Format and Content of a REMS Document Guidance for Industry (US-FDA)

This guidance provides recommendations for the format and content of a risk evaluation and mitigation strategy (REMS) document for a prescription drug product, including a biological drug product.2 A REMS document, which is part of a REMS that is required by FDA, establishes the goals and requirements of the REMS.

This guidance provides recommendations to applicants on drafting proposed REMS documents and converting an already-approved REMS document to a new, standardized format that is clearer, more informative, and supports submission of a REMS document in Structured Product Labeling (SPL) format.

This guidance provides an overview of the types of information that should be included in a REMS document. Additional and more detailed information is provided in a separate guide, REMS Document Technical Conformance Guide, which will be updated periodically and is available on FDA’s website.3 The guide can be used for drafting a REMS document for single product and shared system REMS and includes an outline for drafting a Bifurcated4 REMS document. This guidance and the technical conformance guide are intended to help ensure thatREMS documents are clear, understandable to stakeholders, and to the extent possible, consistent in content and format, and support submission of a REMS document in SPL format.

This guidance does not provide detailed information on the format and content of other documents that are part of a REMS submission, such as the REMS materials5 or the REMS supporting document.6 Furthermore, the guidance does not include information on how to design, implement, and evaluate a REMS or to submit revisions and modifications for a REMS.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.

II. BACKGROUND

A. FDA’s REMS Authority

Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FD&C Act)(21 U.S.C. 355-1) establishes FDA’s REMS authority. A REMS is a required risk management strategy that can include one or more elements to ensure that the benefits of a drug outweigh its risks.

If FDA determines that a REMS is necessary,a patient package insert,7 the Agency may require one or more REMS elements, which could include a Medication Guide, a communication plan and/or certain packaging and safe disposal technologies for drugs that pose a serious risk of abuse or overdose.8 FDA may also require elements to assure safe use (ETASU) as part of a REMS.9 ETASU may be required if the drug has been shown to be effective, but is associated with a specific serious risk and can be approved only if, or would be withdrawn unless, such elements are required as part of a strategy to mitigate a specific serious risk(s) listed in the labeling of the drug. ETASU may be required for drug products initially approved without ETASU when other elements are not sufficient to mitigate a serious risk.

Specifically, ETASU may include one or any combination of the following requirements:

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 be dispensed to patients only in certain health care settings, such as hospitals

• The drug be dispensed to patients with evidence or other documentation of safe use conditions, such as laboratory test results

• Each patient using the drug be subject to monitoring

• Each patient using the drug be enrolled in a registry

If a REMS includes certain ETASU, the REMS may also include an implementation system to enable the applicant to monitor, evaluate, and improve the implementation of the element(s) (e.g., development of a REMS specific website or call center to facilitate enrollment; establishment of electronic databases of certified health care settings)

All REMS should include one or more goals. If the REMS has ETASU, the REMS must include one or more goals to mitigate a specific serious risk listed in the labeling of the drug and for which the ETASU are required.

Finally, REMS generally must include a timetable for submission of assessments of the REMS.13 The timetable for submission of assessments of the REMS must include an assessment by the dates that are 18 months and 3 years after the REMS is initially approved, and an assessment in the 7th year after the REMS is approved, or at another frequency specified in the REMS.

B. FDA’s Considerations for Changing the Format of the REMS Document

Since the approval of the first REMS in 2008, FDA has received public feedback on improving the REMS document.15,16 FDA has revised its recommendations on the format and content of the REMS document in response to the public’s feedback and to provide assistance with drafting a clearer, more informative, and standardized document. Additionally, this format supports submission of REMS documents in SPL format. 

The current format for the REMS document organizes the REMS requirements by who is responsible for implementing the requirement, when the requirement is to be implemented, what action is required, and with what REMS material(s). This format also makes greater use of tables and bulleted lists to better present and organize the information.