COVID-Era Trial Flexibilities, Equity Focus, Could Be Used To Reshape Cancer Study Enrollment

Source : 'The Pink Sheet'

Clinical trial operational and design changes made due to the COVID-19 pandemic are likely to be harnessed to improve the diversity and generalizability of studies long after the current infectious disease outbreak has subsided, US Food and Drug Administration officials indicated.

The agency also hopes to capture some of the momentum from the attention the pandemic had drawn to health inequities in the US and use that focus to encourage more inclusive research.

“I think there are potential lessons and silver linings, so to speak from COIVD-19,” that if continued to be implemented “will have a benefit in terms of broader inclusion of older adults in clinical trials,” Harprett Singh, the associate director for cancer in older adults and special populations at FDA’s Oncology Center of Excellence said during the recent American Society of Clinical Oncology meeting.

“There have been calls to make clinical trials more patient-centered well before COVID-19 and FDA support has been long-standing of decentralization of clinical trials in terms of bringing trial assessments to where patients live and taking advantage of technology, but I do believe that the grand experiment, so to speak, of decentralizing or hybridizing clinical trials in the COVID-19 era will bring lessons forth that will benefit older adults,” Singh added.

While the majority of cancer cases occur in older adults, they tend to make up a small minority of trial participants and this has led to many elderly patients faring worse on the drugs than expected once approved. ("Real-World Data Of Cancer Drugs In Elderly Could Push Regulators Toward Broader Trial Eligibility" "Pink Sheet" )

Strategies that FDA laid out in guidance to help trials continue during COVID-19 that would likely be helpful long term in oncology research enrollment of older adults include allowing certain procedures to be done off-site such as using labs and imaging centers that are closer to patients, shipments of oral drugs or administering IV drugs locally when possible, obtaining remote consent, and using telemedicine when possible, Singh said.

The agency’s existing guidance encourages representation of older adults in all phases of development, including in early studies to inform dose selection and evaluate drug-drug interactions. This is also the ideal time to begin discussing a plan to improve trial representation for other adults and other populations often underrepresented in research.

To help improve study recruitment Singh said she “cannot overstate” the importance of recruiting investigators with expertise in care of adults with cancer. If older adults are not adequately represented in pre-market trials, collection of the data could be done using real world sources like an observational study or registry postmarket and such data could be used to update the geriatric section of the product label, Singh said.

The agency’s regulations “do not specifically provide mandates on what would be acceptable or unacceptable eligibility criteria,” said Lola Fashoyin-Aje, deputy division director and associate director of science and policy to address disparities in FDA’s Oncology Center of Excellence, in another ASCO session.

But she added that “approval of a drug is predicated on data that is pertinent to the study population and relevant to the US population and US medical practice,” and FDA leadership has recently signaled that it may be able to use this aspect of the regulation to require enrollment of particular study populations.("US FDA Exploring Options To Improve Study Of Drugs In Elderly" "Pink Sheet" )

COVID-19 has disproportionately impacted minority communities and those of lower socioeconomic status in the US, leading to a renewed focus on health equity, including getting more representative populations into cancer trials.

“Much of the discourse on diversity inclusion and equity in the past year has focused on addressing the systemic and structural inequities that racial and ethnic minorities face in society at large, including in clinical trials. These issues are long-standing ones, but the increased national and international light shone on these issues in the past year has provided renewed opportunity to examine practices and policies in health care, that contribute to disparities in access to care and outcomes,” said Fashoyin-Aje.

“As a health regulatory organization, primarily overseeing the development of investigational therapeutics for cancer and approving them and as a public health agency our primary interest is in ensuring that drugs we approve, are safe and effective for the intended population. And to do this, the data that are collected through clinical trials conducted as part of the drug development process should reflect the intended population to facilitate generalizability of study results,” she added.

“We really view the underrepresentation of certain subgroups in clinical trials that support FDA approval as a primary priority area for FDA to address,” she said.

Fashoyin-Aje noted that industry operationalization of FDA guidance to improve trial enrollment criteria “has been slow to occur.”

Fashoyin-Aje, said it will be important for to assess how some of the COVID-19 flexibilities “can be carried out successfully in the post-pandemic and across diverse populations."

"There is preliminary anecdotal evidence that underserved populations including those living in rural areas and older adults may not have the access to technology that is needed for things like telemedicine. Therefore as we collectively assess which measures to adopt as standard operating procedures it will be important to assess whether the successes we saw were observed across over all subgroups of patients.”

Fashoyin-Aje said it will also need to assess whether there is local site capacity for decentralized trials in clinical settings where a high proportion of underserved patient populations are treated.

“There may be opportunities for pharmaceutical companies to collaborate with each other and with institutions that deliver care to underserved populations to really strengthen the local infrastructure to support clinical trial decentralization and the OCE has discussed this type of approach with pharmaceutical sponsors,” she said.

But the solutions to getting different patient populations may not be as simple as they seem.

For example, Alison Magnuson, an assistant professor of medicine at University of Rochester Wilmot Cancer Institute, presented data at ASCO showing that while a recent analysis found that only about 10% of Phase III cancer trials included an upper age limit, the age gap is still persisting and in some cases getting worse due to other trial criteria like performance status.

Using performance status – an ECOG of 0 to 1  –  as eligibility criteria was associated with a larger age difference between the trial population and those affected with the disease. Yet she argued that performance status is subjective and investigators often assign older patients a worse status compared to younger patients despite there being no difference in their objective physical activity levels, she said.

Magnuson also noted that studies have shown that there is no association with the presence of an upper age limit or restrictive performance status and success of the trial, so sponsors shouldn’t fear that by being more inclusive their trials are more likely to fail.

“The FDA strongly endorses the idea that patients with performance status which is less than optimal,” and thus more reflective of the broader patient population, "should be included in clinical trials unless there is biologic or clinical rationale that justifies their exclusion, and even that should be constantly reassessed throughout the development program,” Singh said in response to Magnuson’s presentation.

By Sarah Karlin-Smith