To provide best achievable clinical safety is always a challenge in first in human trials. Starting with the decision to proceed from preclinical research to the clinical development of a new drug researchers are confronted with many challenges including creating an appropriate study design, preparing the regulatory documents, conducting the clinical trial and, finally, drawing the right conclusions from the data.
Although the European Medical Agency (EMA) noted that severe adverse reactions as those observed in London, 2006 (TeGenero case) and in Rennes, 2016 (Biotrial case) are extremely rare (3.100 FIH since 2005), a new draft guideline on strategies in FIH and early clinical trials had been filed and will become valid very soon. However, the principles of this guideline are already used by the authorities to evaluate recently submitted First in Human/ early clinical trials.
New Draft Guideline for Risk Mitigation
The new guideline covers considerations on quality aspects, e.g. the investigational medicinal product (IMP) used in preclinical studies should be representative of the IMP used in the later FIH/ early clinical trials, non-clinical aspects, e.g. confirmation that all pivotal non-clinical safety studies are conducted in compliance with GLP and clinical testing strategies and designs, e.g. providing a specific plan to monitor and manage likely AEs as well as procedures and responsibilities for modifying or stopping the trial, if required.
There will be no specific risk classification regarding the IMP; the guideline applies to all new chemical AND biological IMPs. When planning a FIH/ early clinical trial, sponsors and investigators should identify any potential risk factors and implement appropriate risk mitigation strategies in the clinical trial application (CTA). The factors of risk may be derived from recent knowledge regarding the mode of action, the nature of the target, the relevance of animal models and/or findings in non-clinical safety studies.
An important item in the guideline is the dose selection for the above mentioned trials. Trial objectives should be aimed to assess the pharmacokinetic (PK) and pharmacodynamics (PD) profile and the tolerability of the IMP without exposing a large number of subjects.
All available non-clinical information (PD, PK, TK and toxicological profiles, dose or exposure/ effect relationships, etc.) should be taken into account for the calculation of:
- the starting dose (NOAEL, MABEL, state-of-the-art-modelling and ATD)
- dose escalation steps (dose-/ exposure-toxicity, dose-/ exposure-effect relationship → potential AEs to be monitored)
- maximum dose (MTD approach is considered unethical for healthy volunteers).
For the step from single to multiple dosing the specific PK and PD characteristics of the IMP, the available non-clinical safety data, and human PK, PD and safety data from the subjects in previous single dose cohorts should be taken into account. Special attention should be paid to the fact if a linear or a non-linear PK profile has been observed.
A maximum duration of dosing should be stated in the protocol for every cohort. The chosen dose, as well as expected exposure after multiple dosing (Cmax and AUC0-t) should be addressed.
When planning and conducting either a FIH or an early clinical trial, subjects’ safety should override potential time restrictions for logistical reasons.
In general it is not acceptable, e.g. to allow a repetition of a dose level or cohort where that dose has met any of the dose escalation stopping rules. The guideline foresees precautions regarding the subjects within a cohort (e.g. sequential dosing!), between cohorts (e.g. intervals between cohorts guided by non-clinical and clinical PK and PD data) and between study parts. It is mandatory to define clear stopping rules for the individual subjects as well as for the whole clinical trial.
Conclusion
In conclusion it can be stated that it is critical to provide criteria to stop a trial at an adequate time-point taking into account the review of emerging data with special reference to safety. It is essential to assess adverse events with regard to these stopping rules and establish a guided process to decide for a potential continuation/ non-continuation with respect to further cohorts in FIH/ early clinical trials.
If this topic is interesting to you, sign here to watch our next live online seminar! Our experts, Dr. Grit Andersen and Dr. Jorge Arrubla will discuss about the design, conduct and analysis of first into human trials.