The FDA has recently (published April 25, 2024) issued several guidance documents aimed at optimizing cancer trial design and participant selection criteria for clinical trials regulated by CDER and CBER. The eligibility criteria for cancer clinical trials serve two primary purposes: to select the appropriate patient population and to minimize potential risks to participants. However, these criteria can sometimes be overly restrictive, so expanding them to be more inclusive is a key consideration for improving the diversity of trial populations. This recent series of guidance covers various aspects of eligibility criteria, including washout periods and concomitant medications, performance status, and laboratory values. It is expected that these new recommendations will assist interested parties, sponsors, and/or institutional review boards responsible for clinical trials.  

Washout Periods and Concomitant Medications

A washout period is a treatment-free period that allows the effects of a prior treatment or therapy’s effects to be eliminated or reduced to prevent toxicity when starting a new therapy. Washout periods also help prevent misinterpreting trial observations as due to the current therapy when they may be a result of previous therapies.  

Concomitant medications are any medications (prescription or non-prescription) being taken by the patient in addition to the investigational drug(s). Many cancer patients and patients with comorbidities, especially older patients, are taking additional medications. By excluding certain concomitant medications, these patients may be excluded from clinical trials.  

Overly restrictive criteria can limit the patient population, limit access to trials, and result in findings that don’t fully represent the patient population potentially using the drug. Broadening eligibility criteria can enhance the overall accuracy of trial results and provide a more comprehensive understanding of the therapy’s benefit-risk profile across diverse patient populations likely to use the drug. Therefore, it’s important for trial sponsors to review new data about concomitant medications to avoid exclusions or recommend alternatives.  

The new guidance recommends tailoring eligibility criteria more specifically to the investigational treatment, patient population, and trial objectives. It emphasizes a disease- and drug-specific scientific rationale to justify exclusion criteria and provides a general approach to broadening criteria for washout periods and concomitant medications. 

Considerations such as pharmacokinetics/pharmacodynamics (PK/PD) of previous treatments and drug-drug interactions, should inform the duration of washout periods and the management of concomitant medications. This approach aims to minimize unnecessary restrictions and facilitate enrollment in clinical trials. 

The guidance highlights the importance of scientific justifications for time-based washout periods and modifications to concomitant medication regimens in trial eligibility criteria. Patients and caregivers should be informed about these modifications to ensure their understanding and compliance during the trial. 

Performance Status

Performance Status (PS) is a measure of how well a patient is able to carry out the ordinary tasks and activities of daily living. It is one of the most common cancer trial eligibility criteria and is often limited to high-functioning patients with “good” PS, and excludes those patients with “poor” PS. The reasoning for this is because low PS tends to correlate with worse survival rates and patients with low PS may not be able to tolerate treatments. Though patients with poor PS not caused by cancer may still see improvement from the treatments, current PS scales don’t differentiate between causes for low PS. There is also subjectivity when assigning PS scores, with adults older than 65 years often assigned higher scores than younger patients, while PS is a lower indicator of cancer-related mortality in older adults.  Considerations for including patients with low PS emphasizes the importance of scientific justification and appropriate trial design. 

The FDA guidance on Performance status (PS) underscores the need to broaden PS criteria to include a wider range of patients, particularly those with lower PS, to enhance trial diversity and representation. The guidance suggests that unnecessarily restrictive eligibility criteria may slow patient accrual and limit access to trials, leading to results that may not fully represent the patient population that will ultimately use the drug. Broadening eligibility criteria and refining trial design can improve the ability to understand the trial results across a wider, more diverse patient population and provide a more detailed understanding of the benefit and risk profiles of investigational drugs.  

The guidance also acknowledges that there may be disadvantages to broadening eligibility criteria based on PS assessments. By including a broader patient demographic, including those with low PS, there may be increased adverse events that affect whether or not a patient can complete the treatment, their outcomes, and their ability to comply with study procedures. Additionally, the potential for worse trial outcome data interpretation due to the inclusion of patients with low PS could be concerning for sponsors.  

The guidance recommends including patients with lower PS in clinical trials in a way that contributes to a better understanding of the drug’s efficacy and safety profile while maintaining patient safety. It suggests that to gain a more comprehensive understanding of PS, particularly in older patients with cancer, baseline PS assessments can be complemented with emerging patient-reported outcomes and other assessment tools.  

Alternative trial designs and additional assessments of functional status are recommended to help include diverse patient populations in cancer clinical trials. Alternative trial design could involve smaller, pre-specified cohorts that could enroll incrementally and include an early stopping rule based upon safety data. Additional assessments of functional status could include patient-reported outcomes, wearable device data, and comprehensive assessment of patients’ overall health status. 

Laboratory Values

As has been highlighted, eligibility criteria for cancer clinical trials aim to select the appropriate patient population and mitigate risks to trial participants. However, these criteria can be overly restrictive at times, hindering diversity in trial populations. Expanding laboratory value-based eligibility criteria (e.g. minimum blood counts, focused on later phase trials) is a key consideration to improve trial diversity and ensure broader representation across varying demographics. 

Many drugs that pose toxicity risks (to organs directly or are metabolized by those organs) will require laboratory values within a range that shows that the organs are functioning at or above a minimum acceptable level. While clinical trial eligibility criteria are designed to protect trial patients, some clinical trial eligibility criteria may include specific laboratory values even when those safety concerns are not applicable. This can lead to patients being excluded from trials they may otherwise be eligible for. For example, renal or hepatic functions requirements are a common reason for excluding a potential trial participant — and laboratory values can vary based on age and in healthy individuals across race and ethnicity. 

It is crucial to develop criteria based on the drug’s mechanism of action, safety profile, and the need to recruit diverse trial participants to meet study objectives. Eligibility criteria should be adjusted based on accumulating clinical experience (possibly changing from early-stage to late-stage), removing or loosening criteria that are no longer justified by specific safety concerns. The guidance underscores the importance of thoughtful consideration when selecting laboratory-based eligibility criteria. Rather than functioning solely as exclusionary metrics, they should also function to ensure appropriate participant representation in cancer clinical trials, while maintaining safety considerations aligned with the drug’s characteristics and expected use population. 

Conclusion

In summary, these three FDA guidance documents provide valuable insights for sponsors, investigators, and institutional review boards involved in oncology clinical trials. Implementing these recommendations will contribute to more inclusive trial designs, accurate patient selection, and comprehensive assessment of investigational drugs in diverse patient populations. Ultimately, this will improve the translation of trial results outcomes to real-world patient care. 

The three FDA guidance documents are provided below for more in-depth information: 

Cancer Trial Eligibility Criteria: Washout Periods and Concomitant Medications  

Cancer Trial Eligibility Criteria: Performance Status  

Cancer Trial Eligibility Criteria: Laboratory Values  

Comments and suggestions regarding this draft document should be submitted within 60 days of publication (April 25, 2024 publication date, comment closing date June 25, 2024) in the Federal Register of the notice announcing its availability. Submit electronic comments to https://www.regulations.gov.