
Art. 74 Art. 5(2)
Art. 75 Art. 6(2)
Art. 76 Art. 2
Art. 77 Art. 3
Art. 78 Art. 4(1)
Art. 79 Art. 5
Art. 80 Art. 6
Art. 81 Art. 7
Art. 82 Art. 8
Art. 83 Art. 9
▼B
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Art. 84 Art. 10
Art. 85 Art. 9
Art. 86 Art. 1(3) and
(4)
Art. 87 Art. 2
Art. 88 Art. 3(1) to
(6)
Art. 89 Art. 4
Art. 90 Art. 5
Art. 91 Art. 6
Art. 92 Art. 7
Art. 93 Art. 8
Art. 94 Art. 9
Art. 95 Art. 10
Art. 96 Art. 11
Art. 97(1) to
(4)
Art. 12(1) and
(2)
Art. 97(5) Art. 12(4)
Art. 98 Art. 13
Art. 99 Art. 14
Art. 100 Art. 6(3)
▼B
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Art. 101 Art. 29e
Art. 102 Art. 29a
Art. 103 Art. 29c
Art. 104 Art. 29d
Art. 105 Art. 29f
Art. 106(1) Art. 29g
Art. 106(2) Art. 29b, 2nd
paragraph
Art. 107 Art. 29h
Art. 108 Art. 29i
Art. 109 Art. 3(1) to
(3)
Art. 110 Art. 3(4)
Art. 111(1) Art. 26, 1st
and 2nd paragraph
Art. 111(2) Art. 4(1)
Art. 111(3) Art. 26, 3rd
paragraph
Art. 112 Art. 8 Art. 27
Art. 113 Art. 4(2) Art. 4(2)
Art. 114(1) Art. 4(3)
Art. 114(2) Art. 4(3)
▼B
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Art. 115 Art. 4(1)
Art. 116 Art. 11
Art. 117 Art. 28
Art. 118 Art. 29
Art. 119 Art. 4(1)
Art. 120 Art. 2a, 1st
paragraph
Art. 121 Art. 2b Art. 37a
Art. 122 Art. 30
Art. 123 Art. 33
Art. 124 Art. 5
Art. 125 Art. 12 Art. 31 Art. 4(2) Art. 11(2) Art. 12(3)
Art. 126, 1st
paragraph
Art. 21
Art. 126, 2nd
paragraph
Art. 32
Art. 127 Art. 28a
Art. 128 — — — — — — — — — — —
Art. 129 — — — — — — — — — — —
Art. 130 — — — — — — — — — — —
Annex I Annex
▼B
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Annex II — — — — — — — — — — —
Annex III — — — — — — — — — — —
▼B
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