The FDA changed relatively little in finalizing three guidance documents that contain recommendations for constructing cancer trial eligibility criteria involving laboratory values, concomitant treatment and performance status. The concepts they explain may also apply to other clinical areas.
Clinical trial representation: A quick background
- The FDA requires substantial evidence of a drug or biologic product’s safety and effectiveness before it will grant approval. This evidence, provided by “adequate and well-controlled investigations,” requires sponsors to control factors that could affect their studies’ results. Patient enrollment must ensure proper randomization, for example. Trial participants’ health status can’t get in the way of assessing a drug’s clinical effects. Concomitant use of other treatments must be managed. When left uncontrolled, these external factors can confound any subsequent analysis, muddying any evaluation of how well a treatment works and whether it is safe.
- Sponsors often seek to tightly control the variables in their clinical trials, but those efforts can inadvertently decrease diversity. When all the obvious variables that can be controlled are controlled, trial populations can become homogeneous. A homogeneous trial population can mean data are harder to generalize to the broader patient population and may mean individuals who aren’t frequently represented in clinical research are overlooked. These include racial and ethnic minority groups, people who do not have access to traditional clinical trial sites (e.g., rural populations and those with mobility issues), and people with comorbidities, including the frail and elderly.
- To address these concerns, the FDA has issued nearly a dozen guidance documents related to clinical trial eligibility in oncology. These guidance documents have addressed the inclusion of older adults in clinical trials for cancer drugs, the inclusion of patients with existing health issues (such as HIV and other types of cancer), pediatric cancer trial eligibility, the inclusion of pregnant women and adolescent patients in trials, the inclusion of male breast cancer patients and premenopausal women in breast cancer trials, and research in non-curative settings.
Recent FDA work has provided additional guidelines on eligibility in oncology trials
- The FDA has worked closely with the American Society of Clinical Oncology and Friends of Cancer Research to “address overly restrictive cancer clinical trial eligibility criteria.” ASCO and Friends issued a joint research statement in 2017 outlining criteria for including certain populations in trials. Several working groups were formed under the umbrella of this partnership, producing peer-reviewed articles on various issues involving cancer trial enrollment.
- ASCO and Friends in 2021 submitted a trio of “external guidance documents” on three such issues: washout period and concomitant medication, performance status and laboratory values. The documents, which were intended to be the basis of future FDA policymaking, drew on supporting manuscripts developed by the partnership’s working groups earlier that year. They focus on how sponsors can minimize exclusion criteria based on required washout periods, use of concomitant medications, the patient’s performance status and cut points for laboratory testing. Historically, sponsors have erred on the side of excluding complex patients, but this practice can result in approved indications that render these groups ineligible for treatment. And if they are eligible, a drug’s safety and efficacy may not be adequately characterized in similar individuals, raising the chances of unforeseen clinical outcomes.
- The FDA’s Oncology Center of Excellence published draft guidance on these three topics in April 2024. The draft documents make extensive use of the materials compiled by ASCO and Friends. Both the external and FDA versions say that “some eligibility criteria [may] have become commonly accepted over time or used as a template across trials,” with the FDA noting that “such criteria should be carefully considered and be appropriate for a specific trial context.” Both documents note that “unnecessarily restrictive eligibility criteria may slow patient accrual, limit patients’ access to clinical trials, and lead to trial results that do not fully represent treatment effects in the patient population that will ultimately use the drug.” The draft guidance on setting eligibility criteria through laboratory values describes “general principles for selecting laboratory value-based eligibility criteria,” while the draft guidance on concomitant treatment urges sponsors to “consider removing exclusions carried over from earlier trials as increased drug metabolism, clearance, and drug-drug interaction information becomes available.” The draft guidance on performance status, meanwhile, encourages sponsors who choose to use performance scales to carefully consider the implications of doing so. [Read AgencyIQ’s full analysis of the draft guidance here.]
FDA finalizes guidances with few changes
- The FDA finalized all three guidances on July 27, 2026, updating language and making minor revisions but otherwise keeping intact the structure and content of the draft versions. In an email from OCE, the agency cited statistics that fewer than 5% of currently treated cancer patients are enrolled in clinical trials, although more than 70% would be willing to participate. Addressing “stringent and complex clinical trial eligibility criteria” could help boost participation, OCE wrote in the email, which also cited the guidance as helping advance HHS’s Operation TrialBlazer initiative.
- In finalizing the three guidances, the FDA tweaked terminology. Two mentions of “diverse” and “diversity” where changed, in keeping with its past response to early Trump administration executive orders on diversity initiatives and language. (In December, the agency revised its drug trial diversity guidance to instead emphasize participation.) The finalized guidances now specify that one goal of expanding eligibility criteria is to improve the applicability of trial data to U.S. populations, rather than improve the diversity of trial populations, for example. All three guidances also now note that “many of the concepts” they describe could “apply more broadly to other clinical areas.”
- The final guidance on laboratory values adds a new example to illustrate how readings can vary among healthy individuals of different age groups and demographic backgrounds. The so-called Duffy null phenotype, the FDA explains, is widely prevalent among African Americans and is associated with lower white blood cell counts. However, those lower values, which might fall outside of restrictive inclusion criteria, aren’t linked to greater risk of infection. The guidance later references this phenotype in recommending that sponsors account for demographic differences when writing trial enrollment criteria. It also encourages sponsors to consider writing eligibility criteria defined by broad laboratory reference-based ranges that can better accommodate inter-laboratory variation. Finally, the FDA mentions hematology laboratory criteria, which it says should be “carefully considered and broadened” in studies of people with blood cancers.
- The FDA made no material changes to the concomitant treatment guidance beyond those tweaks it made to all three. The document now includes an expanded mention of the effect dietary supplements may have on drug clearance. The final version also consolidates its recommendation on concomitant treatment criteria to two bullets from three, while clarifying that dose modifications of either the drug or concomitant medication can be used in place of excluding patients.
- The final guidance on performance status newly discusses pediatric oncology trials, explaining that some of the guidelines it contains are “specific to inclusion of adult patients” as performance scales can differ for young children. However, it notes that “many” of the general recommendations could still be applicable to pediatric oncology studies. The guidance also newly acknowledges that inclusion of patients with low performance status scores can impact trial retention. These individuals may depend more on caregivers to participate in trials, so sponsors “may consider measures to facilitate retention,” such as decentralized study elements. The FDA also adds a new caution in outlining its recommendations for additional assessments of function status, such as patient-generated physical function and activity data. These assessments, it writes, “should not limit trial eligibility unless there is a scientific and/or clinical rationale for exclusion justified by established safety considerations.”
Analysis
- The FDA received around a dozen comments on each guidance, including supportive feedback from ASCO and Friends. “We are pleased to see that the draft guidance documents’ content and strategies to modernize eligibility criteria for cancer clinical trials build upon the ASCO-Friends recommendations,” the two groups wrote in their comment. The agency made some changes recommended by stakeholder feedback but didn’t take up some of the technical input that was submitted. For instance, ASCO and Friends urged the FDA to amend its laboratory guidance to discourage use of certain laboratory markers and provide its thoughts on flexible testing intervals, which the agency didn’t directly adopt. However, the FDA appears to have incorporated Boehringer Ingelheim’s suggestion to recommend reference ranges rather than absolute values to account for inter-laboratory variation.
- Issuance of the three guidances means the FDA has now finalized recommendations on all eight topics studied by the ASCO and Friends working groups. Together, they provide a consistent framework for considering how eligibility criteria can shape the success and utility of cancer drug trials. “Unnecessarily restrictive eligibility criteria may slow subject accrual, limit patients’ access to clinical trials, and lead to trial results that do not fully represent treatment effects in the patient population that will ultimately use the drug,” the FDA writes in the introduction of the three new guidances. The agency is newly connecting this to its mission under Operation TrialBlazer to boost clinical research conducted in the U.S. Expanding trial criteria to account for demographic patterns specific to the U.S. can make the resulting data more relevant to U.S. usage. The FDA could similarly lean on this recommendation to push sponsors to run trials either based in or including the U.S., as former OCE Director RICHARD PAZDUR has previously done.
Featuring previous research by Laura DiAngelo and Rachel Coe.
To contact the author of this item, please email Ned Pagliarulo ( npagliarulo@agencyiq.com).
To contact the editor of this item, please email Holland Johnson ( hjohnson@agencyiq.com).
Key documents and dates
- Final guidance: Cancer Clinical Trial Eligibility Criteria: Laboratory Values: Guidance for Industry, IRBs, and Clinical Investigators (July 27, 2026)
- Final guidance: Cancer Clinical Trial Eligibility Criteria: Washout Periods and Concomitant Medications: Guidance for Industry, IRBs, and Clinical Investigators (July 27, 2026)
- Final guidance: Cancer Clinical Trial Eligibility Criteria: Performance Status: Guidance for Industry, IRBs, and Clinical Investigators (July 27, 2026)