In the evolving landscape of drug development and regulatory approval, the traditional stronghold of Randomized Controlled Trials (RCTs) is being challenged. The surge in the focus on rare diseases and highly targeted patient populations has catalyzed a paradigm shift toward non-RCT designs, such as Single Arm Trials (SATs), switchover studies, and real-world studies. This shift is a response to the recognition by regulatory bodies, including the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA), of the need for faster access to treatments for underserved patient populations.[1]

SATs have emerged as a key player in drug development, especially in scenarios where traditional RCTs face ethical or practical challenges. SATs, characterized by the absence of a separate control group offer a valuable avenue for assessing the safety and potential efficacy of novel interventions, particularly in early-phase clinical trials.[1,2]

Traditionally, Health Technology Assessment (HTA) bodies favor evidence from RCTs to evaluate the benefits of a new product compared to standard care. However, in situations where direct comparisons through RCTs are not possible between two interventions of interest, indirect treatment comparison (ITC) using methodologies such as network meta-analyses (NMAs), matching-adjusted indirect comparisons (MAIC), and simulated treatment comparisons (STC) come into play. Incorporation of SATs into the indirect treatment comparisons becomes essential because of the valuable clinical evidence contained in SATs pertaining to the condition of interest, and several innovative methodologies have been conceptualized to achieve this, such as using historical controls and using simulations such as Bayesian hierarchical models.[1]

Despite the advantages of SATs, they come with inherent limitations. The absence of internal control arms and randomization makes establishing causal interpretations challenging. To address these challenges, meticulous consideration of biases, including ascertainment and attrition biases, is paramount. External comparators play a pivotal role in mitigating these limitations. Strategies aimed at minimizing biases, such as careful pre-planning to avoid missing data through study design, are critical for ensuring the robustness of SAT submissions.[2]

Finding appropriate comparator cohorts for SATs poses a significant challenge. The standards of patient care can evolve over time and vary between countries. Careful evaluation of past HTA decisions in the target indication(s) and early input from HTA stakeholders is critical. Before designing an external comparator study, a strategic approach is recommended. This involves establishing the need for an external comparator, identifying the factors that will drive success, determining the right external comparator group, collecting external comparator data, and ensuring the most appropriate methodology for comparison to study data. This strategic groundwork is essential to enhance the credibility and relevance of SAT submissions in the HTA landscape.[2, 3]

A significant development in the understanding and regulation of SATs is the EMA reflection paper. This marks the first guidance document by an international medicine regulator specifically addressing key concepts and challenges associated with SATs submitted as pivotal evidence for marketing authorization applications. This initiative aims to enhance the design and conduct of SATs, providing a structured framework for stakeholders.[2-4]

Looking ahead, the future direction of SAT-based submissions calls for a continued emphasis on refining evaluation methodologies, ensuring transparency, and adapting to the evolving nature of drug development. In conclusion, SATs present both challenges and opportunities, underscoring the imperative for a well-considered strategy in navigating this distinctive terrain.

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References

1. Evans SR. Clinical trial structures. J Exp Stroke Transl Med. 2010 Feb 9;3(1):8-18. doi: 10.6030/1939-067x-3.1.8.
2. Patel D, Grimson F, Mihaylova E, et al. Use of external comparators for health technology assessment submissions based on single-arm trials. Value in Health. 2021 Aug 1;24(8):1118-25.
3. Dijkhuis S, Patel D, Foster S, et al. HTA77 The Use and Acceptability of External Comparator Studies to Support Hemato-Oncology Single-Arm Trial Submissions to Health Technology Assessment Bodies. Value in Health. 2022 Dec 1;25(12):S311.
4. Single-arm trials as pivotal evidence for the authorisation of medicines in the EU | European Medicines Agency. Available from: https://www.ema.europa.eu/en/news/single-arm-trials-pivotal-evidence-authorisation-medicines-eu