We describe a structured risk assessment and risk mitigation process that is currently used to evaluate proposed first-in human (FiH) studies. This process balances the inherent risks of an FiH study with maximal protection of subjects. Risk assessment should consider all available data, carefully identifying aspects that may lead to risk for healthy subjects. A structured risk assessment avoids omissions and promotes consistency. Such a risk assessment should be performed for Investigational Products as well as for challenge agents and study procedures. Careful risk assessment recognizes gaps of knowledge and emphasizes that FiH studies are tolerability, not toxicity, studies.

Twenty-four men and 24 women ages 20-77 years received a single 15 mg oral dose of buspirone followed by 4 days of 15 mg tid administration. Plasma concentrations of buspirone and 1-pyrimidinylpiperazine following both single and multiple dosing were determined by RIA and GCMS, respectively. There were no significant differences between the young and elderly of either gender with regard to buspirone AUC, Cmax, Tmax and half-life values. The 1-PP AUC values were higher for young of either gender compared to the corresponding group of elderly subjects and the 1-PP Cmax values were higher for women than men. These differences are unlikely to be of clinical significance. The buspirone and 1-PP AUC values for a dosing interval during multiple dosing are not significantly different than the respective single dose AUC values. Buspirone treatment was well-tolerated by all subjects even though the 45 mg/day dose was 3 times the recommended starting dose in clinical practice. Overall, the lack of marked or consistent differences in buspirone or 1-PP pharmacokinetics in elderly subjects compared to younger subjects of the same gender suggest there is no need to alter the initial dose of buspirone based solely on patient age.

Simultaneous administration of cimetidine and many benzodiazepine anxiolytics has resulted in decreased body clearance and marked prolongation of the half-life of these agents. The pharmacokinetic interaction of buspirone, a new nonbenzodiazepine anxiolytic, and cimetidine was studied in 10 healthy male volunteers. Each received, in order, buspirone 45 mg/day (days 1-7), no drug (days 8-14), cimetidine 1 g/day (days 15-21), buspirone 45 mg/day plus cimetidine 1 g/day (days 22-28), and cimetidine 1 g/day (days 29-31). Buspirone and 1-pyrimidinyl piperazine (1-PP), an active metabolite, pharmacokinetics, urinary excretion of cimetidine, a manual dexterity test, the Stroop color-word interference test, and a visual analog mood scale were evaluated on each treatment. There were no significant (p greater than 0.05) differences among treatments for any measurement except for a slight (31%) but significant (p less than 0.05) increase in the 1-PP Cmax value. These results suggest that within the normal therapeutic dosage ranges for both drugs, it is unlikely that a clinically significant interaction between them will occur.

A cross-section of clinical research professionals convened at the June 2016 Drug Information Association annual meeting in Philadelphia to discuss and critically analyze the first-in-human (FIH) clinical trial conducted by a French CRO with BIA 10-2474 (BIA) under development for pain relief by Bial-Portela & Ca., S.A., that resulted in 6 healthy volunteers hospitalized with serious adverse events, which resulted in 1 death. This paper summarizes the background, presentations, and discussion points of Symposium no. 107 in an effort to share the learnings of our symposium with others who conduct studies. Novel investigational products studied in phase 1 clinical trials propose a heightened risk of adverse events that may not be foreseeable when relying on animal studies to project outcomes in humans. Novelty of molecular structure, drug class, mechanism of action, proper dose selection, pharmacokinetics, and therapeutic window are all contributing factors that heighten risks when transitioning from animal to human trials. The potential for catastrophic events confronts every sponsor/investigator in clinical trials. Minimizing risks to subjects is an essential ethical and scientific mandate for all those involved in the clinical trials. A complex matrix of planning, conducting, and communicating preclinical and clinical observations need to be considered carefully by the Sponsor, Investigator and others during the planning, execution, and interpretation of FIH studies, in order to promote participant safety and study data integrity. Suggestions may be applied to FIH studies, which may provide a new or improved way to address complex system and prevent or mitigate situations such as what occurred with the Bial FIH trial, where seemingly a number of issues coincided in a "perfect storm" and the system failed to sound a warning or detect an issue before a life was tragically lost.

This paper summarizes a discussion that took place at the 52nd Annual DIA Meeting in Philadelphia, PA, on June 30, 2016, titled "Hot-Button Protocol and Operational Issues between Sponsors and Sites in Clinical Pharmacology Studies." The symposium was a moderated panel of phase 1 clinical research experts representing the sponsor, and investigational sites. Conference attendees of similar experience joined in the discussion after commentary by each panelist. The learning objectives of the symposium were (1) to recognize issues that can provoke sponsor/site conflict or diminish conduct efficiency when they arise in the course of preparing to conduct or execution of phase 1 clinical studies, (2) to discuss how to handle such issues with counterparts when they arise and describe ways to negotiate and formulate a successful resolution. Sponsors and sites both have challenges in executing clinical trials on time and within budget. Both need to set and maintain realistic expectations and communicate with honesty, transparency, and timeliness. Achieving this goal will advance the more important take-away message, that developing new drugs requires sound execution of clinical trials.