Industry, patient groups seek changes to FDA’s revised master protocols guidance
Industry and patient groups have asked the US Food and Drug Administration (FDA) to make several changes to its revised draft guidance on master protocols for drugs and biological products. Additionally, two industry groups pushed for greater harmonization with global regulators, while a group representing clinical trial sites questioned the practicality of the guidance when it comes to site-level operations.
In June, FDA proposed revisions to its 2023 draft guidance based on a previous round of stakeholder feedback; the updated guidance includes a new section on evaluating drug effects across multiple diseases, conditions, or disease subtypes in basket trials. (RELATED: FDA revises master protocol guidance with new section on basket trials, Regulatory Focus 22 June 2026)
The revised guidance lays out design and analysis recommendations for clinical trials conducted under a master protocol, defined as a trial protocol with multiple substudies that may have different objectives and require coordination to evaluate several drugs simultaneously across multiple diseases or conditions. The agency noted that the decision to revise the guidance fulfills requirements under the 2022 Food and Drug Omnibus Reform Act (FDORA) to provide clarity on streamlining clinical trial logistics and efficiently collecting and analyzing data.
PhRMA
The Pharmaceutical Research and Manufacturers of America (PhRMA) requested several additional clarifications and changes to the guidance before it is finalized.
Overall, PhRMA was supportive of the changes FDA made to the previous version of the guidance, and noted that the new figures depicting umbrella, basket, and platform trial designs help sponsors better distinguish among the features of each trial design. The group also commended the agency for including statistical approaches for basket trials used to evaluate a single investigational therapy across multiple diseases, and for further clarifying randomization, investigational new drug (IND) submission structures, the application of clinical holds, protocol amendments, and communication among participating sponsors.
"Nevertheless, master protocols continue to present unique scientific, operational, and regulatory challenges that differ substantially from traditional clinical trial designs," said PhRMA. "These challenges become increasingly pronounced as protocols evolve over time, include multiple investigational products or sponsors, incorporate adaptive features, or evaluate therapies across multiple diseases, biomarkers, or patient populations.
"Accordingly, the guidance would benefit from additional clarification in several areas where implementation may otherwise vary considerably among review divisions or create unnecessary uncertainty for sponsors – a challenge that PhRMA has previously noted," the group added.
Notably, PhRMA asked that FDA add additional guidance on the use of Bayesian methodologies with the addition of a dedicated subsection addressing “pre-specification, assessment of temporal drift, dynamic borrowing, and operating characteristic simulations.” The group also asked that FDA ensure that the guidance is consistent with the agency’s 2026 draft guidance on Bayesian methods.
PhRMA also asked FDA to add language stating that a sponsor may submit master protocol information under an existing IND when the same sponsor and review division are overseeing the product development program, and that the sponsor should discuss the approach with the agency. The group said that asking the sponsor to submit a new IND for each master protocol may add unnecessary administrative burdens in such situations.
PhRMA also asked for additional clarity in several areas, including the use of basket trial designs, randomization in master protocols, blinded treatment assignments, adaptive designs, and informed consent. Echoing its previous comments to FDA, the group said that avoiding drug-specific substudy consent may not always be appropriate, including situations where multiple sponsors use the same master protocol, where concerns about confidentiality could hinder substudy-specific consent.
"The Agency’s rationale to avoid substudy-specific consent appears to be aimed at reducing potential issues in comparability between study groups," said PhRMA. "However, as noted in our prior comments, this concern is not applicable in master protocols involving a single drug targeting multiple diseases, or in substudies with different routes of administration.
"Depending on the specific study setting, single consent, modular consent, or a two-stage consent process may be appropriate," the group added. "We also recommend that FDA align with the Master Protocols for Oncology Products Guidance and explicitly acknowledge that, in some circumstances, substudy-specific consent may be appropriate."
Furthermore, PhRMA requested clarification on control groups, protocol amendments, trial oversight, data sharing, and safety governance. More specifically, the group said that safety should be considered in the broader context of the overall product development program rather than in an individual substudy. It said that FDA’s proposed revision to the guidance continues to limit how safety oversight is applied across the master protocols.
"Master protocols frequently involve multiple entities with distinct regulatory responsibilities, including a master protocol sponsor, one or more individual drug sponsors, independent data monitoring committees, contract research organizations, and centralized statistical and operational partners," said PhRMA. "While each sponsor remains responsible for meeting its regulatory obligations under the applicable IND(s), additional guidance regarding coordination of safety activities would facilitate more efficient implementation."
BIO
In its comments, the Biotechnology Innovation Organization (BIO) asked FDA to provide terminology or sample protocol text for the complex design elements discussed in the guidance.
The group said the clear terminology could address control-related elements such as shared control arms, concurrently eligible controls, nonconcurrent controls, drug-specific eligibility criteria, changing randomization ratios, and re-enrollment after washout, as well as blinding-related elements, such as multiple-dummy designs, partial blinding, matched controls, and open-label justification.
"Recommended language for these elements would help ensure protocol text remains precise and aligned with the statistical analysis plan (SAP)," said BIO. "FDA should also clarify which elements are expected to be described in the protocol versus the SAP or a statistical simulation report, particularly for success criteria, interim analyses, borrowing assumptions, treatment effect estimation, and the handling of concurrent or nonconcurrent controls.
"BIO also recommends the guidance clarify how its concurrent-control principles relate to FDA’s guidance on externally controlled trials, given that both address related methodological issues, including borrowing, temporal drift, and exchangeability, even though this guidance excludes external controls from scope," the group added. "Clearer terminology would also help, including distinctions between concurrent and contemporary controls, time-adjusted and cohort-adjusted analyses, and alignment with terminology in the statistical literature."
BIO asked FDA to add language on implementing weighting approaches and reporting effective sample size and other borrowing diagnostics that it said would help improve transparency and consistency across product submissions. Furthermore, it asked for clarity on adaptive platform trials by including the role of adaptive design elements in the guidance, such as common calendar-time interim analyses.
BIO asked for clarity on FDA's expectations regarding randomization in platform trials, particularly regarding the selection and justification of randomization ratios when several investigational products share a common control arm.
"Sponsors would benefit from guidance on when unequal allocation, shared-control allocation, or response-adaptive randomization may be appropriate; how to update randomization probabilities when arms are added, stopped, or otherwise modified; and how to reflect these strategies in simulations used to evaluate operating characteristics," said the group. "This should also clarify when substudy-level randomization may be omitted in platform trials with sequential, non-overlapping substudies, such as when only one substudy is enrolling at a given time or assignment is otherwise driven by eligibility or site availability."
BIO asked FDA to clarify expectations when evaluating operating characteristics, power, precision, control-arm comparability, and Type I error control. It also asked for a clearer taxonomy of multiplicity considerations in master protocols, which it said would help sponsors determine when family-wise error rate control, false-discovery-rate approaches, hierarchical testing, gatekeeping strategies, or other approaches may be appropriate, or when adjustment may be unnecessary.
BIO also asked FDA to clarify expectations for head-to-head comparisons between investigational arms within a master protocol.
"In some platform trials, the availability of contemporaneously randomized investigational arms may support direct comparisons to inform clinical development, regulatory decision-making, or potential labeling," said the group. "Sponsors would benefit from guidance on when such comparisons may be considered exploratory versus confirmatory; how superiority or noninferiority hypotheses between investigational arms should be pre-specified and justified; and how differential timing of arm entry, control-arm sharing, follow-up duration, and potential changes in standard of care should be addressed."
Additionally, BIO asked FDA to expand its recommendations for borrowing across substudy populations in basket trials, provide additional details on safety monitoring and data-sharing expectations in master protocols, and clarify how partial clinical holds may apply to individual substudies under different IND structures. The group also asked the agency to extend the consent-simplification approaches in its existing informed consent guidance to platform trials. It said that single upfront consent forms may become lengthy as new treatment arms are added.
BIO also echoed PhRMA's recommendation to ensure harmonization across regulatory agencies.
"Because umbrella, basket, and platform trials are frequently conducted as multi-regional trials intended to support submissions across jurisdictions, BIO also recommends the guidance encourage early engagement with other health authorities where appropriate, particularly where protocol adaptations, control-arm strategies, or statistical methodologies may affect the global acceptability of the resulting evidence, and reference relevant international initiatives such as ICH E20 to promote consistency in terminology and trial planning across regions," said the group.
SCRS
The Society for Clinical Research Sites (SCRS), which represents more than 12,000 clinical research sites around the word, questioned the operational aspects of the guidance.
“The guidance addresses randomization, control group selection, blinding, and statistical multiplicity in significant technical depth, but it is silent on the operational infrastructure needed, especially at the investigator/site-level, through informed consent management, clinical trial agreement contracting, resourcing study personnel, and IRB reliance – all of which determines whether these master protocol designs can actually be executed as written,” the group wrote.
The group also took issue with the guidance’s handling of site-specific drug availability, raising questions about equity in access to investigational drugs. “This is presented purely as a statistical consideration for control-group selection. Notwithstanding any ethical concerns, this approach has an equally important operational and equity dimension that the guidance does not engage: how sponsors decide which sites offer which arms, and whether that selection process systematically advantages larger, better-resourced institutions over community and independent sites,” SCRS wrote.
NORD
The National Organization for Rare Disorders (NORD) said the revised guidance places a lot of emphasis on the use of traditional control groups but noted that placebo-controlled groups are often not feasible or ethical in rare disease patient populations. The group said the lack of comparative therapies, especially for rare diseases, is an area that has benefited from the use of external control designs.
"NORD urges the FDA to incorporate information from previously promulgated guidance on natural history, real-world evidence (RWE), and comparator arms into its guidance on master protocols," said NORD. "The draft guidance discusses exceptions to a placebo control arm; rather, NORD respectfully suggests that alternatives exist and should be considered more routinely.
"NORD recommends the FDA provide additional guidance on the implementation of these novel trial designs that allow fit for purpose trials for rare diseases," the group added.
