In all cases, the FDA recommends that submissions include a REMS history that outlines all changes made to the REMS since its original approval.

On July 9, 2019, the U.S. Food and Drug Administration (FDA) released a final guidance on changes to approved Risk Evaluation and Mitigation Strategies (REMS). For certain drugs, the FDA may require a REMS as an additional risk management plan to ensure that the benefits of the drug outweigh the risks. The final guidance describes the three different types of changes to an approved REMS, how application holders should submit changes to REMS, and how the FDA will process submissions from application holders for changes to REMS.

Categories of REMS Changes

The FDA categorizes changes to REMS as (1) REMS revisions, (2) minor REMS modifications or (3) major REMS modifications, depending on the extent to which the proposed changes affect the information in the REMS concerning the serious risk or safe use of the drug or the actions that stakeholders must take to comply with the REMS.

1. REMS revisions are editorial in nature and can include updates to the application holder’s contact information or correction of grammatical, formatting and/or typographical errors.
2. Minor REMS modifications consist of changes that have a “limited” effect on the REMS or the actions that stakeholders must take to comply with the REMS. Examples of minor REMS modifications include the addition of an approved new strength or dosage regimen of the drug or the addition of a professional society to the list of required recipients of a Dear Health Care Provider Letter.
3. Major REMS modifications are defined as changes that have a “substantial” effect on the REMS information or stakeholders. Examples of major REMS modifications include the addition of new information about the serious risks associated with the drug or the removal, addition or substantial modification an element of the REMS.

Submission Procedures

Procedures for submitting proposed REMS changes differ based upon their category.

1. REMS revisions should be submitted to the FDA as a “REMS Revision” submission similar to drug correspondence at the time the revisions are implemented. In addition to the submission, REMS revisions should also be documented in the next annual report.
2. Proposed minor REMS modifications should be submitted as a changes-being-effected in 30 days (CBE-30) supplement, and may be implemented 30 days following receipt by the FDA.
3. Proposed major REMS modifications should be submitted as a prior approval supplement (PAS), and must be approved before they are implemented.

In all cases, the FDA recommends that submissions include a REMS history that outlines all changes made to the REMS since its original approval. All proposed REMS modifications (minor or major) initiated by the application holder must also be accompanied by an adequate rationale. However, if the proposed REMS modifications are identical to or consistent with an FDA required modification to the REMS, adequate rationale is not required. If the proposed REMS modification includes changes that differ from those described by FDA, an adequate rationale is still required. If the proposed REMS modifications are due to approved safety labeling changes or to safety labeling changes ordered by FDA, the adequate rationale can be a statement that the changes are submitted due to the approved or ordered safety labeling changes.

FDA Processing for REMS Changes

REMS revisions do not require FDA action, because they are not submitted as supplemental applications. Therefore, REMS revisions can be implemented as soon as the FDA receives the submission.

For minor REMS modifications, the FDA will review and act on proposed changes within 60 days of receipt. Although the application holder can implement proposed changes 30 days after receipt, minor REMS modifications are not considered final until they are approved by the FDA.

The FDA will review and act on proposed major REMS modifications within 180 days of receipt. Proposed major REMS modifications must not be implemented before FDA approval.

Although the FDA will accept a single submission that contains more than one category of proposed REMS changes, the agency will only take one action per supplement. Therefore, a submission with multiple REMS changes will be acted upon within the timeframe of the category with the longest window for review.

For Further Information

If you have any questions about this Alert or would like more information, please contact Frederick R. Ball, Carolyn A. Alenci, Evan J. Muller, any of the attorneys in our Life Sciences, Biotech, Medical Devices, Pharmaceuticals and Biologics Group or the attorney in the firm with whom you are regularly in contact.

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