The Impact of European Regulation on Toxicological Science
(Theme 1: European Regulation and the Science Base)

Dr John Abraham
Mr Michael Charlton


Taking the medicines/pharmaceuticals sector as the main focus, the objectives of this project were:

  • to examine the extent to which EU legislation and policy has influenced the science of toxicology and in particular the effect it has had on regulatory toxicology
  • to provide a preliminary understanding of how differences in toxicological evaluation can arise within different member States of the EU
  • to assess, where possible, the costs and benefits of the Europeanisation of regulatory toxicology as perceived by industry, government regulators and consumer organisations

Main Results

The impact of European regulation on the direction and development of toxicological science can be traced back to 1965 when the then-EC issued its first legislation on pharmaceuticals. Throughout the '70s and '80s the EC issued legislation and guidelines which led to harmonised requirements for toxicological testing throughout the community. All three arms of toxicology - preclinical drug testing in animals, clinical testing in humans and postmarketing surveillance studies (also known as pharmacovigilance) - have been affected (CEC 65/65; CEC 75/318; CEC 83/570; CEC 87/176).

Since 1991 the International Conference on Harmonisation (ICH) has had increasing significance. Representatives to ICH include the US Food and Drug Administration, the regulatory authorities of the European Economic Area, the Japanese Ministry of Health and Welfare and the three pharmaceutical associations based in the US, Europe and Japan. The ICH is now a major force in setting the agenda for toxicological testing requirements (Cone et al, 1993). The ICH is an industry-led organisation, which has made major efforts to increase industrial efficiency by reducing the burden of toxicological testing without compromising safety standards. It has been influential in persuading regulators in the US to abandon 12-month studies in rodents as a routine requirement because they add so little to safety information. However, it is important to note that the ICH shows little signs of developing harmonisation resulting directly in raising safety standards. Discussions about comparative efficacy are also developed within ICH work: this might lead to more efficient drug development, but probably also higher standards of efficacy testing for the industry with associated increased costs. Thus the efficiency drive of the ICH impacts upon toxicology with a particular flavour and with considerable success. But this may be because of its exclusion of wider social groups in discussions of the development of technology - issues and priorities that exhibit dissensus in the wider social environment are transformed into areas of agreement by the bilateral industry- regulator context of the ICH (cf Bodewitz et al 1987).

The EU can also influence the development of toxicology through its research programmes. For example, the EU currently funds a project on pharmacovigilance. This is an essential part of the scientific effort that informs regulatory decisions and it will assume even greater importance as more drugs are introduced to the entire European population within the harmonised EU. Under the EU's 4th framework programme there will be more research on multicultural clinical trials and on the search for 'cheaper, faster and more significant methods for testing the chronic toxicity of compounds' (Contzen and Fracchia, 1992).

The EU's drug regulatory Committee for Proprietary Medicinal Products (CPMP) was established in 1975. The Committee and the multi-state procedure it was to oversee were set up to reduce duplication in regulatory work and to limit divergent regulatory decisions within the Union. The multi-state procedure allows a company holding a marketing authorisation in any one member state to apply for licenses in five or more other member states using, in its application, the original regulatory assessment. If the recipient member state dissents from approval it can seek the advice of the CPMP. The multi-state procedure has had only limited success with the vast majority of the applications resulting in dissention and CPMP intervention. The reasons for dissention require further research, but our preliminary findings suggest that they stem from contrasting assessment philosophies and organisational factors. For instance, the German drug regulatory authority, the BGA, is relatively well resourced and can afford to be very thorough in its assessment procedures. It is also known to raise the most objections within the multi-state procedure. Some regulatory authorities are dominated by specialists (eg Germany), others by generalists (eg Netherlands). In Germany pre-clinical toxicology is seen as an important independent input to regulatory decision-making while in the Netherlands its significance is viewed in the context of clinical and public health developments. Some regulatory authorities are sufficiently well resourced to conduct their own toxicological studies (eg Germany and Sweden), others contract out even some toxicological assessment (eg all preclinical in the Netherlands). In some countries committees make the final decisions, in others committees perform the function of peer review (eg Germany, Sweden), in others their advice is not binding but nonetheless it is usually accepted (eg UK). In Germany the weight of final regulatory decision- making lies with the regulatory scientists who have comprehensive access to the application (the BGA), while in the UK the Committee on the Safety of Medicines (CSM) provides virtually definitive regulatory advice based on the summary assessment of the Medicines Control Agency (MCA). Finally on international differences, in Sweden drug regulation is conducted in a context of relative openness and freedom of information whereas confidentiality procedures prevail in Germany, Netherlands and the UK.

The EU's policy to promote scientific cooperation in matters of toxicological testing has benefited the industry, which has gradually become accustomed to the new procedures for obtaining marketing authorisations in the Union. This has allowed the industry to obtain licences more easily and quickly, enabling it to market products in as many member states as it sees fit. Generally speaking the rapporteur arrangements also favour industry. The rapporteur is the original member state that authorised the product and, in effect, acts on behalf of the manufacturer within European regulatory procedures. The manufacturers choose rapporteurs with whom they have 'good connections' and 'good relations' to assist in getting wider European authorisation.

Consumer organisations have shown considerable interest in securing greater information and transparency about licensing decisions. There is little evidence of much movement away from confidentiality, except for the possibility of a European equivalent of the FDA's Summary Basis of Approval (SBA). But even this modicum of European transparency is likely to be less forthcoming than the SBA. This might not make much difference to British consumers, but it could be a severe cost to Swedish consumers with future integration of the Swedish pharmaceutical sector into the EU. There is some evidence that products marshalled through the EU procedures receive greater attention as a result of more than one competent regulatory authority being involved in the assessment. The differences in assessment between member states are generally felt by some regulators to have been beneficial, providing additional peer review, sometimes exposing flaws and weaknesses in assessment. Thus Europeanisation of regulatory toxicology seems to have created some direct benefits for regulators and indirect benefits for consumers.

Implications for Policy and Practice

Toxicological science is information-intensive, but that information is being under- utilised in European drug regulation. A Europe-wide policy aimed at reducing constraints on the availability of information should be pursued (including licensing information, data on compounds terminated in development and data in failed licensing applications). That would be welcomed by consumer organisations, but it would also benefit industrial toxicology and regulators. Such a policy would reduce unnecessary replication in industrial toxicology and therefore improve the efficiency of the science. European toxicologists already use the American freedom of information laws to obtain information that assists in understanding mechanisms of toxicity.

Furthermore, industry should not be put in a position of developing 'good regulatory relations' with certain rapporteurs because that might distort regulatory priorities. To avoid this, when objections are raised about a product in the multi-state procedure another regulatory authority (not the original approving one) should assume the role of rapporteur. Finally there is a need to widen public participation in the work of such organisations as the ICH so that the agenda for developments in regulatory toxicology can be broadened. The EU should examine ways of encouraging such participation.

References/Further Reading

Bodewitz, H et al 1987 'Regulatory science and the social management of trust in medicine' in Bijker, W.E., Hughes, T., and Pinch, T., eds. The social construction of technological systems. Cambridge: the MIT Press

CEC 65/65

CEC 75/318

CEC 83/570

CEC 87/176

Cone,M et al 1993 'Harmonisation of international registration requirements for pharmaceuticals' in Griffin J.P., ed. Medicines: Regulation, research and risk. Belfast: Q.U.P.

Contzen, J.P. and Fracchia, G.N. 1992 'Pharmaceutical research in the European Community' in Castell, J.V. and Gomez-Lechan M.J. eds. In vitro alternatives to animal pharmaco- toxicology. Madrid: Farmaindustria Serie Cientifica.

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