
[Federal Register Volume 81, Number 131 (Friday, July 8, 2016)]
[Notices]
[Pages 44611-44614]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-16200]


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

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2016-D-1233]


Use of Public Human Genetic Variant Databases To Support Clinical 
Validity for Next Generation Sequencing-Based In Vitro Diagnostics; 
Draft Guidance for Stakeholders and Food and Drug Administration Staff; 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the availability of the draft guidance entitled ``Use of Public Human 
Genetic Variant Databases to Support Clinical Validity for Next 
Generation Sequencing (NGS)-Based In Vitro Diagnostics.'' This draft 
guidance document describes how publicly accessible databases of human 
genetic variants can serve as sources of valid scientific evidence to 
support the clinical validity of genotype-phenotype relationships in 
FDA's regulatory review of next generation sequencing (NGS)-based 
tests. This draft guidance further outlines the process by which 
administrators of genetic variant databases could voluntarily apply to 
FDA for recognition, and how FDA would review such applications and 
periodically reevaluate recognized databases. This draft guidance is 
not final nor is it in effect at this time.

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draft guidance before it begins work on the final version of the 
guidance, submit either electronic or written comments on the draft 
guidance by October 6, 2016.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 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'').

[[Page 44612]]

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-1233 for ``Use of Public Human Genetic Variant Databases to 
Support Clinical Validity for Next Generation Sequencing (NGS)-Based In 
Vitro Diagnostics.'' 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 Public Human Genetic Variant Databases to Support Clinical 
Validity for Next Generation Sequencing (NGS)-Based In Vitro 
Diagnostics'' 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. 4546, Silver Spring, MD 20993-
0002, 301-796-7561, 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

    This draft guidance document describes one part of FDA's effort to 
create a flexible regulatory approach to the oversight of NGS-based 
tests as part of the White House's Precision Medicine Initiative (PMI). 
FDA held two workshops on this issue: ``Use of Databases for 
Establishing the Clinical Relevance of Human Genetic Variants'' on 
November 13, 2015, and ``Patient and Medical Professional Perspectives 
on the Return of Genetic Test Results'' on March 2, 2016. The goal of 
this effort is to help ensure patients receive accurate and meaningful 
results, while promoting innovation in test development. This draft 
guidance document describes how publicly accessible databases of human 
genetic variants can serve as sources of valid scientific evidence to 
support the clinical validity of genotype-phenotype relationships in 
FDA's regulatory review of NGS-based tests. FDA is also issuing a 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'' which is being released concurrently 
elsewhere in this issue of the Federal Register.
    NGS can enable rapid, broad, and deep sequencing of a portion of a 
gene, entire exome(s), or a whole genome and may be used clinically for 
a variety of diagnostic purposes, including risk prediction, diagnosis, 
and treatment selection for a disease or condition. The rapid adoption 
of NGS-based tests in both research and clinical practice is leading to 
identification of an increasing number of genetic variants (e.g., 
pathogenic, benign, and of unknown significance), including rare 
variants that may be unique to a single individual or family. This 
draft guidance document describes FDA's considerations in determining 
whether a genetic variant database is a source of valid scientific 
evidence that could support the clinical validity of an NGS-based test. 
This draft guidance further outlines the process by which 
administrators of genetic variant databases could voluntarily apply to 
FDA for recognition, and how FDA would review such applications and 
periodically reevaluate recognized databases.

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 
Public Human Genetic Variant Databases to Support Clinical Validity for 
Next Generation Sequencing (NGS)-Based In Vitro Diagnostics.'' 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.

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

[[Page 44613]]

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 Public Human Genetic Variant Databases to Support Clinical 
Validity for Next Generation Sequencing (NGS)-Based In Vitro 
Diagnostics'' may send an email request to CDRH-Guidance@fda.hhs.gov to 
receive an electronic copy of the document. Please use the document 
number 16008 to identify the guidance you are requesting.

IV. Paperwork Reduction Act of 1995

    Under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 
3501-3520), Federal Agencies must obtain approval from the Office of 
Management and Budget (OMB) for each collection of information they 
conduct or sponsor. ``Collection of information'' is defined in 44 
U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes Agency requests or 
requirements that members of the public submit reports, keep records, 
or provide information to a third party. Section 3506(c)(2)(A) of the 
PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal Agencies to provide a 
60-day notice in the Federal Register concerning each proposed 
collection of information before submitting the collection to OMB for 
approval. To comply with this requirement, FDA is publishing notice of 
the proposed collection of information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on these topics: (1) Whether the proposed collection 
of information is necessary for the proper performance of FDA's 
functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.

Use of Public Human Genetic Variant Databases To Support Clinical 
Validity for Next Generation Sequencing (NGS)-Based In Vitro 
Diagnostics OMB Control Number 0910--NEW

    The draft guidance document ``Use of Public Human Genetic Variant 
Databases to Support Clinical Validity for Next Generation Sequencing 
(NGS)-Based In Vitro Diagnostics'' describes FDA's considerations in 
determining whether a genetic variant database is a source of valid 
scientific evidence that could support the clinical validity of an NGS-
based test. This draft guidance further outlines the process by which 
administrators \1\ of genetic variant databases could voluntarily apply 
to FDA for recognition, and how FDA would review such applications and 
periodically reevaluate recognized databases. The draft guidance also 
recommends that, at the time of recognition, the database administrator 
make information regarding policies, procedures, and conflicts of 
interest publicly available and accessible on the genetic variant 
database's Web site.
---------------------------------------------------------------------------

    \1\ FDA acknowledges that many databases may not use the term 
``administrator'' or may have a committee of individuals that 
oversee the database. Therefore, for the purpose of this guidance, a 
genetic variant database administrator is the entity or entities 
that oversee database operations.
---------------------------------------------------------------------------

    Based on our experience and the nature of the information, we 
estimate that it will take an average of 80 hours to complete and 
submit an application for recognition. We estimate that maintenance of 
recognition activities will take approximately one-fourth of that time 
(20 hours) annually. We estimate that it will take approximately 1 hour 
to post the information on the Web site.
    Respondents are administrators of genetic databases. Our estimate 
of five respondents per year is based on the current number of 
databases that may meet FDA recommendations for recognition and seek 
such recognition.
    FDA estimates the burden of this collection of information as 
follows:

                                                     Table 1--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of
                              Activity                                  Number of      responses per     Total annual    Average burden    Total hours
                                                                       respondents       respondent       responses       per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
Application for recognition of genetic database....................               5                1                5               80              400
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


                                                   Table 2--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of                       Average burden
                              Activity                                  Number of       records per      Total annual         per          Total hours
                                                                      recordkeepers     recordkeeper       records       recordkeeping
--------------------------------------------------------------------------------------------------------------------------------------------------------
Maintenance of recognition activities..............................               5                1                5               20              100
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.


[[Page 44614]]


                                               Table 3--Estimated Annual Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                         Number of
                              Activity                                  Number of     disclosures per    Total annual    Average burden    Total hours
                                                                       respondents       respondent      disclosures     per disclosure
--------------------------------------------------------------------------------------------------------------------------------------------------------
Public disclosure of policies, procedures, and conflicts of                       5                1                5                1                5
 interest..........................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    This draft guidance also refers to previously approved collections 
of information. These collections of information are subject to review 
by the OMB under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-
3520). 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. The 
collections of information regarding premarket submissions have been 
approved as follows: The collections of information in 21 CFR part 807, 
subpart E, have been approved under OMB control number 0910-0120; and 
the collections of information in 21 CFR part 814, subparts A through 
E, have been approved under OMB control number 0910-0231.

V. Other Issues for Consideration

    The Agency invites comments on the draft guidance document entitled 
``Use of Public Human Genetic Variant Databases to Support Clinical 
Validity for Next Generation Sequencing (NGS)-Based In Vitro 
Diagnostics,'' in general, and on the following questions, in 
particular:
    1. Should the quality recommendations outlined in the guidance 
apply equally to databases of somatic variants and to germline 
variants?
    2. While this document applies to NGS-based tests, FDA expects that 
it may also be relevant to genetic tests that use other technologies 
(e.g., polymerase chain reaction, Sanger sequencing, etc.). Are any 
additional considerations necessary to support the use of these 
databases in the premarket review of tests using technologies other 
than NGS, should FDA decide to apply this approach more broadly in the 
future?
    3. FDA recognizes that the evidence linking specific variants to 
diseases or conditions will change over time, and as such, assertions 
about those variants may also change. If an assertion regarding a 
variant changes over time, how should FDA assess what regulatory 
actions may be appropriate with respect to in IVDs supported by such 
assertions? How often should FDA conduct ongoing review of an FDA-
recognized database?
    4. FDA notes that databases may have ``discordant calls'' with 
other databases, where the assertions for a variant in each database 
vary. While FDA believes that these discordant calls often arise 
because one database has information the other does not and our 
proposed policy will mitigate these issues over time; what, if any, 
action should FDA take when it learns about discordant calls between 
two databases with respect to database recognition or IVDs supported by 
such calls in FDA-recognized databases?
    5. FDA has requested information regarding conflicts of interest 
for curators and personnel of databases seeking FDA recognition. FDA 
acknowledges that many personnel involved with variant curation and 
interpretation may have some connection to NGS test developers. What 
type of information should FDA collect and what policies should it 
implement to mitigate such potential conflicts of interest in FDA-
recognized databases?

    Dated: July 5, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-16200 Filed 7-7-16; 8:45 am]
 BILLING CODE 4164-01-P


