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Background Materials for REMS Standardization and Evalution Public Meeting

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1   Introduction

   1.1   REMS Regulatory History and Previous Stakeholder Feedback

       1.1.1   REMS Regulatory History

       1.1.2   Previous Stakeholder Feedback on REMS

   1.2   The REMS Integration Initiative

       1.2.1   REMS Policy Workgroup

       1.2.2   REMS Evaluation Workgroup

       1.2.3   REMS Design and Standardization Workgroup

2   General REMS Background

    2.1   Development of REMS

    2.2   Approval of REMS

    2.3   The Content of a REMS Submission

3   REMS Tools

    3.1   Communications to Healthcare Providers

       3.1.1   Letters

       3.1.2   Websites

       3.1.3   Journal Information Pieces

    3.2   Training of Healthcare Providers

       3.2.1   Training Materials

       3.2.2   Prescribing Information

       3.2.3   Program Overviews

       3.2.4   Knowledge Assessments

       3.2.5   Other Training Tools

    3.3   Enrollment and Certification of Healthcare Providers

       3.3.1   Enrollment Forms and Prescriber Agreements

   3.4   Initiation of Therapy and Patient Counseling

       3.4.1   Counseling Tools for Healthcare Providers

       3.4.2   Patient-Prescriber Agreements and Patient Enrollment Forms

       3.4.3   Medication Guides and other Patient Educational Materials

       3.4.4   Prescription Order Forms

    3.5   Ongoing Patient Care

       3.5.1   Verification of Benefit and Treatment Maintenance Forms

       3.5.2   Patient Monitoring and Monitoring Forms

       3.5.3   Verification of Safe Use Conditions

       3.5.4   Tools for Managing Care Transitions

   3.6   Adverse Event Reporting

       3.6.1   Patient Registries for Adverse Event Reporting

       3.6.2   Adverse Event Reporting Forms

    3.7   Distribution Controls

       3.7.1   Distributor Enrollment Forms

4   REMS Evaluation

    4.1   Current Methods for Assessing REMS

    4.2   FDA’s Approach to Building a Future REMS Assessment Framework and Guidance

       4.2.1   Factors Driving the Need for Improved REMS Assessment Methodologies

       4.2.2   Principles Guiding the Development a REMS Assessment Framework

       4.2.3   REMS Assessment Framework Options and Feasibility

       4.2.4   REMS Assessment Guidance Development  


1   Introduction

On July 25 and 26, 2013, FDA will hold a public meeting on the standardization and evaluation of Risk Evaluation and Mitigation Strategies (REMS). The purpose of this public meeting is to obtain feedback from stakeholders on: (1) issues and challenges associated with standardizing and assessing REMS for drug and biological products and (2) identifying potential projects that will help standardize REMS and integrate them into the health care delivery system. FDA is seeking information and comments from a broad range of stakeholders, including health care providers, prescribers, patients, pharmacists, distributors, drug manufacturers, vendors, researchers, standards development organizations, and the public.

To help prepare this meeting, FDA has developed this background document to familiarize stakeholders with our experience with REMS since they were first introduced in 2007.

1.1 REMS Regulatory History and Previous Stakeholder Feedback

1.1.1 REMS Regulatory History

REMS were introduced by the Food and Drug Administration Amendments Act (FDAAA) of 2007.1 FDAAA authorizes FDA to require a REMS for a drug if the FDA determines that a REMS is “necessary to ensure the benefits of the drug outweigh the risks of the drug.” The law authorizes FDA to require sponsors submitting new drug applications (NDAs), abbreviated new drug applications (ANDAs), or biologics license applications (BLAs) to submit a proposed REMS as part of such application, if the FDA determines that a REMS is necessary. FDAAA also authorizes FDA to require holders of applications approved without a REMS to submit a proposed REMS if the FDA becomes aware of new safety information and determines that a REMS is necessary to ensure the benefits of the drug outweighs its risks. Sponsors may also propose a REMS for their drugs at any time and submit this proposal to FDA.

Before FDAAA was enacted, FDA approved a small number of drug and biological products with risk minimization action plans (RiskMAPs). Like a REMS, a RiskMAP is a strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits. Many of the principles used to develop RiskMAPs are embodied in the FDAAA REMS provisions as implemented by FDA. Certain products with RiskMAPs that contained elements to assure safe use that were in place prior to the enactment of FDAAA, were deemed to have, in effect, a REMS, and have been or will be converted to a REMS.

If appropriate, a REMS may be approved with elements to assure safe use, otherwise known by its acronym “ETASU.” REMS with ETASU are discussed in various contexts throughout this document. ETASU are established to mitigate a specific and serious risk listed in the labeling of the drug. Depending on the risk, ETASU might include one or more of the following: health care providers who prescribe the drug have particular training or experience, or are specially certified; pharmacies, practitioners, or health care settings that dispense the drug are specially certified; the drug may be dispensed only to patients in certain health care settings (such as in hospitals or infusion centers); the drug is dispensed to patients with evidence or other documentation of safe-use conditions (for example, liver enzyme tests, pregnancy tests); each patient using the drug may be subject to certain monitoring; or each patient using the drug must be enrolled in a registry.

1.1.2 Previous Stakeholder Feedback on REMS

FDA has regularly sought and received stakeholder feedback with regard to REMS in a variety of forums. In July 2010, FDA held a public meeting to obtain input on issues associated with the development and implementation of REMS. In June 2012, FDA held a public workshop to discuss survey methodologies and instruments that can be used to evaluate patients’ and health care providers’ knowledge about the risks of drugs marketed with an approved REMS.

Additionally, FDA has received feedback at a number of advisory committee meetings. FDAAA requires the Agency to bring, at least annually, one or more drugs with REMS with ETASU before the Drug Safety and Risk Management Advisory Committee (DSaRM) to discuss whether the REMS with ETASU assures safe use, is or is not unduly burdensome to patient access, and to the extent practicable, minimizes the burden to the healthcare delivery system. FDA also regularly discusses both pre- and post-approval REMS with ETASUs with various FDA advisory committees when discussing specific product applications.

In 2011, FDA created the REMS Integration Initiative (see Section 1.2), designed to review and improve the agency’s implementation of REMS authorities. A key component of this initiative is stakeholder outreach; through the REMS Integration Initiative, FDA is engaged in ongoing outreach to a wide range of stakeholders to understand how existing REMS programs are working and where opportunities for improvement lie. For example:

  • On March 8, 2013, FDA hosted a meeting with PDUFA stakeholders to inform them of the activities of the REMS Integration Steering Committee’s three Workgroups and to hear their comments on REMS.2
  • From April through June 2013 FDA held a series of fifteen teleconferences with patients and their caregivers, pharmacists working in diverse inpatient and outpatient care settings, and prescribers, about their experience with REMS.
  • On May 16, 2013, the Drug Safety Oversight Board held a meeting with the Agency’s federal partners, including the Veterans Health Administration, Department of Defense, National Institutes of Health, Agency for Healthcare Research and Quality, and the Indian Health Service. FDA’s federal partners offered feedback about how well REMS programs were working for them, and where they saw opportunities for standardization and better integration into their systems.3  
  • On May 23, 2013 FDA participated in a conference on REMS sponsored by Trends Emerging in Risk Management (TERM). At this conference, FDA discussed its REMS assessment framework and received comments from risk management experts drawn from academia, industry and government.4

FDA is also exploring options for expert panel discussion of standardized methods for assessing and characterizing risks and selecting appropriate REMS tools and interventions. In addition to the meetings and teleconferences noted above, FDA announced the opening of a docket, FDA-2013-N-0502, in the May 22, 2013 Federal Register notice of the July 25-26 public meeting on REMS, to receive public comments on REMS.5

This docket will remain open indefinitely, so that stakeholders can continue to submit their comments after the July 25-26 public meeting. (Please note that although the docket will remain open indefinitely, FDA will not be able to consider comments submitted after September 16, 2013 in the report on REMS standardization that will be published in 2014.)

1.2   The REMS Integration Initiative

The goals of the REMS Integration Initiative are to develop guidance on how to apply statutory criteria to determine when a REMS is required, to improve standardization and assessment of REMS, and improve integration of REMS into the existing and evolving healthcare system.

To support the REMS Integration Initiative, the FDA Center for Drug Evaluation and Research (CDER) REMS Integration Steering Committee (RISC) oversees the activities of three workgroups focusing on issues related to REMS policy, REMS evaluation, and REMS design and standardization. Deliverables include fulfillment of commitments FDA made under the Prescription Drug User Fee Act (PDUFA V),6 reauthorized on July 9, 2012 as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012.7

1.2.1   REMS Policy Workgroup

The REMS Policy Workgroup is developing a draft guidance to provide information about how FDA applies the factors specified in Section 505-1(a) of the Food, Drug and Cosmetic Act (FDCA), as well as other factors, to determine whether a REMS is necessary to ensure that the benefits of a drug outweigh the risks. FDA expects to publish this draft guidance in 2014. The guidance will incorporate the considerations FDA takes into account in current benefit-risk assessments of drugs to maximize the Agency’s consistency in decision-making about the need for REMS. The guidance will also provide information about when it may be appropriate to employ measures other than a REMS to address a serious risk. FDA is considering the important characteristics of a drug and its serious risk(s) that would suggest product labeling is insufficient to communicate the drug’s risks and conditions of safe use, thereby failing to provide reasonable assurance that the risks will be appropriately managed within the existing healthcare setting. Information about the specific aspects of the healthcare delivery system that indicate certain REMS elements and/or tools are unnecessary or otherwise redundant is also of interest to FDA, as is the level and type of serious drug risks patients are willing to accept and under what circumstances, and how this should be factored into decisions about REMS.

1.2.2   REMS Evaluation Workgroup

The Evaluation Workgroup is developing an evidence-based approach, including a REMS Assessment Framework, to assess the effectiveness and burden of REMS. The Workgroup is soliciting stakeholder input on ways to set appropriate goals/objectives and performance levels for REMS, and appropriate metrics and measurement systems assessing performance and improvements for behaviors, outcomes, burden and access. FDA expects to publish a draft guidance on evaluation methodologies in 2014. Additional details about the information needs of the Workgroup and the report are included in the Federal Register Notice.8

1.2.3   REMS Design and Standardization Workgroup

The REMS Design and Standardization Workgroup is working to reduce unnecessary variation in REMS by establishing best practices in the design and implementation of REMS. The workgroup recognizes that some variation in REMS is necessary and unavoidable: The risks that REMS seek to address vary, as do the patient populations and settings in which those drugs are used, leading to significant variation in how those risks should be addressed. However, there are cases in which common standards and “best practices” can be established and applied across a range of REMS to make REMS more predictable, more effective, and less burdensome to healthcare providers and patients.

With that in mind, the standardization workgroup has embraced two key goals as it seeks to standardize REMS: (1) the Workgroup seeks to develop standardized and evidence-based methods to characterize risks and identify appropriate interventions so that REMS that address similar risks in similar settings will use similar approaches to mitigate that risk, and (2), to identify and incorporate best practices to maximize the effectiveness of specific REMS tools and minimize their burden. A key part of achieving the second goal is ensuring that these specific REMS tools are integrated into the existing, evolving, and increasingly electronic health care delivery system. 

 2   General REMS Background

2.1   Development of REMS

Once FDA determines that a REMS is necessary to ensure the benefits outweigh the risk, FDA communicates the requirement for the REMS, including the necessary REMS elements (e.g., communication plan REMS, ETASU), to the applicant. The applicant submits a proposed REMS that includes the goals of the REMS, the required elements, and the specific REMS tools (e.g., letters to healthcare providers and professional societies, healthcare provider and patient certification, documentation of safe use conditions). The applicant also includes a proposal for how it plans to assess the effectiveness of the REMS (assessment plan).

FDA reviews the REMS proposal and discusses details of the REMS with the sponsor, including implementation and assessment plans. REMS programs are developed by the individual sponsors and the specifics of these programs are negotiated between the sponsors and FDA. As the REMS is being developed sponsors may engage stakeholders in the development of REMS. For products that are not yet approved, FDA is limited in its ability to discuss a proposed REMS with stakeholders because of the confidential nature of the drug review process.

2.2   Approval of REMS

When a REMS is approved, FDA sends a letter to the sponsor documenting approval of the REMS. These letters describe and clarify the risks that the REMS is intended to mitigate and include a description of the REMS and REMS Assessment Plan. When a REMS is approved, it is the responsibility of the sponsor to implement the REMS program.

Every REMS includes a timetable for submission of assessments of the REMS. Sponsors are required to submit the assessment of their REMS according to the dates specified in the timetable. The statute does not specify how the REMS should be assessed, only that that an assessment of a REMS for a drug shall include, with respect to each goal included in the REMS, an assessment of the extent to which the REMS, including each REMS element, is meeting the goal or whether one or more such goals or elements should be modified.

FDA reviews REMS assessment reports to evaluate whether the REMS is meeting its goals. There are challenges when evaluating the effectiveness of REMS because outcome data are often incomplete or unavailable. Since many drugs with a REMS were approved with a REMS in place, a “pre-REMS” comparison cannot be made. Even when REMs are implemented postmarketing, there are often insufficient data and problems comparing the pre- and post-REMS periods. FDA’s experience with REMS assessments is described in greater detail in section 4.2, “Current Methods for Assessing REMS.”

A REMS may need to be modified in response to a REMS assessment, a reassessment of a product’s benefit-risk profile at the time of approval for a new indication, or the emergence of new safety information. REMS modification may comprise addition, removal, or otherwise changing of any goal, element, or tool of the approved strategy.

2.3   The Content of a REMS Submission

The REMS that are submitted and approved by FDA take the form of a series of documents and materials, which FDA makes available to the public at its approved REMS website. The REMS includes the goals of the REMS, the REMS elements and the requirements under those elements, and the REMS tools.

The Goals section of the REMS document describes the desired safety-related health outcome of the REMS. The format of goals has varied significantly, but goals are often divided into two sections: a heading that describes the overall desired safety or health outcome, and sub-headings that describe the means by which this goal is achieved.

The Elements section of the REMS document describes all of the major components of the REMS, which may include a medication guide, communication plan, ETASU, or an implementation system. REMS for NDAs and BLAs must include a timetable for submission of assessments.

Within the ETASU section of the REMS document are a number of sub-headings describing specific aspects of the REMS’ ETASU. These sub-headings often provide a good overview of the high-level requirements that stakeholders must meet. The language used in the sub-headings is often similar to the language used in section 505-1(f)(3)(A-F) of the Food, Drug and Cosmetic Act to describe FDA’s authorities to require ETASU, but the content of the sub-headings does not necessarily correspond directly to those authorities.

In addition to the REMS document, FDA also reviews and approves “Appended Materials,” which are materials directed towards healthcare providers and patients. These include administrative forms such as enrollment forms for prescribers, patients, and dispensers, as well as training and educational materials. Specific types of appended materials are described in REMS Tools, (see section 3 of this document.)

Details about REMS implementation are typically included in the REMS Supporting Document. The REMS Supporting Document also includes the sponsor’s proposed REMS assessment plan. The REMS Supporting Document is not made available on FDA’s REMS website.

Once approved, the REMS document and the appended materials are the basis for enforcement of the REMS. 

Next section:  3  REMS Tools



1. See 'Food and Drug Administration Amendments Act (FDAAA) of 2007'

2. Minutes of the March 8, 2013 PDUFA stakeholder meeting

3. Summary of the May 16, 2013 Drug Safety Oversight Board meeting

4. The agenda for this summit is available at http://coral.ie.lehigh.edu/~TERM-SUMMIT/

5. www.gpo.gov/fdsys/pkg/FR-2013-05-22/pdf/2013-12124.pdf

6. http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm272170.htm

7. See Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012

8. www.gpo.gov/fdsys/pkg/FR-2013-05-22/pdf/2013-12124.pdf

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