Les Nouveaux Clinical Trials Guidelines Sont Arrives

A sampler from recently published EU documents that set out to guide the way member nations regulate clinical research in Europe.

ust like London buses, you wait for one for ages, and then a whole bunch come along at once. That's what's happened with the European Union's guidelines on how the new clinical trials rules should be applied at national level.

After months of anguished expectation from the clinical trials community across Europe-and just days before the EU member states had to bring in their national rules to give force to the 2001 EU directive1-a plethora of guidance documents suddenly appeared at the end of April.

Companies developing drugs and academia had been loudly critical of the delay and the risk of confusion that a legislative vacuum would create. The final stage in the process is for the new framework to become obligatory-as from May 2004.

The recently released new texts give detailed guidance on

• The request for authorization of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments, and declaration of the end of the trial.

• The application format and documentation to be submitted in an application for an ethics committee opinion on the clinical trial on medicinal products for human use.

• The collection, verification, and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use.

• The European database of suspected unexpected serious adverse reactions.

• The European clinical trials database.

The detailed guidance will be included in the overall notice to applicants that the European Commission publishes to advise companies on what to include in their applications for marketing authorization for new medicines.

The 2001 directive foresaw that the guidelines would be published in time to influence national transposition, by May 2003-so that the rules can come into force at the national level by May 2004. The urgency was underlined by the European Forum for Good Clinical Practice, whose members are drawn from European public and private health research, regulatory authorities, ethics committees, hospitals, patients, and researchers. They argued loudly that the original EU intention to create a research environment in Europe in the interest of improved public health "will be seriously curtailed if the Commission's responsibilities for producing guidance documents do not achieve an adequate European framework." Now that the framework is out in the public domain, the European clinical trials community can give its views on how far the new rules will make Europe-wide clinical trials more feasible and more efficient.

Authorization requests

There's no way of doing justice to this mass of new rules in just one column, but as a taster of what the new guidelines look like, here's a snapshot of how the one on requesting authorization of (and amendments to) a clinical trial shapes up.

It's a 40-page document, about half of which is explanation, the other half taken up with a model application form. (Yes, the application forms are themselves 17 pages long!) The directive required the Commission to work with the member states to prepare detailed guidance on the application itself, and on the documentation to be submitted in support-on the quality and manufacture of the investigational medicinal product, any toxicological and pharmacological tests, the protocol, and clinical information on the investigational medicinal product including the investigator's brochure.

The sponsor must be EU-based or have an EU-based legal representative, and the application must contain the core information required by that member state.

The application must be in the right language for the member state concerned, should also indicate where else applications have been made, and with what outcome (including copies of any ethics committee opinions).

A cover letter must draw attention to any special issues related to the application, such as special trial populations, unusual investigational medicinal products (IMPs), or unusual trial design.

It must contain the number of the trial allocated under the Eudract system, the European clinical trials database, which will identify the protocol for a trial whether conducted at a single site or at multiple sites.

The application should identify the organizations and key individuals responsible for the conduct of the trial. The protocol must be included in the application, and its content and format should comply with the guidance in the EU guideline on Good Clinical Practice (CPMP/ICH/135/95). It should also include all currently authorized amendments, a definition of the end of the trial, and any plan for treating the participants after the trial if that differs from current practice. Among other things, it should include the justification for including subjects who are incapable of giving informed consent.

The investigator's brochure (IB) should be prepared from all available information and evidence that supports the rationale for the proposed clinical trial and the safe use of the investigational medicinal product (IMP) in the trial. And the content, format, and procedures for updating it should comply with the EU Good Clinical Practice guideline.

The dossier on the IMP should give information on quality-including reference products and placebos to be used in the clinical trial and data from nonclinical studies and its clinical use-or justify in the application why information is not provided. The application may cross-refer to the IB for the preclinical and clinical parts of the IMP dossier but, if so, the summaries of preclinical information and clinical information should include data, preferably in tables, providing sufficient detail to allow assessors to reach a decision about the potential toxicity of the IMP and the safety of its use in the proposed trial.

A simplified IMP dossier may be submitted if information related to the IMP has been assessed previously as part of a marketing authorization in any EU member state or as a clinical trial application to the competent authority concerned. For products already marketed in the EU and used in the same form, for the same indications, and with a similar dosing regimen, the sponsor may submit the current version of the Summary of Product Characteristics as the IMP dossier.

A full IMP dossier has to be supplied when the sponsor has not previously submitted any information about the chemical or biological product concerned to the competent authority and cannot cross-refer to information submitted by another sponsor-such as when no marketing authorization exists in any EU member state. The dossier should include summaries of information related to the quality, manufacture, and control of the IMP, nonclinical data, and clinical data. The dossier required will depend on many factors, including the nature of the medicinal product, the stage of its development, the population to be treated, the nature and severity of the disease, and the nature and duration of exposure to the investigational medicinal product.

Summaries of chemical, pharmaceutical, and biological data are required for any IMP. The Directive requires that sponsors supply IMPs for a clinical trial whose manufacture complies with EU rules on good manufacturing practice.

Summaries of nonclinical pharmacology and toxicology data-or justification of why they are omitted-are required for any IMP to be used in the clinical trial, along with a reference list of studies conducted and appropriate literature references. A mere factual summary of the studies conducted is not enough. The sponsor should provide a critical analysis of the available data, including justification for deviations and omissions from the detailed guidance, and an assessment of the safety of the product in the context of the proposed clinical trial.

All studies should be conducted according to currently acceptable state-of-the-art protocols. In addition, where appropriate, they should meet the requirements of good laboratory practice guidelines. The sponsor should justify any deviations from these guidelines and provide a statement of the GLP status of all studies. The test material used in the toxicity studies should be representative of that proposed for clinical trial use in terms of qualitative and quantitative impurity profiles. The preparation of the test material should be subject to appropriate controls to ensure this and thus support the validity of the study.

Previous clinical trial and human experience data should also be provided when available. Compliance with the principles of good clinical practice (GCP) should be confirmed by the sponsor in a statement of the GCP status of all studies. If this is not the case, an explanation or justification should be provided.

An overall risk and benefit assessment should also be provided. Sponsors are expected to offer an integrated summary that critically analyses the nonclinical and clinical data in relation to the potential risks and benefits of the proposed trial. As a guide to what may occur in humans, the sponsor should integrate all the available data, analyze the pharmacological and toxic actions of the IMP, and use the results to suggest possible mechanisms and the exposure required to produce them. Where appropriate, safety margins should be discussed, in terms of relative systemic exposure to the investigational medicinal product. The text should discuss the reason for terminating any study prematurely. The provisions of the EU clinical trials directive should be taken into account when evaluating studies on minors and incapacitated adults. There should also be discussion of the clinical relevance of any findings in the nonclinical and clinical studies, along with any recommendations for further monitoring of effects and safety in the clinical trials.

Notification of amendments

The guideline also covers amendments to the conduct of a clinical trial after its commencement. Amendments that are substantial must be notified to the competent authority and the ethics committee concerned. They may arise from changes to the protocol or from new information relating to the scientific documents in support of the trial. Amendments to the trial are regarded as "substantial" where they are likely to have a significant impact on the safety or physical or mental integrity of the subjects, the scientific value of the trial, the conduct or management of the trial, or the quality or safety of any IMP used in the trial.

Where a substantial amendment affects more than one protocol for a particular investigational medicinal product, the sponsor may make a single notification to the competent authority concerned, provided that the covering letter and notification includes a list of all affected protocols with their Eudract numbers. A cover letter should draw attention to any special issues related to the amendment and indicate where the relevant information or text is in the original application. In the case of substantial amendments that affect information submitted to both the competent authority and the ethics committee, the sponsor should make the notifications in parallel. For substantial amendments to information that only the competent authority assesses, the sponsor should not only submit the amendment to the authority but also notify the ethics committee that they have made the application. Similarly, the sponsor should inform the competent authority of any substantial amendment to information for which only the ethics committee is responsible.

The sponsor may implement a substantial amendment if the ethics committee opinion is favorable and the competent authority has raised no grounds for nonacceptance. For amendments submitted to either the ethics committee alone or the competent authority alone, the sponsor may implement the amendment if the ethics committee opinion is favorable or the competent authority has raised no grounds for nonacceptance.

European authorization?

No such luck!

It might be expected that after completing all this standardized information-and after so many years of discussion of harmonization of clinical trials in Europe-an authorization like this would be good for the whole of the European Union. Not so. The guideline clearly states that authorization of a clinical trial by the competent authority of a member state "will only be valid for a clinical trial conducted in that member state."

References

1. European Parliament, Directive 2001/20/EC of the European Parliament and of the Council of 4 April 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 (EU Official Journal, L121, 5 January 2001. p. 34).

2. The new guidelines can be consulted on http://pharmacos.eudra.org/F2/pharmacos/docs.htm#news.