Industry and Patient Groups Seek Changes to FDA's Revised Master Protocols Guidance
核心洞察
The FDA revised its draft guidance on master protocols in June, adding a new section on basket trials and clarifying randomization, control selection, and informed consent.
PhRMA and BIO requested additional clarifications on Bayesian methods, consent approaches, randomization, and harmonization with global regulators such as ICH E20.
The Society for Clinical Research Sites (搜索) warned the guidance lacks operational detail on site-level infrastructure, while NORD urged broader use of external controls for rare diseases.
The US Food and Drug Administration (搜索) (FDA) has revised its draft guidance on master protocols for drug and biological product development, and industry and patient groups are now seeking further changes before the document is finalized. The revised draft guidance, issued on 22 June, reflects stakeholder feedback received since the original 2023 draft and includes a new section on evaluating drug effects across multiple diseases, conditions, or disease subtypes in basket trials.
The 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.
"FDA is issuing a revised draft guidance in response to public comments received on the original draft requesting that FDA provide additional recommendations on basket trials," said FDA. "Changes from the original draft include more detailed recommendations regarding basket trials and minor changes for clarity on topics such as randomization, choice of control, and informed consent."
Industry Requests for Additional Clarity
The Pharmaceutical Research and Manufacturers of America (搜索) (PhRMA) was broadly supportive of the changes, commending the new figures depicting umbrella, basket, and platform trial designs and the inclusion of statistical approaches for basket trials. However, the group emphasized that master protocols continue to present unique challenges.
"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."
PhRMA requested a dedicated subsection on Bayesian methodologies addressing "pre-specification, assessment of temporal drift, dynamic borrowing, and operating characteristic simulations," and asked that the guidance remain consistent with the agency's 2026 draft guidance on Bayesian methods. The group also asked FDA to clarify that a sponsor may submit master protocol information under an existing investigational new drug (IND) application when the same sponsor and review division oversee the product development program, arguing that requiring a new IND for each master protocol may add unnecessary administrative burdens.
On informed consent, PhRMA pushed back on the agency's rationale for avoiding 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." The group recommended that FDA align with the Master Protocols for Oncology Products Guidance and acknowledge that substudy-specific consent may be appropriate in some circumstances.
The Biotechnology Innovation Organization (搜索) (BIO) asked FDA to provide terminology or sample protocol text for complex design elements, including shared control arms, concurrently eligible controls, nonconcurrent controls, and multiple-dummy designs. "Recommended language for these elements would help ensure protocol text remains precise and aligned with the statistical analysis plan (SAP)," said BIO.
BIO also sought clarity on randomization in platform trials, particularly regarding the selection and justification of randomization ratios when several investigational products share a common control arm. The group asked for guidance on when unequal allocation, shared-control allocation, or response-adaptive randomization may be appropriate, and how to update randomization probabilities when arms are added, stopped, or otherwise modified.
Calls for Global Harmonization
Both PhRMA and BIO urged FDA to harmonize its guidance with international regulators. BIO specifically recommended that the guidance encourage early engagement with other health authorities and reference relevant international initiatives such as ICH E20 to promote consistency in terminology and trial planning across regions.
"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," said the group.
Operational and Rare Disease Concerns
The Society for Clinical Research Sites (搜索) (SCRS), which represents more than 12,000 clinical research sites worldwide, questioned the operational practicality 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.
SCRS also raised equity concerns about site-specific drug availability, arguing that the guidance treats this purely as a statistical consideration for control-group selection. "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.
The National Organization for Rare Disorders (搜索) (NORD) said the revised guidance places significant emphasis on traditional control groups, but noted that placebo-controlled groups are often not feasible or ethical in rare disease patient populations. "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."
Stakeholders can comment on the revised guidance on www.regulations.gov under docket no. FDA-2023-D-5259 until 22 August.