Asking the Impossible of European Understanding?

July 1, 2004

Applied Clinical Trials

Volume 11, Issue 7

To present the new scheme as a time-saver rather than a time-waster, the new guidance points out that the data required is a subset of the data required in any case for the request authorization.

What would a sponsor think if he were suddenly requested to provide (yet again) the following information on a trial? Believe it or not, this is just an abbreviated list:

Full title of the trial; sponsor's protocol code number, name, or abbreviated title of the trial; sponsor identity, details and history of the investigational medicinal products being tested or used as comparator (including pharmaceutical form, route of administration, all strengths to be used, provenance of active substance); details of placebo; details of the medical condition on which the trial is focused; main and secondary objectives; principal inclusion and exclusion criteria; primary endpoints, scope and phase of the trial; design of the trial, sites, dosing and duration; population of trial subjects and details; principal and coordinating investigators; central technical facilities; duties subcontracted; trial monitoring facilities; and ethics committee and protocol details.

It's not just a hypothesis. In Europe it is the new reality. New guidance has just emerged about the functioning of the embryonic EudraCT database, which is intended to provide an overview of clinical trials being conducted in the European Union. This new tool is intended to allow national authorities to compile information on a standardized basis, to communicate with one another and with the European Medicines Agency, to improve oversight of trials and investigational product development, and to enhance protection of subjects.

The system applies to any clinical trial with a site in any of the EU member states-which now number 25 with the inclusion of many central and eastern European and Baltic states in May. The information will cover the content, commencement, and termination of trials and inspections, and will be linked within the Eudravigilance database of reports of suspected unexpected serious adverse reactions reported during clinical trials for investigational medicinal products. EudraCT will also send a message to the competent authorities whenever an entry is made in the database indicating that a trial has been terminated or suspended for safety reasons. It will automatically notify member states when a trial is terminated or suspended anywhere in the EU.

A unique EudraCT number will identify each clinical trial, irrespective of the number of sites or member states involved. This number must be included in the submission of the request for the trial to the competent authorities and ethics committees, and used on any amendments or the end of trial report, as well as on suspected unexpected serious adverse reactions reports.

Each investigational medicinal product will also be identifiable through the Eudravigilance product dictionary, reflecting the requirements for identification of products through their development cycle. Where several active substances are included in one product, these should be individually identified. Where a product that is being used in the trial has a marketing authorization in the EU, the tradename and the marketing authorization number will suffice. Flow diagrams showing the process of sponsor registration and submission of data elements are detailed in the specification and design documents in the system, as well as validation of these and entry into the database by the competent authorities. But the database will not contain individual personal information relating to clinical trial subjects/patients. "Personal data should be protected in accordance with the provisions of Good Clinical Practice," the guidelines say, another challenge for sponsors.

Registration requirements

Each clinical trial needs to be clearly identified in the database before the competent authority assesses it (and before the competent authority provides written authorization for the trial, or takes the decision that there are no grounds for nonacceptance). This is to ensure that the database is a complete database and can fulfill its objectives. In particular, it is necessary to ensure proper reporting and review of suspected unexpected serious adverse reactions.

The requirements imposed on the clinical trial sponsor are numerous. The sponsor is required to notify the competent authority of the end of the trial, or of its early termination. The sponsor is responsible for the accuracy of data submitted to the competent authorities.

Sponsors will have to register with the system in advance-both for security reasons, to protect the system from unauthorized access, and to ensure authentication of the information submitted, by establishing the sponsor as the authentic source of information for that company and in the context of this database. And failure by the sponsor to submit accurate or complete information may be a reason to consider the request submitted to conduct a clinical trial to be invalid.

But in a bid to present the new scheme as a time-saver rather than a time-waster, the new guidance points out that the data required is a subset of the data required in any case for the request for authorization, so it can also be used for submissions to the competent authorities and the Ethics Committees.

"To facilitate the implementation of the database, and to enable search and reporting functions, data will be entered in English whenever possible," the guidance points out. "Where feasible," dropdown menus and picklists may be provided in the official languages of the EU, it adds-but since there are now 19 of these official languages, feasibility is going to be a heavily conditioning factor in the equation. Maltese, for instance, is one of the new official languages of the EU since its May enlargement, but this is spoken by only 300,000 people in the world. In fact, the EU has found it impossible to recruit enough translators and interpreters to fulfill its new task of putting everything into Maltese-and the same problem is likely to emerge with other new official languages spoken by less than 2 million people, such as Estonian, Slovenian, or Latvian, which have also now acquired official European Union status.

All it needs is for the current wave of lobbying for other European languages to win official status to make the sponsor's life complete: how about Catalan or Welsh? Both of these are spoken by as many or more people as many of the EU's new official languages, and the new European Parliament, being elected in mid-June, is sure to put forward plenty of sympathetic arguments in this direction once it gets going later this year.

The new CPMP

Meanwhile, all those still trying to keep a grip on Europe's shifting reality need to take on board a challenge. The CPMP-the key committee of the European Medicines Agency in London-is dead, but has immediately re-emerged with a new membership and a new name.

The reason is that part of the new EU pharmaceutical legislation1 came into force on 20 May 2004-including the administrative changes in the work of the agency. (The remaining parts will be enacted on 20 November 2005.) In fact, the new rules have also changed the name of the agency, so now it will be officially known by its unofficial title, the European Medicines Agency. Absurdly, however, it will continue to use the acronym "EMEA"-which denoted the European Medicines Evaluation Agency, itself a transmogrification from the original title of the European Agency for the Evaluation of Medicines!

The old Committee for Proprietary Medicinal Products, the Agency's senior scientific body for human medicines, has been abolished. Instead it now has a Committee for Medicinal Products for Human Use, to be known as CHMP. The first meeting of the CHMP took place at the beginning of June, with its modified membership.

Now it has 27 members (and the same number of alternates-as substitutes are termed in Brussels): one from each of the now 25 member states, plus Iceland and Norway. The reduction from two members to one member per member state is intended to boost the professionalism of the new committee, making nomination more related to personal expertise than mere ceremony. And because the new rules have come into force just days after Europe grew from 15 to 25 member states, this meeting was also the first time that members from the 10 new member states were fully included in the Committee's work.

But not everything has changed: the new Committee started its three-year term by electing Daniel Brasseur as its chairman and Eric Abadie as its vice-chairman-two key figures in the now-extinct CPMP.

The agency's new 33-member Management Board has also just met, and gave its approval to the new CHMP. It also elected a new chairman, Professor Hannes Wahlroos, director-general of the Finnish National Agency for Medicines. The Management Board has also been slimmed down by the new EU rules: it now has one representative from each of the 25 member states, two representatives of the European Parliament, and two representatives of the European Commission. The revised legislation also adds for the first time two consumer representatives and two representatives of health care professionals (one for doctors and one for veterinarians).

Other changes that came into effect in May include a reinforced role for the agency in giving scientific advice to companies, cooperation with the WHO in giving opinions for the use of medicines outside the EU, and opinions on the compassionate use of unapproved medicines. The agency will be given a stronger role in providing information to patients and the public, including a mandate to develop a database of all medicines approved in the European Union ("EuroPharm"). And small and medium-sized companies can also obtain greater administrative and scientific support.

When the rest of the package comes into effect in November 2005, there will be changes on conditional approvals and fast-track reviews, in addition to an increase in the scope of the centralized procedure.

Meanwhile, the agency is moving rapidly towards its own redefined world. It has recently launched a consultation exercise on its plans for the future-set out in a discussion document entitled "The European Medicines Agency Road Map to 2010: Preparing the Ground for the Future." The paper outlines the agency's strategy to turn itself into "one of the world's foremost regulatory authorities for medicinal products." It plans to be "public health oriented, science-driven and transparent in the way it operates." And its ambition is to meet that familiar two-fold challenge of both protecting patients and encouraging research.

At the same time, the plan tries to find a realistic way of operating in an enlarging Europe. Behind all the weary management-speak about implementing visions and establishing networks of excellence, there is a hard-headed recognition that it is going to be difficult to function in effective partnership when more than 40 national agencies are involved-as EU strategy already foresees. All the more so when the size of the countries and their sophistication and experience in drug regulation varies between Germany, the United Kingdom, or Denmark at one extreme, and Bulgaria, Bosnia-Herzegovina, or Albania at the other.

It may be tough for the clinical trials community around the world to follow what's happening in the agency, but it's pretty tough too for the agency as it tries to react to the new demands imposed on it by politics, geography, science, and history.

References

1. EU pharmaceutical legislation Regulation (EC) No 726/2004, published on 30 April 2004 (OJ 136, 30.4.2004, p. 1).