Phase I - Human Pharmacology: First-in-human Clinical Trials – Risk Mitigation

2. First-in-human Clinical Trials – Risk Mitigation

The European Medicines Agency has issued guidelines on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal product (EMEA/CHMP/SWP/28367/07).

The safety of participants in first-in-human clinical trials can be enhanced by identification and planned mitigation of factors associated with risk. Key aspects to mitigate those risk factors includes:

Study population
Trial sites
First dose
Route and rate of administration
Number of participants per dose increment (cohort)
Sequence and interval between dosing of participants within the same cohort
Dose escalation increments
Transition to next dose cohort
Stopping rules
Maximum Tolerated Dose (MTD)

The higher the potential risk associated with a medicine, the greater the precautionary measures that should be exercised. Potential risk is identified from animal models (safety-toxicology, PK, PD), previous exposure of humans to medicines that have related modes of action, how new the molecular structure of the active substance(s) is (a novelty), and the nature of the target.

Participants in first-in-human studies are not generally expected to derive any therapeutic benefit from participating in the trial. When making the decision of whether the study population should be composed of healthy participants or patients, several factors should be taken into account, such as:

(a) the risks inherent in the type of medicinal product
(b) its molecular target
(c) immediate and potential long term toxicity
(d) the lack of a relevant animal model
(e) the relative presence of the target in healthy participants or in patients; e.g. cancer patients
(f) the possible higher variability in patients
(g) the ability of healthy volunteers to tolerate any potential side effects
(h) the potential pharmacogenomic difference between the targeted patient group and healthy participants
(i) the patients’ ability to benefit from other products or interventions
(j) the predicted therapeutic window of the medication under investigation

When selecting a trial site for first-in-human studies there a number of things to take into consideration.

First-in-human trials should preferably be conducted at a single site.
First-in-human trials should take place in appropriate clinical facilities and be conducted by trained investigators who have acquired the necessary expertise and experience in conducting early phase trials (i.e. Phase I-II) and medical staff with appropriate level of training and previous experience of first-in-human studies.
Units should have immediate access to equipment and staff for an acute emergency and ready availability of Intensive Care Unit facilities.