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The latest wrinkle in the European Union?s clinical trials rules debate comes from modifications of the draft text at the core of its proposal.
The casuists of the Counter-Reformation would have found delight in the European Union debates on clinical trials. The debates offer an intricacy that could feed the appetite of the most avid sophist. But its hard work for the 21st-century clinical trial practitioner to keep abreast of the latest twists in the elaborate rococo design of the EU rules that governor will governhis or her work.
The latest twist comes not from the clinical trials directive itselfstill awaiting full implementation (View from Brussels, Applied Clinical Trials, November 2002)but from the wider debate on the review of all the EUs pharmaceutical rules.
New readers start here. In early 2001 the EU proposed changes to the basic EU rules on medicines authorization, nominally to speed up and improve authorization decisions, to ensure a high level of public health protection, and to simplify the system. These proposals have been debated at length by the 15 EU member states and by the European Parliament, which delivered its first opinion on the proposals in November 2002. A decision, however, is still monthseven yearsaway.
Habitual readers can start here. The EU has modified its draft text for the regulation at the heart of the proposals, its 2001 draft regulation of the European Parliament and of the council laying down community procedures for authorization, supervision, and pharmacovigilance of medicinal products for human and veterinary use and establishing a European Agency for the Evaluation of Medicinal Products. (The new text is available at: europa.eu.int/ eur-lex/en/com/pdf/2002/com2002_0735en01.pdf.) The changes take account of many of the multiple views expressed by the European Parliament, and a new debate will start on that basis. Some changes have direct relevance to clinical trials; many have indirect relevance; and the package as a whole remains a crucial influence on the future shape of European pharmaceutical regulationhowever it finally turns out.
Directly relevant to clinical trials
The new text, drawn up by the European Commission (which is responsible for making legislative proposals in the EU), reflects acceptance of the principle in one of Parliaments amendments relating to the application of the ethical requirements of Directive 2001/20/EC on the implementation of good clinical practice in the conduct of clinical trials on medicines authorized by the EU, and to clinical trials conducted outside the EU on products destined to be authorized by the EU. The new wording reads:
There is also a need to provide for the ethical requirements of Directive 2001/20/EC of the European Parliament and the Council 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 (footnote: Official Journal of the European Communities L 121 of 1.5.2001, p. 34) to apply to medicinal products authorized by the Community. In particular, with respect to clinical trials conducted outside the Community on medicinal products destined to be authorized within the Community, at the time of the evaluation of the application for authorization, it will be verified that these trials were conducted respecting the principles of good clinical practice and the ethical requirements equivalent to the provisions of this Directive.
In some areas, the Commission has accepted the principle of European Parliament amendments, but has not considered changing its proposal accordingly because EU rules already cater to such needs. For instance, an amendment aimed at boosting clinical trials in children is not necessary because the clinical trials directive already contains specific provisions that apply to studies conducted in children. Similarly, the Commission also accepted the principle of another amendment aimed at providing that the new database on medicinal products, which is to be established by the European Commission under the proposals, contains information relating to clinical trials. But in this case too, the Commission says there is no need for any change to its proposal: the addition of such a provision does not appear to be necessary; the Directive on clinical trials already provides for a specific database for clinical trials conducted with a view to the authorization of medicinal products for human use.
Some European Parliament amendments have been turned down flat by the Commission because they cover areas already dealt with or to be dealt with in legislation currently in the pipeline. For instance, the Commission says new obligations are not needed concerning pediatric indications or for a provision obliging the scientific committee to consult experts in pediatrics. The issues concerning medicinal products for pediatric use will be taken up in the future legislative proposal that will be aimed specifically at the questions relating to these medicinal products, it says. Parliament requests to include data concerning pharmaco-vigilance in the database on authorized medicinal products are also excessive, says the Commission.
Indirectly relevant to clinical trialsThe new text also introduces some elements that will speed up processing of applications. For clarity, the Commission has changed the wording of provisions concerning the authorization of certain medicines under exceptional circumstances, as follows:
In exceptional circumstances and following consultation with the applicant, authorization may be granted subject to a requirement to introduce specific procedures, in particular concerning the safety of the medicinal product, for notifying the relevant authorities of any incident related to its use and for any action taken. This authorization may be granted only for objective, verifiable reasons and must be based on one of the grounds set out in annex I to Directive 2001/83/EC. The maintenance of the authorization is bound to the annual reassessment of these requirements.
The Commission has accepted the principle of amendments aimed at permitting the European Agency for the Evaluation of Medicinal Products to recommend conditions relating to the use of certain medicinal products so as to guarantee their safe and effective use. A new point is added to the effect that EMEA committee opinions may contain details of any conditions or restrictions which should be imposed so as to guarantee the safe and effective use of the medicinal product, in particular mechanisms for controlling and monitoring its use and administration.
Likewise, the Commission has endorsed the principle of an accelerated procedure for medicinal products used in certain treatments with a view to making them available to patients more quicklybut has pointed out that this procedure is already foreseen in the initial draft text, and an additional reference is, therefore, not necessary.
The Commission has played a rather cautious hand on some areasnotably on comparative efficacy, which the Parliament called for a reference to, and which many EU member states already use in their national decisions on pricing and reimbursement of medicines. It is important to emphasize that this evaluation should not be considered as a necessary criterion for the application or for the authorization of medicinal products. In effect only the criteria of the quality, safety, and efficacy of the particular medicinal product should be used in the evaluation of medicinal products, explains the Commission. So it is proposing wording as follows:
The Member States have developed an evaluation of the comparative efficacy of medicinal products aimed at positioning a new medicinal product with respect to those that already exist in the same therapeutic class. Similarly, the Council, in its conclusions on medicinal products and public health, adopted on 29 June 2000, emphasized the importance of identifying medicinal products that presented an added therapeutic value. However this evaluation should not be conducted in the context of the marketing authorization for which it is agreed that the fundamental criteria should be retained. It is useful in this respect to allow for the possibility to gather information on the methods used by the Member States to determine the therapeutic benefit obtained by each new medicinal product.
A new article is also introduced to provide for the possibility for the EMEA, at the request of the Commission, to collect information from the competent authorities of the member states in charge of performing evaluations of efficacy compared to that of already authorized medicinal products, worded as follows: At the request of the Commission, the Agency will collect information on the methods used by the competent authorities in the Member States to determine the therapeutic progress contributed by each new medicinal product.
PharmacovigilanceA number of changes have been introduced relating to pharmacovigilance. To provide public funding for the EMEA commensurate with its pharmacovigilance activities, the Commission has reworded its text as follows: In order to ensure full independence, the activities relating to pharmacovigilance, to the operation of communications networks and to market surveillance should receive guaranteed and adequate funding. To allow a role for patients in the communication of adverse effects, it proposes new wording.
to limit the number receiving these communications; in effect it does not seem appropriate that patients should transmit this information directly to marketing authorization holders, without the intervention of a health-care professional or a competent authority who could manage or filter such information.
The Commission goes on,
The holder of the marketing authorization and the competent authorities of the Member States shall ensure that all relevant information about suspected adverse reactions to the medicinal products for human use authorized under this Regulation are brought to the attention of the Agency in accordance with the provisions of this Regulation. Patients shall be encouraged to communicate any adverse reaction to their health-care professionals or to the competent authorities for pharmacovigilance.
To clarify the timelines for the submission of the first updated period in safety report and the contents of these reports, it proposes rewording of its initial draft text as follows.
Unless other requirements have been laid down as a condition of granting of the marketing authorization by the Community, these records shall be submitted in the form of an updated periodical report on safety, to the Agency and Member States immediately upon request or at least every six months during the first two years following the initial placing on the market in the Community, and once a year for the following two years. Thereafter, the reports shall be submitted at three-yearly intervals, or immediately on request. These reports shall be accompanied by a scientific evaluation, notably a benefit-risk analysis of the medicinal product.
To clarify the contents of the guidance to be developed for the collection, verification, and presentation of adverse reaction reports, the Commission rewords its text.
The Commission, in consultation with the Agency, the Member States and interested parties, shall draw up guidance on the collection, verification and presentation of adverse reaction reports. This guidance shall contain, in particular for the benefit of health-care professionals, rules concerning the transmission of information on adverse reactions.
Shaping the future
Some of the changes could make conditions tighter for companies marketing their products. They would allow, for instance, for withdrawal of products if the envisaged tighter postmarketing shows they have a negative benefit/risk analysis. And companies would not be allowed to communicate any information concerning postmarketing data on their products to the general public without the consent of the EMEA.
Other changes the Commission has made could also permit faster processing of authorization applicationscutting to just 15 days the delay for the European Agency for the Evaluation of Medicinal Products to send draft decisions on authorizations to the member states, and for the Commission (which is legally responsible for the final decision) to act. The Commission has also agreed to provide public access to information about all refusals, and the reasons for them. And while it retains its plan to annul the authorization of a product that has not been marketed within three years, it will now allow companies to challenge such decisions in exceptional circumstances and on public health grounds.
Where to from here?
This is still barely the halfway stage in the process. Alongside the draft regulation, a draft directive is also under discussion. The Councils Common Position is not expected early in the new year. And once that emerges, the proposals will then, of course, go back to the European Parliament for second reading. As the European Federation of Pharmaceutical Industries and Associations is warning, it could be 2004 before the new rules are agreed upon.