Importance of Investigator Brochures in Clinical Trials

Role in Regulatory Approval

Investigator brochures are essential documents in the regulatory approval process that precedes clinical trials. A recent study conducted by researchers from Germany and Canada examined the effectiveness of these brochures in facilitating accurate risk-benefit assessments.

Purpose of Early-Phase Clinical Research

The primary goal of early-phase clinical research is to determine the safety and dosing limits of new drugs in human patients. Before initiating research involving novel treatments, several regulatory requirements must be fulfilled. A significant requirement includes risk-benefit assessments conducted by institutional review boards, which largely rely on evidence obtained from preclinical efficacy studies in animals, compiled into investigator brochures.

Impact of Investigator Brochures on Clinical Trial Safety

Reliance of Review Boards and Scientists

Review boards and scientists depend heavily on the information provided in investigator brochures to weigh the potential risks against the benefits of a clinical trial. However, there has been criticism concerning the design and reporting of preclinical data, due to potential biases. This concern prompted a team from Hannover Medical School and McGill University to conduct a systematic review of investigator brochures submitted for privately funded clinical trials, recently published in PLOS Biology.

Study Overview and Findings

The researchers analyzed 109 investigator brochures from trials approved by German review boards between 2010 and 2016. These brochures encompassed data from 708 preclinical efficacy studies and were used in risk-benefit assessments for phase I and II trials across eight of the twelve therapeutic areas identified by the European Medicines Agency. The study authors evaluated the brochures based on their reporting of criteria related to the validity of results, references to published reports, and result direction.

Challenges with Current Investigator Brochures

Incompleteness of Information

The findings revealed that approximately 89% of the preclinical efficacy studies included in the brochures did not reference published peer-reviewed reports. This lack of citation prevents independent review boards from assessing whether most preclinical data had undergone independent evaluation. Additionally, only 20% of the preclinical efficacy studies detailed measures taken to reduce bias, such as baseline characterization, data exclusion, or randomization.

Exclusion of Negative Results

Furthermore, more than 40% of the preclinical efficacy trials documented in the investigator brochures did not include studies that failed to demonstrate an effect. The authors attribute this significant omission to biases in study design, inclusion protocols, and the typically small sample sizes found in preclinical studies.

Limitations of the Study

Due to challenges in accessing investigator brochures, the researchers could not obtain a random sample of the documents. Additionally, only 6% of the brochures pertained to first-in-human studies. Nevertheless, the authors argue that many early-phase trials, even if not first-in-human studies, still involve new indications or drug combinations, making preclinical efficacy studies crucial for the risk-benefit assessment.

Recommendations for Enhancing Transparency

Improving Reporting Practices

The authors suggest that investigator brochures should clearly outline the measures implemented in preclinical studies that support the validity and generalizability of results, including randomization and predetermined study endpoints.

Disclosure of Preclinical Evidence

Moreover, it is essential for investigator brochures to disclose whether they present preclinical efficacy evidence comprehensively and, if not, to specify the criteria used for study inclusion. Such transparency would help prevent selective reporting of results. Future research should focus on how these reporting practices impact the risk-benefit review process.

Source

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.