Opioids: FDA Actions May Silence Call For Moratorium On Approvals

Citizen petition seeks review of all marketed opioids; agency is considering whether new opioids should have comparative benefit over existing drugs.

Public Citizen's call for the US FDA to halt approval of new opioids is unlikely to gain traction given the steps the agency is taking to change the framework for their approval.

Public Citizen and Raeford Brown, chair of FDA's Anesthetic and Analgesic Drug Products Advisory Committee, submitted a citizen petition to FDA calling for a moratorium on approval of new opioids and new opioid formulations until FDA implements recommendations of the National Academies of Sciences, Engineering, and Medicine (NASEM) issued in its July 2017 report on pain management and the opioid epidemic.

They specifically cite the recommendations that FDA complete a review of the safety and effectiveness of all approved opioids and  that the agency incorporate public health considerations into opioid-related regulatory decisions. (Also see "New Opioids: FDA Should Ditch 'Product-Specific Approach,' Science Report Says" - Pink Sheet, 14 Jul, 2017.)

FDA began pursuing the latter recommendation before NASEM's report came out. As one of his first acts as commissioner, Scott Gottlieb announced the formation of the Opioid Policy Steering Committee. One of its initial tasks was to determine if FDA is using the proper policy framework to adequately consider the risk of abuse and misuse as part of the review process. (Also see "Opioid Policy At US FDA To Become 'More Forceful,' Gottlieb Says" - Pink Sheet, 23 May, 2017.)

FDA is considering a framework to evaluate whether new opioid drugs "should offer some comparative benefit over existing drugs."

The committee led a meeting in 2018 to solicit input on how FDA could assist in more appropriate prescribing. And it helped the agency in its work with Congress to expand FDA's authorities included in the Substance Use-Disorder Prevention that Promotes Opioid Recovery and Treatment (SUPPORT) for Patients and Communities Act. Enacted into law in October, the legislation allows FDA to require that a drug be made available in unit dose packaging, among other things.

Last month, Gottlieb issued a statement on FDA's 2019 opioid policy in which he noted that in 2018 the agency also opened a dialogue around the potential for evaluating the comparative benefits and risks of new opioids relative to to other opioids already on the market.

The FDA is "taking new steps to consider a framework to allow us to formally evaluate each candidate opioid in the context of how a novel opioid might fit into the overall therapeutic armamentarium that's available to patients and providers and address the question we're frequently asked as to whether new opioid drugs should offer some comparative benefit over existing drugs," Gottlieb said. "This process could include seeking revisions to statutory authorities to allow us to change the weight we give to meaningful therapeutic differentiation for proposed new opioids, including relative safety or effectiveness advantages over existing treatments."

'Mayhem' Will Continue Without FDA Changes, Ad Com Chair Says

Public Citizen's petition seems geared to focusing attention on the agency's recent approval of AcelRx Pharmaceuticals Inc.'s Dsuvia (sufentail sublingual) rather than actually obtaining a moratorium on approvals.

In a March 21 press call announcing the submission of the petition, Brown and Sidney Wolfe, founder and senior adviser of Public Citizen's Health Research Group, cited the approvals of Dsuvia and Endo Pharmaceuticals Inc.'s reformulated Opana ER as evidence that the agency's current regulatory process is deficient.

Brown said FDA has yet to respond with substantial changes suggested by the National Academies. "If the agency does not change and continues to fail to act on the expert reports that they have in hand, we will continue to observe mayhem related to the public health," Brown stated.

In the very unlikely event that FDA did impose a moratorium on approvals, there is at least one drug application pending at the agency that could be impacted. Nektar Therapeutics' novel mu-opioid agonist NKTR-181 for treatment of opioid-naïve chronic low back pain has an Aug. 29 user fee goal date following a three-month extension. 

Disputing Dsuvia Approval

Public Citizen has issued numerous petitions over the years asking the agency to withdraw drugs from the market or add warnings to drug labeling. The current petition is unusual in that it is co-authored by an FDA advisory committee member. However, Brown, a professor of anesthesiology and pediatrics at the University of Kentucky/Kentucky Children's Hospital, has been an outspoken critic of FDA's opioid policies.

Brown objected to the agency's approval of Dsuvia, predicting that it would lead to diversion, abuse and death within the early months of its availability. (Also see "Public Citizen: US FDA Deliberately Excluded Risk Committee From Dsuvia Panel To Get Positive Vote" - Pink Sheet, 18 Oct, 2018.) He has also criticized FDA for a lack of transparency in its regulatory decision-making process for opioids. (Also see "Opioid Sponsors Enter 2019 At A Crossroads" - Pink Sheet, 31 Dec, 2018.)

The agency's Nov. 2 approval of Dsuvia was controversial as FDA did not convene the full Drug Safety and Risk Management Advisory Committee to evaluate the drug. That committee usually meets with the Anesthetic and Analgesic Drug Products panel to review opioids. In another unsual move, FDA Commissioner Scott Gottlieb defended the approval in a statement explaining the agency's view both on Dsuvia and opioids more broadly. (Also see "Dsuvia Approval May Be Followed By New Opioid Review Paradigm At FDA" - Pink Sheet, 2 Nov, 2018.) 

The petition says FDA and AcelRx did not present information at the advisory committee about previously identified and published risks of intravenous sufentanil diversion and abuse by health care professionals. In addition, it says approval of Dsuvia was predicated on the existence of an opioid REMS, but previous opioid REMS have been unsuccessful in preventing off-label use.

The petition also took issue with Gottlieb's statement that Dsuvia has potential new uses on the battlefield. The Department of Defense supported the development of the drug for use in soldiers injured on the battlefield. But the petition says the NDA was not supported by any controlled clinical trials involving major trauma patients whose injuries would mimic battlefield injuries and the label does not include this indication.

Two members of Congress expressed concern about the approval of Dsuvia. In a Feb. 12 letter to Gottlieb, Sen. Eward Markey, D-MA, and Rep. Diana DeGette, D-CO, requested documents relating to the approval process, including communication between FDA and the US Army Medical Research and Material Command and communications disinviting members of the Drug Safety and Risk Management Advisory Committee to the meeting reviewing Dsuvia.

'Off-Target' On Opana ER

Regarding reformulated Opana ER, the petition says FDA did not appropriately consider documented evidence of the high potential of diversion and intravenous abuse that was available at the time of its approval, and did not act promptly to remove it from the market. The petition also notes that the agency did not convene an advisory committee prior to its approval.

FDA asked Endo to withdraw Opana ER from the market in June 2017 because the drug's reformulation in 2011 resulted in a shift in the preferred route of abuse from intranasal to intravenous. (Also see "Opana ER Should Come Off The US Market, FDA Tells Endo" - Pink Sheet, 8 Jun, 2017.)

The petition quotes a statement Center for Drug Evaluation and Research Director Janet Woodcock made at that time, in which she said the agency made a decision to request Opana ER's withdrawal when it "determined that the product had dangerous unintended consequences."

Woodcock's perception of what constituted timely regulatory action is "dangerously off-target and irresponsible," the petition says.

Wolfe went further in the press call, suggesting Woodcock be replaced. "I think, and this may sound harsh but I've been doing this a long time, I think that getting a new director of drugs at FDA would be an important step while the moratorium is on to ensure that the moratorium will be usefully spent developing this now delayed regulatory framework for opioids," he stated.

Gottlieb's Impact On Opioid Crisis

The petition comes as Gottlieb is set to leave the agency. He made tackling the opioid epidemic one of the primary focuses of his tenure.

In addition to establishing an Opioid Steering Committee, he advocated for new prescribing guidelines and packaging of immediate release opioid pills in blister packages, and called for new trials to assess long-term efficacy. (Also see "Long-Term Opioid Efficacy Studies Will Take Years, Gottlieb Says" - Pink Sheet, 28 Feb, 2019.) He also sought to change the rhetoric on the opioid crisis, focusing on how to prevent new addiction. (Also see "Initiator Or Facilitator? Gottlieb Reflects On First Year As Head Of US FDA" - Pink Sheet, 11 May, 2018.)

In FDA's congressional justification for its fiscal year 2020 budget request, FDA noted new opioids initiatives it intends to implement. They include a "comprehensive systems model of the opioid crisis" and collection and analysis of preclinical, clinical, and real-world data to determine safer analgesic packaging and rational prescribing through evidence-based treatment guidelines. (Also see "Opioids, Old Initiatives Dominate FY 2020 US FDA Funding Increase" - Pink Sheet, 18 Mar, 2019.)