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 a conclusion.
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.