Is it Time for a Major Reexamination of Inclusion/Exclusion Criteria?

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Stringent exclusion criteria sometimes have the unintended consequence of producing clinical trials that fail to represent the “broader patient populations that use approved products,” according to a new summary of a U.S. Food and Drug Administration (FDA) public workshop bringing together voices across the care delivery spectrum.

Inclusion and exclusion criteria aren’t matters to be taken lightly, of course. There are powerful ethical and scientific issues to address throughout the process.

“When designing clinical trials, there is tension between balancing the desire to minimize heterogeneity (“noise”), which can mask a finding of the effect, and the desire to generate data that are generalizable to a broader patient population that is likely to be treated,” according to the new report, “Evaluating Inclusion and Exclusion Criteria in Clinical Trials,” which summarizes an April 16 gathering in Washington, D.C.

Beyond thorny eligibility criteria challenges, workshop participants discussed several other significant barriers faced when working to enroll patients, including:

  • Geographical: Distance from a trial site is an obvious and ongoing issue. “Distributed trial networks, which could allow patients to participate in clinical research via multiple types of care settings, may provide one pathway to increasing enrollment and trial size by eliminating the geographic factor,” the report said.
  • Financial: Pressure to take time off from work is just one example of a potential negative financial consequence for a patient considering participating in a clinical trial. Advocating “thoughtful approaches to lower patient costs,” the FDA noted it had recently updated its guidance on payment and reimbursement of research participants to clarify that paying for travel expenses to and from the clinical trial site and associated costs such as parking and lodging “do not raise issues of undue influence and are generally considered acceptable practice.”
  • Historical Mistrust: After public revelation of human radiation experiments conducted by the U.S. government, forced sterilization and birth control studies on women of color, and other ethically questionable experiments conducted without informed consent, the clinical trial industry must address wariness from the public—particularly among African Americans. “It will require careful attention to communication processes for clinical trial recruitment and participation,” the report said. “Community engagement and outreach to connect communities with the potential benefits of participating in clinical research may represent strategies to overcome this mistrust.”
  • Healthcare Fatigue: This is particularly acute in populations with chronic conditions and in patients who have a “substantial” pill burden.

The report also pulled together some recommendations made by various participants to address some of the challenges, including:

  • Improving Transparency and Increasing Patient Involvement in Clinical Trial Design: The FDA workshop participants called from more transparency in how eligibility criteria are determined. Digging deeper to try to ascertain why patients chose not to participate in a trial is also important. Finally, some participants advised engaging in conversations with providers and clinicians who are not typically part of trial conduct. “Clinicians play a critical role in encouraging patients to participate in clinical trials and could serve as important resources for designing trials that patients will be more likely to participate in,” the report said.
  • Re-examining Inclusion and Exclusion Practices: Too often, rigid thinking hampers taking a fresh look at the logic behind certain parameters. For example, exclusions based on age alone are rarely appropriate, the report said. Heart failure is more prevalent in older adults. In a trial for heart failure, excluding patients over 70 years old would lead to a lack of data for an important component of the hearth failure population, and would lead to a failure to evaluate appropriate doses and needed monitoring in a significant portion of the U.S. population, according to the report.
  • Increasing the Use of Innovative and Alternative Trial Designs and Methods to Support Inclusion: Here, participants advocated reviewing pediatric and open-label safety studies, among other ideas.

Author: Michael Causey