Safety in FIH Trials: A Summary of the Symposium “Fatal Drug Trial in Phase 1: Understanding Risk, Subject Safety, Timelines, and Cost”

Abstract

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.

The Shared Ethical Responsibility of Medically and Non-medically Qualified Experts in Human Drug Development Teams

“…SA.) (Kerbrat et al, 2016 ; Greenberg et al, 2017 ) reminded the scientific community of the consequences for involved human beings. It became a main ethical requirement for effective and safe human drug development, that academic scientists should adopt research methods similar to those used in clinical trials to significantly improve construct validity of their research, especially the internal and external validities of the confirmatory pharmacotherapeutic studies in animals (Kilkenny et al, 2010 ; van der Worp et al, 2010 ; Arrowsmith, 2011 ; Kimmelman and London, 2011 ; de Vries et al, 2014 ; Kimmelman et al, 2014 ).…”

A call to incorporate systems theory and human factors into the existing investigation of harm in clinical research involving healthcare products

“…We do not wish to criticize the value, professionalism and relevance of the detailed reports produced by experts such as the Scientific Group chaired by Professor Duff and the Temporary Specialist Scientific Committee (TSSC) set up by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) . Indeed, we want to be forward looking and build on what we have learnt from these detailed and expert valuable investigations.…”

“…We are addressing the lack of either a prospectively defined or internationally agreed upon system or mechanism for the independent conduct of these investigations and a threshold as to when such investigations should occur. We believe that modern complementary approaches based on organizational science, including systems‐theoretic techniques and human factors, can identify vulnerabilities which, if not tackled, may well allow further tragedies to occur . Systems theory incorporates complex nonlinear relationships (including feedback) among socio‐technical system components to design better a control structure that enforces constraints on the behaviour of the system components .…”