The US Food and Drug Administration (FDA) recently published four draft guidances and one final guidance addressing cancer clinical trial eligibility criteria, which often exclude specific patient populations “without a clear rationale except to avoid potential safety risks in young patients or those with certain conditions,” explained SMS Oncology Director of Medical Affairs, Stephan Winckels MD, PhD.
“The impetus for this release is that the eligibility criteria for these trials is unnecessarily restrictive which ultimately limits patient access to clinical trials leading to results that poorly represent the complete target patient population that will be treated with the approved product in the future,” Nancy Magnier Boxx, MSHS, PA, CCRP, CCRA, director of quality assurance at the Atlantic Research Group (ARG) told us.
For researchers, the changes will affect protocol design and could support master protocols, potentially including staggered cohorts for some patients.
Among the draft guidances is one to encourage the inclusion of patients with human immunodeficiency virus (HIV) as well as hepatitis B (HBV) and hepatitis C virus (HCV) infections, when appropriate, depending on their immune function, therapies, and liver function assessments.
Additionally, as patients live longer with concurrent conditions, such as organ dysfunction and malignancies, Boxx said the FDA is encouraging the inclusion of patients with mild to moderate renal, cardiac, and hepatic dysfunction or impairment. These patients are to be included after pharmacokinetic (PK) and pharmacodynamic (PD) testing is concluded and “the inherent limitations of each dysfunction” assessed.
Patients with a history of prior or current second primary malignancies also are to be included. “This will allow these studies to include an older population that has been unnecessarily excluded due to conditions patients now are living with successfully,” added Boxx.
- Cancer Clinical Trial Eligibility Criteria: Minimum Age for Pediatric Patients; Draft Guidance for Industry
- Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus or Hepatitis C Virus Infections; Draft Guidance for Industry
- Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or Prior or Concurrent Malignancies; Draft Guidance for Industry
- Cancer Clinical Trial Eligibility Criteria: Brain Metastases; Draft Guidance for Industry
- Considerations for the Inclusion of Adolescent Patients in Adult Oncology Clinical Trials; Guidance for Industry
The third of the draft guidances target patients with brain metastasis, the exclusion of which could remove up to two-thirds of the stage IV population, according to guidelines published by the Response Assessment in Neuro-Oncology – Brain Metastases (RANO-BM) group in 2018.
“With the number of patients living with brain metastases rising the FDA feels it is important for this group to be included in early phase trials in cancers where metastases are likely,” Boxx said, explaining that this can be accomplished using separate cohorts or by analyzing patient subsets.
“Even subjects with active brain metastases can be included if their physician feels an immediate CNS treatment is not required,” Boxx explained.
The final guidance provides considerations for the inclusion of adolescent patients in adult oncology trials and follows the publication of the draft guidance last year.
“Pediatric populations are traditionally underrepresented in cancer trials, often for no other reason than that they are younger than 18 years,” said Winckels. According to a study published in 2016, many pediatric trials also go unfinished or unpublished.
Per the guidance, a separate pediatric clinical trial is no longer be necessary if the study “offers the prospect for a direct benefit which outweighs the risk,” explained Boxx. Instead, a pediatric cohort could be used after the initial evaluation of adult safety and dosage data has been obtained.
The changes are expected to have several positive effects, including a decreased risk associated with off label drug use and shortened trial recruitment timeline – the length of which is among one of the key challenges facing drug development.
While the guidances address a range of topics, Winckels said additional topics could be useful as well, such as the concomitant use of immunosuppressants in immunotherapy trials, baseline bone marrow dysfunction in drugs which are not expected to affect blood cells, and life expectancy.
Still, the onus is on the industry – pharma, biotech, and contract research organizations (CROs) – to implement the guidances and provide easier access to oncology clinical trials for more patients, Winckels noted.
Rhonda Critchlow, senior director, oncology operations, PSI CRO, echoed these statements, commenting that for drug development and research, it is increasingly important to expand inclusion criteria.
“But it’s more than just expanding an inclusion criteria – at the end of the day, if patients aren’t aware of trials, they won’t enroll in those trials,” she told us. “As an industry, we should encourage all means of educating and advocating for clinical trials. Only then will we see an increase in pivotal therapies.”