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In April, FDA released a final guidance on Risk Evaluation and Mitigation Strategies (REMS): Modifications & Revisions.

The title is a bit of a misnomer. This is not really a modification or revision of the big issues involved with REMS creation and implementation, but rather gives guidance to companies that already have approved REMS in place and wish to or must change them. It describes which changes will be considered “modifications” and which will be considered “revisions.” Although this sounds rather bureaucratic (well, it is) it is actually important since modifications and revisions are handled differently by FDA. Also of note is that this applies only to individual REMS and not single shared REMS.

The document reviews the history of REMS. In 2009 FDA issued a draft guidance on the format and content of a REMS and addressed the issue of modifications. Basically this stated that changes may be proposed but must not be implemented before approval by FDA.

The FDA Safety and Innovation Act (FDASIA) amended the modifications requirements. This required FDA to act on minor modifications within 60 days and to establish, via a guidance, that some modifications may be implemented without awaiting FDA approval of the submitted modification. FDA was also required to act within 60 days on modifications that require approval and that a REMS assessment is not required with the modification. Only an “adequate rationale” would be required.

This guidance references the regulations on changes (including REMS changes) to products with NDAs, ANDAs and BLAs. See pages 3 & 4 for this brief summary and the CFR references.

Next the FDA goes on to state their policy on REMS changes. Changes will be categorized by their potential effect on the risk message or other REMS requirements such as obligations of the company, of health care providers etc.

Revisions vs. Modifications

There are now two categories: Revisions and modifications. In a nutshell, revisions don’t change the REMS risk message or requirements and are essentially administrative; modifications do change the REMS and are subdivided into major and minor. Revisions need only be noted in the next annual report whereas modifications must be submitted to FDA at the time of the proposed change. More details below.

REMS Revisions

These are defined to be “editorial changes, corrections of typos, changes in the application holder name or address…(and) do not affect the risk message or other REMS requirements.” Changes to a Medication Guide that is a REMS element that meets requirements for annual report submission are considered revisions. Revisions may be implemented following receipt of them by FDA without waiting for approval.

There is a table in the document giving examples of revisions such as change in telephone number of the applicant, typo corrections, change in title of the signatory of a REMS communication, changing the trademark symbol ™ to the registered symbol ® and other minor changes. See the document for details.

REMS Modifications

This section refers to changes that are more significant and change the risk message and/or the REMS requirements. There are two categories:

1) Minor modifications: These are changes that may “nominally” affect the risk message and/or requirements and are submitted as a CBE-30 supplement.

Examples of minor changes include:

2) Major modifications: These changes substantially affect the risk message and/or requirements and must be submitted as a “prior approval supplement” (PAS).

Examples of major changes include:

The rest of the guidance then gives very specific information on exactly how REMS revisions and modifications are to be submitted including a description of the changes, a clean version and a Word track change versions of the material, FDA Form 356h etc. See this guidance for the full and (very) detailed information on submissions, contact information etc.

FDA notes that all approved REMS and appended materials are posted on FDA’s website and that FDA will post updated REMS revisions within 14 days of receipt and modifications within 3 days of approval.


This is clearly a very detailed bureaucratic document covering changes to REMS. This comment is not meant, however, to be pejorative. REMS are critically important in health care and good medication use and any changes to them are similarly important and must be tracked and controlled. FDA has chosen this mechanism to do so. It is seemingly easier to do REMS and their changes than to do and change EU Risk Management plans with ETASU equivalents. Nonetheless, both are quite detailed and bureaucratic.

Clearly revisions are meant to be used for trivial changes that are primarily administrative. Modifications are different. The only areas here that may pose some problems are the determination of minor vs. major modifications. The examples given by FDA are fairly clear though there is still a lot of room for interpretation.

For example, FDA lists in the example table as a major modification:

Is this meant to imply that the addition of a new SAE/SAR such as sudden death, which is listed in the AE section but not the Warnings and Precautions section, is to be considered minor. I would think not and would interpret this as just one example of a safety label change; so I would consider any change in safety to be a major modification. When doing modifications to a REMS, the company should get a broad range of internal opinions (legal, regulatory, drug safety/PV, medical, labeling, risk management etc.) on what is a minor/major modification.

My usual stance has been, for 30 plus years, to be conservative and if there is more than a three minute discussion on whether something is minor vs major, make it major.

In summary, this is an important document for companies handling REMS. They need to ensure that their REMS changes are in compliance with these new requirements.



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