Some Headway in Efforts to Make Clinical Trials More Inclusive

Nancy A. Melville

September 16, 2022

For results from cancer clinical trials to be more generalizable to the real world, there needs to be some loosening of exclusion criteria, say researchers.

A new study concludes that the National Cancer Institute (NCI) is making some headway in its efforts to do this, but the study also shows potential challenges.

"Exclusion of patients with comorbidities is a major barrier for clinical trial enrollment of the diverse populations typically seen in oncology practices," say the authors. The results show that "modernized eligibility criteria can be successfully implemented, but that consistent implementation requires sustained focused effort."

The study was published this month in the Journal of the National Cancer Institute.

In an accompanying editorial, Peter J. O'Dwyer, MD, notes that the efforts are important, although some of the changes may be more easier said than done.

"Clearly, implementation of approaches to expanding patient access and accruing broad representation in cancer clinical trials is a widely shared goal," said O'Dwyer, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.

"Our concern is that methodologies to accomplish the goal should facilitate, not impede, the development of new and more effective treatments, and their broad availability to the public," he said. "Our hope is that incorporation of novel trial designs into the arc of drug development will facilitate both of these needs."

Adherence to the Recommended Criteria Varies

The study, conducted by Andrea M. Denicoff, RN, and researchers with the NCI's Cancer Therapy Evaluation Program (CTEP), reviewed how commonly clinical trials included language in their criteria that the agency had recommended to improve generalizability of trial results across populations.

Recommendations regarded language used for seven major eligibility criteria involving cardiac status; liver and kidney function; HIV status; prior or concurrent malignancies; treated or stable brain metastasis; and new or progressive brain metastases.

The recommendations had been proposed by the American Society of Clinical Oncology (ASCO) in collaboration with Friends of Cancer Research with input from the US Food and Drug Administration (FDA).

Among 122 protocols that were evaluated in the analysis, 69 involved clinical trials in the National Clinical Trials Network, and 44 were for trials in the Experimental Therapeutics Network. All the trials were approved between 2018 and 2020.

Among these trials, 90 involved solid tumors and 32 involved hematologic cancers. Most of the protocols (84%) included an investigational new drug with industry collaborators.

Overall, the eligibility criteria implementation ranged from 54.1% for criteria relating to prior or concurrent malignances to 93.4% for criteria relating to HIV infection.

While about 87% of the protocols contained recommended language relating to their hepatic and renal criteria for the trials, 76.2% included language relating to patients living with HIV.

In some cases, much lower explicit implementation of the language recommendations were observed, including language used in criteria relating to cardiac function (58.2%), prior/concurrent malignancies (34.4%), treated/stable brain metastases (51.2%), and new/progressive brain metastases (15.1%).

Of note, the criteria with the highest compliance involved those with specific laboratory values that could be used to determine eligibility, such as standard blood test evaluations of organ function and HIV status, the authors note.

The inclusion of patients with controlled HIV has improved, and there is strong evidence that HIV-infected patients receiving appropriate antiviral therapy typically fare well in clinical trials and should be more commonly included, the authors note.

"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," they say.

In stepped-up efforts to further improve inclusion of the eligibility criteria in clinical trials, the ASCO/Friends collaboration has added additional recommendations to their proposals, including expanding eligibility criteria for washout periods, concomitant medications, prior therapies, laboratory reference ranges and test intervals, and performance status.

Likewise, the CTEP says it started assigning focused reviewers in 2022 to more closely evaluate trials' eligibility criteria in NCI National Clinical Trials Network (NCTN) and the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) cancer treatment protocols.

"This collaboration with NCTN and ETCTN investigators, FDA, and industry will challenge the restrictive culture in clinical trials eligibility," they write.

"The goal is to have near 100% compliance by recording justification for restrictive criteria or employing the expanded language."

"One Size Does Not Fit All"

In his editorial, O'Dwyer notes that the wide variance of trials that included the recommended language underscores the challenges and that perhaps "one size does not fit all."

"The data are striking at first glance in that adoption of the recommendations is quite heterogeneous," he writes.

In addition to suggesting general resistance to change, the findings may also reflect "real concerns on the part of those designing the trials for their impact on participant safety and the validity of the results," he notes.

"The fact that uptake is high with some but not other recommendations suggests that those designing trials are not simply ignoring them, but likely do not agree with their inclusion."

In further comments to Medscape Medical News, O'Dwyer elaborated that the arguments on both sides have merit.

"Indeed, the arguments on several sides are strong, [including] the need for patient access to trials; the need for trial results to be relevant across our entire population; and the need for rapid and efficient development of new therapies that can be made available broadly."

That being said, the eligibility goals may conflict with some trials' methodologies, he noted.

"As you broaden eligibility criteria, outcomes on both control and investigational arms are at risk of being worse, simply because of the introduction of comorbid factors," O'Dwyer notes.

He added that "eligibility changes alone seem unlikely to achieve the goal of understanding the broad population impact of therapies that appear to be an advance, and more novel methodologies should be considered."

In his editorial, O'Dwyer suggested the utilization of real-world data to address key subpopulation questions.

"This structure could allow greater access at an earlier stage for patients, greater controls for safety, and the assurance that the participation of each patient would contribute meaningfully to the generalizability of results with the new treatment," he explains.

The authors and O'Dwyer have disclosed no relevant financial relationships

J Natl Cancer Inst. Published September 1, 2022. Abstract, Editorial

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