DRW Monthly
May 2008
Issue No. 18

Impact of FDA's Risk Evaluation and Mitigation Strategy (REMS) Requirements on Drug and Biologics Industry

As part of the US Food and Drug Administration's (FDA's) implementation of the Food and Drug Administration Amendments Act of 2007 (FDAAA), the agency has notified 16 holders of drug and biological license applications that they are required to submit a proposed safety plan, or Risk Evaluation and Mitigation Strategy (REMS), by September 21, 2008. A REMS is defined as a strategy to manage a known or potentially serious risk associated with a drug or biological product.(1) REMS submissions will enable FDA to make more informed and substantiated determinations as to whether the benefits of a drug or biological product will outweigh its risks. In addition, if new safety information becomes available, the agency may also require manufacturers to provide a REMS for already approved drugs.

In the March 27th Federal Register, FDA identifies "those drug and biological products deemed to have a REMS" as those that have in effect, (as of March 25, 2008, the effective date of Title IX, subtitle A of FDAAA), "elements to assure safe use" as either required under 21 CFR 312.420 or 21 CFR 601.42 or otherwise agreed by the sponsor. In this context, "elements to assure safe use" are characterized by:

• health care providers with particular training or experience, or are specially certified to prescribe drugs;
• specially certified pharmacies, practitioners, or health care settings that dispense drugs;
• drugs dispensed to patients only in certain health care settings, such as hospitals;
• drugs dispensed to patients with evidence or other documentation of safe use conditions, such as laboratory test results;
• patients using drugs subject to certain monitoring; or
• patients using drugs enrolled in a registry.(2)

These elements have typically appeared in voluntary risk minimization action plans (RiskMAPs) that have been submitted by drug manufacturers to the agency since 2005. FDA's implementation of FDAAA's REM provisions has formalized the drug industry's practice of submitting these voluntary plans. In addition, under the FDAAA, a REMS may include a Medication Guide, a patient package insert, a communication plan for health care providers, an implementation system, restrictions on distribution or use, and a timetable for an assessment of the REMs(3). However, a drug or biological manufacturer who submitted only a Medication Guide prior to the approval of the FDAAA provisions, but provided no "elements to assure safe use", will no longer be "deemed to have a REMs" according to the act's provisions.

It is also worthwhile to mention briefly FDA's enforcement authority which is significant under the REMS provisions. Violations of REMS or a ruling that a drug or biological product is deemed "misbranded" can result in stiff civil monetary penalties of up to $250,000 per violation, or $1 million for all violations adjudicated in a single proceeding. Moreover, "if a violation continues after the sponsor receives a written notice; the penalty is $250,000 for the first 30-day period (or any portion thereof) that the violation continues, not to exceed $1 million for any 30-day period, and not to exceed $10 million for all violations adjudicated for a single proceeding."(4) The agency may, however, take into account whether a company is trying to correct a violation when assessing the civil penalty.

Despite a requirement to comply with stricter obligations, some drug manufacturers are pleased with the agency's implementation of the REMS provisions because it has enabled them to obtain approval for their products. For example, Adolor finds itself to be in a groundbreaking role as manufacturer of Entereg, the first drug product to be subject to the more restrictive provisions of REMS. The company is pleased with its status because it has finally received FDA approval to market its drug product after four years of delay. Entereg currently has the dubious honor of being included among five other drug products that have been stuck in the agency approval process, but is now being allowed to move forward as a consequence of REMS.(5)

On the other hand, there are also companies, particularly biological product manufacturers, who are uncertain as to how and when they will be required to file a REMS for high-risk drugs already on the market. It is apparent that the FDA will need to issue additional guidelines as the program progresses to ensure that industry understands how comply with these provisions. FDA is currently working on an interim guidance for industry that will describe the content and format of proposed REMS and will include a template and model REMS. It would also be helpful if the agency could work cooperatively with drug and biological manufacturers to fine-tune the procedures required to comply with the REMS program.

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