Harmonizing Marketing Approval of Generic Drugs in Europe

The European Union has been given a leadership role in a World Health Organization (WHO) pilot project on the sharing by regulatory authorities across the world of assessment work on the marketing approval of generic medicines. It is a move that has been welcomed by European generic-drug manufacturers, but it is also a move that will highlight the EU’s own difficulties in establishing a harmonized, collaborative approval system for generic drugs among its 28 member states, as well as two other non-EU European states--Norway and Iceland--who comply with the EU licensing system. It will also throw the spotlight on the slow progress in achieving widespread use in Europe of the active substance master file (ASMF) scheme, which would speed up the quality and safety assessment of active ingredients.

The three-year pilot project, which is part of the WHO’s two-year-old International Generic Drug Regulators Pilot (IGDRP) to promote international convergence in generic-drug regulation, aims to provide a model for a permanent system among regulators for sharing work and information on the assessment of generics. Within the pilot scheme, the EU will share with non-EU regulators its assessment reports on the approval of generic drugs within its decentralized licensing procedure, which accounts for the vast majority of marketing authorizations of generic medicines in Europe. The scheme is being led by the EU’s Coordination Group for Mutual Recognition and Decentralized Procedure-Human (CMDh), which runs the decentralized system on behalf of the national medicines agencies.

“(We) strongly support the International Generic Drug Regulators Pilot,” Beata Stepniewska, deputy director general and head of regulatory affairs at the European Generic Medicines Association (EGA), Brussels, told Pharmaceutical Technology. “[The pilot will] enable cooperation between regulators and the industry to increase efficiency while maintaining the highest level standards based on the EU regulatory procedure,” she added.

In addition to the EU, the scheme will also initially involve Australia, Canada, Taiwan, and Switzerland, whose medicines agencies are members of the Heads of Agency Consortium. This consortium already has a generics working group that has been drawing up work-sharing arrangements in the approval of generic medicines. Other members of the IGDRP, including Russia, Brazil, China, Japan, Korea, Mexico, New Zealand, Singapore, and South Africa, may join the pilot scheme later.

“The EU leadership is a quite natural (choice), due to its long experience of managing marketing authorization procedures involving multiple partners,” said Stepniewska. “The decentralized procedure, introduced 10 years ago, was a significant improvement, although there are still some areas that can be improved (further).”

Generic-drug applications increasing
The impetus behind the IGDRP program, which includes EU involvement in exploring work sharing in ASMF activities and inspection of bioequivalence and bioanalytical operations, comes from the need to ease the burden on regulatory agencies dealing with an increasing number of generic-drug applications.

“Regulatory authorities must now also contend with more sophisticated generic-drug products and complex global production and distribution chains,” said Mike Ward, international programs manager, Health Canada’s therapeutics products directorate, in an article on the pilot project (1)

The EU’s decentralized procedure gives generic-drug companies the option of gaining marketing approval for their products in individual member states. They can also obtain authorization in groups of countries under a mutual recognition process under which approval in one country is accepted by the licensing agencies in other states.

The procedure has been a pioneer in work sharing of assessments. “One of the key elements of the decentralized procedures is the concept of work sharing between member states receiving the same application for a marketing authorization,” a spokesperson for the CMDh told Pharmaceutical Technology. “As such, the elements identified by the IGDRP, like using resources for an already-assessed application, are in this way not an issue for the individual member states of the EU as the concept of work sharing is already working well.”

There are, however, problem areas where more uniformity in approaches is needed. These areas include measuring of bioequivalence, the contents of the summary of product characteristics (SmPCs), which should be consistent with the product information on the reference medicine, and dealing with information updates, especially resulting from process variations.

EMA centralized approval system
Generic-drug companies also have the option of having their products approved through the EU centralized approval system run by the European Medicines Agency (EMA). The EMA also arbitrates on disagreements within the CMDh on mutual recognitions and gives scientific opinions on
assessment issues arising from the decentralized process.

There has been a sharp drop, however, in numbers of marketing applications for generic drugs through the centralized process mainly because of restrictions on duplicates or more than one authorization for a drug. The decline has stemmed from a decision four years ago by the European Commission to tighten the rules for centralized approvals in the interest of “transparency and predictability” (2).

The restrictions, which came into effect in 2011, were mainly aimed at large international generic-drug companies wanting to market drugs with, for example, different names, variations in excipients, and fewer indications. The Commission allowed duplicate applications from companies with the same ownership but placed restrictions on, for example, the use of different drug names, manufacturing sites, and excipients. Now the number of generic-drug and hybrid-drug applications under the centralized system has dropped by more than half since the restrictions were introduced. In 2013, they totalled 20 against 45 in 2011.

“[The Commission’s action] effectively reduced the interest of generic companies to use the centralized procedure,” explained Stepniewska. “(It) does not reflect how generic companies operate in the EU 28 national markets. This is really not satisfactory for generic manufacturers, as a lot of them would love to use the centralized procedure, especially in view of significant amount of reference products authorized centrally.”

Ironically, the international generic-drug companies that would like to make more use of the centralized procedure are also those most supportive of the IGDRP initiative, because it also has the potential for providing a means for gaining accelerated access to more markets.

Active substance master file
An important tool for speeding up the assessment process is the use of ASMFs, which enable the valuable know-how of the manufacturer of the active substance to be protected. At the same time, it allows the applicant or marketing authorization holder to take full responsibility for the medicine, including the quality of the active ingredient.

An ASMF is divided into two parts--an ‘open’ part for the applicant that does not contain any confidential information and a ‘closed’ section detailing the intellectual property on the manufacturing process, which provides the basis for the regulatory authority’s assessment of the API’s quality and safety.

Since the publication of the EMA’s first guideline on the ASMF procedure in 2005 (3), the pharmaceutical industry, particularly generic-drug producers, has had difficulties grasping the ASMF process. The section on the ASMF in an EMA question-and-answer document (4) has had to be revised a number of times so that it now extends to seven pages with nine subchapters. With respect to international information sharing, the EU’S ASMF guideline poses problems. Unlike with the other active ingredient drug master file systems, the EU’s ASMF excludes excipients.

The EU has also not yet finalized its own procedure for work sharing of ASMF assessments. At the moment, the same ASMF can be assessed by different EU member states, which can result in duplication of work. This duplication can result in “inefficient use of assessor resources and inconsistent decisions being made on the same date,” according to a statement by the EMA/CMDh Working Group on Active Substance Master File Procedures (5).

The working group was established in 2011 to set up a work-sharing system through a harmonized use of ASMF assessments. “The experience gained by the joint working group will certainly be of benefit to the IGDRP pilot,” an EMA official told Pharmaceutical Technology. In 2013, the working group announced it was launching its own pilot scheme with the objective of rolling out a work-sharing procedure through a stepwise approach. The aim was to begin with a “new ASMF” covering an active substance that had not been assessed. It would extend through the whole lifecycle of the API, in particular its updates derived from variations in processes, which has been a big complication for holders of ASMFs for the generic-drug market.

A challenge for this pilot scheme and, above all, for the major IGDRP EU-led pilot project is that they both require pharmaceutical companies to volunteer to take part in them. The success of the initiative to set up a permanent international information and work-sharing model will depend on the support of the industry right from the beginning.

“Regarding the IGDRP project itself, it is too early to assess how many companies will be interested in participation,” said Stepniewska. “The level of interest may not be even visible at the beginning as the regulatory strategy for [imminent] applications has already been established and may not be easily changeable.”

References
1. M. Ward, WHO Drug Information 28 (1) (2014).
2. European Commission communication ENT/F/2/RSR re: Handling of Duplicate Marketing Authorization Applications (Brussels, March 2010).
3. EMA, CPMP/QWP/227/02 Guideline of Active Substance Master File Procedure (London, April 2005).
4. EMA, EMA/339324/2007 Pre-authorization Procedural Advice for Users of the Centralized Procedure (London, 2007).
5. EMA, EMA/252320/2011 Mandate of the Working Group on Active Substance Master File Procedures (London, May 2011).

About the Author
Sean Milmo is a freelance writer based in Essex, UK, seanmilmo@btconnect.com.