First Time in Human (FTIH), or First in Man (FIM), studies are conducted based on the nonclinical data package submitted to regulatory authorities. Nonclinical toxicology, pharmacology, pharmacokinetics, in vitro assays, etc. conducted with the investigational compound are used to establish a safe starting dose among other parameters. FTIH studies are typically conducted in healthy volunteers utilizing a single dose, dose escalation study design (single ascending dose or SAD study) to identify the maximum tolerated dose and/or dose limiting toxicity.
Typically, regulatory agencies are requiring pre-defined clinical stopping criteria incorporated into clinical protocols based on empirical safety data collected during the conduct of the FTIH study. As such, sponsors will commonly include interim analysis of safety data prior to dose escalation. Also, Nuventra recommends the evaluation of interim pharmacokinetic data between cohorts in a dose escalation study. This will allow an opportunity to confirm or adjust the pharmacokinetic sampling schedule that was originally based on nonclinical data from IND-enabling studies.
Scientific & PK Considerations
A common question from clients is should they include a placebo group or placebo dose in FTIH, single ascending dose studies? More often than not the answer is “yes.” In fact, in one instance, the inclusion of a placebo group in a first-in-human study likely saved an entire drug development program or at least helped avoid the need for additional work in later stage development for the compound. In this example, two subjects appeared to have drug-related cardiac issues during the conduct of a double-blind, placebo-controlled FTIH study. However, when the treatment assignments were unblinded it was determined that both subjects had received a placebo dose.