Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Oct;29(10):1228-1235.
doi: 10.1002/pds.4975. Epub 2020 Mar 11.

Real-world evidence to support regulatory decision-making for medicines: Considerations for external control arms

Mehmet Burcu  1 , Nancy A Dreyer  2 , Jessica M Franklin  3 , Michael D Blum  4 , Cathy W Critchlow  5 , Eleanor M Perfetto  6 , Wei Zhou  1
Affiliations

Real-world evidence to support regulatory decision-making for medicines: Considerations for external control arms

Mehmet Burcu et al. Pharmacoepidemiol Drug Saf. 2020 Oct.

Abstract

Randomized clinical trials (RCTs) are the gold standard in producing clinical evidence of efficacy and safety of medical interventions. More recently, a new paradigm is emerging-specifically within the context of preauthorization regulatory decision-making-for some novel uses of real-world evidence (RWE) from a variety of real-world data (RWD) sources to answer certain clinical questions. Traditionally reserved for rare diseases and other special circumstances, external controls (eg, historical controls) are recognized as a possible type of control arm for single-arm trials. However, creating and analyzing an external control arm using RWD can be challenging since design and analytics may not fully control for all systematic differences (biases). Nonetheless, certain biases can be attenuated using appropriate design and analytical approaches. The main objective of this paper is to improve the scientific rigor in the generation of external control arms using RWD. Here we (a) discuss the rationale and regulatory circumstances appropriate for external control arms, (b) define different types of external control arms, and (c) describe study design elements and approaches to mitigate certain biases in external control arms. This manuscript received endorsement from the International Society for Pharmacoepidemiology (ISPE).

Keywords: external controls; historical controls; pharmacoepidemiology; real-world data; real-world evidence; regulatory decision-making.

PubMed Disclaimer

References

    1. Bothwell LE, Greene JA, Podolsky SH, Jones DS. Assessing the gold standard–lessons from the history of RCTs. N Engl J Med. 2016;374(22):2175‐2181. - PubMed
    1. Basch E, Schrag D. The evolving uses of "real‐world" data. JAMA. 2019;321(14):1359‐1360. - PubMed
    1. Califf RM, Robb MA, Bindman AB, et al. Transforming evidence generation to support health and health care decisions. N Eng J Med. 2016;375(24):2395‐2400. - PubMed
    1. Sherman RE, Anderson SA, Dal Pan GJ, et al. Real‐world evidence‐what is it and what can it tell us? N Eng J Med. 2016;375(23):2293‐2297. - PubMed
    1. U.S. Food and Drug Administration . Sentinel initiative. https://www.fda.gov/safety/fdassentinelinitiative/ucm2007250.htm. Accessed April 1, 2019.