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Efforts to harmonize the fragmented regulatory framework for pharmaceuticals in the European Union continue to be a challenge.
Efforts to gain greater uniformity in the implementation of pharmaceuticals regulations across the European Union are making progress, but it is a slow process. The achievement of more harmonization has not been helped by the rising scepticism among the European electorate about the need for more EU integration. Soon the EU’s 28 member states will be reduced to 27 because of the United Kingdom’s vote, in June 2016, to leave the Union altogether.
The continued fragmentation of the EU medicines market was a prominent issue at the annual regulatory affairs conference held in London in late January 2017 by the Medicines for Europe, previously the European Generic and Biosimilar medicines Association (EGA). The association issued a report (1) in 2015 with proposals for increasing regulatory efficiency in the EU to help bring more generic medicines to European patients more quickly. Among its suggestions was a simplification of the EU’s regulatory system by removing duplication and creating a better balance between regulatory objectives and the administrative burden on pharmaceutical companies. It also urged better use of regulatory resources, quicker and more predictable outcomes of regulatory assessments, and more flexibility.
“Over the past year there has been a lot of small improvements, but they have mostly been tiny,” Caroline Kleinjan, chair of Medicines for Europe’s regulatory and scientific affairs committee, told Pharmaceutical Technology Europe.
“Now we’re looking for some big steps forward. These [steps] may not be made this year but perhaps we’ll make some progress towards achieving them.”
Some major advances in pharmaceuticals regulations would have to be gained through new EU legislation, which EU leaders tend to want to avoid in the current political climate. “A lot can be done within existing regulations,” said Andrzej Rys, health systems, medical products and innovation director, directorate for health and food safety, European Commission, at the meeting.
In the face of claims by some conference participants that a few member states were taking as long as two years to grant marketing or other approvals for products, regulatory officials argued that much progress had been made in reducing such delays. “Only two states have been holding back approvals that long,” said Peter Bachmann, chair of the Co-ordination Group for Mutual Recognition and Decentralized Procedures (CMDh). “It could have been far worse,” he added.
However, in a number of emerging areas of importance in pharmaceuticals--such as pharmacovigilance, serialization of medicine packs, and quality controls in bioequivalence testing--there are pieces of legislation that have not yet been fully implemented or guidelines that have yet to be finalized. The prospect is of more new rules coming into effect, which could be enforced differently by individual member states.
The pharmaceutical industry in Europe is watching carefully the activities of the Regulatory Optimization Group (ROG), which was founded in 2016 by the Heads of Medicines Agencies (HMA), representing the leaders of the national agencies running the EU’s decentralized system for the approval and control of medicines. The CMDh is run through the HMA. The objectives of the new organization, consisting mainly of agency representatives, are to eliminate any unnecessary national requirements for the control of medicines, taking away legal obstacles, and above all, to establish IT technology platforms to meet legislative and operational needs of the EU’s network of medicines agencies.
“A lot of hopes are being pinned on the creation of ROG,” said Kleinjan. “It will have to show us over the next few years how it is going to move things forward. If it doesn’t, the whole exercise is going to be difficult.”
Hugo Hurts, executive director, Medicines Evaluation Board (MEB), Netherlands, commented that “we are hoping that the setting up of ROG will stimulate change once its members agree on what actions to take.”
Some of the issues that the ROG appears to be wanting to tackle are among the current priorities of Medicines for Europe. Kleinjan told the conference that the organization wanted action on reducing duplication, removing national regulatory barriers, more integration of databases, and improvements in the EU-wide IT infrastructure for medicines.
With variations to approved market authorization dossiers, some headway had been made in using, as a source of information on minor variations, a central database set up under the EU’s pharmacovigilance legislation on all medicines on the European market. Updated information on the database, run by the European Medicines Agency (EMA) responsible for the EU’s centralized licensing system, would be accepted by the regulators as equivalent to a notification for minor do-and-tell variations.
There have also been moves toward the simplification of procedures for marketing and other approval applications by centralizing the submissions process for generic drugs and allowing EU-wide single assessments of active substances (SAAS). Work has started on phase one of the Common European Single Submission Portal (CESSP), which is due to be introduced in early 2018 based on a standardized data system for new marketing authorization and extension applications. Later phases will aim to standardize the content of the applications so that their datasets can be reused.
“CESSP is an excellent example of how to bring things together,” Georg Neuwirther, head of IT, Austrian Medicines and Medical Devices Agency (AGES), told the conference. The SAAS project is being handled through the HMA working group on the Active Substance Master File (ASMF) with the objective that active substances would be assessed separately from finished medicines. “The substance standards have been almost finalized,” said Constant van Belkum, MEB deputy director.
APIs are an example of one major area in which extensions of the regulatory obligations of pharmaceutical producers are adding to their administrative burdens. Progress in easing workloads by streamlining the procedures for API and other assessments is being offset by the extra requirements linked to new rules.
Marketing authorization holders (MAHs) are now, for example, obliged to monitor more closely their API supply chains through to the production and distribution of starting materials and sites for testing products and processes. These extra responsibilities are resulting in more information having to be collected and included in marketing authorization applications and in more variation notifications and approvals and other product lifecycle requirements.
Between 2010 and 2014, the average number of variations per marketing authorization increased by 45% to 2.9, Koen Nauwelaerts, quality and regulatory affairs manager, Medicines for Europe, told the meeting. “The addition of extra API sites to be monitored will increase the numbers of variations by two to three times to over 400,000,” he added. “This sort of increase is contrary to the EU’s objectives [on regulatory efficiencies].”
The additional responsibilities with APIs have also been raising other problems for drug companies. One of these is the controversial issue of conflicts of interest stemming from the necessity for third-party audits to be carried out to check standards down the supply chain. MAHs organize audits of the API producers while the active substance manufacturers arrange the auditing of their starting material suppliers.
Some regulators in Europe have decided that supplying APIs and their intermediates creates a commercial relationship with their purchasers and vice versa, which results in a conflict of interests when third-party audits are being carried out. Others have concluded that despite the commercial relationship, the auditing does not constitute a conflict of interests while others are taking a case-by-case approach. The pharmaceutical industry has urged the EU authorities to clarify the matter, but even that might not be enough.
“The CMDh decided at one of its meetings that a business relationship does not in the case of audits constitute a conflict of interests,” Nauwelaerts told Pharmaceutical Technology Europe at the conference. “Yet some agencies are not taking any notice of this decision and are continuing to claim that business relationships do amount to a conflict of interest with audits.”
There have also been proposals that GMP-type standards should be applied to other areas of pharmaceuticals quality control such as the way good clinical practice (GCP) criteria are used in bioequivalence testing of generic drugs. This could result in another new set of stricter rules that will have to be complied with. Susana Almeida, co-chair of the bioequivalence working group at Medicines for Europe, pointed out to the conference that while the results of GMP inspections are published and compliance certificates issued, results of GCP inspections are not, nor are compliance certificates issued. Following breaches in recent years of data requirements for bioequivalence tests, hundreds of marketing authorizations in Europe have been suspended. But a large proportion of the authorizations were found to be inactive, she said.
The discovery of rising numbers of violations of data integrity rules among API and other pharmaceutical producers has prompted several agencies, including EMA, the US Food and Drug Administration, and the World Health Organization, to issue guidelines on data standards. Ignacio Moreno, EU team leader for corporate quality audits at Apotex Inc., highlighted at the conference the difficulty of dealing with a lack of quality culture at pharmaceutical manufacturers, which usually is identified as the root cause of the problem. Quality culture was virtually impossible for inspectors or auditors to measure objectively while data on the subject was open to different interpretations.
In an era of almost infinite amounts of data, the challenge for regulators and industry will be to find ways of ensuring the data are applied and also interpreted consistently.
1. European Generic and Biosimilar Medicines Association (now called Medicines for Europe), Regulatory Efficiency Report 2015 (Brussels, 2015).
Pharmaceutical Technology Europe
Vol. 29, No. 3
When referring to this article, please cite it as S. Milmo, "EU Strives for Regulatory Efficiency," Pharmaceutical Technology Europe 29 (3) March 2017.