Are You Familiar With The Framework For First-In-Human Testing?

By Ed Miseta, Chief Editor, Clinical Leader

In January of this year, a clinical trial tragedy in France claimed the life of one healthy patient and caused serious brain damage in five others. Another clinical trial accident, this one in London in 2006, left six men ill. These accidents are rare, but can happen when an experimental medicine is put in humans for the first time.

Reacting to the most recent accident, in May the French Health Ministry found blame with the two companies involved in the trial, noting Bial and Biotrial were at fault on several counts, including how much of the drug they gave volunteers, how long it took them to inform the government about the problems, and for failing to properly inform the other volunteers. The European Medicines Agency (EMA) is hoping to improve the safety of first-in-human (FiH) clinical trials by reviewing FiH guidelines.

Roger Mills has a lot of experience in clinical trials and has participated in FiH testing. Prior to his recent retirement, Mills served as a professor, cardiologist, VP of medical affairs, and most recently as senior director/clinical lead for a pharmaceutical company. He believes the EMA review of guidelines is a step in the right direction to ensure the safety of future trial participants.

Although FiH dosing is a critical event in the clinical development pathway, Mills believes few clinical trial personnel are familiar with either the theoretical or practical aspects of early human studies. A paper written by Jonathan Kimmelman titled “A Theoretical Framework for Early Human Studies: Uncertainty, Intervention Ensembles, and Boundaries” lays out some of those aspects. Specifically, Mills points to the following:

• Early studies require exposing at least some of the volunteers to doses of compounds that are either inactive or excessive.
• Multiple Phase 1 trials: For example, single ascending doses followed by multiple ascending doses followed by chronic dosing, are aimed at answering different questions. They often precede Phase 2 trials; however, new Phase 1 trials may be conducted long after a drug has completed Phase 2 trials.
• A basic ethical premise is that a series of early studies should be planned to minimize the number of subjects, and their level of risk, while gathering adequate data to support decision making for later-phase trials.
• On the other hand, defining dosing boundaries requires that some patients will receive inactive and/or harmful interventions during the course of drug development. 

Mills also notes there are multiple approaches to study designs for early human dosing trials. The protocols for these trials must incorporate not only a valid trial design, but also the potential need for additional data at some doses, so flexibility is important. Thus, the early ascending dose studies often define blinded cohorts of six to eight individuals who will receive a given active dose and two individuals who will receive a placebo. Dosing may be further stratified so that one of the first four patients to receive a new dose receives placebo and the other three receive the active drug. 

“Typically, the first two individuals in the FiH cohort are dosed on separate days with an appropriate post-dosing observation period,” says Mills. “Subsequently, if no untoward events occur, the number of subjects dosed at a single time might be slowly increased in later cohorts.  However, the safety profile and tolerability of the preceding dose should always be confirmed before escalation to the next dose level.”

With regard to the French study, Mills notes there are two questions that immediately come to mind. First, was the increase from 20 mg to 50 mg daily excessive? Second, given the magnitude of the increase in exposure, was it prudent to have dosed all eight of the cohort volunteers at the same time?

“Even in the best of hands, unexpected and unfortunate events will happen,” he adds. “The only way to absolutely prevent serious and unexpected adverse events is the unacceptable option of not performing clinical trials. Despite the emotional appeal of finding ‘someone who did something wrong,’ we should not be looking for a scapegoat. We should be shaking our heads, realizing any one of us could have been the clinical investigator and keeping this trial in mind when we justify an extra bit of prudent caution with dosing schedules when large increases in exposure are concerned.”