Equitable access to CTs—that is, the opportunity for all patients to access CTs that may offer improved outcomes and the evidence-based standard of care treatment that CTs offer—must be a priority.
Improved access in CTs will benefit individual patients, and improving inclusiveness of trial populations will benefit all patients with a given disease. Clinicians will also have greater confidence in the generalizability of CT data to make informed treatment decisions.
Eligibility criteria (EC), the inclusion and exclusion criteria written into trial protocols by the study sponsor, are intended to ensure patient safety. Overly restrictive EC, however, are a significant impediment to enrollment and equity, because they consistently exclude certain groups, particularly older adults, racial/ethnic minorities, and patients with previous/ongoing chronic medical conditions.
While narrow EC are not intended to discriminate against any individual or group, that is the effect, and it is unacceptable.
This is of concern for SARS-CoV-2 vaccine and therapeutic studies because certain populations—e.g., Black and Hispanic people, older adults, and individuals with certain comorbidities or compromised immune systems, including patients with cancer—are more susceptible to infection and/or have worse outcomes than others. If therapies are not studied in these populations, patient safety may be at risk.1
The American Society of Clinical Oncology and Friends of Cancer Research recently released a joint position statement recommending the inclusion and prioritized recruitment of individuals with cancer on SARS-CoV-2 vaccine trials, from which these patients have thus far been excluded without scientific justification.2
Negative implications of overly restrictive EC also exist in cancer trials, where a disproportionate share of the population is elderly and has comorbidities, and is excluded for those reasons.
Protocol drafting should begin with a presumption of inclusion and only restrict patients where known safety concerns warrant exclusion Since 2016, the U.S. Food and Drug Administration has partnered with ASCO and Friends to address deeply entrenched, overly restrictive EC in cancer CTs. The assertion that many common EC can be broadened to be more inclusive or eliminated completely without compromising patient safety is foundational to this work.
ASCO and Friends, with expert input from FDA, the National Cancer Institute, clinicians and researchers, patients/patient advocates, pharmaceutical industry CT sponsors, and others, have developed paradigm-shifting recommendations for broadening cancer CT eligibility criteria.3
Recommendations that were published in 2017 address common EC that can be expanded safely to increase equity in CT access: minimum enrollment age, HIV infection, presence of brain metastases, prior or concurrent malignancies, and organ dysfunction.
The potential impact of implementing the ASCO-Friends recommendations is considerable: by expanding common EC related to renal function, brain metastases, and prior/concurrent malignancies, nearly twice as many patients could be eligible for oncology CTs, compared to traditional EC 4. Older (aged 75+), female, and sicker (more advanced cancer stage) patients are significantly more likely to be eligible for CTs that use those three ASCO-Friends EC.
In 2018, the NCI updated its Generic Protocol Template for oncology CTs to match closely the ASCO-Friends-endorsed EC and stated that the updated criteria should be included in active and future CT protocols when possible. NCI grantees and contractors that develop NCI-funded trials have been implementing the recommendations.
On the regulatory side, FDA urged the implementation of more inclusive EC in oncology trials sponsored by pharmaceutical companies in Final Guidance for Industry documents.5 The four FDA documents, which align closely with the ASCO-Friends recommendations, assert FDA’s support for broadening EC safely.
The FDA guidance documents set the expectation of inclusivity for trials submitted to the Agency, make it clear that FDA encourages broad enrollment, and allow FDA to request a rationale from sponsors if narrower populations are enrolled.
Inclusivity also comes with potential benefits for sponsors that broaden criteria. If expanded populations are enrolled and efficacy and safety are demonstrated, FDA may grant regulatory benefits, including expanded labeling provisions and reduced post-marketing requirements and commitments.6
For example, tucatinib, a HER2 targeted kinase inhibitor was studied in a breast cancer CTs including patients with brain metastases and demonstrated benefit in both the overall population and this typically excluded subpopulation. The drug was therefore granted an indication in patients with HER2-positive breast cancer specifically including those patients with brain metastases.
Government, industry sponsors, and regulators were engaged as critical partners in development of the ASCO-Friends recommendations. In oncology and all areas of clinical research, recommendations to leave restrictive EC out of CT protocols will advance equitable patient access only if implemented by trial sponsors.
Sponsors not only write EC into CT protocols, but also manage patient eligibility decision-making, either directly or through contract research organizations (CROs). Protocol drafting should begin with a presumption of inclusion and only restrict patients where known safety concerns warrant exclusion.
In the absence of safety data, sponsors could enroll exploratory subpopulations in early development to collect data to ensure that pivotal trial enrollment is representative of the entire patient population.
Industry sponsors hold considerable influence over the conduct and culture of clinical research. While FDA guidance documents carry weight and are useful in sponsor-regulator discussions throughout the regulatory process, they are not typically legally binding.
Increased diversity in clinical trials depends on dialog between investigators and underrepresented communities.
In addition to appropriate EC, outreach efforts advised by community engagement advisory boards can be critically important in developing bidirectional communication between investigators and people who have historically been excluded from studies to improve design and enrollment.
For example, patient advocacy has played a central role in protesting exclusion of people living with HIV from SARS-CoV-2 trials.
Many opportunities exist to expand on these efforts. A second iteration of ASCO-Friends recommendations published in 2021 addresses performance status, laboratory test ranges, prior lines of therapy, washout periods, and concomitant medication exclusions as additional barriers to cancer CT access.7
ASCO’s Targeted Agent and Profiling Utilization Registry (TAPUR™) study demonstrates implementation of broadened EC, as written by ASCO and agreed to by industry collaborators. Additional efforts by the LUNGevity Foundation and FDA are planned to provide broad templated EC for individual disease areas.
Beyond oncology and EC, multi-stakeholder PPPs like those formed by the Clinical Trials Transformation Initiative (CTTI) are advancing CT equity in numerous disease areas. The success of these efforts depends on sustained commitment by all stakeholders to identify and implement actionable solutions to persistent inequities.
- Chastain DB, Osae SP, Henao-Martínez AF, et al: Racial Disproportionality in Covid Clinical Trials. New England Journal of Medicine 383:e59, 2020
- Inclusion of Individuals with Cancer on COVID-19 Vaccine Trials: A Joint Position Statement from the American Society of Clinical Oncology and Friends of Cancer Research. Published June 22, 2021. https://www.asco.org/sites/new-www.asco.org/files/content-files/blog-release/pdf/2021-ASCO-Friends-Vaccine-Trials-Position-Statement.pdf
- Kim ES, Bruinooge SS, Roberts S, et al: Broadening Eligibility Criteria to Make Clinical Trials More Representative: American Society of Clinical Oncology and Friends of Cancer Research Joint Research Statement. Journal of Clinical Oncology 35:3737-3744, 2017
- Harvey RD, Rubinstein WS, Ison G, et al: Impact of broadening clinical trial eligibility criteria for advanced non-small cell lung cancer patients: Real-world analysis. Journal of Clinical Oncology 37, 2019
- U.S. Food and Drug Administration: Oncology Center of Excellence Guidance Documents, 2020, https://www.fda.gov/about-fda/oncology-center-excellence/oncology-center-excellence-guidance-documents
- Beaver JA, Ison G, Pazdur R: Reevaluating Eligibility Criteria — Balancing Patient Protection and Participation in Oncology Trials. New England Journal of Medicine 376:1504-1505, 2017
- Kim ES, Uldrick TS, Schenkel C, et al: Continuing to Broaden Eligibility Criteria to Make Clinical Trials More Representative and Inclusive: ASCO–Friends of Cancer Research Joint Research Statement. Clinical Cancer Research, 2021