The US Food and Drug Administration’s (FDA) has issued a trio of draft guidance documents that aim to promote greater participation and diversity in oncology clinical trials by expanding eligibility criteria. The documents address three areas: laboratory values, washout periods and concomitant medicines, and patient’s performance status.
These new guidance documents stem from FDA’s push over the past five years 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.
All three documents note that “eligibility criteria are sometimes more restrictive than necessary, and expanding eligibility criteria to be more inclusive is one trial design consideration that may improve the diversity of clinical trial populations.”
Laboratory Values
The guidance on laboratory values describes the appropriate use of such values in determining eligibility to participate in clinical trials. It notes that “overly restrictive laboratory-based exclusion criteria can adversely affect accrual and diversity for clinical trials, including cancer trials.”
To increase diversity in these trials, sponsors should customize its laboratory-based eligibility criteria to the drug under investigation, including the investigational drug’s mechanism of action, pharmacokinetics and pharmacodynamics (PK/PD), and anticipated toxicities. For example, if an investigational drug is not expected to cause hepatic toxicity, “hepatic entry criteria should be sufficiently broad to avoid unnecessary exclusions of patients.”
Washout period and concomitant medications
The draft guidance on washout periods and concomitant medication notes that while these factors are commonly included in cancer clinical trials, they “often vary across trials for similar therapeutic classes and diseases and should be appropriate for the trial under consideration.” Washout periods are a treatment-free period between recent treatments and current therapies.
Sponsors that use time-based washout periods should justify the need for these in the protocol and provide data indicating that a washout period is needed avoid exposing patients to unnecessary risks.
The section on concomitant medications notes that sponsors that exclude patients who are taking concomitant medications may be unnecessarily excluding older patients, since this population pool is more inclined to be concurrent medications than younger patients.
The draft states that “patients using concomitant medication should only be excluded from trial participation when clinically relevant known or predicted drug-drug interactions and potential overlapping toxicities will impact the safety of trial participants.”
Performance status
The draft on performance status (PS), which is a measure of how well a patient can perform ordinary tasks and carry out activities of daily living, is “one of the most common eligibility criteria in oncology trials.”
Yet the draft notes that many of these trials are limited to high-functioning participants and exclude lower-functioning patients; these measurements are based on one of two main scales: Eastern Cooperative Oncology Group (ECOG) and Karnofsky (KPS).
It states that “restrictive eligibility criteria may result in a group of trial participants who do not reflect the clinical and demographic diversity of patients with the indicated disease. As a result, the efficacy and safety outcomes experienced by participants with high PS may not adequately predict the outcomes for patients with low PS. Expanding eligibility to include patients with low PS can mitigate this issue.”
For example, he draft notes that excluding older people, who can be deemed lower-performing from these trials, is not supported by the scientific literature. The draft further notes that the use of alternative clinical tools, such as the comprehensive geriatric assessment, “are more descriptive than PS at evaluating older adults’ overall health status and better than KPS at predicting chemotherapy toxicity.”
Sponsors can also use other types of data, such as patient reported outcome assessment data of physical function and role function in measuring patient responses to treatments. Use of these tools were described in FDA’s guidance on core patient-reported outcomes in cancer clinical trials.
This data can “provide both baseline and longitudinal data that can complement clinician-assessed PS.” Also, the use of wearable devices can be explored “to add additional objective activity data to compare with clinician and patient reports.”
The deadline for commenting on the guidances is 25 June.
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