Sooner or later?

FDA's proposed guidance doesn't answer all the questions related to REMS, but "it's a start," said 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 was peppered with questions about when manufacturers should start discussing the need for a REMS with FDA and what kind of information the agency wants to see. Frost acknowledged that FDA examines whether a REMS is needed for every new drug application—even those that end up only with a Medication Guide or nothing—and that it can take time to determine whether the risks associated with a drug are fully characterized and what kind of intervention will help address those risks.

This expanded REMS-evaluation process has generated debate among regulatory experts, as well as FDA officials, about whether sponsors should hold off on submitting a proposed REMS until FDA asks for it, or take initiative and raise the issue before launching pivotal studies. Frost said it could benefit companies to lay out the reasons why a REMS is or is not warranted early in the process. But some lawyers advise manufacturers to avoid the issue if FDA doesn't bring it up.

But OSE officials say they lack the staff to address specific postmarket safety issues until a drug is much further along in the development process. OSE wants to be more involved in the early REMS- development process. But the safety office doesn't have the resources to step in at the end of Phase II if a REMS is just one line item on the meeting agenda, Frost explained.

In comments submitted to FDA regarding the draft REMS guidance, manufacturers urge early collaboration by CDER's new drug review and postmarketing safety offices. Industry also wants a standardized process for FDA review of REMS that would be linked to application-processing criteria established by the Prescription Drug User Fee Act (PDUFA). This topic already is on the agenda for the next round of negotiations on PDUFA, which are beginning this year in order to be in place by 2012. The PDUFA negotiations also are slated to raise the need for more resources to support drug-safety oversight, as well as alternative proposals to separate drug safety and efficacy review operations more clearly within FDA.

Pharmaceutical companies also would like FDA to be responsible for articulating the need for a REMS for drug products, instead of imposing that task on sponsors, as FDAAA currently requires. Manufacturers admit that they often are conflicted about whether a formal postmarketing safety system is warranted for a drug, whereas FDA reviewers have a clearer perspective on what kind of postmarket safety procedures are necessary and likely to benefit public health.

The role of generic-drug manufacturers in implementing REMS is another thorny topic. Generic-drug firms complain that brand companies are using complex REMS requirements to block the former's access to supplies needed to conduct bioequivalence studies, and that special distribution and patient monitoring programs raise the cost of entering a new market. The ESA REMS, for example, adds another hurdle for manufacturers contemplating follow-on biologic versions erythropoietin. Generic-drug makers also face challenges in using a single shared system to implement ETASU requirements such as provider certification and limited distribution, to keep the process manageable for providers.

Although the general thrust of the REMS policy is to increase the role of generic-drug manufacturers in ensuring the safe uses of marketed medicines, generic-drug firms get a break because FDA is charged with carrying out REMS communications plans when generic competition comes into play. The apparent aim is to avoid multiple versions of educational materials and information programs, but it could be difficult for FDA to carry out this mission. The agency won't have a big problem if most communication plans are limited to product launches or to the first few years a drug is on the market, as is usually the case. But too many long-term communications plans would impose a burden on FDA, Frost acknowledged, because the agency has limited resources to manage such programs.

Providers weigh in

Pharmacists and healthcare providers are concerned that too many diverse postmarketing drug safety programs will impose a burden on the healthcare system and patients as well, and that the requirements will drive up costs and limit access to therapies. Oncologists are upset that they were not consulted in developing the REMS for ESAs administered to cancer patients. Unlike the process being used to develop a classwide REMS for long-acting opioids, FDA negotiated the plan directly with Amgen (Thousand Oaks, CA) for Aranesp (darbepoetin) and Johnson & Johnson (New Brunswick, NJ), marketer of Procrit (epoetin). The American Society of Clinical Oncology notes that the REMS requires oncologists to enroll in pharmaceutical educational programs about the importance of limiting use of ESAs for cancer patients, a "duplicative requirement" that oncologists had no opportunity to help develop or review.

Kaiser Permanente, the California-based healthcare plan, similarly wants to have a seat at the table when FDA and drug companies design REMS to ensure they don't raise problems for healthcare providers and pharmacies. Requiring consumers to obtain medicines through select doctors and specialty pharmacies can increase costs for healthcare plans and consumers and may limit access to needed drugs. This concern raises questions about the overall benefits of the REMS program, Kaiser stated in a citizens' petition filed with FDA last year.

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 opioids and other drugs, says Kaiser, warrants regular review of such programs with FDA advisory committees to ensure a more transparent process. Kaiser also wants FDA to review and evaluate complex REMS programs at least annually, and to make these assessments public to help doctors and patients weigh treatment decisions.

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