FDA Panel Rejects New Rule For Psychiatric Drug Testing

With a unanimous 12-0 vote, members of the U.S. Food and Drug Administration (FDA) Psychopharmacologic Drugs Advisory Committee (PDAC) told the agency to reverse its recently implemented requirement calling on drug companies to submit both short-term (eight to 12 week) and longer-term (more than six months) efficacy data as part of an initial application for approval to market a psychiatric medication.

The PDAC members expressed concern that the requirement would slow drug development and timely approval of new medications for the treatment of mental illness. In addition, they expressed concern over how longer-term data should be collected and by whom.

“We'll likely follow your advice,” said Thomas Laughren, M.D., acting director of the FDA's Division of Psychiatry Products. Laughren officially spoke for the agency at a day-long public hearing late last month.

Legally, the FDA is not bound by the votes of its advisory panels. Historically, it has nearly always followed its committees' leads, although there have been notable exceptions recently in areas other than psychiatric drug products.

The unanimous “no” vote was in response to the first of a list of 12 questions Laughren had submitted to the PDAC for its consideration. Of the 12 questions (some multipart), formal votes were requested for four, with the remainder of the questions intended only to generate discussion. The PDAC's answer to the first question, “Is it a reasonable expectation that a sponsor would have accumulated data for both acute and longer-term efficacy trials at the time of filing of an application for a drug treatment for major depressive disorder?” seemed to be a foregone conclusion nearly from the outset of the hearing. Indeed, of those speaking throughout the hearing, Laughren seemed to be the only one who supported the notion.

Yet, several members of the PDAC expressed concern over how the public might view the panel's “no” vote. Some members said they feared that the panel's vote would be considered a rebuke to the FDA for attempting to require “a higher standard of evidence” for approval of psychiatric medications.

In an unusual move, the PDAC unanimously voted to approve the release of a public statement saying: “The advisory committee recognizes the need for evidence to inform clinical practice regarding long-term treatment efficacy, without potentially slowing progress of new drug development. We encourage collaborative efforts by industry, the National Institutes of Health, and the FDA to further research on long-term treatment.”

At the end of the day, the remaining questions that the FDA had presented to the PDAC were not directly addressed, and no further votes were taken.

An unusual coalition involving 10 pharmaceutical companies (all of which are direct competitors in the psychiatric drug market) provided nearly three hours of joint testimony on how the requirement for long-term data at the time of initial filing would effect the drug-development process. The overwhelming message was that the requirement would significantly slow down drug development, perhaps obstructing it altogether. Bringing psychiatric medications to the market would take longer and be more costly, the companies said.

“Both acute and long-term efficacy data are needed for psychiatric disorders that are recurrent or chronic; everyone agrees with that,” said Frederick Goodwin, M.D., a professor of psychiatry at George Washington University, who introduced the companies' joint testimony. “But [an indication to treat an acute episode and an indication for maintenance treatment] are very different indications and should not be made interdependent.”

Yet, FDA's Laughren argued throughout the day for requiring“ longer-term data,” saying at the outset that “most psychiatric illnesses are chronic, and all psychiatric illnesses for which psychiatric drugs have approved indications in the U.S. are chronic.”

Even so, he emphasized, all of the drugs currently approved for psychiatric illnesses gained their approvals with short-term efficacy data (generally eight to 12 weeks). In contrast, he noted, “most treatment guidelines for chronic psychiatric illness” recommend between four and six months of medication treatment.

“Clinicians,” he said, “have generally not had sufficient evidence base to support what is the standard of practice.”

Regulatory Environment Shifting

Prior to six months ago, new medications for psychiatric indications were routinely approved on the basis of two randomized, placebo-controlled clinical trials, lasting eight to 12 weeks, that showed a drug was efficacious for the indication sought and safe to use.

Recognizing the need for longer-term data, the FDA increasingly over the last several years has added postmarketing research commitments (commonly known as Phase IV clinical trials) to drug-approval letters. Phase IV commitments have often included requests to complete longer-term studies generally ranging from six to 12 months and focused on maintenance of efficacy and/or relapse prevention.

On new drug applications (NDAs) for medications to treat mental illnesses, the FDA has often asked drug companies to complete “randomized withdrawal studies” in which patients receive initial treatment on an open-label basis for a minimum period. Those patients who meet response criteria and remain stable are then randomly assigned to either continue on medication or switch to placebo. The endpoint in this type of trial is usually either time to relapse or some measure of relapse rate.

However, beyond requirements for pediatric studies (imposed under the Pediatric Research Equity Act of 2003), Laughren reminded committee members,“ I'm not aware of any regulatory way to enforce Phase IV requirements.”

Simply put, the FDA can ask manufacturers to complete Phase IV commitments, but has no regulatory authority to require their completion. As a result, many requested studies have not been completed in a timely manner, and some have not been completed at all.

Laughren said he would estimate that “70 percent to 80 percent of requests for Phase IV studies are completed by manufacturers; however, it often takes three to five years for the FDA to get the data.” Industry representatives at the hearing generally agreed with those statements.

Last spring, however, the FDA began asking drug manufacturers to submit evidence of both short-term and long-term efficacy for drugs intended to treat mental illness at the time the company submits its NDA, rather than on the tail end of the approval process.

“[The FDA] has been thinking about this issue for a long time,” Laughren said. The agency, he continued, has over the last six months required data from a randomized withdrawal trial in which patients who have responded to the medication have been stable for at least six months prior to being randomized to continue medication or switched to placebo. After patients are randomized, they must be followed for at least six months, making the minimum duration of the clinical trial one year.

“This proposed policy has been met with considerable resistance and questions,” Laughren told PDAC members, “and for this reason, we thought it would be useful to bring this general issue to the committee for discussion.”

In essence, Laughren was asking the PDAC to endorse the proposed policy, giving the agency's efforts to collect long-term data more credence.

Longer-Term Studies Disease-Centric

The PDAC's discussion of the proposed up-front requirement for long-term data was so heavily weighted against endorsing the requirement that PDAC chair, Wayne Goodman, M.D., a professor of psychiatry at the University of Florida College of Medicine, challenged committee members to discuss any possible benefit to voting yes, “if only to play devil's advocate.”

It appeared that no one discounted the need for long-term data on the effectiveness and safety of psychiatric medications; however, several PDAC members questioned Laughren on the intention behind bringing the question before the advisory committee. PDAC consumer representative Jean Bronstein, R.N., M.S., asked, “Is the intent here simply to give the FDA stronger teeth to require long-term data?”

Laughren responded, “The issue is [that] we know that clinicians are going to prescribe these medications long term, if they are working for a patient. Right now, that prescribing is done without the benefit of any data.”

He noted that other countries already require drug manufacturers to submit long-term data, most notably the European Union (Original article: see box).

The majority of the discussion then appeared to center around two key questions: How should long-term data be collected? And who should be responsible for collecting it?

Nearly all of those who spoke at the meeting expressed concern that a blanket requirement for long-term data would prove problematic. The primary reason cited was the vast differences in treatment response both with different medications in the same disorder and between different disorders. Many expressed the need to tailor long-term research to specific disorders, using different methods or different types of studies in different disorders.

With respect to who should collect long-term data, PDAC members noted that it is already actively collected in large “real-world” effectiveness trials funded by the National Institute of Mental Health (NIMH), such as the recently reported data on antipsychotic medications from the CATIE trial (Psychiatric News, October 21). NIMH has conducted large effectiveness trials of medications for depression, bipolar disorder, schizophrenia, and Alzheimer's disease.

“That's what NIMH is for though, it fills that role,” said PDAC Chair Goodman.

That prompted a quick, but light response from Matthew Rudorfer, M.D., acting chief of the Adult Treatment and Preventive Interventions Research Branch at NIMH. “They wouldn't let me bring the checkbook today,” said Rudorfer, who is also a voting member of the PDAC.

More seriously, he continued, “Some forms of research are better at framing different questions. The regulatory setting is good for acute efficacy data, but maybe it is not the right venue for getting at the longer-term data.”

Information on the public advisory committee hearing is posted at<www.fda.gov/ohrms/dockets/ac/cder05.html#Psychopharmacologic>.▪