FDA Broadens Cancer Trial Eligibility With 5 New Guidance Documents

Scott Gottlieb, the commissioner of the U.S. Food and Drug Administration (FDA) may be on his way out, but the agency continues its activities. The FDA, as part of efforts to update clinical trial eligibility criteria, published four draft guidance documents on cancer clinical trial criteria and one final draft on adolescents in adult oncology trials.

The four draft guidances were developed by the FDA with feedback from the American Society of Clinical Oncology and Friends of Cancer Research. The focus is largely on what the minimum age should be for pediatric patients, guidelines related to patients with HIV, hepatitis B or C, with organ dysfunction or previous cancers, and patients with cancer that has spread to the brain.

“Overly restrictive eligibility criteria may slow patient accrual, limit patients’ access to clinical trials and lead to trial results that don’t fully represent treatment effects in the patient population that will ultimately receive the drug,” stated Gottlieb.

The guidance on minimum age for pediatric patients describes how sponsors of clinical trials that want to include pediatric patients in adult cancer trials should evaluate pediatric formulations, accounting for age, size, physiologic condition and the treatment needs of the patients. This focuses on patients aged 2 years to 12, noting—and this seems obvious—that children under the age of two “may be particularly vulnerable to expected and unanticipated toxicity due to developmental concerns and age-dependent maturation of metabolic enzyme systems and organ functions,” and should not be included in adult cancer trials, except for in rare cases.

For patients with HIV, and Hepatitis B and C infections, the guidance tries to be more inclusive for this patient population in cancer trials, noting that it “is justified in many cases, and may accelerate the development of effective therapies in cancer patients with these chronic infections.”

In terms of the guidelines for organ dysfunction or previous or ongoing cancers, the agency’s eligibility criteria recommendations focus on the patients’ renal function, cardiac function and hepatic function. “By excluding individuals from cancer clinical trials who have major organ dysfunction or previous or concurrent cancers, trial recruitment favors younger patients, which may not be fully representative of the population for whom the drug will be indicated,” the FDA stated.

The guidelines for brain metastases noted that about 70,000 U.S. cancer patients are diagnosed with brain cancers. They discuss how these patients can be included in clinical trials, stating, “The incidence of brain metastases is increasing in patients with certain malignancies such as melanoma, lung cancer, and breast cancer. However, the patients with brain metastases have historically been excluded from clinical trials due to concerns of poor functional status, shortened life expectancy, or increased risk of toxicity.”

And finally, the final guidance on including adolescent patients in adult cancer trials gave recommendations for appropriate inclusion criteria, dosing and pharmacokinetic (PK) evaluations, safety monitoring, and ethical requirements. In particular, the agency says that this cohort should only be enrolled in first-in-human or dose-escalation trials after the first adult PK and toxicity data are acquired, and only in early phase trials if they have relapsed or refractory cancer, or a cancer with no standard curative treatments available.

On the one hand, you can argue, as the agency seems to be doing, that the earlier guidelines weren’t completely based on clear scientific or clinical rationales, so the new guidelines were long overdue. On the other hand, biopharma companies have an incentive to select patient populations that not only provide the best chances of a drug’s success, but also provide the cleanest, most easily analyzed data for a specific disease without possible complications from trial participants with other conditions and treatment histories. However, the new guidelines will likely make it easier for patients to gain entry to clinical trials and provide much-needed clarity for pediatric and adolescent patients’ participation in adult clinical cancer trials.

The guidelines for adolescents are final. The other four are draft guidance and as yet are not binding.