In June 2026, FDA issued the following guidance for industry; Master Protocols for Drug and Biological Product Development. This guidance revises and replaces the draft guidance issued in December 2023.
The new guidance outlines the different types of Master Protocols (umbrella, basket, and platform), and indicates the possibility that a Master Protocol may contain more than one trial type. FDA provides some interesting and helpful insights for Master Protocol Sponsors and details on how FDA expects these protocols to be submitted to FDA. As we see in many of the recently issued FDA guidances, FDA is suggesting that there be early communication with the Agency prior to filing a Master Protocol.
Regulatory Expectations
Among the interesting take-away messages from a regulatory perspective are the following general expectations:
- Each Master Protocol will be submitted under its own IND.
- Each therapeutic agent, drug or biologic, being studied in a Master Protocol is expected to have undergone previous human clinical testing and will, therefore, be the subject of its own individual IND.
- In some cases, a portion of the study that relates to a single agent in a single disease, condition, or disease type may be the subject of a substudy. In some cases, individual substudies also will be submitted to FDA under their own INDs.
- A current Investigator’s Brochure must be available for each agent. Exceptions for agents without a US IND must be discussed with FDA in the pre-IND phase.
- For the individual agents being studied under the Master Protocol, information can be submitted by reference to the respective INDs for each product.
A Master Protocol must be submitted by a single Master Protocol Sponsor regardless of whether the Sponsor is the sponsor of the INDs for the individual agents being studied in the Master Protocol. Written permission to reference an IND from an IND sponsor that is not the Master Protocol Sponsor is required by FDA.
FDA recommends that the Master Protocol be discussed with FDA prior to submission and suggests that this be done as a Pre-IND meeting. Acknowledging the complexities of Master Protocols, FDA also mentions that multiple meetings may be needed prior to the IND submission.
This guidance focusses on randomized studies using a Master Protocol to demonstrate safety and efficacy of the agents being studied. There is the assumption that early clinical trials have been conducted with each agent. Depending on the study design, Master Protocols can be used to generate many different types of data including proof-of-concept, dose-ranging, effectiveness, and safety. The objectives will be directly linked to the study design and analysis plans.
Much of the discussion in this guidance focusses on important elements in both the design and analysis of these studies including the following:
Randomization
Care should be taken in determining the most appropriate randomization scheme, especially in situations where multiple agents are being tested and agents may be added or discontinued during the trial. Considerations include whether to allocate more participants to the control arm when comparing multiple drugs to a shared control arm, whether the randomization ratio between the control and an individual drug should change over time as the number of drugs being evaluated changes (as in a platform trial), and whether to allow participants who complete one drug-specific study to later be randomized to a different drug-specific study.
Control Group
The types of control groups discussed in the guidance are concurrent and nonconcurrent. In a platform trial with a single control arm, participants who are randomized to the control arm prior to the entry of a new drug to the platform would not have had the opportunity to be randomized to the new drug. Thus, these controls are considered nonconcurrently randomized and should typically be excluded from the primary comparison with that drug in order to preserve the randomization. If the use of nonconcurrent control data is being considered by the sponsor, this should be discussed with the Agency in advance, including the justification and proposed methods for evaluating and addressing potential bias.
Informed Consent
A portion of the guidance focuses on the most appropriate way to obtain informed consent and maintain the integrity of each substudy within the Master Protocol. When one gets into the details, this part of the process can be complicated. In particular, the informed consent should include all treatments the participant could potentially receive. When comparing multiple drugs to a shared control arm in drug-specific substudies, having separate substudy consent may introduce bias if there are differences in the participants who would consent to one substudy versus another. The timing of informed consent updates also becomes important as new agents are added or new information is added on certain agents.
Treatment Blinding
Blinding of participants and treating physicians to treatment is another area that requires significant evaluation to avoid bias. While double-blind is the gold standard, this can be challenging with multiple agents and different routes of administration and dosing schedules.
Adaptive Design
Many Master Protocols include adaptive designs for early determination of efficacy or futility or to modify the sample size or randomization ratio. However, incorporating adaptive methodologies in Master Protocols requires careful thought and evaluation due to the unique challenges they present. For example, how does one conduct an interim analysis for a drug-specific substudy and ensure that the dissemination of the results does not disclose information about the efficacy of drugs from other substudies that share the same control arm.
Comparison Between Drugs
In a Master Protocol evaluating multiple drugs, the primary focus is usually to compare each agent to a control arm. That said, the same umbrella or platform trial can be used to compare two or more agents to each other. When these types of comparisons are being made, they should be prespecified in the statistical analysis plan (SAP).
Multiple Diseases
When the Master Protocol includes multiple diseases, as in a basket trial, there is the opportunity to leverage data across the substudies to evaluate the average drug effect. If this is one of the objectives, this guidance identifies issues to consider in determining if this would be appropriate based on the proposed trial design, substudy populations, and statistical analysis methods.
Multiplicity
Although Master Protocols include multiple comparisons involving the primary endpoint, FDA does not generally recommend the use of multiplicity adjustments, especially when the individual trial objectives could otherwise be evaluated in independent clinical trials where such adjustments are not made.
Comparison Between Drugs
The guidance also discusses oversight committees and recommends that a central institutional review board (IRB) review the protocol, consents, and other relevant documents. In addition, the use of an independent, external data monitoring committee (DMC) is recommended. As many Master Protocols include agents from multiple sponsors, data sharing agreements may also be useful.
This new guidance provides useful information for consideration on the design, development and execution of Master Protocols. We at PROMETRIKA are strategically positioned to assist our sponsors with their clinical development programs including those that include Master Protocols and adaptive designs.
