81_FR_44745 81 FR 44614 - Use of Standards in the Food and Drug Administration's Regulatory Oversight of Next Generation Sequencing-Based In Vitro Diagnostics Used for Diagnosing Germline Diseases; Draft Guidance for Stakeholders and Food and Drug Administration Staff; Availability

81 FR 44614 - Use of Standards in the Food and Drug Administration's Regulatory Oversight of Next Generation Sequencing-Based In Vitro Diagnostics Used for Diagnosing Germline Diseases; Draft Guidance for Stakeholders and Food and Drug Administration Staff; Availability

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 81, Issue 131 (July 8, 2016)

Page Range44614-44616
FR Document2016-16201

The Food and Drug Administration (FDA or Agency) is announcing the availability of the draft guidance entitled ``Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases.'' As part of the White House's Precision Medicine Initiative (PMI),\1\ FDA is issuing this draft guidance to provide FDA's proposed approach on the content and possible use of standards in providing oversight for targeted and whole exome human DNA sequencing (WES) NGS-based tests intended to aid in the diagnosis of individuals with suspected germline diseases or other conditions. This document provides recommendations for designing, developing, and validating NGS-based tests for germline diseases, and also discusses possible use of FDA-recognized standards for regulatory oversight of these tests. These recommendations are based on FDA's understanding of the tools and processes needed to run an NGS-based test along with the design and analytical validation considerations appropriate for such tests. This draft guidance is not final nor is it in effect at this time. ---------------------------------------------------------------------------

Federal Register, Volume 81 Issue 131 (Friday, July 8, 2016)
[Federal Register Volume 81, Number 131 (Friday, July 8, 2016)]
[Notices]
[Pages 44614-44616]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2016-16201]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-D-1270]


Use of Standards in the Food and Drug Administration's Regulatory 
Oversight of Next Generation Sequencing-Based In Vitro Diagnostics Used 
for Diagnosing Germline Diseases; Draft Guidance for Stakeholders and 
Food and Drug Administration Staff; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of the draft guidance entitled ``Use of Standards in 
FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In 
Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases.'' As 
part of the White House's Precision Medicine Initiative (PMI),\1\ FDA 
is issuing this draft guidance to provide FDA's proposed approach on 
the content and possible use of standards in providing oversight for 
targeted and whole exome human DNA sequencing (WES) NGS-based tests 
intended to aid in the diagnosis of individuals with suspected germline 
diseases or other conditions. This document provides recommendations 
for designing, developing, and validating NGS-based tests for germline 
diseases, and also discusses possible use of FDA-recognized standards 
for regulatory oversight of these tests. These recommendations are 
based on FDA's understanding of the tools and processes needed to run 
an NGS-based test along with the design and analytical validation 
considerations appropriate for such tests. This draft guidance is not 
final nor is it in effect at this time.
---------------------------------------------------------------------------

    \1\ The Precision Medicine Initiative found on the White House's 
Web site at: https://www.whitehouse.gov/precision-medicine.

DATES: Although you can comment on any guidance at any time (see 21 CFR 
10.115(g)(5)), to ensure that the Agency considers your comment of this 
draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
---------------------------------------------------------------------------
guidance by October 6, 2016.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to http://www.regulations.gov 
will be posted to

[[Page 44615]]

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 http://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): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of 
Dockets Management, 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-2016-D-1270 for ``Use of Standards in FDA Regulatory Oversight of 
Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used 
for Diagnosing Germline Diseases.'' Received comments will be placed in 
the docket and, except for those submitted as ``Confidential 
Submissions,'' publicly viewable at http://www.regulations.gov or at 
the Division of Dockets Management 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 http://www.regulations.gov. 
Submit both copies to the Division of Dockets Management. 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: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to http://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 Division of Dockets Management, 5630 Fishers 
Lane, Rm. 1061, Rockville, MD 20852.
    An electronic copy of the guidance document is available for 
download from the Internet. See the SUPPLEMENTARY INFORMATION section 
for information on electronic access to the guidance. Submit written 
requests for a single hard copy of the draft guidance document entitled 
``Use of Standards in FDA Regulatory Oversight of Next Generation 
Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing 
Germline Diseases'' to the Office of the Center Director, Guidance and 
Policy Development, Center for Devices and Radiological Health, Food 
and Drug Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. 5431, 
Silver Spring, MD 20993-0002; or the Office of Communication, Outreach, 
and Development, Center for Biologics Evaluation and Research, 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 request.

FOR FURTHER INFORMATION CONTACT: Personalized Medicine Staff, Center 
for Devices and Radiological Health, Food and Drug Administration, 
10903 New Hampshire Ave., Bldg. 66, Rm. 4544, Silver Spring, MD 20993-
0002, 301-796-6206; or [email protected]; 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.

SUPPLEMENTARY INFORMATION:

I. Background

    As part of the PMI, FDA is committed to implementing a flexible and 
adaptive regulatory oversight approach, which fosters innovation and 
simultaneously assures that patients have access to accurate and 
meaningful test results. FDA held two public workshops on this issue: 
``Optimizing FDA's Regulatory Oversight of Next Generation Sequencing 
Diagnostic Tests Public Workshop'' held on February 20, 2015, and 
``Standards Based Approach to Analytical Performance Evaluation of Next 
Generation Sequencing In Vitro Diagnostic Tests'' held on November 12, 
2016. This guidance document, when finalized, provides recommendations 
for designing, developing, and validating for targeted and whole exome 
human DNA sequencing (WES) NGS-based tests intended to aid in the 
diagnosis of individuals with suspected germline diseases or other 
conditions (hereinafter referred to as ``NGS-based tests for germline 
diseases'' or ``NGS-based tests''). It also outlines considerations for 
possibly classifying certain NGS-based tests for germline diseases in 
class II and exempting them from premarket notification requirements. 
Upon finalization of this guidance, these recommendations should be 
used as guidelines for test developers for premarket submissions. 
However, the longer-term goal is for these recommendations to form the 
basis for standards that FDA could recognize or for special controls 
and/or conditions for premarket notification (510(k)) exemption. FDA is 
also issuing a draft guidance entitled ``Use of Public Human Genetic 
Variant Databases to Support Clinical Validity for Next Generation 
Sequencing (NGS)-Based In Vitro Diagnostics'' which is being issued 
concurrently elsewhere in this issue of the Federal Register.

II. Significance of Guidance

    This draft guidance is being issued consistent with FDA's good 
guidance practices regulation (21 CFR 10.115). The draft guidance, when 
finalized, will represent the current thinking of FDA on use of 
standards in FDA regulatory oversight of NGS-based IVDs used for 
diagnosing germline diseases. 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

[[Page 44616]]

it satisfies the requirements of the applicable statutes and 
regulations.

III. Electronic Access

    Persons interested in obtaining a copy of the draft guidance may do 
so by downloading an electronic copy from the Internet. A search 
capability for all Center for Devices and Radiological Health guidance 
documents is available at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm, and for 
Center for Biologics Evaluation and Research guidance documents is 
available at http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Guidance 
documents are also available at http://www.regulations.gov. Persons 
unable to download an electronic copy of ``Use of Standards in FDA 
Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro 
Diagnostics (IVDs) Used for Diagnosing Germline Diseases'' may send an 
email request to [email protected] to receive an electronic 
copy of the document. Please use the document number 16009 to identify 
the guidance you are requesting.

IV. Paperwork Reduction Act of 1995

    This guidance refers 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 part 807, subpart E, regarding 
premarket notification submissions, have been approved under OMB 
control number 0910-0120; the collections of information in 21 CFR part 
801 and 21 CFR 809.10, regarding labeling, have been approved under OMB 
control number 0910-0485; the collections of information in 21 CFR part 
814, subparts A through E, regarding premarket approval, have been 
approved under OMB control number 0910-0231; the collections of 
information in 21 CFR part 820, regarding the quality system 
regulation, have been approved under OMB control number 0910-0073; and 
the collections of information in the guidance document ``Requests for 
Feedback on Medical Device Submissions: The Pre-Submission Program and 
Meetings with Food and Drug Administration Staff'' have been approved 
under OMB control number 0910-0756.

V. Other Issues for Consideration

    The Agency invites comments on the draft guidance document entitled 
``Use of Standards in FDA Regulatory Oversight of Next Generation 
Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing 
Germline Diseases,'' in general, and on the following questions, in 
particular:
    1. Does the draft guidance content adequately address the 
analytical performance of targeted and whole exome human DNA sequencing 
(WES) NGS-based tests intended to aid in the diagnosis of individuals 
with suspected germline diseases or other conditions (referred to as 
``NGS-based tests for germline diseases'' or ``NGS-based tests'' in the 
guidance)? For example, do the recommendations outlined in the draft 
guidance adequately address the analytical performance of NGS-based 
tests used as an aid in diagnosis of patients with signs and symptoms 
of developmental delay or intellectual disability, undiagnosed 
diseases, or hereditary cancer syndromes? If not, what additional test 
design, development, or validation activities are necessary for 
analytical validation of such tests? Are there specific indications 
within this broad intended use that require different or additional 
test design, development, or validation activities from those described 
in the draft guidance?
    2. Do the recommendations in the draft guidance adequately address 
the analytical validation of NGS-based tests that use targeted panels 
or WES? Targeted sequencing panels? Are there differences between the 
use of targeted panels and WES that were not adequately distinguished 
in the recommendations described in the draft guidance?
    3. The recommendations in this document focus on WES and targeted 
NGS-based tests for germline diseases. Are the recommendations outlined 
in the guidance sufficient to address analytical validation for whole 
genome sequencing (WGS) NGS-based tests for germline diseases? If not, 
what additional test design, development, and validation activities are 
needed to address the analytical validation of such tests?
    4. Accuracy is generally described using an agreement, typically 
positive and negative percent agreement (PPA and NPA), between a new 
test and an accepted reference method. For NGS-based tests, positive 
predictive value (PPV) may be a more meaningful metric than NPA when 
calculating the likelihood that a variant call detected by the test is 
a true positive. If PPV is calculated using only analytical results 
without taking into account prevalence in a population, it is sometimes 
called ``technical'' PPV (TPPV) to distinguish it from prevalence-based 
PPV. What are the benefits and weaknesses to assessing NGS-based test 
accuracy using TPPV in addition to PPA and NPA, or instead of NPA?
    5. Are the minimum performance thresholds presented in this draft 
guidance appropriate, or are alternative thresholds more appropriate? 
Are there ``best ways'' to determine acceptable thresholds for each 
metric? Are there performance metrics that do not require minimum 
thresholds? Are there test scenarios where minimum thresholds are not 
useful or relevant?
    6. How can bias and over-fitting be minimized or accounted for if 
known ``reference'' samples are used as comparators in accuracy 
studies?

    Dated: July 5, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-16201 Filed 7-7-16; 8:45 am]
 BILLING CODE 4164-01-P



                                                    44614                                        Federal Register / Vol. 81, No. 131 / Friday, July 8, 2016 / Notices

                                                                                                    TABLE 3—ESTIMATED ANNUAL THIRD-PARTY DISCLOSURE BURDEN 1
                                                                                                                                                                     Number of            Total            Average
                                                                                                                                                   Number of         disclosures
                                                                                           Activity                                                                                      annual           burden per        Total hours
                                                                                                                                                  respondents            per           disclosures        disclosure
                                                                                                                                                                     respondent

                                                    Public disclosure of policies, procedures, and conflicts of
                                                      interest ..............................................................................          5                   1                5                  1                  5
                                                       1   There are no capital costs or operating and maintenance costs associated with this collection of information.


                                                      This draft guidance also refers to                                      actions may be appropriate with respect                   SUMMARY:    The Food and Drug
                                                    previously approved collections of                                        to in IVDs supported by such assertions?                  Administration (FDA or Agency) is
                                                    information. These collections of                                         How often should FDA conduct ongoing                      announcing the availability of the draft
                                                    information are subject to review by the                                  review of an FDA-recognized database?                     guidance entitled ‘‘Use of Standards in
                                                    OMB under the Paperwork Reduction                                            4. FDA notes that databases may have                   FDA Regulatory Oversight of Next
                                                    Act of 1995 (44 U.S.C. 3501–3520). The                                    ‘‘discordant calls’’ with other databases,                Generation Sequencing (NGS)-Based In
                                                    collections of information in the                                         where the assertions for a variant in                     Vitro Diagnostics (IVDs) Used for
                                                    guidance document ‘‘Requests for                                          each database vary. While FDA believes                    Diagnosing Germline Diseases.’’ As part
                                                    Feedback on Medical Device                                                that these discordant calls often arise                   of the White House’s Precision
                                                    Submissions: The Pre-Submission                                           because one database has information                      Medicine Initiative (PMI),1 FDA is
                                                    Program and Meetings with Food and                                        the other does not and our proposed                       issuing this draft guidance to provide
                                                    Drug Administration Staff’’ have been                                     policy will mitigate these issues over                    FDA’s proposed approach on the
                                                    approved under OMB control number                                         time; what, if any, action should FDA                     content and possible use of standards in
                                                    0910–0756. The collections of                                             take when it learns about discordant                      providing oversight for targeted and
                                                    information regarding premarket                                           calls between two databases with                          whole exome human DNA sequencing
                                                    submissions have been approved as                                         respect to database recognition or IVDs                   (WES) NGS-based tests intended to aid
                                                    follows: The collections of information                                   supported by such calls in FDA-                           in the diagnosis of individuals with
                                                    in 21 CFR part 807, subpart E, have been                                  recognized databases?                                     suspected germline diseases or other
                                                    approved under OMB control number                                            5. FDA has requested information                       conditions. This document provides
                                                    0910–0120; and the collections of                                         regarding conflicts of interest for                       recommendations for designing,
                                                    information in 21 CFR part 814,                                           curators and personnel of databases                       developing, and validating NGS-based
                                                    subparts A through E, have been                                           seeking FDA recognition. FDA                              tests for germline diseases, and also
                                                    approved under OMB control number                                         acknowledges that many personnel                          discusses possible use of FDA-
                                                    0910–0231.                                                                involved with variant curation and                        recognized standards for regulatory
                                                                                                                              interpretation may have some                              oversight of these tests. These
                                                    V. Other Issues for Consideration
                                                                                                                              connection to NGS test developers.                        recommendations are based on FDA’s
                                                       The Agency invites comments on the                                     What type of information should FDA                       understanding of the tools and
                                                    draft guidance document entitled ‘‘Use                                    collect and what policies should it                       processes needed to run an NGS-based
                                                    of Public Human Genetic Variant                                           implement to mitigate such potential                      test along with the design and analytical
                                                    Databases to Support Clinical Validity                                    conflicts of interest in FDA-recognized                   validation considerations appropriate
                                                    for Next Generation Sequencing (NGS)-                                     databases?                                                for such tests. This draft guidance is not
                                                    Based In Vitro Diagnostics,’’ in general,                                   Dated: July 5, 2016.                                    final nor is it in effect at this time.
                                                    and on the following questions, in                                                                                                  DATES: Although you can comment on
                                                                                                                              Leslie Kux,
                                                    particular:                                                                                                                         any guidance at any time (see 21 CFR
                                                                                                                              Associate Commissioner for Policy.
                                                       1. Should the quality                                                                                                            10.115(g)(5)), to ensure that the Agency
                                                    recommendations outlined in the                                           [FR Doc. 2016–16200 Filed 7–7–16; 8:45 am]
                                                                                                                                                                                        considers your comment of this draft
                                                    guidance apply equally to databases of                                    BILLING CODE 4164–01–P
                                                                                                                                                                                        guidance before it begins work on the
                                                    somatic variants and to germline                                                                                                    final version of the guidance, submit
                                                    variants?                                                                                                                           either electronic or written comments
                                                       2. While this document applies to                                      DEPARTMENT OF HEALTH AND
                                                                                                                              HUMAN SERVICES                                            on the draft guidance by October 6,
                                                    NGS-based tests, FDA expects that it                                                                                                2016.
                                                    may also be relevant to genetic tests that                                Food and Drug Administration
                                                    use other technologies (e.g., polymerase                                                                                            ADDRESSES:       You may submit comments
                                                    chain reaction, Sanger sequencing, etc.).                                 [Docket No. FDA–2016–D–1270]                              as follows:
                                                    Are any additional considerations                                                                                                   Electronic Submissions
                                                    necessary to support the use of these                                     Use of Standards in the Food and Drug
                                                                                                                              Administration’s Regulatory Oversight                       Submit electronic comments in the
                                                    databases in the premarket review of
                                                                                                                              of Next Generation Sequencing-Based                       following way:
                                                    tests using technologies other than NGS,
                                                                                                                              In Vitro Diagnostics Used for                               • Federal eRulemaking Portal: http://
                                                    should FDA decide to apply this
asabaliauskas on DSK3SPTVN1PROD with NOTICES




                                                                                                                              Diagnosing Germline Diseases; Draft                       www.regulations.gov. Follow the
                                                    approach more broadly in the future?
                                                                                                                              Guidance for Stakeholders and Food                        instructions for submitting comments.
                                                       3. FDA recognizes that the evidence
                                                                                                                              and Drug Administration Staff;                            Comments submitted electronically,
                                                    linking specific variants to diseases or
                                                                                                                              Availability                                              including attachments, to http://
                                                    conditions will change over time, and as
                                                                                                                                                                                        www.regulations.gov will be posted to
                                                    such, assertions about those variants                                     AGENCY:           Food and Drug Administration,
                                                    may also change. If an assertion                                          HHS.                                                       1 The Precision Medicine Initiative found on the
                                                    regarding a variant changes over time,                                                                                              White House’s Web site at: https://
                                                                                                                              ACTION:       Notice of availability.
                                                    how should FDA assess what regulatory                                                                                               www.whitehouse.gov/precision-medicine.



                                               VerDate Sep<11>2014         17:00 Jul 07, 2016       Jkt 238001       PO 00000       Frm 00035      Fmt 4703   Sfmt 4703   E:\FR\FM\08JYN1.SGM   08JYN1


                                                                                      Federal Register / Vol. 81, No. 131 / Friday, July 8, 2016 / Notices                                           44615

                                                    the docket unchanged. Because your                       claimed confidential information                      Evaluation and Research, Food and
                                                    comment will be made public, you are                     redacted/blacked out, will be available               Drug Administration, 10903 New
                                                    solely responsible for ensuring that your                for public viewing and posted on http://              Hampshire Ave., Bldg. 71, Rm. 7301,
                                                    comment does not include any                             www.regulations.gov. Submit both                      Silver Spring, MD 20993–0002, 240–
                                                    confidential information that you or a                   copies to the Division of Dockets                     402–7911.
                                                    third party may not wish to be posted,                   Management. If you do not wish your                   SUPPLEMENTARY INFORMATION:
                                                    such as medical information, your or                     name and contact information to be
                                                    anyone else’s Social Security number, or                 made publicly available, you can                      I. Background
                                                    confidential business information, such                  provide this information on the cover                    As part of the PMI, FDA is committed
                                                    as a manufacturing process. Please note                  sheet and not in the body of your                     to implementing a flexible and adaptive
                                                    that if you include your name, contact                   comments and you must identify this                   regulatory oversight approach, which
                                                    information, or other information that                   information as ‘‘confidential.’’ Any                  fosters innovation and simultaneously
                                                    identifies you in the body of your                       information marked as ‘‘confidential’’                assures that patients have access to
                                                    comments, that information will be                       will not be disclosed except in                       accurate and meaningful test results.
                                                    posted on http://www.regulations.gov.                    accordance with 21 CFR 10.20 and other                FDA held two public workshops on this
                                                      • If you want to submit a comment                      applicable disclosure law. For more                   issue: ‘‘Optimizing FDA’s Regulatory
                                                    with confidential information that you                   information about FDA’s posting of                    Oversight of Next Generation
                                                    do not wish to be made available to the                  comments to public dockets, see 80 FR                 Sequencing Diagnostic Tests Public
                                                    public, submit the comment as a                          56469, September 18, 2015, or access                  Workshop’’ held on February 20, 2015,
                                                    written/paper submission and in the                      the information at: http://www.fda.gov/               and ‘‘Standards Based Approach to
                                                    manner detailed (see ‘‘Written/Paper                     regulatoryinformation/dockets/                        Analytical Performance Evaluation of
                                                    Submissions’’ and ‘‘Instructions’’).                     default.htm.                                          Next Generation Sequencing In Vitro
                                                    Written/Paper Submissions                                  Docket: For access to the docket to                 Diagnostic Tests’’ held on November 12,
                                                                                                             read background documents or the                      2016. This guidance document, when
                                                       Submit written/paper submissions as                   electronic and written/paper comments
                                                    follows:                                                                                                       finalized, provides recommendations for
                                                                                                             received, go to http://www.regulations
                                                       • Mail/Hand delivery/Courier (for                                                                           designing, developing, and validating
                                                                                                             .gov and insert the docket number,                    for targeted and whole exome human
                                                    written/paper submissions): Division of
                                                                                                             found in brackets in the heading of this              DNA sequencing (WES) NGS-based tests
                                                    Dockets Management (HFA–305), Food
                                                                                                             document, into the ‘‘Search’’ box and                 intended to aid in the diagnosis of
                                                    and Drug Administration, 5630 Fishers
                                                                                                             follow the prompts and/or go to the                   individuals with suspected germline
                                                    Lane, Rm. 1061, Rockville, MD 20852.
                                                       • For written/paper comments                          Division of Dockets Management, 5630                  diseases or other conditions (hereinafter
                                                    submitted to the Division of Dockets                     Fishers Lane, Rm. 1061, Rockville, MD                 referred to as ‘‘NGS-based tests for
                                                    Management, FDA will post your                           20852.                                                germline diseases’’ or ‘‘NGS-based
                                                                                                               An electronic copy of the guidance                  tests’’). It also outlines considerations
                                                    comment, as well as any attachments,
                                                                                                             document is available for download                    for possibly classifying certain NGS-
                                                    except for information submitted,
                                                                                                             from the Internet. See the                            based tests for germline diseases in class
                                                    marked and identified, as confidential,
                                                                                                             SUPPLEMENTARY INFORMATION section for
                                                    if submitted as detailed in                                                                                    II and exempting them from premarket
                                                                                                             information on electronic access to the               notification requirements. Upon
                                                    ‘‘Instructions.’’
                                                       Instructions: All submissions received                guidance. Submit written requests for a               finalization of this guidance, these
                                                    must include the Docket No. FDA–                         single hard copy of the draft guidance                recommendations should be used as
                                                    2016–D–1270 for ‘‘Use of Standards in                    document entitled ‘‘Use of Standards in               guidelines for test developers for
                                                    FDA Regulatory Oversight of Next                         FDA Regulatory Oversight of Next                      premarket submissions. However, the
                                                    Generation Sequencing (NGS)-Based In                     Generation Sequencing (NGS)-Based In                  longer-term goal is for these
                                                    Vitro Diagnostics (IVDs) Used for                        Vitro Diagnostics (IVDs) Used for                     recommendations to form the basis for
                                                    Diagnosing Germline Diseases.’’                          Diagnosing Germline Diseases’’ to the                 standards that FDA could recognize or
                                                    Received comments will be placed in                      Office of the Center Director, Guidance               for special controls and/or conditions
                                                    the docket and, except for those                         and Policy Development, Center for                    for premarket notification (510(k))
                                                    submitted as ‘‘Confidential                              Devices and Radiological Health, Food                 exemption. FDA is also issuing a draft
                                                    Submissions,’’ publicly viewable at                      and Drug Administration, 10903 New                    guidance entitled ‘‘Use of Public Human
                                                    http://www.regulations.gov or at the                     Hampshire Ave., Bldg. 66, Rm. 5431,                   Genetic Variant Databases to Support
                                                    Division of Dockets Management                           Silver Spring, MD 20993–0002; or the                  Clinical Validity for Next Generation
                                                    between 9 a.m. and 4 p.m., Monday                        Office of Communication, Outreach, and                Sequencing (NGS)-Based In Vitro
                                                    through Friday.                                          Development, Center for Biologics                     Diagnostics’’ which is being issued
                                                       • Confidential Submissions—To                         Evaluation and Research, Food and                     concurrently elsewhere in this issue of
                                                    submit a comment with confidential                       Drug Administration, 10903 New                        the Federal Register.
                                                    information that you do not wish to be                   Hampshire Ave., Bldg. 71, Rm. 3128,
                                                                                                             Silver Spring, MD 20993–0002. Send                    II. Significance of Guidance
                                                    made publicly available, submit your
                                                    comments only as a written/paper                         one self-addressed adhesive label to                    This draft guidance is being issued
                                                    submission. You should submit two                        assist that office in processing your                 consistent with FDA’s good guidance
                                                    copies total. One copy will include the                  request.                                              practices regulation (21 CFR 10.115).
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                                                    information you claim to be confidential                 FOR FURTHER INFORMATION CONTACT:                      The draft guidance, when finalized, will
                                                    with a heading or cover note that states                 Personalized Medicine Staff, Center for               represent the current thinking of FDA
                                                    ‘‘THIS DOCUMENT CONTAINS                                 Devices and Radiological Health, Food                 on use of standards in FDA regulatory
                                                    CONFIDENTIAL INFORMATION.’’ The                          and Drug Administration, 10903 New                    oversight of NGS-based IVDs used for
                                                    Agency will review this copy, including                  Hampshire Ave., Bldg. 66, Rm. 4544,                   diagnosing germline diseases. It does
                                                    the claimed confidential information, in                 Silver Spring, MD 20993–0002, 301–                    not establish any rights for any person
                                                    its consideration of comments. The                       796–6206; or PMI@fda.hhs.gov; or                      and is not binding on FDA or the public.
                                                    second copy, which will have the                         Stephen Ripley, Center for Biologics                  You can use an alternative approach if


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                                                    44616                             Federal Register / Vol. 81, No. 131 / Friday, July 8, 2016 / Notices

                                                    it satisfies the requirements of the                     V. Other Issues for Consideration                     calculated using only analytical results
                                                    applicable statutes and regulations.                        The Agency invites comments on the                 without taking into account prevalence
                                                                                                             draft guidance document entitled ‘‘Use                in a population, it is sometimes called
                                                    III. Electronic Access                                                                                         ‘‘technical’’ PPV (TPPV) to distinguish it
                                                                                                             of Standards in FDA Regulatory
                                                       Persons interested in obtaining a copy                Oversight of Next Generation                          from prevalence-based PPV. What are
                                                    of the draft guidance may do so by                       Sequencing (NGS)-Based In Vitro                       the benefits and weaknesses to assessing
                                                    downloading an electronic copy from                      Diagnostics (IVDs) Used for Diagnosing                NGS-based test accuracy using TPPV in
                                                    the Internet. A search capability for all                Germline Diseases,’’ in general, and on               addition to PPA and NPA, or instead of
                                                    Center for Devices and Radiological                      the following questions, in particular:               NPA?
                                                    Health guidance documents is available                      1. Does the draft guidance content                    5. Are the minimum performance
                                                    at http://www.fda.gov/MedicalDevices/                    adequately address the analytical                     thresholds presented in this draft
                                                    DeviceRegulationandGuidance/                             performance of targeted and whole                     guidance appropriate, or are alternative
                                                    GuidanceDocuments/default.htm, and                       exome human DNA sequencing (WES)                      thresholds more appropriate? Are there
                                                    for Center for Biologics Evaluation and                  NGS-based tests intended to aid in the                ‘‘best ways’’ to determine acceptable
                                                    Research guidance documents is                           diagnosis of individuals with suspected               thresholds for each metric? Are there
                                                    available at http://www.fda.gov/                         germline diseases or other conditions                 performance metrics that do not require
                                                    BiologicsBloodVaccines/                                  (referred to as ‘‘NGS-based tests for                 minimum thresholds? Are there test
                                                                                                             germline diseases’’ or ‘‘NGS-based tests’’            scenarios where minimum thresholds
                                                    GuidanceCompliance
                                                                                                             in the guidance)? For example, do the                 are not useful or relevant?
                                                    RegulatoryInformation/Guidances/
                                                                                                             recommendations outlined in the draft                    6. How can bias and over-fitting be
                                                    default.htm. Guidance documents are
                                                                                                             guidance adequately address the                       minimized or accounted for if known
                                                    also available at http://
                                                                                                             analytical performance of NGS-based                   ‘‘reference’’ samples are used as
                                                    www.regulations.gov. Persons unable to
                                                                                                             tests used as an aid in diagnosis of                  comparators in accuracy studies?
                                                    download an electronic copy of ‘‘Use of
                                                    Standards in FDA Regulatory Oversight                    patients with signs and symptoms of                     Dated: July 5, 2016.
                                                    of Next Generation Sequencing (NGS)-                     developmental delay or intellectual                   Leslie Kux,
                                                    Based In Vitro Diagnostics (IVDs) Used                   disability, undiagnosed diseases, or                  Associate Commissioner for Policy.
                                                    for Diagnosing Germline Diseases’’ may                   hereditary cancer syndromes? If not,                  [FR Doc. 2016–16201 Filed 7–7–16; 8:45 am]
                                                    send an email request to CDRH-                           what additional test design,                          BILLING CODE 4164–01–P
                                                    Guidance@fda.hhs.gov to receive an                       development, or validation activities are
                                                    electronic copy of the document. Please                  necessary for analytical validation of
                                                    use the document number 16009 to                         such tests? Are there specific                        DEPARTMENT OF HEALTH AND
                                                    identify the guidance you are                            indications within this broad intended                HUMAN SERVICES
                                                    requesting.                                              use that require different or additional
                                                                                                             test design, development, or validation               Food and Drug Administration
                                                    IV. Paperwork Reduction Act of 1995                      activities from those described in the
                                                                                                                                                                   [Docket No. FDA–2014–N–1206]
                                                                                                             draft guidance?
                                                      This guidance refers to previously                        2. Do the recommendations in the
                                                    approved collections of information                                                                            Authorization of Emergency Use of an
                                                                                                             draft guidance adequately address the                 In Vitro Diagnostic Device for
                                                    found in FDA regulations. These                          analytical validation of NGS-based tests
                                                    collections of information are subject to                                                                      Detection of Ebola Zaire Virus;
                                                                                                             that use targeted panels or WES?                      Availability
                                                    review by the Office of Management and                   Targeted sequencing panels? Are there
                                                    Budget (OMB) under the Paperwork                         differences between the use of targeted               AGENCY:    Food and Drug Administration,
                                                    Reduction Act of 1995 (44 U.S.C. 3501–                   panels and WES that were not                          HHS.
                                                    3520). The collections of information in                 adequately distinguished in the                       ACTION:   Notice.
                                                    21 CFR part 807, subpart E, regarding                    recommendations described in the draft
                                                    premarket notification submissions,                      guidance?                                             SUMMARY:   The Food and Drug
                                                    have been approved under OMB control                        3. The recommendations in this                     Administration (FDA) is announcing the
                                                    number 0910–0120; the collections of                     document focus on WES and targeted                    issuance of an Emergency Use
                                                    information in 21 CFR part 801 and 21                    NGS-based tests for germline diseases.                Authorization (EUA) (the Authorization)
                                                    CFR 809.10, regarding labeling, have                     Are the recommendations outlined in                   for an in vitro diagnostic device for
                                                    been approved under OMB control                          the guidance sufficient to address                    detection of the Ebola Zaire virus in
                                                    number 0910–0485; the collections of                     analytical validation for whole genome                response to the Ebola virus outbreak in
                                                    information in 21 CFR part 814,                          sequencing (WGS) NGS-based tests for                  West Africa. FDA issued this
                                                    subparts A through E, regarding                          germline diseases? If not, what                       Authorization under the Federal Food,
                                                    premarket approval, have been                            additional test design, development,                  Drug, and Cosmetic Act (the FD&C Act),
                                                    approved under OMB control number                        and validation activities are needed to               as requested by Biocartis NV. The
                                                    0910–0231; the collections of                            address the analytical validation of such             Authorization contains, among other
                                                    information in 21 CFR part 820,                          tests?                                                things, conditions on the emergency use
                                                    regarding the quality system regulation,                    4. Accuracy is generally described                 of the authorized in vitro diagnostic
                                                    have been approved under OMB control                     using an agreement, typically positive                device. The Authorization follows the
asabaliauskas on DSK3SPTVN1PROD with NOTICES




                                                    number 0910–0073; and the collections                    and negative percent agreement (PPA                   September 22, 2006, determination by
                                                    of information in the guidance                           and NPA), between a new test and an                   then-Secretary of the Department of
                                                    document ‘‘Requests for Feedback on                      accepted reference method. For NGS-                   Homeland Security (DHS), Michael
                                                    Medical Device Submissions: The Pre-                     based tests, positive predictive value                Chertoff, that the Ebola virus presents a
                                                    Submission Program and Meetings with                     (PPV) may be a more meaningful metric                 material threat against the U.S.
                                                    Food and Drug Administration Staff’’                     than NPA when calculating the                         population sufficient to affect national
                                                    have been approved under OMB control                     likelihood that a variant call detected by            security. On the basis of such
                                                    number 0910–0756.                                        the test is a true positive. If PPV is                determination, the Secretary of Health


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Document Created: 2016-07-08 00:17:39
Document Modified: 2016-07-08 00:17:39
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionNotices
ActionNotice of availability.
DatesAlthough you can comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the Agency considers your comment of this draft guidance before it begins work on the final version of the guidance, submit either electronic or written comments on the draft
ContactPersonalized Medicine Staff, Center for Devices and Radiological Health, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 66, Rm. 4544, Silver Spring, MD 20993- 0002, 301-796-6206; or [email protected]; 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.
FR Citation81 FR 44614 

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