Generics Industry Prescribes Remedies For EU Regulatory Sprawl

Over the 50 years that the EU pharmaceutical legislation has been in place, great progress has been made in terms of improving the quality, safety and efficacy of medicines, and a significant effort has been expended in building a strong European regulatory structure and harmonized European standards.

However, where generic medicines are concerned, the current regulatory systems, and the way they are implemented, do not always support the objectives of timely access and operational efficiency, and there is a need to find more ways of improving the European marketing authorization systems.

These are among the conclusions of a new report presented by the European Generic and Biosimilar Medicines Association (EGA) on the evening of Sep. 28, the day the European Commission held a conference to mark the 50th anniversary of the EU medicines legislation coming into effect in January 1965.

The EGA says that the experience of its member companies has shown that there is a great deal of room for simplifying the EU regulatory system by removing unnecessary duplications, reducing administrative burdens, supporting a single development program for generic medicines globally, and promoting the effective use of IT systems.

In its highly detailed report, the EGA looks at a range of issues such as the EU drug approval procedures, lifecycle maintenance for generic drugs, pharmacovigilance, and the regulatory fee structure.

According to Beata Stepniewska, the EGA's regulatory affairs director, the critical issues for the generics industry are maintenance of, and variations to, marketing authorizations. Over the past few years, there has been a 45% rise in the number of variations, and there is a great deal of duplication because variations have to be done separately in each EU member state, which means an unnecessarily heavy workload for both companies and regulators, Stepniewska told Scrip on the margins of the commission conference.

She said the report was a valuable overview and analysis of the regulatory system for generics, with a great deal of data based on thousands of regulatory procedures the EGA's member companies had been through. The proposals put forward in the report would be a "win-win" for companies and regulators alike, she added.

The EGA said it "calls on the EMA and national agencies to implement these recommendations to simplify the EU regulatory environment."

The report identifies a range of what it sees as weak points in the EU regulatory system, and puts forward a raft of proposals for rectifying them.

Variations

EGA member companies have seen a progressive increase in the number and scope of variations, including several administrative and minor changes, where it is hard to identify the benefits for patients and better protection of public health, the report says. "This trend needs to be reversed so that industry and authority regulatory resources can focus on activities that have the most impact on public health and deliver more benefit for patients, such as for example implementing important safety information changes quickly."

It also says that over time, variations to active pharmaceutical ingredients (APIs) could be better regulated by making the holder of the active substance master file (ASMF) a more independent operator in the regulatory systems, with companies being able to ask for an assessment of the ASMF separately from the product dossier and being responsible for its maintenance (similarly to the concept of the European Pharmacopoeia Certificate of Suitability).

Centralized Procedure

At present, generic products can use the EU's centralized procedure, but only if the reference drug also took that route. The report suggests that to encourage more companies to register generic medicines via the centralized procedure, the marketing authorization process could be more tailored and its eligibility criteria widened. For example, allowing generics access to the procedure when the originator product was not approved via the centralized procedure would increase access to the procedure and help boost the availability of generic medicines throughout the EU.

Pharmacovigilance

While the new EU pharmacovigilance legislation of 2012 has brought several improvements, the full benefits have yet to be achieved, according to the report. Further measures, such as the simplification of risk management plans and removing duplication in periodic safety update reports (PSURs) and some signal detection activities would help unlock the efficiency benefits, it says.

In order to deliver the intended benefits from the 2012 pharmacovigilance legislation, the following should be done, the report recommends:

• stop duplication of signal detection in the Eudravigilance database;
• introduce the single submission of PSURs per active substance;
• simplify the periodic benefit risk evaluation report format;
• simplify the risk management plan format for standard generic medicines and make just one EU assessment; and
• streamline the content of post-approval safety studies (PASS) to avoid the unintended consequence of companies withdrawing from the market.

Non-EU Reference Drugs

As for allowable reference products, the EGA notes that the guideline on "Similar Biological Medicinal Products" has been amended and now explicitly permits sourcing of the reference product from other regions outside the EU with stringent regulatory requirements comparable to those of Europe.

The same should now be done for generic medicines, the association says: "It should now be officially confirmed that sourcing of the reference product from a non-EU territory with high regulatory standards is accepted for single R&D programmes of generic medicines." It says the EU guideline on the investigation of bioequivalence should be amended to explicitly allow the sourcing of the reference product from other world regions with high regulatory standards.

Stepniewska conceded, however, that to do this would not be straightforward: not only would the EU guideline on bioequivalence have to be amended to explicitly allow the sourcing of the reference product from another world region, it was "also important to get countries like the US and Canada on board."

Telematics

The report makes several proposals to improve the use of telematics tools to support regulatory processes. For example, the effective use of IT systems "can be a powerful enabling tool for regulatory efficiency across Europe," it says, and it would be helpful to link systems and make greater use of databases, accelerate procedural efficiency, accuracy and at the same time remove redundant infrastructure.

It suggests that the EGA should be a key partner in setting out the road map for the implementation of the future ISO IDMP (identification of medicinal products) standard and for the long term EU regulatory telematics strategy.

Stepniewska said that a huge amount of data is provided by companies on their products, but frequently they are asked to provide the same information more than once because it is not kept in a form where it is easily accessible to regulators. "There are lots of examples of duplication, for example where the authorities have to handle the same change for, say, 30 different suppliers." One answer, she said, was to keep one set of information that the regulators could check without having to request it from all the companies concerned.

Fees

Turning to the structure of regulatory fees, the report says the fees for new product approvals should be better differentiated between reference member states (RMS) and concerned member states (CMS) to reflect the different assessment responsibilities. "Thus, the level of fees charged by many concerned member states should be reduced to reflect lower workloads. In view of significant increases in the number of variations and associated maintenance fees over recent years, incentives need to be introduced stimulating the authorities to optimise the variations process."

One possible solution, it suggests, could be an annual flat fee for the maintenance of marketing authorizations, as is already the case in a few member states. This would cover all maintenance costs including variations.

It also suggests that the fee structure for variations should be reshaped so that maintenance fees, in the first renewal period after marketing authorization is granted, are lower than initial submission fees. Fees for grouped variations should always be less than fees for a Type II variation.

This article has also been published inScrip Regulatory Affairs. Scrip Intelligence brings selected complementary coverage from our sister publications to our subscribers.