Cole Werble

	By Cole Werble and Ramsey Baghdadi, Prevision Policy, LLC

FDA has been building toward a final structure for the opioid REMS for some time. FDA announced in February 2009 that it would require all opioids to carry a REMS program (see story, p. 1). Opioid abuse is a priority because opioid poisoning deaths were the top cause of drug poisonings in 2006 (14,000 deaths compared to 21,000 deaths due to poisonings from all other drugs).

	FDA decided to take a class approach to the opioid REMS as a way to avoid the burdens and potential inequities of different plans for different related brands. FDA learned quickly that getting a group of companies to agree on a consensus plan was a much larger task than anticipated. The REMS opioid effort has been a major learning experience for the agency in the early stages of development of these post-marketing control programs. As such, it is drawing much management attention.

	In early May, FDA met with stakeholders from the healthcare provider, pharmacy, and patient communities for two days. A larger public two-day meeting on May 27-28 followed with more than 100 individual comments. The agency also received over 2,000 submitted comments.

	The project has grown within FDA. The agency formed a multidisciplinary Opioid REMS Steering Committee from throughout the Center for Drug Evaluation & Research. Eight working groups have been formed to deal with scope, prescriber education, pharmacist education, patient education, pharmacy systems, patient access to pain medication, metrics and public communication, according to FDA.

	In December, FDA held a public hearing to listen to recommendations from an industry opioid working group on how to develop the REMS. At the meeting, top FDA officials expressed frustration at the lack of real specifics provided by sponsors.

	So far, the industry working group has tried to design communication/education programs: a MedGuide, “dear healthcare prescriber” and pharmacist letters, and a provider training program. FDA is likely to push for more controls. Among the restrictive models for the class REMS are Cephalon’s Fentora (fentanyl buccal tablet), and BioDelivery Sciences/Meda Pharmaceuticals’ Onsolis (fentanyl buccal soluble film).

	At the December public meeting, sponsors rejected the idea of patient registries saying it would limit access. Many of the pieces of the REMS should be voluntary, the working group argued. The working group also said that a mandatory program that would allow prescribers and pharmacists to opt out was not a viable solution.

	But tight control will have highly placed advocates within FDA. FDA Deputy Commissioner Joshua Sharfstein was involved in programs to address opioid addiction while head of the Baltimore Health Dept. Sharfstein is saying in public that control of “intentional misuse” is high on the list of the agency’s “Safe Use” initiative.

	There are fundamentally three elements that must be mastered for a company to convince FDA that the new formulation is more abuse-resistant than existing formulations.

	1. Formulation: Designing a combination of active ingredients with antagonists or with excipients that are difficult to separate from active ingredient.

	2. Test methodologies: Devising ways to convince FDA that the formulations are tough to abuse without providing a cookbook of how to pull the drugs apart.

	3. Marketplace controls: Convincing FDA that the company knows how, and is committed to, controlling the product and promotion in the marketplace.

	FDA is planning a public meeting in the spring to discuss a class-wide risk evaluation and mitigation strategies (REMS) program for opioid drugs. The date is not set; however, we would target May as the most likely month for the meeting based on the recent pace of developments. FDA has left open the window for public comments until October 2010, meaning a full resolution is unlikely before the end of the year.

	The spring public meeting should provide more insight into how FDA plans to proceed with the REMS program and its stringency. We also believe FDA is heading towards more restrictive and hands-on postmarket controls than have been recommended by the opioid manufacturers. 

> Cole Werble and Ramsey Baghdadi represent Prevision Policy, LLC, exclusive consultants to the Washington Research Group/Concept Capital, a division of Sanders Morris Harris, Inc. 

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