The proposed REMS for all extended-use opioids expands this program to a level far exceeding that of other risk-management
efforts. The proposal covers 24 brand and generic opioid products, including fentanyl patches and oral drugs formulated with
oxycodone, hydromorphone, methadone, morphine, and oxymorphone. Roughly 23 million prescriptions of these extended-release
painkillers are dispensed annually to about 4 million patients in the US, according to SDI data.
Even more opioid products are subject to abuse. The Substance Abuse and Mental Health Services Administration (SAMHSA) reports
that about 12.5 million Americans over age 12 took pain relievers for nonmedical use in 2007. This growing trend has underscored
the need for substance-abuse programs.
In Washington This Month
FDA is focusing on long-acting opioids because they are linked to serious adverse effects such as respiratory distress if
prescribed to inappropriate patients or in excessive doses. The drugs also are prone to abuse because they can be crushed
or dissolved, allowing individuals to take a large dose all at once. FDA did not include immediate-release painkillers in
the current initiative because these drugs are less associated with safety problems and abuse, but some patient advocates
want all opioids placed under strict controls.
Federal officials are loath to pull these products off the market because opioids are vital treatments for managing chronic,
severe pain in many individuals. The long-acting drugs allow patients to reduce the amount of medication taken each day and
enhance pain management. FDA hopes that extensive and coordinated risk-management strategies will reduce prescribing to patients
unable to tolerate strong medicines, while also curbing inappropriate use. FDA seeks to better inform patients about the serious
dangers associated with these drugs, to expand training for health professionals as to proper prescribing, and to improve
tracking and surveillance of how the drugs are used.
Unfortunately, 10 years of risk management for Purdue Pharma's (Stamford, CT) OxyContin (oxycodone) and other painkillers
have not stemmed the serious adverse reactions and overdosing. Current strategies for intervening with this problem "are inadequate,"
said Bob Rappaport, director of the Division of Anesthesia, Analgesia, and Rheumatology Products in FDA's Center for Drug
Evaluation and Research (CDER), at a meeting with manufacturers in March 2009, to discuss the goals and design of a REMS for
the opioid class. FDA sent letters last February inviting 16 brand and generic-drug firms to the meeting, including Purdue
Pharma, Johnson & Johnson's (New Brunswick, NJ) Ortho-McNeil-Janssen, Actavis (Morristown, NJ), Teva (Petach Tikva, Israel),
and Covidien's (Mansfield, MA) Mallinckrodt. An Industry Working Group of 25 companies is hashing out the details of a class
REMS program. In his presentation, Rappaport warned that if the project is not successful, "we cannot guarantee that these
products will remain on the market."
Another FDA meeting in February with physicians, pharmacists, and patient advocates similarly aimed to elicit support from
health professionals and patient groups for the opioid REMS project. Agency officials explained how FDA and other government
agencies regulate pain medications and how a class REMS program might be established.
FDA followed these initial sessions with an open public meeting in May to allow all parties to hear each others' proposals
and concerns. A panel headed by CDER Deputy Director Douglas Throckmorton and John Jenkins, director of CDER's Office of New
Drugs, listened to more than 70 speakers. Parents of teens who had died from OxyContin overdoses demanded that FDA remove
these dangerous drugs from the market. Representatives of the community of patients who suffer chronic pain insisted on continued
access to these medicines and warned that restricted distribution systems and complex oversight programs could be harmful
to patients and costly to the healthcare system.
Physicians supported additional training and certification for pain management, but pharmacists raised concerns that redundant
educational programs could complicate operations. Pharmacists and distributors said they already had tight controls and tracking
systems to prevent drug diversion and didn't want new certification requirements or additional regulations. Hospital and nursing-home
pharmacists, moreover, sought exemptions from REMS restrictions for their closed treatment systems that they consider less
open to error and abuse. In addition, the usual cadre of vendors and consultants used the public meeting to tout proprietary
educational programs, information systems, and tools for measuring program effectiveness.
The class REMS is unique in that it requires brand and generic manufacturers to jointly devise a single, shared system to
monitor safety and the risks of dozens of products. Pharmacists and providers don't want different education, training, and
certification programs from each company; they emphasize the importance of a uniform platform that fits pharmacy work flows
and a certification program tied to the existing Drug Enforcement Agency (DEA) registration system.
Manufacturers urged strong participation by prescribers and dispensers in the program, as well as support from DEA, state
licensing boards, and other parties. But the degree to which companies should collaborate to implement a shared system is
clearly a source of tension. Some generic-drug companies raised concerns that brand manufacturers will devise programs to
fit proprietary marketing and surveillance activities that would rule out participation by generic-drug firms. Kimberly France,
director of product and patient safety at Covidien, urged guidance from FDA about how shared systems could work, noting a
history of risk-management programs that favor innovators. Covidien and other generic-drug makers also want a separate REMS
for methadone products because they are used to treat drug addiction as well as pain.
A compromise could involve some shared elements, along with specific REMS activities for different companies and products.
Manufacturers proposed that Medication Guides remain product-specific, but that industry develop a general fact sheet for
all products in the class. Brand companies acknowledged that allowing industry to provide educational materials to health
professionals raises concerns, but it's not clear who else could do it. Everyone prefers the idea of a single certification
program and uniform prescriber–patient agreements, but manufacturers don't want full responsibility for devising and administering
such a huge project. And surveillance is tricky, said France, because current systems can't distinguish products by dosage
form, let alone for each manufacturer. Controls on prescription refills raise access concerns, as do proposals for a database
of all certified providers and a patient registry.
FDA is digesting the proposals from the May meeting, along with detailed written comments that were submitted in June. CDER
officials hope to present a REMS proposal to advisory committees later this year. Meanwhile, Jenkins suggested that manufacturers
could take certain immediate actions to enhance product safety while the agency finalizes and tests a long-term program. FDA
will examine whether safety concerns warrant expanding REMS to include all opioids, not just long-acting products, but the
agency is wary of making the project larger than it already is.
Once FDA issues a REMS proposal for opioid drugs, it will be up to each manufacturer to file and carry out an implementation
plan. FDA says it won't hold up the review and approval of new opioid products in the pipeline while REMS is under development,
but will continue to grant priority review status to drugs in this class to speed new products to market. Purdue Pharma is
seeking FDA approval of a new oxycodone product, but FDA has questioned how well the drug will deter abuse. Similarly, FDA
is examining King Pharmaceuticals's (Bristol, TN) applications for two new formulations, Embeda (morphine) and Remoxy (oxycodone),
that include antiabuse claims.
Broader risk management
Success with the opioid REMS may encourage similar FDA initiatives to enhance the safety of other widely prescribed drugs.
Developing the class REMS provides an opportunity for FDA and industry to explore new ways to establish postapproval controls
and develop educational programs, according to CDER's Throckmorton. In recent years, FDA has requested stronger label warnings
and other risk-management strategies for several drugs that raised safety concerns such as COX-2 inhibitors, antidepressants,
and antiepileptics. Additional comprehensive safety programs may be on the horizon. For example, FDA is working on a REMS
for erythropoiesis-stimulating agents and may consider similar efforts for botulinum-toxin products and for high-dose acetaminophen
products, which have been associated with liver toxicity.
FDA wants industry to take REMS requirements seriously. CDER's Division of Drug Marketing, Advertising, and Communications
warned Gilead Sciences (Foster City, CA) in February 2009 about statements at a scientific conference that the risk-management
plan for its Letairis (ambrisentran) pulmonary hypertension drug was "not that big of a deal," despite serious risk of liver
injury associated with the drug.
The agency also is cracking down on unapproved painkillers as part of a three-year campaign to remove from the market any
drugs that lack FDA approval and raise safety issues. In 2007, CDER's Office of Compliance required dozens of firms to remove
about 200 unapproved hydrocodone products from the market to curb safety problems and reduce confusion with those painkillers
approved for marketing. In March 2009, CDER sent Warning Letters to nine manufacturers, ordering them to halt the production
and distribution of 14 unapproved narcotic painkillers containing hydromorphone, oxycodone, and morphine. A few weeks later,
though, FDA had to do an abrupt about-face when patient advocates complained that this action would deny access to a high-concentrate
morphine sulfate oral solution desperately needed by hospice patients in severe pain. The problem illustrates the fine line
FDA has to walk between curbing the inappropriate use of risky medicines and ensuring that legitimate patients get the vital
drugs that they need.
For information about FDA's transparency efforts, see Jill's blog post, "Transparency and Safety".
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, email@example.com