The European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use (CHMP) has adopted a draft guideline on requirements for first-in-man trials of high-risk medicinal products.

The draft guideline, which has gone out for two months’ public consultation, 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 was prepared by experts in clinical and non-clinical research from the national competent authorities and CHMP working parties, building on the principles laid down in European legislation and existing guidelines.

The document covers 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. It touches many of the same bases as the final report released last November by an Expert Scientific Group on Phase I clinical trials, set up by the UK government under the chairmanship of Sir Gordon Duff.

For example, the draft EU guideline echoes that report in recommending that, when defining an appropriate early development programme for high-risk medicinal products, information “needs to be integrated from many sources and frequently reviewed in an iterative process”. It also follows the Duff recommendations in suggesting that a Minimal Anticipated Biological Effect Level (MABEL), rather than the traditional No Observed Adverse Effect Level (NOAEL), is the best approach to calculating first doses of high-risk medicinal products in humans.

In general, the draft guideline says, the safety of the participants is paramount in designing first-in-man studies. “Decisions on strategies for development of a new medicine and the experimental approaches used to assemble information relevant to the safety of first-in-man clinical trials must be science-based, made and justified on a case-by-case basis,” it adds.

A potentially high-risk medicinal product is defined in the 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.

Once the two-month consultation period is over, the EMEA will hold a meeting with key stakeholders (the European Commission, national regulators, the pharmaceutical industry, patient and healthcare professional organisations, academia and learned societies) to consider the feedback and finalise the guideline for publication.