By Sugato De (VP, Regulatory Strategy, Head of Medtech) and Michelle Hoffner O’Connor (Clinical Strategy Scientist II)
On December 21, 2023, the Food and Drug Administration (FDA) issued a draft guidance entitled “Master Protocols for Drug and Biological Product Development.” Master protocols originated as an efficient mechanism to determine which therapies may drive the most optimal response for a specific disease or condition (e.g., umbrella or platform trials). The definition has since expanded to include basket trials, which are intended to evaluate a single medical product for multiple diseases or conditions. Ultimately, the goal of these study designs is to improve the decision-making process that enables the developer to target the right treatments for the right patients. The release of this guidance distills considerations for the design and conduct of master protocols and may serve as a tipping point that will encourage more companies to consider these approaches to support drug and biologic development.
Evolution of Master Protocols
The concept of using master protocols in drug development has long held incredible promise in refining and accelerating development timelines for companies. Until relatively recently, the lack of informative guidance from FDA on the topic served as a barrier to companies considering innovative master protocol approaches. In recent years, FDA issued guidances that cover the master protocol considerations for:
- COVID-19 (2021),
- oncology (2022),
- early-stage cell and gene therapy products (2022).
The relative complexity of these trial designs demands that they are designed and executed to obtain reliable data to support marketing authorizations, while also ensuring appropriate patient protections. The new guidance, while not final, offers a strategic construct for master protocols that is broad and agnostic to the target indication.
Key Components of the Draft Guidance
The draft guidance concisely discusses multiple attributes of a master protocol including:
- randomization and blinding strategies
- the use of appropriate control groups
- statistical considerations (e.g., multiplicity, comparisons between treatment groups)
- safety evaluation
This provides companies with a roadmap for designing regulatorily compliant master protocols.
FDA explicitly points out that each element of the proposed study design must be selected and justified in the context of its intent (e.g., to define a dose, demonstrate proof of concept and/or establish safety and effectiveness). Internal concurrent controls are favored over both internal nonconcurrent controls as well as external control groups. Neither of the latter options is ruled out entirely as the guidance states that they may be justified in rare circumstances.
Although the Agency acknowledges there are unique challenges associated with blinding in umbrella and platform trials, ensuring that both subjects and investigators are completely blinded remains a priority (particularly when the trial results will be used to support safety and effectiveness in marketing authorizations). Partially-blinded strategies may be potentially acceptable if sources of potential bias can be mitigated, but in cases where bias cannot be controlled, FDA generally is not a proponent of using multiplicity adjustments to reduce the chance of erroneous findings. Instead, sponsors will need to ensure their studies have optimal power to clearly demonstrate clinical effectiveness of their product(s).
Limitations and Considerations
It should be noted that the clear focus of the draft guidance is on umbrella and platform trials, which are intended to evaluate multiple medical products for a disease or condition. While some concepts may be useful to consider for early-phase or exploratory trials or to satisfy post-marketing commitments, the recommendations in this guidance do not apply to a master protocol evaluating first-in-human drugs. Basket trials, which evaluate a medical product for multiple diseases or disease subtypes, are also not discussed, limiting the usefulness of this guidance to those who are seeking to expedite evaluation of a product in multiple indications. We believe that these gaps could be appropriately addressed prior to the finalization of the draft guidance. In addition, the guidance for oncology products provides some information that may be broadly applicable to non-oncology indications, particularly for biomarker-based populations.
Embracing Master Protocols for Biotech Success
For Biotech companies in particular, Allucent strongly believes that the benefits of using master protocol techniques to accelerate development outweigh the challenges involved in study design, justification to FDA, and ultimately execution. For some therapies and indications (e.g., platform therapies for oncology), we believe that companies using master protocols appropriately may outpace competitors that continue to operate using sequential standalone trials. FDA is clearly advocating for increased engagement in the space by introducing a specific Pre-IND meeting identifier for master protocols – REQUEST FOR MEETING – MASTER PROTOCOL (Meeting Type B). Hypothetically, this identifier may encourage increased consistency in input from FDA by facilitating more coordination between CDER and CBER review divisions.
Knowledge is power, and FDA is making a continued effort to empower a wider range of companies with the knowledge to reap the benefits of accelerating development programs and maximizing the amount and quality of data collected from a research effort. Master protocols may not be a fit for all development programs, but Allucent strongly believes that consideration should be given to the approach early in development.
Our A-Team of experts, comprising of industry-leading clinical and regulatory strategy, medical, biometrics, and clinical pharmacology professionals, can help you in assessing the benefits of a master protocol approach and partner with you in navigating the potential challenges to help ensure the success of your development program.