FDA Struggles with Risk Management and Drug Safety

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Pharmaceutical Technology, Pharmaceutical Technology-09-02-2010, Volume 34, Issue 9

Weighing the pros and cons of REMS for bringing risky products to market.

Jill Wechsler Intense public scrutiny of drug-safety issues is prompting the US Food and Drug Administration to take a closer look at its program for establishing Risk Evaluation and Mitigation Strategies (REMS) for new and existing medicines. The most restrictive REMS programs—those that include Elements to Assure Safe Use (ETASU)—are intended to apply only to high-risk products that cannot come to market without special safety controls. Healthcare providers and drug manufacturers, however, feel that the entire REMS program is overused, thereby raising costs and interfering with patient treatment.

REMS are at the center of many drug-safety cases and market-approval discussions. After a highly publicized review of the risks associated with GlaxoSmithKline's (GSK, London) diabetes treatment Avandia (rosoglitazone), advisory committee members voted to keep the drug on the market provided that FDA impose strict controls on prescribing through a restrictive REMS. Recent scrutiny of new antiobesity therapies indicates that manufacturers of these drugs will need to present fairly extensive REMS plans in order to enter the market. And the ongoing debate over devising a classwide REMS for long-acting opioids reflects the difficulties in imposing added safeguards on therapies that are in high demand but associated with dangerous abuse.

Although manufacturers are willing to implement these costly and sometimes cumbersome programs to meet FDA postmarketing safety requirements, doctors, pharmacists, and other healthcare providers are alarmed by the proliferation of new requirements for drug prescribing and dispensing. Health providers regard the new educational and patient-registration programs as a significant burden on their operations and on the healthcare system. Payers similarly are concerned about added costs, while consumers are caught between their desire for access to treatment and the need to avoid adverse events.

Recent advisory committees convened to evaluate proposed new drugs have debated these issues, as did participants at a two-day FDA public meeting in July on the REMS program. The shape and scope of REMS requirements have become central topics in discussions about revising the Prescription Drug User Fee program (PDUFA). Pharmaceutical companies and health professionals have begun to build the case for reform, with an eye on the user-fee renewal legislation slated for enactment by 2012.

Too many REMS

At the July public meeting, Janet Woodcock, director of FDA's Center for Drug Evaluation and Research (CDER), acknowledged that the REMS program established by the FDA Amendments Act of 2007 (FDAAA) "is not perfect" and that FDA is looking for input from all stakeholders on "how we might remodel our house." FDA also published a draft guidance in October 2009 on what information manufacturers should include in REMS proposals and is reviewing comments on that document.

Everyone at the meeting acknowledged the importance of REMS in ensuring safe drug use. They also highlighted the unintended consequences of added postmarketing requirements at both ends of the REMS spectrum: more diverse Medication Guides as well as a growing number of highly restricted REMS with ETASU. The general complaint is that too many types of REMS exist and that FDA has not justified the need for special risk-management requirements. To date, the agency has approved more than 120 REMS, including 15 with ETASU, a number that Woodcock acknowledged has led to a proliferation of restrictions and requirements.

Pharmacists, physicians, and healthcare leaders outlined a host of burdens and costs imposed by multiple REMS and the paperwork involved in documenting compliance. Physicians complained of what they saw as redundant and unnecessary educational and training programs and policies that don't make sense. Why do providers have to enroll male patients in the iPledge program for isotretinoin which is designed to prevent pregnancy? asked Kaiser Permanente pharmacist Richard Wagner. Oncologists have been particularly vocal in opposing added educational requirements, noting that they are well trained to use chemotherapies that can be highly toxic. Pharmacists described how training, compliance tracking, and patient counseling takes time and interferes with pharmacy operations.


The most objectionable REMS feature for pharmacists and providers is the limited distribution systems for high-risk drugs. These requirements permit prescribing only by certain well-informed specialists and dispensing by designated specialty pharmacies that can verify appropriate use and patient understanding of the risks. Retail pharmacists complain that such systems steer patients away from regular pharmacies, while hospitals and health plans cite added costs and difficulties in obtaining therapies from restricted sources.

Seeking remedies

The solutions to these problems are not obvious. Industry agrees with providers that multiple REMS programs impose added recordkeeping and compliance requirements and threaten to delay patient access to needed therapy. But although some stakeholders seek more standardization and uniformity in REMS plans to minimize new educational programs, manufacturers generally fear that a one-size-fits-all approach will not work. They argue that there are too many diverse products with various indications for different patient groups.

Pharmaceutical companies would like FDA to play a larger role in explaining to providers the need for educational and distribution requirements, said Jeffrey Francer, assistant general counsel of the Pharmaceutical Research and Manufacturers of America (PhRMA) at the public FDA meeting. He proposed that FDA spell out in action letters on new drugs why a REMS is needed, what risks are being addressed, and why other risk-management tools are insufficient to protect patients. CDER's Office of Surveillance and Epidemiology, moreover, should conduct "systematic outreach to patient and provider groups" to explain how the agency weighs the benefits of a REMS against the added burdens imposed on patients and providers, he said.

PhRMA's main proposal, Francer added, is to simplify MedGuide production and oversight by separating this activity from the REMS program, as it was before the enactment of FDAAA in 2007. Then, MedGuides were considered part of labeling, and not related to specific risk-management plans. Now, as part of the REMS program, manufacturers also have to establish program goals, monitor how well pharmacists and providers distribute the information, and develop timetables for assessing the plans. The extra requirements generate a lot of paperwork for both industry and FDA that does not necessarily improve patient care.

Providers complain of excess MedGuides for patients to review, often repeatedly. Kidney-dialysis patients, for example, have to examine the same risk information at every monthly treatment session, a requirement that physicians find burdensome and ineffective. Woodcock acknowledged that paper MedGuides are not the optimal way to provide patients with information and said that FDA plans to develop a patient-information leaflet using modern communication science. Several stakeholders support that approach and the development of templates or standardized formats for MedGuides to reduce confusion for providers and for patients. However, pulling MedGuides out of REMS would require Congressional action, as would an FDA effort to establish a single document for describing drug risks and benefits.

Another industry goal is to streamline the process for modifying established REMS by reducing the number of changes that require prior approval. The current policy creates unnecessary delays and wastes FDA resources, said Andrew Emmett, director for science and regulatory affairs at the Biotechnology Industry Organization. He proposed a tiered approach to REMS modifications that would allow sponsors to merely notify FDA of administrative and technical changes and limit prior approval to those revisions that affect the main goals, timetable, or implementation system of a REMS.

Although manufacturers welcome support from providers for curbing the scope and number of REMS, they are leery about third parties playing a more prominent role in REMS development and approval, something that pharmacists, physicians, and health plans are demanding. At the public meeting, providers called for a more transparent REMS development process so that they will be aware of upcoming risk-management programs and have an opportunity to weigh in early on specific proposals. Steven Russek, vice-president and chief clinical officer of Medco's Accredo Health Group, observed that drug manufacturers informally seek advice on what works in risk management, but then go back to negotiate with FDA. "Then it's silent," he said, "and then a REMS pops up."

It's not clear how or when FDA could consult third parties on REMS proposals. Before approving a drug for market, confidentiality restrictions prevent the agency from indicating that a REMS is under discussion, explained Jane Axelrad, director of CDER's Office of Regulatory Policy. "How can we meet early with sponsors to discuss REMS to avoid delay," queried John Jenkins, director of CDER's Office of New Drugs, when "consumers see early agreement on REMS lacking in transparency?"

Promoting competition

An added challenge is whether REMS programs erect barriers to generic-drug development and marketing. There is general agreement that generic and innovator products should use a shared risk-management system to avoid unnecessary multiple approaches. Achieving that goal, however, raises questions about who controls the risk program and how costs should be shared—both for REMS developed for drugs before generic competition begins, and for those that are modified after generic competition starts.

FDAAA specifies that a REMS should not prevent generic drugs from entering the market and includes provisions that provide considerable relief for generic-drug makers during REMS implementation. FDAAA requires FDA, rather than generic-drug firms, to operate REMS communication plans for generic drugs, primarily to avoid creating multiple educational and information programs for providers. Generic-drug firms, unlike brand companies, are not required to assess the effectiveness of REMS programs.

But generic-drug manufacturers complain of innovator tactics that can slow down market authorization. Brand manufacturers, they claim, cite limited distribution systems imposed by highly restrictive REMS programs as an excuse for denying the release of products for bioequivalence testing needed to develop generic versions of a drug. Health plans and payers fear similar tactics by developers of follow-on biologics, which generally involve more risky therapies that likely will be subject to restrictive REMS requirements.

Restricted distribution programs also thwart open competition by preventing capable specialty pharmacies from dispensing certain drugs, according to Kaiser Permanente. The health plan has its own in-house pharmacy operation with specialty pharmacy services, and says that having to purchase a drug through an outside distributor adds to costs and delays access to drugs.

More collaboration

Added support for REMS and other postmarketing drug-safety programs, such as the proposed safety initiative for long-acting opioids, could come from FDA's Safe Use initiative. The agency launched Safe Use last November to encourage agency collaboration with healthcare providers, patient groups and other government agencies on programs to promote the safe use of medical products. FDA aims to identify drugs associated with potential harm and to devise plans to work with hospitals, doctors, nurses, patient groups, and others on ways to mitigate these risks. These programs could involve distributing information to consumers and improving packaging and dosing devices.

In some situations, however, FDA's hands are tied. The agency has authority to regulate drug manufacturers, but cannot regulate health professionals or the practice of medicine. The agency, therefore, cannot require a medical society to add certain information on a new drug to a medical education program or mandate that physicians take a certain educational program.

Consequently, FDA must impose REMS requirements on regulated companies, even though such action may put the agency in the awkward position of requiring manufacturers to "influence healthcare," Woodcock pointed out. Many healthcare providers and payers are leery of manufacturer involvement in continuing medical-education programs and reject many pharmaceutical-funded initiatives as overly promotional. These concerns will continue to shape REMS programs and efforts to ensure the safe use of drugs throughout the healthcare system.

Voluntary REMS are not enough

In July, FDA asked two advisory committees to weigh its proposal for preventing the misuse and abuse of long-acting opioid painkillers. The response reveals just how difficult it is for the agency to find a comfortable middle ground between ensuring the safe use of risky products and maintaining patient access to needed therapy. Despite more than a year of collaborative efforts by manufacturers and consultations with stakeholders, the members of the Anesthetic and Life Support and Drug Safety and Risk Management Advisory Committees voted overwhelmingly (25 to 10) to reject FDA’s proposed classwide REMS plan, which relies on a voluntary educational program for prescribers to curb illegal use of these drugs. The practitioners and academics on the panels said that FDA’s plan was too weak and unlikely to to stop unsafe use of these potentially dangerous products. Instead, they urged a much tougher approach, with mandatory training for prescribers linked to an assessment of competencies and licensure. They also called for extending the program to immediate-release opioid products, which some panel members consider just as dangerous as the long-acting drugs.

FDA officials said they lack the authority and resources to adopt these recommendations. The agency previously has mandated the training of health professionals, but for much smaller product classes involving far fewer practitioners, explained John Jenkins, director of CDER’s Office of New Drugs. More than 700,000 providers are authorized to prescribe long-acting opioids to some 4 million patients, and a mandatory educational program could place a large burden on the healthcare system. Broadening the REMS to all opioids would only compound the problem.

One option is to link prescribing of opioids to the federal Drug Enforcement Agency (DEA) registration system, which oversees the prescribing and dispensing of controlled substances. Such a move would require legislation that links training on opioids use to obtaining a DEA prescriber-registration number. FDA still may launch its voluntary opioid REMS while waiting for Congress to act. Alternatively, the agency could ask manufacturers to devise a new program that limits opioid prescribing to providers who complete mandated training and are listed in a registry of qualifying physicians. The goal still would be a single educational and registration system, designed by brand and generic-drug manufacturers that hopefully would continue to work together.

Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, jwechsler@advanstar.com.