REMS Raise Concerns for Biotech Products - The FDA is expanding postmarketing safety requirements, despite limited resources to manage these added responsibilities. - BioPharm International


REMS Raise Concerns for Biotech Products
The FDA is expanding postmarketing safety requirements, despite limited resources to manage these added responsibilities.

BioPharm International
Volume 23, Issue 4


The FDA's draft guidance doesn't answer all the questions related to REMS, but "it's a start," commented Kathleen Frost, associate director for regulatory policy in the Office for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,

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