Innovation, clinical development and study enrolment could suffer if too broad or vague a definition of potentially high-risk medicinal products is adopted in a European guideline on first-in-man (FIM) trials, the pharmaceutical and biotechnology industries have warned.

What exactly constitutes a “high-risk” compound was a particular bone of contention in responses to a public consultation on the draft Guideline on requirements for first-in-man clinical trials for potential high-risk medicinal products, released by the European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) in March. As part of the consultation process, the EMEA held a workshop on the draft guideline at its headquarters in London last week.

The document, which the agency plans to finalise “in the coming weeks,” was drawn up by national regulators in the European Union, together with the EMEA and the European Commission, in response to the disastrous Phase I trial of TeGenero's monoclonal antibody TGN1412 at Northwick Park Hospital in London last year. It addressed the quality, non-clinical and clinical aspects of the transition from animal or in vitro studies to first exposure in humans, including the calculation of first doses in humans, subsequent dose escalation and risk management.

The draft guideline echoed in some respects the final report released in November 2006 by a UK Expert Scientific Group on Phase I clinical trials, set up by the government under the chairmanship of Sir Gordon Duff. For example, it followed the Duff recommendations in suggesting that a Minimal Anticipated Biological Effect Level (MABEL), rather than the traditional No Observed Adverse Effect Level (NOAEL), was the best approach to calculating first doses of high-risk medicinal products in humans.

A potentially high-risk medicinal product was defined in the CHMP’s draft guideline as one where “there are concerns that serious adverse reactions in first-in-man clinical trials may occur,” taking into account the experimental drug’s mode of action, the nature of its target and the availability of relevant animal models.

High response rate

The CHMP’s proposals drew 200 pages’ worth of comments from 57 parties representing the pharmaceutical and biotechnology industries, contract research organisations, clinical research organisations, ethics committees, academia, healthcare professionals, animal welfare interests and patient groups.

Summing up the responses, the EMEA’s Dr Jean-Marc Vidal told the workshop that the draft guideline had generally been welcomed as a lucid and detailed overview of a complex issue that would help to establish a clear and efficient assessment process for both applicants and regulators.

However, there were also concerns that the draft guideline was too general, encouraging a potentially unproductive ‘checklist' approach, and that some of the recommendations were already covered by existing guidelines. More specifically, some respondents felt the definition of high-risk medicinal products in section 4.1 of the guideline was too vague and could stigmatise both new compounds and first-in-man testing of those compounds.

The fear was that, if section 4.1 was taken as read, virtually any new compound could be regarded as high-risk, noted Christian Schneider of Germany’s Paul-Ehrlich Institute at the EMEA workshop. Another worry was that national competent authorities would put their own, non-harmonised interpretation on the definition. Instead, it was proposed, high-risk medicinal products could be narrowed down to more specific classes of compound, such as agonists (as suggested in the Duff report), monoclonal antibodies (mAbs) or even just full-length mAbs.

Dose selection and trial design

The European Federation of Pharmaceutical Industries and Associations (EFPIA), which itself received more than 120 pages of comment on the draft guideline, said risk in FIM trials was linked in particular to dose selection and the clinical trial design. Rather than applying a catch-all definition, the guideline should stay focused on risk-mitigation principles and strategies through non-clinical data integration and appropriate study designs, the EFPIA argued. Accordingly, the document’s title should be altered to Guideline on risk management strategies and dose-setting for first-in-human clinical trials.

It was the trial design that resulted in acceptable or unacceptable risks to humans in FIM studies, and this design in turn was influenced by all the available non-clinical and human-derived data, EFPIA commented. The industry already had “extensive” experience of dealing with ‘high-risk’ molecules such as oncology products, it added, while the degree of caution required would vary on a case-by-case basis according to the associated biological and toxicological knowledge and the sponsor’s confidence in the predictive value of non-clinical models. Risk was a continuum and not a dichotomy of high versus low, EFPIA said.

For the European Association for Bioindustries, EuropaBio, there were two possibilities for tightening up the draft guideline: either covering all first-in-man studies and concentrating on risk-mitigation strategies, or restricting the guideline to FIM trials for high-risk products, in which case there needed to be a clear definition of what “high-risk” meant.

Similar concerns were expressed by the European CRO Federation, EUCROF, which also highlighted other grey areas in the draft guideline, such as the advice on sequential dosing (both acute and repeat administrations) and the definition of appropriate clinical facilities for FIM trials.

EUCROF further suggested that the protection of trial subjects could be enhanced by an accreditation system for centres that conducted FIM or non-therapeutic clinical studies (as was recently proposed by the UK’s Medicines and Healthcare products Regulatory Agency/MHRA), a national or European database of health volunteers and other participants in non-therapeutic studies, and by restricting the fees that healthy volunteers could earn per study or per year.