Human Drug Trials Negatively Impacted by Poor Reporting, Design of Animal Studies

Poor preclinical animal study designs and reporting may affect the ethical review of proposed human drug trials, according to a new study published in PLOS Biology.

Proper study design and reporting of data from animal trials are necessary to ensure that volunteering patients in human drug trials are not subjected to undue risk.

In the study, the researchers evaluated how preclinical design and reporting in “investigator brochures” affected the assessment of evidence strength of preclinical findings.

Investigator brochures are documents used by regulatory authorities and ethics committees to assess the potential efficacy of drugs that are being tested in patients for the first time. According to their analysis, the researchers stated that most of the documents lacked the necessary information to systematically appraise the strength of evidence supporting trials.

Of the more than 700 animal studies found in the investigator brochures, the researchers found that:

• Less than one-fifth of investigator brochures referenced animal studies that had been through a peer-reviewed publication process.
• Less than 20% of animal studies that tested the efficacy of the new drug described the use of simple techniques, such as randomized blinding or sample size calculation, that can reduce the effects of bias.
• Only 4% did not show positive effects of treatment.

The researchers indicated that, with each group being a median size of 8 animals, the studies had limited ability to measure treatment effects precisely and should have resulted in more negative study results. The findings suggest that publication bias is likely, the researchers noted.

Overall, the researchers offered recommendations for improving the effective use of preclinical information for risk-benefit assessment in phase 1 and phase 2 trials.

• Investigator brochures should describe measures taken in pre-clinical efficacy studies (PCESs) to support clinical generalizability.
• Investigator brochures should state whether they are presenting the totality of preclinical evidence, and if not, how data were selected for inclusion.

Increased transparency and improved reporting is important to assess preclinical studies, according to the authors. However, this alone is unlikely to solve problems related to risk of bias in preclinical evidence, the researchers noted. They recommended that regulators develop standards for the design and reporting of PCESs to be included in investigator brochures to ensure that information is available to assess the strength of evidence.

Reference

Wieschowski S, Lim Chin WW, Federico C, et al. Preclinical efficacy studies in investigator brochures: Do they enable risk-benefit assessment? PLOS Biology. 2018. https://doi.org/10.1371/journal.pbio.2004879