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Human Genetic Variant Databases To Support Clinical Validity for Next Generation Sequencing-Based In Vitro Diagnostics; Draft Guidance for Stakeholders and Food and Drug Administration Staff; Availability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The Food and Drug Administration (FDA or Agency) is announcing the availability of the draft guidance entitled “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro Diagnostics.” This draft guidance document describes how publicly accessible databases of human genetic variants can serve as sources of valid scientific evidence to support the clinical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 This draft guidance further outlines the process by which administrators of genetic variant databases could voluntarily apply to FDA for recognition, and how FDA would review such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 This draft guidance is not final nor is it in effect at this time.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comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the Agency considers your comment of this draft guidance before it begins work on the final version of the guidance, submit either electronic or written comments on the draft guidance by October 6, 2016.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”).

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 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 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.

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:

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?