82 FR 34538 - M4E(R2): The Common Technical Document-Efficacy; International Council for Harmonisation; Guidance for Industry; Availability
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration Federal Register Volume 82, Issue 141 (July 25, 2017)
Food and Drug Administration
Federal Register Volume 82, Issue 141 (July 25, 2017)
| Page Range | 34538-34540 | |
| FR Document | 2017-15534 |
[Federal Register Volume 82, Number 141 (Tuesday, July 25, 2017)] [Notices] [Pages 34538-34540] From the Federal Register Online [www.thefederalregister.org] [FR Doc No: 2017-15534] ----------------------------------------------------------------------- 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. ----------------------------------------------------------------------- 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 [[Page 34539]] 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.thefederalregister.org/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
![34538 Federal Register / Vol. 82, No. 141 / Tuesday, July 25, 2017 / Notices
development. One of the goals of solvents and PDEs that could be added use an alternative approach if it satisfies
harmonization is to identify and then to the tables and list based on adequate the requirements of the applicable
reduce differences in technical toxicity data. In the Federal Register of statutes and regulations.
requirements for drug development February 12, 2002 (67 FR 6542), FDA
II. Electronic Access
among regulatory agencies. briefly described the process for
ICH was organized to provide an proposing future revisions to the PDE. Persons with access to the Internet
opportunity for harmonization In the same notice, the Agency may obtain the document at https://
initiatives to be developed with input announced its decision to delink the www.fda.gov/Drugs/Guidance
from both regulatory and industry tables and list from the Q3C guidance ComplianceRegulatoryInformation/
representatives. FDA also seeks input and create a stand-alone document Guidances/default.htm, https://
from consumer representatives and entitled ‘‘Q3C: Tables and List’’ to www.fda.gov/BiologicsBloodVaccines/
others. ICH is concerned with facilitate making changes recommended GuidanceCompliance
harmonization of technical by ICH, available at https:// RegulatoryInformation/Guidances/
requirements for the registration of www.fda.gov/downloads/drugs/ default.htm, or https://
pharmaceutical products for human use guidancecomplianceregulatory www.regulations.gov.
among regulators around the world. The information/guidances/ucm073395.pdf. Dated: July 18, 2017.
six founding members of the ICH are: The ‘‘Q3C: Tables and List’’ has been Anna K. Abram,
The European Commission; the updated as of January 2017 to include
European Federation of Pharmaceutical Deputy Commissioner for Policy, Planning,
the recommended PDE for triethylamine
Legislation, and Analysis.
Industries Associations; the Japanese and methylisobutylketone.
[FR Doc. 2017–15537 Filed 7–24–17; 8:45 am]
Ministry of Health, Labour, and Welfare; In the Federal Register of October 16,
the Japanese Pharmaceutical 2015 (80 FR 62537), FDA published a BILLING CODE 4164–01–P
Manufacturers Association; CDER and notice announcing the availability of
CBER, FDA; and the Pharmaceutical draft recommendations for the PDEs for
Research and Manufacturers of America. two solvents, trimethylamine and DEPARTMENT OF HEALTH AND
The Standing Members of the ICH methylisobutylketone, according to the HUMAN SERVICES
Association include Health Canada and maintenance procedures for the Food and Drug Administration
Swissmedic. Any party eligible as a guidance entitled ‘‘Q3C Impurities:
Member in accordance with the ICH Residual Solvents,’’ available at https:// [Docket No. FDA–2015–D–3235]
Articles of Association can apply for www.fda.gov/ucm/groups/fdagov-
membership in writing to the ICH public/@fdagov-drugs-gen/documents/ M4E(R2): The Common Technical
Secretariat. The ICH Secretariat, which document/ucm073394.pdf. The notice Document—Efficacy; International
coordinates the preparation of gave interested persons an opportunity Council for Harmonisation; Guidance
documentation, operates as an to submit comments by December 15, for Industry; Availability
international nonprofit organization and 2015. After consideration of the AGENCY: Food and Drug Administration,
is funded by the Members of the ICH comments received and revisions to the HHS.
Association. The ICH Assembly is the guidance, a final draft of the
ACTION: Notice of availability.
overarching body of the Association and recommendations was submitted to the
includes representatives from each of ICH Assembly and endorsed by the SUMMARY: The Food and Drug
the ICH members and observers. regulatory agencies in November 2016. Administration (FDA or Agency) is
In the Federal Register of December The guidance provides a new PDE for announcing the availability of a
24, 1997 (62 FR 67377), FDA published the solvent trimethylamine and a guidance entitled ‘‘M4E(R2): The CTD—
a notice announcing the availability of revised PDE for the solvent Efficacy.’’ The guidance was prepared
the ICH guidance for industry entitled methylisobutylketone. In addition, the under the auspices of the International
‘‘Q3C Impurities: Residual Solvents.’’ data used to derive the PDEs are Council for Harmonisation (ICH),
The guidance makes recommendations summarized. Revisions made to the formerly the International Conference
as to what amounts of residual solvents final guidance as a result of comments on Harmonisation. The guidance revises
are considered toxicologically include a modification of the PDE for the ICH guidance ‘‘M4E: The CTD—
acceptable for some residual solvents. methylisobutylketone from 22.6 Efficacy’’ (M4E guidance). The revised
Upon issuance in 1997, the text and milligrams (mg)/day to 45 mg/day based guidance standardizes the presentation
appendix 1 of the guidance contained on reconsideration of the severity of of benefit-risk information in regulatory
several tables and a list of solvents effects identified in rat studies and the submissions, providing greater
categorizing residual solvents by human relevance of effects identified in specificity on the format and structure
toxicity, classes 1 through 3, with class mouse carcinogenicity study. The
of benefit-risk information. This
1 being the most toxic. The ICH Quality recommendation to place
revision is intended to facilitate
Expert Working Group (EWG) agreed methylisobutylketone into class 2
communication among regulators and
that the PDE could be modified if remains. The ‘‘Q3C: Tables and List’’
industry.
reliable and more relevant toxicity data has been updated as of January 2017 to
were brought to the attention of the include the recommended PDE for DATES: Submit either electronic or
group and the modified PDE could triethylamine and written comments on Agency guidance’s
result in a revision of the tables and list. methylisobutylketone. at any time.
In 1999, ICH instituted a Q3C This guidance is being issued ADDRESSES: You may submit comments
mstockstill on DSK30JT082PROD with NOTICES
maintenance agreement and formed a consistent with FDA’s good guidance as follows:
maintenance EWG (Q3C EWG). The practices regulation (21 CFR 10.115).
agreement provided for the revisitation The guidance represents the current Electronic Submissions
of solvent PDEs and allowed for minor thinking of FDA on ‘‘Q3C Impurities: Submit electronic comments in the
changes to the tables and list that Residual Solvents.’’ It does not establish following way:
include the existing PDEs. The any rights for any person and is not • Federal eRulemaking Portal:
agreement also provided for new binding on FDA or the public. You can https://www.regulations.gov. Follow the
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![34540 Federal Register / Vol. 82, No. 141 / Tuesday, July 25, 2017 / Notices
a final draft of the guidance was revisions in section 2.5.6. In addition, January 10, 2017 and effective on
submitted to the ICH Assembly and the revised guidance changes the February 11, 2017.
endorsed by the regulatory agencies on numbering and the section headings for FOR FURTHER INFORMATION CONTACT:
June 16, 2016. consistency. Segaran Pillai, Ph.D., Director, Office of
Regulatory authorities approve drugs This guidance is being issued Laboratory Science and Safety, Office of
that are demonstrated to be safe and consistent with FDA’s good guidance the Commissioner, Food and Drug
effective for human use. The meaning of practices regulation (21 CFR 10.115). Administration, White Oak Bldg. 1, Rm.
‘‘safe’’ has historically been interpreted The guidance represents the current 2218, 10903 New Hampshire Ave.,
to mean that the benefits of the drug thinking of FDA on this topic. It does Silver Spring, MD 20993–0002, 240–
outweigh its risks. This benefit-risk not establish any rights for any person 402–2856.
assessment of pharmaceuticals is the and is not binding on FDA or the public. SUPPLEMENTARY INFORMATION: Part D,
fundamental basis of regulatory You can use an alternative approach if Chapter D–B, (Food and Drug
decision-making. In the last several it satisfies the requirements of the Administration), the Statement of
years, providing greater structure for the applicable statutes and regulations. This Organization, Functions, and
benefit-risk assessment has been an guidance is not subject to Executive Delegations of Authority for the
important topic in drug regulation. The Order 12866. Department of Health and Human
M4E guidance directs applicants to
include their conclusions on benefits II. Paperwork Reduction Act of 1995 Services (35 FR 3685, February 25,
and risks in the Clinical Overview of 1970, 60 FR 56606, November 9, 1995,
This guidance refers to previously 64 FR 36361, July 6, 1999, 72 FR 50112,
Module 2 of the Common Technical approved collections of information that
Document (CTD) under section 2.5.6. August 30, 2007, 74 FR 41713, August
are subject to review by the Office of 18, 2009, and 76 FR 45270, July 28,
Although general guidance is provided
Management and Budget (OMB) under 2011) is amended to reflect the
in the M4E guidance regarding the
the Paperwork Reduction Act of 1995 reorganization of the Office of the
expected content of section 2.5.6, no
(44 U.S.C. 3501–3520). The collections Commissioner and the Office of
further structure is suggested to aid
of information in 21 CFR parts 312 and Operations.
industry in developing the benefit-risk
314 have been approved under OMB This reorganization establishes the
assessment. As a result, regulators
control numbers 0910–0014 and 0910– Office of Laboratory Science and Safety,
observe a high degree of variability in
0001, respectively. and will authorize the consolidation of
the approaches taken by applicants in
presenting this information. This III. Electronic Access the laboratory science, safety functions,
variability may not facilitate efficient and program activities across FDA
communication of industry views to Persons with access to the Internet under one organizational component
regulators. Although regulators and may obtain the guidance at https:// that will report directly to the Office of
industry have developed approaches for www.regulations.gov, http:// the Commissioner. The Employee Safety
structured benefit-risk assessment and www.fda.gov/Drugs/Guidance and Environmental Management Staff
these approaches may take different ComplianceRegulatoryInformation/ will be realigned from the Office of
forms, there is a common thread evident Guidances/default.htm, or http:// Safety, Security and Crisis Management
that can inform harmonization of the www.fda.gov/BiologicsBloodVaccines/ to the Office of Laboratory Science and
format and structure of benefit-risk GuidanceCompliance Safety. As a result of the staff
assessments provided by applicants in RegulatoryInformation/Guidances/ realignment the Office of Safety,
their regulatory submissions. default.htm. Security and Crisis Management within
The revised M4E(R2) guidance Dated: July 18, 2017. the Office of Operations will be re-titled
provides more specific guidance Anna K. Abram, to the Office of Security and Emergency
regarding the format and structure of the Deputy Commissioner for Policy, Planning,
Management. The Office of Crisis
benefit-risk assessment in section 2.5.6. Legislation, and Analysis. Management within the newly titled
Section 2.5.6 is divided into four [FR Doc. 2017–15534 Filed 7–24–17; 8:45 am]
Office of Security and Emergency
subsections: (1) Therapeutic context, (2) Management will change its title to the
BILLING CODE 4164–01–P
Benefit, (3) Risk, and (4) Benefit-Risk Office of Emergency Management.
Assessment. Each subsection describes Additionally, the Office of Security and
the aspects that are most pertinent to the DEPARTMENT OF HEALTH AND Emergency Management has established
benefit-risk assessment. This guidance HUMAN SERVICES the Emergency Planning, Evaluation,
also lists characteristics that should be and Exercise Staff, and the Program
considered when identifying and Food and Drug Administration Operations and Coordination Staff
describing key benefits and key risks of within the Office of Emergency
the medicinal product. Recognizing that Office of the Commissioner; Statement Management.
there are many reasonable approaches of Organization, Functions, and The Food and Drug Administration,
for conducting a benefit-risk assessment, Delegations of Authority Office of the Commissioner (OC), has
M4E(R2) does not specify a particular been restructured as follows:
approach to be used by industry. AGENCY: Food and Drug Administration, DA. ORGANIZATION. The Office of
However, the document does offer HHS. the Commissioner is headed by the
specific guidance on the major elements ACTION: Notice. Commissioner of Food and Drugs and
that should be included in the benefit- includes the following organizational
mstockstill on DSK30JT082PROD with NOTICES
risk assessment. Furthermore, the SUMMARY: The Food and Drug units:
revised guidance does not dictate an Administration (FDA), Office of the Office of the Commissioner (DA)
approach used by a regulator in Commissioner (OC), and Office of Office of the Chief Counsel (DAA)
conducting a benefit-risk assessment. Operations (OO) have modified their Office of the Executive Secretariat
This guidance also revises other structures. This new organizational (DAB)
sections of the guidance for structure was approved by the Secretary Executive Secretariat Staff (DAB1)
clarification, given the proposed of Health and Human Services on Freedom of Information Staff (DAB2)
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Document Created: 2018-10-24 11:20:32
Document Modified: 2018-10-24 11:20:32
| Category | Regulatory Information | |
| Collection | Federal Register | |
| sudoc Class | AE 2.7: GS 4.107: AE 2.106: | |
| Publisher | Office of the Federal Register, National Archives and Records Administration | |
| Section | Notices | |
| Action | Notice of availability. | |
| Dates | Submit either electronic or written comments on Agency guidance's at any time. | |
| 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. | |
| FR Citation | 82 FR 34538 |
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