advamed | - october 6, 2016...division of dockets management (hfa-305) docket no. fda-2016-d-1233...

October 6, 2016

Division of Dockets Management (HFA-305)

Food and Drug Administration

5630 Fishers Lane, Room 1061

Rockville, MD 20852

Re: Docket No. FDA-2016-D-1233; Draft Guidance for Stakeholders and Food and

Drug Administration Staff; Use of Public Human Genetic Variant Databases to

Support Clinical Validity for Next Generation Sequencing (NGS)-Based In Vitro

Diagnostics

Dear Sir or Madam:

On behalf of AdvaMedDx, a Division of the Advanced Medical Technology Association

(AdvaMed), we provide these comments in response to the Food and Drug

Administration (FDA) draft guidance “Use of Public Human Genetic Variant Databases

to Support Clinical Validity for Next Generational Sequencing (NGS)-Based In Vitro

Diagnostics” (hereinafter “guidance”).

AdvaMedDx member companies produce advanced, in vitro diagnostic tests (or “IVDs”)

that facilitate evidence-based medicine, improve quality of patient care, enable early

detection of disease and reduce overall health care costs. Functioning as an association

within AdvaMed, AdvaMedDx is the only multi-faceted, policy organization that deals

exclusively with issues facing in vitro diagnostic companies in the United States and

abroad. Our membership includes manufacturers engaged in the development of

innovative diagnostic technologies supporting personalized medicine from next

generation sequencing to complex multi-analyte technologies to a breadth of advanced

molecular diagnostics helping deliver cutting edge care to patients worldwide.

GENERAL COMMENTS

AdvaMedDx commends the FDA (or “Agency”) for the development of this draft

guidance, which sets forth a highly innovative and flexible approach on evidence

generation for in vitro (IVD) technologies while recognizing the critical importance that

tests have adequate clinical performance. Such adaptive approaches will go far to

promote scientific progress and robust innovation by diagnostic developers of NGS-based

assays as well as other revolutionary tests that are moving high quality precision

medicine into the U.S. healthcare system. We strongly support FDA efforts to encourage

the development of human genetic variant databases of genotype-phenotype information.

As with other IVDs, an inaccurate next generation sequencing (NGS) test can present

significant risk to patients and lead to patients receiving the wrong diagnosis, wrong

treatment, or no treatment at all even when effective therapy is available, and

Division of Dockets Management (HFA-305) Docket No. FDA-2016-D-1233

October 6, 2016

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can also impose unnecessary costs on the healthcare system. We believe this Agency

activity fits well with the Administration’s Precision Medicine Initiative and the Cancer

Moonshot through a modernized regulatory approach to support personalized medicine

research and new product development.

Through these novel regulatory approaches, FDA can strike the right balance of benefit

and risk and ensure timely access to new innovative tests. We believe this approach to

support clinical validity will go far to improve quality, support predictability in test

development, speed time to market, encourage innovation, and provide greater confidence in

a given test result. To that end, FDA should extend wider application of this proposed

approach to support the clinical validity of other diagnostic tests. Examples of other

technologies include multiplex polymerase chain reaction (PCR), single nucleotide

polymorphism (SNP), and microarray technologies, all of which provide tremendous

benefits for patients.

Furthermore, all efforts should be made to ensure equitable application of the approach

for all interested developers, whether laboratory or traditional IVD manufacturers, from

test development and modifications through the product lifecycle. While that appears to

be the intent of FDA, any final approach should be clear that it is not limited by type of

developer. We also recommend that the guidance more clearly recognize that databases

may be proprietary or public and clarify which portions of the guidance would apply to

proprietary databases.

AdvaMedDx has long supported a flexible risk based regulatory approach that can better

leverage existing available data to help bring new diagnostics to market. Thus, we

strongly endorse FDA’s proposed concept of appropriately developed and curated

databases to support clinical significance and that such assertions and underlying data

may be submitted by test developers as part of premarket review submission to establish

clinical validity without submission, in some cases, of additional clinical data regarding a

variant. Further, we agree wholeheartedly that a one-analyte-at-a-time approach is

neither appropriate nor feasible for complex multi-analyte technologies. Whether it is a

new or existing database, it is also imperative that the databases are carefully

implemented.

Of utmost importance in this initiative, we support transparency and accuracy related to

supporting information and intended use/clinical claims. Further, we echo the FDA’s

statements regarding the importance of database procedures, data sources, and criteria

used for curation and variant interpretation. Such transparency is critical as it allows for

improved understanding of the confidence in the genotypic-phenotypic correlations and

facilitates comparisons between databases as needed.

Again, we applaud the Agency’s commitment to advancing the field through this

innovative proposal and holding of its workshop on September 23. We appreciate the

opportunity to provide our comments, which are intended to support diagnostics

innovation and foster advancement of personalized medicine. Our specific comments


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follow with accompanying recommendations to assist FDA as it works to finalize this

guidance and associated FDA Genetic Variant Database Recognition Process. The line-

numbered guidance is also attached to assist with review.

Sincerely,

/s/

Khatereh Calleja

Senior Vice President, Technology and Regulatory Affairs

Technology and Regulatory Affairs


October 6, 2016

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ADVAMEDDX SPECIFIC COMMENTS ON

FDA Draft Guidance

Use of Public Genetic Variant Databases to Support Clinical Validity for NGS-Based IVDs

Edit No. – Comment number Proposed Change – Proposed change to the guidance

Section –Section of the guidance Comment/Rationale – Reason for proposed change

Line No. – Guidance line number

Edit

No. Section

Line

No.

Proposed Change Comment/Rationale

1

II. Background

161-164

Clarify what FDA means by “qualified

experts.”

While we agree that qualified experts should

make such informed conclusions, we would

appreciate a definition or criteria for this term in

the context of this guidance.

2

II. Background

174-175

Delete the following: “Accordingly, FDA

believes that summary literature is inferior in

this respect to data available for independent

evaluation.”

We have concerns that the statement as drafted

infers that all literature is inferior by nature to

any available data and that such literature is not

valid scientific evidence. We strongly disagree

with any such categorical declaration of

evidentiary quality. Literature can play a vastly

important role, particularly in a rapidly moving

area such as sequencing. Although some

literature may be inferior, some data may be as

well. This reference should be removed from the

document.


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Edit

No. Section

Line

No.


3

IV.

Recommendations to

Support Recognition

of Such Databases as

Sources of Valid

Scientific Evidence

Supporting Clinical

Validity of Tests

230

Define “validated methods.” It is not clear what the threshold is for “validated

methods.” For example, this could relate to

CLIA-validated methods or other clinical

laboratory process-related validations. Validated

methods will change over time, so this should be

adaptable and not overly prescriptive in nature.

4

IV:A.

Recommendations to

Support Recognition


Sources of Valid

Scientific Evidence

Supporting Clinical

Validity of Tests—

Database Procedures

and Operations

General

We suggest that FDA recognized databases use

modern web best practices (e.g., standard

application programming interface-based

access, scalable cloud storage for data

preservation including old versions).

This could allow users to simultaneously access

variant interpretations in different recognized

databases, facilitating improved visibility of the

range of potential genotype-phenotype

correlations and the corresponding supporting

evidence. Use of such practices could also

provide additional transparency regarding

discordant calls and changing variant

interpretations, which were concerns identified

by the Agency in the Federal Register notice

accompanying the release of this draft guidance.


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Edit

No. Section

Line

No.


5

IV:A.

Recommendations to

Support Recognition


Sources of Valid

Scientific Evidence

Supporting Clinical


Database Procedures

and Operations

253-259

We suggest that version control for databases be

specifically described and applied to other

aspects of the databases in addition to the

assertions (e.g., new evidence sources or new

laboratories should be tracked and versioned).

This section is not well-defined. While the draft

guidance specifically calls out version control for

SOPs (beginning on line 253), version control of

the database itself is not explicitly mentioned in

this section apart from a later reference to

“versioning of assertions” (see line 350).

6

IV:A.

Recommendations to

Support Recognition


Sources of Valid

Scientific Evidence

Supporting Clinical


Database Procedures

and Operations

286-290

Consider recommending standard database

format.

We understand that genetic variant databases

may vary considerably. In light of likely

availability of multiple databases and to promote

interoperability, we recommend that databases

use a standard format where at all possible rather

than simply reference the use of “commonly

accepted data formats.” Alternatively and at a

minimum, some examples would be helpful to

elucidate thinking.


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Edit

No. Section

Line

No.


7 IV:B.

Recommendations to

Support Recognition


Sources of Valid

Scientific Evidence

Supporting Clinical


Data Quality

299

Specify the nomenclature that should be used. While we agree that standardized nomenclature

should be used, we do not believe that a standard

nomenclature exists to date. We recommend that

FDA specify a nomenclature that should be used.

8 IV:B.

Recommendations to

Support Recognition


Sources of Valid

Scientific Evidence

Supporting Clinical


Data Quality

309-311

Consider providing an overall summary metric

to convey the confidence in the

methods/sources used to identify the variant.

At present, the draft guidance describes data

quality attributes including metadata regarding

the technical characteristics of the test (lines 309-

311). We suggest that FDA-recognized

databases not only provide such details (e.g.,

reference sequence version or build, instrument,

software, bioinformatics tools, etc.), but they

could also provide an overall summary metric to

convey the technical confidence in variant

identification.


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Edit

No. Section

Line

No.


9

IV:C.

Recommendations to

Support Recognition


Sources of Valid

Scientific Evidence

Supporting Clinical


Curation, Variant

Interpretation and

Assertions

318 et. al.

Consider providing an overall summary metric

to convey the confidence in the

methods/sources to identify the association. For

example, associations based on literature

including a larger number of participants could

receive a higher confidence score. Similarly,

functional evidence of genotype-phenotype

relationships (such as in animal models or in

vitro assays) could also increase confidence in

the reported association.

Additionally, we suggest that the relationship of

the variant and association with respect to

ethnicity or haplotype group be reported, when

such information is available.

Similar to the previous comment. In Section IV:

C, the guidance document describes

recommendations regarding the processes for

curation, variant interpretation and assertions.

We suggest that FDA-recognized databases not

only identify the sources of information (e.g.,

clinical practice guidelines, peer-reviewed

literature), but they could also provide an overall

summary metric to convey the confidence in the

variant association.

10

IV:C.

Recommendations to

Support Recognition


Sources of Valid

Scientific Evidence

Supporting Clinical


Curation, Variant

Interpretation and

Assertions

341-342

Clarify what is meant by “conditions of use.” While it appears that FDA may be referring to

“indications for use,” it is not clear. Consistent

and recognized terminology should be used to

avoid confusion.


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Edit

No. Section

Line

No.


11

V.

FDA’s Genetic

Variant Database

Recognition Process

General and

403-406

Revise the scope section to more clearly

recognize that databases may be proprietary or

public and clarify which portions of this

guidance would apply to proprietary databases.

Consistent with our general comments, the

guidance should explicitly recognize that

databases may be proprietary or public. At

present, the only portion of the draft guidance

that acknowledges that databases may also be

proprietary is lines 403 – 406. In the scope

section of the guidance, the FDA should clearly

articulate that, while the focus of this guidance is

on public databases, proprietary databases may

be acceptable. To that end, FDA should clarify

which portions of the guidance would apply to

proprietary databases. For example, certain

aspects of the draft guidance, such as curation,

variant interpretation, and assertions, should be

applicable to both proprietary and public

databases.

12

V:B.

FDA’s Genetic

Variant Database

Recognition

Process— Use of

Third Parties

496-502

General comment We support FDA’s proposed concept of using

third parties to assist with genetic variant

database recognition.


October 6, 2016

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Edit

No. Section

Line

No.


13

V:B.

Use of Data and

Assertions from

Recognized Genetic

Variant Databases

515

Add the following text to the end of line 515:

“Furthermore, should a class II NGS-based test

rely on an FDA-recognized database to support

clinical validity, the FDA may consider it for

exemption from premarket notification

requirements.1 “

“1 FDA has not yet determined how reliance on

an FDA-recognized database could be

demonstrated by an NGS test developer to

support exemption from premarket notification

requirements and plans to discuss this in future

guidance documents.”

FDA’s draft guidance on “Use of Standards in

FDA Regulatory Oversight of Next Generation

Sequencing (NGS)-Based In Vitro Diagnostics

(IVDs) Used for Diagnosing Germline Diseases”

sets forth the possibility that class II NGS-based

tests for germline disease could be exempt from

premarket notification based on conformity with

recognized standards to support analytical

validity, but the guidance does not provide

information on the clinical validation

requirements necessary to achieve such

premarket exemption. We recommend that such

information be provided in this draft guidance

and have provided recommended language that

supports the public health and reflects a risk

based approach to support timely access to new

innovation in precision medicine.

Contains Nonbinding Recommendations Draft – Not For Implementation

Use of Public Human Genetic Variant

1

Databases to Support Clinical Validity 2

for Next Generation Sequencing 3

(NGS)-Based In Vitro Diagnostics 456

Draft Guidance for Stakeholders and 7

Food and Drug Administration Staff 8

9DRAFT GUIDANCE 10

11This draft guidance document is being distributed for comment purposes only. 12

13Document issued on July 8, 2016. 14

15You should submit comments and suggestions regarding this draft document within 90 days of 16publication in the Federal Register of the notice announcing the availability of the draft 17guidance. Submit electronic comments to http://www.regulations.gov. Submit written 18comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 195630 Fishers Lane, rm. 1061, Rockville, MD 20852. Identify all comments with the docket 20number listed in the notice of availability that publishes in the Federal Register. 21

22For questions about this document concerning devices regulated by CDRH, contact Personalized 23Medicine Staff at 301-796-6206 or [email protected]. For questions regarding this document as 24applied to devices regulated by CBER, contact the Office of Communication, Outreach and 25Development in CBER at 1-800-835-4709 or 240-402-8010 or by email at [email protected]. 26

2728 29

U.S. Department of Health and Human Services 30 Food and Drug Administration 31

Center for Devices and Radiological Health 32 Office of In Vitro Diagnostics and Radiological Health 33

34 Center for Biologics Evaluation and Research 35

36

http://www.regulations.gov/


Preface

37

38

Additional Copies 3940

CDRH 41Additional copies are available from the Internet. You may also send an e-mail request to [email protected] to receive a copy of the guidance. Please use the document number 16008 43to identify the guidance you are requesting. 44

4546

CBER 47Additional copies are available from the Center for Biologics Evaluation and Research (CBER), by 48written request, Office of Communication, Outreach, and Development (OCOD), 10903 New 49Hampshire Ave., Bldg. 71, Room 3128, Silver Spring, MD 20993-0002, or by calling 1-800-835-504709 or 240-402-8010, by email, [email protected] or from the Internet at 51http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidan52ces/default.htm. 53

54

mailto:[email protected]

mailto:[email protected]


Table of Contents

55

56I. Introduction ....................................................................................................................... 157

II. Background ....................................................................................................................... 158

III. Scope................................................................................................................................... 459

IV. Recommendations to Support Recognition of Publicly Accessible Genetic Variant 60

Databases of Human Genetic Variants as Sources of Valid Scientific Evidence 61

Supporting Clinical Validity of NGS Tests ..................................................................... 462

A. Database Procedures and Operations .................................................................... 563

B. Data Quality .......................................................................................................... 664

C. Curation, Variant Interpretation and Assertions ................................................... 765

D. Professional Training and Conflicts of Interest ..................................................... 866

V. FDA’s Genetic Variant Database Recognition Process ................................................. 867

A. Recognition Process for Genetic Variant Databases ............................................. 968

1. Submission for Recognition ............................................................................. 969

2. FDA Review of Genetic Variant Database Policies and Procedures ............... 970

3. Maintenance of FDA Recognition ................................................................. 1071

B. Use of Third Parties ............................................................................................. 1172

C. Use of Data and Assertions from Recognized Genetic Variant Databases ......... 1173

74


Use of Public Human Genetic Variant

1

75

Databases to Support Clinical Validity 76

for Next Generation Sequencing 77

(NGS)-Based In Vitro Diagnostics 787980

Draft Guidance for Stakeholders and 81

Food and Drug Administration Staff 8283

This draft guidance, when finalized, will represent the current thinking of the Food and Drug 84Administration (FDA or Agency) on this topic. It does not establish any rights for any person 85and is not binding on FDA or the public. You can use an alternative approach if it satisfies 86the requirements of the applicable statutes and regulations. To discuss an alternative 87approach, contact the FDA staff or Office responsible for this guidance as listed on the title 88page. 89

90I. Introduction 91

92This draft guidance document describes one part of FDA’s effort to create a flexible and adaptive 93regulatory approach to the oversight of next generation sequencing (NGS)-based tests as part of 94the Precision Medicine Initiative (PMI). The goal of this effort is to help ensure patients receive 95accurate and meaningful results, while promoting innovation in test development. This draft 96guidance document describes how publicly accessible databases of human genetic variants can 97serve as sources of valid scientific evidence to support the clinical validity of genotype-98phenotype relationships in FDA’s regulatory review of NGS-based tests. 99

100FDA’s guidance documents, including this guidance document, do not establish legally 101enforceable responsibilities. Instead, guidance documents describe the Agency’s current thinking 102on a topic and should be viewed only as recommendations, unless specific regulatory or statutory 103requirements are cited. The use of the word should in Agency guidance means that something is 104suggested or recommended, but not required. 105

106II. Background 107

108NGS can enable rapid, broad, and deep sequencing of a portion of a gene, an entire exome(s), or 109a whole genome and may be used clinically for a variety of diagnostic purposes, including risk 110

https://www.whitehouse.gov/precision-medicine


prediction, diagnosis, and treatment selection for a disease or condition. The rapid adoption of

2

111NGS-based tests in both research and clinical practice is leading to identification of an increasing 112number of genetic variants, including rare variants that may be unique to a single individual or 113family. Understanding the clinical significance of these genetic variants holds great promise for 114the future of personalized medicine. 115

116Although the importance of genetic variant data aggregation is widely recognized, today much of 117the data that would be useful to support clinical validity of NGS-based tests is generally stored in 118a manner in which it is not publicly accessible. Aggregation of clinical genotype-phenotype 119associations and evaluation of the level of evidence underlying these associations under a well-120defined process will continue to promote more rapid translation of genetic information into 121useful clinical evidence. 122

123For the purposes of this draft guidance document, a “genetic variant database” is a publicly 124accessible database of human genetic variants that aggregates and curates reports of human 125phenotype-genotype relationships to a disease or condition with publicly available 126documentation of evidence supporting those linkages. Genetic variant databases may also 127include assertions1 about specific genotype-phenotype correlations. 128

129FDA believes that the aggregation,2 curation,3 and interpretation4 of clinical genotype-phenotype 130associations in genetic variant databases could support the clinical validity of claims made about 131a variant detected by an NGS-based test and a disease or condition. In relying on assertions in 132genetic variant databases that follow the recommendations in this guidance, FDA hopes to 133encourage the deposition of variant information in such databases, reduce regulatory burden on 134test developers, and spur advancements in the interpretation and implementation of precision 135medicine. 136

137Publicly Accessible Databases of Human Genetic Variants as Sources of Valid Scientific 138Evidence Supporting Clinical Validity 139

140To determine whether an NGS-based test has a reasonable assurance of safety and effectiveness, 141the Agency relies upon the review of valid scientific evidence to support the analytical and 142clinical performance of the test. Valid scientific evidence is defined as evidence from well-143controlled investigations, partially controlled studies, studies and objective trials without 144matched controls, well-documented case histories conducted by qualified experts, and reports of 145significant human experience with a marketed device, from which it can fairly and responsibly 146 1 For the purposes of this guidance, an assertion is the informed assessment of a genotype-phenotype correlation (or lack thereof) given the current state of knowledge for a particular variant. An assertion is generally noted in the genetic variant database entry for a particular variant (e.g., benign, drug resistant, etc.). 2 For the purposes of this guidance, the term aggregation refers to the process by which variant data are systematically input into a genetic variant database. This process may require that data conform to specified formats. 3 For the purposes of this guidance, curation refers to the process by which data regarding a specific variant are collected from various sources, annotated, and maintained over time. 4 For the purposes of this guidance, the term interpretation refers to the process by which genetic variant database personnel evaluate the evidence regarding a linkage between a genetic variant and a disease or condition and make an assertion about that linkage (or lack thereof).


be concluded by qualified experts that there is a reasonable assurance of safety and

3

147effectiveness.5 In determining whether a particular NGS test has a reasonable assurance of safety 148and effectiveness, FDA must determine, based on valid scientific evidence that “in a significant 149portion of the target population, the use of the device for its intended uses and conditions of use, 150when accompanied by adequate directions for use and warnings against unsafe use, will provide 151clinically significant results.”6 152

153The evidence residing in many genetic variant databases has been collected from multiple 154sources that can meet the valid scientific evidence definition, such as evidence from well-155controlled clinical investigations, clinical evidence generated in CLIA (Clinical Laboratory 156Improvement Amendments of 1988)-certified laboratories, published peer-reviewed literature, 157and certain case study reports. Some organizations that are currently developing genetic variant 158databases have adopted protocols and methodologies (e.g., quality measures) and/or external 159guidelines (e.g., from professional societies or standards development organizations) for 160evidence aggregation, curation, and interpretation practices. While interpretation processes may 161vary across databases and organizations, they typically involve the use of qualified experts who 162make informed conclusions about the presence or absence of a genetic variant and its meaning 163for a particular disease or clinical decision. 164

165Further, there are several parallels between the standards set forth by well-recognized 166professional guidelines for variant interpretation and FDA review of clinical validity. Personnel 167interpreting variants use a range of evidence, including the types and positions of variants, 168inheritance, prevalence, well-established functional studies, and prior knowledge of gene-disease 169relationships. Generally, the standards for use of evidence appear to parallel the types of 170evidence appropriate to support an FDA premarket submission. Under 21 CFR 860.7(c)(2), 171isolated case reports, random experience, reports lacking sufficient details to permit scientific 172evaluation, and unsubstantiated opinions are not regarded as valid scientific evidence. 173Accordingly, FDA believes that summary literature is inferior in this respect to data available for 174independent evaluation. FDA assesses clinical validity based on the totality of available 175evidence provided in a given submission. Similarly, well-recognized professional guidelines 176dictate that database personnel interpreting variants integrate multiple lines of evidence to make 177an assertion of clinical validity. 178

179The Agency believes such practices help assure the quality of data and assertions within genetic 180variant databases and has built upon these approaches in developing the recommendations in this 181guidance. 182

183FDA has long believed that public access to data is important so that all interested persons (e.g., 184healthcare providers and patients) can make the best medical treatment decisions. To that end, 185for all IVDs that have received clearance or de novo classification from FDA since November 1862003, FDA has published a Decision Summary containing a review of the analytical and clinical 187validity data and other information submitted by the applicant to support the submission and 188

5 21 CFR 860.7(c)(2). 6 21 CFR 860.7(e)(1).


FDA’s justification for clearing or classifying the IVD; FDA is also required to publish

4

189Summaries of Safety and Effectiveness Data for approved PMAs under section 520(h) of the 190Federal Food, Drug and Cosmetic Act (FD&C Act) (21 U.S.C. 360j(h)).7 FDA believes that 191similar public availability and access to data contained in genetic variant databases is important 192to patients and healthcare providers in order to make fully informed medical decisions. 193

194FDA believes that if genetic variant databases follow the recommendations in this document, 195including transparency regarding evidence evaluation, and obtain FDA recognition as described 196below, the data and assertions within would generally constitute valid scientific evidence that can 197be used to support clinical validity. 198

199III. Scope 200

201This draft guidance document describes FDA’s considerations in determining whether a genetic 202variant database is a source of valid scientific evidence that could support the clinical validity of 203an NGS-based test in a premarket submission. This draft guidance further outlines the process by 204which administrators8 of publicly accessible genetic variant databases could voluntarily apply to 205FDA for recognition, and how FDA would review such applications and periodically reevaluate 206recognized databases. 207

208The genetic variant databases discussed in this draft guidance only include those that contain 209human genetic variants, and do not include databases used for microbial genome identification 210and detection of antimicrobial resistance and virulence markers. This draft guidance does not 211apply to software used to classify and interpret genetic variants, but instead, only regards use of 212curated databases using expert human interpretation. 213

214IV. Recommendations to Support Recognition of Publicly 215

Accessible Genetic Variant Databases of Human 216

Genetic Variants as Sources of Valid Scientific Evidence 217

Supporting Clinical Validity of NGS Tests 218219

FDA believes that evidence contained in a genetic variant database that conforms to the 220recommendations described below would generally constitute valid scientific evidence that can 221be used to support the clinical validity of an NGS-based test. 222

223FDA believes that such a genetic variant database would: (1) operate in a manner that provides 224sufficient information and assurances regarding the quality of source data and its evidence 225

7 No Decision Summaries or Summaries of Safety and Effectiveness Data are posted for those devices for which the applicant failed to demonstrate substantial equivalence or a reasonable assurance of safety and effectiveness. 8 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 purposes of this guidance, a genetic variant database administrator is the entity or entities that oversee database operations.


review and variant assertions; (2) provide transparency regarding its data sources and its

5

226operations, particularly around how variant evidence is evaluated and interpreted; (3) collect, 227store, and report data and conclusions in compliance with all applicable requirements regarding 228protected health information, patient privacy, research subject protections, and data security; and 229(4) house sequence information generated by validated methods. 230

231In the subsections below, FDA discusses recommendations for the operation of a genetic variant 232database, and the aggregation, curation, and interpretation of data therein, so that such data 233would generally constitute valid scientific evidence supportive of clinical validity. FDA 234acknowledges that individual genetic variant databases may have different, but equally 235scientifically valid, approaches to assuring data quality, clinical relevance, data security, patient 236privacy, and transparency. Additionally, FDA recognizes that several professional societies have 237or are developing guidelines for genetic variant curation and interpretation that may differ 238depending upon discipline, but may each be appropriate in the context of the intended use. 239Genetic variant database administrators should focus on ensuring that their procedures and 240quality requirements are sufficiently robust to provide a high degree of confidence in their 241conclusions regarding genotype-phenotype associations. 242

243A. Database Procedures and Operations 244

245Transparency and Public Accessibility: FDA recommends that genetic variant database 246administrators make publicly available sufficient information regarding data sources and 247standard operating procedures (SOPs) for evaluation and interpretation of evidence to allow FDA 248and the public to understand the criteria and processes used to collect and interpret evidence 249about variants and enable patients and healthcare providers to make fully informed medical 250decisions. 251

252SOP Version Control: SOPs should define how variant information is aggregated, curated, and 253interpreted. These SOPs should be documented and versioned. Changes to SOPs should be 254clearly documented with sufficiently detailed information regarding the change accompanied by 255any necessary explanation to ensure all stakeholders understand any limitations created by or 256implications of the change in procedure. To maintain quality variant assertions and ensure that 257genetic variant database operations keep pace with advances in technology and scientific 258knowledge, operations and SOPs should be reviewed at least on an annual basis. 259

260Data Preservation: FDA recommends that genetic variant database administrators have 261processes in place for assessing overall database stability and architecture and for ensuring that 262data linkages are properly maintained. When a genetic variant database contains linkages to 263secondary databases, the genetic variant database administrator should have predefined processes 264in place to recognize changes to the secondary databases and account for them in version control 265of the primary database. FDA recommends genetic variant database administrator back-up the 266database on a regular basis so that it can be reinstated as necessary. 267

268Genetic variant database administrators should have a plan in place to ensure database content 269and processes are preserved in the event a genetic variant database ceases operations 270permanently or temporarily (e.g., a database loses funding, infrastructure upgrades). A location 271


to deposit data, including versioning information and supporting SOPs and documentation, in the

6

272event that the genetic variant database ceases operation should be identified. 273

274Security and Privacy: Genetic variant database operations must be in compliance with all 275applicable federal laws and regulations (e.g., the Health Insurance Portability and Accountability 276Act, the Genetic Information Nondiscrimination Act, the Privacy Act, the Federal Policy for the 277Protection of Human Subjects (“Common Rule”), etc.) regarding protected health information, 278patient privacy, research involving human subjects, and data security, as applicable. It is the 279responsibility of the genetic variant database administrator to identify the applicable laws and 280regulations and to assure that any requirements are addressed. Genetic variant database 281administrators should also put in place adequate security measures to ensure the protection and 282privacy of patient and protected health information and provide training for database staff on 283security and privacy protection. 284

285Data formats: To facilitate genetic variant database use for regulatory purposes and to help 286assure the accuracy and quality of variant assertions, genetic variant database administrators 287should employ commonly accepted data formats and identify which format is in use by the 288genetic database. This standardization will help minimize ambiguity regarding variants and 289better enable comparisons of variant assertions between different databases or other entities. 290

291B. Data Quality 292

293It is essential that the data and information regarding genotypes and phenotypes or clinical 294information placed into the genetic variant database are of sufficient quality, and based on 295current scientific knowledge, in order for there to be a reasonable assurance that the assertions 296made linking specific genetic variants to diseases or conditions are accurate. 297

298Nomenclature: To aid in the accurate interpretation of genetic variants, genetic variant databases 299should use consistent nomenclature that is widely accepted by the genomics community for gene 300names and/or symbols, genomic coordinates, variants, described clinical and functional 301characteristics, and classifications. The genetic variant database administrator should also make 302available a detailed description of which nomenclature is used to allow FDA and external users 303to accurately interpret the information presented. 304

305Metadata: Variant data in the genetic variant database should be accompanied by metadata, 306including the number of independent laboratories and/or studies reporting the variant 307classification, name of the laboratory(ies) that reported the variant, the name of the test used to 308detect the variant, and, to the extent possible, details of the technical characteristics of the test 309that was used (e.g., reference sequence version or build, instrument, software, bioinformatics 310tools, etc.) and variant characteristics (e.g., zygosity, phasing, and segregation). Genetic variant 311databases should clearly and transparently document evidence source(s) used to support variant 312interpretation (e.g., literature, well-documented case histories, etc.). 313

314Data Uniqueness: Genetic variant database operations should also include methods to ensure that 315individual data points (e.g., a variant from one individual for a particular phenotype) are not 316represented more than once in the database. 317


C. Curation, Variant Interpretation and Assertions

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318319

The processes that genetic variant database personnel use for curation and variant interpretation 320should be based on well-defined SOPs and carried out by qualified professionals. 321

322Curation and Variant Interpretation: Written SOPs for curation and variant interpretation, 323including evaluation of data from clinical practice guidelines, peer-reviewed literature, and pre-324curated knowledge bases, should be available to the public for review. SOPs should generally 325include validated decision matrices, such as those based on well-recognized professional 326guidelines. All genetic variant database curation and interpretation rules, and future 327modifications of those rules, should be explained and made available to the public. Furthermore, 328if curated data or variant interpretations from other sources are to be integrated into the genetic 329variant database, then the curation and interpretation processes and data quality of those outside 330sources should be audited by the database administrator on a regular basis. Each interpretation 331should be performed independently by at least two qualified and trained professionals, as 332discussed below, and genetic variant databases should have SOPs for resolving differences in 333interpretation. Providing SOPs publicly for each of these activities will allow outside users to 334evaluate the evidence used in variant interpretation and thereby promote the consistency of 335interpretation. 336

337FDA believes that use of publicly available decision matrices9 for variant interpretation that are 338based on rigorous professional guidelines is central to assuring that assertions from genetic 339variant databases constitute valid scientific evidence supporting the clinical validity of a test. 340FDA reviewers must evaluate evidence in the context of a test’s intended use and conditions of 341use, including specific facts about genes or diseases under consideration (e.g., population 342incidence of a disease, variant incidence) into their review. See 21 CFR 860.7(e)(1). Similarly, 343such factors should be incorporated into a finalized decision matrix. 344

345Assertions: The types of evidence that personnel interpreting variants may use for an 346interpretation, and their corresponding strengths, should be defined, and combined into a scoring 347system. Assertions within an FDA-recognized genetic variant database should be appropriate to 348the level of certainty and the nature of the genotype-phenotype relationship and be adequately 349supported. Assertions should be versioned, such that changes in assertions over time are 350recorded and maintained. Assertions and the evidence underlying them should be truthful and not 351misleading and be made in language that is clear and understandable. In order to be FDA-352recognized, a genetic variant database should not include any recommendations regarding 353clinical treatment or diagnosis. 354

355For example, it is appropriate for an assertion to include descriptive language about a variant 356such as responder, non-responder, pathogenic, benign, likely pathogenic, likely benign, variant 357of unknown significance, etc. as long as such language is truthful, not misleading, and supported 358by adequate evidence detailed within the genetic variant database. FDA believes that it is 359

9 For the purposes of this guidance, a decision matrix is an evidence-based tool used to guide the interpretation of the genotype-phenotype relationship between variants and diseases or conditions.


generally not scientifically appropriate to make a definitive assertion (e.g., pathogenic) about the

8

360clinical validity of a variant based on a single piece of evidence, or on only weak evidence. 361Assertions that a particular genotype-phenotype association is clinically valid should generally 362involve multiple lines of evidence and, at a minimum, should identify a primary source of 363scientific evidence and other supporting evidence. Further, wherever appropriate to avoid any 364potential misunderstanding regarding the strength of the evidence supporting an assertion, the 365assertion should include a clear description of the evidence associated with it. 366

367D. Professional Training and Conflicts of Interest 368

369Professional Training: FDA recognizes that many different types of genetics professionals may 370be involved in the curatorial and interpretive process as part of a team (e.g., genetic counselors, 371Ph.D.-level scientists, physicians). Adequate training and expertise of personnel interpreting 372variants plays an important role in the quality of variant review and interpretation. FDA believes 373that interpretation should be performed by qualified professionals with appropriate levels of 374oversight in place (e.g., multiple levels of review). Personnel interpreting variants should have 375received adequate training and there should be methodologies in place, such as proficiency 376testing, to ensure that such personnel meet and maintain high quality standards over time. 377

378Finally, curation procedures should ensure that all data has been collected in compliance with all 379applicable requirements for protecting patient health information and research involving human 380subjects. 381

382Conflicts of Interest: Conflicts of interest, especially financial ones, could introduce bias and 383undermine the quality of variant interpretations in genetic variant databases, as well as the 384confidence in such interpretations, if not adequately mitigated. To be considered for recognition 385by FDA, efforts should be made to minimize, and make transparent, any potential conflicts of 386interest pertaining to a genetic variant database or its personnel. 387

388V. FDA’s Genetic Variant Database Recognition Process 389

390FDA believes that data and assertions from genetic variant databases that follow the 391recommendations discussed in this document would generally constitute valid scientific evidence 392supportive of clinical validity in a premarket submission. Therefore, FDA intends to implement a 393recognition process10 for publicly accessible genetic variant databases and their assertions to 394streamline premarket review of NGS tests. Specific variant assertions and underlying data from a 395recognized genetic variant database could generally be submitted by NGS-test developers as part 396of their premarket review submission, if applicable, in some cases without submission of 397additional clinical data regarding that variant. 398

399

10 The genetic variant database recognition process discussed in this document may be viewed as analogous to the standards recognition process under section 514 of the FD&C Act (21 U.S.C. 360d), but would not be conducted under this provision.


Participation in the FDA database recognition process is voluntary and participation would not

9

400subject the database to FDA oversight, beyond that needed to retain the recognition. For genetic 401variant database administrators who wish to undergo voluntary recognition, this section describes 402FDA’s recommended process for genetic variant database recognition. When evidence from 403proprietary sources or genetic variant databases that have not been recognized by FDA are used 404to support the clinical performance of an NGS-based test, detailed information regarding such 405sources of evidence should be included in the premarket submission for that test. 406

407FDA intends for its process for recognition of genetic variant databases to involve three steps: 408(1) voluntary submission of detailed information about the database; (2) FDA review of genetic 409variant database policies and procedures for obtaining and maintaining data and making variant 410assertions; and (3) maintenance of FDA recognition of a database. These steps are discussed in 411detail below. 412

413A. Recognition Process for Genetic Variant Databases 414

4151. Submission for Recognition 416

417Administrators of genetic variant databases seeking to have their assertions be considered by 418FDA as valid scientific evidence that could provide support for the clinical validity of NGS-419based tests should make a voluntary submission to FDA for genetic variant database recognition. 420Such a submission should demonstrate that the recommendations in this document have been 421followed. FDA encourages genetic variant database administrators seeking recognition of their 422genetic variant database to contact FDA through the Pre-Submission Program11 prior to 423submission. 424

4252. FDA Review of Genetic Variant Database Policies and 426

Procedures 427428

The intent of this section is to provide additional information to genetic variant database 429administrators regarding the type of documentation that should be provided to FDA staff for the 430purpose of voluntary genetic variant database recognition. Complete documentation should 431address all of the recommendations in this guidance. 432

433The following types of documents, which show that the recommendations in this guidance have 434been followed, should be submitted in an application for recognition: 435

436· Statement of the types of variants the genetic variant database assertions address (e.g., 437

germline, somatic) 438· SOPs, policies or other documents related to the following: 439

o General operation of the genetic variant database 440 11 Further information about the Pre-Submission Program can be found in the FDA guidance document entitled “Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff.”

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf


o Patient health information confidentiality and privacy

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441o Data security 442o Curation, variant interpretation, and reinterpretation 443o Training for curation, interpretation, privacy and security, and other relevant 444

activities 445· Documentation of personnel qualifications 446· Data preservation plan 447· Conflict of interest policies and disclosures of conflicts of interest 448· Validation studies for interpretation SOPs 449

450As part of its recognition process, FDA may verify variant assertions, as appropriate, to assure 451they are supported and that the genetic variant database is following its SOPs. 452

453Prior to recognition, FDA generally intends to treat this information confidentially and not 454publicly disclose it except as required by law.12 At the time of recognition, the database 455administrator should make this information publicly available and accessible on the genetic 456variant database’s website. FDA also intends to make available on its own website a list of all 457FDA-recognized genetic variant databases and other relevant, public information about those 458databases. 459

4603. Maintenance of FDA Recognition 461

462FDA intends to review FDA-recognized databases regularly on a set schedule to verify they 463continue to follow their SOPs and the recommendations in this guidance. As part of the 464continuing database recognition process, FDA would consider the following when evaluating 465genetic variant databases for NGS-based tests: 466

467a. Processes should incorporate multiple lines of scientific evidence, where 468

available, with appropriate weights. 469b. Processes should use a tiered system of assertions (e.g., pathogenic, likely 470

pathogenic, etc.) and adequately describe the meanings of each tier. 471c. Genetic variant databases should implement a decision matrix based on validated 472

SOPs or rigorous professional guidelines that incorporate unique details of the 473gene/disease being evaluated, where available or applicable. 474

d. Genetic variant databases should include validation of the decision matrix. 475e. All guidelines, decision matrices, and details supporting each variant’s 476

interpretation should be made available to the public. 477478

Continued transparency about methods and assertions will play a critical role in maintaining 479confidence in a genetic variant database and thus, to maintaining recognition. FDA believes that 480it is important that users and the public have access to information about the capabilities and 481

12 See, e.g., the FD&C Act sections 301(j) (21 U.S.C. 331(j)) and 520(c) (21 U.S.C. 360j(c)), the Trade Secrets Act, 18 U.S.C. 1905, the Freedom of Information Act, 5 U.S.C. 552, and FDA’s regulations covering information disclosure at 21 CFR part 20.


limitations of a genetic variant database so that patients and healthcare providers can make fully

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482informed medical decisions. Genetic variant database administrators should document and make 483publicly accessible any changes or updates to the database SOPs on its website. FDA plans to 484periodically review its recognition of a genetic variant database based upon this transparently 485documented and publicly available information. As part of this process, FDA will verify that 486updates to SOPs, as described in Section IV, have been posted. FDA may also “spot-check” 487assertions about genetic variants to assure they continue to be supported and that the genetic 488variant database continues to follow its SOPs for interpretation. If the genetic variant database is 489not maintained according to the specifications under which it was originally recognized, FDA 490may withdraw recognition. If recognition is withdrawn, it would be unlikely that FDA would 491consider assertions from such a genetic variant database to constitute valid scientific evidence 492supportive of the clinical validity of a test, and FDA would assess what regulatory actions may 493be appropriate with respect to IVDs supported by such assertions. 494

495B. Use of Third Parties 496

497FDA has an established third party 510(k) review program for eligible medical devices.13 For 498genetic variant databases, FDA may consider utilizing third parties to assist with genetic variant 499database recognition in the future. FDA seeks to work with interested parties that have 500experience with genetic variant databases and NGS-based tests and can comply with FDA 501policies, including those regarding screening for conflicts of interest. 502

503C. Use of Data and Assertions from Recognized Genetic 504

Variant Databases 505506

Data from FDA-recognized genetic variant databases would generally constitute valid scientific 507evidence that can be used to support the clinical validity of the genotype-phenotype relationships 508embodied in the assertions from such databases provided in a premarket submission. Under this 509policy, FDA expects that test developers will be able to use FDA-recognized genetic variant 510databases to establish, at least in part, the clinical validity of their test. For premarket 511submissions that rely upon genetic variant databases recognized by FDA, the Agency may 512determine that submission of any additional valid scientific evidence for certain variant 513assertions found in these genetic variant databases is not necessary, depending on the sufficiency 514of the evidence for these assertions. 515

13 For additional information, including guidance documents on the topic, please see FDA’s Third Party Review Program.

http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/thirdparyreview/default.htm

http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/thirdparyreview/default.htm

advamed | - october 6, 2016...division of dockets management (hfa-305) docket no. fda-2016-d-1233...

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