Intense public scrutiny of drug safety issues is prompting the Food and Drug Administration to take a closer look at its program
for establishing Risk Evaluation and Mitigation Strategies (REMS). The most restrictive REMS programs with Elements to Assure
Safe Use (ETASU) are intended to apply only to those very high-risk products that cannot come to market without special safety
controls. Health care providers, as well as manufacturers, feel that the program is being overused, raising costs and interfering
with patient treatment.
REMS are at the center of ongoing discussions about drug safety, clinical research, and market approval of new medical products.
The shape and scope of REMS requirements, moreover, has become a central topic related to revising the Prescription Drug User
Fee program, which is slated for renewal by 2012.
The highly-publicized review of the risks associated with GlaxoSmithKline's diabetes treatment Avandia (rosoglitazone) led
advisory committee members to recommend keeping the drug on the market, provided that FDA impose strict controls on prescribing
through a highly restrictive REMS. Recent scrutiny of new anti-obesity therapies indicates that sponsors of these drugs will
need to present fairly extensive REMS plans to get on the market; advisory committee members opposed approval of Vivus's Qnexa
at a July advisory meeting largely because its slim REMS outline for a voluntary program to prevent pregnancy was considered
And the ongoing debate over devising a classwide REMS for long-acting opioids reflects the difficulties in imposing added
safeguards on high-risk therapies that are in high demand by patients. Despite more than a year of collaborative efforts by
manufacturers and multiple consultations with stakeholders, in July the members of two 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 is too weak and unlikely
to really do much to stop unsafe use of these potentially dangerous products; they proposed that sponsors institute mandatory
training for prescribers that are linked to assessment of competencies and licensure.
While sponsors are willing to implement these costly and sometimes cumbersome programs to meet FDA postmarketing safety requirements,
doctors, pharmacists, and other health care providers are alarmed by the proliferation of new requirements for drug prescribing
and dispensing. Health providers regard much of the new educational and patient registration programs as a significant burden
on their operations and on the health care 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.
In addition to advisory committee discussions of REMS for proposed new drugs, these issues were debated at a two-day FDA public
meeting in July on the REMS program. 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
sponsors should include in REMS proposals and is reviewing comments on that document.
Everyone at the meeting acknowledged the importance of REMS in assuring safe drug use. They also highlighted the unintended
consequences of added postmarketing requirements at both ends of the REMS spectrum: too many diverse Medication Guides, as
well as a growing number of highly-restricted REMS with ETASU. So far, FDA 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 health care leaders outlined a host of burdens and costs imposed by multiple REMS and the paperwork
involved in documenting compliance. Physicians complained of redundant and unnecessary educational and training programs and
policies that don't make sense. 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, tracking compliance,
and patient counseling takes time and interferes with pharmacy operations.
Providers similarly complained of too many different MedGuides for patients to review. Woodcock acknowledged that paper MedGuides
are not the optimal way to provide patients with information and that FDA hopes to develop an improved patient information
leaflet. Manufacturers proposed separating MedGuides from the REMS program, as it was prior to enactment of FDAAA in 2007.
Then, MedGuides were considered part of labeling, and manufacturers did not have to establish program goals and develop timetables
for assessment. However, pulling MedGuides out of REMS requires Congressional action, as would an FDA effort to establish
a single document for describing drug risks and benefits; such proposals could be part of the PDUFA package.
Probably the most objectionable REMS feature for pharmacists and providers is the limited distribution systems for high-risk
drugs that permit prescribing by only 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.