EU’s New Post-Authorization Variations Framework Comes Under Scrutiny

The European Union’s system for post-authorization variations has been given a major shake-up in recent years with the help of close consultation with the pharmaceutical industry. Companies in some pharmaceutical sectors are still trying to adjust to the novel rules and procedures covering changes ranging from small packaging modifications to alterations of manufacturing processes. The legislation on the new system, as amended in 2012, came fully into effect in August 2013 (1).

“The feedback from our members is that they still need time to adapt to the recent changes,” says Miriam Gargesi, healthcare biotechnology director at the European Association for Bioindustries (EuropaBio), Brussels, in an interview with Pharmaceutical Technology. “The [new] EU system for dealing with applications for post-authorization approvals is very complex and still in an implementation phase.”

Other segments, however, particularly for generic medicines, are pressing for yet more simplification and streamlining to speed up the regulatory process for variations not just for the sake of greater efficiencies but also to reduce costs.

Implications for generic medicines manufacturers

For generic medicines manufacturers and suppliers, the regulatory costs of variations have become a major burden as the numbers of post-marketing notifications and authorizations have increased rapidly during the past few years, according to a survey of its members by the European Generic and Biosimilars Medicines Association (EGA).

The number of variations per marketing authorization each year has gone up by approximately 45% during the past five years, Beata Stepniewska, EGA’s deputy director-general and head of regulatory affairs, informs Pharmaceutical Technology. EGA also claims that the survey shows a big rise in fees paid by companies to agencies for regulatory work on variations. “Based on data gathered on an average of more than 16,500 marketing authorizations each year over a four-year timeframe, the variation fees per marketing authorization per year appear to have increased by 45%,” adds Stepniewska.

Most generic-drug companies use the EU’s decentralized procedure (DCP) operated by national regulatory agencies for variations submission. But there also appears to have been a steep rise in variations applications through the centralized procedure run by the European Medicines Agency (EMA). From April 2014 to March 2015, the numbers of pre-submission queries being handled by the agency rose from an average of 150 per month in the first three months to approximately 200 in the last quarter, according to EMA figures (2). Despite the increase in queries, the agency has been able to maintain a relatively quick response time with 90% of the 2200 queries during the year receiving replies within five days.

Much of the provisions of the new system are laid down in the EU’s Regulation 1234/2008 (3), which was soon amended by Regulation 712/2012 (1), mainly to clarify the process of variation approvals by single national agencies. Also the EU’s pharmacovigilance legislation, as contained in directive 2010/84 (4) and which started to be implemented in 2012, is relevant to the variations system through its article 57 (4) on the creation of a database of details of market authorizations. This database can provide a source of information of minor alterations to marketing authorizations.

New groupings and worksharing schemes

The objective of the 2008 regulation (2), which replaced two previous ones on variations approved in 2003, was to establish “a simpler, clearer, and more flexible legal framework while guaranteeing the same level of public health protection,” according to its preamble. It splits variations into four main categories. Applications are to be detailed in the guidelines that will be regularly updated, particularly as a result of scientific and technical advances.

A type IA variation is one that has a “minimal or no impact at all” on the quality, safety, or efficacy of medicines, while type II, which is the highest variation level, may have a “significant impact.” An “extension” involves a change to an active substance or to the strength, pharmaceutical form, and route of administration of a medicine. Type IB variations are those that are neither minor or major or an extension.

To ease the administrative work on changes, the regulation introduced a system of grouping, in a single submission, of similar or linked variations held by the same marketing authorization holder. Variation relating to a manufacturing process improvement, for example, can be put into a single grouping. To avoid duplication in the regulatory work on variations covering several marketing authorizations, a worksharing scheme was also established under the regulation to enable one national agency or EMA to assess similar changes to different medicines on behalf of other national authorities.

Regulatory agencies claim that on the whole the new groupings and worksharing schemes have made the variations assessment procedure faster and more efficient. “[They] increase efficiency by avoiding the complexity of running parallel-related procedures and by ensuring consistency in the assessment of the same changes across products,” explains an EMA official. They also help to streamline some specific processes, such as that for evaluating changes to active substance master files (ASMF). “Worksharing of ASMF assessments reduces the frequent updating of ASMFs and [as a result] the regulatory burden on national authorities, ASMF holders, and marketing authorization holders,” the official says.

Additional workload, more delays, and higher costs

On the contrary, pharmaceutical companies complain that the grouping and worksharing arrangements can lead to more delays than previously in the processing of variations, while at the same time pushing up costs. “In practice, the system does not appear to have been drastically simplified,” says Stepniewska. She cited, as an example, the need for details of individual variations within a grouping, whereas previously, combinations of multiple minor changes could be filed as a type II variation. “There is no reduction in the administrative workload,” she continues. “Some companies also report an additional workload associated with the need for a regulatory authority’s confirmation that a proposed grouping is acceptable.”

National agencies are sometimes not accepting variations in groupings because they would take too long to assess due to their number and complexity, according to the European Federation of Pharmaceutical Industries and Associations (EFPIA). The association estimates that with worksharing, the CMDh (the co-ordination group running the DCP mutual recognition procedure) can take as long as four weeks to allocate the assessment task to an individual member state. “This adds a significant delay to variation processing timelines, which does not encourage the use of the work-sharing scheme by marketing authorization holders,” says an EFPIA spokesman.

In a guideline on worksharing (5), the CMDh outlines processes that could take as long as 150 days with the inclusion of a “clock-off” period to allow for the supply of supplementary information by the marketing authorization holder and its assessment. National agencies are generally having difficulties meeting the time limits on the completion of assessments as stipulated in the EU’s variations legislation. “Less than one out of five variation procedures for type IB and II currently starts on time,” says Stepniewska.

Speeding up variations assessments

EGA and other pharmaceutical industry associations want to speed up the way variations to APIs are handled by eliminating the need for similar API variations to be evaluated separately by different agencies. “Our member companies report that they are dedicating a growing part of their marketing authorization maintenance activity to API-related changes,” Stepniewska explains. “It is certainly not desirable to continue having multiple non-synchronized, uncoordinated procedures where, in effect, the regulatory information to be assessed is identical.”

The solution could be for API producers to be given the responsibility of dealing with the regulatory aspects of changes to their products. “[There could be] a certification-based procedure for all APIs to facilitate and speed up the submission and maintenance of API regulatory information through a direct relationship between regulatory authorities and API manufacturers,” Stepniewska says.

Another concern is the amount of information from GMP certificates being required by some agencies for variations assessments. “There should be a way to exclude routine GMP-compliance activities from the variation process,” says the EFPIA spokesperson. “One suggestion is to have a centralized database in the EU for all licence holders to give the complete GMP status of API suppliers so that this [information] could be accessible to all EU national authorities and the EMA.”

Despite the introduction of the new variations system, their assessment is still being dogged by different approaches by national agencies. “There have been improvements since the implementation of the amended regulation,” says the EFPIA spokesperson. “But there are still some differences in approvals for type IB and II categories across national authorities.” There are even differences between agencies in the classification of variations indicating that there is still work to be done in even removing basic regulatory inconsistencies in the EU’s variations procedure.

References                                                                

1. EU Regulation, Amendments to Regulation 1234/2008 on the examination of variations (Brussels, August 2012).

2. A. Ganan and I. Gravanis, “Procedure Management of Variations,” presentation at EMA meeting: Industry Stakeholder Platform on the Operation of the Centralized Procedure (London, April 24 2015).

3. EU Regulation 1234/2008, Examination of variations to the terms of marketing authorizations (Brussels, November 2008).

4. EU Directive 2010/84/EU, Pharmacovigilance directive on medicinal products for human use (Brussels, December 2010).

5. CMDh, Best Practice Guide on Worksharing. CMDh/297/2013/Rev, February 2015 (London, February 2015).

Article Details
Vol. 39, No. 6
Pages: 18–20
Citation: When referring to this article, please cite it as S. Milmo, “EU’s New Post-Authorization Variations Framework Comes Under Scrutiny,” Pharmaceutical Technology39 (6) 2015.