Once again, the opioid abuse crisis is putting a new FDA leader on the defensive.

As 2016 begins, FDA is hitting the reset button on its approach to prescription opioid pain drug regulation, announcing February 4 that it is initiating a “far-reaching action plan” to assess its approach to opioid medications. That plan was framed as a careful rethinking of the agency’s already extensive work in the area – though it was also more directly a response to “holds” placed on the confirmation of Robert Califf as FDA commissioner by Senate Democrats concerned about the agency’s recent and—as they see it—overly liberal policies regarding opioid pain therapies.

Califf’s potential tenure as commissioner is thus beginning on something like the same note as former Commissioner Margaret Hamburg’s, although the political dynamics are very different.

Hamburg’s nomination and confirmation were almost entirely uneventful at the start of the Obama Administration in 2009. However, once the Republicans took over Congress in 2011, Hamburg was greeted roughly by the new leadership when Appropriations Committee Chairman Hal Rogers (R-Kentucky) politely but unmistakably read her the riot act over the agency’s response to OxyContin abuse.

Over the next four years, Hamburg managed to steer a very careful path between the demands for access to effective treatments for chronic pain and the concerns about diversion and abuse—to the point that Rogers spoke warmly about her tenure when she left the agency a year ago. Also see "A Fitting Farewell: Hamburg Earns Praise From Rep. Rogers In Final Approps Hearing" - Pink Sheet, 16 March, 2015.

Now, however, it is two Senate Democrats Ed Markey (D-Mass.) and Joe Manchin (D-W.Va.), who threatened to block Califf’s appointment to succeed Hamburg because they aren’t happy with the balance FDA has struck.

The action plan announcement was made by Califf in his current role as Deputy Commissioner for Medical Products and Tobacco, “along with other FDA leaders.”

Key elements in the FDA plan include: re-assessing the benefit/risk approval framework for opioids, a new policy for consulting with advisory committees on opioids without abuse-deterrent properties and those for pediatric indications, stronger postmarketing requirements for extended-release/long-acting opioids, pending changes to the labeling for immediate-release opioids, and pending updates to the REMS for ER/LA opioids.

It also comes amid a much broader elevation in the national political dialogue about opioid abuse, which has been a prominent campaign theme in early Presidential primary states – most notably, New Hampshire. FDA’s announcement fits in with other Obama Administration efforts to highlight new actions, includinga White House proposal to invest $1.1 billion to address opioid abuse as part of the President’s final budget request.

Risk/Benefit Framework Will Be Starting Point

The most immediate milestone mentioned in FDA’s plan: the agency will seek advice from its Science Board March to re-assess the risk/benefit approval framework for opioid use. The agency is also building in a new incentive for abuse deterrent formulations by instituting a guaranteed advisory committee review for products that lack ADF features.

The risk/benefit review is part of an ongoing effort that goes to the core of opioid approvals and labeled indications. FDA notes that it is already working with the National Academy of Medicine for help developing a framework and taking into account risks of misuse by other people who obtain opioids.

The new advisory committee policy is an interesting twist on past practices. FDA says it will hold them before approving any NDA for an opioid that does not have abuse-deterrent properties, but will hold them for abuse-deterrent formulation opioids “when they raise novel issues.” In addition, they will consult with the Pediatric Advisory Committee on a framework for pediatric opioid labeling “before any new labeling is approved.”

The blanket policy here is important and should placate some of FDA’s critics, but it is not clear how exactly current practice will change. FDA’s recent practice has been to review ADFs—arguably because they all raise “novel issues”—while non ADF products are typically 505(b)(2) approvals without committee review.

The agency has taken heat for approvingPurdue Pharma LP’s OxyContin for certain pediatric patients in August 2013. FDA did not hold an advisory committee meeting for that supplemental application.

The other decision FDA has taken a lot of heat from was its approval of Zogenix Inc.’s Zohydro single-entity hydrocodone with no abuse-deterrent properties. That decision did go to an advisory committee, consistent with this new advisory committee policy. FDA, however, went against the committee’s vote in approving the drug.

Another concrete action: FDA is developing changes to the labeling for immediate release opioids, including warnings and safety info that “incorporate elements similar to” the ER/LA opioid labeling update that occurred in 2013. The plan stops short of explicitly calling for an IR REMS program analogous to the ER/LA class REMS.

In September 2013, FDA updated the labeling for ER/LA opioids, changing their indication to “for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate” and clarifying that they should be reserved for “use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain” and that they are “not indicated as an ad-needed” analgesic.

FDA says it does intend to update its REMS program requirement for the long-acting products. The agency will first consider advisory committee recommendations and a “review of existing requirements.” That presumably signals yet another upcoming committee review as part of the plan – and it should be an interesting one. FDA’s advisors previously discussed (and voted against) the REMS proposal in 2010.

Key among the committee’s objections in 2010 was the fact that the REMS did not include mandatory prescriber education and that it doesn’t apply to IR products.

FDA’s proposed “outcome” for this action item is to increase providers who receive training. FDA has been interested in mandatory prescriber education since the REMS was released in 2011 but has said it needs legislation to tie such education to DEA licensing. A number of bills have come forward to do that, but none have yet become law.

Revised Post-Marketing Study Requirements

The agency says it has already taken steps to update the post-marketing requirements for ER/LA opioids. FDA said in the press release for the action plan that it is strengthening requirements for postmarket data, and that it expects the requirements to lead to “the most comprehensive data ever collected in the field of pain medicine and treatments for opioid use disorder.”

FDA updated its Opioid Timeline webpage with an entry for February 4, saying that the agency “released five postmarketing (PMR) requirements announced on September 13, 2013 and replaced them with eleven PMRs (ten postmarketing studies and one clinical trial) because the ten postmarketing observational studies and one clinical trial include refined measures for assessing the known serious risks of misuse, abuse, addiction, overdose, and death.”

FDA also notes that it will issue draft guidance on recommendations for approval standards for generic abuse-deterrent formulations, and calls release of the guidance a “high priority.”

That may mean quicker release for the draft guidance, which has been on FDA’s regulatory agenda in 2015 and in 2016. The 2016 agenda also included a guidance on “In-vitro Methods for Evaluation of Abuse Deterrent Properties of Opioid Products.”

However, it bears noting that approval of generic versions of opioids moves counter to the broader pressure on FDA to restrict and limit availability. While there is plenty of outrage that brand companies may be profiting from evergreening opioid formulations, this is not a classic situation where generic approvals are a priority for FDA’s critics on the Democratic side.

The agency also says it is “reviewing options, including over-the-counter availability” to make naloxone more accessible to treat opioids and referred to its November approval of Narcan naloxone nasal spray. FDA has not yet approved an OTC product, but has approved the nasal spray and 2013’s Evzio auto-injector as easy-to-use formulations. Following Evzio approval, FDA said that it wasn’t approved as an OTC because the company did not submit an OTC application. FDA has been working in this area for years and interest in an OTC product has come up on Capitol Hill, particularly from Rep. Michael Burgess (R-Tex.).

The press release describes FDA’s “renewed effort” as falling within the context of the HHS evidence-based initiative on opioid abuse and as supportive of the CDC’s current work on guidelines for prescribing guidelines for chronic pain. The agency said it will provide updates on progress on regular basis.

The immediate reaction from Markey and Manchin was not positive – but the Senate is now scheduled to proceed with Califf’s nomination. That may be the most important first sign of success from the new policy.

FDA Opioid Action Plan Means More Advisory Committees And A New Look At REMS, PMRs

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