FDA Guidances Recommend Broadened Eligibility, New Strategies for Trials

March 18, 2019

The FDA has issued several guidance documents in the past week that the agency hopes will help researchers get a handle on patient selection for increasingly complex trials.

Five of the guidances — four draft and one final — focus on giving access to experimental medicines to traditionally more vulnerable cancer patients, including children, HIV patients and hepatitis C sufferers. The guidances underline an emerging truth that trials are increasingly becoming front-line care to many patients.

“The overall purpose of this series … is to encourage a broadening of eligibility criteria to allow more people participating in clinical trials of drugs and biological products for the treatment of cancer,” the agency said, in announcing the new documents. “Including patients with the conditions covered by the guidances will allow for trial results that better represent the patient population that will use the drug or biological product.”

The final guidance, which lays out considerations for adding adolescents to adult cancer trials, makes this truth explicit when it says that regulators are worried that younger patients “may have delayed access to potentially effective therapies.”

Cancers in young people can be very different from those in adults, the agency acknowledges, but several kinds—especially soft tissue or bone cancer, central nervous system tumors, leukemias, lymphomas and melanoma — are similar enough to the adult versions that sponsors should consider enrolling adolescents in trials, too.

In first-in-human trials, sponsors can enroll adolescents after they’ve obtained pharmacokinetic and toxicity data, and the adolescents should have relapsed cancers or have diseases that are so refractory that they have no other option. Sponsors should follow any body-size adjusting dose recommendations for adolescents as well as adults but should find a minimum body weight for fixed doses, the final guidance states.

The new cancer guidances have been a long time coming, says Lindsay McNair, chief medical officer for WIRB-Copernicus Group. “The formalization and support of the agency’s position in the draft guidance is helpful and provides additional details for sponsors.”

“Ultimately,” McNair tells CenterWatch, “the guidances support the goal of everyone in clinical research, which is to generate rigorous and clear study data on which to base drug approvals and treatment decisions for the largest number of patients.”

In one of the four draft cancer guidances, the FDA recommends that children be included in adult trials if sponsors can demonstrate that the risk of a trial is outweighed by the potential benefits and there are “adequate provisions” for getting children to assent to the trial. Other considerations include whether natural histories and preliminary adult studies show that children will have a similar response to a given drug, and if animal, lab or computer models suggest that they will benefit. The guidance also specifies that sponsors test children at lower doses than adults in the early phases of a trial.

The remaining cancer documents include recommendations that:

Patients with cancers that often metastasize into the brain be included in early trials;

  • Sponsors consider patients’ kidney, heart or liver functions when considering whether to enroll patients with organ failure into clinical trials; and
  • HIV or hepatitis patients be considered for oncology trials as long as their immune functions or HIV treatments won’t skew any results.
  • In a separate release last week, the FDA issued a final guidance focusing on improving patient selection and a draft guidance on trial monitoring.

The final guidance encourages trial sponsors and designers to use “enrichment strategies,” which focus patient selection on one or more characteristics that can more clearly demonstrate the safety and/or effectiveness of the drug or biologic in selected populations. These approaches can allow signal detection in smaller clinical trials, or trials of shorter duration, compared to ones that are open to “all comers,” the agency’s final guidance on enrichment strategies says.

Sponsors might consider such enrichment strategies as choosing patients with a biomarker characterizing their disease in a narrow range or identifying high-risk or more responsive patients.

Also issued last week is a draft Q&A guidance on risk-based approaches to monitoring clinical investigations. The document expands on the FDA’s 2013 risk-based monitoring guidance, offering recommendations on how to focus monitoring activities on important and likely risks to investigation quality, such as risks to human subjects and data integrity. Sponsors also need to consider risks that are less likely to occur but that would have a major impact on the trial’s quality, the guidance says.

The document also addresses the content of a risk-based monitoring plan and how to follow up on and communicate monitoring results.

Read the guidances here:


-By Bill Myers