By Marites T. Woon, Associate Director, Nonclinical, and Jessica Lee, VP, Regulatory Strategy, Head, Cell / Gene Therapy
Exponential advancements in oncology continue to drive personalized medicine and biomarker-driven therapeutics into reality. The development of innovative therapies to treat serious diseases remains a frontrunner across drug and cell and gene therapy (CGT) pipelines, with oncology leading as one of the top targeted disease areas1,2. This focus is reflected in the more than 200 oncology drugs and eight anticancer CGT products approved to date3,4. While the outlook is promising, key challenges remain, requiring effective solutions and a reimagining of conventional approaches to overcome them.
Overview of Master Protocols
In an effort to expedite the development of anticancer drugs or biologics, the FDA issued guidance on the use of master protocols5. A master protocol is broadly defined as an approach intended to accelerate the development of innovative therapies under a single framework. As such, it can be used during different stages of drug development, including in early / exploratory-phase trials with the preliminary purpose of signal detection or late / pivotal-phase trials to support marketing applications. Note that master protocols are not intended for the conduct of first-in-human (FIH) clinical trials and typically require an established recommended Phase II dose (RP2D) for each investigational product. Key benefits to the conduct of clinical trials under a master protocol include:
- Flexibility – a master protocol obviates the need for multiple clinical protocols by allowing the simultaneous study of multiple therapies or multiple indications / diseases with different objectives to be evaluated in parallel under a single infrastructure.
- Efficiency – a master protocol, by using centralized data capture systems, allows a more streamlined approach towards data collection and analytics, mitigating operational challenges (e.g., cost, capabilities) and reducing study time.
Master Protocol Designs
Master protocols are typically designed in one of the following ways5.
Evaluation of a monotherapy (or in combination) across multiple diseases or targets. These are tissue-agnostic, biomarker-driven (biomarker-directed eligibility) trials characterized by i) multiple single-arm trials without an internal control and ii) activity-estimating trials with the objective response rate (ORR) as the primary endpoint.
Simultaneous evaluation of multiple therapies (as a monotherapy or in combination) for a specific disease or condition. This clinical trial design allows for more efficient product development, with the capacity for internal controls.
Platform (Adaptive) Trial
Allows the evaluation of multiple therapies for a single disease in a perpetual manner. Under this paradigm, investigational therapies may enter and exit the trial based on decision algorithms.
Other Master Protocol Considerations
According to a comprehensive analysis by Park et al. in 2019, 83 clinical studies were conducted under a master protocol using the basket (49), umbrella (18) and platform (16) designs7. Their findings confirm the narrow application of master protocols, with 76 of 83 clinical trials evaluating investigational anticancer products7.
While the use of master protocols is expected to increase in the coming years, an obvious tradeoff to the flexibility and efficiency master protocols provide is the complexity by which such trials are conducted. Challenges are further compounded when master protocols are used to investigate complex CGT products in disease areas with which the industry has limited experience. Therefore, it is critical that master protocols are:
- well-designed to ensure the accurate interpretation of data and findings; and
- well-conducted, with properly trained teams to safeguard the safety of patients and ensure the integrity of data.
Additional considerations to hedge against the unpredictability and increased complexity with the use of master protocols include5:
- Common Concurrent Arm – in the context of umbrella and platform trials, consider evaluating multiple anticancer therapies against the current standard of care (SOC) as the control arm to appropriately interpret the data. In general, it is highly recommended that primary analyses in umbrella and platform trials utilize only concurrent control data to minimize bias.
- Novel Combination Regimen of Two or More Investigational Drugs – the assessment of a combination product requires a scientifically based rationale, with a comprehensive understanding of the safety and efficacy of each investigational product based on nonclinical findings. Note that demonstrating the contribution of each investigational drug in novel combinations, to the extent possible, is needed and may first require identification of a safe dose(s) through a dose-finding phase.
- Statistical Analysis Plan – the conduct of substudies within a master protocol requires careful consideration of the statistical analysis plan (SAP), including detailed and specific methodology as well as justifications for study design components such as sample size.
Moving Forward with a Master Protocol
Given the complex nature of trials conducted under a master protocol, another critical consideration is early engagement with the appropriate clinical review division of the FDA. (5) Open communication with and corresponding feedback from the FDA are intended to ensure the adequate design and conduct of subsequent clinical trials. In support of this interaction and the success of such promising trials, our team of industry and regulatory experts at Allucent is committed to helping drive these initiatives.
Contact us today to learn more about how Allucent can support your next trial.
1 DeFrancesco L. Drug pipeline 4Q20. Nat Biotechnol. 2021 Feb;39(2):131-132.
2 American Society of Gene and Cell Therapy. https://asgct.org/global/documents/asgct-citeline-q3-2022-report.aspx.
3 Benjamin DJ, Xu A, Lythgoe MP, Prasad V. Cancer Drug Approvals That Displaced Existing Standard-of-Care Therapies, 2016-2021. JAMA Netw Open. 2022 Mar 1;5(3):e222265.
4 U.S. Food & Drug Administration. Approved Cellular and Gene Therapy Products. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.
5 U.S. Food & Drug Administration. Guidance for Industry. Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics. March 2022. https://www.fda.gov/media/120721/download.
6 U.S. Food & Drug Administration. Guidance for Industry. Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial. September 2021. https://www.fda.gov/media/152536/download.
7 Park JJH, Siden E, Zoratti MJ, Dron L, Harari O, Singer J, Lester RT, Thorlund K, Mills EJ. Systematic review of basket trials, umbrella trials, and platform trials: a landscape analysis of master protocols. Trials. 2019 Sep 18;20(1):572.