On 20 July 2017, the EMA published the updated guideline on first-in-man (also known as phase I) clinical trials. First-in-man trials often carry the greatest risks, and have been the ones that generate the biggest headlines when they have gone wrong, for example the Phase I trial in France by Bial-Portela & CA SA in 2016. The new guideline, which applies not only to first-in-man trials, but also to all ‘early phase clinical trials’ that generate initial knowledge on tolerability, safety, pharmacokinetics and pharmacodynamics, aims to ensure such trials are conducted as safely as possible, and assists sponsors in the transition from non-clinical to early clinical development.
The original version of the guideline, published in 2007, set out details of the data needed to enable appropriate design and to allow initiation of treatment in patients. However, there was a view that such guidance should be updated to better reflect current practices, and the lessons learnt when such trials have gone wrong. In particular, it is acknowledged that there is now a more integrated, and incremental, approach to product development, with sponsors conducting several steps of clinical development within a single clinical trial, so incremental decisions on next steps can be taken.
It is difficult to predict how a new product will be tolerated by people before it is actually studied in humans. As such, early clinical development has an intrinsic uncertainty in relation to both the possible benefits and risks of the drug under development. The trial sponsor has a responsibility to defined this uncertainty, based on the particular drug and target disease, and to provide a description of how those risks will be mitigated in the trial.
To assist sponsors, the guideline sets out the following risk mitigation strategies that should be undertaken when planning and implementing first-in-man trials:
- Quality: Ensuring adequate quality of the product. Specific areas to be addressed include determination of strength and potency, qualification of the material used and reliability of (very) small doses.
- Non-clinical: Generating robust non-clinical data in pharmacodynamics, pharmacokinetics and toxicology, and understanding how this translates to human subjects. The guideline advises conducting additional non-clinical testing to obtain data for the risk assessment, which may include, for example, generating data to support the assessment of the relevance of animal models by describing the similarity to human with regards to in vitro metabolic profiles.
- Dosing: Appropriate dose selection and escalation. One of the key aspects of first-in-man trials is the dosing used, and how this is increased as the trial progresses. Dose selection should be aimed at a “reasonably rapid attainment of the trial objections […], without exposing large numbers of patients”. As such, it is important that robust scientific rationale is used in the selection of the starting dose, for dose escalation and defining maximum exposure, and decision-making criteria should be described in detail. All available non-clinical information should be taken into consideration, and clinical data emerging during the trial will also need to be reviewed. The guideline notes that experience, both non-clinical and clinical, with molecules having a similar mode of action can also be useful.
- Risk minimisation: Risk minimisation activities should be proportionate to the degree of uncertainty and the potential risks identified. The guideline aims to address as far as possible, the important issues that may need consideration during the design of a study, such as choice of population, route of administration, number of subjects, and sequence and intervals of dosing.
The guideline comes into effect on 1 February 2018.