EU Guidance on Guidance

It had to happen. After some 30 years of pumping out guidelines on how to conduct trials on medicines, the European Union has decided it is time to put out a guideline on creating its guidelines. So, to add to the meters-thick pile of guidance that has emerged over the decades, there is now another 14-page document setting out why the guidelines exist, how they are developed, and how the procedure will work as further guidelines are produced.

Peter O'Donnell

It's a meritorious exercise by the European Medicines Agency (EMEA)—which, 10 years ago, took over the task of guideline production from the European Commission. For the first time, the question of how decisions are taken on whether new guidance is needed is being explicitly raised.

It's just a little surprising that it has taken so long to get here. The guidelines have conditioned the working life of everyone involved in clinical trials in Europe for a generation. They have obliged EU regulators and EU drug company managers to sit through countless hours of meetings, of consultation, of amendments to amendments. They have even provided part of the staple diet of this column since it began more than a decade ago.

The EMEA document that has now been published claims to set out "a consistent and transparent approach to assess the need for guidance and the impact for interested parties and competent authorities"—or, as some distinguished but somewhat irreverent members of the international clinical trials community have been known occasionally to term them, "the incompetent authorities." The new procedure will come into effect for all draft and final guidelines published by the EMEA after 1 September 2005. Those who want to read the full document for themselves can do so on http://www.emea.eu.int/pdfs/human/regaffair/2414304en.pdf. But since many readers of ACT are already busy enough coping with the guidelines that are already out there, without having to plough through a guideline on guidelines, here's the quick overview.

"A key part of EMEA work"

First of all, there's going to be no getting away from them. "Pharmaceutical guidelines provide essential information to be taken into account in the research and development of new medicines... They are a key part of the Agency's work," says the EMEA uncompromisingly.

As before there will be a wide range of guidelines, including: regulatory guidelines; scientific guidelines related to quality, safety, and efficacy; guidelines on good clinical practice; pharmacovigilance; orphan medicinal products designation; good manufacturing practice; herbal medicinal products; good distribution practice; and good laboratory practice.

With respect to GCP, the new document merely states that "Specific provisions apply for good clinical practice for investigational medicinal products for human use. Directive 2001/20/EC is the framework legislation and provides for additional directives, accompanying guidelines and detailed guidance documents."

But the document provides more food for thought under the heading of "Scientific Guidelines related to Quality, Safety and Efficacy." It insists that in assembling the dossier for an application for a marketing authorization, "applicants shall take into account the scientific guidelines (including core summary of product characteristics, where applicable) relating to the quality, safety and efficacy of medicinal products as adopted by ... the Committee for Medicinal Products for Human Use (CHMP)." These scientific guidelines "aim to provide a basis for practical harmonisation of the manner in which member states and EMEA interpret and apply the detailed requirements for the demonstration of quality, safety and efficacy. They are intended to give guidance to applicants and/or sponsors in planning the overall pharmaceutical product development, as well as the non-clinical and clinical tests and studies of a compound intended to be used as human or veterinary medicinal products and to facilitate the preparation of applications for marketing authorisations by the pharmaceutical industry."

Drafting a guideline

Topics will be selected on the basis of lists of subjects drawn up by the EMEA's scientific committees and their working parties, with a possibility for input at any time from member states, members of the scientific committees, from international activities and from interested parties—which are illustratively indicated as "the European pharmaceutical industry, European human and animal health professional groups, learned societies, patients' associations." The need for a new guideline may be triggered by frequently encountered problems with established products or by questions raised in the course the development of new products, technologies, practices or therapeutic areas. And new legislation—or obligations within the International Conference on Harmonisation—may also require the production of new guidelines.

The steps to be followed

The crucial changes in the procedure relate to the way guidelines will normally be developed in the future. The document sets out a step-by-step approach as follows (although exceptions could be made):

1. Selection of topic and inclusion in the relevant EMEA work programs

2. Appointment of rapporteur

3. Development of concept paper

4. Adoption and release for consultation of concept paper

5. Preparation of initial draft guideline

6. Release for consultation of draft guideline

7. Collection of comments

8. Preparation of final version of guideline

9. Adoption of final guideline for publication

10. Implementation

Once a topic has been selected, a rapporteur (and co-rapporteur if appropriate) is appointed from the relevant working party or scientific advisory group, to draft the concept paper—and any subsequent guidelines. The concept paper is a short public document highlighting the need for a discussion on specific issues, innovations or controversial key-points, at any stage of the development of products. It should identify the issues to be covered, and may discuss possible options, but should not recommend solutions. If specific interested parties are likely to be affected, they should be identified by the rapporteur to ensure appropriate consultation. And any exceptional cases where a new guideline will apply to medicines already on the market must be justified.

Once a concept paper has been adopted by the relevant committee, it is normally released for three months consultation to interested parties (and "specific procedures to ensure proactive and appropriate consultation" of patients, disease-specific patient organizations, and health care professionals will be developed). All comments will be considered in the development of the future guideline, and any justified concerns over the underlying principles may lead the EMEA to re-discuss aspects of the concept paper. But a concept paper will normally not be revised, as it will in any case be superseded by the subsequent guideline.

A start may be made to preparing the initial draft guideline during the consultation period, in particular where an issue of particular urgency is being addressed. The rapporteur prepares the draft text, which takes into account the comments received during the consultation, and the rapporteur may consult appropriate experts to provide further input. The text should indicate if there is only limited experience of the selected area of development, or where knowledge is fast evolving, requiring the need for subsequent updates and flexibility.

This draft is considered by the relevant EMEA working party and revised as necessary by the rapporteur, and when its members are satisfied, the text is released for consultation, normally for up to six months. Interested parties are encouraged to highlight inconsistencies of the proposed draft guidelines with related guidelines in other regions. Comments are normally expected from non-EU regulatory authorities, European industry associations, scientific or academic societies, and patient or consumer groups and health care professionals. Comments are considered and will be systematically published (unless they contain commercially confidential information and/or the author has specifically objected to publication). At this stage, the EMEA may convene a meeting with relevant interested parties to discuss aspects of a draft guideline. The rapporteur will prepare an overview of the main comments, explaining why they have—or have not—been accepted.

In line with the consultation, the text is revised, and when finalized it is submitted to the relevant scientific committee or other group for adoption, together with a proposed date for implementation. The committee and/or the European Commission adopts the final guideline, which is then published.

Guidelines normally come into operation six months after their adoption. Applicants may choose to apply a guideline before then, but competent authorities should wait until this period has expired before requiring the guideline to be taken into account. In some circumstances it may not be possible for applicants to fully comply with new guidelines within this timeframe (for instance where data were generated from trials started before the implementation of the new guideline), and the applicant should consider whether departure from the new guideline can be justified.

Reaction to industry comments

Some of the pharmaceutical industry comments made to the EMEA during the consultation process on this guideline were ignored as being outside the scope of the exercise. This is a pity, since they included requests such as "Reduction in data requirements should be achieved while maintaining measures proportional to the risk," or "Specific mandate to be given to scientific committees by a responsible body to consider the risk/benefit of rationalising data requirements," or "Guidelines should address the issue in a manner that minimises the impact on product development costs and medicines availability," or "Increase of data requirements restrains development of products for minor uses and minor species."

The uniformly terse reply of the EMEA to all these comments was: "Outside the scope of this procedure."

An even more trenchant comment—"Industry should not have to justify noncompliance with not legally binding guidelines"—was equally dismissed: "Not agreed," said EMEA; "The guidelines are applicable unless justified."

Now, at least, the organizations that made these comments have the chance to assess how far their views have been taken into account!