Document ID: FDA-2015-D-3235-0007
Agency: fda
Document Type: Notice
Title: M4E(R2): The Common Technical Document—Efficacy; International
Council for Harmonisation; Guidance for Industry; Availability
Posted Date: 2017-07-25T04:00Z

[Federal Register Volume 82, Number 141 (Tuesday, July 25, 2017)]
[Notices]
[Pages 34538-34540]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-15534]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2015-D-3235]

M4E(R2): The Common Technical Document--Efficacy; International 
Council for Harmonisation; Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a guidance entitled ``M4E(R2): The CTD--Efficacy.'' 
The guidance was prepared under the auspices of the International 
Council for Harmonisation (ICH), formerly the International Conference 
on Harmonisation. The guidance revises the ICH guidance ``M4E: The 
CTD--Efficacy'' (M4E guidance). The revised guidance standardizes the 
presentation of benefit-risk information in regulatory submissions, 
providing greater specificity on the format and structure of benefit-
risk information. This revision is intended to facilitate communication 
among regulators and industry.

DATES: Submit either electronic or written comments on Agency 
guidance's at any time.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the

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instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2015-D-3235 for ``M4E(R2): The Common Technical Document--Efficacy; 
International Council for Harmonisation; Guidance for Industry; 
Availability.'' Received comments will be placed in the docket and, 
except for those submitted as ``Confidential Submissions,'' publicly 
viewable at https://www.regulations.gov or at the Dockets Management 
Staff between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will 
review this copy, including the claimed confidential information, in 
its consideration of comments. The second copy, which will have the 
claimed confidential information redacted/blacked out, will be 
available for public viewing and posted on https://www.regulations.gov. 
Submit both copies to the Dockets Management Staff. If you do not wish 
your name and contact information to be made publicly available, you 
can provide this information on the cover sheet and not in the body of 
your comments and you must identify this information as 
``confidential.'' Any information marked as ``confidential'' will not 
be disclosed except in accordance with 21 CFR 10.20 and other 
applicable disclosure law. For more information about FDA's posting of 
comments to public dockets, see 80 FR 56469, September 18, 2015, or 
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.
    Submit written requests for single copies of this guidance to the 
Division of Drug Information, Center for Drug Evaluation and Research 
(CDER), 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 (CBER), 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. The guidance may also be obtained by mail by calling 
CBER at 1-800-835-4709 or 240-402-8010. See the SUPPLEMENTARY 
INFORMATION section for electronic access to the guidance document.

FOR FURTHER INFORMATION CONTACT: 
    Regarding the guidance: Pujita Vaidya, Center for Drug Evaluation 
and Research, Food and Drug Administration, 10903 New Hampshire Ave., 
Bldg. 51, Rm. 1144, Silver Spring, MD 20993-0002, 301-796-0684; or 
Steve 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.
    Regarding the ICH: Amanda Roache, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, Rm. 1176, Silver Spring, MD 20993-0002, 301-796-4548.

SUPPLEMENTARY INFORMATION: 

I. Background

    In recent years, many important initiatives have been undertaken by 
regulatory authorities and industry associations to promote 
international harmonization of regulatory requirements. FDA has 
participated in many meetings designed to enhance harmonization and is 
committed to seeking scientifically based harmonized technical 
procedures for pharmaceutical development. One of the goals of 
harmonization is to identify and then reduce differences in technical 
requirements for drug development among regulatory agencies.
    ICH was organized to provide an opportunity for harmonization 
initiatives to be developed with input from both regulatory and 
industry representatives. FDA also seeks input from consumer 
representatives and others. ICH is concerned with harmonization of 
technical requirements for the registration of pharmaceutical products 
for human use among regulators around the world. The six founding 
members of the ICH are the European Commission; the European Federation 
of Pharmaceutical Industries Associations; the Japanese Ministry of 
Health, Labour, and Welfare; the Japanese Pharmaceutical Manufacturers 
Association; CDER and CBER, FDA; and the Pharmaceutical Research and 
Manufacturers of America. The Standing Members of the ICH Association 
include Health Canada and Swissmedic. Any party eligible as a Member in 
accordance with the ICH Articles of Association can apply for 
membership in writing to the ICH Secretariat. The ICH Secretariat, 
which coordinates the preparation of documentation, operates as an 
international nonprofit organization and is funded by the Members of 
the ICH Association.
    The ICH Assembly is the overarching body of the association and 
includes representatives from each of the ICH members and observers.
    In the Federal Register of October 2, 2015 (80 FR 59785), FDA 
published a notice announcing the availability of a draft guidance 
entitled ``M4E(R2): The CTD--Efficacy.'' The notice gave interested 
persons an opportunity to submit comments by December 1, 2015.
    After consideration of the comments received and revisions to the 
guidance,

[[Page 34540]]

a final draft of the guidance was submitted to the ICH Assembly and 
endorsed by the regulatory agencies on June 16, 2016.
    Regulatory authorities approve drugs that are demonstrated to be 
safe and effective for human use. The meaning of ``safe'' has 
historically been interpreted to mean that the benefits of the drug 
outweigh its risks. This benefit-risk assessment of pharmaceuticals is 
the fundamental basis of regulatory decision-making. In the last 
several years, providing greater structure for the benefit-risk 
assessment has been an important topic in drug regulation. The M4E 
guidance directs applicants to include their conclusions on benefits 
and risks in the Clinical Overview of Module 2 of the Common Technical 
Document (CTD) under section 2.5.6. Although general guidance is 
provided in the M4E guidance regarding the expected content of section 
2.5.6, no further structure is suggested to aid industry in developing 
the benefit-risk assessment. As a result, regulators observe a high 
degree of variability in the approaches taken by applicants in 
presenting this information. This variability may not facilitate 
efficient communication of industry views to regulators. Although 
regulators and industry have developed approaches for structured 
benefit-risk assessment and these approaches may take different forms, 
there is a common thread evident that can inform harmonization of the 
format and structure of benefit-risk assessments provided by applicants 
in their regulatory submissions.
    The revised M4E(R2) guidance provides more specific guidance 
regarding the format and structure of the benefit-risk assessment in 
section 2.5.6. Section 2.5.6 is divided into four subsections: (1) 
Therapeutic context, (2) Benefit, (3) Risk, and (4) Benefit-Risk 
Assessment. Each subsection describes the aspects that are most 
pertinent to the benefit-risk assessment. This guidance also lists 
characteristics that should be considered when identifying and 
describing key benefits and key risks of the medicinal product. 
Recognizing that there are many reasonable approaches for conducting a 
benefit-risk assessment, M4E(R2) does not specify a particular approach 
to be used by industry. However, the document does offer specific 
guidance on the major elements that should be included in the benefit-
risk assessment. Furthermore, the revised guidance does not dictate an 
approach used by a regulator in conducting a benefit-risk assessment.
    This guidance also revises other sections of the guidance for 
clarification, given the proposed revisions in section 2.5.6. In 
addition, the revised guidance changes the numbering and the section 
headings for consistency.
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). The guidance represents the 
current thinking of FDA on this topic. It does not establish any rights 
for any person and is not binding on FDA or the public. You can use an 
alternative approach if it satisfies the requirements of the applicable 
statutes and regulations. This guidance is not subject to Executive 
Order 12866.

II. Paperwork Reduction Act of 1995

    This guidance refers to previously approved collections of 
information 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 collections of information in 21 CFR parts 312 and 314 have 
been approved under OMB control numbers 0910-0014 and 0910-0001, 
respectively.

III. Electronic Access

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

    Dated: July 18, 2017.
Anna K. Abram,
Deputy Commissioner for Policy, Planning, Legislation, and Analysis.
[FR Doc. 2017-15534 Filed 7-24-17; 8:45 am]
 BILLING CODE 4164-01-P