Checklist for Building a Successful Risk Evaluation and Mitigation Strategy (REMS) Program

What is REMS?

A Risk Evaluation and Mitigation Strategy (REMS) is a critical component of modern pharmaceutical regulation, designed to ensure that medications with serious safety risks are used safely and effectively. Established by the FDA under the FDA Amendments Act of 2007, REMS programs provide essential information and tools to both patients and healthcare providers. By informing stakeholders about the risks associated with specific drugs, REMS programs aim to prevent misuse and enhance patient safety. The FDA can mandate a REMS at various stages of a drug's lifecycle — either pre- or post-approval — based on safety evaluations and emerging data. A REMS can be linked to a specific drug or to a drug class that shares common risk/benefit characteristics.

Why is REMS Important?

The implementation of REMS programs is crucial because they impact pharmaceutical companies, patients, and the entire healthcare ecosystem. Various stakeholders, including prescribers, pharmacies, and insurance providers, are influenced by these programs. REMS foster a collaborative approach to medication safety, protecting public health and maintaining healthcare integrity.

For pharmaceutical companies, REMS are essential for regulatory compliance and market access, demonstrating a commitment to patient safety and enhancing their reputation. Healthcare providers gain critical information through REMS that aids in informed decision-making and improves patient outcomes. Patients benefit from educational materials that promote safe medication use and early recognition of adverse effects. Pharmacies ensure compliance by meeting REMS requirements before dispensing medications. Insurance providers use REMS to guide coverage decisions, manage risks, and potentially lower healthcare costs. Regulatory bodies like the FDA rely on REMS to ensure that the benefits of medications outweigh their risks, safeguarding public health.

Navigating the Regulatory Landscape

Title 21 of the Code of Federal Regulations (CFR) outlines the criteria for when the FDA can require a REMS. These guidelines, while broad, depend on factors such as the population size, the severity of the disease, potential adverse events, and the expected benefits and duration of treatment.

REMS Requirements: Pre- and post-approval

A REMS can be required both pre- and post-approval. In a pre-approval scenario, the FDA may require a REMS if the drug's risks are significant compared to its benefits, allowing expedited approval for sponsors who address these concerns through a REMS. Before REMS programs, sponsors might receive a Complete Response Letter (CRL), indicating an unacceptable risk-benefit profile and a need for more data. Now, the FDA may approve the drug with an appropriate REMS bypassing prolonged regulatory delays.

Post-approval REMS can be required if new safety information emerges helping ensure ongoing drug safety as it reaches wider populations. New safety data often arise through adverse event reporting after approval, reflecting clinical use and expanded patient exposure.

REMS Factors to Consider

The FDA evaluates several factors to determine the necessity of a REMS, including:

• Size of the population likely to use the drug
• Severity of the disease
• Expected drug benefits
• Duration of treatment
• Severity of known or potential adverse events 
• Regulatory precedents

REMS Checklist: Five Essential Components

A REMS program must include five core components:

• Administrative Information
• REMS Goals
• REMS Requirements
• REMS Assessment Timetable
• REMS Materials

1. Administrative Information

Document all relevant administrative details, such as applicant numbers, approval dates, and revision history to ensure transparency and maintain a clear record.

2. REMS Goals

The REMS Goals section should define the primary health outcomes the REMS aims to achieve. Since risk mitigation goals are not always directly measurable, intermediate measurable objectives that signal progress. For instance, a REMS for a drug with renal toxicity might reduce renal failure risks, with measurable objectives like regular serum creatinine testing and appropriate follow-up management based on the results.

3. REMS Requirements

Define the responsibilities of both REMS participants and applicants. REMS participants may include stakeholders in clinical assessment, prescribing, dispensing, administering, or monitoring or distributing the drug—such as healthcare providers, patients, pharmacies, and wholesalers.

REMS Participant Requirements

Outline the activities that participants must undertake under the REMS with Elements That Assure Safe Use (ETASU). Applicants are responsible for ensuring compliance and addressing any noncompliance. If no specific requirements apply, omit this sections from the REMS document.

Requirements should be organized into tables, with separate tables for each participant type. Include columns for the participant's role, timing of requirements, specific actions, and the materials needed for compliance.

Key components

• REMS Participant: Identifies the stakeholders involved, such as prescribers, patients, pharmacies, and distributors.
• Timing: Indicates when the requirements should be fulfilled.
• Requirement: Specifies actions, such as monitoring patient reactions or enrolling patients in the REMS.
• REMS Material: Refers to compliance documents, which should be hyperlinked in tables and included in the REMS document.

REMS Applicant Requirements

Outline the responsibilities, typically including:

• Training Development: Create REMS training materials for healthcare providers, with knowledge assessments and a delivery method (e.g., online, in-person).
• Communication: Develop and distribute REMS materials on risks and safe drug use, specifying recipients, material types, dissemination methods, and timing.
• Operational Support: Establish systems, like databases and call centers, to facilitate REMS compliance.
• Compliance Monitoring: Evaluate participant compliance with REMS requirements through audits and ensuring effective process function.

4. REMS Assessment Timetable

Specifies the intervals for submitting REMS assessments, ensuring regular evaluations.

5. REMS Materials

If the FDA deems a REMS is necessary, the agency may require one or more REMS materials, including enrollment forms, educational resources, medication guide, patient inserts, counseling tools, and patient-provider agreements. Materials should be organized by participant relevance, with actual materials appended (except for the medication guide).

REMS Key Points & Takeaways

• The FDA can mandate a REMS if additional safety measures are required. Drug sponsors are responsible for REMS development, which the FDA reviews and approves.
• REMS may be required pre- or post-approval.
• Each REMS has unique safety measures specific to the associated risks of a drug or drug class.
• Healthcare professionals and distributors may need to follow safety procedures before prescribing, shipping, or dispensing a drug.

ProPharma Can Help with REMS

Has the FDA required you to develop a REMS program for your product? We can assist you in creating and implementing a successful REMS program that complies with FDA requirements. To learn more about our services and how we can help you achieve successful interactions with the FDA, contact us today.

Reference:

FDA Guidance for Industry: Format and Content of a REMS Document