FDA REMS to Promote Closer Ties to Healthcare Professionals

A recent article from the Food Drug Law Institute (FDLI) Update Magazine, discussed a recent session entitled “The Impact of Safety, Risk Communications, and Product Liability on Advertising and Promotion Strategies.” The session was moderated by Geoffrey M. Levitt, Senior Vice President & Associate General Counsel, Regulatory & Policy, Pfizer, Inc., and Vice Chair, FDLI Board of Director.  

During the session, James N. Czaban, Chair, FDA Practice Group, Wiley Rein LLP and Michael McCaughan, Editor, The RPM Report and Founding Member, Prevision Policy LLC, discussed risk evaluation and mitigation strategy (REMS) and other marketing issues.  

This was an important session in light of FDA’s recent focus on REMS for opioids, and the release of the agency’s new blueprint on the topic.

Background of REMS

In September 2007, the Food and Drug Administration Amendments Act (FDAAA) were signed into law providing the FDA with expanded authority.  One of the new provisions gave FDA the authority to require that companies submit Risk Evaluation and Mitigation Strategies (REMS) when deemed necessary to ensure that a drug or biological product’s benefits outweigh the risks.

FDA may now require REMS for any New Drug Application (NDA), Abbreviated New Drug Application (ANDA), or Biologic License Application (BLA) at any stage of the product lifecycle when the FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks.

If the FDA requires a REMS, the manufacturer has 120 days to submit a proposed REMS if it is for a marketed drug. For a new drug, the manufacturer must include the proposed REMS as part of its NDA submission.  Once approved, the REMS creates enforceable obligations for the manufacturer and the FDA.

REMS Requirements

To assist manufacturers in developing REMS, the FDA issued a guidance for industry in September 2009.  Additionally, FDA has outlined the specific elements that should be included in the proposed document.  FDA recommended that the proposed REMS should be concise and specific and include the goal(s) along with the explicit components that will be developed to ensure that the drug will be used safely and appropriately.  The manufacturer should also describe how it intends to evaluate whether the REMS is meeting its goal(s) and objective(s) at various time points from the time of launch and beyond.

FDA also more recently issued REMS guidance last March.

Failure to comply with FDA REMS requirements can render the company’s drug misbranded and result in substantial penalties (e.g., $250,000 to $1 million cap per violation; $1 million to $10 million cap per proceeding). Proposed REMS may contain any of the following elements:

• Medication Guide – Document written for patients highlighting important safety information about the drug; this document must be distributed by the pharmacist to every patient receiving the drug.
• Communication Plan – Plan to educate healthcare professionals on the safe and appropriate use of the drug and consists of tools and materials that will be disseminated to the appropriate stakeholders.
• Elements to Assure Safe Use (EASU) – These are strictly controlled systems or requirements put into place to enforce the appropriate use of a drug. Examples of EASUs include physician certification requirements in order to prescribe the drug, patient enrollment in a central registry, distribution of the drug restricted to certain specialty pharmacies, etc.
• Implementation Plan – A description of how certain EASUs will be implemented.
• Timetable for Submission of Assessments – The frequency of assessment of the REMS performance with regard to meeting the goal(s) and objective(s). FDA requires that assessments be conducted at 18 months, 3 years, and 7 years post-launch, at a minimum. Results of these evaluations must be reported to the FDA and will determine whether additional actions or modifications to the REMS program are required.

A drug’s REMS program may not require the provision of all the components above, as the specific components a REMS program employs will vary based on the severity of the risks, the population likely to be exposed, and other factors. Most common REMS only require the provision of a medication guide. While REMS components are not uniform, some do and will contain new provisions and requirements for physicians and other certified health care providers.  

REMS Discussion 

McCaughan identified the impact of a shift in the regulatory scheme, especially with the implementation of “mini-Sentinel” and the soon-to be implementation of the Sentinel system mandated under the Food and Drug Administration Amendments Act of 2007 (FDAAA).   During this explanation, McCaughan observed two models. 

The first model is REMS as mandated under section 901 of FDAAA—that is, the letter of the law—but also the “spirit” of REMS.  Both elements of this model confirm the value of marketing, according to McCaughan insomuch as they work through sponsors via the regulation. 

The second model McCaughan identified was Sentinel.  As FDLI noted, “under this model, FDA works outside the traditional biopharmaceutical sponsors via collaborations.  This model, therefore, challenges the central role of the sponsor in product communication.”  He noted that while the Sentinel model has “revolutionary implications,” it has only had a “modest impact so far.”  Levitt noted that “if Sentinel does what it is supposed to do, the program may provide more structure, but if not, some other structure or program will.” 

McCaughan also recognized that FDA’s focus on approval is not just safety and that the agency “must consider efficacy, the population needing a particular drug, and why it is needed, in a patient-centered risk/benefit analysis.” In this new model, the sponsor is not the center, but neither is FDA, McCaughan asserted.  “Safety surveillance is the focus, but comparative effectiveness research is the implication.” 

Consequently, Czaban’s presentation on drug marketing in “the Age of REMS” focused more on identifying the “silver lining” to REMS.  He suggested that “REMS could provide an incentive for further development of a drug and might not merely impose marketing restrictions that make it “impossible” to sell.”  For example, he asserted that REMS would “result in closer ties to healthcare professionals through required marketing strategies and multiple marketing tactics.”  He recognized that many positive qualities of REMS include: 

• Requirements for direct mail,
• Requirements to run print advertising in journals,
• Targeting and using key opinion leaders in speaker bureaus,
• Collaboration between marketing and medical science liaisons, and
• Targeting and tracking prescribers.  

Stepping back to look at the big picture, Czaban concluded that REMS are a burden, but also an opportunity from the marketing perspective.  The key, he identified, is how healthcare professionals view the “barrage” of REMS information, and how (or if) their behavior changes in response.