Doubts are nearing crescendo level on the merits of the European Union’s regulation of clinical trials—and not only within the European pharmaceutical industry. Investigators, ethics committees, and the regulatory authorities themselves are starting to question just how feasible the impending changes are as the EU buckles on the final implementation details of its 2001 directive on clinical trials (pharmacos. eudra.org/F2/eudralex/vol-1/new_v1/ dir2001-20_en.pdf), with its formidable range of new data requirements.¹

Brasseur’s reservations
“It won’t be so easy to implement it in the current system,” Applied Clinical Trials was told at the start of September by no lesser figure than Daniel Brasseur, MD and chairman of the Committee for Proprietary Medicinal Products (CPMP) at the European Agency for the Evaluation of Medicinal Products (EMEA). Brasseur, speaking both as a leading academic clinician and in his formal role as the head of Europe’s principal scientific body for the evaluation of medicines, openly admitted that problems exist both with the current functioning of the clinical trials rules, and with the prospect of more than a dozen new detailed guidelines and subsidiary directives due to come into force next year.

This body of rules may lead to the generation of large quantities of clinical trials data, according to Brasseur. “But there is no guarantee that it will be of benefit,” he said.

Brasseur’s remarks suggest a lack of overall strategy in the approach to medicines regulation in Europe. The EMEA is currently undergoing administrative reorganization, he pointed out. The major review of the entire body of European pharmaceutical rules now underway leaves many of the established procedures and practices for drug registration and review open to question. Enlargement of the EU is just around the corner, with the prospect of membership increasing from the current 15 member states to 25 by 2004. On top of that, the new clinical trials rules agreed to in 2001, which emphasize good clinical practice (GCP), are now in the final stages of implementation—including this large body of highly detailed extra guidelines. Handling all the details simultaneously and successfully is a major challenge, Brasseur indicated—particularly since the new guidelines will not necessarily fill all the gaps.

Making the new rules work will be one thing. But making intelligent use of the material generated by the new rules will be quite another, he went on. “It will be a major administrative burden principally for the EMEA, rather than the CPMP itself, and I have some sympathy with them for the workload they will have to cope with,” he said.

Brasseur’s concerns relate not merely to the size of the task, but also to its utility. “The question is, who will be interested in all this data?” he asked. “What is an ethics committee to make of all this information? They are interested in ethical questions. But this is the sort of material for an institutional review on a scientific basis, which an ethics committee is neither equipped nor mandated to carry out—and does not wish to. Its role is to make ethical assessments.”

Guidelines and guidance
Heavy criticism of the new rules is coming in from all sides. Brasseur spoke to ACT at the end of a meeting he attended in Brussels of the European Forum for Good Clinical Practice (EFGCP), at which a long sequence of diverse experts pointed out concerns over the dozen or so texts that the European Commission is now finalizing as its detailed implementation rules for the European Commission’s proposed “List of implementing texts of Directive 2001/20/EC.” These texts provide detailed guidance on specific areas of GCP, including principles, submissions to ethics committees and to competent regulatory authorities, databases, adverse reactions, inspections, and good manufacturing practice compliance (many of these proposals have been summarized or highlighted in this column over recent months). They will determine responsibilities on the part of sponsors, investigators, ethics committees, and regulatory authorities in the practice of conducting clinical trials in Europe.

Comments came from many people, including representatives from ethics committees, patient organizations, regulatory agencies, industry, academia, and specific research areas such as oncology and pediatrics. EFGCP chairman Roger Bickerstaffe, of Solvay Pharmaceuticals, summarized the discussion, noting that because of overlap, things are described differently from one document to another, with much imprecision in the way they’re described in addition to a great deal of redundancy and uncertainty. “You’re required to collect so much data that the question arises as to how to derive a signal from it,” Bickerstaffe said, adding: “Industry itself will find it difficult, and regulatory authorities simply aren’t in a position to do so.”

Doubts and questions about guidelines and guidance dogged the meeting.

GCP and medicinal products for human use. On the “Detailed guidelines on the principles of good clinical practice in the conduct in the EU of clinical trials on medicinal products for human use,” questions were raised about whether the responsibilities of the various GCP actors are set out sufficiently clearly, and about how consistent these requirements are with ICH GCP.

Application format and documentation. On the “Detailed guidance on the application format and documentation to be submitted in an application for an ethics committee opinion on a clinical trial on a medicinal product for human use,” the questions covered the extent to which this guidance meets the needs and expectations of ethics committees, researchers, and sponsors, and whether the guidance is sufficient. Doubts were expressed about the extent to which it will contribute to efficiency in review, to improved subject protection, to reducing the workload for ethics committees, and to increased speed of review.

Request for authorization. On the “Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities in the European Union, notification of substantial amendments and declaration of the end of a clinical trial,” and the “Detailed guidelines on the trial master file and archiving to implement the directive on Clinical Trials on medicinal products for human use,” anxieties related to how far the guidance provides for a harmonized EU approach to the commencement and conduct of clinical trials, whether it provides for sufficient protection of clinical trials subjects within and across member states and in non-EU countries, and whether the requirements are sufficient or excessive.

SUSAR. Participants expressed worries over the definitions and procedures for reporting suspected unexpected serious adverse reactions (SUSAR) when the meeting examined the “Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use” and the “Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance—Clinical Trial Module).” Participants offered conflicting views over the extent to which the guidance provides standards for uniformity and efficiency, and to what extent research subjects in clinical trials will be better protected.

Databases. On the “Detailed guidance on the European clinical trials database (EUDRACT Database)” and “Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions (Eudravigilance—Clinical Trial Module),” queries were raised over what oversight these databases actually provide the European regulatory authorities. Uncertainties remain on how data will be received, codified, and entered into the databases, and over who will have access, how confidentiality will be guaranteed, and how the databases will be linked.

Inspectors and inspection. When the meeting discussed the “Detailed guidelines on inspection procedures for the verification of GCP compliance to implement the directive on Clinical Trials on medicinal products for human use” and the “Detailed guidelines on the qualifications of inspectors who should verify compliance in clinical trials with the provisions of Good Clinical Practice for an investigational medicinal product to implement the directive on Clinical Trials on medicinal products for human use,” questions were raised over what will be the inspection process in the European Union, how inspections will be coordinated within and across member states and with non-EU countries, what standards will be used for inspecting clinical trials, how inspection results will be communicated, and to whom they will be available.

Real questions arise over the extent to which these guidance documents will improve the European clinical trials environment for the benefit of researchers, research organizations, and above all, subjects, EFGCP states in its meeting documentation. “The past 12 years of debate on European GCP and the need for a general European clinical trials framework is very much at stake in the specifics of what this set of guidance proposes,” the EFGCP document states, adding that the general consensus achieved by the 2001 Directive is under threat, because of specific concerns about the way these “leftover” issues are being handled in terms of detailed guidance. The broad consensus among the critics is that the texts go beyond current European Union GCP and ICH GCP, adding new guidance based on the legal framework provided by Directive 2001/20/EC.

A “disappointed dream”
Much of the criticism leveled at the texts focused on the inconsistencies and redundancies but, above all, on the extensiveness and the provision for member states to add further rules of their own. A Turkish participant at the EFGCP meeting expressed bewilderment and disappointment at what had emerged. “In Turkey, we want to be more involved in European trials, and we are anxious to upgrade our understanding so we can do that. I came here expecting to learn how the European Union wants us to do things. But I find that there are contradictions even in what Europe wants.” A Wellcome Trust delegate warned that the catchall nature of the new rules, with their heavy requirements on data generation, would imperil clinical trials in the noncommercial sector.

Roger Bickerstaffe spoke of a “disappointed dream,” noting that when the initial concept of an EU regime for clinical trials was floated in the early 1990s, the aim was to make things easier for everyone—from sponsors and investigators to subjects—through a process of harmonization. But, he told Applied Clinical Trials, this objective has been lost. Instead, what has emerged is an accumulation of all the national requirements.

As Jean-Pierre Tassignon, an EFGCP member, put it in his concluding remarks to the meeting: “The dream was of a single European regulatory environment for clinical trials and an improved competitive environment for EU. The dream was of a solution to the real losses occurring in Europe because the EU was too slow, partly because of slow clinical trial authorization, particularly through ethics committee—but this has changed.” Increased focus on safety, and decreased capacity by the European Commission to impose itself on the EU member states, has robbed the exercise of its original objective. On one of the central questions—trial authorization—the new documents threaten to extend controls so that it will no longer be just a matter of submitting data and getting an approval number and presenting a final report. “It is being turned into a system of constant reporting in minor detail,” he said.

Tassignon told ACT afterwards: “The tendency of member states is to go further all the time. And the Commission is protecting the prerogatives of the member states.” For them, he said, safeguarding their right to regulate at a national level—particularly on authorizations, inspections, and ethics committees—is the principal concern. “For member states this is a matter of life and death—and we are caught in the middle,” he said. Too much detail exists, for instance, about the requirements on misconduct or the prior details of subjects per center. “Our dream as patients, ethics committees, investigators, and sponsors is to have a rethink of all these documents in an integrated way to eliminate inconsistencies,” Tassignon concluded.

Members of the EFGCP are very worried. “The final shape of these guidance documents will determine the EU regulatory framework for clinical trials in the future,” the organization states. And EFGCP members aren’t happy with the shape that is emerging.

References
1. European Parliament, Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 (European Parliament, Brussels, Belgium, 2001).