2020-21624. E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential-Questions and Answers; International Council for Harmonisation; Draft Guidance for Industry; Availability  

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    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    The Food and Drug Administration (FDA or Agency) is announcing the availability of a draft guidance for industry entitled “E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential—Questions and Answers.” The draft guidance was prepared under the auspices of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), formerly the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 of Technical Requirements for Registration of Pharmaceuticals for Human Use. The draft guidance contains revised questions and answers (Q&As) for the ICH guidance for industry “E14 Clinical Evaluation of the QT/QTc Interval Prolongation and Proarrhythmic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 The draft guidance is intended to provide a harmonized approach to integrate nonclinical and clinical information for proarrhythmia risk assessment to streamline drug development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.

    DATES:

    Submit either electronic or written comments on the draft guidance by November 30, 2020 to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance.

    ADDRESSES:

    You may submit comments on any guidance 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 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 Start Printed Page 61754heading 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.

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    FOR FURTHER INFORMATION CONTACT:

    Regarding the guidance: David Strauss, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 64, Rm. 2072, Silver Spring, MD 20993-0002, 301-796-6323; 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.

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    SUPPLEMENTARY INFORMATION:

    I. Background

    FDA is announcing the availability of a draft guidance for industry entitled “E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential—Questions and Answers.” The draft 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 July 2020, the ICH Assembly endorsed the draft guideline entitled “E14 and S7B Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential—Questions and Answers” and agreed that the guideline should be made available for public comment. The draft guideline is the product of the E14 and S7B Implementation Working Group of the ICH. Comments about this draft will be considered by FDA and the ICH E14 and S7B Implementation Working Group.

    The draft 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 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 6.1). For ICH S7B, new 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 1.1 and 1.2); best-practice considerations for in vitro (ICH S7B Q&As 2.1 to 2.5) and in vivo (ICH S7B Q&As 3.1 to 3.5) studies; and principles for proarrhythmia models, including in silico (ICH S7B Q&As 4.1 to 4.3). The draft 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. FDA seeks public comment on all aspects of these draft Q&As; of note, ICH E14 Q&A 6.1 encourages public comment on how to define the lack of clinically relevant QT prolongation in the context of this Q&A.

    This draft guidance has been left in the original ICH format. The final guidance will be reformatted and edited to conform with FDA's good guidance practices regulation (21 CFR 10.115) and style before publication. The draft guidance, when finalized, will represent 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.Start Printed Page 61755

    II. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this draft guidance contains no collection of information. Therefore, clearance by the Office of Management and Budget under the Paperwork Reduction Act of 1995 is not required.

    III. 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, or https://www.fda.gov/​vaccines-blood-biologics/​guidance-compliance-regulatory-information-biologics/​biologics-guidances.

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    Dated: September 25, 2020.

    Lauren K. Roth,

    Associate Commissioner for Policy.

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    [FR Doc. 2020-21624 Filed 9-29-20; 8:45 am]

    BILLING CODE 4164-01-P

Document Information

Published:
09/30/2020
Department:
Health and Human Services Department
Agency:
Food and Drug Administration
EntryType:
Notice
Action:
Notice of availability.
Document Number:
2020-21624
Dates:
Submit either electronic or written comments on the draft guidance by November 30, 2020 to ensure that the Agency considers your comment on this draft guidance before it begins work on the final version of the guidance.
Pages:
61753-61755 (3 pages)
Docket Numbers:
Docket No. FDA-2020-D-1791
SectionNoes:
PDF File:
2020-21624.pdf