Minimizing Patient Burden Through the Use of Historical Subject-Level Data in Innovative Confirmatory Clinical Trials: Review of Methods and Opportunities

Abstract

The goal of clinical trial research is to deliver safe and efficacious new treatments to patients in need in a timely and cost-effective manner. There is precedent in using historical control data to reduce the number of concurrent control subjects required in developing medicines for rare diseases and other areas of unmet need. The purpose of this paper is to provide a review for a regulatory and industry audience of the current state of relevant statistical methods, and of the uptake of these approaches and the opportunities for broader use of historical data in confirmatory clinical trials. General principles to consider when incorporating historical control data in a new trial are presented. Bayesian and frequentist approaches are outlined including how the operating characteristics for such a trial can be obtained. Finally, examples of approved new treatments that incorporated historical controls in their confirmatory trials are presented.

Beyond Randomized Clinical Trials: Use of External Controls

“…The two main approaches for a valid use of external control information rely on meta‐analytic and propensity score methods . Meta‐analytic methods model the unexplained heterogeneity between the source data and account for this when extrapolating to the target.…”

“…23 The two main approaches for a valid use of external control information rely on meta-analytic and propensity score methods. 24 Metaanalytic methods model the unexplained heterogeneity between the source data and account for this when extrapolating to the target. We describe a case study further below to illustrate the meta-analytic approach for a planned RCT in children with multiple sclerosis (MS), where data from several past clinical trials in adults and children enable borrowing of strength for the target trial.…”

Blinatumomab vs historic standard‐of‐care treatment for minimal residual disease in adults with B‐cell precursor acute lymphoblastic leukaemia

“…The prior comparison between blinatumomab and historic SOC treatment in patients with relapsed/refractory Ph‐negative BCP‐ALL was similar to the results in the randomised phase 3 study . Additionally, other studies have also compared novel treatment combinations to historic data to evaluate clinical benefit …”

“…Similarly, other studies evaluating treatment outcomes among ALL patients have also used propensity score adjustment to compare two distinct study populations . Overall, the approach of using historic controls and propensity score statistical methods has provided important context for the effect of novel treatments in rare diseases with unmet need …”

“…43,44 Overall, the approach of using historic controls and propensity score statistical methods has provided important context for the effect of novel treatments in rare diseases with unmet need. [43][44][45] The objective of this study was to compare RFS and OS between patients with MRD-positive BCP-ALL treated with blinatumomab in a single-arm, phase 2 study 12 and patients with MRD-positive disease from a historic data set who were treated with SOC, 33 employing weighted and propensity score analyses. The primary blinatumomab-treatment group, median RFS was 7.8 months and median OS was 25.9 months in the SOC-treated group.…”