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The FDA is expanding postmarketing safety requirements, despite limited resources to manage these added responsibilities.
The Food and Drug Administration is requiring Risk Evaluation and Mitigation Strategies (REMS) on most new drugs and biotech therapies, creating uncertainty among manufacturers as to what information the agency wants, and when. While many REMS programs require only distribution of a Medication Guide to patients, they all carry timetables for periodic assessment, which is turning out to be a serious challenge.
Compounding these problems is a growing number of REMS for drug classes, which are more complex to establish and administer. The FDA recently finalized a REMS for erythropoiesis-stimulating agents (ESAs) used in cancer treatment and called for a class-wide REMS for long acting asthma drugs. A broader REMS for ESAs in renal treatment is in the works; additional initiatives may be launched for anti-seizure drugs and for antidepressants; and work continues on a multi-product REMS for long-acting opioid drugs.
Meanwhile, the FDA is struggling to review and monitor these programs with limited staff and resources. The result is delays in providing needed guidance for industry and in answering many questions about how to implement REMS procedures. FDA staffers are mulling over dozens of comments to a draft guidance on REMS format and assessment that was issued last September. In addition to concerns raised by drug and biotech manufacturers, pharmacists, health plans and payers fear that too many REMS will impose added burdens on the nation's medical system and will raise healthcare costs overall.
The FDA has approved nearly 100 new REMS since the program went into effect in March 2008, as required by the FDA Amendments Act of 2007 (FDAAA). Most REMS (71) only involve MedGuides, but 23 also require communication plans that usually involve letters to healthcare providers. In addition, the FDA has determined that 16 drugs that already had restrictive risk management programs before FDAAA were deemed to have REMS under the new policy. Those manufacturers had to submit REMS plans, but so far, the FDA has approved only two of them.
The FDA also can determine that a REMS is needed for other already-approved drugs based on the emergence of new safety information. In such cases, the manufacturer has to file a prior-approval efficacy supplement outlining its REMS plan. The drug can stay on the market during the months it takes FDA to approve such supplements, but that raises compliance uncertainties. Although revisions to a REMS require prior approval, sponsors can inform the FDA of labeling changes through a changes-being-effected supplement. This leaves manufacturers in a quandary over whether to update labeling right away to reflect new safety issues, or to wait for approval of changes to the REMS.
The most risky therapies have to establish REMS programs with elements to assure safe use (ETASU). These may involve a range of costly and complex risk management programs: training and certification of health professionals; limited product distribution; and patient monitoring, testing, or enrollment in registries.
All REMS programs, even MedGuide-only versions, require periodic assessment to determine if the program is meeting stated goals. FDAAA stipulates that assessments must be conducted at 18 months, three years, and seven years following product approval, but the FDA may call for earlier assessment at six months or one year for particularly high-risk products.
The big issue with assessments is how manufacturers should evaluate a REMS's success. "Measuring the number of MedGuides handed out is easy; assessing the public health impact is much more difficult," noted Wayne Pines of APCO Worldwide at a February seminar on REMS sponsored by the Food and Drug Law Institute (FDLI). A clear definition of objectives is important because manufacturers that fail to meet goals could face stiff fines and penalties. It's not obvious, though, how a drug company could compel pharmacies to distribute MedGuides or follow dispensing requirements.
The FDA's draft guidance doesn't answer all the questions related to REMS, but "it's a start," commented Kathleen Frost, associate director for regulatory policy in the Office for Surveillance and Epidemiology (OSE) in FDA's Center for Drug Evaluation and Research (CDER). At the FDLI meeting, Frost acknowledged that FDA examines whether a REMS is needed for every new drug application (NDA) and biologics license application—even those that end up only with a MedGuide—and it can take time to determine if product risks are fully characterized and how best to address safety concerns.
A main source of confusion for manufacturers is when to start discussing the need for a REMS with the FDA and what kind of information the agency wants to see. Regulatory experts differ on whether sponsors should hold off on submitting a proposed REMS until the FDA asks for it, or be proactive and bring up the issue before launching pivotal studies. The main risk is that if FDA reviewers decide that a drug needs a REMS after an application is under review, that could generate a complete response letter and delay approval for months.
New drug review officials in CDER have been urging manufacturers to initiate discussion of REMS issues as early as end-of-Phase-2 meetings to avoid delay in approval and to ensure that they collect necessary information on product risks and safety issues during Phase 3. These later studies may need to evaluate physician instructions for administering complex treatments, ease in identifying side effects, impact of packaging on appropriate product use, and effectiveness of educational materials. But OSE officials say they don't have the resources to step in at every EOP2 meeting and generally prefer to delay the REMS evaluation until later in the product's development process.
In commenting on the FDA's draft REMS guidance, manufacturers urged earlier collaboration by CDER efficacy and safety review offices and a standardized process for REMS evaluation linked to metrics established by the Prescription Drug User Fee programs (PDUFA). The topic already is on industry's agenda for PDUFA 5 negotiations that will begin this year.
Using REMS requirements to block market competition is another thorny topic. Generics makers complain that limited distribution programs block access to innovator supplies and that a REMS for ESAs adds another hurdle for manufacturers contemplating biosimilar versions of EPO. But generics firms get a break because the FDA is supposed to manage drug communications plans when generic competition comes into play to avoid multiple versions of the same materials. This won't be a problem for the agency if most communication plans are limited to product launches, but too many long-term communications plans would impose a burden on the FDA's limited resources.
Pharmacists and healthcare providers also are concerned that they too may be overwhelmed by more extensive postmarketing safety programs and want a say in the design and implementation of REMS. Oncologists are particularly upset that they were not consulted when the FDA developed the ESA REMS with Amgen for Aranesp (darbepoetin) and Johnson & Johnson, marketer of Procrit (epoetin), which requires doctors to enroll in additional educational programs.
Kaiser Permanente has filed a citizens petition with the FDA seeking advisory committee review of complex REMS so that health plans can comment on these proposals. Requiring patients to obtain medicines through select doctors and specialty pharmacies, says Kaiser, can increase costs for health plans and for consumers, limit access to needed medicines, and raise questions about the overall benefits of the REMS program.
These issues have not been a problem so far because most REMS with ETASU have involved drugs for relatively small patient populations. But the prospect of mega-REMS for extended-use opioids and other widely used drugs may warrant a more transparent process with input from plans and providers. And complex REMS programs should be reviewed annually, says Kaiser, with assessments made public to help doctors and patients weigh treatment options fully.
Jill Wechsler is BioPharm International's Washington editor, Chevy Chase, MD, 301.656.4634, firstname.lastname@example.org