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Using Single Arm Trials for HTA Submissions: Dr. Heeg and Maria Rizzo

A randomized clinical trial (RCT) is the gold standard approach to demonstrate the efficacy and safety of novel therapies. Randomization avoids selection bias and confounding and therefore RCTs allow for causal inference. As such, RCTs offer the highest quality of evidence to demonstrate if treatments work, compared to other approaches.

With the growing number of highly specialized products, regulators in both Unites States and Europe have started to accept single arm trial submissions with limited patient numbers, follow up and surrogate outcomes for serious, life-threatening, and orphan diseases. Consequently, Health Technology Appraisal (HTA) bodies are increasingly required to make decisions on whether the added benefit of a new technology, based on evidence from pivotal single arm trials, are worth the additional costs compared to standard of care. The challenge in making this decision, is the comparator evidence used in submissions to HTA bodies based on single arm trials is often heterogeneous [1]. Hence, the potential for bias is high, further increasing the uncertainty for health authorities to make decisions on added benefit and value.

The Issue Panel “Do Single-Arm Trials Bring Peril to Network Meta-Analyses (NMAs)?” at the Virtual ISPOR EUROPE 2021 will address the question regarding the suitability of NMAs in determining the comparative effectiveness for highly specialized products, given the growing use of single-arm trials for reimbursement decisions. During this presentation, Vice President Health Economics at Cytel, Dr. Bart Heeg will argue that the bottle neck for the acceptability of single-arm trials for HTAs are not the limitations of NMAs, but in the selection of the historical/synthetic control arm, which are external control data used to evaluate the comparative effectiveness of an intervention.[2] To increase certainty for HTA bodies in the added benefit of a new technology evaluated in a single arm trial, one should systematically consider how to design the synthetic/historical control arm as early as the single arm Phase 2 protocol design stage to ensure an optimal (least biased) control arm for HTA purposes. Dr. Heeg shares a list of protocol criteria that should be assessed when selecting external controls.

In terms of NMA methodology, only in very specific circumstances will regulators accept a single arm trial in indications where RCTs have already been conducted. So, only in very few instances would single arm trials need to be added to existing networks for an NMA. If this was required, there are several published methods that can be applied that also consider the additional uncertainty of incorporating single arm trials in NMAs. [3-6]

Click the button to learn more about the Cytel sessions at Virtual ISPOR EUROPE 2021.

Download Session Schedule

With thanks to Dr. Bart Heeg, Maria Rizzo and Radek Wasiak, PhD.

References :
[1] Patel D et al. Use of External Comparators for Health Technology Assessment Submissions Based on Single-Arm Trials. Value Health. 2021 Aug;24(8):1118-1125.

[2] Thorlund K, Dron L, Park JJH, Mills EJ. Synthetic and External Controls in Clinical Trials – A Primer for Researchers. Clin Epidemiol. 2020;12:457-467.

[3] Jenkins, D.A., Hussein, H., Martina, R. et al. Methods for the inclusion of real-world evidence in network meta-analysis. BMC Med Res Methodol 21, 207 (2021). https://doi.org/10.1186/s12874-021-01399-3

[4] Efthimiou et al. 2017. GetReal Work Package 4. Combining randomized and non-randomized evidence in network meta-analysis. Stat Med. Apr 15;36(8):1210-1226.

[5] Leahy J, et al. Incorporating single-arm evidence into a network meta-analysis using aggregate level matching: Assessing the impact. Stat Med. 2019 Jun 30;38(14):2505-2523.

[6] Thom HH, et al. Network meta-analysis combining individual patient and aggregate data from a mixture of study designs with an application to pulmonary arterial hypertension. BMC Med Res Methodol. 2015 Apr 12;15:34.



About the Author of Blog:

Mansha Sachdev specializes in content creation and knowledge management. She holds an MBA degree and has 11 years of experience in handling various facets of marketing, across industries. At Cytel, Mansha is a Content Marketing Manager and is responsible for producing informative content that is related to the pharmaceutical and medical devices industries.


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