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Do investigator brochures enable accurate risk assessments of clinical trials?

Investigator brochures are key documents in the regulatory approval process before initiating clinical trials. A recent study by German and Canadian researchers investigated just how effective these documents are at enabling accurate risk-benefit assessments.

The main purpose of early-phase clinical research is to establish the safety and dosing limits of new drugs in human patients. When investigating novel treatments, there are several regulatory requirements before the research can be initiated in humans.

One of the requirements involves risk-benefit assessments by an institutional review board. This assessment is based largely on evidence gathered from pre-clinical efficacy studies in animals, which is compiled into documents called investigator brochures.

Clinical trial safety depends on the accuracy of investigator brochures

Review boards and scientists rely heavily on investigator brochures to evaluate whether the potential risks of a trial outweigh the potential benefits of the trial. Scientists have criticized the design and reporting of pre-clinical data due to some biases that may inherent. This led a team of researchers in Hannover Medical School and McGill University to undertake a systematic review of institutional brochures submitted for privately funded clinical trials, which was recently published in PLOS Biology.

The researchers gathered a total of 109 investigator brochures for trials approved by German review boards between 2010 and 2016. These brochures reported on 708 preclinical efficacy studies and had been used in risk-benefit assessments of phase I and II trials spanning eight of the 12 therapeutic areas identified by the European Medicine Agency. The study authors then rated these studies on their reporting of criteria related to the validity of their results, their referencing of published reports, and the direction of their results.

Most investigator brochures are incomplete

Approximately 89% of the preclinical efficacy studies included in the brochures did not refer to published peer-reviewed reports, preventing the independent review boards from knowing whether most pre-clinical data had been independently evaluated. Reporting on measures to reduce bias was also notably absent, with only 20% of the pre-clinical efficacy studies detailing procedures for baseline characterization, exclusion of data, or randomization.

Lastly, over 40% of preclinical efficacy trials in the investigator brochures did not include studies that failed to demonstrate an effect. The authors attribute this unusually large effect to bias in study design and study inclusion protocols, and the small study sample sizes common to preclinical studies.

Due to difficulties in accessing investigator brochures, the investigators were not able to obtain a random sample of the documents. A second limitation was that only 6% of the investigator brochures were for first-in-human studies. However, the study authors maintain that many early-phase trials, which may not be a first-in-human study, still involve new indications or drug combinations, for which preclinical efficacy studies are still a vital aspect of the risk-benefit assessment.

Recommendations for improved transparency

The authors recommend that investigator brochures outline measures taken in pre-clinical studies to support the validity and generalizability of their results, such as randomization and pre-selecting study endpoints.

More importantly, investigator brochures should disclose whether they are presenting preclinical efficacy evidence in full and if not, what criteria were used for study inclusion. This would increase transparency and prevent selective reporting of results. Future studies should be focused on how these reporting practices influence the risk-benefit review process.

Written by Agustin Dominguez Iino, BSc

Reference: 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 Apr 5;16(4):e2004879. doi: 10.1371/journal.pbio.2004879. eCollection 2018 Apr.



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