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Eligibility Criteria Can Limit Patient Access

November 14, 2023

Mid-November 2023

Ruth Jessen Hickman, MD

Ruth Jessen Hickman, MD, is a freelance medical and science writer based in Bloomington, Indiana.

Eligibility criteria for clinical trials have important implications for patient safety and generalizability. An analysis of acute leukemia trials recently published in Hematologica underscores the importance of thoughtfully and consistently employing such criteria to safely increase patient inclusion.1

This work is in line with the U.S. Food and Drug Administration’s (FDA) efforts to encourage broadening eligibility criteria where safe and appropriate, in concert with the Food and Drug Omnibus Reform Act of 2022. By using scientifically justified criteria for eligibility, fewer patients are unnecessarily excluded, and more diverse populations may participate in trials. Overly restrictive criteria can also hamper overall study accrual and prevent benefits from access to investigational interventions for historically marginalized groups.2,3

Other work in hematology suggests that overly narrow eligibility criteria may play a role in underrepresentation of some racial and ethnic groups in clinical trials. For example, a recent retrospective study in multiple myeloma found that Black and other racial subgroups had higher ineligibility rates compared to white patients.4

“If you don’t have equitable representation in a trial, then you don’t know how well the trial actually works across the population,” said Andrew Hantel, MD, faculty member at Dana-Farber Cancer Institute in Boston and lead author of the Haematologica paper. He also pointed out that differences between trial and real-world populations contribute to the frequent discrepancies between trial outcomes and the poorer outcomes later seen in the general population.

The researchers performed a retrospective study of 250 eligible phase II and phase III trials of acute leukemia that took place from January 1, 2010, to December 31, 2019.1

“We were asking if there was a gap between what’s known about the safety of drugs at the time the trial was conducted and the eligibility criteria used because that gap could be used to safely expand representation and potentially enhance diversity,” Dr. Hantel said.

Using multivariable analyses, the team assessed the concordance between eligibility criteria and safety data. For example, a study that excluded patients with hepatitis C, even though reactivation of the virus or relevant drug-drug interactions were not known to be associated with the drugs being tested, was coded as discordant; a study that did not exclude such patients even if one of these safety signals was present was also coded discordant.

The team did find concordance between infectious disease criteria and risk (for example, HIV, hepatitis B and C), but overall, they found limited justifications for acute leukemia criteria. For example, concordant use of ejection fraction criteria, bilirubin levels, liver function tests, and renal function tests was 35%, 68%, 59%, and 68%, respectively.1

Even when the criteria were overall concordant with safety data, the eligibility criteria were generally more restrictive than necessary. For example, bilirubin limits were more restrictive than necessary in 76% of trials. Dr. Hantel and colleagues also found that the eligibility criteria used varied widely among the studies.1

Dr. Hantel pointed out that the retrospective nature of the study was an inherent limitation. Additionally, the researchers did not have complete (unpublished) data and context from all the studies to consider in their analysis.

The team also found that data from phase III trials were not more concordant than those from phase II trials. This indicates that later phase studies may roll over their initial eligibility criteria into later trials without attempting to broaden them, even if safety signals are not seen.

Dr. Hantel shared a key takeaway for designing such studies. “At every subsequent study phase, we should look to reassess and potentially expand the clinical trial eligibility criteria to better match the real-world population, if safety signals allow.” In the end, this may promote studies that better reflect regimens’ efficacy and safety in the actual population that will be treated.

Any conflicts of interest declared by the authors can be found in the original article.

References

  1. Hantel A, Luskin MR, Khan I, et al. Use, variability, and justification of eligibility criteria for phase II and III clinical trials in acute leukemia [published online ahead of print, 2023 Aug 10]. Haematologica. doi: 10.3324/haematol.2023.283723.
  2. Duggal M, Sacks L, Vasisht KP. Eligibility criteria and clinical trials: an FDA perspective. Contemp Clin Trials. 2021;109:106515.
  3. Food and Drug Omnibus Reform Act of 2022. Washington, DC: 117th United States Congress; 2022.
  4. Kanapuru B, Fernandes LL, Baines A, et al. Eligibility criteria and enrollment of a diverse racial and ethnic population in multiple myeloma clinical trials. Blood. 2023;142(3):235-243.

Perspectives

We walk a fine line in defining clinical trial eligibility criteria for cancer treatments. If we make them too broad, we may lose our intended patient population – trees within a forest – of trial enrollees who may or may not live longer or live better from an intervention. This could obfuscate a beneficial effect or wrongly attribute an untoward consequence to a drug, when that consequence may be due to a comorbid condition that existed before the trial started. But if we make eligibility criteria too narrow, a drug may be approved by the FDA based on outcomes in a heroically healthy group of people who don’t reflect the rest of us who reside in the foothills of Mount Olympus or the patients we hope to treat with the drug.

The study by Hantel et al.1 explored whether eligibility criteria in 250 phase II and III acute leukemia trials conducted over a 10-year period reflected known safety signals in the drugs being investigated. The investigators reported on concordance, meaning the presence of an eligibility criterion with a known drug safety signal or absence of the criterion without a signal. While concordance for individual organ function eligibility criteria ranged from 46% to 86% (for example, concordance for cardiac ejection fraction eligibility criteria and chemotherapy known to have congestive heart failure risk was 46%), formal statistical testing did not find significant concordance between organ function eligibility criteria and known drug safety risks. Interestingly, industry sponsorship of trials was more often associated with hepatitis exclusions, while academic sponsorship led to more bilirubin and renal function exclusions.

Previous studies have shown that eligibility criteria for hematologic malignancy trials do not reflect known drug safety signals, nor have realized drug adverse events (AEs) been reported from those trials.2 Similarly, patients enrolled to Southwest Oncology Group leukemia trials who were found after the fact to have been ineligible had similar rates of AEs and remission as those patients deemed eligible3 – meaning, eligibility criteria for those trials were unnecessarily restrictive.

Those of us who design clinical trials have agency in this. We can write eligibility criteria that describe the patients we see every day and that don’t exclude vulnerable patient populations who are more likely to have comorbidities related to organ dysfunction so they can be represented in trials too. We’ve established that clinical trials in leukemia, and hematologic malignancies writ large, have overly restrictive eligibility criteria. Now it’s time to do something about it.

Mikkael A. Sekeres, MD, MS
Chief, Division of Hematology and Professor of Medicine
Sylvester Comprehensive Cancer Center,
University of Miami

Conflict of Interest Statement: Dr. Sekeres has served on advisory boards for Bristol Myers Squibb, Kurome, and Novartis.

References

  1. Hantel A, Luskin MR, Khan I, et al. Use, variability, and justification of eligibility criteria for phase II and III clinical trials in acute leukemia [published online ahead of print, 2023 Aug 10]. Haematologica. doi: 10.3324/haematol.2023.283723.
  2. Statler A, Radivoyevitch T, Siebenaller C, et al. The relationship between eligibility criteria and adverse events in randomized controlled trials of hematologic malignancies. Leukemia. 2017;31(8):1808-1815.
  3. Statler A, Othus M, Erba HP, et al. Comparable outcomes of patients eligible vs ineligible for SWOG leukemia studies. Blood. 2018;131(25):2782-2788.

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