New guidances on cancer clinical trial eligibility continue pushing the US Food and Drug Administration opinion that overly restrictive criteria often are not necessary and can hinder drug development.
The three final guidances released July 27 are aimed at cancer clinical trials, but the agency said the recommendations could impact drug development in other diseases. The documents cover laboratory values, performance status and washout periods and concomitant medications used as eligibility criteria.
The guidances were developed from workshops with the Friends of Cancer Research and American Society of Clinical Oncology and finalized documents issued in 2024 with seemingly minor changes.
The FDA said expanding eligibility criteria may improve trial data applicability to US populations.
“The agency recognizes that some eligibility criteria may have become commonly accepted over time or used as a template across trials, but such criteria should be carefully considered and be appropriate for a specific trial context,” the FDA wrote. “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 said the three guidances are part of the Health and Human Services Department’s Operation Trialblazer campaign, which is intended to streamline drug development in the US amid growing competition from other countries. The upcoming FDA user fee reauthorization also could include legislation connected to the initiative. (See sidebar.)
Operation Trialblazer includes the FDA IND reform pilot program, which allows qualified research institutions to help sponsors develop protocols for first-in-human clinical trials before submission.
But the FDA has argued for years that sponsors should refrain from overly restrictive clinical trial eligibility criteria. Agency officials have said sponsors should increase the participation of patients 75 and older, as well as those with psychiatric and other conditions.
Including Low PS Patients Could Improve ‘External Validity’ Of Results
The FDA listed several advantages to including cancer patients with low performance status, a measure of their ability to perform ordinary tasks and conduct activities of daily living. Typically, trials are limited to patients with “good” PS.
The guidance states including low PS patients could speed accrual and improve the “external validity of trial results” because efficacy and safety data in high PS patients may not predict outcomes for low PS subjects.
But the guidance also states that low PS trial participants could increase adverse events, as well as impact retention and outcomes data.
The agency said lower PS patients should be included in trials “in a way that contributes to a greater understanding of the efficacy and safety profile of the investigational drug while maintaining subject safety.”
Alternative trial designs and additional functional status assessments should be considered to ensure more low PS patients can participate, the agency said in the guidance.
Restrictive Lab Value Criteria Only Necessary To Avert Safety Concerns
The FDA wrote lab values only should be used as exclusion criteria “when clearly necessary to mitigate potential safety concerns.” The agency also recommended using clinical data to adjust lab value criteria as drugs advance in development.
The agency said lab value eligibility criteria should be customized for the drug in development and potentially expanded to account for inter-lab variation.
In addition, the FDA suggested demographic differences in lab test results and their impact across populations should be understood when determining eligibility criteria.
“Given natural variations in laboratory values among people that may be associated with race and ethnicity, those criteria that are included should be sufficiently broad to allow for these natural variations,” the agency said.
Washout Period Criteria Can Hinder Enrollment
In the guidance for washout periods, which are treatment-free periods to allow the effects of prior therapies to be eliminated, the agency said undue restrictions on concomitant medications could hinder enrollment and preferentially exclude older patients.
“Instead of excluding patients using interacting concomitant medications, sponsors may also consider modification of the dosage or regimen of the investigational anti-cancer agent or the concomitant medications,” the FDA said.
The agency also wrote that time-based washout periods should be scientifically justified and relevant PK/PD of the prior therapy should be considered.
“A washout period may be appropriate if prior therapy can result in delayed anti-tumor effects, if one of the objectives of a trial is an estimate of anti-tumor effects of an investigational drug,” the FDA said.