Change Eligibility Rules for More Diverse Clinical Trials?

Expanding eligibility criteria is a strategy for improving the inclusion of traditionally underrepresented populations in clinical trials, according to a study. The results were published in NEJM Evidence by Maneet Kaur, PhD, epidemiologist and senior scientist at Flatiron Health, New York, and colleagues. Flatiron Health is an independent member company of the Roche group and sponsor of the study. 

“Certain populations have been historically underrepresented in clinical trials. Broadening eligibility criteria is one approach to inclusive clinical research and achieving enrollment goals. How broadened trial eligibility criteria affect the diversity of eligible participants is unknown,” the researchers wrote.

“The topic addressed by Kaur and colleagues is certainly not new. As early as 1997, the National Cancer Institute noted that overly restrictive criteria in clinical trials led to results with poor reproducibility in the real world,” Celeste Cagnazzo, biologist manager at the AOU Città della Salute e della Scienza in Turin, Italy, and president of the Italian Group of Data Managers-Clinical Research Coordinators, told Univadis Italy.

Pros and Cons

Using a national database of health data, researchers identified a retrospective cohort of 235,234 patients diagnosed with 22 types of cancer and treated with systemic therapy. “We evaluated strict vs broadened eligibility criteria using performance status and liver, kidney, and hematologic function around first line of therapy,” the authors wrote.

Under the more restrictive criteria, less than half (48%) of the identified patients were eligible, and the likelihood of exclusion was higher for women, the elderly, Latin Americans, non-Latin black individuals, and patients with low socioeconomic status. Broadening the criteria increased the number of eligible patients by 78%, with particularly significant increases for historically underrepresented groups such as women, the elderly, and certain ethnicities.

Expanding eligibility criteria could be a step toward including the entire population in clinical trials. Experts explain that defining eligibility criteria is not so simple, however, and despite the interest of the medical-scientific community and regulatory bodies, the issue of truly equitable population inclusion in clinical trials has not yet been definitively resolved. “It’s about finding a balance between the internal and external validity of the study,” said Cagnazzo. In other words, it is necessary to use criteria that ensure the safety of enrolled subjects and achieve internal validity, which is not easy when particularly fragile subjects are involved. At the same time, data that can be translated into the real world (external validity) are needed. Otherwise, there is a risk, for example, of marketing a drug that will cause much higher toxicity than expected.

Collective Effort

The definitions of “restrictive” and “expanded” cannot be the same for all tumors, according to an accompanying editorial by Ramya Ramaswami, MBBS, Lasker clinical research scholar at the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland, and Thomas S. Uldrick, MD, deputy head of global oncology at the Fred Hutchinson Cancer Center in Seattle, Washington.

Eligibility criteria can be structured and defined in various ways. “Expanding current criteria means paying more attention to internal validity and patient safety, but it undoubtedly leads to a series of advantages in terms of external validity,” said Cagnazzo. “These data could also be useful for defining eligibility criteria, but for this to become the norm, they need to be collected correctly and systematically and made accessible. In Italy, this is still very difficult,” she explained. The European Medicine Agency also emphasizes the importance of real-world data, going as far as to accept these data even for dossiers related to requests for marketing authorization of a drug.

A fundamental issue is the updating of eligibility criteria, according to Cagnazzo. “Criteria should be updated in light of new therapies. Once, treatments were very toxic, so it was worth being more restrictive, but today the situation has changed,” she said. For example, researchers may consider including patients with performance status scores above 0 and 1, which are limits on physical function often used in current studies. They also may consider including older patients, because, given demographic changes, limiting inclusion to under age 65 years is problematic.

Some progress has already been made. Today, patients with brain metastases or infections from hepatitis B and C viruses can be included in trials, given certain precautions, but much remains to be done.

“In Italy, given the composition of the population and the presence of a National Health System, we feel less the burden of criteria related to ethnicity or socioeconomic status, but generally, inclusivity problems are not different from country to country,” said Cagnazzo. “A clearer stance from regulatory authorities is needed, along with pressure from the scientific community. Furthermore, it would be useful to ‘mess up’ expertise a bit. That is, to support the exchange between public and private sectors and between different experts to achieve the common goal of well-designed studies that are truly useful to patients.” 

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. 

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