As part of a push to transform clinical trial eligibility criteria that have been accepted over time without a clear scientific or clinical rationale, the FDA on Tuesday published four draft guidance documents on cancer clinical trial eligibility criteria and one final guidance on including adolescents in adult oncology trials.
The four drafts, developed by the FDA with input from the American Society of Clinical Oncology and Friends of Cancer Research, focus on minimum age for pediatric patients; patients with HIV, hepatitis B or C viruses; patients with organ dysfunction or prior or current malignancies; and patients with brain metastases.
“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,” FDA Commissioner Scott Gottlieb said, noting how the draft guidances offer new recommendations for broadening cancer trial eligibility criteria.
Minimum Age for Pediatric Patients
This seven-page draft guidance explains how sponsors seeking to include pediatric patient populations in adult cancer trials should evaluate pediatric formulations, taking into account the age, size, physiologic condition and the treatment needs of pediatric patients.
The draft notes the types of evidence that could support inclusion of patients from two years of age to under age twelve, clarifying 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 function, children < 2 years should not be included in adult cancer trials. In rare instances, infants beyond the neonatal period may be appropriate candidates for select new drugs. However, enrollment of children < 2 years of age is best reserved for exceptional cases and only after consultation with the FDA.”
In addition, the draft features potential ways to include pediatric patients in early phase trials after a sufficient number of adult patients have been evaluated to provide adequate safety and toxicity data.
For late-phase trials, the draft says: “The minimum age of eligibility specified in late-phase trials should be tailored to the biology of the disease under study, the scientific objectives of the trial, and the existing data regarding the mechanism of action and safety profile of the drug.”
Patients with HIV, Hepatitis B Virus or Hepatitis C Virus Infections
This eight-page draft guidance explains how 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.”
The recommendations in the draft for eligibility criteria for patients with cancer and concurrent HIV infection “are focused on evaluation of immune function and HIV therapy,” while the recommendations for those “with cancer who have evidence of chronic HBV or with current or history of HCV are focused on liver-related laboratories and HBV/HCV therapy.”
Organ Dysfunction or Prior or Concurrent Malignancies
This six-page draft guidance features recommendations for eligibility criteria for patients with organ dysfunction in cancer clinical trials, focusing on renal function, cardiac function and hepatic function, in addition to recommendations for eligibility criteria for patients with cancer who have a history of prior or concurrent second primary malignancies.
“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 explains.
“For example, in initial dose finding or preliminary activity-estimating or proof-of-concept studies, patients with a history of prior or concurrent second primary malignancies should not be excluded,” the draft says.
As about 70,000 patients living with cancer in the US are diagnosed with brain metastases, this six-page draft guidance explains how such patients should be included in clinical trials to create a better understanding of the efficacy and safety profile of the investigational drug while maintaining patient safety.
“The incidence of brain metastases is increasing in patients with certain malignancies such as melanoma, lung cancer, and breast cancer. However, 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,” the guidance says.
It also explains how patients with cancers that metastasize to the brain should be included in early phase trials “either in separate cohorts or in cohorts with planned subset analyses to assess preliminary efficacy and toxicity in patients with brain metastases. In cases where there is a strong rationale for exclusion, the rationale should be described in the trial protocol.”
Including Adolescent Patients in Adult Oncology Clinical Trials
This four-page final guidance provides recommendations for the appropriate inclusion criteria, dosing and pharmacokinetic (PK) evaluations, safety monitoring, and ethical requirements for enrolling adolescent patients in adult oncology trials.
The FDA says that adolescents should only be enrolled in first-in-human or dose-escalation trials after initial adult PK and toxicity data are obtained. The agency also says that adolescent patients should only be enrolled in early phase trials when they have relapsed or refractory cancer, or a cancer with no curative standard treatment available.
As far as changes between the draft and final, the FDA said: “All the public comments received on the draft guidance have been considered and the guidance has been revised as appropriate.”
First published in Regulatory Focus™ by the Regulatory Affairs Professionals Society, the largest global organization of and for those involved with the regulation of healthcare products. Click here for more information.
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