NIMH Assesses Future Research Priorities

After results of two large clinical trials designed to guide treatment of depression and psychosis appear in the next three months, the National Institute of Mental Health (NIMH) must confront what to study in future trials and how best to study it.

NIMH funded the soon-to-be-published Sequenced Treatment Alternatives to Relieve Depression (STAR-D), the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), and two other conceptually similar studies. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) is still under way. Treatment for Adolescents with Depression Study (TADS) was published last year and set a standard for STAR-D and CATIE.

“If they are as conclusive as TADS, I'll be a very happy institute director,” said NIMH Director Thomas Insel, M.D., in an interview. The four studies, covering thousands of patients, marked a major shift in the institute's approach to clinical trials.

“Beginning five or six years ago, we changed the culture and moved away from classic efficacy randomized, controlled trials,” he said. NIMH invested $144 million in four large clinical trials designed to guide practical treatment. Given the results of the $17 million TADS, the only one of the four to be published to date, the investment was worthwhile, he added.

Focus Needs to Shift Away From FDA

Two questions looming for Insel and others involved in building the evidence base for psychiatric therapies are, What next? And who's paying for it? That next step should focus on large trials, designed simply, with substantial public health benefits, rather than on the safety and efficacy data needed for Food and Drug Administration (FDA) approval, suggested some researchers.

“Once the FDA approves a drug, deciding how it should be used in clinical practice is the job of the National Institutes of Health and the scientific community,” said Barry Lebowitz, Ph.D., a professor of psychiatry at the University of California, San Diego, and a former NIMH researcher. “In a large, simple trial, doctors learn the best ways to use a new drug in their usual patients, over the long term.”

Efficacy trials, conducted to support a new drug's application for FDA approval or to expand its indications, ask if the therapy works under ideal conditions. They use highly selective, relatively homogeneous samples and intensive, narrowly focused assessment strategies. Their smaller size, with patients numbering in the hundreds, is powered to detect differences of 20 percent to 30 percent, wrote John March, M.D., M.P.H., and five colleagues in the May American Journal of Psychiatry.

In contrast, practical clinical trials seek to find out the balance between benefit and harm in treatments as they are used in everyday clinical practice. They draw on a larger sample, typically 1,000 or more patients, to detect differences on the order of 2.5 percent to 10 percent. The greater number of patients is more likely to reveal both common (<1 in 500), uncommon (1 in 500 to 1 in 1000), and rare (1 in 10,000) adverse events than the smaller trials.

“Results in practice are often different— better or worse—than clinical trials,” said Lebowitz. “There's a broader range of settings and patients, so you're likely to see a broader range of results.”

Researchers' Support Expected

Researchers should favor the large practical trials and maintenance of an infrastructure to support and operate them, said March, a professor of child and adolescent psychiatry at Duke University and a principal investigator on TADS. These studies would be more generally applicable than industry-sponsored efficacy trials. They would include diverse patient populations, address questions that are clinically meaningful and adaptable to day-to-day clinical practice, and have enough statistical power to detect small to moderate effects, wrote March. (They chose the term “practical clinical trial,” although others have called such research “large, simple trials.”)

Such large trials have been used for years in cardiology and pediatric oncology, for example, said March. They have also appeared more recently in psychiatry. Britain's Bipolar Affective Disorder: Lithium Anticonvulsant Evaluation is now under way. The International Suicide Prevention Trial has recruited 980 patients at 56 sites in 11 countries to test the effects of clozapine and olanzapine in reducing suicidality.

The problem as both March and Insel see it is who will run the next set of big trials, and where will the money come from?

“The development of a stable, practical clinical-trial infrastructure, including establishing a coordinating center or centers, remains a necessary step toward the implementation of the practical clinical trials model in mental health care,” said March and colleagues. Such an infrastructure network can keep investigators on track with procedural consistency and uncomplicated documentation.

The NIMH created such networks to carry out its recent trials, but they won't necessarily continue beyond the trials' conclusions. An advisory group appointed by Insel is already discussing the question of how to continue the clinical trials networks.

“Should we retain the separate structures of STAR-D and the others or merge them into one network?” said Insel. “We've made a fairly large investment, and we're ready to build on it. The problem is funding.”

NIMH's budget received a big boost five or six years ago, but funding increases throughout NIH are flat now.

Pharmaceutical companies are “unlikely” to contribute to a clinical-trials network if results might put profits at risk, according to March. Insel doesn't rule out their participation, however, given recent reminders of the manufacturers' need to discover and report data on the outcomes of their products: “In a consortium arrangement with multiple companies, they could get something and we could get something that we all need.”

“A provision in the new Medicare act allows the Centers for Medicare and Medicaid Services to do comparative studies if it affects payment for drugs,” added Lebowitz. It “may be another good partner for NIMH.”

Deciding just what avenues to fund won't be easy either, said Insel. The institute's goal is to help clinicians make the right decisions for treatment, yet it's hard to predict years in advance which lines of inquiry will make the greatest impact. The NIMH advisory group will look into issues such as polypharmacy, comparing side effects, atypical antipsychotics and the metabolic syndrome, and how to predict which individuals will respond to a given treatment.

The report, “The Case for Practical Clinical Trials in Psychiatry,” is posted online at<http://ajp.psychiatryonline.org/cgi/content/full/162/5/836>.▪

Am J Psychiatry 2005 162 836