The Food and Drug Administration is requiring Risk Evaluation and Mitigation Strategies (REMS) on most new drugs and biotech
therapies, creating uncertainty among manufacturers as to what information the agency wants, and when. While many REMS programs
require only distribution of a Medication Guide to patients, they all carry timetables for periodic assessment, which is turning
out to be a serious challenge.
Compounding these problems is a growing number of REMS for drug classes, which are more complex to establish and administer.
The FDA recently finalized a REMS for erythropoiesis-stimulating agents (ESAs) used in cancer treatment and called for a class-wide
REMS for long acting asthma drugs. A broader REMS for ESAs in renal treatment is in the works; additional initiatives may
be launched for anti-seizure drugs and for antidepressants; and work continues on a multi-product REMS for long-acting opioid
Meanwhile, the FDA is struggling to review and monitor these programs with limited staff and resources. The result is delays
in providing needed guidance for industry and in answering many questions about how to implement REMS procedures. FDA staffers
are mulling over dozens of comments to a draft guidance on REMS format and assessment that was issued last September. In addition
to concerns raised by drug and biotech manufacturers, pharmacists, health plans and payers fear that too many REMS will impose
added burdens on the nation's medical system and will raise healthcare costs overall.
ETASU AND ASSESSMENTS
The FDA has approved nearly 100 new REMS since the program went into effect in March 2008, as required by the FDA Amendments
Act of 2007 (FDAAA). Most REMS (71) only involve MedGuides, but 23 also require communication plans that usually involve letters
to healthcare providers. In addition, the FDA has determined that 16 drugs that already had restrictive risk management programs
before FDAAA were deemed to have REMS under the new policy. Those manufacturers had to submit REMS plans, but so far, the
FDA has approved only two of them.
The FDA also can determine that a REMS is needed for other already-approved drugs based on the emergence of new safety information.
In such cases, 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, but that raises compliance uncertainties. Although
revisions to a REMS require prior approval, sponsors can inform the FDA of labeling changes through a changes-being-effected
supplement. This leaves manufacturers in a quandary over whether to update labeling right away to reflect new safety issues,
or to wait for approval of changes to the REMS.
The most risky therapies have to establish REMS programs with elements to assure safe use (ETASU). These may involve a range
of costly and complex risk management programs: training and certification of health professionals; limited product distribution;
and patient monitoring, testing, or enrollment in registries.
All REMS programs, even MedGuide-only versions, require periodic assessment to determine if the program is meeting stated
goals. FDAAA stipulates that assessments must be conducted at 18 months, three years, and seven years following product approval,
but the FDA may call for earlier assessment at six months or one year for particularly high-risk products.
The big issue with assessments is how manufacturers should evaluate a REMS's success. "Measuring the number of MedGuides handed
out is easy; assessing the public health impact is much more difficult," noted Wayne Pines of APCO Worldwide at a February
seminar on REMS sponsored by the Food and Drug Law Institute (FDLI). A clear definition of objectives is important because
manufacturers that fail to meet goals could face stiff fines and penalties. It's not obvious, though, how a drug company could
compel pharmacies to distribute MedGuides or follow dispensing requirements.