On July 9, 2019, the U.S. Food & Drug Administration (FDA) released the final guidance document “Risk Evaluation and Mitigation Strategies: Modifications and Revisions Guidance for Industry,” which provides information regarding “changes to approved risk evaluation and mitigation strategies (REMS),” the application process for proposed changes to REMS, and “how the FDA will process submissions.”

Not every pharmaceutical product approved by the FDA requires a REMS. “A REMS is a required risk management plan that uses tools beyond the prescribing information (the package insert) to ensure that the benefits of certain drugs outweigh their risks.” Following a REMS submission, an application holder might be inclined to submit proposed changes, or the FDA might require the submission of proposed changes. Application holders who find themselves in either position may turn to this final guidance document for direction.

Categories of REMS Changes

The FDA final guidance document categorizes changes to REMS as (1) REMS revisions, (2) minor REMS modifications, and (3) major REMS modifications according to the degree of their potential effect on one or more of the following:

• “The information provided in the REMS related to the serious risk(s) associated with the drug”

• “The safe use of the drug”

• “The actions that the application holder, patients, health care providers, and other stakeholders must take to comply with the REMS.”

It is important that application holders appropriately categorize the proposed changes prior to their submission to the FDA. As explained in the final guidance document, categorization affects what the application holder submits to the FDA, the timeline for FDA review and action, and the timeline of the implementation of the proposed changes.

REMS Revisions

Superficial changes are referred to as “REMS revisions,” defined as editorial in nature because they “do not affect [the] information contained in the REMS document and/or REMS materials about the serious risk or safe use of the drug” or “[the] actions application holders, patients, health care providers, or other stakeholders must take to comply with the REMS, or the REMS materials that support those actions.”

The final guidance document provides the following non-comprehensive list of examples that would qualify as REMS revisions:

• “Changes in the application holder name or address to reflect transfer of application ownership”

• “Updates to the application holder’s contact information”

• “Editorial changes such as . . . [c]hanging the application holder’s signatory for a Dear Health Care Provider” as well as “[c]hanging a trademark symbol . . . to the registered trademark symbol”

• “Correction of grammatical, formatting, and/or typographical errors”

• “Changes to a Medication Guide that is an element of a REMS” such as “changes in the application holder’s name and/or place of business,” “[i]nsertions of the date of the most recent revision of the Medication Guide,” and “[a]ddition of the side effects statement and toll-free number for reporting adverse events to a Medication Guide.”

Based on the nature and scope of the changes, REMS revisions are the easiest to propose and implement. Unlike REMS modifications, REMS revisions do not require the submission of a supplemental application. However, application holders must still notify the FDA of the REMS revisions. Since FDA action is not required, the changes can be implemented “following receipt by the FDA.”

REMS Modifications

The substantive changes are referred to as REMS modifications, which can be either minor or major.

Minor REMS Modifications

If a change has a limited effect on “information contained in the REMS about the serious risk or safe use of the drug” or “on the actions application holders, patients, health care providers, or other stakeholders must take to comply with the REMS” it is considered a minor REMS modification. This type of modification is the least substantive.

The following is a non-comprehensive list of examples that the FDA would consider minor REMS modifications:

• “Addition of an approved new strength or dosage regimen of the drug”

• “Addition of an authorized generic”

• “Adding a professional society to the list of required recipients of a Dear Health Care Provider Letter”

• “Changing an existing health care provider or patient enrollment form to collect additional demographic information.”

Once an application holder submits a supplemental application for proposed minor REMS modifications, they generally have some leeway regarding when they can implement the proposed modifications. Even though the FDA has 60 days “to review and act on” the proposed changes, an application holder can implement the changes “30 days after receipt by the FDA.” However, the changes “are not considered final until approved by the FDA.” Despite this flexibility, “if the FDA informs the application holder (within 14 days of receipt) that information necessary for the FDA to act on the submission is missing, the application holder should delay implementation.”

Major REMS Modifications

The changes that are most substantive in nature are referred to as major REMS modifications. These changes have a substantial effect on information contained in the REMS about the serious risk or safe use of the drug or on the actions application holders, patients, health care providers, or other stakeholders must take to comply with the REMS.

The FDA would classify modifications consistent with the following non-comprehensive list of examples as major REMS modifications:

• “Addition, removal, or change to a REMS goal”

• “Addition of new information about the serious risks associated with the drug”

• “Addition of a new indication for use that may alter the serious risks (in relation to benefits) of the drug for the new patient population”

• “Addition of new information about drug administration that affects patient safety”

• “Extensive changes to a patient brochure to better educate patients about the serious risk(s) of the drug”

• “Modification that proposes releasing the REMS requirement.”

Due to the seriousness of these changes, an application holder must submit a supplemental application and is prohibited from implementing the modifications during the FDA’s 180-day period “to review and act on” the proposed changes.

Adequate Rationale for REMS Modifications

As explained in the final guidance document, “[all] proposed REMS modifications (minor and major) initiated by the application holder must include an adequate rationale.” The adequate rationale may include the following:

• “The reason(s) why the proposed modification is necessary”

• “The potential effect of the proposed modification on how the REMS addresses the serious risk(s) for which the REMS was required, on patient access to the drug, and/or on the burden on the health care delivery system”

• “Other appropriate evidence or data to support the proposed change.”

However, if a proposed REMS modification is in connection with an efficacy supplement for a new indication for use, the adequate rational should include different information.

Conclusion

The final guidance document demonstrates the importance of classification. Even though the categories lend themselves to a certain level of intuitiveness, it is imperative to consult the FDA final guidance document and seek advice from the FDA “in accordance with established FDA procedures” if need be. Otherwise, the misclassification of proposed changes would delay the distribution of potentially helpful information.