
[Federal Register Volume 81, Number 131 (Friday, July 8, 2016)]
[Notices]
[Pages 44614-44616]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-16201]


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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for Diagnosing Germline Diseases; Draft Guidance for Stakeholders and 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.

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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the availability of the draft guidance entitled ``Use of Standards in 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is issuing this draft guidance to provide FDA's proposed approach on 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 This draft guidance is not 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.
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    \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draft guidance before it begins work on the final version of the 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 
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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 PMI@fda.hhs.gov; 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 CDRH-Guidance@fda.hhs.gov 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


