Manufacturers Face New Risk-Management Requirements

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Pharmaceutical Technology, Pharmaceutical Technology-07-02-2009, Volume 33, Issue 7

REMS to improve the safe use of opioids may lead to controls on other high-risk medicines.

The abuse and misuse of opioid painkillers is out of control, and the US Food and Drug Administration wants to defuse this serious public-health crisis. Previous risk-mitigation programs have failed to halt the inappropriate use of these drugs, prompting FDA to put more teeth into oversight through the Risk Evaluation and Mitigation Strategies (REMS) program established by the FDA Amendments Act of 2007 (FDAAA). FDA has called on manufacturers and other interested parties to help devise a workable REMS that will ensure continued access to medications essential for patients suffering from chronic pain, but also curb inappropriate prescribing, unintentional overdosing, and intentional abuse.

Jill Wechsler

The opioid REMS project reflects FDA's interest in building on the host of provisions in FDAAA designed to ensure drug safety through the entire product life cycle. In addition to the REMS program, the statute gives the agency the power to require postapproval label changes when new safety issues arise and to crack down on manufacturers that fail to conduct agreed-on postmarketing studies. FDAAA also requires companies to list extensive clinical trial information and study results on the public website. The listing is another way to ensure that safety issues that arise during clinical research are fully disclosed to regulatory authorities and to the public.

Implementing the FDAAA REMS program has been complex and time-consuming because it has required FDA to assess and update existing risk-management programs for dozens of drugs, while also developing new policies to fit its enhanced authorities. In March 2008, FDA identified some 24 manufacturers with marketed drugs such as isotretinoin, thalidomide, mifepristone, alosetron, and clozapine, that already had risk-management plans in place and thus were deemed to have REMS.

Under FDAAA, REMS may consist of simply a Medication Guide and a timetable for evaluating the drug product after 18 months, three years, and seven years after approval. More elaborate REMS programs may require a communication plan for conveying safety information to prescribers, pharmacists, and patients through Dear Doctor letters and notices to professional societies, state licensing boards, and medical journals. Makers of the highest-risk drugs also have to establish Elements to Assure Safe Use, which can include special training or certification of healthcare providers and pharmacists, limited distribution programs to ensure that a drug is dispensed only to patients who meet certain criteria, patient monitoring to identify adverse reactions, and enrollment of patients in registries for long-term oversight. Most of the products deemed to have REMS already supported many of the REMS provisions, but manufacturers had to submit proposals describing how their programs fit new REMS requirements. During the past 18 months, FDA has approved REMS for approximately 50 products, including drugs already on the market as well as new treatments.

Difficult class

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.


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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.

Getting together

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,