FDA Examines Eligibility Criteria in Clinical Trial Design and Product Development


Applied Clinical Trials

Recent legislation authorizes further assessment of FDA eligibility policies and of NIH research standards.

Efforts to devise more informed and productive clinical research programs, while also addressing demands for expanded access to experimental therapies, has focused attention on the role of inclusion/exclusion criteria in clinical research. Sponsors design clinical trials to demonstrate efficacy of a drug on a target population, usually including sufficient subgroups to support broader product use. More innovative and adaptive trial designs may facilitate including certain rare disease populations and demographic minorities that also may benefit from treatment, but with an eye to avoiding requirements that could add to the cost and challenges in conducting necessary studies.

FDA is exploring these issues, as discussed at a recent public workshop on Evaluating Inclusion and Exclusion Criteria in Clinical Trials in Washington, D.C., organized by the Duke Margolis Center for Health Policy in collaboration with FDA. While these issues have been reviewed frequently in the past, recent legislation authorizes further assessment of FDA eligibility policies and of National Institutes of Health (NIH) research standards.

The experts at the Duke workshop noted that while more restrictive eligibility criteria may be appropriate for early stage clinical trials when little is known about product safety and efficacy, enrollment of more diverse populations is desirable for later studies to help ensure that a therapy is approved for all patients likely to benefit. Restricting patient enrollment may prevent generalizability of study findings to broader populations, limit development of risk and outcomes information for certain groups, and undermine reimbursement and coverage decisions by health plans and payers.

The regulators and research community thus are re-examining enrollment criteria for clinical trials to avoid underrepresentation of relevant populations and to assess how eligibility criteria impact patient access to investigational drugs. Robert Temple, deputy director for clinical science at the Center for Drug Evaluation and Research (CDER), reviewed the tradeoffs for sponsors in limiting variability in study populations. He noted that FDA has long advised against excluding particular subgroups such as the elderly and women and that labeling for new therapies requires information on subgroup differences in indications, dosage, and adverse reactions.

Including older individuals in clinical trials also is important in gaining coverage for Medicare populations, and the Centers for Medicare and Medicaid Services considers these issues in assessing reimbursement for new drugs and medical products. As part of ongoing NIH review of whether its policies sufficiently support the inclusion of all ages in funded research, as required by the 21st Century Cures legislation, an agency task force organized a workshop in June 2017 on inclusion of patients of varying ages. That has led to policy revisions requiring that all NIH-funded projects include a plan for including pediatric populations. Another NIH task force recently issued a report on research involving pregnant and lactating women, a topic also addressed in recent FDA guidance [see https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM603873.pdf].

The Duke workshop similarly discussed issues related to including children of different ages in research, as well as older adults and patients with multiple chronic conditions. Sponsors noted how the collection of more subgroup data may affect selection of study sites, contract research organizations, and investigators. And participants explored how innovative clinical trial design and access to more real world data may shape these issues.

The workshop concluded with a discussion of how strategies for including patients with serious conditions in clinical trials may provide patients early access to experimental therapies under “compassionate use” programs. While sponsors now regularly consult with patients and advocates on protocol design and access issues, industry remains concerned that results from highly inclusive studies may undermine regulatory submissions, particularly by generating additional safety signals. One strategy may be to organize parallel studies outside the controlled clinical trial environment, provided that such efforts don’t limit enrollment in registration trials by patients fearing treatment with placebo or less effective controls. The research community is looking for FDA to provide more guidance on how it may interpret data and adverse event reports from expanded access studies.

A summary and report on these issues will be published within three months. Further information on the Duke workshop is available at https://healthpolicy.duke.edu/events/evaluating-inclusion-and-exclusion-criteria-clinical-trials.


Jill Wechsler is the Washington Correspondent for Applied Clinical Trials.

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