Clinical Trials in the EU

These principles of GCP have been incorporated into regulations that govern the initiation and conduct of clinical trials. The process for undertaking clinical trials in the EU and the US shall now be examined. 

Two directives were recently introduced to harmonise the conduct of clinical trials in the EU. These are  

Clinical trials shall be conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects 

The rights, safety, and well-being of the trial subjects should prevail over the interests of science or society Prior assessment should indicate that the anticipated benefits would outweigh any foreseeable risks or inconveniences The medical care given to, and medical decisions made on behalf of subjects should always be the responsibility of qualified medical personnel 

Freely given informed consent should be obtained from every subject 

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Duration of Repeated Dose Toxicity Studies to Support Phase 1 and Phase 2 Clinical Trials in the EU, and Phase 1, 2, and 3 Clinical Trials in the United... 

The following table describes the duration of repeat toxicity studies to support phase III clinical trials in the EU and Marketing in all regions1. 

With a view to harmonising the controls on clinical trials, a draft Directive concerning the conduct of clinical trials in the EU was submitted to the European Parliament by the Commission in September 1997. After three years of difficult negotiations, a EU Directive aimed at harmonising the requirements for clinical trials in the European Union was finally agreed on 4 April 2001 by the European Parliament and Council and formally adopted in May 2001 with a three-year transition period for its implementation by 1 May 2004. 

The initiation and management of multinational clinical trials in the EU therefore requires considerable coordination and effort. The centralized coordination of the national procedures is essential to make sense of the complexity, ensure consistency, and to avoid duplication of effort, thus saving time and money. Therefore, to transform the presently cumbersome disparate situation through the EU CT Directive into a single set... 

Table 6.1 Duration of repeated-dose toxicity studies to support Phase I and Phase II clinical trials in the EU, and Phase I, II, and III clinical trials in the USA and Japan"...

At present, the EU Directives covering medical products are all directed at the marketing of such products. There is currently a draft Directive aimed at harmonizing the requirements for clinical trials in the EU. 

The relevant regulations governing the conduct of clinical trials in the U S are shown in Table 5.4. As they also reflect the principles of GCP, they are quite similar in requirements to those of the E U. However, because they apply to a single jurisdiction, they are framed to provide more prescriptive detail than can be found in the equivalent EU directives. Similarly, they are supported by the ICH- and FDA-specific guidelines. As most of the practices are the same as discussed in the previous section, the chapter will now just examine some of the aspects that are unique to the US regulations. 

Data from 6 months of administration in nonrodents should be available before the initiation of clinical trials longer than 3 months. Alternatively, if applicable, data from a 9-month nonrodent study should be available before the treatment duration exceeds that which is supported by the available toxicity studies. dTo support Phase I and II Trials in the EU AND Phase I, II and III Trials in the U.S. and Japan. 

There are slight differences in the requirements for the European Union, the United States, and Japan. Duration to support Phase III trials in the EU, when they differ from the other data, is given in parentheses. Readers are referred to Guidance for Industry M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, EDA, Rockville, MD, 1997. http //www.fda.gov/cder/guidance/1855fnl.pdf [accessed September 20,2007]. 

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. 

Since the implementation of the EU Directive 2001/20/EEC on clinical trials in the United Kingdom on 1 May 2004, all clinical trials now... 

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. 

With a view to harmonizing the conduct of clinical trials across the EU, Directive 2001/20/EEC was finally agreed on 14 December 2000, and was formally adopted in May 2001 with a three-year transition for its implementation. 

Clinical trial provisions and controls vary greatly between EU Member States at present. However, the legislative basis and the procedures involved in initiating clinical trials in the UK will change following the imminent adoption of a new EU Directive relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. The contents of this Directive are summarised briefly in a later section of this chapter and its implementation in all Member States is required by 1 May 2004. 

An IND application must be submitted to the FDA prior to the first clinical trial in the United States. In Europe, IMPD/CTA submission is required, and the content and expectations may vary country-to-country. For IND/IMPD EIH studies, the project team must plan for the manufacture and release of clinical trial materials as well as for the IND/IMPD documentation. A regulatory submission may not be required in certain ex-US/EU countries if the study is conducted in volunteers. For a study in volunteers not requiring an IND/IMPD, documentation needs are reduced but all other activities remain the same. 

EU Directives 2001/20/EC and 2005/28/EC set out the new rules and regulations for the approval and conduct of clinical trials in Europe. Member states had to enact the Directives into national legislation and put them into effect by May 1,2004. 

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 the past, various individuals and organisations have claimed to own the data produced from a clinical trial, including the state, the sponsor, the investigator and, in some cases, the patient or study subject. It is certainly true that with the advent of the EU Directive on Data Protection, the claim of ownership to his or her data by the patient or study subject has been strengthened. Unfortunately, there is no clear ownership of clinical data except that of society. Even then, society needs to respect the confidentiality and other wishes of individual subjects who have been clinical trial participants. Is there a difference in ownership between data produced from product-driven research to that produced in policy-driven therapeutic research ... 

Patent protection under general law usually lasts for up to around 20 years. This creates a difficulty in relation to medicinal products, as it can take some 12 years for the products to undergo research, development, the extensive clinical trials that are required in order to obtain a marketing authorisation and the authorisation process itself. These steps are also extremely expensive. The amount of time that remains during which the patent holder can exploit his patent and recoup his massive investment can be severely curtailed in relation to medicinal products. For this reason, the European Community has provided a form of additional patent-related protection for medicinal products authorised within the European Community, by means of a Supplementary Protection Certificate. A patent holder may apply for a certificate that takes effect at the end of the term of the basic patent, for a period equal to the period that elapsed between the date on which the application for the basic patent was lodged and the date of the first authorisation to place a product derived from the patent on the market in the Community, reduced by a period of 5 years. The maximum duration of the certificate is 5 years. The certificate applies to all medicinal products derived from the basic patent, but the additional time that can be obtained under the SPC is calculated in relation to the first product derived from the patent, authorised in the EU. 

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