Rules and Regulations. Notice of availability

Agency: Food and Drug Administration, HHS
Action: Notice of availability
Citation: FR Doc. 2022-18515 · Docket No. FDA-2020-D-1791

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 This guidance finalizes the draft guidance of the same title issued in September 2020.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.

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 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]