It now appears that the US Food and Drug Administration wants a Risk Evaluation and Mitigation Strategy (REMS) for most
new drug products, an approach that is having a noticeable impact on drug development and regulatory strategies. Manufacturers
are confused about what information the agency wants, and when, and uncertain about how to devise and implement multiple REMS
programs. In many cases, FDA requires manufacturers to issue only a Medication Guide for distribution to patients. All REMS
carry timetables for periodic assessment, however, which is turning out to be a serious headache for the industry.
Compounding the difficulties is a growing number of REMS for drug classes, which are more complex to establish and administer.
In February, FDA finalized a REMS for erythropoiesis-stimulating agents (ESAs) used in cancer treatment, a process that took
two years, and called for a class-wide REMS for long-acting asthma drugs. A broader REMS for ESAs in renal-disease treatment
is in the works, and additional initiatives may be launched for antiseizure drugs and antidepressants, among other risky medicines.
Negotiations continue for a multiproduct REMS for long-acting opioid drugs (see the July 2009 edition of this column in Pharmaceutical Technology for more information).
In Washington this month
A primary problem with these new REMS requirements is that FDA lacks the resources to review multiple REMS plans and their
subsequent revisions. The agency also has to find time to develop policies for implementing postmarketing safety programs
(see sidebar, "No new money") and to answer questions about how to comply with REMS procedures. FDA staffers are mulling over
dozens of comments about a draft guidance on REMS format and assessment that was issued in September 2009. Pharmaceutical
and biotechnology manufacturers have raised concerns about the program, as have pharmacists, health insurers, and payers who
fear that too many REMS will impose added burdens and costs on the nation's healthcare system.
No new money
Assessments for already approved and high-risk drugs
At issue is the large number of REMS requested by FDA under the FDA Amendments Act of 2007 (FDAAA). The agency has approved
some 100 new REMS since the program went into effect in March 2008. Most (71) call on manufacturers to provide only Medication
Guides for pharmacists to give patients, but 23 also require communication plans that usually involve letters to healthcare
providers informing them of safety issues.
In addition, FDA determined that 16 drugs from 24 sponsors that already had restrictive risk-management programs prior to
the enactment of FDAAA were deemed to have REMS under the new policy. Those manufacturers, which include some generic-drug
makers, had to submit REMS plans, but so far, FDA has approved only two of them.
FDA also has authority to determine whether a REMS is needed for other approved drugs based on the emergence of new safety
information. To establish or revise a REMS for a marketed product, 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,
thus, creating a compliance quandary for manufacturers. Sponsors can update labels quickly by filing changes-being-effected
supplements, but revisions to a REMS require prior approval. Thus, it's unclear whether manufacturers should change labeling
immediately to reflect new safety issues, or wait for approval of revisions to a REMS.
Sponsors of the riskiest drugs have to establish REMS programs with Elements to Assure Safe Use (ETASU). In these instances,
training and certification of health professionals may be required. In addition, FDAAA requirements call for limited distribution
of the drug to certain healthcare settings, patient monitoring and testing, and enrollment of patients in registries for long-term
evaluation. The need for later assessment may prompt manufacturers to compile databases of all certified prescribers and enrolled
patients, monitor distribution and dispensing, and track duration of treatment.
In fact, all REMS programs, even those that only need Medication Guides, require periodic assessment to determine whether
they are meeting goals. FDAAA stipulates that assessments must be conducted at least 18 months, three years, and seven years
following market approval, but FDA may seek earlier assessment at six months or one year for particularly high-risk products.
An assessment could indicate that the REMS program is no longer needed, but it's not clear what criteria would support such
It's important for manufacturers to fully define their REMS' goals in terms of specific measurable objectives, because failure
to achieve those benchmarks could carry serious legal consequences. Manufacturers that fail to meet stated goals, whether
for distributing Medication Guides or signing up prescribers for educational programs, could face stiff fines and penalties.
The details regarding what manufacturers need to do to conduct an appropriate assessment, however, are not clear, points out
attorney Howard Dorfman of Ropes and Gray in New York. "Will a pharma company be liable if CVS doesn't hand out MedGuides
in a timely way?" he asked at a seminar on the REMS program in February sponsored by the Food and Drug Law Institute (FDLI).
REMS assessment is the hardest thing, said Wayne Pines of APCO Worldwide, a strategic communications firm, at the meeting.
"Measuring the number of MedGuides handed out is easy; assessing the public-health impact is much more difficult."
At the same time, complying with REMS requirements could provide added protection for manufacturers against future product
liability suits. A firm that meets all REMS requirements, along with other postmarketing policies established by FDAAA, may
gain support for a preemption defense against lawsuits, Dorfman noted. Clear guidelines on what constitutes success in REMS
implementation and in establishing sound pharmacovigilance programs would support that strategy.