EU Proposes Authorization Changes

September 1, 2001

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-09-01-2001,

Patients, research companies, and regulatory authorities may all benefit from proposed changes to current pharmaceutical legislation, but the proposals will provoke much debate.

Patients, research companies, and regulatory authorities may all benefit from proposed changes to current pharmaceutical legislation, but the proposals will provoke much debate.


The European Commission is determined to improve the possibilities for innovative medicines to win authorization in Europe. Proposals it presented in mid-July envisage some significant reforms of current pharmaceutical legislation in the European Union. These reforms are heavily geared towards speeding better medicines to patients and boosting the European pharmaceutical industrys ability to compete at world level in drug design and development.

The proposalsknown as Review 2001will shake up many aspects of European Union (EU) drug regulation, from marketing authorizations to intellectual property rights, from advertising to generic competition. And they aim to give something to everyonepatients, research companies, generic product manufacturers, and regulatory authorities responsible for human health care. According to the Commission, patients will benefit from increasing access to new and innovative medicines, from more and better information for selected prescription medicines, and from reinforced monitoring of products after launch. The research-based pharmaceutical industry should benefit from clearer procedures, faster processing for innovative products, and some improvement in intellectual property protection. The generic pharmaceuticals industry should benefit from the right to perform earlier tests on the products they are copying. And the public in general should benefit from better transparency.

The proposed legislation
The proposals take the form of three pieces of draft legislation:

  • regulation on marketing authorizations and the functioning of the EMEA
  • directive on medicinal products for human use
  • directive on veterinary medicinal products. Text of the drafts can be found on the Web at dg3.eudra.org/F2/review/index.htm. Following are the main themes of the reforms.

Expanded centralized authorization. The London-based EMEA (European Agency for the Evaluation of Medicinal Products), in operation since 1995, is to be retained and reinforced, along with its centralized European procedure for the authorization of new medicines. All new medicines based on new chemical entities will be required to use this procedureuntil now it was optional for them, and mandatory only for biotechnology-derived products. The centralized procedure will also be open, on an optional basis, to any other product for which the applicant shows that the product constitutes a significant innovation or that there is an EU interest for patients.

Improved evaluation process. The evaluation process will be enhanced, with strengthened scientific committees and new working groups and access to experts. The Commission wants EMEA to acquire an increased and flexible scientific expertise, which could be developed in-house or by establishing communication channels outside the agency. The EMEA will use this expertise to provide early scientific advice to companies developing new products, in particular to small and medium companies developing biotechnological or innovative products. And to ensure better coherence, the EMEA will incorporate the Committee on Orphan Medicinal Products and a new Committee on Herbal Medicinal Products, a new advisory board of national authorities with a consultative function on authorization procedures, and a modified management board with representation from patients and industry.

Fast-track registration. To speed assessment and decision procedures so that slow development does not neutralize the benefits of innovative products, the Commission proposes a U.S.-style fast-track registration procedure for products of significant therapeutic interest. When a company undertakes to perform additional monitoring and clinical studies for subsequent review, the Commission proposes a conditional marketing authorization. Valid for one year, it would apply to products with an important expected health benefitsuch as for life-threatening conditions where there is no effective therapy. It also proposes a Europe-wide system for compassionate-use availability of medicines before authorization.

The end of five-yearly renewals. The proposal removes the five-yearly renewal procedure for marketing authorizations, replacing it with reinforced pharmacovigilance and information sharing provisions. Periodic safety reports, in the context of pharmacovigilance, will have to be prepared and reviewed more frequently than in the current system. The removal of the renewal procedure is largely compensated by a strengthening in pharmacovigilance requirements, explained the European Commissioner responsible for the proposals, Erkii Liikanen. This means that there will be an obligation for companies to monitor and analyze all adverse drug reactions.

Modified authorization procedures
Under these new proposals, any product may be granted marketing authorization through the EUs centralized procedure, provided that the applicant shows that the medicinal product is a significant therapeutic, scientific, or technical innovation or that an authorization is of interest at EU level to patients or to animal health. An authorization may also be granted subject to certain specific obligations (such as the provision of additional clinical trials data), to be reviewed annually by the EMEA. A Commission regulation will determine the circumstances and arrangements for granting authorizations under this rule. In exceptional circumstances, authorization may also be granted under specific conditions (such as delivery by hospital consultants only, or for highly specific conditions), which the EMEA must reassess annually. Continuation of the initial authorization may be linked to the reassessment of these conditions.

When an application is submitted for products of major interest from the point of view of public health and in particular from the point of view of therapeutic innovation, the applicant may request an accelerated assessment procedure. If the committee accepts the application, the normal 210-day time limit is reduced to 150 days.

Compassionate use. Products not yet authorized for human use, but potentially of major interest from the point of view of public health, may be made available to certain patients for compassionate reasons. Where compassionate use is envisaged, the Committee for Proprietary Medicinal Products, after consulting the manufacturer or the applicant, may adopt recommendations on the conditions for use, the conditions for distribution, and the patients targeted. Member states will have to take appropriate measures to ensure that the recommendations can be implemented at national level. The EMEA will have to keep an up-to-date list of the products covered by this provision. Civil or criminal liability of the manufacturer or the applicant for marketing authorization will remain unaffected. And no product administered for compassionate reasons may be the subject of a paid transaction, except in special cases determined beforehand in national legislation.

The EU rules on good clinical practice in the conduct of clinical trials will remain valid for such use. Once actual marketing of a product previously administered for compassionate reasons takes placefollowing the granting of a marketing authorizationthe restrictions on charging will no longer apply.

New assistance for applicants
The EMEA is to set up structures and procedures for giving advice to companies, particularly regarding the development of new therapies. The advice will cover the conduct of the tests and trials necessary to demonstrate quality, safety, and efficacy. Each EMEA committee will have to establish a standing working party with the sole remit of providing scientific advice to companies. In the case of limited markets, the EMEA is to provide help to pharmaceutical companies at the time of submission of their applications. Such help is to include, in particular, taking over responsibility for some translations.

The EMEA will formally acquire the new Committees on Orphan Medicinal Products, and on Herbal Medicinal Products. Its principal scientific body, the Committee for Proprietary Medicinal Products, may be accompanied by experts in specific scientific or technical fields. In addition, it may co-opt a maximum of five additional members chosen on the basis of their specific scientific competence. Its committees will have new powers to establish working parties and expert groups, and to include in their rules of procedure precise procedures for delegating certain tasks to these working parties. And EMEA and Commission staff will be entitled to attend all the meetings of the committees and working parties.

The EMEA will have duties to ensure early identification of potential sources of conflict between its scientific opinions and those of other EU bodies carrying out a similar task, and to work towards resolving them. The agency will have a new advisory board to give nonbinding advice on any point concerning its activities regarding the procedures for authorizing medicinal products. This board will consist of one representative from each national authority, the EMEA executive director, and representatives of the Commission.

Upgraded pharmacovigilance requirements
Companies will have to provide the competent authorities with any information relevant to the evaluation of the risks and benefits of a medicinal product, including appropriate information on post-authorization safety studies. The qualified person for pharmacovigilance will have to reside in the EU. And marketing authorization holders will be required to record and report all suspected serious adverse reactions of which they can reasonably be expected to have knowledge. They must report immediately to the member state on whose territory the incident occurred and to the EMEA, no later than fifteen days following receipt of the information.

After the first four years of marketing, periodic safety updates will have to be submitted every three years (instead of the current five years). The EMEAs role is to be expanded to explicitly cover supervision and pharmacovigilance. And the EMEA is to make available information on adverse reactions, through a database permanently accessible by all member states.

Except in exceptional circumstances, adverse reactions are to be communicated electronically. To facilitate the exchange of information on pharmacovigilance within the EU, the Commission will draw up guidelines (after consulting the EMEA, the member states, and interested parties) on the collection, verification, and presentation of adverse reaction reports. The guidelines will include technical requirements for electronic exchange of pharmacovigilance information in accordance with internationally agreed formats. The agency will also have to publish a reference to an internationally agreed medical terminology, which marketing authorization holders will be obliged to use for reporting of adverse reactions.

And in the context of pharmacovigilance particularly, the authorization holder will have to provide all information on the sales or prescription volumes at EU level and by member state, at the request of the EMEA.

Proposing sweeping changes as they do, the draft directives in Review 2001 will provoke a wide range of responses. And even when the Commission formally makes its final proposals in the autumn, after linguistic and other amendments to the current draft, the debates in the European Parliament and the Council of Ministers are expected to take several years. Even optimists agree it could be 2006 before the first changes reach the statute book.

German dispute pending
Meanwhile, on one of the pharmacovigilance questions which will be reinforced by the new proposals, the European Commission is already locked in a battle with the EUs biggest member state. The Commission has rejected a request from Germany to maintain more stringent rules on drug safety monitoring than are required by EU law. Germanys request, says the Commission, is admissible, but unfoundedand therefore must be rejected.

The conflict has arisen from Germanys wish to retain its own legal requirement on drug manufacturers to inform the German authorities of any adverse drug reaction. EU law, modified in 2000 (by Commission Directive 2000/38), requires drug companies to report all adverse drug reactions in the EU to the authorities in the member state concerned, and to report all unexpected drug reactions in non-EU countries to the EMEA and to the authorities in the member state where the product is authorized.

Germany has defended its request on the grounds that its more extensive requirements are necessary for the protection of human life and health. But the Commission says there is no such risk in the EU systemneither the current system nor the new, more electronically-based network of drug safety information that will come fully into effect from 2002 under the terms of Directive 2000/38. Nevertheless, Germany has also brought a case against the Commission Directive in the European Court of Justice, seeking its annulment. That case is still pending.

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