On September 30th, FDA issued draft guidance, “Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments and Proposed REMS Modifications”. While much of this draft guidance is a codification of what’s already been happening in practice over the past 2 years, there are some interesting aspects in the guidance for those working in the REMS space to contemplate. This is the fifth in an ongoing series of blog articles about this important document.
Our first four articles covered the background of FDAAA and REMS, an overview of a REMS submission and greater detail about the “Proposed REMS” and “REMS Supporting Document”, and REMS submissions and communications with FDA.
In this fifth and final article, we address our preliminary interpretation of the draft guidance, as well as opportunities for industry to respond and propose further improvements.
Our preliminary review and interpretation is that there is much in the draft REMS guidance that is promising for manufacturers; in particular:
- FDA is retaining much from its previous RiskMAP guidance rather than introducing a significantly different approach. In practice, FDA has been implementing more frequent REMS than before but these have tended to be less restrictive. It appears that the desire to intervene appropriately without restricting access will continue.
- FDA is also reinforcing its RiskMAP guidance assessment expectations about the need to pre-define target levels of REMS performance over time. This answers one of the most frequently asked questions we hear from manufacturers, though it does not yet answer what is a reasonable target level to propose.
- That being said, FDA appears to be anticipating that upcoming REMS assessments will yield information that may require modifications to previous REMS programs to make them more or less robust. For most programs with only Medication Guides, this could mean improved or additional patient education (e.g., drug fact boxes), as well as Communications Plan elements for healthcare providers that emphasize counseling patients.
- FDA has introduced the possibility of modifying either REMS goals and/or elements based on assessment findings and potentially limiting REMS assessments to the initial 3-year period following launch. This may warrant manufacturers proposing more frequent (e.g., annual) REMS assessments over the initial 3 years to provide the data they need to justify a future reduction or the discontinuation of further assessments.
- FDA is opening the door to manufacturers to voluntarily conduct additional risk management activities outside of a REMS, which raises the importance of making strategic design decisions about which elements to include inside or outside of a REMS. These voluntary activities could include:
- Complementary benefit risk education/communication elements to enhance early REMS performance and increase likelihood of achieving goals
- Surrogate measures of REMS effectiveness (e.g., reach, distribution, awareness, and compliance) to be able to document early indicators of progress towards goal and whether early adjustments are needed
- More frequent assessments of overall REMS performance than was agreed in the initial timetable for submission of assessments to identify the need for early modifications
- FDA is requesting information about how a manufacturer has staffed and organized that portion of its organization responsible for REMS development and assessment. Manufacturers may need to rethink their staffing plans as a result of this request for additional organizational accountability.
Opportunities remain for manufacturers to work with FDA to propose enhancements to this draft REMS guidance, including:
- Defining more evidence-based risk assessment and benefit-risk assessment methodologies. Gaining agreement of REMS design based on evidence may help with consistency for particular risks and between programs.
- Clarifying FDA expectations of NDA and ANDA holders at the time of and after first ANDA approval. The guidance appears to indicate that requirements will lessen at the time of ANDA approval, but also leaves open to interpretation how this will be enforced.
- Proposing additional and/or enhanced REMS elements to improve REMS effectiveness. Many of the elements described in the guidance are essentially the same of those that have been used in the past. Enhancements to these past elements could include:
- New or improved patient tools to supplement or replace Medication Guides, such as drug fact boxes
- New or improved Communications Plan tools that employ adult learning principles, learning systems (e.g., simulations), and/or enabling tools (e.g., checklists) that have been used in other industries and could help support health care provider education and compliance
- New or improved Elements to Assure Safe Use and Implementation Systems to replace legacy systems with alternatives to increase effectiveness without reducing access
- Clarifying how manufacturers can design and assure FDA that voluntary risk management activities outside of a REMS will be initiated, managed, and reported. Do such elements have to be limited to only labeling? Are they under the jurisdiction of DDMAC? Is there a separate contractual obligation or opportunity?
- How to collectively begin to evolve a science of pharmaceutical benefit-risk management?