The FDA issued a series of guidances to increase enrollment in clinical trials by expanding eligibility criteria. Targeted at industry, the guidances provide information about designing trials that include groups of patients that are typically excluded, such as those with HIV, hepatitis, or other comorbidities.

Historically, cancer clinical trials have been highly selective, enrolling homogenous groups of patients to achieve clear efficacy and safety signals with the drugs they're testing. However, regulatory agencies are now attempting to broaden trial enrollment to increase patient access, speed up accrual, and better reflect patients typically seen in oncology practices. To this end, the FDA released a series of guidances that outline strategies to expand eligibility criteria.

“Cancer patients are often unnecessarily restricted from participating in trials,” says former FDA Commissioner Scott Gottlieb, MD. The goal of the guidances, he says, is “to shift the design of oncology clinical trials to be more representative of the patients that may ultimately benefit from novel treatments.”

Targeted at industry, the guidances provide information about designing trials that include patients with organ dysfunction or previous or concurrent malignancies, HIV or hepatitis B or C infections, and brain metastases, including considerations such as immune and organ function, medications patients may be taking, and the extent of metastases. The guidances also lay out dosage, safety, and ethical factors relevant to including children and adolescents in adult oncology trials.

The FDA guidances build on position statements from the American Society of Clinical Oncology and Friends of Cancer Research.

“Our goal is to be cautious, but also to be inclusive,” says Percy Ivy, MD, of the NCI, a coauthor of one of the statements. “It's a balancing act—you're trying to pick a population where you can get a clear, straightforward answer, and yet, at the same time, include the most patients.” Ivy adds that regulatory agencies are first broadening eligibility criteria when there is a strong scientific rationale for doing so.

For example, cancer trials often exclude patients with HIV even though newer HIV treatments have dramatically improved the health of these patients. “The reality is that it wouldn't make sense to exclude a patient just because there is a positivity when they are living a fulfilling life without any kind of restriction,” explains Fernanda Arnaldez, MD, also of the NCI. Similarly, recent research has shown that patients with brain metastases, another oft-excluded group, can benefit from trial therapies.

For Keith Flaherty, MD, of Massachusetts General Hospital in Boston, the guidances are a positive development. He notes that information on therapies is often confined to what is learned during clinical trials, “and we constrain eligibility in a way that really heightens this limited sampling problem.”

Flaherty adds, however, that there are other obstacles to increasing enrollment: For example, cost and logistical challenges limit participation by community-based practices. A possible solution, he notes, is to gather efficacy data from a range of patients after drugs are approved. “Basically, drugs get onto the market and then it's just a complete dark space. I think we would all feel much more comfortable that it's OK to do trials initially in quite constrained populations as long as you've got the ability to really monitor in the general population,” he says.

Charles Fuchs, MD, MPH, of Yale University in New Haven, CT, says that researchers need to be thoughtful about broadening trial participation. “I am all for the inclusion of patients with other comorbid conditions; we just have to be careful to do it in a way that doesn't confound or complicate the questions we're trying to ask,” he says, adding that trials should be designed to stratify patients based on comorbidities or other complicating medical conditions.

“The FDA guidances really offer a lot of interesting ideas about inclusivity, and that, I think, is important in expanding the impact of cancer research,” he says. “The next step is, how comfortable are investigators and industry sponsors going to be with designing studies like that?” –Catherine Caruso