Tackling Regulatory Challenges of EU’s Variations Framework

The European Union’s medicines licensing agencies have committed themselves in a strategy document in December 2015 (1) to ease the regulatory burden on the pharmaceutical industry by being more efficient in their control of pharmaceuticals throughout product lifecycles. This pledge has been raising the hope of the generic medicines industry. One of the generic medicines industry’s priorities is the reduction of the costs and administrative difficulties that occur when complying with variations regulations for keeping authorization dossiers up to date.

Problems with variations rules were a major topic at an annual regulatory and scientific regulatory affairs conference in London in January 2016, which was organized by the European Generic and Biosimilar medicines Association (EGA). Approximately a third of the 200 participants were regulators with most of the remainder from the industry.

As the EU’s pharmaceuticals regulations have been tightened up in recent years, the submissions on variations to regulatory agencies--comprising the London-based European Medicines Agency at the center and a network of national agencies in the EU’s 28 member states--have increased substantially. As a result, variations have been taking up a rising proportion of the pharmaceutical industry’s regulatory costs.

Variations requirements
Pharmaceutical producers and importers are required to provide regulators with even more information about changes to their medicines, such as modifications to manufacturing processes, improvements or extensions to formulations, and even minor additions such as alterations to names and addresses. The industry is seeing many of the variations requirements as being the imposition of an unfair weight of responsibility on their shoulders.

The current regulatory requirements are laid down by an EU legislation (2) approved in 2008, which came into force in August 2013. The aim was to provide clearer rules by dividing the variations into four main categories. Two of these are type IA, which have “minimal or no impact at all” on the quality, safety, or efficacy of medicines and type II, which can have a “significant impact.” An “extension” category covers changes to an active substance or the strength, pharmaceutical form, and route of administration of a medicine. Type IB variations are changes that are neither minor, major, nor an extension.

Although the legislation’s main objective was to simplify rules on the notification and approval of variations, a series of guidelines have had to be issued to clarify their application. At the same time, new EU pharmacovigilance legislation (3) was introduced, which brought in additional requirements for information of variations in the quality, safety, and efficacy of medicines after their launch on the market. This new legislation also had to be clarified by guidelines, the latest of which was issued in the form of a questions and answers document (4) in January 2016.

“Guidance covering matters that should be clearly described in legislation has increased the regulatory work load of the industry,” Susana Pereira, a principal regulatory affairs officer at Teva Pharmaceutical Industries, told the conference (5). An increasing proportion of variations are now related to details about the production, origin, and composition of APIs. This follows the migration of API manufacture out of Europe and North America to China and India, which has considerably complicated the supply chains for active substances, mainly used in generic medicines. At the same time, rules on good manufacturing practice (GMP) have been made stricter and broader while GMP inspections of API facilities have become more rigorous. A lot of additional variations information is being generated by the more stringent application of GMP.

API changes and GMP rules
The average number of variations per marketing authorization per year had increased by 45% in the five years leading up to 2014 (5), the equivalent to one additional variation per authorization. Variations in APIs are a major factor behind this increase. Up to 60% of quality variations submitted by marketing authorization holders (MAHs) are now related to API changes, said Pereira (5). New interpretation of regulatory data requirements had led to rises of up to 300% in the variations related to the API supply chain, with a high proportion relating to GMP matters, she added (5).

With the addition of stricter GMP rules and the new requirements under the pharmacovigilance legislation, “variations have become a mechanism to implement new legal obligations,” Pereira claimed. The result was rises in regulatory costs covering the maintenance of a product’s lifecycle to a level that is higher than the authorization costs for the marketing of the medicine. “This imbalance can lead to the withdrawal of a medicine from the market, particularly if the cost of maintenance is higher than the product’s profit,” she warned (5). Instead of taking a drug off the market, a company may delay process improvements or hold back other changes that would reduce the medicine’s cost.

Companies are also choosing carefully the regulatory authorities to which they are submitting variations, particularly because of differences in the fees they charge. These costs can range from zero to up to $1544 (€1400) for type IA variations; up to $1654 (€1500) for type IB; and up to $19,852 (€18,000) for type II, Pereira said. “The current system doesn’t create incentives for [national licensing authorities] to implement cost-effective mechanisms,” she added.

Other speakers pointed out how certain aspects of API manufacture were increasing the requirements for variations information, often as a result of the interpretation of regulations made in guidelines. Marieke van Dalen, global regulatory specialist at Aspen Oss B.V., a Dutch API producer, said that a recent trend was a requirement for information on starting and even pre-starting materials, even including the names and addresses of the suppliers. This information was passed to the MAH before being added to the authorization dossier. Some authorities also wanted information on the analytical methods used in the validation of the starting materials and their intermediates.

Joseph Bondin, executive director, quality operations, at the generic-drug producer Actavis, gave examples of how much information had to be provided when an outsourced API manufacture introduced intermediates from new producers with new testing sites. In one example, details of as many as 12 additional players in the API supply chain had to be submitted because of changes in the suppliers of intermediates. As a result of new regulatory interpretations of the information requirements on API intermediates, he warned that there could be a two- to three-fold increase in the total number of variations, which in 2015 averaged just under three variations per marketing authorization per year (6).

“This increase seems contradictory to several EU policies,” he said. “[These policies include] have effective and fit regulatory systems that foster supply-chain resilience to prevent temporary supply disruptions.” In addition, it would seem to refute the value of the systems adopted by pharmaceutical companies themselves to validate the quality of intermediates, even though these could be based on quality guidelines proposed by the International Conference on Harmonization (ICH).

Recommendations for improvements
In a regulatory efficiency report (7) published in September 2015, the EGA recommended a series of specific improvements to the EU regulatory system on variations. These recommendations include reliance on the new database system of Identification of Medical Products (IDMP) to make the API supply chain more transparent. It proposed that API information should be limited to details about the final API manufacturer. Information on other involved sites, such as intermediate producers, would be managed through the drug manufacturers quality systems and regulators’ GMP inspections.

Much greater use, as a source of required variations data, could be made of the central European inventory of information on medicines and active substances, which is being set up under the EU’s pharmacovigilance legislation. Under article 57 of the law, companies have to provide up-to-date post-marketing information on their products relating to quality, safety, and efficacy (3).

Regulators at the conference reiterated their commitment to making regulatory compliance easier and less costly for the pharmaceutical industry, particularly for the generic-drug sector. Noel Wathion, the EMA’s deputy executive director, stressed that the article 57 database and the implementation of IDMP would be used to improve the cost-effectiveness of regulations for generic and biosimilar medicines within the EU’s regulatory network. The regulators, however, were unable to make pledges about specific measures, particularly on the vexed issue of variations. This issue seems likely to remain a matter of grievance among generic-drug companies for some time.

References
1. European Medicines Agency (EMA) and Heads of Medicines Agencies (HMA), EU Medicines Agencies Network Strategy to 2020: Working Together to Improve Health (London, Dec. 17, 2015).
2. EC Regulation No. 1234/2008 The examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products (Brussels, Nov. 24, 2008).
3. EC Regulation No. 1235/2010, Amending as regards pharmacovigilance of medicinal products for human use, Regulation No. 726/2004 laying down community procedures for the authorization and supervision of medicinal products for human and veterinary use (Brussels, Dec. 15, 2010).
4. EMA, Practical questions and answers to support the implementation of the variations guidelines in the centralised procedure, EMA/427505/2013 (London, Jan. 18, 2016).
5. S.Pereira, “Challenges of the Current Variations System,” presentation at the EGA Regulatory and Scientific Affairs Conference (London, Jan. 28-29, 2016).  
6. J.Bondin, “Management of the Active Substance Regulatory Dossier,” presentation at the EGA Regulatory and Scientific Affairs Conference (London, Jan. 28-29, 2016).
7. European Generic and Biosimilar medicines Association (EGA), An Efficient Regulatory System for Patient Access to New Generic Medicines (Brussels, September 2015). 

Article DetailsPharmaceutical Technology 
Vol. 40, No. 3
Pages: 22–24

Citation:
When referring to this article, please cite it as S. Milmo, "Tackling Regulatory Challenges of EU’s Variations Framework," Pharmaceutical Technology 40 (3) 2016.