The American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) jointly issued new recommendations to further efforts to broaden eligibility criteria in cancer clinical trials with the goal of making clinical trials more accessible to patients. The joint recommendations are detailed in a series of articles published in Clinical Cancer Research, a journal of the American Association for Cancer Research. The series provides a comprehensive examination of eligibility criteria for cancer clinical trials with recommendations to address five specific areas: treatment washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and patient performance status.
“Clinical trial access must be recognized as a health equity issue. Overly restrictive eligibility criteria without scientific justification has led to an underrepresentation of older adults, racial/ethnic and sexual/gender minorities, and patients with well-managed comorbidities,” said ASCO President Lori J. Pierce, MD, FASTRO, FASCO. “We’re proud to continue our collaboration with Friends of Cancer Research to make eligibility criteria less restrictive so that clinical trial populations can be more inclusive and representative of cancer patient populations and improve results for all patients.”
Trial eligibility criteria are designed to protect participant safety and define an appropriate study population. However, overly restrictive eligibility criteria can limit the participation of patients in a clinical trial who share critical characteristics with those likely to be treated based on the study’s results. These restrictions make it hard for clinicians to fully understand how a more diverse patient population typically seen in clinical practice will respond to a therapy post-approval. Overly restrictive eligibility criteria can also reduce patient access to potentially life-prolonging novel treatments and slow down the generation of research results. Using recommendations made by ASCO and Friends in 2017, a new analysis of data from CancerLinQ Discovery® (CancerLinQ’s deidentified real-world data product for researchers) found that expanding just three common eligibility criteria—renal function measures, presence of brain metastases, and history of prior malignancy—increases the percentage of lung cancer patients potentially eligible for clinical trials almost twofold.
To address this issue, ASCO and Friends worked with stakeholders throughout the cancer research community to develop evidence-based, consensus recommendations that are focused on expanding eligibility criteria to make trial populations more reflective of the general cancer population, reduce clinical trial complexity, and exclude patients from trials only where it is warranted due to safety concerns. Implementation of the recommendations, ASCO and Friends assert, can expedite patient recruitment, accelerate learning, decrease trial ‘failure rate’ due to slow enrollment, increase opportunities for patient participation and benefit, and make trial results more generalizable to the population that would use the treatment in routine clinical care.
“As new cancer therapies are being developed, we must think broadly about how eligibility criteria are determined.” said Jeff Allen, PhD, President & CEO of Friends of Cancer Research. “We need to find an optimal balance between improving patient access to clinical trials and the methods used for robust evaluation of safety and efficacy of new therapies. Modernizing eligibility criteria for enrollment will bring more trials to more patients, and ultimately help inform the optimal use of new medicines more quickly.”
The recommendations published today were developed by stakeholders from ASCO, Friends, academic and community research sites, the Food and Drug Administration (FDA), National Cancer Institute (NCI), patient advocates and advocacy groups, NCI National Clinical Trials Network Groups, and the pharma-biotech industry.
New Recommendations Build on Ongoing Work to Expand Eligibility Criteria and Simplify Trial Operations
In 2016, ASCO, Friends, and FDA formed a collaboration to address overly restrictive cancer clinical trial eligibility criteria. Project leadership selected five criteria that commonly lead to the exclusion of specific patient populations from clinical trials (brain metastases, minimum age for enrollment, HIV status, organ dysfunction, and prior or concurrent malignancies) and tasked multi-stakeholder working groups with recommending less restrictive eligibility criteria addressing these five factors. An ASCO-Friends Joint Research Statement and supporting working group papers were published in the Journal of Clinical Oncology in 2017.
As a result of efforts by ASCO and Friends to disseminate and encourage implementation of those recommendations, in September 2018 NCI revised protocol template language based on the recommendations, stating that the updated criteria should be implemented where possible in active protocols and included in future Experimental Therapeutics Clinical Trials Network and National Clinical Trials Network trial protocols. Additionally, in July 2020, FDA released four final guidance documents recommending broadening eligibility criteria related to brain metastases, HIV and Hepatitis B/C infections, organ dysfunction and prior/concurrent malignancies, and minimum age requirements.
ASCO and Friends will continue to work closely with FDA, NCI, trial sponsors, institutional review boards (IRBs), contract research organizations (CROs), and patient groups to disseminate the latest recommendations, share analyses, and help to successfully implement changes in protocols to broaden eligibility criteria appropriately.
More detailed information on each article is provided below.
Overview: This article provides an overview of the ASCO and Friends eligibility criteria initiative, outlines goals and rationale, and describes the process used to develop the recommendations. The article also provides a summary of the working groups’ recommendations.
Background: Washout periods for prior treatments and interventions limit timely accrual and may prevent patient enrollment without adding safety measures or preventing misinterpretation of efficacy results. Excluding patients who require concomitant medications (other medications taken by the patient that are unrelated to the investigational treatment) for other illnesses or supportive care management limits understanding of the investigational agent’s tolerability and dosing in those likely to receive the treatment post-approval and excludes many older patients with co-morbid illnesses.
This working group recommends the use of less restrictive requirements for prior therapy washout periods and concomitant medication in most instances. Specifically:
- Time-based washout periods should be removed from protocol eligibility criteria in most cases.
- Relevant clinical and laboratory parameters should be used in place of time-based washout periods to address safety considerations.
- Potential trial participants should have recovered from clinically significant adverse events of their most recent therapy/intervention prior to enrollment.
- Concomitant medications use should only exclude patients from trial participation when clinically relevant known or predicted drug-drug interactions or potential overlapping toxicities will impact safety or efficacy.
Background: Performance status (PS) is one of the most common eligibility criteria, often limiting clinical trial populations to highly functional and minimally symptomatic individuals who do not reflect the populations afflicted with the disease. Existing PS tools are inherently subjective and invite bias, and PS does not reliably predict outcomes for older adults.
- Patients with reduced PS should be included unless there is a scientific and/or clinical rationale for exclusion justified by established safety considerations. PS eligibility criteria should be continually re-evaluated and modified throughout the clinical development process to reflect accumulated safety data of the investigational treatment.
- Investigators should consider alternate trial designs, such as pre-specified cohorts with lower PS that are exempt from the primary analysis, to encourage inclusion of these patients.
- Investigators should consider additional assessments to better characterize the functional status of ECOG PS2 patients and patients aged ≥65.
Background: Laboratory test-related eligibility criteria may exclude a significant portion of patients from clinical trials unnecessarily and can have disproportionate impact on patients according to age, gender, race, and ethnicity.
The proposed recommendations help guide appropriate use of laboratory tests and testing intervals to safely enable increased clinical trial accrual and provide more relevant data that better mirror oncology patient populations. Specifically, the article recommends:
- Laboratory test results should only be used as exclusion criteria when scientifically justified and when abnormal test results confer safety concerns.
- Laboratory reference values should account for potential normal variations due to race, ethnicity, age, sex, and gender identity.
- Routine re-assessment of laboratory test-based exclusion criteria should be conducted during the course of clinical research and drug development.
- Investigators should consider increasing the intervals between protocol-specified tests to help reduce patient burden and rely more on routine clinical testing.
Background: A patient’s prior therapies—including number or type—are often used either as exclusion or inclusion criteria for enrollment into clinical trials.
The multi-stakeholder working group has recommended:
- Patients should be eligible for clinical trials regardless of the number or type of prior therapies and without a requirement to have received a specific therapy prior to enrollment unless there is a scientific or clinical rationale.
- Prior therapy could be used to determine eligibility in the following cases:
- If the agents being studied target a specific mechanism or pathway that could potentially interact with a prior therapy.
- If the study design requires that all patients begin protocol-specified treatment at the same point in the disease trajectory.
- In randomized clinical studies, if the therapy in the control arm is not appropriate for the patient due to previous therapies received.
- Trial designers should consider conducting evaluation separately from the primary endpoint analysis for participants who have received prior therapies.
Overview: An analysis of real-world data from the CancerLinQ® Discovery database shows that expansion of three common eligibility criteria—renal function measures, presence of brain metastases, and history of prior malignancy—increases the number of patients with lung cancer in the dataset analyzed who are potentially eligible to enroll in a trial almost two-fold. This analysis was conducted in a population with advanced non-small cell lung cancer, although the paper suggests that the findings are likely applicable to other advanced malignancies.