Implementing Historical Controls in Oncology Trials

Abstract

Drug development in oncology has broadened from mainly considering randomized clinical trials to also including single-arm trials tailored for very specific subtypes of cancer. They often use historical controls, and this article discusses benefits and risks of this paradigm and provide various regulatory and statistical considerations. While leveraging the information brought by historical controls could potentially shorten development time and reduce the number of patients enrolled, a careful selection of the past studies, a prespecified statistical analysis accounting for the heterogeneity between studies, and early engagement with regulators will be key to success. Although both the European Medicines Agency and the U.S. Food and Drug Administration have already approved medicines based on nonrandomized experiments, the evidentiary package can be perceived as less comprehensive than randomized experiments. Use of historical controls, therefore, is better suited for cases of high unmet clinical need, where the disease course is well characterized and the primary endpoint is objective. Implications for Practice: Incorporating historical data in single-arm oncology trials has the potential to accelerate drug development and to reduce the number of patients enrolled, compared with standard randomized controlled clinical trials. Given the lack of blinding and randomization, such an approach is better suited for cases of high unmet clinical need and/or difficult experimental situations, in which the trajectory of the disease is well characterized and the endpoint can be measured objectively. Careful pre-specification and selection of the historical data, matching of the patient characteristics with the concurrent trial data, and innovative statistical methodologies accounting for between-study variation will be needed. Early engagement with regulators (e.g., via Scientific Advice) is highly recommended.