Clinical Trials Need to be More Inclusive, Experts Say
Children, seniors, and chronic disease patients need more options
- Joyce Frieden,
WASHINGTON -- Clinical trial organizers should work to get traditionally excluded populations into clinical trials, several speakers said at a meeting sponsored by the FDA and Duke University.
Up to 59% of the U.S. population is comprised of people who are typically not included in clinical trials -- children, the elderly, and people with intellectual or physical disabilities, Catherine Spong, MD, deputy director of the National Institute for Child Health and Human Development, in Bethesda, Maryland, said Monday at a public workshop on evaluating inclusion and exclusion criteria in clinical trials. "If you look at all of these groups that are underrepresented ... a minority of people are included in research that's providing the evidence we so desperately need to help determine how to take care of people, so I think it's really important for us to take note."
In a Journal of the American Medical Association
"We clearly have the ability to include [these groups] but how do we make sure that actually happens, and how do we do that in a responsible way?" she asked. "[It's not right] to exclude someone just because it's not an easy population to deal with, or it's not an easy population to get consent for, or for a reason that might not be medically appropriate."
Children are a particularly difficult group when it comes to clinical trial inclusion. It's ironic that although children were the reason that several major drug-related laws were passed -- for example, the federal Food, Drug, and Cosmetic Act of 1938 was passed after 107 people, including many children, died from taking the antibiotic sulfanilamide -- children are now being excluded from drug trials that help determine whether a particular medication is safe to take, said Robert "Skip" Nelson, MD, PhD, senior director for pediatric drug development at Johnson & Johnson, in New Brunswick, New Jersey.
However, no one wants to have to expose children to drugs or devices unnecessarily, so researchers also should have other ways to take children into account, he said. "There is a moral obligation to design adult clinical trials to support pediatric extrapolation," he said. "If you're not putting kids into [a particular] trial, you need to think about how that trial can be used to extrapolate to kids."
Kathleen Neville, MD, director of the Experimental Therapeutics Program at Arkansas Children's Hospital in Little Rock, agreed. "If adult trials are set up with multiple doses, even with biologics and new treatments, we can extrapolate to children," she said. And if trials are performed on children, researchers should work to reduce the time lag -- often several years -- between the time the adult trial is run and another one is run on children. "Even if [the two trials] are not concurrent, there needs to be much less time lag."
Donna Cryer, president and CEO of the Global Liver Institute here, spoke for another constituency often left out of trials: patients with chronic illnesses such as chronic liver disease. "Using liver enzymes as exclusion [criteria] has serious implications," she said. "We need more sophisticated understanding of liver disease ... and of safety concerns that may derail therapeutics." She also argued against "permanent" screening failure for liver disease patients. Instead, Cryer suggested "allowing [patients] who may have failed an inclusion criteria like cutoff for liver enzymes, to try again to be included in the trial" by letting them be tested more than once.
Indeed, the exclusion of patients with any chronic disease from clinical trials can be a problem, said Anand Parekh, MD, MPH, chief medical advisor at the Bipartisan Policy Center here. "Most adults have a chronic condition; many have multiple chronic conditions," he said. For instance, "approximately 66% of Medicare beneficiaries have two or more chronic conditions; 15% have six or more. And individuals with chronic kidney disease will have on average five or more chronic conditions."
Their exclusion is particularly unfortunate, since "individuals with more chronic conditions were associated with higher willingness to participate" in clinical trials, Parekh said, citing a survey of 1,440 people.
One way to get around the exclusion issue is to have "expanded access" trials, in which patients who don't meet the inclusion criteria will still get to try the drug. But even there, questions remain. "Expanded access does [present] another opportunity to get data you can't get in a clinical trial setting," said Kumar Budur, MD, group medical director at AbbVie in Chicago. "One issue is how much safety data do you want to have before you feel comfortable [initiating] expanded access? We want to make sure we have some meaningful data before we approve expanded access."
There are several options for changing the way clinical trials are performed in order to include more people, said Rajeshwari Sridhara, PhD, director of the biometrics division in the biostatistics office at the FDA's Center for Drug Evaluation and Research. For example, trial participants can be stratified into low-risk and high-risk populations, and two trials could be performed: a randomized controlled trial on the low-risk population and a single-arm cohort trial on the high-risk population.
Another idea would be to perform a phase I safety study in the low-risk population and then, if no safety concerns arose, both low-risk and high-risk participants could eventually go into a phase III trial without stratification, Sridhara said. A third option would be to test the high-risk population in a post-marketing study; that might include the possibility of testing the approved dose of the drug against a lower dose.
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