MI ‘signal’ seen with one drug, but not others
Experts said they hoped a recent FDA advisory panel recommendation against requiring randomized controlled cardiovascular outcomes trials for new drugs to treat constipation associated with use of opioids would unblock the field for more such medications.
Opioid-induced constipation (OIC) “is a real problem,” said Eugene Viscusi, MD, professor of anesthesiology and director of acute pain management at Thomas Jefferson University, in Philadelphia. Additional drugs in development “are at a critical point that if the FDA required long-term studies, the market would be very limited.”
Many physicians are unaware that these drugs are available, while others have been concerned about cardiovascular risk, said Dr. Viscusi, who noted he has frequently prescribed the two FDA-approved peripherally acting opioid receptor antagonists (PAMORAs), methylnaltrexone bromide (Relistor, Salix) and alvimopan (Entereg, Cubist), with good results. The advisory committee’s conclusion “was the outcome I was hoping for,” he said. “There’s not really enough evidence that these long-term safety trials would be required. I’m now optimistic that additional drugs will become available for a very unmet need in the chronic pain community.”
Divided Panel
In a close decision following a lengthy meeting in June, 12 of the 24 panelists on the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted against requiring cardiovascular outcomes trials; seven recommended the agency require trials for all PAMORAs and five recommended the agency require trials for Entereg and similar biologics. The group largely agreed that cardiovascular studies can be conducted as postmarketing surveillance, with the exception of alvimopan, and they should last at least a year to sufficiently assess long-term outcomes.
Both alvimopan and methylnaltrexone bromide are approved only for specific situations. Alvimopan is restricted to hospitalized patients with postoperative ileus and capped at 15 doses, and only hospitals that register in the Entereg Access Support and Education (E.A.S.E.) program may offer the drug. Methylnaltrexone bromide is approved for short-term treatment in patients with advanced illness receiving palliative care.
Alvimopan’s restrictions stem from data from one clinical trial by former m anufacturer GlaxoSmithKline, which hinted at an increased risk for myocardial infarction (MI) associated with the drug. In that study, from the mid-2000s, seven patients taking alvimopan experienced MIs, compared with none taking placebo.
“Whether the [cardiovascular] signal is true or not, it is a signal about a major complication for an elective medication, and therefore it must be studied carefully,” said Mitchell Cappell, MD, PhD, section head of gastroenterology and hepatology at William Beaumont Hospital, in Royal Oak, Mich. “I do trust that the FDA will come to a fair, equitable decision to this dilemma.”
During the meeting, committee members heard from pharmaceutical companies Cubist, Salix, AstraZeneca/Nektar (manufacturer of naloxegol/Movantik, which is under review for FDA approval), Theravance (manufacturer of investigational PAMORA axelopran), Develco Pharma Schweiz (manufacturer of naloxone, approved for opioid overdose) and several physician consultants paid by the manufacturers. Manufacturers presented clinical trial data on their respective medications. Only alvimopan was shown to have any link to MI, and only in one trial testing the medication for long-term use. Cubist is not pursuing long-term use of the drug.
Bill McCarberg, MD, a consultant and president-elect of the American Academy of Pain Medicine, noted that although opioids are “lifesavers,” OIC is prevalent and laxatives often are not effective.
William Mezzanotte, MD, MPH, vice president for global medicines development at AstraZeneca, said the imbalance in MI seen with alvimopan has not been observed in any other trial of alvimopan, in trials of other PAMORAs or in the literature. “PAMORAS that demonstrate a favorable risk–benefit profile in Phase III studies can be safely approved for the treatment of chronic OIC in patients with noncancer pain without the need for cardiovascular outcomes trials,” Dr. Mezzanotte said.
For several hours, panelists debated whether the presented data suggested the presence of a cardiovascular safety signal associated with the drugs, whether the signal related to just alvimopan versus all PAMORAs and if the signal had a plausible biological explanation. Overall, the committee felt there was a signal, although moderate at most, from alvimopan and that there was insufficient information to determine the presence or absence of a class effect.
Dr. Cappell, who voted in favor of outcomes trials, said at the meeting that his decision would depend on cost. Randomized controlled trials can be “overly aggressive,” he noted, so he advocated for postmarketing observational studies.
But Milton Packer, MD, professor and chair of clinical sciences at the University of Texas Southwestern Medical Center, in Dallas, said trials are always feasible. An estimated 116 million Americans are in chronic pain, he said. Of those 116 million, 16% take opioids—and many of them wind up constipated and in need of treatment. “We routinely ask sponsors for cardiovascular outcomes trials when the consequences are a lot smaller than this one,” he said.
Sonia Hernndez-Daz, MD, DrPH, director of the pharmacoepidemiology program at the Harvard School of Public Health, in Boston, questioned whether the panel would have been convened at all except for the single, unreplicated GlaxoSmithKline trial.
There is no word yet on when the FDA will make its decision. “We cannot comment on future rulemaking,” said spokesman Jeff Ventura.