Jill Wechsler

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 drugs.

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 FDA staffers are mulling over dozens of comments to a draft guidance on REMS format and assessment that was issued last September.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.

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.