Revised definition of ‘clinical trials’ rattles autism researchers

Autism researchers in the United States are anxious about new government rules designed to boost the transparency of studies involving people. The red tape may paralyze promising projects, researchers say.

The U.S. National Institutes of Health (NIH) plans to enforce the new rules, which are based on a revised definition of ‘clinical trials,’ beginning in January 2018. The regulations would apply only to research funded by the agency.

The term ‘clinical trial’ has traditionally been reserved for studies testing drugs or behavioral therapies in people. But the new definition’s interpretation of ‘intervention’ and ‘outcome’ could apply even to studies of basic biological mechanisms.

What that means is that a brain imaging study that tests a person’s memory under conditions that interfere with memory might count as a clinical trial. This example has inflamed researchers because it seems far from clinical.

“By some readings of this case, virtually all basic research still counts as a clinical trial,” says Nancy Kanwisher, Walter A. Rosenblith Professor of Cognitive Neuroscience at the Massachusetts Institute of Technology (MIT).

Others’ comments are sharper, going so far as to call the new rules “frankly insane.”

The changes have been in the works for more than three years. But they mostly escaped researchers’ notice until August, when the agency released guidance on a rigorous new grant application.

Since then, more than 3,500 researchers have signed open letters to NIH director Francis Collins, urging the agency to seek more input from researchers before implementing the regulations.

In response to this overwhelming response, NIH officials revised the list of hypothetical studies in early September. But the guidelines are still ambiguous, researchers say.

Defining moments:

The NIH first released the revised definition of ‘clinical trial’ in 2014. The same year, the agency also proposed requiring researchers to register their results online. Agency staff invited feedback on these changes and received more than 200 comments from scientists and the general public. Many of the comments were supportive of the change.

The revised definition involves the four components that have always defined clinical trials, says Lawrence Scahill, professor of pediatrics at Emory University in Atlanta, who has worked on 18 clinical trials. Studies that meet the definition involve human participants, track an intervention’s effects, use a design that evaluates the outcomes of the intervention, and those outcomes are related to health or behavior.

“It’s not a brand-new chapter they’re opening up here,” Scahill says.

In 2016, using the comments and following a recommendation of the Government Accountability Office — a nonpartisan government watchdog group — agency officials announced that starting in January 2017, researchers conducting studies now defined as clinical trials must undergo clinical-practice training, register their studies at clinicaltrials.gov and report their results within a year of collecting their data. (Clinical trials begun before 2017 are not required to comply with the policy.)

These rules are designed to make sure researchers do not “needlessly duplicate results,” NIH officials said in an editorial published in the Journal of the American Medical Association after the changes were announced last year.

The agency has a duty to be a good steward of taxpayer money, Michael Lauer, deputy director for extramural research at the agency, told Spectrum. Results from more than half of NIH-funded trials are reported either late or never released publicly at all, Lauer says; this problem is well known.

Study volunteers should also get to see the results, Lauer adds. “People who participate in experiments think they’re contributing to science,” he says. If the results are never made public, “those participants are being misled.”

Missed signals:

Despite the protracted timeline, large numbers of researchers missed the rule changes and the call for comments, says Adina Roskies, Helman Family Distinguished Professor of Philosophy at Dartmouth College in New Hampshire. Roskies published a sharp critique of the policy changes in Neuron earlier this month.

“You’re not going to get the responses from the people who are actually being affected by this change who never knew the change applied to them,” she says.

Many researchers only caught wind of the revised regulations when, as guidance for the new grant applications, the NIH released a list of hypothetical studies that do or do not meet the new criteria for a clinical trial.

The rules have seeded enormous confusion among scientists. Lauer says he has received dozens of queries from researchers who want to know if the new regulations will affect their work. In about 90 percent of the cases, he says, the answer is ‘no.’

To address some of the confusion, he has explained the NIH’s concerns about transparency and clarified the differences between observational versus interventional studies in multiple blog posts on the agency’s website. Researchers have flooded the comments section of these posts to voice their worries.

The rules set a high entry bar for researchers involved in discovery science, which sometimes requires more open-ended hypotheses than clinical trials, Kanwisher wrote in one comment. And the regulations “will mislead the public, obstruct scientific progress and create mountains of red tape for everyone involved,” wrote Lauren Hallion, research assistant professor of psychology at the University of Pittsburgh.

Because the new definition of clinical trial no longer has the common-sense meaning it once had, it may also confuse participants into thinking they are helping to test treatments, says John Gabrieli, professor of brain and cognitive sciences at MIT.

Instead of trying to fit clinical standards to basic research, the NIH could have instead added reporting requirements to grant applications for basic research, some say.

“I think the problem arises when you try to take the basic behavioral science peg and squish it into the clinical trials hole; it just doesn’t really fit very well,” says Jeremy Wolfe, professor of ophthalmology and radiology at Harvard University.

In the meantime, NIH officials are continuing to answer scientists’ questions through email. “We see these as living documents,” Lauer says of the guidelines.