Samantha Hoopes, PhD, RAC is a Research Scientist at Rho involved in clinical operations management and regulatory submissions.  Samantha has over 10 years of scientific writing and editing experience and has served as lead author on clinical and regulatory documents for product development programs for a variety of therapeutic areas.

In January 2019, the Food and Drug Administration (FDA) released 2 draft guidance documents regarding assessment of Risk Evaluation and Mitigation Strategies (REMS).  Both of these draft guidances are under a comment period through 02 April 2019.  These documents are meant to provide industry additional information to more accurately assess the effectiveness of their REMS.

The Food and Drug Administration Amendments Act (FDAAA) created section 505-1 of the Food, Drug, and Cosmetic (FD&C) Act, which authorizes FDA to require Risk Evaluation and Mitigation Strategies for certain prescription drug and biologic products if the FDA determines that it is needed to ensure the benefits of the drug/biologic outweigh the risks (FDA REMS history webpage).  REMS are required in cases where there are specific serious risks related to a product and are not meant as a means to mitigate all adverse events.  Risk Evaluation and Mitigation Strategies can consist of a Medication Guide, a package insert, and/or a communication plan to inform key audiences about the risks of the product.  A REMS should be designed with specific risk mitigation goals consisting of specific objectives and safety-related outcomes.  The objectives should include metrics to indicate the program is meeting its goals when a goal cannot be measured directly.  As of 05 March 2019, FDA has approved 76 REMS.  Assessments evaluating the effectiveness of the REMS must be submitted 18 months, 3 years, and 7 years after the strategy is approved, or at other intervals specified in the strategy.  While REMS assessments are required in accordance with 505-1 of the FD&C Act, it does not describe how to design and conduct these assessments.

One of the recently released draft guidance documents, “REMS Assessment:  Planning and Reporting Guidance for Industry,” describes how to develop a REMS Assessment Plan.  A REMS Assessment Plan is a specific plan for how the applicant intends to assess the performance of the REMS in meeting its risk mitigation goals and objectives.  A REMS Assessment Plan should include the categories for evaluation and proposed process and/or outcome metrics.  The categories and some example metrics are provided in the table below.

While the above categories are meant to be broadly applied to REMS, there are some products for which a REMS with elements to assure safe use (ETASU) are required to allow patients safe access to drugs with known serious risks that would otherwise not be approved.  The FD&C Act states that the ETASU should not be unduly burdensome on patient access and the burden on the health care delivery system should be minimized.  This draft guidance also provides information on how to specifically assess both barriers to patient assess and burden on the health care delivery system when ETASU is required with a REMS.

Performance thresholds related to metrics should be specified in order to assess whether the REMS is meeting its goals and objectives.  The REMS Assessment Plan should specify a performance threshold for each health outcome of interest, if feasible.  If the health outcomes of interest for the REMS are difficult to measure directly, performance thresholds should be specified for surrogate metrics.  Proposed steps to achieve the performance threshold should also be noted in the event results indicate the threshold was not met. 

One or more data sources may inform the different categories in a REMS Assessment Plan.  Description and justification of the data source(s) and methodological approaches for assessing specific REMS goals and objectives should also be submitted to the FDA in support of the assessment plan.  Some sources of data could include:

• Applicant’s REMS data
  • Data may come from a database of certified/enrolled prescribers, dispensers, healthcare settings, distributors, or patients that may be required with the REMS.
• Drug utilization data
  • If a drug utilization study is included in a REMS Assessment Plan, it should describe the source of the data, rationale for use of the data source, data collection methodology, design and analytical approaches, and any limitations.
• Postmarketing adverse event data
  • Postmarketing adverse event data to be collected should be specified in the REMS Assessment Plan and focus on further characterizing the risk, capturing patient outcomes, and determining whether safe use conditions were met.
• Observational/epidemiology data
  • This guidance does not recommend a specific pharmaco-epidemiology study design as FDA intends to exercise a flexible approach; however, any potential challenges and limitations should be clearly stated in the study proposal.
• Root cause analysis data
  • FDA states that root cause analysis best practices consist of the development and use of a predefined protocol and a team-based reconstruction of each issue via retrospective review and interviews.
• Stakeholder outreach data
  • The guidance states that data from key stakeholders, such as prescribers, pharmacists, other healthcare professionals, and patients can inform the applicant and FDA about the impact of the program on the healthcare delivery system, patient access to the drug, and opportunities for improvement.
• Surveys

Surveys are commonly used to evaluate provider and patient understanding of the serious risks associated with, and safe use of, the product.

The “REMS Assessment:  Planning and Reporting Guidance for Industry” draft guidance also addresses how to submit the REMS Assessment Plan and REMS Assessment Reports to the FDA.  Appendices in this draft guidance include an example REMS Assessment Plan overview and additional examples of metrics.

Another draft guidance, “Survey Methodologies to Assess REMS Goals that Relate to Knowledge,” was recently released and provides best practices for survey design, conduct, and data analysis, to evaluate knowledge of REMS risks and safe use conditions.  This guidance describes the key information that should be included in the assessment survey protocol and the survey report of the results.  The guidance discusses endpoints, sample populations, sample size, participant recruitment, statistical considerations, and factors that may influence selection of survey administration modality, either self-administration or use of a trained interviewer.  Recommendations are provided for development of the survey questionnaire, including specific considerations for both patient and health care provider surveys.

It is important to note that FDA acknowledges there are limitations to assessments in cases of infrequently prescribed products, safety outcomes that occur rarely, and REMS establishment at initial approval where there may not be relevant baseline data for comparison (e.g., incidence of risk associated with the drug or drug use patterns).  REMS Assessment Plans should be developed to thoroughly assess effectiveness of the REMS by including more than 1 metric, data source, and methodology, and also acknowledging limitations and potential challenges.  FDA encourages anyone preparing a REMS to develop novel methods for assessing REMS effectiveness that may be appropriate for their specific product.

The FDA is accepting comments on both of these draft guidance documents, “REMS Assessment:  Planning and Reporting Guidance for Industry” and “Survey Methodologies to Assess REMS Goals that Relate to Knowledge,” through 02 April 2019.