Long-Term Opioid Efficacy Studies Will Take Years, Gottlieb Says

Trials will be mandated as part of new authority granted by SUPPORT Act and are intended to determine whether opioid efficacy decreases with long-term use.

Opioid manufacturers soon will be required to assess opioid efficacy changes during long-term use, but any labeling changes that may result likely are years away.

US FDA Commissioner Scott Gottlieb said the agency in "the next several months" will mandate that opioid manufacturers conduct randomized withdrawal studies to determine whether chronic use of opioids results in diminished efficacy. Those trials may be completed in a year, he told the House Appropriations Committee Subcommittee on Agriculture, Rural Development, FDA and Related Agencies Feb. 27.

But another year will be required before a read-out of the study results is available, Gottlieb added, meaning labeling changes should not be expected soon. He said the agency needs better evidence to justify any regulatory decisions.

"As much as it seems intuitive that there's declining efficacy with prolonged administration of opioids, and there is some evidence in the literature to suggest that, there isn't evidence that meets the statutory standard that we're required to meet in order to effect regulatory change," he told the subcommittee.

"We need to conduct rigorous, prospective, randomized trials," Gottlieb added. "Those do take time to conduct, but they can inform the basis for enduring regulatory change, which is what I think we need in this space."

The 2018 Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act, included additional postmarketing authority allowing FDA to mandate studies assessing whether efficacy changes over time.

The legislation also required FDA guidance on when postmarketing studies assessing a drug's efficacy reductions would be required and how the risk-benefit calculus may change. The guidance is due by Oct. 24.

Gottlieb appeared at the House hearing to discuss FDA operations following the government shutdown that encompassed parts of December and January. The agency was forced to adjust its inspection schedule because of the so-called "lapse period," but Gottlieb assured the committee that it will meet user fee goals for drugs and most other products. (See sidebar.)

Studies Could Help FDA Curb Long-Term Use

Gottlieb said further restrictions on long-term opioid use could be implemented depending on the study results.

"If we're able to demonstrate that there's a decline in effectiveness with prolonged administration of these drugs in rigorous studies, which is the types of studies that we're mandating, we could act to restrict the labels further to contraindicate certain use to narrow the circumstances when opioids could be used in a long-term fashion," he said.

The studies are not the first looking at long-term opioid use that FDA has required. In 2013, the agency mandated postmarketing studies of opioid products to evaluate long-term use, including the risk of developing increased sensitivity to pain and the potential for misuse, abuse, addiction, overdose and death.  (Also see " US FDA kicks 'moderate' out of ER/LA opioid pain indication, adds postmarket studies requirement " - Pink Sheet, 12 Sep, 2013.) A class-wide labeling change was finalized in 2014. (Also see "Regulating in an Era of Increasingly Sophisticated Medicines – Striking the Balance Between Patient Benefits and Risks" - Pink Sheet, 24 Apr, 2014.)

FDA released its Opioid Action Plan in 2016, which included adjustments to the 2013 postmarketing requirements. The plan also called for an advisory committee meeting before approving new opioids without abuse-deterrent properties. (Also see "FDA Opioid Action Plan Could Help Clear Califf Nomination Roadblock" - Pink Sheet, 8 Feb, 2016.)

In addition, FDA is working with the National Academies of Sciences, Engineering and Medicine to write evidence-based prescribing guidelines for opioid use and incorporate them into labeling, which may include clinical trials. (Also see "US FDA Likely Cannot Force Sponsors To Fund Opioid Prescribing Guideline Trials" - Pink Sheet, 28 Nov, 2018.)

2001 OxyContin Labeling Change Likely Wrong, Gottlieb Says

The subcommittee discussion began when Rep. Henry Cuellar, D-TX, asked why labeling of Purdue Pharma LP's OxyContin (oxycodone) was not changed after studies suggested negative long-term effects.

Gottlieb admitted that in a 2001 labeling change for the product that was intended to restrict its use likely backfired.

"I think in retrospect the agency probably got some of the wording in that change wrong," he said. "The agency at the time was trying to obviate the use of extended release drugs just to situations where patients had syndromes that required longer term use of opioids."

In 2001, the agency changed the OxyContin label to state that the drug was intended for management of moderate to severe pain when an around-the-clock opioid is needed for an extended period. The agency also wrote in the label that the product was not appropriate for "as needed" pain and added a boxed warning for dependence and abuse potential. (Also see "FDA Opioid Analgesic Labeling Guidance Will Highlight Drug Abuse Potential" - Pink Sheet, 30 Jul, 2001.)

Gottlieb intends to change the review paradigm for opioid products. As part of the approval of AcelRx Pharmaceuticals Inc.'s Dsuvia (sufentanil sublingual), he said FDA should no longer consider opioids independently, but in the context of the existing treatment armamentarium. (Also see "Dsuvia Approval May Be Followed By New Opioid Review Paradigm At FDA" - Pink Sheet, 2 Nov, 2018.)

FDA also wants to mandate packaging changes for opioid products to discourage physicians from prescribing more doses than necessary. (Also see "Opioid Packaging: Is Non-Inferiority Enough For A New Claim?" - Pink Sheet, 12 Dec, 2017.)

The agency's 2018 Strategic Policy Roadmap included several other opioid-related activities, including more research on abuse-deterrent formulations and their review. (Also see "Opioid, NME, And Generic Drugs Changes Plotted In US FDA's 2018 Policy Roadmap" - Pink Sheet, 24 Jan, 2018.)

An advisory committee also recently discussed over-the-counter availability of naloxone (Also see "OTC Switch For Naloxone Finding Interest Among Sponsors" - Pink Sheet, 19 Dec, 2018.), and FDA announced research grants to create clinical outcomes assessments for trials testing opioid sparring drugs for acute pain and other products. (Also see "US FDA Targets Migraine, Schizophrenia And Opioid Sparing Drugs For Clinical Outcome Assessment Development" - Pink Sheet, 25 Feb, 2019.)