Use of External Control Arms in Novel Drug Approvals By U.S. Food and Drug Administration: A Targeted Review
Speaker(s)
Gupta P1, Kumar J2, Shaikh J3, Ken-Opurum J4
1Axtria, Gurugram, HR, India, 2Axtria, Gurugram, Haryana, India, 3Axtria, Hyderabad, AP, India, 4Axtria, Berkley Heights, NJ, USA
OBJECTIVES: Randomized controlled trials (RCTs) are considered gold standards in research, ensuring rigorous evaluation of interventions. However, the landscape has evolved with the incorporation of external control arms (ECAs), where RCTs may not be feasible due to patient heterogeneity, limited patients, and ethical concerns. This study aims to assess the utilization and implications of ECAs in novel drug approvals (NDAs) by the U.S. Food and Drug Administration (USFDA).
METHODS: NDAs from 2017–2023 were identified using USFDA electronic database. USFDA labels, approval letters and review documents for NDAs were searched using keywords such as “historical controls” or “external control” or “natural history study” or “synthetic control arm” to identify approvals where ECAs were used in pivotal trials. Details pertaining to approval year, disease area, and sources of ECA were analyzed and categorized.
RESULTS: Over the last 6 years, 349 NDAs got approved out of which 10% were utilizing ECAs in their pivotal analysis. ECA based submissions have increased over time (2017 [n=4] to 2023 [n=11]), suggesting the increasing acceptance by USFDA. Primarily, ECAs were used in oncology (40%) and endocrinology (14.3%) due to the limited patient cohorts, often posing challenges for conducting RCTs. ECAs were derived from retrospective studies (28.6%), previously published data (28.6%), clinical trials (25.7%), prospective studies (8.57%) and others (8.57%). Majority of the NDAs were granted orphan drug designation (85.7%). Although the ECAs based regulatory approvals have increased, Centre for Drug Evaluation and Research’s assessments suggested pharmaceutical companies to carefully consider the selection bias, heterogeneity, and confounding factors associated with use of ECAs.
CONCLUSIONS: Increased acceptance of ECAs by the regulatory agencies signifies their transformative role in improving the efficiency and ethical considerations of clinical trials in conditions with limited patient cohorts. However, careful considerations are required to address potential biases associated with ECAs and to ensure validity of comparisons.
Code
HPR57
Topic
Health Policy & Regulatory
Topic Subcategory
Approval & Labeling
Disease
No Additional Disease & Conditions/Specialized Treatment Areas