FDA Call to Action on Opioids Met With Skepticism

Alicia Ault

February 23, 2016

The US Food and Drug Administration's (FDA's) recent announcement that it would re-evaluate its labeling and review policies for opioids seems to be largely a political move designed to fend off congressional critics, say pain management and addiction medicine specialists.

The agency's action plan, announced on February 4, included a call for a re-examination of the risk-benefit paradigm for opioids, changes to immediate-release opioid labeling, improved access to naloxone, and new advisory committee meetings to address pediatric approval issues and any new opioid that does not have abuse-deterrent properties.

"It's obviously a reaction to the pressure they're getting from Congress," Edward Michna, MD, director of the Pain Trials Center at Brigham and Women's Hospital and instructor at Harvard Medical School, Boston, Massachusetts, told Medscape Medical News. Dr Michna, a board member of the American Pain Society, said he believes the FDA's plan doesn't go much beyond what it has already been doing.

Andrew Kolodny, MD, executive director for Physicians for Responsible Opioid Prescribing, said he believed that the FDA announcement was prompted by several senators announcing that they would block a vote on the nomination of Robert Califf, MD, for FDA commissioner. "This is, at least in part, a public relations effort," Dr Kolodny told Medscape Medical News.

Dr Califf's nomination was unanimously approved by a Senate committee in January. But a handful of senators then announced "holds" on the confirmation — an informal process that lets their colleagues know that they would filibuster the nomination when it went to the floor for a vote. Sen. Edward J. Markey (D-Mass) and Joe Manchin (D-WVa) both gave impassioned speeches opposing his nomination because of what they said was the FDA's weak response to opioid misuse.

The agency's plan did not alleviate concerns, said Sen. Markey, who vowed in a statement to continue his opposition "until the FDA commits to convene advisory committees of outside experts for all its opioid approval decisions."

The FDA's proposals are "a step in the right direction, but they are not enough given the devastating impact that opioid abuse and overdose death has had on our country," said Sen. Manchin, in a statement of his own.

The FDA declined a request for interviews for this report. In a call with reporters announcing the opioid plan, Dr Califf said it was not a direct response to the senatorial holds. However, he said, "it's fair to say we heard what Congress had to say."

On February 22, the Senate voted 80 to 6 to invoke cloture and move forward with Dr Califf's nomination as FDA commissioner, surpassing the 60 votes needed to invoke the procedure, and removing the holds that had been put on the proceedings. Senators Manchin and Markey were among those who voted "no" for cloture.

Despite the opposition, the Senate confirmed Dr Califf as FDA Commissioner earlier today.

Anger Over Lack of Advisory Panels

Congressional outrage began building in 2013, when the FDA approved the long-acting opioid single-entity hydrocodone bitartrate extended-release capsules (Zohydro ER, Zogenix). An advisory committee had voted 11-2 against approval, citing concerns about abuse.

Sen. Manchin specifically cited the Zohydro decision as an example of an agency misstep. He and Sen. Markey also said that advisory panels should have been convened for a number of more recent opioid approvals, including two in 2014: hydrocodone bitartrate ( Hysingla ER , Purdue Pharma) and oxycodone hydrochloride and naloxone hydrochloride extended-release tablets ( Targiniq ER , Purdue Pharma).

Members of Congress have also criticized the agency for its 2015 approval of OxyContin (Purdue Pharm) for pediatric use, a decision made without the input of a panel of outside experts.

Dr Michna called reactions to that approval "political grandstanding." He believes the agency followed the letter of the law in soliciting pediatric studies and carefully weighing the risk-benefit profile before awarding approval.

The FDA will now hold additional Pediatric Advisory Committee meetings to address opioid use in children and panel meetings for any opioid not in an abuse-deterrent form. That does not go far enough for the senators. "I believe the FDA should use the advisory committee's expert advice for all opioid medications, including abuse-deterrent formulations, which are just as addictive and can be just as deadly as non-abuse deterrent opioids," said Sen Manchin.

He also called on the FDA "to commit to adhering to the recommendations that the advisory committee puts forward."

Advisory panels for non–abuse-deterrent opioids are "totally meaningless" because all the opioids in development incorporate abuse-deterrent properties, said Dr Kolodny, who is also medical director of Phoenix House, New York, New York, a national nonprofit addiction treatment agency.

And abuse-deterrent forms don't discourage the most common way opioids are abused — orally, Kelly Clark, MD, president-elect of the American Society of Addiction Medicine (ASAM), told Medscape Medical News. "There is not an abuse deterrent for that approach," she said.

The FDA's call to action "is extremely important," given that opioid overdose is the leading cause of injury-related death, with 19,000 deaths a year, said Dr Clark. Two million Americans had a substance use disorder involving prescription pain relievers in 2014, and more than four million Americans over age 12 years reported current nonmedical use of pain relievers, according to the Substance Abuse and Mental Health Services Administration.

ASAM applauds the FDA's proposal to consider a risk evaluation and mitigation strategy (REMS) program for immediate-release opioids, said Dr Clark. The organization has sought an extension of REMS — put in place for long-acting opioids in 2012.

Dr Michna, who is also director of the Pain Trials Center at Brigham and Women's Hospital, agreed that REMS should be applied to all opioids. The FDA had taken on long-acting forms first because they were perceived to be the biggest problem, he said.

"I am not so critical of the FDA," said Dr Michna, adding that he thought the agency was on top of the opioid problem before other government entities.

What More Can the FDA Do?

Dr Kolodny thinks the FDA dropped the ball years ago by allowing almost unbridled marketing of opioids. "The bulk of prescribing is for conditions where the benefits don't outweigh the risks," he said.

The agency will be consulting with its Science Board and with the National Academy of Sciences to review the risks and benefits of opioids — which could be a "game changer," said Dr Kolodny, as it might end up narrowing the conditions that are appropriate for prescribing.

Dr Michna said he looks forward to getting more evidence to help guide prescribing, including which patients may be appropriate candidates for long-term use, and whether such use might be harmful. The FDA will require such long-term studies.

But he also said that physicians should be compensated for additional time spent on screening patients for risk for misuse and addiction and following up, including checking on prescription drug monitoring programs.

Dr Kolodny and Dr Clark, however, believe that there's no such thing as a screen to detect who might get into trouble with opioids.

Repeated exposure is what puts someone at risk for addiction, said Dr Kolodny. "We shouldn't teach prescribers we can turn [opioid use] into something that's safe and effective," he said, adding that he believed the class was not safe and effective for most conditions.

Dr Clark agreed. "The primary risk factor for a person to become addicted to opioids is they're human," she said.

Dr Michna reports that he has consulted for Purdue, Teva, and INSYS. Dr Kolodny and Dr Clark have disclosed no relevant financial relationships.

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