FDA is starting the process of developing a classwide Risk Evaluation & Mitigation Strategy for potent opioid drug products - with the resulting program expected to be the most extensive REMS required by the agency since the implementation of the FDA Amendments Act.

While the risk management program itself has yet to be developed, the scope of the program will be "relatively massive" compared to past REMS, Office of New Drugs Director John Jenkins acknowledged during a Feb. 9 media briefing.

Given the size of the opioid market - 21 million prescriptions written for opioids every year for 3.7 million patients - "this is going to be the largest risk management effort we've undertaken," Jenkins said. "That's orders of magnitude greater than the other programs we have in place now."

Opioids Joins The REMS Class

The reason for the classwide effort is twofold: a requirement under FDAAA that innovators and generics share the same REMS (as with Accutane /isotretinoin), and a need to avoid undue burden on the health care system, Jenkins said in an interview (see ¹ Also see "The Downside Of REMS: An Over-Taxed Health Care System – FDA’s Jenkins" - Pink Sheet, 16 February, 2009.).

FDA has required just one classwide REMS thus far, for fluoroquinolone antibiotics, although that program is on the lower end of the REMS scale, requiring only a Medication Guide (² Also see "Fluoroquinolone REMS Will Survey Patients, Doctors on Understanding of Risk" - Pink Sheet, 14 July, 2008., p. 9). The agency is also considering classwide REMS for erythropoietin products, anti-epileptics and antidepressants (³ Also see "ESA Meta-Analysis Underscores Survival Risk" - Pink Sheet, 3 October, 2008.).

But opioids will mark the first time FDA has instituted a classwide REMS with elements to assure safe use. The opioid class REMS will encompass 24 marketed products - both brands and generics - from 16 different manufacturers, which were notified by FDA of its decision by letter on Feb. 6.

The focus of the classwide program will be on products that FDA says are most prone to abuse: extended-release products and transdermal patches, including fentanyl, methadone and oxycodone (see chart: " ⁴ Classwide REMS For Opioids "). Immediate-release opioids and transmucosal products will not be affected, but will likely require their own individual REMS, Jenkins said.

What Can REMS Do That Risk Plans Didn't?

Most of the opioids set to get a REMS already have Medication Guides, patient package inserts and boxed warnings. So what can REMS do that these programs haven't already tried?

For one, Jenkins noted, the current risk programs are voluntary, and are mainly education- and surveillance-based: they have not required, for example, mandatory training for or registration of prescribing physicians.

"It's clear that the voluntary programs have not been successful in getting us where we need to go with maintaining access to legitimate patients and dramatically decreasing the serious adverse event reports," Jenkins said. The class REMS, in contrast, will go further with some of the elements to ensure safe use.

As scheduled narcotics, opioids have some restrictions on prescribing and distribution, and physicians are required to register with the Drug Enforcement Agency.

But prescribing physicians are not required to complete any training or certification, Jenkins notes, and the DEA registration does not require any demonstration of competence, beyond having a medical license and being in good standing with the state medical board.

"The programs really haven't included what we would traditionally think of as elements to ensure safe use, or restricted distribution elements," said Jenkins, hinting at what the opioid REMS might look like. Mandatory training and registration of doctors, and a restriction distribution system are also among the elements that FDA is considering.

REMS In The Works For Some Time

FDA has been concerned for some time about the potential abuse of potent opioid products, and has been aware of problems specific to extended-release opioids since 2000. But it was not until passage of FDAAA that the agency felt it could undertake this kind of comprehensive program.

The agency signaled it was investigating a classwide REMS for potent opioids in response to calls for such a program during the advisory committee review of Pain Therapeutics' Remoxy (abuse-resistant oxycodone) and King Pharmaceutical's Embeda (abuse-resistant morphine) in November 2008 (⁵ [A#00700470003], p. 7).

At the time, FDA's Division of Anesthesia, Analgesia and Rheumatology Products Director Bob Rappaport indicated that it would take some time before the agency fully understood its authorities to impose a classwide REMS for opioids.

While FDA appears to have addressed those questions in relatively short order, the class REMS for opioid drug products will not be developed overnight, but will be drawn out over the next months as FDA reaches out to stakeholders for input.

After a series of closed-door meetings starting March 3 with drug sponsors, other federal agencies, health professional groups, the pain and addiction communities, and patient and consumer advocates, FDA will hold an open public meeting in late spring/early summer.

FDA already has a "pretty good outline" on what it thinks the REMS should include, but wants to involve stakeholders before finalizing anything. "After we've collected all that information, we will write to all the companies involved to tell them exactly what we think the program needs to be." At that point the six-month clock for implementation will begin ticking.

Jenkins said that it is likely that legitimate patients will see changes in new procedures in obtaining opioids, but he hopes to make those procedures not so intrusive that it impacts their ability to receive those products, while at the same time having an impact on safe use.

What About The Other Opioids?

Products not on FDA's list may still require a REMS. Two fentanyl products - Alza's Ionsys (fentanyl hydrochloride) and Cephalon's Actiq (fentanyl citrate) - were approved with risk management programs that were deemed to be REMS; those programs have been submitted to FDA and are under review (⁶ Also see "REMS Take Effect; FDA Identifies 16 Products With RiskMAPs That Qualify" - Pink Sheet, 31 March, 2008., p. 7).

It is also unclear whether pending NDAs for opioids, such as Remoxy and Embeda, will be put on hold until the classwide REMS is finalized. Applications for pending products involve legal questions that are still under review at FDA (see ⁷ Also see "Opioid Approval Delay? Class REMS Poses Legal Questions For Pending Drugs" - Pink Sheet, 16 February, 2009.).

As the manufacturer for Avinza (extended-release morphine), King will be involved in the discussions with FDA. The company said it has been invited to the March 3 meeting, but that FDA has not notified it whether the REMS in development will affect the review timeline for its pending products.

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

Record-Setting REMS: FDA’s Classwide Opioid Program Will Be “Massive”

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