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
Review
. 2024 Nov;58(6):1214-1232.
doi: 10.1007/s43441-024-00693-8. Epub 2024 Sep 16.

A Framework for the Use and Likelihood of Regulatory Acceptance of Single-Arm Trials

Disha Subramaniam  1   2 , Colin Anderson-Smits  3 , Rebecca Rubinstein  4   5 , Sydney T Thai  4 , Rose Purcell  3 , Cynthia Girman  4   5
Affiliations
Review

A Framework for the Use and Likelihood of Regulatory Acceptance of Single-Arm Trials

Disha Subramaniam et al. Ther Innov Regul Sci. 2024 Nov.

Abstract

Background: Single-arm clinical trials (SAT) are common in drug and biologic submissions for rare or life-threatening conditions, especially when no therapeutic options exist. External control arms (ECAs) improve interpretation of SATs but pose methodological and regulatory challenges.

Objective: Through narrative reviews and expert input, we developed a framework for considerations that might influence regulatory use and likelihood of regulatory acceptance of an SAT, identifying non-oncology first indication approvals as an area of interest. We systematically analyzed FDA and EMA approvals using SATs as pivotal evidence. The framework guided outcome abstraction on regulatory responses.

Methods: We examined all non-oncology FDA and EMA drug and biologic approvals for first indications from 2019 to 2022 to identify those with SAT as pivotal safety or efficacy evidence. We abstracted outcomes, key study design features, regulator responses to SAT and (where applicable) ECA design, and product label content.

Results: Among 20 SAT-based FDA approvals and 17 SAT-based EMA approvals, most common indications were progressive rare diseases with high unmet need/limited therapeutic options and a natural history without spontaneous improvement. Of the types of comparators, most were natural history cohorts (45% FDA; 47% EMA) and baseline controls (40% FDA; 47% EMA). Common critiques were of non-contemporaneous ECAs, subjective endpoints, and baseline covariate imbalance between arms.

Conclusion: Based on recent FDA and EMA approvals, the likelihood of regulatory success for SATs with ECAs depends on many design, analytic, and data quality considerations. Our framework is useful in early drug development when considering SAT strategies for evidence generation.

Keywords: External-control-arm; Open-label-studies; Single-arm-trials; Uncontrolled-trials.

PubMed Disclaimer

Conflict of interest statement

None related to content of manuscript. Authors C.A. and R.P are employed by Takeda Pharmaceuticals and own stock in the company. CERobs Consulting received funding from Takeda Pharmaceuticals for this work. C.G., D.S., R.R., and S.T.T. have no financial interests to disclose.

Figures

Figure 1
Figure 1
A framework for determining the likelihood of regulatory acceptance of a Single Arm Study. Footnote: Top of figure shows factors regulatory decisions believed to be less likely (on left) for regulatory acceptance of a single arm trial (SATs), with increasing likelihood for decisions moving to the right of graph. Bottom left part of figure reflects considerations that may increase the likelihood of regulatory acceptance of SATs, while the right side shows those that may decrease likelihood of SAT acceptance, depending on regulatory decision. The scope of this study is novel approvals, indicated on the far left end of the spectrum.
Figure 2
Figure 2
A framework for determining the likelihood of regulatory acceptance of an External Control Arm. Footnote: Data considerations and methodological considerations that are less likely (left of graph) or more likely (right of graph) to lead to regulatory acceptance of an external control arm.
Figure 3
Figure 3
Inclusion and exclusion criteria flowchart for selection of 37 FDA and EMA approvals into final analysis.
See this image and copyright information in PMC

References

    1. Uzzan M, Bouhnik Y, Abreu M, et al. Declining enrolment and other challenges in IBD clinical trials: causes and potential solutions. J Crohn’s Colitis. 2023;17(7):1066–78. 10.1093/ecco-jcc/jjad020. - PubMed
    1. Chiodo GT, Tolle SW, Bevan L. Placebo-controlled trials: good science or medical neglect? West J Med. 2000;172(4):271–3. 10.1136/ewjm.172.4.271. - PMC - PubMed
    1. Groth SW. Honorarium or coercion: use of incentives for participants in clinical research. J N Y State Nurses Assoc. 2010;41(1):11–22. - PMC - PubMed
    1. Joppi R, Bertele’ V, Garattini S. Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU. Eur J Clin Pharmacol. 2023. 10.1007/s00228-012-1423-2 - PubMed
    1. Beaver JA, Howie LJ, Pelosof L, et al. A 25-year experience of US Food and Drug Administration accelerated approval of malignant hematology and oncology drugs and biologics: a review. JAMA Oncol. 2018;4(6):849–56. 10.1001/jamaoncol.2017.5618. - PubMed

Publication types