Document ID: FDA-2020-D-1791-0009
Agency: fda
Document Type: Notice
Title: E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential—Questions and Answers; International Council for Harmonisation; Guidance for Industry;
Availability
Posted Date: 2022-08-29T04:00Z

[Federal Register Volume 87, Number 166 (Monday, August 29, 2022)]
[Notices]
[Pages 52786-52788]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-18515]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-D-1791]

E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential--Questions and 
Answers; 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 final guidance for industry entitled ``E14 and 
S7B Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential--Questions and Answers.'' The guidance was 
prepared under the auspices of the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH), formerly the International Conference on Harmonisation. The 
guidance contains revised questions and answers (Q&As) for the ICH 
guidance for industry ``E14 Clinical Evaluation of the QT/QTc Interval 
Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs'' 
and new Q&As for the ICH guidance for industry ``S7B Nonclinical 
Evaluation of the Potential for Delayed Ventricular Repolarization (QT 
Interval Prolongation) by Human Pharmaceuticals'' that provide 
recommendations on considerations for an integrated risk assessment 
combining nonclinical and clinical data--in particular, at later stages 
of drug development when clinical data are available. The guidance is 
intended to provide a harmonized approach to integrate nonclinical and 
clinical information for proarrhythmia risk assessment to streamline 
drug development and provide clarity on regulatory decision making. 
This guidance finalizes the draft guidance of the same title issued in 
September 2020.

DATES: The announcement of the guidance is published in the Federal 
Register on August 29, 2022.

ADDRESSES: You may submit either electronic or written comments on 
Agency guidances at any time as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the 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-2020-D-1791 for ``E14 and S7B Clinical and Nonclinical Evaluation 
of QT/QTc Interval Prolongation and Proarrhythmic Potential--Questions 
and Answers.'' 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, 240-402-7500.
     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

[[Page 52787]]

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.govinfo.gov/content/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, 240-402-7500.
    You may submit comments on any guidance at any time (see 21 CFR 
10.115(g)(5)).
    Submit written requests for single copies of this 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 (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: Devi Kozeli, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
22, Rm. 4183, Silver Spring, MD 20993-0002, 301-796-1128; 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: Jill Adleberg, Center for Drug Evaluation and 
Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 
51, Rm. 6364, Silver Spring, MD 20993-0002, 301-796-5259.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry 
entitled ``E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential--Questions and 
Answers.'' The guidance was prepared under the auspices of ICH. ICH has 
the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, high-quality medicines are developed, 
registered, and maintained in the most resource-efficient manner.
    By harmonizing the regulatory requirements in regions around the 
world, ICH guidelines have substantially reduced duplicative clinical 
studies, prevented unnecessary animal studies, standardized the 
reporting of important safety information, standardized marketing 
application submissions, and made many other improvements in the 
quality of global drug development and manufacturing and the products 
available to patients.
    The six Founding Members of the ICH are FDA; the Pharmaceutical 
Research and Manufacturers of America; the European Commission; the 
European Federation of Pharmaceutical Industries Associations; the 
Japanese Ministry of Health, Labour, and Welfare; and the Japanese 
Pharmaceutical Manufacturers Association. The Standing Members of the 
ICH Association include Health Canada and Swissmedic. Additionally, the 
Membership of ICH has expanded to include other regulatory authorities 
and industry associations from around the world (https://www.ich.org/).
    ICH works by involving technical experts from both regulators and 
industry parties in detailed technical harmonization work and the 
application of a science-based approach to harmonization through a 
consensus-driven process that results in the development of ICH 
guidelines. The regulators around the world are committed to 
consistently adopting these consensus-based guidelines, realizing the 
benefits for patients and for industry.
    As a Founding Regulatory Member of ICH, FDA plays a major role in 
the development of each of the ICH guidelines, which FDA then adopts 
and issues as guidance for industry. FDA's guidance documents do not 
establish legally enforceable responsibilities. Instead, they describe 
the Agency's current thinking on a topic and should be viewed only as 
recommendations, unless specific regulatory or statutory requirements 
are cited.
    In the Federal Register of September 30, 2020 (85 FR 61753), FDA 
published a notice announcing the availability of a draft guidance 
entitled ``E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc 
Interval Prolongation and Proarrhythmic Potential--Questions and 
Answers.'' The notice gave interested persons an opportunity to submit 
comments by November 30, 2020.
    After consideration of the comments received and revisions to the 
guideline, a final draft of the guideline was submitted to the ICH 
Assembly and endorsed by the regulatory agencies in February 2022.
    This guidance finalizes the draft guidance issued on September 30, 
2020. The guidance contains revised Q&As about the ICH guidance for 
industry ``E14 Clinical Evaluation of the QT/QTc Interval Prolongation 
and Proarrhythmic Potential for Non-Antiarrhythmic Drugs'' and new Q&As 
about the ICH guidance for industry ``S7B Nonclinical Evaluation of the 
Potential for Delayed Ventricular Repolarization (QT Interval 
Prolongation) by Human Pharmaceuticals'' that provide recommendations 
on considerations for an integrated risk assessment combining 
nonclinical and clinical data--in particular, at later stages of drug 
development when clinical data are available. For ICH E14, revised Q&As 
provide recommendations for how an integrated nonclinical and clinical 
risk assessment can be particularly valuable under scenarios when a 
sufficiently high multiple of maximum therapeutic exposure cannot be 
achieved (ICH E14 Q&A Q12 (5.1)); and under scenarios where a placebo-
controlled comparison is not possible, safety considerations preclude 
administering supratherapeutic doses to obtain high clinical exposures 
and/or safety or tolerability prohibit the use of the product in 
healthy participants (ICH E14 Q&A Q13 (6.1)). For ICH S7B, new

[[Page 52788]]

Q&As provide recommendations on an integrated risk assessment and how 
it can inform the design of clinical investigations and the 
interpretation of their results (ICH S7B Q&As Q17 (1.1) and Q18 (1.2)); 
best-practice considerations for in vitro (ICH S7B Q&As Q 19 (2.1) to 
Q23 (2.5)) and in vivo (ICH S7B Q&As Q24 (3.1) to Q28 (3.5)) studies; 
and principles for proarrhythmia models, including in silico (ICH S7B 
Q&As Q30 (4.1) and 4.2). The guidance is intended to provide a 
harmonized approach to integrate nonclinical and clinical information 
for proarrhythmia risk assessment to streamline drug development and 
provide clarity on regulatory decision making.
    This guidance is being issued consistent with FDA's good guidance 
practices regulation (21 CFR 10.115). This guidance represents the 
current thinking of FDA on ``E14 and S7B Clinical and Nonclinical 
Evaluation of QT/QTc Interval Prolongation and Proarrhythmic 
Potential--Questions and Answers.'' 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. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does 
refer to previously approved FDA collections of information. Therefore, 
clearance by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not 
required for this guidance. The previously approved collections of 
information are subject to review by OMB under the PRA. The collections 
of information for submitting investigational new drug applications are 
approved under OMB control number 0910-0014. The collections of 
information for submitting new drug applications are approved under OMB 
control number 0910-0001. The collections of information for submitting 
biologics license applications are approved under OMB control number 
0910-0338.

II. Electronic Access

    Persons with access to the internet may obtain the draft guidance 
at https://www.regulations.gov, https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances.

    Dated: August 22, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-18515 Filed 8-26-22; 8:45 am]
BILLING CODE 4164-01-P