Investigator brochures for phase I/II trials lack information on the robustness of preclinical safety studies

Abstract

Aim: Meaningful and ethical phase I/II trials can only be conducted with supportive prospective risk-benefit assessment. This relies largely on preclinical animal studies addressing the safety and efficacy of treatments. These studies are reported in an Investigator's Brochure (IB) to inform ethics review boards and regulatory authorities. Our study investigated the extent, reporting quality and accessibility of preclinical safety studies (PCSSs) compiled in IBs.

Methods: We analysed a sample of 46 IBs for phase I/II trials approved at a leading German university medical centre from 2010 to 2016. We extracted all PCSSs presented in the 46 IBs and assessed them for reporting on methodological measures to reduce validity threats.

Results: The 46 IBs included 777 PCSSs. Blinded outcome assessment, randomization and sample size calculation were reported for fewer than 1% of studies. Only 5% of the PCSSs provided a reference to published data. Compliance with Good Laboratory Practice (GLP) guidance was reported for 52% of PCSSs, but the GLP document itself does not include any relevant methodological requirements for the reduction of validity threats.

Conclusion: Scarce reporting in IBs and the very limited publicly available data on PCSSs make it almost impossible for investigators to critically evaluate the robustness of preclinical evidence of drug safety. Combined with recent findings on the presentation of preclinical efficacy studies in IBs, we conclude that the current reporting patterns in IBs strongly limit the independent review of evidential support for early human trials. Regulatory authorities and IRBs should require better reporting in IBs.

Keywords: bioethics; drug development; drug safety; research ethics; translational research.