Preclinical efficacy studies in investigator brochures: Do they enable risk–benefit assessment?

Abstract

Human protection policies require favorable risk–benefit judgments prior to launch of clinical trials. For phase I and II trials, evidence for such judgment often stems from preclinical efficacy studies (PCESs). We undertook a systematic investigation of application materials (investigator brochures [IBs]) presented for ethics review for phase I and II trials to assess the content and properties of PCESs contained in them. Using a sample of 109 IBs most recently approved at 3 institutional review boards based at German Medical Faculties between the years 2010–2016, we identified 708 unique PCESs. We then rated all identified PCESs for their reporting on study elements that help to address validity threats, whether they referenced published reports, and the direction of their results. Altogether, the 109 IBs reported on 708 PCESs. Less than 5% of all PCESs described elements essential for reducing validity threats such as randomization, sample size calculation, and blinded outcome assessment. For most PCESs (89%), no reference to a published report was provided. Only 6% of all PCESs reported an outcome demonstrating no effect. For the majority of IBs (82%), all PCESs were described as reporting positive findings. Our results show that most IBs for phase I/II studies did not allow evaluators to systematically appraise the strength of the supporting preclinical findings. The very rare reporting of PCESs that demonstrated no effect raises concerns about potential design or reporting biases. Poor PCES design and reporting thwart risk–benefit evaluation during ethical review of phase I/II studies.

How well are Phase 2 cancer trial publications supported by preclinical efficacy evidence?

“…Study protocols might have contained citations to preclinical studies that were absent in publications. Nevertheless, one previous study suggests that 82% of protocols for early phase trials did not cite any published preclinical efficacy studies . Finally, researchers may have cited matching evidence elsewhere in the text.…”

“…Preclinical efficacy evidence thus furnishes an ethical basis for exposing patients to unproven interventions. It also supports valid interpretation of trial results . Trial findings that are consistent with strong preclinical efficacy evidence are less likely to be attributable to false positivity, while trial results that contradict preclinical efficacy reports provide insight into the relationship between animal models and human disease.…”

“…Various commentators have questioned the quality of design and reporting of preclinical studies in cancer . At the same time, preclinical evidence supporting early clinical hypotheses is often limited in quantity . In several instances, early phase trials launched based on equivocal preclinical evidence have resulted in unsuccessful drug development efforts, yet drug regulators often grant sponsors and academic investigators wide discretion on the preclinical rationale for launching early phase trials .…”

“…1,2 At the same time, preclinical evidence supporting early clinical hypotheses is often limited in quantity. [3][4][5] In several instances, early phase trials launched based on equivocal preclinical evidence have resulted in unsuccessful drug development efforts, 6,7 yet drug regulators often grant sponsors and academic investigators wide discretion on the preclinical rationale for launching early phase trials. [3][4][5] The extent to which ethics committees evaluate preclinical support when reviewing protocols is unclear.…”

“…A previous report found provision of preclinical studies of efficacy in investigator brochures for Phases 1 and 2 trials to be limited. 4 Reporting guidelines for trials 9 urge researchers to describe the evidentiary rationale for their study in trial publications. The present study examined the extent to which Phase 2 trials testing novel anticancer drugs cite preclinical and clinical evidence matching the indication and drug tested in the trial.…”