Eligibility Criteria Framework Sets a Model for Industry, Upcoming FDA Guidance
A broad collaboration among regulators, academia, the nonprofit sector and sponsors has developed a framework for creating less restrictive eligibility criteria for lung cancer trials that can be applied across the oncology research sector and beyond.
A multistakeholder working group led by the LUNGevity Foundation and involving researchers and policymakers from the FDA, the University of Texas Southwestern, the European Medicines Agency, the National Cancer Institute and a variety of sponsors aimed to help investigators and sponsors think critically about the needs of specific trials rather than defaulting to often-used general criteria that could unnecessarily limit the participant pool.
The resulting model, published in JAMA Oncology, will form the basis of an upcoming FDA draft guidance on eligibility for stage IV non-small cell lung cancer (NSCLC) trials. Although the agency has not indicated when it will release the guidance, the public comment period that would follow is likely to garner valuable feedback on eligibility that could be applied beyond this specific area of research.
David Gerber, professor of internal medicine and population & data sciences and associate director of clinical research at UT Southwestern Medical Center, says that, to his knowledge, this eligibility criteria framework is the first of its kind in oncology.
“Studies have suggested that stringent eligibility criteria are the primary reason for nonenrollment, slow accrual and failure to complete trials,” Gerber, who is the lead author of the article, told CenterWatch Weekly. “Unrealistic eligibility — even if the treatment under investigation is exciting and promising — may be sufficient reason to decline participation.”
To avoid this problem, the working group’s framework encourages a step-by-step analysis of a trial’s target population, starting at the top with the necessary characteristics of the disease to be studied and progressing through consideration of tests, such as biomarker assessments, to be applied, other conditions that could impact trial results, and potential participants’ past or current experience with the disease.
Trials with overly broad exclusion terms create criteria that are difficult to meet, particularly in oncology, says Jimmy Bechtel, vice president of site engagement for the Society of Clinical Research Sites (SCRS).
Sponsors and CROs are trying to cram too much into one protocol, Bechtel said. “It’s largely the result of those writing the protocols not understanding how their asks will play out operationally,” he said.
“There are so many layers in between the protocol designers and the sites that these protocol writers don’t get how difficult some of these asks will be for sites to execute,” he said, “nor do they understand that the patients that qualify for the trials they are designing don’t exist.”
Bechtel says some level of standardization of eligibility criteria can be a boon, as it gives sites a sense of what to expect from trial to trial and can help accelerate the protocol development process. But some criteria are so tight and restricting to enrollment that sponsors are forced to take another stab at the protocol design.
Luckily, organizations like SCRS do convene groups that deliver feedback on protocols to sponsors, and this can make a big difference, he said. Sponsors can be receptive enough to feedback to change their criteria, but it’s best when it arrives early and before the protocol goes live, he cautioned.
Once enrollment starts, it’s wise for sites to start recording the reasons why they fail to enroll, Gerber added. “This feedback to sponsors serves not only to explain local challenges but also may occasionally be incorporated into trial amendments.”
In Gerber’s view, small trials across a limited number of sites are the most likely to be open to site input, while larger trials across dozens of sites are likely more rigid. Still, with the current oncology landscape complicated by enrollment difficulties, feedback from sites that have firsthand experience with the disease being studied will likely be taken seriously, he believes.
In recent years, the FDA has issued guidance on eligibility criteria with a near exclusive focus on oncology, but in November 2020 published a final guidance on increasing trial diversity in general that addresses eligibility criteria. It’s also on record as a strong advocate for sponsors loosening their criteria where they can to improve trial access. Most recently, it released final guidance urging sponsors and investigators to allow patients who haven’t taken existing treatment options to join noncurable cancer trials (CenterWatch Weekly, Aug. 1).
For now, the oncology criteria development model presented by the multistakeholder working group presents 13 factors to be tackled in order:
- Disease stage;
- Performance status;
- Hematological parameters;
- Brain metastases;
- Liver function;
- Kidney function;
- Cardiac function;
- Hepatitis B and C viruses;
- “Other” (inclusion and exclusion criteria specifically pertaining to the investigational agent(s) of the trial); and
- Prior or concurrent cancer.
Stakeholders widely agreed that sponsors and investigators should first consider patient disease stage and histologic features, for example. But discussion on biomarkers, which involved both the biomarker results required of patients and the tests to obtain them, was not so straightforward and is still ongoing.
“If these changes are successful, they could make clinical trials for lung cancer, as well as other cancers, more powerful and more representative,” said Gerber. “Despite clinical differences among cancer types and stages, key principles of trial design — among them eligibility criteria — are similar across various malignancies. If this framework is found to be effective, similar approaches could be taken in other disease areas,” he said.
Access the JAMA Oncology article here: https://bit.ly/3BXiElN.