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FDA Releases Draft Guidances to Promote Clinical Trial Design Efficiency

On September 28, 2018, the U.S. Food and Drug Administration (FDA) released two draft guidances for industry. The purpose, according to FDA Commissioner Scott Gottlieb, M.D., is to modernize the approach to clinical trial design in efforts to (1) make clinical trials more efficient while maintaining patient safety and (2) increase the amount of information concerning product safety and benefits. The two draft guidances are entitled: “Master Protocols – Efficient Clinical Trial Design Strategies to Expedite Development of Cancer Drugs and Biologics” and “Adaptive Designs for Clinical Trials of Drug and Biologics.” This is the second of the two-part blog series describing the updates to the agency’s recommended approach to incorporating master protocols in clinical trials of new drugs and biological products for the treatment of cancer. The first of the two-part blog series described FDA’s recommended considerations to “adaptive designs” used in clinical trials.

In brief, the “Master Protocols Guidance” provides FDA recommendations to sponsors that desire the opportunity to run several related oncology studies concurrently under a master protocol, defined as “a protocol designed with multiple substudies, which may have different objectives and involves coordinated efforts to evaluate one or more investigational drugs in one or more disease subtypes within the overall trial structure.” This would give sponsors the ability to expand the reach of their oncology clinical studies to observe safety and efficacy in multiple subtype populations, disease subtypes, drug combinations and/or dosages.  Master protocols may be utilized to provide data for exploratory purposes or to support a marketing application.

Running an oncology clinical trial with a master protocol potentially benefits the sponsor by allowing the sponsor to concurrently evaluate multiple studies that may have different objectives, thus potentially saving time and costs as compared to running separate clinical trials. However, FDA also acknowledges that a master protocol may introduce challenges that, if not properly addressed, can increase risk to study subjects or delay the development of the product. Therefore, FDA released this guidance to provide recommendations to sponsors that are considering incorporating a master protocol into their clinical trial design to help them avoid unnecessary delay in the IND review process.

In the Master Protocol Guidance, FDA describes two types of master protocol designs: (1) the “basket trial” design and (2) the “umbrella trial” design. The basket trial is designed to test a single investigational oncology drug or drug combination in different populations (e.g., disease subtypes, biomarkers, demographic characteristics, etc.). FDA states that each substudy within a basket trial should include specific objectives, the scientific rationale for inclusion of each population, and a detailed statistical analysis plan that includes sample size justification and stopping rules for futility. In contrast, the umbrella trial is usually designed to evaluate multiple investigational oncology drugs administered as single drugs or as drug combinations in a single disease population. FDA reminds sponsors that appropriate dosages should be established for each investigational drug in Phase 2 studies prior to evaluation of the drug in a master protocol. Because umbrella trials can be used to compare the activity of investigational drug(s) in randomized controlled studies with a common control arm, FDA strongly recommends that the control arm be the standard of care (SOC) for the target population, noting that the SOC may change over time as newer treatments are adopted.

Additionally, FDA provides specific design considerations that sponsors are strongly recommended to address in their master protocols:

  • If sponsors are investigating a novel combination of two or more investigational drugs, the master protocol should summarize available safety, pharmacology, and preliminary efficacy data for each investigational drug; the biological rationale for use of the drugs in combination instead of individually; and evidence, if any, the interaction of the drugs when used together.
  • If sponsors are investigating drugs that target multiple biomarkers, the master protocol should include a prespecified plan for allocating patients who are potentially eligible for more than one substudy.
  • If sponsors seek to potentially add, expand, or discontinue treatment arms, sponsors should ensure that the master protocol and its associated statistical analysis plan (SAP) describe the conditions that would result in making such adaptations.
  • If sponsors anticipate utilizing the results from one or more of the substudies in support of a marketing application, the master protocol should describe and provide the charter for an independent radiologic review committee to perform blinded tumor-based assessments, a charter for an independent data monitoring committee (IDMC) to monitor efficacy results and safety results or alternatively an independent safety assessment committee (ISAC). The charter should authorize these committees to conduct prespecified and ad hoc assessments of efficacy, safety, and futility and recommend protocol modifications or other appropriate actions (i.e., adjusting sample size; discontinuing the substudy based on futility or substantial evidence of efficacy).
  • If sponsors are utilizing master protocols to evaluate biomarker-defined populations, the master protocol should explain why the use of the biomarker is appropriate and also include a validated in vitro diagnostic (IVD) test.

According to the Master Protocol Guidance, each sponsor will need to submit each master protocol as a new IND. When submitting an IND with a master protocol, the sponsor should consider the following:

  • The master protocol should be the only trial conducted under the IND;
  • The master protocol should be submitted to either CDER or CBER for review of the primary indication(s). If more than one indication is being investigated, the IND should be submitted to the most appropriate clinical review division within the Office of Hematology and Oncology Products in CDER or CBER, taking into account the population to be studied.
  • In addition to the elements required to be included in an IND submission under 21 CFR Part 312, the master protocol should include:
    • A detailed description of the trial design as text and as a visual illustration;
    • Procedures for sample acquisition, handling, and testing of biomarkers, if appropriate;
    • Identification of all substudies;
    • A description of all committee groups responsible for patient safety monitoring;
    • A description of the plan for submitting interim safety and efficacy results; and
    • The proposed informed consent document.

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As mentioned above, incorporating master protocols into a clinical development program may have advantages, as these studies may reduce burdens associated with conducting separate studies and increase product speed to market.  If these benefits are realized, the end result may be improved patient access to therapeutic oncology interventions and lower costs of drugs through reduced development costs and greater competition.  However, concurrent evaluation of multiple oncology drugs and/or disease populations within a single trial is complex. Therefore, it is important that the trials are well-designed and well-conducted to ensure research subject safety and obtain quality clinical study data in support of drug or biological product approval. This guidance provides a glimpse of FDA’s approach to modernizing product development. Sponsors and stakeholders with an interest in developing their products under a master protocol are strongly encouraged to review this guidance and submit comments to FDA by November 30, 2018.

©2020 Epstein Becker & Green, P.C. All rights reserved.National Law Review, Volume VIII, Number 290

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About this Author

Daniel Kim, Epsten Becker Law Firm, Washington DC, Healthcare law
Associate

DANIEL KIM is an Associate in the Health Care and Life Sciences practice, in the Washington, DC, office of Epstein Becker Green. He will be focusing his practice on FDA marketing approval of medical devices and pharmaceutical, reimbursement and compliance matters affecting health care medical device manufacturers, telehealth and telemedicine, HIPAA privacy and security, regulatory health care due diligence, and compliance issues.

Mr. Kim received his J.D., cum laude, from American University Washington College of Law....

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