Clinical Trials Directive

European Union, Clinical Trials Directive (2001/20/EC), Official Journal of the European Communities L121, pp34—44, 2001. 

European clinical trial products do not currently require manufacture to GMP however, a new clinical trial directive is undergoing implementation and will necessitate the manufacture to GMP in licensed premises. 

All formulations for administration to humans must be prepared in compliance with good manufacturing practice (GMP) and the certificates of analysis must be provided. The European Clinical Trials Directive requires that details of the formulations be provided to, and approved by, regulatory authorities and a qualified person at the investigator site(s). In principle, the Directive has been in force throughout the EU since May 2004 though it has been implemented at various times in different member states. The Directive applies to healthy volimteer as weU as patient studies. The requirements for pharmaceutical products for administration to humans are summarised in Box 4.6. 

Two other documents are relevant to clinical trials the World Health Organisation (WHO) Guidelines for Good Clinical Practice for trials on pharmaceutical products, still used for clinical trials in some parts of the world, and the new EU Clinical Trial Directive. ... 

In Europe generally, considerable variation in composition and in procedures occurs between lECs. Membership frequently depends on individuals who are willing to give their time without payment. Also, suitable members for this t)q)e of review board often have limited time. The new Clinical Trial Directive should provide the incentive for greater uniformity. A single lEC wiU give an opinion on a multicentre study within 60 days. 

In Europe, the new EU Clinical Trial Directive requires all, non-commercial and commercial, clinical trials to be conducted to the GCP standard. 

Finally, article 84.9 states that the operation of this article is without prejudice to the operation of the clinical trials Directive 211 /20/ EC and the national provisions for compassionate use in article 5 of Directive 2001 /83/ EC. 

In the United Kingdom, healthy volunteer studies were subject to self-regulation by the pharmaceutical industry and consequently only the clinical trials in patients had to be covered by a CTC. However, as stated earlier, clinical trials in the UK are now regulated under EU Clinical Trials Directive (2001/20/EEC) fully implemented in the UK. 

The EU Clinical Trials Directive contains specific provisions regarding the conduct of clinical trials, including multicentre trials, on human subjects. It defines clinical trial as any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to... 

Prior to the introduction of EU Clinical Trials Directive, there were four ways of seeking approval for the commencement of clinical trials in the United Kingdom. These were by means of a Clinical Trial Certificate (CTC), a Clinical Trial Exemption (CTX), a Doctor s and Dentist s Exemption (DDX) or as a Clinical Trial on a Marketed Product (CTMP). Each required provision of a detailed protocol of the proposed trial. 

This clinical trial Directive was among the most contentious to be implemented and much has been written on its merits, demerits and effect on pharmaceutical research (for example, see References 1-7). 

Boyce M, Warrington S. Analysis of 312 studies of investigational medicinal products in healthy subjects to assess the impact of European Union Clinical Trial Directive. Int J Pharm Med 2002 16 179-184. 

Kurz R, Crawley FP. The Clinical Trial Directive s ethical impact on research into disease that cause incapacity and diseases of chUdren perspectives from non-commercially fimded research in hospitals. Int ] Pharm Med 2003 17 7-9. 

Baeyens AJ. Impact of the European Clinical Trials Directive on academic clinical research. Med Law 2004 23 103-110. 

The FDA has clarified the minimum requirements for an IND submission in three areas chemistry, toxicology reports (draft) and size (2-3 volumes, each 3" thick) in an attempt to relax current practices somewhat, to the level required for a UK CTX. However, full reports are to be provided within a short time after the initial drafts. (Conversely, however, information needed to conduct human studies in the European Union has increased, recently, with the implementation of the Clinical Trial Directive.)... 

It should be noted that our proposal goes considerably beyond the current proposal of FDA to create a looser Phase 0 stage for first-in-man pharmacokinetic and similar activities. Our proposal would cover all early human studies through clinical proof-of-concept, which usually occurs in Phase 2a. Only in the large pivotal studies (Phases 2b-3), when there is more assurance that the drug candidate has a solid chance of getting to an NDA submission, would the full formal IND filing be necessary. (These proposals are the opposite of what has been introduced by the EC Clinical trial Directive, see Chapter 17.)... 

Clinical trials and clinical trial authorizations in the European Union are controlled under the Clinical Trial Directive, 2001/20/EC [9], and all member states are bound by its requirements. Under the provisions of the Directive, a clinical trial is an investigation in human subjects that is intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of one or more medicinal products, identify any adverse reactions or study the absorption, distribution, metabolism, and excretion, with the object of ascertaining the safety and/or efficacy of those products. This definition includes pharmacokinetic studies. 

The Clinical Trials Directive now requires the filing of a clinical trial application for bioequivalence studies in normal volunteers or patients. In the United States, an IND is always needed if the generic drug is without an approved innovator in the United States, is radioactive or is a cytotoxic. However, when single- or multiple-dose studies in normal volunteers do not exceed the approved clinical dose sizes and there will be retention samples available for inspection, then there can be exemption from the need to file an IND. An IND is needed for a multiple-dose bioequivalence study, when it is not preceded by a singledose study. The usual protections for human subjects are required, and, of course, these include an approval from the Institutional Review Board. 

The European Clinical Trials Directive has now standardized the submissions to regulatory authorities needed for phase I studies within the European Community. The data in support of such submissions are now more or less the same as for an IND in the United States, and there is comparable institutional review board/ethics committee review and oversight on both sides of the North Atlantic. The preclinical manager must keep a close eye on the pace of such studies so that the preclinical testing for phase I in humans, which is usually rate limiting, causes as little delay as possible. 

Hence, the standards for conducting clinical trials must be known before they can be applied. Standards are either international (e.g. ICH GCP), European (e.g. European Union Clinical Trials Directive (2001) and GCP Directive (2005)), national (i.e. national drug laws and GCP regulations) or even more local, such as State laws in the United States (Isidor and Kaltmann, 1999). Apart from the regulations, the clinical trial protocol, SOPs and other internal or external instructions document procedures how the trial should be carried out from start to finish. Compliance with these standards is expected. 

The Clinical Trials Directive requires the integration of the GCP guidelines into the national law of all MS (which had not been the case in some MS before May 2004). Local regulatory authorities now carry the burden of inspecting for compliance with both GCP and the GMP guidelines for investigational drugs. Inspections take place at both sponsor s facilities and clinical trial sites. 

The European clinical trial directive has the central objective of protecting subjects taking part in medical research. The principles within Declaration of Helsinki (as amended) are now integrated into the legal framework by inclusion in the GCP guidelines (and also the GMP guidelines, see next section). Briefly, these principles are the following ... 

Directive EEC/2001/20 of the European Parliament and of the Council of April 4,2001 on the approximation of the laws, regulations and administrative provisions of the Member states relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use (The new Clinical Trial Directive). 

As well as domestic legislation, there is extensive European legislation governing member states. The European Community has over the years established measures to harmonize the regulation of medicines throughout Europe. In 2001, all European Community Directives adopted between 1965 and 1999 on the regulation of medicines were consolidated into a Community Code . At the time, the Code could not incorporate the new Clinical Trials Directive harmonizing EU controls on the approval and conduct of clinical trials (i.e. Directive 2001/20/EC). The Community Code has, however, since been amended to take into account the Directive s ethics. 

In Western Europe, in spite of the Clinical Trials Directive, there is still no uniformity in the order of approval/submission of documentation by the various parties involved. For example, although all countries now require review and approval of phase I clinical protocols, in some countries, approval of a study by the local or national ethics committee is required before documentation is submitted to the competent national authorities, whereas in others, this order is reversed. The documentation that is required to be submitted to the authorities is also quite variable (Table 50.2). Some countries require brief summaries of available information, whereas others require detailed information on the preclinical, pharmacy, chemistry and other clinical data to be submitted. 

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