FDA Expands Patient Inclusion Criteria for Cancer Clinical Trials

The FDA this week published 4 draft guidances and 1 final guidance in an effort to broaden patient participation in cancer clinical trials and to promote the inclusion of pediatric patients and patients with comorbidities that can occur alongside cancer, in an effort to increase patient accrual, broaden patients’ access to clinical trials, and lead to trial results that better represent treatment effects in the real world.

“When drug developers design a clinical trial, they identify eligibility criteria to define what types of patients qualify for participation in the trial. They base the eligibility criteria on factors such as the mechanism of action of the drug, characteristics of the disease, the expected toxicities of the investigational drug, and the ability to recruit trial participants from the patient population to meet the objectives of the clinical trial,” said FDA Commissioner Scott Gottlieb, MD, in a statement.

“However, in trials testing treatments for cancer, some eligibility criteria have become commonly accepted over time or used as a template across trials without a clear scientific or clinical rationale or justification. In other cases, eligibility criteria can be deliberately restrictive, even though it is not clinically merited. As a result, cancer patients are often unnecessarily restricted from participating in trials.”

Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients; Draft Guidance for Industry

The first guidance, “Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients; Draft Guidance for Industry,” discussed minimum age eligibility criteria for pediatric patients in cancer clinical trials. The guidance also addressed specific situations in which the inclusion of pediatric patients may be appropriate based on “disease biology and clinical course, molecular target of the investigational drug, and/or its molecular mechanism.”

Traditionally, pediatric patients have not been included in adult clinical trials that generally specify that a patient must be 18 years or older to be included. Typically, pediatric trials of the same drug have been initiated after 1 or more adult clinical trials have been completed, or after the drug or treatment had received initial FDA approval for adults. This has “delayed the development of and access to potentially effective new cancer drugs for the pediatric population," according to the guidance. This guidance makes recommendations for the inclusion of pediatric populations including both children, aged 2 to 11 years, and adolescents, aged 11 to 17 years.

Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus Infections Guidance for Industry

The next guidance provided recommendations for the inclusion of patients with cancer who also have HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) infections. Historically, patients with cancer who have such comorbidities are often excluded from clinical trials despite the fact that HIV and HBV infections can be chronically managed, and HCV can be cured with antiviral therapy. “Expanding cancer clinical trial eligibility to be more inclusive of patients with HIV, HBV, or HCV infections is justified in many cases, and may accelerate the development of effective therapies in cancer patients with these chronic infections,” read the guidance.

FDA recommendations include considering clinical trial eligibility based on CD4+ T cell counts, history of AIDS-defining opportunistic infections, and exclusion of specific antiretroviral therapy drugs, among others.

Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies Guidance for Industry

The FDA noted that patients with organ dysfunction are often excluded from clinical trials, “regardless of knowledge of the metabolic pathways and excretory routes of the investigational drug.” Due to the increasing lifespan of the general population, the number of patients with comorbid renal disease, cardiac disease, and hepatic dysfunction are also increasing. By excluding patients from cancer clinical trials who also have organ dysfunction, trial recruitment inherently favors younger patients which may not fully represent the population for whom the drug will be indicated to treat.

The FDA recommended that for patients with organ dysfunction, where pharmacokinetics and major routes of elimination are not well understood, “it is reasonable to enroll only patients with relatively preserved organ function (primarily renal and hepatic) in cancer clinical trials. As data on toxicity including preclinical and clinical toxicity, [pharmacokinetics], and/or pharmacodynamics become available during drug development, protocols should be revised to include patients with compromised organ function where safe parameters regarding dosage adjustments have been determined,” read the guidance.

Cancer Clinical Trial Eligibility Criteria: Brain Metastases Guidance for Industry

In the final draft guidance included in the package, the FDA explained that 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.

Each year, an estimated 70,000 patients living with cancer in the United States are diagnosed with brain metastases. Certain malignancies, such as melanoma, lung cancer, and breast cancer, have shown an increasing incidence of brain metastases. The FDA wrote that “patients with cancers that commonly metastasize to the brain (eg, lung cancer, breast cancer, melanoma) should be included in early drug development trials, either in separate cohorts or in cohorts with planned subset analyses to assess preliminary efficacy and toxicity in patients with brain metastases.”

Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials Guidance for Industry

The final guidance document delivered within this package focused on the inclusion of pediatric patients who have cancers similar in histology and biologic behavior to those found in adults. The FDA offered guidelines around including adolescent patients after some initial adult pharmacokinetic and toxicity data are obtained. Additionally, in terms of dose escalation, for drugs with body size-adjusted dosing for adults “adolescent patients should receive the same body size-adjusted dose (mg/kg or mg/m²) that is administered in adults. Safety monitoring data in such a trial should also be examined for any age-related differences.

“The FDA issued new recommendations for broadening cancer trial eligibility criteria that are designed to help address these challenges. A clinical trial that’s more representative of the patient population can maximize the generalizability of the trial results and the ability to understand the therapy’s benefit-risk profile across the patient population likely to receive the drug in clinical practice,” said Gottlieb.