Balancing the Three-Legged Stool

The FDA Amendments Act of 2007 (FDAAA) is the most sweeping legislation affecting drug regulation in decades. It dwarfs PDUFA and constitutes major reform on multiple levels, transforming drug development and commercialization in the United States. The first wave of Risk Evaluation and Mitigation Strategies (REMS) mandated under FDAAA are due next month to the FDA to help ensure drug benefits outweigh risks. While this form of FDA oversight is not new, determining which drugs will be considered for REMS is a science that continues to evolve.

Jeffrey J. Stoddard, MD

A REMS program describes precisely how a drug will be prescribed in such a manner to help assure safe use and outlines the mechanisms by which prescribers and patients will be warned of the major risks associated with the drug. A timetable for submission of REMS assessments is also included, often with mandates related to risk communication, restricted distribution and dispensing, patient monitoring, and enrollment in patient registries. Under FDAAA, a REMS may be requested if the FDA believes a drug's risk–benefit balance may be shifting toward unfavorable.

The March 27th Federal Register notice identifying 16 "deemed drugs" may have led some to believe that only those drugs requiring a Performance Linked Access (PLA) system would be considered for REMS. However, the most recent product approvals (post-FDAAA passage) make it clear that drugs with only a Medication Guide are considered for REMS. Moreover, these approved REMS include specifications regarding the frequency of reporting and, perhaps more importantly, the content of the assessment, or REMS program evaluation.

For example, the REMS for one recently approved drug specified that the assessment must include:

• A survey of patients' understanding of the serious risk

• A report on periodic assessment of the distribution and dispensing of the Medication Guide in accordance with regulations

• A report of failures to adhere to distribution and dispensing requirements, and actions taken to address noncompliance.

The FDA's new authority may hasten the approval of at least some drugs, but most importantly the FDA is clearly willing to exercise its new authority and will certainly expect compliance.

REMS are new only in name. The concept, formalized via statutory language in FDAAA, has a rich history. The basic concept of maintaining access to the benefit that a drug can offer while minimizing its risk has long been central to prescription drug regulation, even for drugs with risk profiles that put them in a special category.

The evolution of REMS as a paradigm has now reached a stage where REMS programs routinely encompass multiple elements and functions. Not all functions apply to all REMS programs—there is no one-size-fits-all approach. Moreover, REMS programs evolve over time. Understanding the structural and operational elements of REMS, knowing how and when to apply each element, and creating workable, integrated, systems-based approaches whereby REMS functions are built into commercialization structures is not simple.

These programs by their very nature are likely to be in constant flux. The landscape on which they exist evolves and the programs themselves must inevitably evolve and adapt, not only to incorporate new technologies but to help assure that the three-legged stool of benefit, risk, and burden remains balanced.

Jeffrey J. Stoddard, MD, Vice President of Risk Management and Postmarketing Programs, Covance