Clinical Trial Patient Inclusion and Exclusion Criteria Need an Overhaul, Say Experts

April 23, 2018

Clinical trial patient inclusion and exclusion criteria are far too rigid, often based on outdated notions, and the whole subject needs to be reimagined to include a more representative sample of the population.

That was the consensus at a public workshop sponsored by the FDA and Duke University last week that evaluated inclusion and exclusion criteria.

The inclusion of individuals who have what has been traditionally seen as confounding conditions makes research harder to do, but the result is study outcomes that more accurately reflect the population, said many who spoke at the meeting.

Another common thread: More inclusive studies also assure populations typically excluded from studies that the drugs that get approved are safe for them specifically because they were represented in the trials.

Up to 59 percent of the U.S. population is made of groups who are usually not included in clinical trials, said Catherine Spong, deputy director of the National Institute for Child Health and Human Development (NICHD) at the meeting.

The groups most often excluded? Children, the elderly, pregnant women, lactating women, people with chronic diseases, people with intellectual or physical disabilities, people with mental health diagnoses and those in organ failure, said Spong and others at the meeting.

Explained Dawn Corbett, inclusion policy officer in the National Institutes of Health’s Office of Extramural Research, NIH’s research on exclusion shows that those who take part in research are younger and healthier than the population that will eventually have access to the drug beings studied. They are also more heavily skewed toward Caucasians.

To move toward more inclusiveness, Corbett said, the research sector has to stop relying on “cut and paste exclusions” — just using the exclusion guidelines that have often been employed in the past instead of thinking through the exclusions that actually make sense for individual studies.

“We have exclusion criteria that are unjustified,” said Rebecca Dresser, medical ethicist and professor at Washington University in St. Louis, and author of the 2017 book Silent Partners: Human Subjects and Research Ethics. “They are bad when based on tradition or a narrow minded view.”

For example, children have historically been left out of trials due to research gone awry in the 1930s that resulted in more than 100 deaths. The 1938 Food, Drug, and Cosmetic Act has kept kids out of trials that may harm them.

But, now kids are excluded from trials that help determine whether medicines are safe for them, said Robert “Skip” Nelson, senior director for pediatric drug development at Johnson & Johnson. That leaves researchers having to extrapolate results from adults onto kids, which is an inexact science, to say the least. And it leaves kids taking medicines at doses that may not be right for them.

Seniors are usually left out of trials too, because of the oft-used cut-and-paste inclusion stand-by of “18 to 65,” said Mark Supiano, chief of the geriatrics division at the University of Utah School of Medicine. The irony there is that so many drug therapies are aimed at seniors and their functionality. To better target seniors, researchers have to be better about including them, he said.

“We can’t just extrapolate from the adult population of 40 year olds to 80 and 90 year olds,” Supiano said. “We need to have involvement early on in order to get these functional measures across. I encourage the early involvement of experts in geriatrics and gerontology in the design of trials cross the lifespan.”

The exclusion of patients with chronic diseases also makes little sense but it is common, said Anand Parekh, chief medical advisor at the Bipartisan Policy Center. Parekh said that approximately 66 percent of Medicare beneficiaries have two or more chronic conditions, and that 15 percent have six or more. And they are usually excluded from research, though this is the population that has shown it is quite willing to participate in research, according to a recent survey of 1,440 people, he said.

To be more inclusive, one could place participants into low-risk and high-risk groups and perform essentially two trials, one using a randomized controlled method and the other, a single-arm cohort trial, suggested Rajeshwari Sridhara, director of the biometrics division in the biostatistics office at the FDA’s Center for Drug Evaluation and Research.

Or, he said, researchers could consider performing a phase I study in the low-risk group only, and if all went well, marry high-risk and low-risk groups for the phase III study.

While those in the field consider new, more inclusive designs and approaches, those who watch the space say it’s going to take more of a large, cultural shift.

“We need to think through this and not just look for the easiest people to get into the study,” said the NIH’s Corbett. “We understand that this is going to take more effort, but while we make our trials easier, we’re limiting the external validity of them. This is really going to be a culture change for us. It’s going to take the entire scientific community.”

 -By Suz Redfearn