This report confirms that adverse events in phase I studies are very common, usually of minor intensity and rarely severe; even though exceptional, life-threatening adverse events are possible. Adverse events occurring in phase I are rarely published, leading to lack of information. Thus, authors invite clinical research organization (CROs) and phase-I centres to regularly publicise at least severe adverse events; they also suggest that the life-threatening adverse events reported to health authorities should be publicised, for example by the World Health Organization (WHO).

The key aims of this paper are to provide clinical pharmacologists with data, reference values or changes obtained in the real conditions of Phase I study implementation, and to propose relevant limits, either for screening as inclusion limits, or during studies as LAE limits. Thus, these data, reference values and specific limits improve the capacity to screen healthy volunteers and to analyse LAEs during Phase I studies.

No abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • After the TGN1412 incident in London, the European authorities reinforced the safety requirements for first‐entry‐into‐man (FIM) studies. Their recommendations on risk management included a risk minimization strategy based on clearly defined stopping rules. However to date, there are no approved grading scales for clinical adverse events or safety findings to support dose escalation and to define stopping rules in order to mitigate the risks for healthy subjects participating in FIM trials. WHAT THIS STUDY ADDS • This paper proposes standardized methods for the grading of safety data (adverse events, laboratory tests, electrocardiogram and vital sign findings) based on relevant criteria. The proposed grading scale provides support both for dose escalation and the design of stopping rules. The derived safety thresholds are applicable at either an individual subject level or at a cohort level, and are specifically adapted to young male healthy subjects, who represent the majority of the subjects participating in FIM trials. AIM To propose a relevant grading scale for clinical adverse events or laboratory results, electrocardiogram (ECG) and vital sign findings supporting both dose escalation and stopping decisions in first‐entry‐into‐man (FIM) studies conducted in young healthy subjects. METHODS A three‐level scale was used for the proposed grading system. The grading is directly derived from the observed severity of discontinuous variables, as are most of clinical adverse events. A ‘combined method’ based on normal ranges and spontaneous variation is suggested for grading the findings which are continuous variables mainly numerical in nature. One grade, at the subject level, and one algorithm, at the cohort level, support the proposed decision rules. This work was managed by a Club Phase I working group. RESULTS Examples of grade 1, 2 and 3 limits are given for the most frequent clinical adverse events and laboratory tests, ECG and vital sign findings. When available, the proposed NIH and FDA limits are also provided. The safety recommendation is to use the grade 2 at least as an alert for caution and the grade 3 as a maximum for stopping, applying the algorithm at the cohort level. CONCLUSIONS This paper proposes a safety grading system based on relevant criteria which might be used by investigators and sponsors to support and rationalize dose escalation decisions in healthy young subject FIM studies. These proposals are designed not to be a guideline but some ‘points to consider’ helping the dose escalation process. This paper supports the recent reinforcement of the safety requirements for FIM studies by European authorities.

Healthy volunteers selection is one of the foundations for phase I results. Safety for volunteers, quality of data and reliability for study results depend on healthy volunteers selection. The selection aim is not to choose normal subjects but to exclude every people with diseases or risk factors which could result in increased danger for themselves or confuse the interpretation of study results. The selection procedure needs to define a list of relevant disease to be excluded depending on phase I objectives (tolerability, pharmacokinetic, pharmacodynamic). The choice of diseases is based on frequency, potential risk for the subjects or for the study. The selection is mainly a clinical process but because of asymptomatic diseases a laboratory screening is necessary and useful. This laboratory screening requires that a basic common list of relevant tests be determined and an appropriate method of cut-off point determination based on an evaluation of the risk of disease. According to the drug or the objective of the study adaptation of the procedure must be carried out. The percentage of erroneous inclusion of subjects is the best validation criterion for selection. The use of such a selection methodology by the author's group in Lyon results in a 50% exclusion for 494 first seen subjects with only 1% erroneous inclusion and 6% exclusion for laboratory test anomalies.