Published May 23, 2013
Merck & Co's experimental insomnia drug moved a step closer to U.S. approval on Wednesday after a panel of medical experts said it is effective and safe at lower doses.
The advisory panel was convened to help the U.S. Food and Drug Administration decide whether to approve the drug, suvorexant, which would be the first in a new class of sedatives that block chemicals in the brain called orexins that help keep people awake. The drugs are designed to help people fall asleep and stay asleep.
On Monday, the FDA's internal reviewers published a report expressing concern about suvorexant's potential to cause next-day sleepiness and impaired driving. They asked the committee to consider whether patients should be started at a lower dose than that recommended by Merck.
Merck proposed that elderly patients start by taking 15 milligrams of the drug and increase that to 30 if necessary. The company recommended non-elderly adults start on 20 milligrams and increase to 40 milligrams if needed.
On Wednesday, the FDA reiterated its opinion that there was little evidence in Merck's data to show that the higher dose was more effective than the lower dose, and considerable evidence to show it was less safe.
The FDA's reviewers pointed to an increase in the risk - especially at the higher doses - of suicidal thoughts and behaviors, impaired driving, and severe sleep disturbances.
Speaking for the FDA, Dr. Ronald Farkas noted cases in which patients had reported sleep paralysis and terrifying hallucinations. He also expressed the agency's concern about the drug's impact on driving.
"What we are trying to prevent is criminal prosecution of patients taking their drug as prescribed," he said.
The FDA's views were echoed by those of several patient advocacy groups.
"Like its predecessors, suvorexant's marginal benefit in extending overnight sleep time by a few minutes is achieved at the expense of prolonged, next-day drowsiness, with potentially fatal consequences," said Dr. Sammy Almashat, a researcher with Public Citizen's Health Research Group who noted that suvorexant stays in the body longer than all but one other sleep drug.
Still, the panel voted 13 to 3, with one abstention, that the drug could be used safely at the 15 and 20 milligram doses. It voted 8-7, with two abstentions, that the drug is not safe at 30 and 40 milligrams.
Merck celebrated the vote, saying in a statement that it was "excited about the potential of suvorexant as a new and different approach to treating insomnia."
The FDA is not bound to follow the advice of its advisory panels but typically does so.
The FDA had asked the panel to consider whether patients should start with a 10 milligram dose, saying data from a smaller trial showed that amount might work for some people. Merck disputed that, saying 10 milligrams would not be effective.
The FDA also asked the panel if Merck should conduct an additional trial to further evaluate a 10 milligram dose. The panel voted against that. Some agreed that 10 milligrams would not be effective. Others agreed in principal with a lower starting dose, but most said a new trial would not add meaningfully to the information already in hand.
"When you have something new you don't know everything you would like to know," said Dr. Christian Guilleminault, a professor at Stanford University School of Medicine. However, he added: "I'm not sure that doing another study is going to bring us much more."
The FDA's concerns come amid a broader review of the safety of sleeping pills following hundreds of reports of driving accidents involving people taking zolpidem, the active ingredient in Sanofi SA's Ambien.
About 60 million prescriptions for these drugs were written in the United States in 2011, according to healthcare research firm I.M.S. Of those, roughly 40 million contained zolpidem.
In January, the FDA told drugmakers they should lower the recommended dose of zolpidem in women to 5 milligrams from 10 for immediate-release products including Ambien, Edluar and Zolpimist. The agency said doses for extended-release products should also be cut in half.
Dr. Jason Todd, a panel member and staff neurologist at NorthEast Neurology in Concord, North Carolina, said patients are adjusting to the lower dosing recommendations for Ambien.
"Before the recent changes I almost never saw a patient who would take 5 milligrams and stay with it," he said. "Now that 5 milligrams is recommended people are OK with 5 milligrams."
The panel's ultimate recommendation surprised some analysts who had expected, based on the FDA's review, that the meeting would be more contentious.
"Based on the overall discussion today and the voting of the panel, we believe that the probability of FDA approval for suvorexant has gone up meaningfully," Mark Schoenebaum, an analyst at ISI Group, said in a research note.
Having said that, he said: "We admit that predicting a final FDA decision is difficult."