FDA's Opioid REMS Proposal Has Narrow Focus On Education

Faced with data gaps, inadequate metrics and the need to maintain access to therapies, FDA takes a narrow approach to addressing long-acting and extended-release opioid abuse and misuse in its proposed Risk Evaluation and Mitigation Strategy for the painkillers.

The REMS unveiled by FDA June 28 foregoes the more restrictive options of prescriber and patient registries and instead relies on sponsors' ability to instruct physicians on how to identify appropriate patients and to teach patients to properly handle the drugs (see chart: " ¹ FDA's Guide To Mitigating Risks Of Long-Acting Opioids ").

Because the administrative burden of registries could prompt some physicians and pharmacies to cease prescribing and dispensing the opioid products and adversely affect access, FDA decided to "not include these requirements at this time," Bob Rappaport, director of CDER's Division of Anesthesia and Analgesia Products, explains in a memo to members of the Life Support Drugs and Drug Safety and Risk Management Advisory Committees who will meet July 22-23 to critique the REMS proposal.

But this does not mean registries will not be on the agenda in the future. The key to avoiding that route to opioid risk management is understanding whether, once implemented, the REMS reduces serious outcomes from the misuse and abuse of the LA/ER opioids. That information "will determine whether additional efforts or future REMS modifications are necessary," Rappaport notes.

Sponsors, FDA To Find New Metrics

That task may be the most difficult one facing sponsors. Assessing REMS effectiveness is complicated by the insufficiency of existing databases and the potential for confounders, such as policy changes and product introductions, according to an internal agency working group on the opioid REMS metrics. Rappaport notes that metrics and data sources should focus on outcomes related to both extended-release products as well as immediate-release opioids.

Before the various REMS go into effect, sponsors will have to establish baseline metrics for prescriber/patient knowledge, behaviors and health outcomes so there is a benchmark for evaluating improvement. Measures should be taken at the time the REMS is approved and as additional elements are introduced, the working group said in its final report, noting that the required REMS assessment schedule should be adjusted accordingly.

While FDA wants to see a picture of use and abuse for all opioids, it takes a narrow approach in applying the REMS. An internal working group on the scope of the opioid REMS had recommended that the risk management plan be broadened to all opioid drugs. To balance the burden of wider application, the group suggested the REMS require only prescriber education. The panel's concerns centered on the potential for under- and non-treatment and the use of inappropriate substitutes with their own safety issues.

Rappaport concedes that immediate-release opioids pose serious risks when used improperly, but maintains that broadening the REMS to those products "is difficult to justify based on the difference in magnitude of adverse outcomes associated with the products." The broader REMS would place a greater burden on the health care system, he says, and suggests that misuse and abuse of IR products "is more appropriately addressed through other actions with appropriate stakeholders.

Adding to the complexity and administrative burden of the LA/ER opioid REMS for FDA is that the agency must negotiate strategies for each product. The FDA Amendments Act does not give the agency "authority to require a single REMS for a class of products," Office of New Drugs Associate Director Mwango Kashoki noted during the Drug Information Association annual meeting in Washington, D.C. Although the risk may be similar within a class of drugs, each REMS must be written by a sponsor for a particular drug. "The REMS would be applied individually to those products. We can't require the use or institution of a class-wide REMS under the statute," she said.

Accordingly, FDA will inform LA/ER opioid sponsors about what to include in a REMS once the agency makes a final decision on the requirements. That will follow the advisory committee discussion and the review of additional public comments, which are due to the agency by Oct. 19. The affected products include long-acting and extended-release formulations containing fentanyl, hydromorphone, methadone, oxycodone and oxymorphone.

- Cathy Dombrowski ( ² [email protected] )