Notice2022-18515
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
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Published
August 29, 2022
Issuing agencies
Health and Human Services DepartmentFood and Drug Administration
Abstract
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 This guidance finalizes the draft guidance of the same title issued in September 2020.
Full Text
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<title>Federal Register, Volume 87 Issue 166 (Monday, August 29, 2022)</title>
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[Federal Register Volume 87, Number 166 (Monday, August 29, 2022)]
[Notices]
[Pages 52786-52788]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[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:
<bullet> Federal eRulemaking Portal: <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to <a href="https://www.regulations.gov">https://www.regulations.gov</a>
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>.
<bullet> 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:
<bullet> 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.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a> or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
<bullet> 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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>. 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: <a href="https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf">https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf</a>.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to <a href="https://www.regulations.gov">https://www.regulations.gov</a> 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 (<a href="https://www.ich.org/">https://www.ich.org/</a>).
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 <a href="https://www.regulations.gov">https://www.regulations.gov</a>, <a href="https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs">https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs</a>, <a href="https://www.fda.gov/regulatory-information/search-fda-guidance-documents">https://www.fda.gov/regulatory-information/search-fda-guidance-documents</a>, or <a href="https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances">https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances</a>.
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
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