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Modification versus Revision: It Matters a Great Deal When it Comes to Your REMS

April 30, 2015 | Mark A. Cierpial, PhD, RAC, Chief Executive Officer | Regulatory Affairs

Modification – “The act or process of changing parts of something” According to a recent guidance issued by the FDA, modifications and revisions are not the same thing when it comes to changes to approved Risk Evaluation and Mitigation Strategies.

Need to update your REMS? Read on!

Revision – “A change or set of changes that corrects or improves something”

What are REMS?
Risk Evaluation and Mitigation Strategies, or REMS, are risk management plans which FDA sometimes requires for certain marketed products to ensure that their benefits outweigh their risks.

Standard risk management techniques for all products include describing the risks and benefits of the product in its labeling and performing required safety reporting.

Components of a REMS go beyond these standard techniques, and can include elements such as patient registries, prescriber certifications, dear healthcare provider letters, etc.

All REMS are required to include a timetable for submission of assessments of the REMS. These REMS assessments are an evaluation of the extent to which each of the REMS elements are meeting the goals and objectives of the REMS, and whether or not the goals, objectives, or REMS elements should be modified.

Image courtesy of Stuart Miles at

In additional to the requirement for REMS assessments, a REMS for a particular drug may also include:

  • a Medication Guide as provided for under CFR 21 Part 208,
  • a patient package insert if such insert may help mitigate a serious risk of the drug,
  • a communication plan to health care providers if the plan may support implementation of an element of the strategy, and
  • various “Elements to Assure Safe Use” (ETASU).

Birth of the REMS
Authorization for the FDA to require a REMS came in 2007 with passage of the Food and Drug Administration Amendments Act (FDAAA).

Consistent with the Act, FDA issued a draft guidance in 2009 which provided guidance to industry on the format and content of a proposed REMS, as well as the content of REMS assessments and proposed modifications of approved REMS.

riIn the guidance, FDA stated that any and all proposed modifications to an approved REMS, including proposed changes to materials that are appended to the REMS document (eg, Medication Guide, enrollment forms, dear health care professional letters), must be submitted to the FDA in the form of a prior approval supplement (PAS) and must include a REMS assessment. As you know, changes made to an NDA via a PAS cannot be implemented until approved by the FDA.

Image courtesy of Stuart Miles

FDASIA Changes
With the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA), the REMS modification provisions were changed and FDA was required to do the following:

  • Review and act on proposed minor modifications to an approved REMS within 60 days
  • Establish, through guidance, that certain modifications can be implemented following notification to FDA (rather than prior approval)
  • Review and act on modifications being made to align a REMS with approved safety label changes within 60 days
  • No longer require submission of a REMS assessment with proposed modifications (only an adequate rationale for the proposed change is required)

Earlier this month, FDA issued a Guidance for Industry entitled, “Risk Evaluation and Mitigations Strategies: Modifications and Revisions” which describes how FDA intends to implement the FDASIA changes.

Revisions versus Modifications
According to the new guidance, changes to an approved REMS will be classified as either “revisions” or “modifications” depending on the degree to which they may affect the risk message (ie, the information provided in the REMS about the serious risks or safe use of the drug) and/or REMS requirements. REMS modifications are further divided into “minor” and “major” modifications.REMS revisions can be submitted and implemented immediately (ie, CBE-0; changes being effected in 0 days). They must also be documented in the next annual report.REMS modifications must be submitted as either CBE-30 supplements (minor modifications; changes being effected in 30 days) or prior approval supplements (major modification).

REMS Major Modification: PAS

REMS Minor Modification: CBE-30

REMS Revision: CBE-0

What Qualifies as a REMS Revision?
FDA has determined that the following changes do not affect the REMS risk message or other REMS requirements:

  • Change in the application holder name
  • Updating of contact information for the current application holder
  • Correcting grammatical, formatting, and/or typographical errors
  • Changing the application holder’s signatory for a Dear Heath Care Provider Letter
  • Adding or changing the proprietary or established name
  • Changing a trademark symbol from ™ to ®
  • Changes in the approved package count configuration that result in changes to the REMS appended materials (eg, a change in NDC numbers)
  • Certain changes to a Medication Guide that is an element of a REMS

How are REMS Modifications Classified?
Any proposed change to an approved REMS not listed above (as a revision) will be considered to be a REMS modification by the FDA.

REMS modifications are further divided into minor modifications and major modifications. Minor modifications are those that may nominally affect the risk message and/or nominally change the REMS requirements, whereas major modifications are those that may substantially affect the risk message, and/or substantially change the REMS requirements.

Examples of minor modifications include, but are not limited to:

  • Expanding the enrollment process to include online registration, in addition to enrollment via email or fax
  • Creation of a new enrollment form that is similar in content to the currently approved enrollment form, to accommodate existing processes within closed health care systems
  • Changing the health care provider enrollment form(s) to collect an additional piece of demographic data such as a prescriber’s medical specialty, or providers’ unique identifier
  • Addition of a new strength or dosage form of the drug to the REMS document and/or the appended REMS material
  • Re-ordering the risk information in the appended REMS material
  • Changes to the graphics in the appended REMS materials, including changing the manufacturer’s logo or the logo for the REMS program

Examples of major modifications include, but are not limited to:

  • Addition, removal, or change to a REMS goal
  • Changes to the timetable for submission of REMS assessments that alter the frequency and/or number of the assessments
  • Changes to an ETASU to modify the verification process required before the drug will be dispensed to patients
  • Removing the Medication Guide as an element of the REMS
  • Adding a new letter to health professional societies to the communication plan
  • Changes related to drug administration that affect patient safety
  • Changing the name of the REMS program to add or remove wording that affects the risk message

Need regulatory help?
IMPACT has experienced regulatory affairs professionals ready to assist you. If you would like to discuss your specific needs, please contact us or give IMPACT a call today at (919) 899-9248.

Category: Regulatory Affairs
Keywords: REMS

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