Master Protocols for Drug and Biological Product Development; Guidance for Industry; Draft Guidance

Mark Obermeyer, an independent researcher, argues that the FDA failed to follow its own "Master Protocols" by not identifying and quantifying long-term adverse events associated with nasopharyngeal swabs during the COVID-19 pandemic. He contends that these swabs caused accelerated infections and increased mortality, and he advocates for the immediate discontinuation of the procedure in favor of safer alternatives.

Daiichi Sankyo, a global pharmaceutical company, submitted comments providing specific technical feedback and requests for clarification on the draft guidance for master protocols. They advocate for more detailed guidance on oncology trials, randomization practicalities, and the inclusion of combination regimens.

Pharmaceutical Research Manufacturers of America (PhRMA) supports the FDA's draft guidance on master protocols for drug and biological product development, noting it aligns with previous recommendations and mandates. They suggest specific improvements, such as expanding the discussion on basket trials, clarifying combination therapy scope, and refining definitions for substudies and informed consent.

Arnold Ventures, a philanthropy focused on evidence-based policy, supports the development of master protocols for clinical trials but recommends specific enhancements to the draft guidance. They argue for stronger requirements for randomization to internal control groups, more emphasis on double-blinded trials over partially blinded ones, and clearer expectations for statistical analysis plans regarding interim results and concurrent enrollment.

Boehringer Ingelheim Pharmaceuticals, Inc. provides comments on the draft guidance for Master Protocols for Drug and Biological Product Development. The company supports the general direction of the guidance but suggests specific clarifications regarding sponsor responsibilities, randomization methods for irrational ratios, operational burdens of changing ratios, and the inclusion of control patients in primary analyses.

The Methodology Working Party of the European Medicines Agency submitted comments providing technical feedback and suggestions for the finalization of the draft guidance. They offer specific recommendations on clarifying adaptive design features, multiplicity, and the scope of basket trials within the master protocols.

AstraZeneca supports the draft guidance on Master Protocols for Drug and Biological Product Development, noting it is timely and supportive of innovation. The company suggests expanding the guidance to include more detail on basket trials, precision medicine, rare diseases, and practical considerations like patient centricity and sample size estimation.

The commenter, likely a pharmaceutical or clinical research company, provides specific technical feedback on the draft guidance for master protocols. They suggest clarifying language regarding randomization ratios, informed consent procedures for platform trials, and the distinction between sub-study and overarching protocol amendments to improve practical feasibility and patient experience.

The Multi-Regional Clinical Trials Center (MRCT Center) of Brigham and Women's Hospital and Harvard supports the FDA's effort to extend master protocol guidance beyond the COVID-19 pandemic. They provide specific feedback on definitions, scope, informed consent, and data sharing, while requesting further clarification on rare disease trials and multi-national considerations.

The Biotechnology Innovation Organization (BIO) supports the draft guidance on Master Protocols for Drug and Biological Product Development, noting that it comprehensively summarizes common practices. However, the organization provides numerous specific recommendations to improve the guidance, including clarifying definitions, expanding the scope to include basket trials and pediatrics, and providing more detail on adaptive designs and sample size considerations.

The Oncology / Immuno-Oncology subteam of the Innovative Design Scientific Working Group (IDSWG), representing several pharmaceutical companies and independent consultants, provides detailed technical feedback on the draft guidance. They request specific clarifications on trial definitions, statistical methodologies (such as adaptive randomization and multiplicity), and operational considerations like IRB structures and informed consent.

The Coalition for Epidemic Preparedness Innovations (CEPI) supports the use of master protocols as a tool for responding to public health emergencies and developing vaccines. They suggest expanding the guidance to include more details on diverse technologies and diseases, as well as clarifying ownership of INDs for multiple products.

The commenter, likely an academic or researcher given the citation of a peer-reviewed medical journal, supports the guidance but suggests refining the definition of "concurrent control" to be broader for platform trials. They also advocate for including specific requirements regarding "Participant Randomization Schemes" to ensure valid data interpretation in data-sharing arrangements.

The Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, representing an academic institution, supports the draft guidance but requests specific modifications to improve its practical application. They argue for language that acknowledges the balance between statistical risks and operational feasibility, specifically advocating for a two-step informed consent process and more flexibility for rare disease studies.

A group of researchers and industry experts (including representatives from Berry Consultants, Novartis, and various universities/pharmaceutical companies) provided technical feedback on the draft guidance. They suggest refining terminology, clarifying randomization and blinding options, and adding specific sections on adaptive features unique to platform trials.

The commenter, representing a group of researchers/academics, suggests specific technical clarifications to the draft guidance regarding Type I error rate control. They argue that the guidance should explicitly reference the "Error Rate per Family" (ERpF) to clarify how the FDA controls incorrect regulatory approvals across multiple studies and platform trials.

Halloran Consulting Group provides specific feedback and requests for clarification on the draft guidance for master protocols in drug and biological product development. They suggest adding more practical details, such as FAQs, diagrams, and specific guidance on data integrity, multi-sponsor relationships, and international harmonization.

The Alliance for Regenerative Medicine (ARM) supports the development of master protocols to accelerate drug development, particularly for rare diseases. They provide specific recommendations to clarify the guidance regarding biomarkers, trial designs for cellular and gene therapies, and IND cross-referencing.

The commenter expresses extreme hostility toward the FDA, accusing the agency of corruption, negligence, and being in the pocket of "Big Pharma." They argue that the agency should be closed down, defunded, and subjected to a criminal investigation.

Certara, a pharmaceutical services company, supports the draft guidance on Master Protocols but requests several specific clarifications and additions. Their suggestions include expanding the scope to include combination therapies, providing more detailed examples of trial designs (like umbrella and platform trials), and clarifying regulatory requirements for IND submissions and data sharing.

Unlearn.AI, Inc., a company developing machine learning methods for clinical trials, supports the draft guidance on Master Protocols. They advocate for the inclusion of specific, standardized evaluation approaches for innovative methods like AI/ML and Bayesian designs to foster trust and stimulate innovation.

The commenter suggests that the guidance should provide more specific criteria for determining when a control arm can be depowered, particularly regarding changes in the standard of care. They also recommend including language on how master protocols can support combined Phase 1, 2, and 3 trials for genetic-based treatments to encourage smaller companies to develop gene therapies.

Dr. Sara L Colby, a physician, expresses frustration regarding Medicare's coverage of Humira and the lack of cost-effective home injection options compared to office infusions. However, her comment focuses on Medicare coverage policies and drug pricing rather than the specific "Master Protocols for Drug and Biological Product Development" guidance.

The commenter provides technical feedback regarding the statistical allocation ratios for umbrella trials in drug development. They argue that the current recommendations may not be optimal for trials where experimental arms enter at different times or have overlapping populations, citing specific research for a more complex formula.