Implementing Modernized Eligibility Criteria in US National Cancer Institute Clinical Trials

Abstract

In 2018, the Cancer Therapy Evaluation Program (CTEP) at the US National Cancer Institute published new protocol template language that focused on organ function and prior and concurrent cancers in an effort to modernize eligibility criteria for cancer treatment trials. We conducted an analysis of CTEP-supported trials to evaluate the uptake and incorporation of the new language. The analysis included evaluation of 122 protocols approved in the years 2018-2020 for inclusion of the modernized eligibility criteria and consistency with new protocol template language related to 7 major eligibility criteria. These were cardiac function, liver function, kidney function, HIV status, prior and/or concurrent malignancies, treated and/or stable brain metastasis, and new and/or progressive brain metastases. Overall, CTEP trials evaluated in this period demonstrated that eligibility criteria were implemented to a relatively high degree ranging from a low of 54.1% for prior and/or concurrent malignancies to a high of 93.4% for eligibility criteria related to HIV infection. The findings demonstrate that modernized eligibility criteria can be successfully implemented but that consistent implementation requires sustained focused effort. As a result of these findings, CTEP began a new initiative in January 2022 that incorporates a specific review of eligibility criteria for new protocols to promote and improve consistency with the modernization effort.

The American Society of Clinical Oncology and the Friends of Cancer Research (ASCO-Friends) led a collaborative initiative to modernize eligibility criteria to make cancer clinical trials access less restrictive and therefore representative of cancer patient populations (1,2). Exclusion of patients with comorbidities is a major barrier for clinical trial enrollment of the diverse populations typically seen in oncology practices. Expanding eligibility criteria has the potential to enhance the generalizability of trial results to wider patient populations and reduce cancer health disparities by increasing access to trials and potentially life-prolonging therapies.

Successful clinical trials generate progress against cancer and reduce the burden of disease. Eligibility criteria in clinical trials are important to define the study population and protect the safety of participants. However, restrictive eligibility criteria exacerbate health disparities by hindering access to trials among those with comorbidities. Higher rates of chronic comorbidities occur in minority and underserved populations, resulting in underrepresented and minority populations being disproportionately affected by restrictive eligibility criteria (3). Restrictive eligibility criteria also results in generally healthier people participating in clinical trials, which then produces trial results that are less reflective of the broader cancer population (4). ASCO-Friends led a national initiative including industry, the US Food and Drug Administration (FDA), the US National Cancer Institute (NCI), advocates, and clinical investigators to modernize eligibility criteria. This resulted in a series of peer-reviewed articles in 2017 and 2021 with guidelines to broaden eligibility criteria (1,2). The FDA published similar support and guidance in 2017 and 2020 on reevaluating eligibility criteria and enhancing diversity in clinical trial populations (5,6).

The Cancer Therapy Evaluation Program (CTEP) is a key clinical component of NCI’s extensive national cancer research program. The clinical trial portfolio spans all phases of clinical development and includes domestic and international cancer treatment trials. CTEP oversees clinical trials that can be conducted in more than 2000 sites around the United States and other countries. The NCI National Clinical Trials Network (NCTN) and the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) together enroll more than 25 000 cancer patients annually onto cancer treatment trials. In addition, there are other CTEP-supported smaller networks and consortia that conduct specialized cancer clinical trials. NCI trials are often conducted through collaborations with industry, thereby availing patients with a wide range of cancer diagnoses the opportunity for access to experimental treatments, including in rare cancer subtypes. To ensure those individuals with the diseases under study have access, NCI trials must have inclusive eligibility criteria when scientifically justified that will allow broader participation (7).

CTEP incorporated the 2017 ASCO-Friends modernized eligibility criteria guidelines and, where possible, created protocol template inclusion language to be used in CTEP-supported trials. The modified templates were distributed and publicly accessible in September 2018. Networks and centers conducting clinical trials through CTEP were asked to implement the new template language in their studies as a default and to provide appropriate rationale whenever eligibility criteria restrictions were necessary. After the eligibility criteria guidelines were in use for several years, CTEP evaluated its clinical trial portfolio for implementation of modernized eligibility criteria (8).

Methods for Assessing Implementation

Clinical cancer therapy investigational protocols first approved by CTEP between November 1, 2018, and April 30, 2020, were evaluated retrospectively for implementation of the modernized eligibility criteria template language. The most recently approved protocol version was used for the evaluation. The analysis was focused on eligibility related to brain metastases, HIV infection, prior or concurrent malignancies, and organ dysfunction (cardiac, liver, and kidney). We also evaluated protocols for minimum age for enrollment. All protocols were evaluated by 2 or more NCI clinicians (1 or more medical oncologists and an oncology nurse practitioner), as well as 2 advanced degree information specialists. All reviewers had to reach consensus on implementation. If consensus was not reached, an additional CTEP senior investigator was consulted to adjudicate. Each criterion was scored as implemented, not implemented, or not addressed. If a specific eligibility criterion was not addressed in the protocol, it was presumed that patients with that criterion would be eligible for the protocol. We therefore categorized the findings as “explicitly implemented,” “not addressed,” and “composite implementation” to reflect overall technical trial eligibility. If a particular criterion was irrelevant for a trial, it was excluded in the analysis. For example, the age eligibility criterion was not scored in protocols with a pediatric focus or in malignancies primarily seen in adults (eg, prostate cancer), and brain metastasis was not scored for trials of nonmetastatic disease or for central nervous system tumors.

Results

Between November 1, 2018, and April 30, 2020, 122 cancer treatment trials were approved by CTEP and evaluated for eligibility criteria implementation. Of the trials, 71% (87) were early phase I, II, and I/II trials, and 29% (35) were later phase II/III and III trials. Of the protocols, 102 (84%) included an investigational new drug with industry collaborators. There were 104 adult and 18 pediatric studies. Of the 122 trials, 69 were conducted by the NCTN, and 44 were conducted by the ETCTN. Other CTEP-supported consortia led the remaining 9 protocols. There were 90 trials in solid tumors and 32 were in hematologic cancers. Only 6 trials were considered relevant to implementing expanded age criteria for patients aged younger than 18 years, and 3 (50%) of these were consistent with the modernized age eligibility criterion.

Table 1 shows the percentages of protocols that implemented each modernized eligibility criterion (except age). The highest explicit compliance with the modernized eligibility criteria was seen in liver function (87%), kidney function (86.1%), and HIV status (76.2%). Lower explicit implementation rates were seen for cardiac function (58.2%), prior and/or concurrent malignancies (34.4%), treated and/or stable brain metastases (51.2%), and new and/or progressive brain metastases (15.1%). The denominator for treated and/or stable and new and/or progressive brain metastases was 86 trials, because those with a nonmetastatic cancer or those in primary central nervous system tumors were not relevant for these eligibility criteria. Silence in protocols on eligibility criteria of interest ranged from 4.9% for kidney function to 47.7% for new and/or progressive brain metastases. The overall composite implementation inclusive of the protocols silent on eligibility criteria ranged from 54.1% for prior and/or concurrent malignancies to 93.4% for HIV infection.

Table 1.

Expanded eligibility implementation: trials approved between November 1, 2018, and April 30, 2020

Modernized eligibility criteria category	Liver function	Kidney function	HIV	Cardiac function	Prior/Concurrent malignancies	Treated/Stable brain metastases	New/Progressive brain metastases
No. of analyzable trials	122	122	122	122	122	86a	86a
Criteria explicitly implemented, %	87	86.1	76.2	58.2	34.4	51.2	15.1
Criteria not addressed, %	5.7	4.9	17.2	10.7	19.7	32.5	47.7
Composite implementation, %b	92.7	91	93.4	68.9	54.1	83.7	62.8

^aCriterion not relevant for trials in nonmetastatic disease and primary central nervous system cancers.

^bSum of those explicitly implemented and not addressed.

Discussion

This analysis revealed a range of compliance with modernized eligibility criteria across the criteria. This was not unexpected because although CTEP published revised templates using modernized eligibility language, there was no focused programmatic process in place to ensure implementation across the clinical trials enterprise. Eligibility criteria with the highest compliance were those where a specific laboratory value can be used to determine eligibility. These included standard blood test evaluations of organ function and HIV status. The areas where compliance was found to be lower were those that require some balance between subjective and objective measures of composite data, such as New York Heart Association scoring for cardiac function. Similarly, the need for obtaining and interpreting multiple brain imaging timepoints for evaluation of brain metastasis poses challenges relevant to expanding eligibility criteria.

The high concordance for HIV inclusion was expected but not as high as we would have predicted. In 2007, CTEP leveraged NCI funds from the NIH Office of AIDS Research specifically to perform research into this issue with the intent of including persons living with HIV and cancer onto NCI clinical trials. The research showed HIV did not adversely affect either autologous or allogeneic transplant outcomes and found that the incidence of newly diagnosed HIV in cancer clinics is too low to recommend routine HIV testing unless the cancer is highly HIV associated (9-11). Consequently, CTEP had been working to include persons living with HIV onto cancer clinical trials well before the ASCO-Friends initiative. Even so, only 75% of trials contained the requested templated language for HIV inclusion. Omission of a specific eligibility criterion, such as HIV infection, was presumed in this analysis to be inclusive for such patients. Using a metric for compliance that was a composite of explicit implementation of a criterion and silence for a criterion displayed an overall higher rate of implementation of modernized eligibility criteria in this analysis. However, practice habits may not translate into greater inclusion of patients in clinical trials where there is not a specific positive eligibility criterion to do so. For example, the long-standing practice of reflexively excluding those with HIV from cancer clinical trials seems unlikely to change without proactive inclusion criteria. Because the effort to expand eligibility is in response to national efforts advocating the need for change, silence may not answer the stakeholders’ call. Whether to omit certain explicit eligibility criteria from a given protocol is a matter of judgment, but overcoming enculturated barriers for expanding eligibility cannot reasonably rely solely on silence.

Another important finding from this exercise was the recurring issue of conflicting eligibility criteria language found in protocols. For example, a protocol that correctly included a modernized eligibility criterion using the CTEP template language in its inclusion criteria section also had a subsequent contradictory statement in a separate exclusion criteria section, which nullified the prior inclusive eligibility statement. This points to the difficulty reviewers may encounter when working to ensure implementation of expanded eligibility criteria.

Improving generalizability and accrual by expanding eligibility is not just an abstract construct. For example, an analysis of 328 patients seen in clinic with non-small cell lung cancer showed that only 32% met eligibility criteria for randomized phase III trials (12). Ultimately, the question is whether the effort to expand eligibility will translate into less exclusion of those with comorbid conditions. Follow-up research to evaluate this question will inform this essential issue. However, it is critical to first create the changes in eligibility to make that a viable research question for later focus. To solve the problem of slow accrual for a given clinical trial, investigators often view the eligibility section as the easiest modifiable action to correct the problem. Analysis of CTEP-supported trials requiring slow accrual corrective action plans identified many concerns, but one of the most proposed corrective actions was to modify the eligibility of the study (13). Formulating inclusive eligibility criteria from the start is not only justified but essential toward streamlining clinical trials so findings are quickly generated from successful completion of trials. For example, in 1103 early phase trials identified on CT.gov (clinicaltrials.gov), 86% of trials restricted patients with a history of prior cancers (14). This is unlikely to be a justifiable restriction in a substantial number of cases and probably reflects the cultural status quo in writing clinical trial eligibility rather than having a thoughtful scientific and patient-centric approach. As cancer clinical trials are increasingly driven by molecular targeted therapies and the ensuant smaller pool of patients with “the disease,” the broadening of eligibility criteria becomes imperative (15,16).

New recommendations from ASCO-Friends were published in May 2021 to expand eligibility criteria for washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and performance status (2). CTEP will work to implement these modernized criteria as well.

Although the ASCO-Friends guidelines emphasize the lowering of age requirements for clinical trials, our analysis did not inform well on implementation of the age criterion. This is in part because the NCTN groups, including the Children’s Oncology Group, conduct studies appropriate for focus in adult or children, leaving no age group devoid of clinical trials for the diseases being studied. Additionally, whenever appropriate for a specific disease, the NCTN conducts trials for adolescents and young adults that include younger ages. The CTEP model in this regard differs from industry or other organizations. Still, we think the general approach we have outlined in our analysis applies for age; other organizations may wish to evaluate or to improve implementation of lower age eligibility for their own clinical trials.

Our analysis demonstrates that uptake for modernized eligibility criteria was variably implemented after publication of new template language. When these results were presented to the NCI Clinical Trials and Translational Research Advisory Committee Strategic Planning Working Group as part of its 2030 strategic vision for NCI’s clinical trials, the group recommended NCI conduct a focused effort to fully implement ASCO-Friends modernized eligibility criteria into clinical trials (17).

In January 2022, CTEP began assigning focused reviewers to evaluate eligibility criteria during its official review of NCTN and ETCTN cancer treatment protocols. The goal is to identify restrictive eligibility criteria early in the protocol development process and collaborate with investigators, industry, and FDA partners to broaden eligibility criteria where medically and scientifically appropriate. This collaboration with NCTN and ETCTN investigators, FDA, and industry will challenge the restrictive culture in clinical trials eligibility. This will be accomplished in part by requiring protocols to include clear scientific and/or clinical rationale justifying the need to restrict any eligibility criterion. CTEP will track progress prospectively with plans to report findings from this initiative in the future so that all stakeholders, including and especially patients and advocates, can be informed and to improve the ASCO-Friends guidelines as they continue to evolve. The goal is to have near 100% compliance by recording justification for restrictive criteria or employing the expanded language.

Eligibility criteria must be as broad as safely possible to achieve diverse and representative populations in clinical trials. Our experience shows that implementation requires a sustained and focused effort. Simply publishing template language and expecting implementation is not sufficient to achieve broadened eligibly criteria in clinical trials. Using HIV as an example, CTEP senior staff had multiple discussions with clinical trial investigators, industry collaborators, and FDA reviewers between 2007 and the present that has ultimately yielded near universal acceptance for including those with well-controlled HIV onto cancer treatment trials (18). The goal at CTEP is to incorporate the ASCO-Friends guidelines and to therefore make NCI trials a national model for inclusiveness. Our established collaborations with the FDA and industry partners are integral to achieving this goal. Our experience highlights the key element to ensure implementation—trial sponsors must be committed to the effort and leverage-specific resources focused on the details of eligibility criteria in each clinical trial. Clinical trial enrollment is a complex issue, and ongoing critical assessment of eligibility criteria is essential to achieve the right balance between expanding criteria while ensuring patient safety. With less restrictive eligibility criteria translating into study conclusions that are more relevant to the broader patient population, we can make faster progress in the discovery of new targeted cancer therapies that will benefit more people.

Funding

No funding was used for this commentary.

Notes

Role of the funder: Not applicable.

Disclosures: The authors have no relevant conflicts of interest.

Author contributions: Formal Analysis: JZ, KHW, AMD, RFL; Writing—Original Draft: TTT, AMD; Writing—Review & Editing: AMD, SPI, TTT, MMM, RFL; Supervision: AMD, SPI, MMM, RFL; Project Administration: JZ, KHW.

Prior presentation: Denicoff AM, Ivy PS, Worthington KH, Zhao J, Seibel N, Mishkin GE, Mooney MM, and Little RF. National Cancer Institute implementation of the American Society of Clinical Oncology and Friends of Cancer Research broadening clinical trials eligibility criteria. Chicago, IL. American Society of Clinical Oncology Annual Meeting; June 2021.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.