FDA finalizes three guidances to broaden cancer clinical trial eligibility

The US Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) has finalized a trio of guidance documents to promote greater participation and diversity in oncology clinical trials. The documents address three areas: a patient’s performance status, laboratory values, and washout periods.

Fewer than 5% of cancer patients currently undergoing treatment are enrolled in clinical trials, despite over 70% expressing a willingness to participate, according to a LinkedIn post from OCE. The guidance documents posted 27 July “address one reason for this low participation rate -- stringent and complex clinical trial eligibility criteria.”

The guidance documents note that “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 documents finalize draft versions released in April 2024 (RELATED: FDA issues three guidances to expand cancer clinical trial eligibility, Regulatory Focus, 29 April 2024).

Finalization of these guidances is meant to “advance one of the goals of HHS’ Operation Trialblazer Initiative, a coordinated federal initiative designed to accelerate drug development and reclaim America’s edge in clinical research,” according to OCE (RELATED: HHS and FDA propose clinical trial reforms to expedite drug development, Regulatory Focus 3 June 2026).

Issuance of these guidance documents also stems from the FDA’s push, going back to 2019, to broaden the criteria to participate in oncology clinical trials of investigational drugs or biological products regulated by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) on the premise that some sponsors are using eligibility criteria that are not based on sound science (RELATED: FDA Unveils 5 Guidances on Broadening Cancer Clinical Trial Eligibility, Regulatory Focus, 12 March 2019).

Each document focuses on a specific area where “rigid eligibility criteria” can limit participation.

Eligibility criteria   
The final guidance on “Cancer Clinical Trial Eligibility Criteria: Performance Status Guidance for industry, IRBs, and Clinical Investigators,” addresses the use of performance status (PS), which FDA called a “yardstick” to measure how well a patient can perform ordinary tasks and carry out activities of daily living, which is “one of the most common eligibility criteria in oncology trials.”

The guidance states that “many trials are limited to high-functioning subjects (i.e., good PS) and exclude lower-functioning subjects (i.e., poor PS) based on one of two main scales: Eastern Cooperative Oncology Group (ECOG) and Karnofsky (KPS).”

The guidance recommends broadening eligibility criteria to include patients with a wider range of performance status, as announced by the FDA in the Federal Register.

According to the FDA, the changes from the draft to the final guidance include updates on additional considerations for sponsors, specifically regarding the impact of including patients with lower performance status on trial retention and sample size, as well as minor revisions for clarity.

The final guidance includes a note stating that pediatric patients are not to be included in these clinical trials. “Because PS may be based on a different scale for younger pediatric patients (e.g., Lansky) and inclusion of pediatric patients may also be subject to unique considerations, the recommendations in this guidance are specific to inclusion of adult patients in oncology trials. However, many of the general considerations and recommendations in this guidance may be applicable to pediatric oncology trials.”

Washout period 

The final guidance on "Cancer Clinical Trial Eligibility Criteria: Washout Periods and Concomitant Medications" encourages sponsors to assess the need for time-based washout periods between stopping a cancer drug and starting an experimental drug. Additionally, the guidance includes provisions for patients who are taking other medications, as stated in the OCE announcement.

The guidance states that “washout periods and concomitant medication exclusions are commonly included in cancer clinical trials. However, these exclusions often vary across trials for similar therapeutic classes and diseases and should be appropriate for the trial under consideration.”

Instead, FDA states that “eligibility criteria should be tailored to the population being studied and the goals of the clinical investigation. For that reason, the recommendations in this guidance reflect a general approach to broadening eligibility criteria related to washout periods and concomitant medications, rather than providing specific or prescriptive criteria.”

The guidance states that exclusion criteria should be justified with a disease- and drug-specific scientific rationale as opposed to vague statements. For example, sponsors should avoid statements such as, “Exclude patients taking concomitant medications.”

According to FDA, the final guidance includes minor revisions for clarification compared to the draft.

One change is the addition of text to clarify the meaning of washout period. It states that “This treatment-free period is intended to allow a prior therapy and/or its effects on the body to be eliminated or reduced to acceptable levels preventing additional toxicity and/or interfering with the pharmacokinetics/pharmacodynamics (PK/PD) of the investigational drug when a new therapy is started.”

Laboratory values 

The final guidance on "Cancer Clinical Trial Eligibility Criteria: Laboratory Values" outlines the general principles for selecting laboratory-based eligibility criteria, such as minimum blood counts, when choosing patients for cancer trials. The guidance emphasizes that overly strict laboratory-based exclusion criteria can negatively impact patient enrollment and the diversity of populations in clinical trials, including those for cancer.

The guidance includes recommendations for selecting appropriate laboratory values “to avoid unjustified exclusions of trial subjects.”

Changes made from the draft to the final guidance include minor clarifications, said FDA.

There is additional text in the background section addressing laboratory value abnormalities.

The guidance states that “Laboratory value abnormalities may also represent manifestations of the underlying malignancy or comorbidities that do not otherwise preclude safe participation in a clinical trial. Additionally, laboratory values may vary among healthy individuals across different age groups (e.g., pediatric patients), and racial and ethnic populations. For example, the Duffy null phenotype has a high prevalence in African Americans and is associated with lower absolute neutrophil counts but not with greater risk of infection. Laboratory-value criteria that do not take these differences into account can hamper efforts to enroll a representative population. Furthermore, overly restrictive laboratory-value criteria may result in exclusion of patients from trials of potentially beneficial treatments.”

Eligibility criteria; Notice on eligibility criteria; Washout period; Laboratory values