82 FR 49371 - In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies, and Clinical Drug Interaction Studies-Study Design, Data Analysis, and Clinical Implications; Draft Guidances for Industry; Availability
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration Federal Register Volume 82, Issue 205 (October 25, 2017)
Food and Drug Administration
Federal Register Volume 82, Issue 205 (October 25, 2017)
| Page Range | 49371-49373 | |
| FR Document | 2017-23102 |
[Federal Register Volume 82, Number 205 (Wednesday, October 25, 2017)] [Notices] [Pages 49371-49373] From the Federal Register Online [www.thefederalregister.org] [FR Doc No: 2017-23102] ======================================================================= ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2017-D-5961] In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies, and Clinical Drug Interaction Studies--Study Design, Data Analysis, and Clinical Implications; Draft Guidances for Industry; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice of availability. ----------------------------------------------------------------------- [[Page 49372]] SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing the availability of two draft guidances for industry entitled ``In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies'' (in vitro DDI guidance) and ``Clinical Drug Interaction Studies--Study Design, Data Analysis, and Clinical Implications'' (clinical DDI guidance). These two draft guidances will update and replace the revised draft guidance for industry entitled ``Drug Interaction Studies--Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations'' issued February 21, 2012 (2012 draft guidance). These draft guidances are intended to assist drug developers in the planning and evaluation of drug-drug interaction (DDI) potential during drug development. In particular, the in vitro DDI guidance focuses on in vitro experimental approaches for evaluating metabolizing enzyme- and transporter-based drug interaction potential and how to extrapolate in vitro data to decide on the need for clinical DDI studies. The clinical DDI guidance focuses on clinical studies that evaluate the potential for DDIs, which alter a drug's pharmacokinetics by modulating the effects of drug metabolizing enzymes and transporters, and advises sponsors on the timing and design of the clinical studies, interpretation of the results, and options for managing DDIs in patients. Together, these two draft guidances describe a systematic, risk-based approach to the assessment of DDIs. DATES: Submit either electronic or written comments on these draft guidances by January 23, 2018 to ensure that the Agency considers your comment on these two draft guidances before it begins work on the final versions of these guidances. 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-2017-D-5961 for ``In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies, and Clinical Drug Interaction Studies-- Study Design, Data Analysis, and Clinical Implications; Draft Guidances 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. You may submit comments on any guidance at any time (see 21 CFR 10.115(g)(5)). Submit written requests for single copies of the draft guidances 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. Send one self-addressed adhesive label to assist that office in processing your requests. See the SUPPLEMENTARY INFORMATION section for electronic access to the draft guidance documents. FOR FURTHER INFORMATION CONTACT: Lauren Brum, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 3188, Silver Spring, MD 20903-0002, 301- 796-5008, or [email protected]. SUPPLEMENTARY INFORMATION: I. Background FDA is announcing the availability of two draft guidances for industry entitled ``In Vitro Metabolism- and Transporter-Mediated Drug- Drug Interaction Studies'' and ``Clinical Drug Interaction Studies-- Study Design, Data Analysis, and Clinical Implications.'' The concomitant use of more than one medication in a patient is common. Unanticipated, unrecognized, or mismanaged DDIs are an important cause of morbidity and mortality associated with prescription drug use and has occasionally been the basis for withdrawal of approved drugs from the market. In some instances, understanding how to safely manage a DDI can allow approval of a drug that would otherwise have an unacceptable [[Page 49373]] level of risk. Clinically relevant DDIs between an investigational drug and other drugs should therefore: (1) Be defined during drug development as part of an adequate assessment of the drug's overall benefit/risk profile; (2) be known at the time of the drug's approval; and (3) be communicated in labeling. These two draft guidances are intended to assist drug developers in the planning and evaluation of DDI potential during drug development. In particular, the in vitro DDI guidance focuses on in vitro experimental approaches for evaluating metabolizing enzyme- and transporter-based drug interaction potential, and how to extrapolate in vitro data to decide on the need for clinical DDI studies. The appendix of the in vitro DDI guidance includes considerations in the choice of in vitro experimental systems, key issues regarding in vitro experimental conditions, and a more detailed explanation of model-based DDI prediction strategies. If in vitro assessments indicate the need to conduct clinical DDI studies, sponsors should consult the related clinical DDI guidance. The clinical DDI guidance focuses on clinical studies that evaluate DDIs that alter a drug's pharmacokinetics by modulating the effects of drug metabolizing enzymes and/or transporters and advises sponsors on the timing and design of the clinical studies, interpretation of the results, and options for DDI management in patients. Together, the two draft guidances describe a systematic, risk-based approach to evaluation and communication of DDIs. In the Federal Register of February 21, 2012 (77 FR 9946), FDA announced the availability of a revised draft guidance entitled ``Drug Interaction Studies--Study Design, Data Analysis, Implications for Dosing, and Labeling Recommendations.'' We received comments on the 2012 draft guidance and have considered these comments while updating the information in the two draft guidances. In addition, new developments in the field have been incorporated to reflect the Agency's current thinking. The Agency decided to divide the 2012 draft guidance into two guidances with one focusing on in vitro DDI evaluation and the other focusing on clinical DDI evaluation. We are publishing the two draft guidances to collect additional public comments. These new draft guidances focus on metabolism- and transporter-based drug interactions. Other types of interactions, e.g., drug-therapeutic protein interactions and pH-dependent drug interactions, are not included. Separate guidances will be developed to cover other types of DDIs. In addition, a draft guidance specific to Section 7 (Drug Interactions) labeling will be developed to delineate the communication of DDI information in labeling. These two draft guidances are being issued consistent with FDA's good guidance practices regulation (21 CFR 10.115). These draft guidances, when finalized, will represent the Agency's current thinking on ``In Vitro Metabolism- and Transporter-Mediated Drug-Drug Interaction Studies'' and ``Clinical Drug Interaction Studies--Study Design, Data Analysis, and Clinical Implications.'' 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. These guidances are not subject to Executive Order 12866. II. Paperwork Reduction Act of 1995 These draft guidances refer to previously approved collections of information found in FDA regulations. These collections of information 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 314.50(d) have been approved under OMB control number 0910-0001. III. Electronic Access Persons with access to the internet may obtain the draft guidance at either https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or https://www.regulations.gov. Dated: October 19, 2017. Anna K. Abram, Deputy Commissioner for Policy, Planning, Legislation, and Analysis. [FR Doc. 2017-23102 Filed 10-24-17; 8:45 am] BILLING CODE 4164-01-P
![Federal Register / Vol. 82, No. 205 / Wednesday, October 25, 2017 / Notices 49371
Estimated annual burden hours: FR applicant prior to an interview and what clearly unwarranted invasion of
28: 3,500 hours, FR 28s: 33 hours, FR may be required of the applicant if he personal privacy, and would be kept
28i: 75 hours, Total: 3,608 hours. or she is offered a position (for example, confidential. However, the release of
General description of report: The transcripts, medical examination, or information such as the educational and
Application for Employment with the drug test). professional qualifications of applicants
Board of Governors of the Federal The FR 28s is comprised of four would not likely constitute a clearly
Reserve System (Application) collects sections: (1) Name and gender, in which unwarranted invasion of personal
information to determine the the applicant is asked to check the box privacy and would not be kept
qualifications and availability of that corresponds to gender or check ‘‘I confidential.
applicants for employment with the do not wish to disclose’’, (2) position for Current actions: On July 28, 2017, the
Board of Governors of the Federal which the applicant is applying, (3) Federal Reserve published a notice in
Reserve System (Board). The FR 28 ethnicity self-identification, in which the Federal Register (82 FR 35202)
collects information on education and the applicant is asked to choose requesting public comment for 60 days
training, employment record, military between Hispanic or Latino or Not on the extension, with revision, of the
service record, and other information Hispanic or Latino, or ‘‘I do not wish to Application for Employment with the
since the time the applicant left high disclose,’’ and (4) race self- Board of Governors of the Federal
school. Included with the FR 28 are two identification, in which the applicant is Reserve System. The Board proposed
supplemental questionnaires: (1) The asked to choose one or more among minor revisions to the FR 28 form,
Applicant’s Voluntary Self- American Indian or Alaskan Native, including (1) adding fields in the
Identification Form (FR 28s), which Asian, Black or African-American, employment history section for job type,
collects information on the applicant’s Native Hawaiian or Other Pacific shift, employee status, and desired
gender and ethnic group and (2) The Islander, White, or ‘‘I do not wish to compensation, (2) adding fields in the
Research Assistant Candidate Survey of disclose.’’ The Board uses this education and training section for issue
Interests (FR 28i), which collects information to comply with federal and expiration date for certifications
information from candidates applying equal employment opportunity (EEO) and professional licenses, (3) adding
for Research Assistant (RA) positions on recordkeeping and reporting fields in the references section for
their level of interest in economics and requirements, other legal requirements, relationship, type, and length of
related areas. The Board receives and as an input to its self-analysis of relationship with the reference, and (4)
approximately 3,500 applications per hiring practices. Information collected adding fields in the submission section
year, both solicited and unsolicited, on the FR 28s has no bearing on the to allow for withdrawal of the
from members of the public who would determination of an applicant’s job- application and a request for the
like to be considered for employment at related qualifications and completion of applicant to provide a reason for
the Board. Since the applicant is usually the self-identification form is voluntary. withdrawal. In addition, the Board
either hired by the Board or finds other The FR 28i is comprised of three proposed to revise the FR 28i by adding
employment within the two years that sections in which research assistant a section to allow an open-ended
the Board retains the Application, the candidates are asked to rate their level response by applicants to describe how
applicant generally files the Application of interest in categories of economics they have demonstrated attributes that
once. and related research areas, experience are displayed by successful research
The Application is comprised of eight with various software packages and assistants in the Economics Divisions.
sections: Background, Education and statistical programming languages, and The comment period for this notice
Training, Employment Record, Military interest in pursuing educational expired on September 26, 2017. The
Service Record, References, General, opportunities after leaving the Board. Board did not receive any comments.
Remarks, and Notes. The first six The FR 28i helps to streamline the The revisions will be implemented as
sections collect information on specific recruitment process. proposed.
aspects of the applicant’s qualifications. Legal authorization and Board of Governors of the Federal Reserve
The Background section collects name, confidentiality: The Board’s Legal System, October 20, 2017.
address, telephone, and citizenship Division has determined that the Ann E. Misback,
information and the position for which Application (including the two
Secretary of the Board.
the applicant is applying. The supplemental questionnaires) is
[FR Doc. 2017–23150 Filed 10–24–17; 8:45 am]
Education and Training section collects required to obtain the benefit of Board
employment. It is authorized pursuant BILLING CODE 6210–01–P
detailed information on the applicant’s
educational history and skills set. The to sections 10(4) and 11(1) of the
Employment Record section collects a Federal Reserve Act, which provide the
chronological summary of work Federal Reserve Board broad authority DEPARTMENT OF HEALTH AND
experience. The Military Service Record over employment of staff (12 U.S.C. 244 HUMAN SERVICES
section collects information on service and 248(l)). Information provided on the
Application (including the two Food and Drug Administration
branch, rank, duties, and discharge. The
References section collects information supplemental questionnaires) will be [Docket No. FDA–2017–D–5961]
on three references. The General section kept confidential under exemption
collects information on criminal (b)(6) of the Freedom of Information Act In Vitro Metabolism- and Transporter-
records, discharge from employment, (FOIA) to the extent that the disclosure Mediated Drug-Drug Interaction
of information ‘‘would constitute a Studies, and Clinical Drug Interaction
sradovich on DSK3GMQ082PROD with NOTICES
willingness to travel, and relations to or
acquaintances with Board staff or clearly unwarranted invasion of Studies—Study Design, Data Analysis,
officers and directors of financial personal privacy.’’ (5 U.S.C. 552(b)(6)). and Clinical Implications; Draft
institutions. The Remarks section For example, the release of information Guidances for Industry; Availability
provides the applicant an opportunity to such as an applicant’s date of birth, AGENCY: Food and Drug Administration,
provide further information regarding address, phone number, and personal HHS.
his or her qualifications. The Notes information regarding any references
ACTION: Notice of availability.
section explains what is required of the provided would likely constitute a
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![Federal Register / Vol. 82, No. 205 / Wednesday, October 25, 2017 / Notices 49373
level of risk. Clinically relevant DDIs guidances will be developed to cover announcing the availability of the draft
between an investigational drug and other types of DDIs. In addition, a draft guidance entitled ‘‘Breakthrough
other drugs should therefore: (1) Be guidance specific to Section 7 (Drug Devices Program; Draft Guidance for
defined during drug development as Interactions) labeling will be developed Industry and Food and Drug
part of an adequate assessment of the to delineate the communication of DDI Administration Staff.’’ This guidance
drug’s overall benefit/risk profile; (2) be information in labeling. document describes policies that FDA
known at the time of the drug’s These two draft guidances are being intends to use to implement the new
approval; and (3) be communicated in issued consistent with FDA’s good Breakthrough Devices Program,
labeling. These two draft guidances are guidance practices regulation (21 CFR established by the 21st Century Cures
intended to assist drug developers in the 10.115). These draft guidances, when Act (Cures Act). The Breakthrough
planning and evaluation of DDI finalized, will represent the Agency’s Devices Program supersedes and
potential during drug development. In current thinking on ‘‘In Vitro combines elements from FDA’s
particular, the in vitro DDI guidance Metabolism- and Transporter-Mediated Expedited Access Pathway (EAP),
focuses on in vitro experimental Drug-Drug Interaction Studies’’ and which was intended to facilitate the
approaches for evaluating metabolizing ‘‘Clinical Drug Interaction Studies— development and expedite review of
enzyme- and transporter-based drug Study Design, Data Analysis, and breakthrough technologies, as well as
interaction potential, and how to Clinical Implications.’’ It does not the Priority Review Program, which
extrapolate in vitro data to decide on the establish any rights for any person and implemented statutory criteria for
need for clinical DDI studies. The is not binding on FDA or the public. granting priority review to premarket
appendix of the in vitro DDI guidance You can use an alternative approach if approval applications (PMAs) and
includes considerations in the choice of it satisfies the requirements of the applied those criteria to other types of
in vitro experimental systems, key applicable statutes and regulations. premarket submissions for medical
issues regarding in vitro experimental These guidances are not subject to devices. This draft guidance clarifies
conditions, and a more detailed Executive Order 12866. certain principles and features of the
explanation of model-based DDI new program, the designation criteria
prediction strategies. If in vitro II. Paperwork Reduction Act of 1995
for Breakthrough Devices, the
assessments indicate the need to These draft guidances refer to designation request review process, the
conduct clinical DDI studies, sponsors previously approved collections of process for withdrawing from the
should consult the related clinical DDI information found in FDA regulations. program, as well as the recommended
guidance. The clinical DDI guidance These collections of information are information device manufacturers
focuses on clinical studies that evaluate subject to review by the Office of should provide in their designation
DDIs that alter a drug’s Management and Budget (OMB) under request for entrance into the program.
pharmacokinetics by modulating the the Paperwork Reduction Act of 1995 This draft guidance is not final nor is it
effects of drug metabolizing enzymes (44 U.S.C. 3501–3520). The collections in effect at this time.
and/or transporters and advises of information in 21 CFR 314.50(d) have
sponsors on the timing and design of the been approved under OMB control DATES: Submit either electronic or
clinical studies, interpretation of the number 0910–0001. written comments on the draft guidance
results, and options for DDI by December 26, 2017 to ensure that the
management in patients. Together, the III. Electronic Access Agency considers your comment on this
two draft guidances describe a Persons with access to the internet draft guidance before it begins work on
systematic, risk-based approach to may obtain the draft guidance at either the final version of the guidance.
evaluation and communication of DDIs. https://www.fda.gov/Drugs/Guidance ADDRESSES: You may submit comments
In the Federal Register of February ComplianceRegulatoryInformation/ on any guidance at any time as follows:
21, 2012 (77 FR 9946), FDA announced Guidances/default.htm or https://
the availability of a revised draft www.regulations.gov. Electronic Submissions
guidance entitled ‘‘Drug Interaction Dated: October 19, 2017. Submit electronic comments in the
Studies—Study Design, Data Analysis, Anna K. Abram, following way:
Implications for Dosing, and Labeling
Recommendations.’’ We received
Deputy Commissioner for Policy, Planning, • Federal eRulemaking Portal:
Legislation, and Analysis. https://www.regulations.gov. Follow the
comments on the 2012 draft guidance
[FR Doc. 2017–23102 Filed 10–24–17; 8:45 am] instructions for submitting comments.
and have considered these comments
while updating the information in the BILLING CODE 4164–01–P Comments submitted electronically,
two draft guidances. In addition, new including attachments, to https://
developments in the field have been www.regulations.gov will be posted to
DEPARTMENT OF HEALTH AND the docket unchanged. Because your
incorporated to reflect the Agency’s
HUMAN SERVICES comment will be made public, you are
current thinking.
The Agency decided to divide the solely responsible for ensuring that your
Food and Drug Administration
2012 draft guidance into two guidances comment does not include any
with one focusing on in vitro DDI [Docket No. FDA–2017–D–5966] confidential information that you or a
evaluation and the other focusing on third party may not wish to be posted,
clinical DDI evaluation. We are Breakthrough Devices Program; Draft such as medical information, your or
Guidance for Industry and Food and anyone else’s Social Security number, or
sradovich on DSK3GMQ082PROD with NOTICES
publishing the two draft guidances to
collect additional public comments. Drug Administration Staff; Availability confidential business information, such
These new draft guidances focus on AGENCY: Food and Drug Administration, as a manufacturing process. Please note
metabolism- and transporter-based drug HHS. that if you include your name, contact
interactions. Other types of interactions, ACTION: Notice of availability. information, or other information that
e.g., drug-therapeutic protein identifies you in the body of your
interactions and pH-dependent drug SUMMARY: The Food and Drug comments, that information will be
interactions, are not included. Separate Administration (FDA or Agency) is posted on https://www.regulations.gov.
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Document Created: 2017-10-25 01:17:40
Document Modified: 2017-10-25 01:17:40
| 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 these draft guidances by January 23, 2018 to ensure that the Agency considers your comment on these two draft guidances before it begins work on the final versions of these guidances. | |
| Contact | Lauren Brum, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, Rm. 3188, Silver Spring, MD 20903-0002, 301- 796-5008, or [email protected] | |
| FR Citation | 82 FR 49371 |
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