By Marites T. Woon, PhD (Associate Director, Nonclinical) and Jessica Lee, MD, PhD (Principal, Global Head Cell & Gene Therapy)
According to a report by the American Society of Gene and Cell Therapy, oncology remains one of the top areas of focus for investigational cell and gene therapy (CGT) products in Q1 of 20231, underscoring the continued need for transformative solutions. Between 2002 and 2021, the FDA granted approvals to 176 new malignant hematology and oncology indications based on single-arm trials2. This includes 116 (66%) accelerated approvals and 60 (34%) traditional approvals, with response rate as the most common endpoint used (173 of 176 [98%]) to support the approval of these single-arm trials2. Single-arm trials which demonstrate durable objective response rates (ORR; e.g., proportion of patients who achieve a response) have traditionally been utilized to inform the benefit-risk profile of oncologic agents in a context-dependent manner and most commonly will lead to accelerated approval. However, in certain scenarios, single-arm trials can lead to regular approval depending on the specific clinical context. For example, durable ORR which directly reflects clinical benefit can serve as the basis for regular approval in some cutaneous malignancies (e.g., cutaneous squamous cell carcinoma and basal cell carcinoma).
The use of clinical evidence from single-arm trials, however, has not been without challenges. Recent communications from the European Medicines Agency (EMA) and FDA signal a potential shift in this previously accepted paradigm3,4. Here, we describe single-arm trials and key considerations to support navigating this evolving landscape.
In general, single-arm clinical trials are designed to evaluate the safety and efficacy of an investigational product over time in a target population. Described below are key features in the applicability and potential limitations of single-arm trials4,5.
Applicability of Single-arm Trials
While randomized clinical trials remain the “gold standard” in evaluating the safety and efficacy of investigational treatments (e.g., product or intervention), single-arm trials have been a common development strategy to support regulatory approval and, therefore, allowed for transformative therapies to be made available to patients expeditiously.
In oncology, single‑arm trials may be leveraged under the following scenario:
- randomization is not feasible or ethical
- the mechanism of action of the oncologic agent is supported by strong scientific rationale and/or nonclinical data
- the oncologic agent produces substantial, durable tumor responses that clearly exceed those offered by existing or available therapies
- the natural history of the disease is well-defined or characterized, including most malignant diseases with the oncologic agent usually intended for a well-defined patient population
- the study endpoint is objective, with success based on compelling or substantial evidence of a change in the established disease progression
- an external control is very similar to patients or concomitant treatments in the study.
Potential Limitations of Single-arm Trials
- Every patient in a single-arm trial receives the investigational treatment for which outcomes are observed. This aspect of the design reflects a lack of randomization and blinding typically in place to address known and unknown bias and allow for a robust examination of the relationship between the outcome from an investigational treatment relative to another. In contrast, randomized clinical trials assign participants in a random and blinded fashion to receive the investigational or comparator treatment and measure outcomes between groups.
- A single-arm trial design may result in a smaller noncomparative safety data set, especially in the context of indications (e.g., rare disease or cancer) for which there is a limited patient population to recruit from. Rare serious adverse events (SAEs), for example, may not be readily identified – and for those that are, may not be attributable to the investigational treatment itself.
- Single-arm trials typically do not adequately characterize time-to-event endpoints (e.g., early endpoints such as progression-free survival [PFS] or time to progression [TTP] and long-term endpoints such as overall survival) due to variability in the natural history of many cancer types.
- A common clinical endpoint in single-arm trials is measurement of the ORR. However, low to modest response rates typically indicate the investigational treatment ineffective and unlikely to predict clinical benefit.
Moving Forward with Single-arm Trials
As we previously communicated, there are 4 programs available to support expediting oncology treatments to patients in need6. One such expedited program – accelerated approval – requires that the product have an effect on surrogate endpoints such as response rate (e.g., tumor regression) which may be predictive of clinical benefit for the treatment of serious or life-threatening indications6. However, oncologic agents granted accelerated approval based on single-arm trials are required to meet the same statutory standards for effectiveness and safety as those granted traditional approval (e.g., demonstrate substantial evidence of effectiveness and sufficient information to demonstrate that the oncologic agent is safe)7. Moreover, in oncology, single-arm trials which demonstrate ORR of large magnitude and durability is an established mechanism for accelerated approval (and in some cases, traditional) with the majority of those approved based on ORR considered as breakthrough or transformative therapies. At the crux of it, bringing life-changing therapies to patients sooner is a meaningful endeavor that requires careful consideration of various facets of product development and regulatory pathways. To the extent possible, limitations in the design of trials – whether single-arm or randomized – require mitigation of risks and context-dependent decisions that take into consideration the totality of the available information.
For support in navigating the regulatory complexities of single-arm trials, Allucent’s A-team is here to partner with you and provide expert guidance. Contact us today.
Allucent brings new therapies to light by solving the distinct challenges of small and mid-sized biotech companies. We’re a global provider of comprehensive drug development and clinical research solutions, including regulatory and drug development consulting, clinical trial operations, biometrics, and clinical pharmacology across a variety of therapeutic areas. Our individualized partnership approach provides experience-driven insights and expertise to assist clients in successfully navigating the complexities of delivering novel treatments to patients.
For more details about how the A-Team can support your drug development programs, contact us today.
1 American Society of Gene and Cell Therapy. https://asgct.org/global/documents/asgct-citeline-q1-2023-report.aspx.
2 Agrawal S, Arora S, Amiri-Kordestani L, de Claro RA, Fashoyin-Aje L, Gormley N, Kim T, Lemery S, Mehta GU, Scott EC, Singh H, Tang S, Theoret MR, Pazdur R, Kluetz PG, Beaver JA. Use of Single-Arm Trials for US Food and Drug Administration Drug Approval in Oncology, 2002-2021. JAMA Oncol. 2023 Feb 1;9(2):266-272.
3 European Medicines Agency. Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorization. Considerations on evidence from single-arm trials. April 17, 2023. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-establishing-efficacy-based-single-arm-trials-submitted-pivotal-evidence-marketing_en.pdf.
4 U.S. Food & Drug Administration. Guidance for Industry. Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics. March 2023. https://www.fda.gov/media/166431/download.
5 U.S. Food & Drug Administration. Guidance for Industry. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. December 2018. https://www.fda.gov/media/71195/download.
6 “Expediting Treatments to Oncology Patients in Need: Understanding the FDA’s Accelerated Pathways.” Resources, March 10, 2022. Allucent. https://www.allucent.com/resources/blog/expediting-treatments-oncology-patients-need-understanding-fdas-accelerated-pathways.
7 U.S. Food & Drug Administration. Guidance for Industry. Expedited Programs for Serious Conditions – Drugs and Biologics. May 2014. https://www.fda.gov/media/86377/download.