The Interaction Between European Medicines Regulation and Toxicological Science
(Theme 1: European Regulation and the Science Base)

Dr John Abraham
Dr Graham Lewis


Objectives

To examine how European drug regulation, in the form of the EU multi-state procedure, utilises toxicological expertise, and how that discipline responds to the demand for supra-nationally affiliated experts.

To assess how European approval procedures, both multi-state and decentralised (i.e. with non-binding and binding expert advice structures) have been received by industry scientists, government regulators, and consumer organisations.

To compare the performance of European and national marketing authorisation procedures by reference to: the scientific standards used; extent and flexibility of industry consultation, scientific resources available for regulatory review, and the viability in the view of interest groups affected.

In the light of the results generated, to consider the likely and desirable future directions of EU medicines regulation, and to offer concrete and practical policy proposals.


Methodology

Senior pharmaceutical industry toxicology/safety assessment scientists and regulatory affairs officials, and senior scientists in regulatory authorities, in three member states, Germany, Sweden, the UK, and at the EU level, were interviewed in order to collect views and experiences on the European multi-state authorisation procedure. This objective was extended to include views and opinions on the new (i.e. post Jan. 1 1995) decentralised/centralised authorisation procedures. Industry interviewees were drawn from a cross-section of firms, as far as possible, focusing on companies which submitted products to the multi-state procedure, and in the case of scientific personnel, individuals,who are, or have been, active in the development of European and/or International Conference on Harmonisation (ICH) technical guidelines.

A second important theme was the identification of case-study products, in order to explore their passage through European and national approval routes in the respective member states. Several candidates were identified and formal request made to the companies concerned for access to data and their participation in the study. Responses to these requests were negative. Success in developing industry-based case study material was hampered primarily by concerns over confidentiality, and to a much lesser extent, by wider economic upheavals and resource constraints within the pharmaceutical industry globally.

In parallel with requests for industry co-operation, material was also sought through the Swedish Medical Products Agency (MPA) utilising Sweden's "freedom of information" statutes, the Freedom of the Press Act and the Secrecy Act. This source of information has been little used by researchers to date and the theoretical and practical limits of this routewere explored. The interest in this aspect of the research is heightened by the fact that one of the main concerns expressed during domestic debate over accession to the EU was whether Sweden could maintain its traditional stance towards information access in the face of member states traditionally hostile to increased EU transparency. In other words, will Sweden be forced to comply with existing EU practice or will membership encourage greater institutional "openness"? Interview and other material was also collected from the Nordic Council on Medicines (NLN). The NLN, which for many years has developed harmonised policies for Sweden, Norway, Denmark, Finland and Iceland, believes it has had an important influence on the development of European guidelines for testing requirements, although this claim is contested by other sources in Sweden. In addition to collecting interview data and documentary evidence from the three 'research countries', data on the ICH was also compiled and analysed.


Preliminary Results

The primary driving force for the harmonisation of approval procedures and testing requirements in Europe is the creation of a single market for pharmaceutical products. The study focused on the European multi-state authorisation procedure over the period 1985-94, and its replacement, the decentralised (mutual recognition) procedure introduced in 1995 and, to a lesser extent, the centralised procedure for biotechnology and other innovative drugs, introduced at the same time.

  1. The multi-state procedure was a system of mutual recognition by member states, coupled with a system of non-binding expert arbitration where recognition was refused. However, despite this legal and technical framework, mutual recognition effectively never occurred. The research has shown that considerable scepticism pervades industry's views on the multi-state procedure. To a limited extent, this feeling has carried over to the new decentralised procedure, although many industry scientists and regulatory affairs officials believe the new system to be an improvement on the previous one and are willing to withhold judgement until they have gained more experience. Also, the industry must confront the fact that in 1998 national approval routes will disappear (assuming the timetable presently agreed is adhered to) and virtually all marketing authorisations will become European licenses. This prospect is leading to intense debate in the industry on appropriate corporate strategy in the face of a rapidly changing regulatory environment.

  2. There is no single all-encompassing perspective towards the multi-state procedure in the industry. For example, several large firms refused to be involved at all in European authorisation routes, although this position is slowly changing as companies recognise the need to gain experience ready for 1998. Non-participation was because large firms have the resources to successfully utilise well-established national approval routes, while small and medium companies have tended to be more attracted to the possible resource and marketing benefits of European authorisation routes. The majority of multi-state applications were thus made by small and medium companies. It must be remembered however, that the overwhelming bulk of applications remain national applications, although this will change with regard to new active substances as 1998 approaches.

  3. The outcome for firms which participated in the multi-state procedure has been mixed. Some companies believe their interests have been served by choosing the mutual recognition route, though any benefit is obviously difficult to measure, while at least one major global player is refusing to use the European route again until compelled to in 1998. Overall, many industry scientists consider that non-recognition by member states was often based on "non-scientific" reasons, leading to delays in approval and a loss of system credibility.

  4. The decentralised (mutual recognition) procedure was introduced as a response to industry criticism of the multi-state procedure and to compel member states to accept product evaluations carried out by other states. A key change was the strengthening of the EU expert advisory committee, the Committee for Proprietary Medicinal Products (CPMP) by making the committee's recommendations binding on all member states. Evidence to date suggests that member states' authorities are showing greater willingness to recognise authorisations granted by other states, with only a few applications going into the CPMP arbitration process.

  5. Making European mutual recognition a success in the pharmaceutical sector is a priority of the European Commission. One development aimed at ensuring this happens is the establishment of the Mutual Recognition Facilitation Group (MRFG), an 'informal' body comprising the heads of all national regulatory authorities in the EU, which has been 'bolted-on' to the CPMP.

  6. Industry scientists believe that European harmonisation has led to a general improvement or "levelling-up" of safety standards, though it is hard to show conclusive evidence that this is the case. The refusal to recognise assessments carried out by another member state, i.e. lack of mutual recognition, is variously ascribed to differences in competence between regulatory agencies, differences in "medical culture" between countries, and differences in interpretation which inevitably arise among scientists assessing the same data.

  7. Regulators however are more circumspect, at least in the countries we have examined. MPA scientists, for example, expressed concern over possible lowering of safety standards due to EU-imposed assessment time scales and increasing competition between national authorities.

  8. The study also explored the significance of the International Conference on Harmonisation (ICH) for European guidelines and procedures and the global harmonisation of testing requirements. The ICH, comprising industry and regulatory authorities of the USA, Japan and the EU, is likely to be more important to developments in regulatory toxicology than procedural changes in EU requirements and is already having a key impact on these. The ICH initiative represents the first attempt to harmonise technical standards across the three regions and therefore provides an extremely important model. The ICH process has led to a reduction in technical requirements in some areas. Key findings here include the fact that ICH is largely industry driven; and that relatively few companies and individual scientists actively participate in ICH developments, a situation viewed with concern by the scientists involved. There are conflicting views amongst participants on whether ICH negotiating positions are usually "two-sided", i.e. between industry and regulators, or "three-sided", i.e. between regions.

  9. There are wide variations in the extent of organised consumer interest in medicines harmonisation across Europe. Overall, consumers organisations have little input into the decision-making process in either the European arena or in the context of ICH. There are limited moves to expand the information made available to other parties, with the introduction of the European Public Assessment Report (EPAR) for biotechnology and innovative products approved under the EU's centralised procedure. There is pressure to extend this development to products authorised via the mutual recognition route.


References/Further Reading

A C Cartwright and B R Matthews, (eds), Pharmaceutical Product Licensing: requirements for Europe, Ellis Horwood Ltd., Chichester, (1991)

M Cone, P F D'Arcy, D W G Harron, 'Harmonisation of International Registration Requirements for Pharmaceuticals' in: J L Griffin (ed.), Medicines: Regulation, Research, and Risk. Queen's University Press, Belfast (1993).

European Commission, The Rules Governing Medicinal Products in the European Union, Vol. I-III, Luxembourg. (Available from: HMSO Publications, London)

ICH, Guidelines, International Conference on Harmonisation (ICH). (Available from: ICH Secretariat, PO Box 9, Geneva 18, Switzerland)

D Jefferys, 'The new pharmaceutical regulatory procedures for Europe' Trends in Pharmaceutical Sciences, Vol. 16, pp 226-231.


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