The European Medicines Agency (EMEA) has backed away from a catch-all definition of potentially high-risk medicinal products in its final guideline on first-in-human (FIH) clinical trials.

The definitive version adopted this month by the EMEA’s Committee for Medicinal Products for Human Use (CHMP) and scheduled to take effect on 1 September 2007 conspicuously lacks any specific definition of a high-risk compound. Instead, it talks about identifying risk factors and applying risk mitigation strategies when planning a FIH study with an investigational medicinal product.

This is in line with suggestions by industry that the guideline should concentrate on risk mitigation rather than attempt to pin down – with potentially damaging consequences – what a “high-risk” product actually is. Pointedly, the document is now called a Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products, rather than a Guideline on requirements for first-in-man clinical trials for potential high-risk medicinal products as before.

The new title reflects the position taken by the European Federation of Pharmaceutical Industries and Associations (EFPIA), to the effect that risk is a continuum linked to issues such as dose selection and trial design, rather than a dichotomy of high versus low.

Critics of the definition in Section 4.1 of the draft guideline feared it would cover, and potentially stigmatise, virtually any new compound while encouraging non-harmonised interpretations by national regulators. Among the 200 pages of comments submitted on the CHMP’s proposals, the pharmaceutical and biotechnology industries warned that innovation, clinical development and study enrolment could suffer if the parameters for high risk were too broad or vague.

In the draft guideline, Section 4.1 characterised a potentially high-risk medicinal product 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. These latter three conditions remain in the final guideline, along with more detailed explanations on why, say, a novel mechanism of action or a particular drug target might be problematic.

The definition of “high-risk” has gone, however. In a markedly shorter preamble to Section 4.1, the final guideline says only that predicting “potential severe adverse reactions for the first-in-human use of an investigational medicinal product involves the identification of the factors of risk”. The scope of the guideline (Section 2) has been widened to include “all new chemical and biological investigational medicinal products except gene and cell therapy medicinal products”.

The full guideline can be downloaded from the EMEA’s website at It covers a number of quality, non-clinical and clinical issues around FIH trials, ranging from compound characterisation to the relevance of animal models, pharmacodynamics and pharmacokinetics, toxicology, first doses in humans, protocol design, safety precautions and suitable facilities.

The European Commission’s ad hoc group on clinical trials is looking at the implications of the FIH guideline for its own guidance documents on procedural matters such as trial applications and information given to study participants.