By Deborah Borfitz 

October 20, 2022 | For patients with lung cancer, meeting the eligibility criteria for clinical trials has been a major roadblock to their participation. Over time, studies have grown more complex and expensive and sponsors, eager to optimize the scientific yield of a trial, have become incredibly strict about who meets the enrollment requirements, according to David Gerber, M.D., associate director of clinical research at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center. 

In response to this untenable situation, the LUNGevity Foundation organized a group of investigators, regulatory authorities, advocates, and industry representatives to consider ways to simplify and harmonize eligibility criteria in clinical trials for advanced non-small cell lung cancer, says Gerber. Those recommendations will form the backbone of upcoming draft guidance to be issued by the U.S. Food and Drug Administration (FDA). 

Frustrated by some of the inefficiencies in the design and conduct of clinical trials, Gerber launched a research program more than a decade ago looking at entrenched practices around study eligibility, procedures, and drug interactions. He was invited to join and help lead the group effort to develop a framework for lung cancer clinical trial eligibility criteria, which was recently published in JAMA Oncology (DOI: 10.1001/jamaoncol.2022.1664) and if embraced by sponsors should make it easier to include more patients in their studies. 

Collaborators included clinicians and representatives from the pharmaceutical industry, the National Cancer Institute, the FDA, the European Medicines Agency, and the LUNGevity Foundation. The group has made provisional recommendations related to 13 eligibility criterion—from stage and histologic features of disease to prior or concurrent cancer. 

Their work serves as a model for similar efforts now underway for other cancers. But industry sponsors have historically been slow to change their ways, even when regulators attempt to steer them in new directions, notes Gerber. 

Nearly a decade ago, the FDA came out with final guidance on risk-based monitoring of clinical investigations, encouraging greater use of centralized monitoring practices that deemphasize on-site visits. Yet, until the COVID pandemic struck, industry almost unilaterally continued to require in-person study monitoring, says Gerber, who co-authored an editorial on this point last year (JCO Oncology Practice, DOI: 10.1200/OP.21.00524). 

The FDA guidance also states that less intent patient monitoring is acceptable when routine laboratory tests are being performed that don’t address a protocol-specified safety or efficacy endpoint. In other words, it isn’t always necessary to do central confirmation of tests that are commonly available and well done in a systematic fashion by local labs, he says, although this has long been the industry norm. 

Necessary Compromise 

Among the provisional recommendations made by the working group, specific to eligibility criteria for lung cancer trials, is that biomarker testing be “appropriately demonstrated.” The general language is a compromise, says Gerber. 

Clinicians favored allowing enrolling clinical trial sites to perform biomarker testing to save time, effort, and money, he continues. Industry representatives wanted more information about biomarker assays which, when used as part of the study screening process, are required to be clinically validated per FDA regulation. The group overall believed it may be sufficient for established companion diagnostics, when used for patient screening, to simply be centrally confirmed. 

Another recommendation on the final list is for study eligibility criteria to allow the inclusion of patients with prior or concurrent cancer if the earlier cancer won’t interfere with the safety or efficacy assessment of the investigational agent. This is a major departure from traditional clinical trial practices where individuals with prior cancers are broadly excluded from lung cancer studies, says Gerber, including stage 1 prostate cancer that is so common and slow-growing that the government no longer recommends men be universally screened. 

A third provisional recommendation makes clear that patients with treated and stable brain metastases may be enrolled in a lung cancer clinical trial. So, too, can patients with untreated, asymptomatic brain metastasis and those with leptomeningeal disease if there’s a low likelihood that they’ll need near-term central nervous system (CNS)-directed therapy and CNS activity of the study therapy is likely. 

“Brain metastases are very common in lung cancer,” notes Gerber, occurring in up to 40% of patients. It is also “very common for patients to have brain metastases at the time they are diagnosed, not because they have symptoms, but because a brain MRI [was performed that detected it].” 

The tumors may be incredibly small, on the order of 2-3 millimeters, and neither be causing symptoms nor likely to cause problems soon, he explains. Outside of a clinical trial, the treatment regimen of such patients wouldn’t start with radiation or surgery for the brain metastasis because it would unnecessarily delay the start of medical therapy to address the primary cancer. 

Perennial Issues 

As a medical oncologist and researcher, Gerber has firsthand experience with the realities of lung cancer clinical trials. He had a patient drive 90 minutes to discuss an enrolling study, only to be dissuaded by the required daily in-person visits for the first five days. 

On another occasion, Gerber had a patient with metastatic lung cancer who wanted to go on a trial for cancer treatment until he learned about the requirement that tissue from an earlier biopsy be submitted through central confirmation by the study sponsor, even though local testing had already demonstrated the needed enrollment biomarker. “Neither I as the treating physician nor the patient thought that a three-week delay was in his best interest.” 

Then there was the patient newly diagnosed with metastatic lung cancer who had hoped to enroll in a clinical trial, but Gerber couldn’t find a single study where he’d qualify because, four years earlier, he had stage 1 prostate cancer that was cured. “It was the only reason he wasn’t eligible for the trial,” says Gerber. “He didn’t have heart disease, he didn’t have bad lung disease, his kidney and liver function were good, his functional status was good, and I didn’t think it was in any way rational to exclude that patient.” 

Gerber knows of what he speaks, having conducted studies showing how common it is for clinical trials to exclude people with an earlier cancer—and how that doesn’t appear to interfere with subsequent studies for advanced cancer in terms of the ability to administer treatment safely and effectively or analyze the findings.  

Another perennial issue with eligibility criteria for lung cancer studies involves concomitant medications that might theoretically interact with the study medicine or affect the patient’s electrocardiogram, he adds. The problem is that lung cancer patients, who have an average age at diagnosis of 70 years, are typically on several medications. 

In their provisional recommendations for standardizing lung cancer eligibility criteria, the working group placed drug-drug interactions in a miscellaneous category with other criteria specific to the targeted agent and/or its mechanism of action that would require investigators and sponsors to draft trial-specific eligibility criteria. 

Complex and often overly restrictive inclusion and exclusion criteria have created substantial barriers to patient access to novel therapies, hindered efforts to recruit and retain participants, and limited generalizability of trial results, says Gerber. Fewer healthcare centers can conduct trials as currently designed. Even at centers where studies are offered, fewer patients match the eligibility criteria or are able to undergo the required procedures to enroll. 

While many studies today have layers of complexity and inefficiencies tied to the involvement of more intermediaries, technologies, and countries, oncology trials are inherently even more complicated because standard treatment can be onerous, he continues. Most other conditions, such as hypertension and diabetes, don’t require infusion therapy and frequent imaging tests and may also involve fewer blood draws. 

Pandemic-Inspired Policies 

Beyond eligibility criteria, which is the sole focus of the FDA’s forthcoming draft guidance for industry, many other inefficiencies have long plagued lung cancer clinical trials—some of which have been on hiatus during the COVID-19 pandemic, notes Gerber. The FDA and National Institutes of Health have issued guidance on possible adjustments to conventional clinical research practice during the COVID public health emergency that include remote consent, telehealth visits, off-site procedures, shipment of therapy, and remote study monitoring. 

For perspective, prior to COVID patients in oncology trials were generally required to pick up oral study drugs even if (as is often the case) they were already approved medicines, Gerber cites as an example. But now sponsors have leeway to ship study drugs directly to patients’ homes, as has been standard practice over the past two decades for patients on oral cancer therapies being treated outside of a trial who are doing well. 

Gerber has studied the perceptions of clinical research professionals to the multiple profound changes in clinical research now in place. In a survey that he conducted in May 2020 and again in November 2020, opinions about the COVID-19-related clinical research changes were generally favorable but not everyone felt that they should continue in the future (JCO Oncology Practice, DOI: 10.1200/OP.21.00169 and Journal of the National Comprehensive Cancer Network, DOI: 10.6004/jnccn.2020.7643). Notably, those more likely to recommend their continuance were people who had the greatest personal experience with the adjustments, and those who had been working in the field of clinical research for the longest. 

It is not yet known if the changes will remain once the COVID public health emergency is declared over, Gerber says. But some of those allowances relate not only to how regulatory authorities feel about things, but the willingness of insurance companies to continue paying for trial-related expenses that are part of standard cancer care, such as telehealth visits with patients. 

Insurers could decide to stop paying for virtual visits, or at least those happening between investigators and patients who live in different states, says Gerber. “The Oklahoma border is 90 minutes from here, for example, so it may not matter how the FDA and sponsors feel about trials if it is no longer feasible to use telehealth [in the context of] routine care.” 

A First Step 

The allowances to standard practices have been in place for two and a half years now and unquestionably improved the trial recruitment and retention situation relative to what it would otherwise be, Gerber says. But the pandemic also shifted resources to other priorities and helped fuel the “great resignation” across the clinical trial industry, leaving many clinical research centers understaffed as more of the job hunters seek, if not demand, remote positions. 

Had COVID not happened but the adjustments to conventional clinical research practices were nonetheless made, he says, “my very strong educated guess would be that we would be enrolling more patients into trials than before, and we’d be retaining more of them on those studies.” But the reality is that there was and still is a pandemic, and the newly published recommendations on how to determine eligibility criteria for lung cancer trials is but a first step in the right direction in filling studies and enabling a sufficiently diverse group of patients to participate. 

Importantly, study sponsors will also need to recognize the urgency to follow the FDA’s counsel to revise and simplify long-standing approaches to trial eligibility, Gerber quickly adds. As it is, only about 5% of all cancer patients enroll in a clinical trial, and just 11% of participants identify as a racial or ethnic minority.