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.
The main risk for manufacturers is that if FDA staffers decide a drug needs a REMS after an application review has begun,
the decision could lead to a Complete Response letter and put approval on hold for months. To avoid such delays, CDER efficacy
review officials have been urging manufacturers to start discussing REMS issues as early as end of Phase II meetings to ensure
that they collect necessary information on product risks and safety management during Phase III. These later studies may need
to evaluate physician instructions for administering complex treatments, patient-monitoring procedures, ease in identifying
side effects, impact of packaging on appropriate product use, and the effectiveness of educational materials.
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, firstname.lastname@example.org