On September 30th, FDA issued its long awaited draft guidance, “Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments and Proposed REMS Modifications”. While much of this draft guidance is a codification of what’s already been happening in practice over the past 2 years, there are a few interesting surprises (depicted in bold below) for those working in the REMS space to contemplate. This is the third in an ongoing series of blog articles about this important document.

Our first two articles covered the background of FDAAA and REMS relative to RiskMAPs and those RiskMAPs deemed to be REMS, an overview of a REMS submission, and greater detail about the more concise “proposed REMS” component of the REMS document submission. This article details the content of the more comprehensive “REMS Supporting Document”, which explains the rationale for, and supporting information about, the proposed REMS. A template for the REMS Supporting Document can be found on the www.fda.gov website.

In general, the REMS Supporting Document should include background, goals, supporting information about REMS elements, the REMS assessment plan, and other relevant information sections, as detailed below. It should include a description of how and when each element will be implemented and the rationale for timelines and milestones. If any activity is not going to be implemented at REMS approval, the document should state the rationale for the implementation schedule.

1. Background– Explanation of why a REMS is needed and a summary of how the Proposed REMS would ensure that the benefits outweigh the risks. For an approved product, a description of the new safety information that makes a REMS necessary should be included. The background section should also cover:

a. Risk characterization – Description of the risk (magnitude, severity, frequency), populations at risk, background incidence, preventability or reversibility, and preservation of benefits. It should also address the factors FDA uses to assess whether a REMS is needed to assure benefits outweigh risks: population size, seriousness of the underlying condition and expected benefit of the product, duration of treatment exposure, the risks and benefits of alternative treatments, and whether or not the drug is a NCE.

b. Regulatory precedents – Successes and failures of actions by regulators, health care systems, or manufacturers in mitigating the risks for the current or analogous products, and how any risk management plans submitted to other regulators support or are different than the Proposed REMS.

c. Other supportive evidence – Relevant past experiences, such as compatibility with existing product and health care delivery systems, avoiding implementation of ineffective tools, and other past experiences with similar products or programs. Brief descriptions of the evidence of effectiveness of each element may be included.

2. Goals – Rationale for the proposed goals and how each element and objective will contribute to achieving each goal. In addition to stating at least one overall REMS goal, goals should be stated for each Element to Assure Safe Use (if present).

3. Supporting information about proposed elements – Why the element(s) and tool(s) were chosen and how each will contribute to achieving the goal(s). Each element should be thoroughly described, together with any tools proposed to be implemented, how each will mitigate the risk, how each will conform with similar elements or tools for other products with similar risks, and whether each is compatible with existing product distribution and dispensing systems. The evidence of element and tool effectiveness should be provided including, if applicable, results from pretesting or when these will be submitted. It should also note any input from patients or other stakeholders and the feasibility regarding the feasibility of the REMS.

a. Elements to Assure Safe Use – Considerations for how to ensure access and minimize burden should also be addressed, including how the elements correspond to the risk, how the risk will be mitigated, verification that the mitigation elements are not unduly burdensome, how the burden on the health care delivery system will be minimized, and how the elements are designed to be compatible with established product distribution systems

b. Implementation Systems – Rationale and supporting information for the proposed implementation system, including methods for monitoring and evaluating implementation, and plans for improving implementation should be describe

c. Timetable for Submission of Assessment – Rationale and supporting information for the timetable should be provided, together with the rationale for the interval and planned dates for assessment submissions

4. REMS Assessment Plan – Rationale and supporting information for the plan to assess the REMS. Assessments should include evaluation of the extent to which each of the REMS elements are meeting the goals and whether the goals or the REMS elements should be modified. Plans to obtain this information should also be included.

a. This section should describe:

• iProposed evaluation methods (including measurements or measures with rationales) for overall REMS and each element
• Targeted values for each measure and the timeframe for achieving them, with expected best and worst case scenarios, related interpretations, and what will trigger REMS modification
• Type of data collected, as well as nature and timing of collection, analysis, audits, or monitoring to assess performance of each individual REMS element in achieving the REMS goals
• Plans to assess unintended or unfavorable consequences after implementation

b. Specific assessment instruments and methods should be included in the REMS Supporting Document. If not possible, the Supporting Document should be updated at least 90 days before the assessment is conducted to include the instrument and methodology and submitted as a new or modified document with changes marked and highlighted.

c. For REMS with Medication Guides, information needed for assessment should include a survey of patient understanding, report on periodic assessment of distribution and dispensing of the Medication Guide, and report of failures to adhere and corrective actions taken.

• If a product is distributed in a unit-of-use package that includes a Medication Guide with product dispensed to a single patient, then reports of distribution adherence are not needed

d. May include information describing the rationale and description of all elements proposed

e. Should include detail to identify the need for changes to the REMS and any corrective actions taken

f. All REMS assessments should include information about any post approval or clinical trial to investigate a safety issue

• For post approval studies, include status of each study and difficulties completing the study
• For post approval trials, include status, number enrolled, expected completion, difficulties completing and registration information
• Registration information with respect to registry and results databank requirements

5. Other relevant information – Information on the positions within the company responsible for REMS policy, management and implementation, including organizational charts that include these positions, as well as other relevant information not included elsewhere.

In subsequent postings, we will be covering “Section IV – REMS Assessment and Proposed REMS Modification Submissions” and “Section V – Communicating with FDA Regarding REMS”.

Written by Gary Slatko of Paragon Rx
October 7th, 2009