Document ID: FDA-2014-D-1747-0001
Agency: fda
Document Type: Notice
Title: Risk Evaluation and Mitigation Strategies: Modifications and
Revisions; Guidance for Industry; Availability
Posted Date: 2015-04-07T04:00Z

[Federal Register Volume 80, Number 66 (Tuesday, April 7, 2015)]
[Notices]
[Pages 18629-18631]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2015-08015]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2014-D-1747]

Risk Evaluation and Mitigation Strategies: Modifications and 
Revisions; Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a guidance for industry entitled ``Risk Evaluation and 
Mitigation Strategies: Modifications and Revisions.'' This guidance 
provides information on how FDA will define and process submissions for 
modifications and revisions to risk evaluation and mitigation 
strategies (REMS), as well as information on what types of changes to 
approved REMS will be considered modifications of the REMS and what 
types of changes will be considered revisions of the REMS. There are 
different procedures for submission of REMS modifications and revisions 
to FDA as well as different timeframes for FDA review and action of 
such changes. In addition, this guidance provides information on how 
REMS modifications and revisions should be submitted to FDA and how FDA 
intends to review and act on these submissions. The definitions of REMS 
modifications and revisions apply to all types of REMS.

DATES: Although you can comment on any guidance at any time (see 21 CFR 
10.115(g)(5)), to ensure that the Agency considers your comment on this 
guidance before it begins work on the final version of the guidance, 
submit either electronic or written comments on the guidance by June 8, 
2015. Submit either electronic or written comments concerning the 
proposed collection of information by June 8, 2015.

ADDRESSES: Submit written requests for single copies of the guidance to 
the Division of Drug Information, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10001 New Hampshire Ave. 
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002; or the 
Office of Communication, Outreach, and Development, Center for 
Biologics Evaluation and Research, Food and Drug Administration, 10903 
New Hampshire Ave. Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. 
Send one self-addressed adhesive label to assist that office in 
processing your requests. See the SUPPLEMENTARY INFORMATION section for 
electronic access to the guidance document.
    Submit electronic comments on the guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Kristen Everett, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave. Bldg. 22, Rm. 6484, Silver Spring, MD 20993-0002, 301-
796-0453; or Stephen Ripley, Center for Biologics Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave. Bldg. 
71, Rm. 7301, Silver Spring, MD 20993-0002, 240-402-7911.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``Risk Evaluation and Mitigation Strategies: Modifications and 
Revisions.'' This guidance provides information on what types of 
changes to approved REMS will be considered modifications and what 
types of changes will be considered revisions. See section 505-1(h) of 
the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 355-
1(h)). This guidance also provides information on how REMS 
modifications and revisions should be submitted to FDA and how FDA 
intends to review and act on these submissions.
    If FDA determines that a REMS is necessary to ensure that the 
benefits of a drug outweigh its risks, FDA is authorized to require a 
REMS for such drugs under section 505-1 of the FD&C Act,\1\ added by 
section 901 of the Food and Drug Administration Amendments Act of 2007 
(Pub. L. 110-85).\2\ Section 505-1(g) and (h) of the FD&C Act include 
provisions for the assessment and modification of an approved REMS.
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    \1\ Section 505-1 of the FD&C Act applies to applications for 
prescription drugs submitted under subsection 505(b) (i.e., new drug 
applications) or (j) (i.e., abbreviated new drug applications) of 
the FD&C Act (21 U.S.C. 355) and applications under section 351 of 
the Public Health Service Act (i.e., biologics license 
applications).
    \2\ See http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmendmentsActof2007/default.htm.
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    In 2009, FDA issued draft guidance on the format and content of 
REMS, REMS assessments, and proposed REMS modifications. In that 
guidance, based on the language of section 505-1(g) and (h) of the FD&C 
Act before the amendments made by the Food and Drug Administration 
Safety and Innovation Act (Pub. L. 112-144) (FDASIA), FDA stated that 
any proposed modification to an approved REMS, including proposed 
changes to materials that are appended to the REMS document, must be 
submitted as a proposed REMS modification in the form of a prior 
approval supplement and must include a REMS assessment. The guidance 
stated that the proposed

[[Page 18630]]

modification(s) may not be implemented until approved by FDA.
    FDASIA amended the REMS modification provisions under section 505-
1(g) and (h) of the FD&C Act. Section 505-1(h), as amended by FDASIA, 
requires FDA to review and act on proposed ``minor modifications,'' as 
defined in guidance, within 60 days.\3\ It also requires FDA to 
establish, through guidance, that ``certain modifications'' can be 
implemented following notification to FDA.\4\ In addition, FDASIA 
requires FDA to review and act on REMS modifications due to approved 
safety label changes, or to a safety label change that FDA has directed 
the application holder to make pursuant to section 505(o)(4) of the 
FD&C Act within 60 days.\5\ Finally, FDASIA specifies that proposed 
REMS modifications no longer require submission of a REMS assessment; 
instead, proposed modifications must include an adequate rationale for 
the proposed changes. This guidance is issued pursuant to section 505-
1(h)(2)(A)(ii), (h)(2)(A)(iii), and (h)(2)(A)(iv) of the FD&C Act.
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    \3\ See section 505-1(h)(2)(A)(ii) of the FD&C Act.
    \4\ See section 505-1(h)(2)(A)(iv) of the FD&C Act.
    \5\ See section 505-1(h)(2)(A)(iii) of the FD&C Act.
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    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). This guidance, except for the 
portion setting forth the submission procedures for REMS revisions, is 
being implemented without prior public comment because the Agency has 
determined that prior public participation is not feasible or 
appropriate (21 CFR 10.115(g)(2)). The Agency made this determination 
because, consistent with the requirements of FDASIA, FDA is issuing 
this guidance to establish a less burdensome policy and process for 
submitting certain changes to REMS that is consistent with public 
health. Although the guidance document is immediately in effect, except 
for the submission procedures for REMS revisions, it remains subject to 
comment in accordance with the Agency's good guidance practices. 
Insofar as this guidance establishes the modifications to an approved 
REMS that may be implemented following notification to the Secretary 
under section 505-1(h)(2)(A)(iv)--here referred to as REMS revisions--
it has binding effect, except for the portion of the guidance setting 
forth the submission procedure for REMS revisions, which will, when 
final, have binding effect.

II. Paperwork Reduction Act of 1995

    This guidance contains information collection provisions that are 
subject to review by the Office of Management and Budget (OMB) under 
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The title, 
description, and respondent description of the information collection 
are given under this section with an estimate of the annual reporting 
burden. Included in the estimate is the time for reviewing 
instructions, searching existing data sources, gathering and 
maintaining the data needed, and completing and reviewing the 
collection of information.
    We invite comments on these topics: (1) Whether the proposed 
collection of information is necessary for the proper performance of 
FDA's functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.
    Title: Guidance for Industry on Risk Evaluation and Mitigation 
Strategies: Modifications and Revisions
    Description: The guidance provides information on submitting to FDA 
modifications and revisions to approved REMS for approved new drug 
applications (NDAs), abbreviated new drug applications (ANDAs), or 
biologics license applications (BLAs).
    REMS modifications are submitted to FDA as supplements to approved 
NDAs under 21 CFR 314.70 and for ANDAs under 21 CFR 314.97, and as 
supplements to approved BLAs under 21 CFR 601.12. The burden hours for 
preparing and submitting supplements to NDAs and ANDAs is approved by 
OMB under control number 0910-0001, and for BLAs under control number 
0910-0338.
    Concerning REMS revisions, application holders should include the 
following information in each submission: (1) A full description of the 
changes to the REMS and/or appended materials, the date the changes 
will be implemented, and a REMS history that outlines all changes made 
to the REMS since its approval; (2) a clean Word version of the revised 
REMS and all appended REMS materials; (3) a redlined (tracked changes) 
Word version of the revised REMS and revised appended REMS materials 
that shows the changes from the previous versions; (4) an updated REMS 
supporting document, if needed; and (5) Form FDA 356h indicating that 
the submission is a REMS revision. (Form FDA 356h is approved by OMB 
under control number 0910-0338.) Each REMS revision that is submitted 
to FDA should also be documented in the next annual report for the 
application under 21 CFR 314.81(b)(2) (the burden hours for preparing 
and submitting annual reports for NDAs and ANDAs is approved by OMB 
under control number 0910-0001, and for BLAs under control number 0910-
0338). All subsequent REMS submissions (i.e., proposed modifications or 
additional REMS revisions) should include previously implemented REMS 
revisions in the REMS document and appended materials, and should be 
noted in the REMS history.
    Currently, there are 117 application holders with approved REMS 
that include 152 drugs. Based on FDA's current review of REMS 
submissions for approved NDAs, ANDAs, and BLAs, and anticipating an 
average of 1 REMS revision across the entire group of REMS, we estimate 
that annually a total of approximately 117 application holders 
(``Number of Respondents'' in table 1) will submit to FDA approximately 
152 REMS revision submissions (``Total Annual Responses'' in table 1) 
as described in this document and in the guidance. We also estimate 
that it will take an application holder approximately 30 hours to 
prepare and submit to FDA each REMS revision (``Average Burden per 
Response'' in table 1).
    The total estimated reporting burden for the guidance is as 
follows:

[[Page 18631]]

                                                     Table 1--Estimated Annual Reporting Burden \1\
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                                                                                         Number of
Guidance for industry on risk evaluation and mitigation strategies:     Number of      responses per     Total annual    Average burden    Total hours
                    modifications and revisions                        respondents       respondent       responses       per response
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REMS revisions.....................................................             117                1              152               30            4,560
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

III. Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

IV. Electronic Access

    Persons with access to the Internet may obtain the document at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm, or http://www.regulations.gov.

    Dated: April 2, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-08015 Filed 4-6-15; 8:45 am]
BILLING CODE CODE 4164-01-P