FDA Draft Guidance Encourages Broader Inclusion Criteria in Oncology Trials

The U.S. Food and Drug Administration (FDA) released a series of draft guidance documents aimed at encouraging sponsors to broaden eligibility criteria in cancer clinical trials.

Released in April 2024, these guidances build upon previous recommendations from the agency. They include considerations for laboratory values, performance status, and washout periods/concomitant medications. 

Historically, strict eligibility criteria have been used in oncology trials to define patient populations and mitigate potential risks. However, the FDA argues that these criteria are sometimes more restrictive than necessary, potentially limiting patient access, slowing trial accrual, and leading to study populations that do not fully represent the real-world patient population. By appropriately broadening eligibility criteria, the agency believes trials can improve the generalizability of results and better characterize the benefit-risk profile of investigational therapies. 

Key points from the FDA documents on patient inclusion criteria 

Read: Cancer Clinical Trial Eligibility Criteria: Laboratory Values 

• Lab value-based eligibility criteria should be customized to the investigational drug's mechanism of action, pharmacokinetics/pharmacodynamics (PK/PD), and anticipated toxicities. 
• Criteria should only be as restrictive as necessary to ensure patient safety. Inter-laboratory variation and potential demographic differences in lab ranges should be accounted for. 
• As drugs progress through development, eligibility criteria should be routinely reassessed and adjusted based on accruing clinical data. 

Read: Cancer Clinical Trial Eligibility Criteria: Performance Status

• Patients with ECOG performance status 2 (or KPS 60-70) should be included in trials unless there is a clear scientific or clinical rationale for exclusion. 
• Eligibility criteria should reflect the intended patient population in clinical practice. Restrictions should be re-evaluated as safety data accumulate through the development process. 
• Alternative trial designs (e.g. separate cohorts) can be considered if low performance status is a concern. Patient-reported outcomes and geriatric assessments may provide a more comprehensive view of functional status. 

Read: Cancer Clinical Trial Eligibility Criteria: Washout Periods and Concomitant Medications

• Washout periods should account for the PK/PD of prior therapies. Time-based criteria should be scientifically justified and protocol-specified. Clinical parameters are preferred over fixed time periods where appropriate. 
• Concomitant medication exclusions should be based on clearly-defined safety concerns, such as known drug-drug interactions or overlapping toxicities. Unnecessary restrictions should be avoided. 
• Protocols should specify whether concomitant medication use warrants dose modifications. Patients should be informed of any required adjustments. 

The guidance documents emphasize that eligibility criteria must still protect patient safety and be scientifically justified. However, in many cases, the FDA believes criteria can be broadened, especially in later-stage trials, to better reflect the realities of clinical practice. 

Addressing concerns around broadening clinical trial eligibility

Importantly, the FDA acknowledges potential sponsor concerns that broadening eligibility may lead to higher rates of adverse events. They stress, however, that this possibility does not outweigh the importance of representing the real-world population, and that randomized trials are well-equipped to characterize safety regardless of baseline status. Unnecessarily restricting enrollment based on laboratory values or performance status may have little benefit, whereas thoughtful broadening of criteria can facilitate speedier accrual and potentially reduce the need for post-marketing studies in populations initially excluded from pivotal trials.

These draft guidances are part of an ongoing effort by the FDA to modernize eligibility criteria in cancer trials, a process that has included previous recommendations on brain metastases, HIV/hepatitis status, and organ dysfunction or prior malignancies. The agency has also focused on inclusion of older adults and pediatric/adolescent populations. 

Key takeaway

The lab values, performance status, and washout/concomitant medication guidance documents are currently in draft form and open for public comment. The FDA encourages sponsors to review the recommendations and consider how they may apply to their development programs.  

By proactively broadening eligibility criteria where appropriate, sponsors may be able to accelerate trial timelines, expand patient access, and generate data more applicable to the post-approval treatment population. While eligibility decisions must always prioritize patient safety, these guidance documents provide a framework for modernizing criteria and advancing the goal of representative clinical trials in oncology.