Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Two Article 30 Referrals – Comparison and experiences, with a main focus on the different implementations in cooperation with the same agency ***

Stephanie Laubner (Abschlußjahr: 2013)

Summary
Language: English
Article 30 referrals (regarding Directive 2001/83/EC) are so-called “Divergent decision referrals”. This type of referral is triggered when Member States have adopted different decisions over the years for some medicines and there is a need to harmonise across the EU.
They can be initiated by any MS, the EC or the MAH of a particular medicinal product. Article 30 referrals will either be initiated by the CMD(h) that publishes a list yearly with products forwarded by the member states that are due to be harmonised or by MSs, applicants or MAHs who would like to start a referral to clarify the matter of divergent decisions of MSs.
The opportunity to see two Article 30 referrals regarding Directive 2001/83/EC1 in short succession within one company and with the own competent authority/national agency as rapporteur and also RMS afterwards is not given often.
For the drug substances Atorvastatin and Fluconazole two Article 30 referral procedures established successively within a short time by the CMD(h) with BfArM as rapporteur and RMS afterwards.
Fluconazole was approved in several all European countries, Atorvastatin even in all European countries. Atorvastatin existed as a number of national licences as well as licences that had been approved via an MRP. Fluconazole was approved purely nationally only. For the Atorvastatin MRP products, an identical product information had already existed. But for the nationally licensed products as well as for the Fluconazole products that were nationally approved as well, the product information varied a lot.
For this reason, both products were included in the CMD(h) list and, thus, had to be referred.
The Atorvastatin referral began in December 2009 and ended about one year later. The Fluconazole referral began three months after the Atorvastatin referral and ended in September 2011, 1.5 years later. For Atorvastatin the existence of the MRP appeared as advantage for the duration of the procedures. The fact that the MRP texts as well as the MRP Module 3 were already harmonised was very helpful regarding the referral procedure. The EU-SmPC and the MRP Module 3 were used as references. The agencies therefore did not raise so many questions and the MAH did not require so much time to prepare the answers.
For Fluconazole, the situation was a bit different. No real reference for the texts and Module 3 was available. The CDS was used for some parts and the CSP for other parts.
Because of the large number of questions the referral procedure was longer compared with that for Atorvastatin.
After the CD, the necessary Type IA implementation variations were submitted instantaneously. For both product families several RUPs with other agencies as interim RMS, such as the Italian, Spanish and Finnish agencies for Atorvastatin, and the French and Austrian agencies for Fluconazole, had to be conducted in order to create licences that were still missing in Germany. These licences were necessary to include the duplicates from other countries into the BfArM RMS-ship. The RMS-ship switches were carried out immediately after finalising the RUPs.
For Atorvastatin, an Art. 29 [of Regulation (EU) No 1901/2006] referral was executed in parallel. That led to the implementation of the children-friendly chewable tablets that had been included into the still ongoing Art. 30 MRPs.
Many questions raised during the Art. 30 referral procedures could be solved with BfArM in a short and easy way. For some pivotal questions, an official Scientific Advice meeting was necessary that led to a clear further strategy – but in conclusion the cooperation was exemplary.
It could be seen that it is not possible to predict the outcome of a referral procedure as so many criteria influence it. These criteria are based on texts and quality dossiers, the number of licences that are included in the Art. 30 referral procedures, the agencies that take over the RMS-ship and the agencies that act as interim RMSs.
Another challenge is to maintain harmonisation with licences that have been approved after conclusion of the Article 30 procedure. This will require additional quality and/or labelling variations for the MAH to align all licences with the same active substance again.
Generally it can be concluded that the experience with these Art. 30 referral procedures and their implementations described here showed that BfArM is a pragmatic agency that often acts in cooperation with and not against the MAH and leads to the wish that other agencies will act in a similar pragmatic way.
Pages: 55
Annexes: 6, Pages: 2