FDA finalizes guidance on broader cancer trial eligibility

Regulatory NewsRegulatory News | 10 July 2020 |  By 

In four final guidances published today, the US Food and Drug Administration (FDA) outlines cancer trial eligibility criteria considerations for individuals with several specific clinical conditions. Another guidance addresses minimum age considerations for inclusion of pediatric patients in cancer clinical trials.
The guidances, issued jointly by FDA’s Centers for Drug Evaluation and Research and Biologics Evaluation and Research (CDER and CBER), provide considerations for balancing the importance of including children and those with some serious health conditions in cancer clinical trials against ethical and data quality considerations.
“Unnecessarily restrictive eligibility criteria may slow patient accrual, limit patients’ access to clinical trials, and lead to trial results that do not fully represent treatment effects in the patient population that will ultimately use the drug,” said FDA  in its guidance for inclusion of pediatric patients. “Broadening cancer trial eligibility criteria can maximize the generalizability of trial results and the ability to understand the therapy’s benefit-risk profile across the patient population likely to use the drug in clinical practice and should be considered to avoid jeopardizing patient safety.”
The guidances examined and refreshed an approach to clinical trial eligibility that was, in some cases, stagnant, said the FDA in its guidance for inclusion of patients with brain metastases. The agency noted that “[S]ome eligibility criteria have become commonly accepted over time or used as a template across trials without clear scientific or clinical rationale. Unnecessarily restrictive eligibility criteria may slow patient accrual, limit patients’ access to clinical trials, and lead to trial results that do not fully represent treatment effects in the patient population that will ultimately use the drug.”
The FDA issued these four final guidances after publishing them as drafts in March 2019. After public consultation, clarification and some additional condition-specific details were added to the guidances. (RELATED: FDA unveils 5 guidances on broadening cancer clinical trial eligibility, Regulatory Focus, 12 March 2019)

Patients with brain metastases
A primary concern with including patients with known brain metastases in clinical trials of cancer therapies has been that many agents have the potential for serious central nervous system (CNS) toxicities; differentiating the clinical manifestations of brain metastases from CNS toxicity of a study drug can be difficult.
Now, the accessibility of high-quality medical imaging can help differentiate toxicity from metastatic progression, so regular imaging should be scheduled for patients with brain metastases. Baseline CNS screening should be considered for studies of certain drugs, such as those that can increase the risk of bleeding or lower the seizure threshold.
The guidance provides detailed recommendations for inclusion of patients with treated or stable brain metastases, those with active brain metastases, and those with leptomeningeal metastases. Considerations for exclusion criteria area also reviewed.
“Patients with brain metastases should be included in clinical trials in a way that contributes to a greater understanding of the efficacy and safety profile of the investigational drug while maintaining patient safety,” said the FDA in the guidance. “Patients with brain metastases should be included in early drug development trials to facilitate the collection of data to inform the development of eligibility criteria in later-phase trials.”
Patients with hepatitis B or C virus, or HIV infection
The updated guidance for including patients with HIV and hepatitis B virus (HBV) infections recognizes that these conditions can be well-managed for many patients. Patients with hepatitis C virus infections  (HCV) can be cured, notes this guidance.
“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,” according to the guidance.
Eligibility for patients with HIV should take into account CD4+ T-cell counts and history of any AIDS-defining opportunistic infections, as well as the timing of antiretroviral therapy initiation. Patients taking certain therapies may need to be excluded -- or may not be able to take those therapies while on-study -- because of the potential for drug-drug interactions.
Participation of patients with HBV and HCV should, in general, be guided by the same liver-related laboratory eligibility criteria as the general population, except where a known hepatic or biliary cancer affects these values. 
Patients with HBV should be on antiviral suppression therapy, when possible. Patients with a history of HCV should generally have completed curative therapy before beginning cancer therapy.
Patients with organ dysfunction or prior or concurrent malignancies
In this guidance, FDA acknowledges that the general population is living longer, and living with more comorbidities and cancers.
“By excluding individuals from cancer clinical trials who have major organ dysfunction or previous or concurrent cancers, trial recruitment may favor younger patients, which may not be fully representative of the population for whom the drug will be indicated,” notes the FDA in the guidance. “Designing cancer clinical trials that include patients with organ dysfunction and prior or concurrent malignancies and including this information in the labeling promotes the safe and effective use of these products across a broader patient population likely to use the drug in clinical practice.”
The guidance addresses inclusion of patients with renal dysfunction, advising that eligibility criteria use glomerular filtration rate rather than absolute serum creatinine levels, applying these criteria consistently through the drug development process. Prospective dose adjustment may mitigate risks when renal dysfunction is expected to result in increased systemic exposure to an investigational drug. Also, provisions should be made to study drug clearance and dosage adjustment for patients on renal dialysis.
Patients with cardiovascular dysfunction may be included, depending largely on risk for heart failure and the risk for prolongation of the corrected Q-T interval in the cardiac cycle.
Hepatic metabolic dysfunction is not as readily addressed through laboratory testing as other major organ dysfunction, so a variety of markers can be considered for assessment of trial eligibility for these patients, according to the guidance. Patients with severe hepatic impairment should only be included in cancer clinical trials after direct discussion with FDA. Patients with mild to moderate hepatic impairment may be appropriate for clinical trial participation “when the available nonclinical and clinical data, including [pharmacokinetic] and [pharmacodynamic] data, indicate that inclusion of these patients does not present an unreasonable risk to patients,” according to the guidance.
Generally, patients with prior and concurrent malignancies should be eligible for enrollment in clinical trials, whether the tumor is of the same or different type than that studied in the trial, according to the guidance.
Considerations for inclusion of pediatric patients in cancer clinical trials
This FDA guidance notes that compelling reasons exist to include pediatric patients in even early-stage cancer clinical trials. “Early evaluation and development of potentially effective drugs, particularly targeted drugs, in pediatric patients may provide information on safe and effective use, therefore reducing risks associated with off label use, and accelerate the development of effective, innovative therapies for pediatric patients,” said the agency.
The guidance outlines ethical and regulatory considerations for including pediatric cancer patients in adult clinical trials. Pediatric oncology experts should be involved in designing, approving, and overseeing trials that plan to enroll pediatric patients. Where possible, in vitro evidence, including in silico studies may be adequate to support inclusion of pediatric patients, says the guidance.
Especially for pediatric cancer patients with no standard curative options, early-phase clinical trial participation can be considered when existing data point to activity of the studied treatment against the child’s cancer. When a first-in-human drug trial is constructed, trialists can plan for an expansion cohort to include pediatric patients when sufficient safety, dosing, and efficacy data are available from the adult study population.
The guidance also lays out several practical tactics regarding dosing that maximize pediatric participant safety while permitting inclusion of pediatric patients in cancer clinical trials.
Regarding pediatric participation in late-phase trials, “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, safety profile, and preliminary efficacy information,” says the guidance.
Separately, a final guidance issued in 2019 addresses inclusion of adolescents in cancer clinical trials.


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