Bart’s Corner: FDA’s New REMS Guidance

Apr 29, 2015

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

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 In 2009 FDA issued a draft guidance on the format and content of a REMS and addressed the issue of modifications.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:

  • “The mailing list for the Dear Health Care Professional Letter will consist of health care of any specialty providers in the field of cardiology…”
  • “[Company] will maintain a database of certified prescribers in the REMS program. [Company] will ensure that monitor the database to ascertain that prescribers’ certification requirements are met.”
  • Expanding enrollment processes to include on line registration in addition to email and fax.
  • Creating a new enrollment form or changing a current one to collect additional demographic data
  • Adding a new dosage strength or formulation
  • Adding or removing or changing information about other drugs mentioned in REMS material such as adding a newly approve drug to a class of drugs mentioned in the REMS
  • Changes to graphics or logos
  • Reordering risk information in REMS materials

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:

  • A change to a REMS goal such as changing the original goal from “To reduce the risk of misuse…” to “To reduce the risk of abuse and misuse…”
  • Adding a new letter to health professional societies in the communication plan
  • Removing the REMS website from the communication plan or as an ETASU
  • Changing the prescriber enrollment form to remove an attestation that the prescriber understands the serious risks of the drug
  • Adding or removing an education tool (e.g. slide deck, brochure)
  • Changes to the demographic information in the enrollment form
  • Adding new safety information about already included serious risks
  • Expansion of the patient population after the approval of a new indication
  • Changes to drug administration
  • Changes in the frequency or timing a required laboratory test
  • Changing the name of the REMS program that alters the risk message
  • Certain changes in the Medication Guide (see this guidance and the referenced CFR requirements for supplement submission and waivers)
  • Modifications that end REMS requirements entirely
  • Modifications due to safety labeling changes. The example given is: Changes to the WARNINGS and PRECAUTIONS section of the product label.

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:

  • Modifications due to safety labeling changes. The example given is: Changes to the WARNINGS and PRECAUTIONS section of the product label.

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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