US FDA drug reviewers argue that enrolling more heterogeneous patient populations could result in fewer postmarketing requirements and earlier satisfaction of pediatric study obligations.
The US FDA’s push to expand oncology trial eligibility criteria includes highlighting the regulatory benefits for sponsors who pursue such strategies.
Broadening eligibility criteria to include cohorts of patient populations historically excluded from cancer trials could lead to fewer postmarketing safety requirements, representatives from FDA’s Office of Hematology and Oncology Products (OHOP) and Oncology Center of Excellence (OCE) said in a New England Journal of Medicine perspective piece April 20.
“Postmarketing requirements or commitments for examining safety and pharmacokinetics in patients with organ impairment might become unnecessary if adequate information were derived from subgroups examined in a larger trial,” FDA said.
“Although the primary objective of eligibility criteria has been protecting patients, rational reconsideration of these criteria may lead to a more accurate description of a drug’s safety and efficacy in the patients who will ultimately receive the drug.” – FDA
It’s possible that Pediatric Research Equity Act study requirements could be addressed by including children in adult trials, and sponsors also may be able to satisfy FDA written requests issued under the Best Pharmaceuticals for Children Act and gain additional marketing exclusivity, the article suggests.
In addition, expanded marketing claims may flow from broader eligibility criteria, authors Julia Beaver, Gwynn Ison and Richard Pazdur said. Beaver and Ison are medical officers in OHOP’s Division of Oncology Products I. Pazdur is director of both OHOP and OCE, which cuts across FDA’s drug, biologic and device centers. (Also see “Oncology Center of Excellence Open For Business: Podcast With US FDA’s Richard Pazdur” – Pink Sheet, 11 Apr, 2017.)
The agency views supporting broader trial eligibility are not new, as the subject is increasingly becoming a discussion point for FDA oncology drug review staff in public forums.
For example, the issue has come up at the last two Friends of Cancer Research (FOCR) annual meetings. (Also see “FDA’s Pazdur To Patient Advocates: Focus On Issues That ‘Drive The Show'” – Pink Sheet, 17 Nov, 2015.) In 2016, the agency, FOCR and the American Society of Clinical Oncology launched an initiative to reassess the current approach to determining clinical trial eligibility.
The NEJM piece builds upon a draft issue brief presented at the FOCR annual meeting in November and may be FDA’s most prominent position statement to date aimed at encouraging sponsors and investigators to broaden eligibility criteria in a way that more closely reflects a drug’s likely real-world use without undermining a development program.
Unjustified Categorical Exclusions
Clinical trial eligibility criteria are designed to protect patients from undue harm, define the study population and permit collection of safety and efficacy data in the intended population, Beaver, et al. said. However, eligibility criteria frequently are copied from one protocol to another “without due consideration of different drug classes or patient populations; investigators thus lack a sound clinical rationale for excluding certain patients.”
Unnecessarily strict eligibility criteria can result in limited patient access to cancer trials, slow accrual and failure to capture the heterogeneity of the patient population that will use the drug after approval, the NEJM article states. “A logical approach to defining eligibility could allow for detection of safety signals in early clinical trials that use broad eligibility criteria and permit modification of subsequent criteria throughout the drug-development process as knowledge emerges.”
The FDA staffers point to several patient subgroups that have been historically and categorically excluded from trials without a clear reason. These include HIV-positive patients, those with a prior history of cancer or brain metastases, individuals with organ dysfunction, and patients under age 18.
These are the same subgroups for which a multi-stakeholder group proposed a path toward greater trial inclusion at the most recent FOCR annual meeting. (Also see “Cancer Trials: Broader Eligibility Criteria Could Mean Novel Labeling Claims” – Pink Sheet, 5 Dec, 2016.)
The agency suggests that HIV-positive patients should be included in trials if they have CD4+ counts exceeding a certain threshold and have no opportunistic infections.
Instead of excluding all patients with prior malignancies, “permitting inclusion of patients who have had previous cancer of stages and types that have low potential for recurrence, or whose recurrence is unlikely after the period that has since elapsed, would be a more rational approach,” the article states.
Including brain metastases patients, except for those with current seizures or taking drugs with known interactions, would permit initial examination of a study drug’s central nervous system penetration and related efficacy and safety, the staffers said. Patients with liver, kidney or other organ dysfunction should be included unless the drug’s excretion or metabolism is relevant to these pathways.
Expediting Pediatric Development
FDA also sees an opportunity to expedite pediatric drug development by adopting a progressive development approach for patients younger than 18 years of age. “After safety and dosing information is available for adults, pediatric patients 12 years of age or older could be enrolled in adult trials, followed by younger children once safety has been established in the adolescent cohort.”
The agency suggests adapting the use of seamless clinical trials, in which the time between development phases is eliminated, by enrolling pediatric expansion cohorts of progressively younger age patients based on the emerging safety information generated from older children.
Spurring the development of pediatric therapeutics has been cited as a top priority for the newly formed OCE, and OHOP has been pushing sponsors to conduct pediatric studies earlier by issuing written requests earlier in the development process. (Also see “Pediatric Drug Development A Priority For US FDA’s New Oncology Center Of Excellence” – Pink Sheet, 22 Feb, 2017.)
FDA suggests sponsors design an appropriately powered primary efficacy analysis using a population based on conventional eligibility criteria, with a descriptive analysis of safety and efficacy in the more inclusive population.
The agency reviewers give a nod to industry concerns that enrolling more heterogeneous patient populations could result in findings of lesser efficacy and greater toxicity, potentially jeopardizing regulatory approval.
“An appropriately powered primary efficacy analysis using a population selected on the basis of more conventional eligibility criteria, with a descriptive analysis of safety and efficacy in the more inclusive population, could mitigate this risk,” the FDA officials say.
“Although the primary objective of eligibility criteria has been protecting patients, rational reconsideration of these criteria may lead to a more accurate description of a drug’s safety and efficacy in the patients who will ultimately receive the drug – and could expedite the development of prescribing information while maintaining safety.”