Historical Controls in Clinical Trials: Promise and Pharmacogenomic Pitfalls
This review examines how historical placebo control data from past RCTs could reduce trial burden and accelerate drug development, particularly in rare diseases. It identifies unmeasured pharmacogenomic heterogeneity as a key confounding factor when borrowing external controls across populations. For laboratories involved in clinical trial biomarker programmes, the paper highlights the importance of genotyping in both active and historical control arms to reduce bias.
The original study
Historical Controls in Randomized Clinical Trials: Opportunities and Challenges.
- Authors
- Hall KT, Vase L, Tobias DK, Dashti HT, Vollert J, Kaptchuk TJ, et al.
- Journal
- Clinical pharmacology and therapeutics
- Type
- Journal Article, Research Support, Non-U.S. Gov't, Review
- PMID
- 32602555
Original abstract
Randomized control trials (RCTs) with placebo are the gold standard for determining efficacy of novel pharmaceutical treatments. Since their inception, over 75 years ago, researchers have amassed a large body of underutilized data on outcomes in the placebo control arms of these trials. Although rare disease indications have used these historical placebo data as synthetic controls to reduce burden on patients and accelerate drug discovery, broad use of historical controls is in its infancy. Large-scale historical placebo data could be leveraged to benefit both drug developers and patients if warehoused and made more available to guide trial design and analysis. Here, we examine challenges in utilizing historical controls related to heterogeneity in trial design, outcome ascertainment, patient characteristics, and unmeasured pharmacogenomic effects. We then discuss the advantages and disadvantages of current approaches and propose a path forward to broader use of historical controls in RCTs.