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Informing single-arm clinical trials with external controls

Randomized controlled trials are the accepted standard for evaluating investigational therapies, but such trials are sometimes not an option for reasons of ethics or feasibility. Here, we discuss opportunities to address evidence gaps by using historical clinical trial data and real-world data in external control arms for single-arm trials, as well as the associated challenges.
  1. Ruthie Davi

    1. Medidata Solutions, New York, NY, USA.

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  2. Nirosha Mahendraratnam

    1. Duke Margolis Center for Health Policy, Washington, DC, USA.

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  3. Arnaub Chatterjee

    1. Medidata Solutions, New York, NY, USA.

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  4. C. Jill Dawson

    1. Consultant to Medidata Solutions, Danville, CA, USA.

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  5. Rachel Sherman

    1. Department of Population Health, Harvard Pilgrim Health Care institute, Boston, MA, USA.

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Control arms in randomized clinical trials (RCTs) have a key role in isolating the effects of the medical product from those caused by other factors. However, in some cases — such as phase II trials in oncology where no effective standard of care exists, or trials for rare diseases with a very small number of eligible patients — a concurrent (placebo, active or no treatment) control may not be feasible or ethical. In these cases, single-arm trials are often used, but this remains controversial because of the difficulty of distinguishing treatment effects from other factors1. This means such trials may provide preliminary support of activity, but are typically inadequate for quantification of the treatment effects and an understanding of possible biases.

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Nature Reviews Drug Discovery 19, 821-822 (2020)

doi: https://doi.org/10.1038/d41573-020-00146-5

References

  1. Grayling, M. J., Dimairo, M., Mander, A. P., Jaki, T. F. A review of perspectives on the use of randomization in phase II oncology trials. J. Natl Cancer Inst. 111, 1255–1262 (2019).

    Article  PubMed  Google Scholar 

  2. Austin, P. C. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav. Res. 46, 399–424 (2011).

    Article  PubMed  Google Scholar 

  3. Gokbuget, N. et al. Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia. Blood Cancer J. 6, e473 (2016).

    Article  PubMed  Google Scholar 

  4. Cave, A., Kurz, X. & Arlett, P. Real-world data for regulatory decision making: challenges and possible solutions for Europe. Clin. Pharmacol. Ther. 106, 36–39 (2019).

    Article  PubMed  Google Scholar 

  5. Sherman, R. E. et al. Accelerating development of scientific evidence for medical products within the existing US regulatory framework. Nat. Rev. Drug Discov. 16, 297–298 (2017).

    Article  PubMed  Google Scholar 

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Competing Interests

Medidata Solutions provides data and services related to external control arms. R. Davi and A. Chatterjee are employees of Medidata Solutions and C. J. Dawson is a contractor of Medidata Solutions.

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