The time required by regulatory authorities to process variations to dossiers often represents a possible bottleneck to amend and update the documentation related to medical products. A report from Medicines for Europe, the association representing the generic and biosimilar industry, asks the European authorities for a revision of the current framework in order to include new digital technologies within the regulatory process, so to optimise its speed and efficiency. “The political objective for health is clear: Europe must have an adequate and sustainable supply of affordable medicines to meet public health needs. Our industry is a key partner to achieve these goals, currently supplying almost 70% of prescription medicines in Europe. Regulatory affairs can contribute significantly to these objectives by capitalising on digital technology and by making optimal use of the scientific resources of regulators and industry”, commented the president of  Medicines for Europe, Christoph Stoller.

Need to innovate the regulatory framework 

The proposed revision of the system governing regulatory variations should be pursued by the van der Leyen Commission, says the report, as one of the goals for its mandate. A possible tool to be used is represented by a targeted revision of the EC/1234/2008 regulationconcerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products”, that is in force since 2010.

The great increase in the number of variations submitted each year by a single marketing authorisation holder (MAH) is one of the reasons of the request made by Medicines for Europe. The Falsified Medicines directive and the Brexit are other elements assumed to contribute the +75% increase observed in the period 2010-2018. Many of these were classified as minor variations (type IA or notifications), a category representing just less than the total number of variations; according to the report, they should be looked at as mainly administrative ones, thus not needing for scientific assessment and without any added valued for patients. Another quite big contribution to the overall number of variations pending at EMA is represented by the requests for line extension for marketing authorisation originally obtained through the centralised procedure. 

The filing and management of minor variations by mean of digital tools would greatly improve the efficiency of the system, says the report, with up to 65% decrease of the workload for regulatory authorities. The corresponding resources may then be redirected towards other priority objectives. A particularly hot issue, also with respect to the current coronavirus epidemic and its impact on the pharmaceutical supply chain (see the dedicated article in this newsletter), is represented by the low appeal the possibility to register alternative API’s suppliers is playing for pharmaceutical companies, adds the report. 

Useful examples to inspire the transition

The innovation of the system governing regulatory variations, suggests Medicines for Europe, may follow the same process already used at the European level to create the SPOR database (Substance, Product, Organisation and Referential) and the PMS Target Operating Model (TOM), this last representing a model process able to ensure quality and consistency of data, and their exchange between the pharmaceutical industry and regulatory authorities. 

Work-sharing procedures would also need to be optimised, as they represent the operative process used to group variations and recommendations ex art. 5 of the EC/1234/2008 regulation. According to the industrial association, the introduction of grouping practices would have been a cause for the observed increase in the number of variations, and the generated benefits are considered to be limited due to higher costs and biases across different regulatory bodies on what can or cannot be grouped. 

Even if it should be possible to file type IA variations within 12 months, this possibility is still not fully implemented, says the report, due to issues with systems for document management and electronic filing of the required documentation. Furthermore, the overall picture is far more complex as companies need to  include in the dossier more information on the supply chain for active ingredients and file multiple variations in different European countries for products authorised using the decentralised or mutual recognition procedures. 

The proposals for improvement

The report from Medicines for Europe asks a periodic revision of the Annex to the Variations Classification Guideline, in order to keep it always updated to scientific progress. The Association suggests using EMA’s guidelines, not the one published by the European Commission, as this last one requires a longer and more complex process to be amended. Article 5 of the Variations Regulation establishes the procedure to ask the EU Commission for the classification of new variations not yet included in the Regulation; according to the report, some 50 recommendations would be already pending, waiting for final decision. 

A risk-based approach should become the “new normal” also with respect to filing and processing of variations, is the suggestion made by Medicines for Europe, as it is already widely diffuse to manage many other activities typical of the pharmaceutical life cycle. This is true also with respect to biological medicines having a well characterised use and herbal medicines. According to the report, the proposed approach would help to overcome classical type II variations, which refer to manufacturing processes, and specific exclusions that currently do not allow the filing of type IA variations. 

The report also asks for a new guideline specific for vaccines’ variations, which should be added as a new Annex to the already existing guideline. The model is represented by the corresponding WHO guideline, with the ultimate goal to better harmonise both requirements and processes at the international level. The revision of the Variations Classification Guideline should also include new requirements arising from the Medical Device Regulation. The report also discusses a wide set of practical examples, taking into consideration possible issues and how to solve them.

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