A finalized Risk Evaluation and Mitigation Strategy for opioids is a long way off - possibly more than a year - and FDA expects additional stakeholder and industry meetings, as well as a multidisciplinary advisory committee to take place before a program is set in stone.

"We've learned from our experience with risk management programs and our experience over the last year with REMS that putting together a complicated REMS program is a time-consuming enterprise," said FDA Office of New Drugs Director John Jenkins.

"There needs to be time spent by the manufacturers putting together the proposed program; they need to submit it to us; we need time to review it; there's often a lot of back-and-forth comments and revisions that need to occur," he continued. "So this is not something that can be done very quickly."

Largest REMS Ever

At a press conference that followed the agency's public meeting on May 27-28 regarding the development of an opioid REMS, Jenkins attempted to delicately answer the question of what FDA can realistically accomplish for the REMS this year.

"Keep in mind the scale of this program is worlds of magnitude larger than the previous largest risk management program with restricted distribution," Jenkins said, referring to the acne drug isotretinoin(Roche's Accutane and generics).

Last year there were 20,000 isotretinoin prescribers and roughly 1 million prescriptions filled, compared to sustained-release opioids, for which there were 375,000 prescribers and 26 million prescriptions doled out.

If FDA was to broaden the REMS to include the entire opioid class, the program would account for approximately 200 million prescriptions per year.

"So if nothing else, just the time it would take to put in place training program for the prescribers - I think we heard 60,00 pharmacies in the U.S. - it is a major undertaking that will take time."

At the outset of the opioid REMS development, the agency estimated it would take approximately 120 days to implement such a plan. But after the public meeting, it became clear that its task is much bigger than originally thought.

"FDA should consider an extended development period due to the unprecedented level of multi-sponsor involvement," said Karla Anderson, managing director, Life Sciences Commercial Operations at BearingPoint. "The time and effort needed increases exponentially with the number of manufacturers."

It took three years to develop Accutane's iPledge program, which replaced a previous version, and Anderson estimated that it would take at least a year to develop a REMS for opioids.

For sponsors, the extended development timeline prolongs their uncertainly, but also creates more opportunities to influence the process.

Quick Fixes In The Interim

But all this is not to say the agency will not take action and implement some quick fixes while the mammoth REMS is being finalized.

"We plan to work through it as expeditiously as we can," Jenkins said. "One of our goals when we go back and regroup and start thinking about what we heard, is are there short-term, deliverable goals - even independent of a required REMS - that we can undertake to try to start having an impact now."

One quick fix advocates of greater restrictions on opioids suggested at the meeting is changing labeling so that the drugs would only be available to cancer patients and through compassionate use to non-cancer patients.

At the other end of the spectrum, the National Pain Foundation called on FDA to expedite the approval of abuse-resistant opioids pending at the agency. FDA said the drugs already have priority status, and they could come on the market even before the REMS is being finalized, but they remain unapproved because their tamper-proof claims are being verified (see ¹ Also see "Opioids Pending At FDA Held Up By Anti-Abuse Claims, Not REMS Planning" - Pink Sheet, 8 June, 2009.).

The meeting also featured suggestions about what the design of the final REMS program should be.

Pharmaceutical companies suggested piggybacking a prescriber/dispenser certification program onto the Drug Enforcement Administration registration program (² Also see "REMS For Opioids: Industry Considering Prescriber, Dispenser Certification" - Pink Sheet, 28 May, 2009.).

Other presenters more involved in law enforcement stressed the need for the REMS to include increased efforts of drug diversion ³ Also see "Opioid REMS Should Go Further And Focus On Drug Diversion, Consultants Say" - Pink Sheet, 28 May, 2009.).

Many presenters at the meeting touted a pilot program as a way to "test" certain proposed components, but FDA was not too keen on how to go about implementing one (⁴ Also see "Opioid REMS Pilot Program Urged At Public Meeting" - Pink Sheet, 27 May, 2009.).

Who Will FDA Side With?

The creation of this REMS sets a precedence in that it is not only trying to control the risks associated with opioids for legitimate patients, but also for non-patients who abuse the drugs.

This unusual dynamic has pit patient and drug advocates against one another, with one side calling for the drugs to be taken off the market and the other side asking the agency to recognize the need for the drugs to remain accessible (⁵ Also see "REMS Meeting For Opioids Shows Key Role Of Patients" - Pink Sheet, 26 May, 2009.).

In a wrap-up speech at the end of the two days, Jenkins pleaded with the attendees to understand the difficult position FDA finds itself in trying to devise an all-encompassing REMS.

"We're committed to doing our part, but it's also important for everyone to recognize that we don't have a magic wand that we can wave," he said. "We're part of the solution, but we're going to have to leverage our resources, partners and authorities to work on this."

"I wish we could tell you we can solve the problem ourselves, but we don't have those resources or authorities," Jenkins continued.

"This is related to prescribers making the right decisions, patients doing the right things with their drugs, people who are not patients knowing to stay away from them."

Jenkins underscored the challenges in creating an opioid REMS, noting, "Opioids are extremely effective drugs for the treatment of pain, but they are also extremely dangerous, and the range between the extremely effective and extremely dangerous is not wide."

What's Next?

Jenkins said that FDA recognizes that further public input will probably be needed before the program is put into place - in addition to stakeholder and industry meetings - and that it would come in the form of a joint advisory committee meeting with the Anesthesia and Life Support, the Drug Risk and Evaluation and the Risk Communication committees.

For now, the docket to submit comments on the opioid REMS is open until the end of June, after which FDA will digest the recommendations and attempt to design the program.

"We will need to work our way through and glean what we can from those documents to create a program that we think works and will be workable," Jenkins said.

"It's not going to be to anyone's benefit if we come up with a program that is not workable or has a negative impact on the health care industry."

- Lauren Smith (lauren.smith@elsevier.com)

REMS For Opioids Still Has A Long Road Ahead; Advisory Committee Is Likely

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