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FDA Explains how Companies can Modify a Drug Safety Assurance Plan

Posted 06 April 2015 | By Alexander Gaffney, RAC

FDA Explains how Companies can Modify a Drug Safety Assurance Plan

A new guidance document issued by the US Food and Drug Administration (FDA) explains the process by which pharmaceutical companies can make changes to policies intended to control the use of, and sometimes access to, potentially dangerous drugs.


The policies, known as Risk Evaluation and Mitigation Strategies (REMS), were first created under the 2007 Food and Drug Administration Amendments Act (FDAAA) and are meant to ensure the safe use of potentially risky products that might otherwise not be approved for use.

For example, Celgene's Thalomid (thalidomide) is a cancer drug intended to help patients diagnosed with multiple myeloma. However, the drug, which was originally marketed as a morning sickness treatment, is also infamous for causing horrific birth defects and fetal deaths. To ensure that multiple myeloma patients could obtain the drug without putting pregnant women at risk, Thalomid is controlled by a REMS (the "S.T.E.P.S." program) which includes counseling about the risks of the drug, required pregnancy testing for females, required contraception and a ban on sperm donation for males and required regular surveys of patients taking the drug. Patients who fail to complete or consent to any of the REMS program's requirements are not permitted to obtain the drug.

These heavy limits on the use of the drug, known as Elements to Assure Safe Use (ETASU), are generally the most restrictive elements of any REMS plan. However, not all REMS plans are as restrictive. Other REMS elements used to account for the risks of a drug include communication plans, Medication Guides (MedGuides) and implementation plans.

REMS are generally approved by FDA at the time of a drug's approval, and are required when FDA determines "that safety measures are needed beyond the professional labeling to ensure that a drug's benefits outweigh its risks." The plans are developed by the sponsor of the drug being approved, and then modified or approved by FDA.

Some drugs may have REMS applied to them after approval, such as if FDA becomes aware of new safety risks or if FDA determines that all drugs in a particular class of products should be subject to the same REMS plans (e.g. extended-release and long-acting opioids).

Learn more about REMS on FDA's website.

Changing a REMS

But what happens when a manufacturer wants to make changes to a REMS, including lessening its various restrictions?

FDA's latest guidance document, Risk Evaluation and Mitigation Strategies: Modifications and Revisions, explains how pharmaceutical companies can modify or revise a REMS plan using an FDA-approved process.

As of 2009, when FDA issued a draft guidance on REMS modifications, the agency required changes to a REMS to be made using a prior approval supplement (PAS)—an application which requires FDA's approval before the changes proposed in the application can go into effect. FDA reserves PAS applications for so-called "major changes" which have the potential to substantially impact the safety or efficacy of a drug.

The major downside to a PAS application, as opposed to other change notification types, is that it can take FDA months to review a PAS. A related change notification type known as a changes being effected (CBE) application, meanwhile, takes anywhere between zero and 30 days to take effect.

However, under the 2012 Food and Drug Administration Safety and Innovation Act (FDASIA), FDA was ordered to change the way in which it reviews requests for modifications and revisions to an approved REMS. Many "minor modifications" are now able to be reviewed within 60 days, and other modifications may be made even more quickly using a CBE application so long as there is an "adequate rationale for the proposed changes."

Explaining the Guidance

FDA's overriding policy is to categorize changes to REMS "by the degree of their potential effect on the risk message and/or other REMS requirements," FDA explains in its latest guidance.

FDA categorizes its changes into two types: revisions and modifications.

Revisions are defined by FDA as being editorial in nature, such as corrections of typographical errors or changes to a company's address. These changes typically have no bearing at all to the safety or efficacy of a drug product. Revisions should be submitted to FDA as part of a company's annual report, FDA said.

Modifications are defined by FDA as being more substantial in nature and effect than revisions. They include both minor and major changes to a REMS, such as changes to the requirements of a REMS or the warnings it conveys to a patient.

Minor modifications may be submitted to FDA using a CBE-30 supplement, which allows a sponsor to carry out changes if FDA has not responded to a request within 30 days. Major changes, however, will still require the submission of a PAS.

The guidance document contains extensive examples of what constitutes each type of change to a REMS. FDA notes that all changes should be accompanied by a "detailed description of the REMS changes," as well as an "adequate rationale for the proposed change(s)."

"This allows FDA to determine quickly if the appropriate submission category has been used," regulators explained.

Applicants should also include a history of the REMS "that outlines all changes made to the REMS since its approval." If any applicant has multiple changes they wish to be considered at the same time, they should be submitted in the same package, FDA recommended. Those changes would then be reviewed "concurrently."


Risk Evaluation and Mitigation Strategies: Modifications and Revisions (FR)


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