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U.S. Department of Health and Human Services

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Questions and Answers on the Federal Register Notice on Drugs and Biological Products Deemed to Have Risk Evaluation and Mitigation Strategies

Federal Register Notice [HTML] [PDF]

1. What is FDA conveying in this notice?

FDA is identifying drugs and biological products approved/licensed before the provisions of the Title IX of Subtitle A of the Food and Drug Administration Amendments Act (FDAAA) took effect (March 25, 2008) that are deemed to have a Risk Evaluation and Mitigation Strategy (REMS). Under FDAAA, sponsors of these drug and biological products must submit a proposed REMS by September 21, 2008. This is the first notice FDA has issued under the new drug safety authorities in FDAAA.

2. Why is FDA asking for these REMS to be submitted?

Section 909 of FDAAA states that all sponsors of drugs and biological products approved/licensed before section 901 takes effect (March 25, 2008) with elements to assure safe use will be deemed to have REMS and must submit proposed REMS by September 21, 2008. FDA is identifying those drugs and biological products that were approved/licensed with elements to assure safe use that are deemed to have REMS under this provision.

3. What is a Risk Evaluation and Mitigation Strategy?

A Risk Evaluation and Mitigation Strategy (REMS) is a strategy to manage a known or potential serious risk associated with a drug or biological product. A REMS will be required if FDA finds that a REMS is necessary to ensure that the benefits of the drug or biological product outweigh the risks of the product, and FDA notifies the sponsor. A REMS can include a Medication Guide, Patient Package Insert, a communication plan, elements to assure safe use, and an implementation system, and must include a timetable for assessment of the REMS. Some drug and biological products that previously were approved/licensed with risk minimization action plans (RiskMAPs) will now be deemed to have REMS.

4. What are “elements to assure safe use”?

Elements to assure safe use as defined in FDAAA include:

  1. Health care providers who prescribe the drug have particular training or experience, or are specially certified;
  2. pharmacies, practitioners, or health care settings that dispense the drug are specially certified;
  3. the drug is dispensed to patients only in certain health care settings, such as hospitals;
  4. the drug is dispensed to patients with evidence or other documentation of safe use conditions, such as laboratory test results;
  5. each patient using the drug is subject to certain monitoring; or
  6. each patient using the drug is enrolled in a registry (see section 505-1(f)(3) of the Act).

5. How did FDA identify these first drugs and biological products as needing a REMS?

Under section 909 of FDAAA, all sponsors of drug and biological products approved/licensed before section 901 takes effect (March 25, 2008) with elements to assure safe use (either required under 21 CFR 314.520 or 21 CFR 601.42, or otherwise agreed to by the sponsor) will be deemed to have a REMS and must submit a proposed REMS by September 21, 2008. FDA examined its databases to identify drugs and biological products that were approved/licensed with such elements and has listed them in the Federal Register notice.

6. What happens if sponsors fail to submit their proposed REMS within 180 days from March 25, 2008?

A sponsor deemed to have a REMS who fails to submit a proposed REMS within 180 days may be subject to enforcement action, including civil money penalties.

7. Why are those approved drugs and biological products that only have Medication Guides not required to submit a REMS?

FDAAA states that only those drug and biological products that have elements to assure safe use (see question 3) would be deemed to have REMS. Although Medication Guides may be elements of future REMS, a drug or biological product approved before March 25, 2008, the effective date of Title IX, Subtitle A, that only had a Medication Guide and no elements to assure safe use as defined in FDAAA was not deemed to have a REMS in FDAAA.

8. What criteria are being used to identify companies that will need to develop and submit REMS in the future?

A: FDAAA contains criteria for when FDA can require a REMS, and certain factors we must consider in designing a REMS. We will apply the statutory criteria for drug and biological products that are pending approval/licensure. For drug and biological products that have already been approved/licensed, if FDA becomes aware of new safety information, we will determine whether a REMS is necessary. We intend to issue guidance to industry on the format and content of a proposed REMS; see also question 13.

9. What is the relationship between REMS and existing regulations that require restricted distribution (21 CFR Part 314, Subpart H and 21 CFR 600, Subpart E)?

A: There is substantial overlap between the requirements of Subparts H and E and the statutory criteria for REMS. FDA is considering whether any regulation changes will be necessary to clarify the requirements.

10. When will a decision be made for a specific application that a REMS is needed?

During the approval process, FDA will determine whether a REMS is required to ensure that the benefits of the drug or biological product outweigh the risks. If so, FDA will require the sponsor of the application to submit a proposed REMS and the REMS will be approved when the drug or biological product is approved/licensed. If a product is already approved/licensed and FDA becomes aware of new safety information that suggests a REMS is necessary to ensure that the benefits of the drug or biological product outweigh the risks, it will require a REMS.

11. What is new safety information?

New safety information is defined in FDAAA as:

“Information derived from a clinical trial, an adverse event report, a postapproval study, or peer-reviewed biomedical literature; data derived from the postmarket risk identification and analysis system…or other scientific data deemed appropriate by the Secretary about a serious risk or an unexpected serious risk associated with use of the drug that the Secretary has become aware of (that may be based on a new analysis of existing information) since the drug was approved, since the REMS was required, or since the last assessment of the approved REMS; or the effectiveness of the approved REMS obtained since the last assessment of the strategy.” (See 505-1(b)(3) of the Act).

12. Can FDA hold up approvals if a company has not submitted a REMS prior to the PDUFA date? Do we envision this to be a problem?

If we determine that a REMS is necessary to ensure that the benefits of the drug or biological product outweigh the risks, we will not approve/license the product without a REMS. We have previously approved drug and biological products with RiskMAPs while still meeting our PDUFA goals.

13. What is FDA’s enforcement authority under this FDAAA provision?

FDA may impose civil monetary penalties for violations of the REMS provisions or the drug or biological product can be deemed misbranded, and FDA could obtain injunctive relief. FDAAA state that the penalties may not exceed $250 thousand per violation, or $1 million for all violations adjudicated in a single proceeding. If a violation continues after the sponsor receives written notice, the penalty is $250 thousand for the first 30-day period (or any portion thereof) that the violation continues, not to exceed $1 million for any 30-day period, and not to exceed $10 million for all violations adjudicated in a single proceeding. FDA may take into consideration whether the company is making efforts to correct the violation when determining the amount of a civil penalty.

14. What are the next steps?

We are working on an interim Guidance for industry that will describe the content and format of a proposed REMS. It will include a template and a model REMS. We are also working to revise the Guidance for Industry: Development and Use of Risk Minimization Action Plans, March 2005. When the proposed REMS are submitted for products deemed to have REMS, we will review and approve them.

 

Date created: March 26, 2008, updated March 27, 2008