
[Federal Register Volume 80, Number 191 (Friday, October 2, 2015)]
[Notices]
[Pages 59785-59786]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-25122]



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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 
Conference on Harmonisation; Draft Guidance for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of a draft guidance entitled ``M4E(R2): The CTD--
Efficacy'' (M4E(R2)). The draft guidance was prepared under the 
auspices of the International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH). 
In August 2001, FDA made available guidance on preparing the efficacy 
components of an application file in the common technical document 
(CTD) format (``M4E: The CTD--Efficacy'' (M4E guidance)). This draft 
guidance revises the M4E guidance. The revised draft guidance 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: 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this draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by December 1, 2015.

ADDRESSES: Submit written requests for single copies of the draft 
guidance to the Division of Drug Information (HFD-240), Center for Drug 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 
the office in processing your requests. The draft guidance may also be 
obtained by mail by calling CBER at 1-800-835-4709 or 240-402-7800. See 
the SUPPLEMENTARY INFORMATION section for electronic access to the 
draft guidance document.
    Submit electronic comments on the draft 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: 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 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.
    Regarding the ICH: Michelle Limoli, Center for Drug Evaluation and 
Research, International Programs, Food and Drug Administration, 10903 
New Hampshire Ave., Bldg. 71, Rm. 7212, Silver Spring, MD 20993-0002, 
301-796-8377.

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 and harmonized technical 
procedures for pharmaceutical development. One of the goals of 
harmonization is to identify and reduce differences in technical 
requirements for drug development among regulatory Agencies.
    ICH was organized to provide an opportunity for tripartite 
harmonization initiatives to be developed with input from both 
regulatory and industry representatives. FDA also seeks input from 
other interested stakeholders. ICH is concerned with harmonization of 
technical requirements for the registration of pharmaceutical products 
among three regions: Europe, Japan, and North America. The eight ICH 
sponsors 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; the Pharmaceutical Research and 
Manufacturers of America; Health Canada; and Swissmedic. The ICH 
Secretariat, which coordinates the preparation of documentation, is 
provided by the International Federation of Pharmaceutical 
Manufacturers Associations (IFPMA). The ICH Steering Committee includes 
representatives from each of the ICH sponsors and the IFPMA, as well as 
observers such as the World Health Organization. In August 2015, the 
ICH Steering Committee agreed that a draft guidance entitled ``M4E(R2): 
The CTD--Efficacy'' should be made available for public comment. The 
draft guidance is the product of the M4E(R2) Expert Working Group of 
the ICH. Comments about this draft will be considered by FDA and the 
Expert Working Group.
    ICH M4E(R2) revises the M4E guidance (made available in August 
2001), which covers the Clinical Overview and Clinical Summary of 
Module 2 of the CTD and the Clinical Study Reports of Module 5. The 
revised draft guidance provides more specific guidance regarding the 
format and structure of the benefit-risk assessment in section 2.5.6; 
it also revises other sections of the guidance for clarification, given 
the proposed revisions in section 2.5.6. In addition, the revised draft 
guidance changes the numbering and the section headings for 
consistency.
    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 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

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assessments provided by applicants in their regulatory submissions.
    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, consistent with the 
concept paper that laid the groundwork for the Expert Working Group, 
the revised draft guidance does not dictate an approach used by a 
regulator in conducting a benefit-risk assessment.
    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent 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.

II. 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.

III. Electronic Access

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

    Dated: September 28, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-25122 Filed 10-1-15; 8:45 am]
 BILLING CODE 4164-01-P


