Penn Bioethics Seminar | Daniel Strech, MD, PhD

Evidence-based risk-benefit assessment of phase I/II trials

Before funding or approving a phase I/II trial experts review its scientific validity, social value, risk-benefit ratio, and other trial-related aspects. But do reviewers also assess whether the preclinical and clinical evidence presented in the study protocol and investigator brochure provide sufficient support for the planned trial? Experts from industry and academia argued that insufficient (preclinical) evidential support plays a major role for the high failure rates in clinical research [1-3]. Our analyses of investigator brochures for phase I/II trials demonstrate that these documents do not allow a meaningful review of the evidential support [4, 5]. Furthermore, we found that FDA/EMA guidance documents as well as textbooks for drug discovery and development do not provide meaningful guidance on the issue of evidential support [6]. In my presentation, I will introduce and discuss the relevant studies. I will further argue that those responsible for the oversight of translational research should develop and implement requirements for reviewing the evidential support of phase I/II trials.

[1] Begley CG, Ellis LM. Drug development: Raise standards for preclinical cancer research. Nature. 2012;483:531-3.
[2] Prinz F, Schlange T, Asadullah K. Believe it or not: how much can we rely on published data on potential drug targets? Nat Rev Drug Discov. 2011;10:712.
[3] Kimmelman J, Federico C. Consider drug efficacy before first-in-human trials. Nature. 2017;542:25-7.
[4] Wieschowski S, Chin WWL, Federico C, Sievers S, Kimmelman J, Strech D. Preclinical efficacy studies in investigator brochures: Do they enable risk-benefit assessment? PLoS Biol. 2018;16:e2004879.
[5] Yasinski E. Study questions animal efficacy data behind trials. Science. 2018;360:142.
[6] Langhof H, Chin WWL, Wieschowski S, Federico C, Kimmelman J, Strech D. Preclinical efficacy in therapeutic area guidelines from FDA and EMA: A cross-sectional study. Br J Pharmacol. 2018.

Daniel Strech, MD, PhD, is a full professor at Charité – University Hospital Berlin and chairs the research group “Translational Bioethics” at the QUEST-Center, Berlin Institute of Health (BIH). He studied medicine and philosophy and worked for two years as a physician and researcher in the field of psychiatry. Since 2006, he worked in the fields of research ethics and health policy analysis at the Universities of Tuebingen, Zurich, and at Hannover Medical School. His work focuses on practice-oriented challenges in risk-benefit assessment, informed consent, and other areas of evidence-based decision making in research and health care. Further information: https://www.bihealth.org/en/research/quest-center/team/research-group-strech/