re: docket no. fda-2016-d-0971: administration …...entitled ‘fda-argos: fda database for...

September 12, 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RE: Docket No. FDA-2016-D-0971: Draft Guidance for Industry and Food and Drug

Administration Staff; Infectious Disease Next Generation Sequencing Based

Diagnostic Devices: Microbial Identification and Detection of Antimicrobial

Resistance and Virulence Markers

Dear Sir/Madam:

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

(AdvaMed), we respectfully submit these comments in response to the FDA’s “Draft

Guidance for Industry and Food and Drug Administration (FDA) Staff: Infectious

Disease Next Generation Sequencing (NGS) Based Diagnostic Devices: Microbial

Identification and Detection of Antimicrobial Resistance and Virulence Markers”

(hereinafter “ID Guidance”).

AdvaMedDx member companies produce advanced, in vitro diagnostic tests 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 the advancement of the public health and

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 appreciates the efforts of FDA to share its thinking regarding its regulation

of NGS-based diagnostics. In addition to issuing the ID Guidance, FDA recently

published in the Federal Register two related Draft Guidances for Industry and FDA

Staff: 1) “Use of Standards in FDA Regulatory Oversight of NGS-Based In Vitro

Diagnostic (IVDs) Used for Diagnosing Germline Diseases (July 8, 2016) and 2) “Use of

Public Human Genetic Variant Databases to Support Clinical Validity for NGS-Based In

Vitro Diagnostics” (July 8, 2016).

Division of Dockets Management (HFA-305) September 12, 2016

of 14

We applaud the tremendous efforts by FDA to develop these guidances and extensive

communications and outreach for public feedback. Through a series of public

workshops, FDA has proposed and received feedback on a number of innovative

regulatory concepts such as better leveraging of standards to support analytical validity,

use of curated databases for establishing the clinical validity of a test, application of a

representative variant approach to support validation, improved transparency of

information to patients and healthcare professionals, and the use of regulatory-grade

genomic sequences as an alternative comparator for clinical evaluation. We appreciate

FDA efforts to support flexible, risk-based regulatory approaches that help promote

patient access to diagnostic technologies.

FDA has incorporated a number of useful concepts into the ID Guidance. Furthermore,

AdvaMedDx believes that this proposed guidance should be reviewed and further

harmonized in the broader context of FDA regulation of NGS-based diagnostics to ensure

a more consistent and cohesive approach in all three guidances. We generally encourage

consistency in scientific and regulatory recommendations across these guidances where at

all possible. More specifically, we believe FDA should promote this goal of consistency

by incorporating the following concepts into the ID Guidance:

Set forth FDA’s process and criteria when contemplating recognition of standards

developed by the scientific community or standard development organizations

that incorporate analytical validation requirements for infectious disease NGS-

based tests.

Permit use of a declaration of conformity with FDA-recognized standards by

developers of infectious disease NGS-based tests in premarket submissions.

Consider special controls and/or conditions of exemption that could be developed

to provide a reasonable assurance of safety and effectiveness for infectious

disease NGS-based tests without necessarily the need for a 510(k), where

appropriate.

AdvaMedDx appreciates the opportunity to provide our comments, which are intended to

support diagnostics innovation and foster advancement of personalized medicine. Our

specific comments follow with accompanying recommendations to assist FDA. Please

do not hesitate to contact me at 202-434-7230 or [email protected] if you have any

questions.

Respectfully submitted,

/s/

Jamie K. Wolszon, JD

Associate Vice President

Technology and Regulatory Affairs

mailto:[email protected]

September 12, 2016 of 14 Docket No. FDA-2016-D-0971

AdvaMedDx Comments on Infectious Disease Next Generation Sequencing Based Diagnostic Devices:

Microbial Identification and Detection of Antimicrobial Resistance and Virulence Markers;

Draft Guidance for Industry and Food and Drug Administration Staff

Additions are indicated in underline. Removals are indicated in strike out.

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Proposed Change Comment: Rationale/Justification for Change

1. lereneG

Clarify whether the ID Guidance would apply to profiling

applications that consist of characterizing microbial

populations through identification and determination of

relative proportions, and if so, whether different

performance analyses might apply.

It is unclear whether these applications are currently included

within the scope of the ID Guidance.

2. lereneG Add Discussion of Limit of Quantitation (“LOQ”) Sequencing has the potential of delivering quantitative results,

but LoQ is not mentioned in the ID Guidance.

3. General

Define “regulatory grade.”

We understand and appreciate the need for databases to be

populated with “regulatory-grade target sequences” and, given

their importance, would appreciate clarity in how the FDA

defines “regulatory grade.” Although the Appendix provides

some details on the constitution of a “regulatory-grade

database,” we recommend that this term be clearly defined and

articulated in the ID Guidance.

4. lereneG

Add Center for Biologics Evaluation and Research

(“CBER”) to the ID Guidance. In the alternative, clarify

that NGS HIV tests are excluded from the scope of the

ID Guidance.

Per the inter-center agreement between CBER and CDRH,

CBER has lead responsibility for all HIV tests and for tests

intended for use to screen the blood supply or tissue and cellular

products. While the ID Guidance explicitly excludes (lines 143-

146) tests intended for use to screen the blood supply or tissue

and cellular products from its scope, it does not exclude HIV

tests, and in fact mentions HIV tests as an example. Yet, the ID

Guidance makes no reference to CBER.


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5. 130-132

Revise as follows: “In contrast to human sequencing

diagnostics, infectious disease sequencing diagnostics

generally require rapid and actionable results,

sometimes within hours, as delayed or incorrect initial

diagnoses can result in fatalities.”

Human sequencing diagnostics also generally require rapid and

actionable results.

6. 132-135

Revise as follows: “Furthermore, the broad range of

specimen types (e.g., urine, blood, cerebrospinal fluid

(CSF), stool, sputum, etc.) and the large diversity of the

infectious disease agents that can be present in the

sample do not allow straightforward pre-analytical,

biochemical, or bioinformatics processes.”

Variation in pre-analytical processing steps is not unique to

assays for infectious agents. Moreover, the bioinformatics pre-

analytical processes are the same, i.e., searching against known

databases for nucleic acid sequences.

7. 138

Revise as follows: “The opportunity for repeat testing is

expected to may be limited due to a frequently small

specimen quantity (e.g., Cerebrospinal fluid (CSF)) and

the necessity to make a prompt and timely infectious

disease treatment decision for the patient.”

Small specimen quantity is not unique to ID NGS tests.

Moreover, while the opportunity for repeat testing may be small

for direct tests, for other tests (e.g., gastrointestinal pathogens),

the specimen may be abundant or be cultured (e.g., blood).


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8. 146-147

Add footnote to: “The inclusion of certain targets (e.g.,

Hepatitis B, Hepatitis C, HPV and HIV*) could elevate

the classification of the device to Class III, and FDA

encourages you to contact the Agency for additional

guidance.” The footnote would state: “CBER has lead

responsibility for HIV tests. For questions about HIV

NGS tests, please contact CBER.”

In the alternative, if CBER does not opt to be a co-

author of the ID Guidance, revise as follows: “The

inclusion of certain targets (e.g., Hepatitis B, Hepatitis C,

and HPV and HIV)…”

As discussed above, CBER has lead responsibility per the inter-

center agreement for HIV tests, yet CBER is not mentioned in

the ID Guidance. We recommend that CBER be included in the

ID Guidance. However, in the alternative, we would remove the

reference to HIV in this example.

9. 148-149

Revise as follows: “In addition, FDA recommends that

sponsors contact the Agency prior to undertaking any

clinical or analytical validation studies to discuss

whether additional recommendations are available due

to new advancements in this fast moving field. We

recommend that the sponsor utilize the Pre-Submission

process outlined in the guidance for Industry and Food

and Drug Administration Staff: “Requests for Feedback

on Medical Device Submissions: The Pre-Submission

Program and Meetings with Food and Drug

Administration Staff.”

The existing FDA Guidance for Industry and Food and Drug

Administration Staff: “Requests for Feedback on Medical Device

Submissions: The Pre-Submission Program and Meetings with

Food and Drug Administration Staff” is utilized heavily by

manufacturers, yet this guidance is not referenced in this section

of the ID Guidance. We recommend adding wording that points

manufacturers to this guidance in this section of the ID

Guidance.


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10. 175-178

Revise as follows: “An Infectious Disease NGS Dx

device differs from traditional diagnostic devices in that it

may be targeted to detect specific organisms or markers

and could simultaneously detect multiple organisms

present in a sample during a single run.”

This sentence applies equally to any multiplex device. Please

distinguish within the ID Guidance what applies to NGS and

multiplex devices versus what is unique to ID NGS devices.

11. 221-231

Re-title Section IIB. to “Databases as an Alternative

Comparator Method for Clinical Evaluation” and revise

the ensuing paragraph to: “FDA, in collaboration with

various federal agencies, has developed the database

entitled ‘FDA-ARGOS: FDA dAtabase for Regulatory

Grade micrObial Sequences; BioProject 231221.’ “To

promote a least burdensome regulatory approach for

devices that incorporate Infectious Disease NGS Dx

technology, FDA proposes the use of an alternative

comparator method for clinical evaluation that relies

heavily on public databases populated with regulatory-

grade target sequences. Such databases may be public

or proprietary and supply a set of validated regulatory-

grade microbial genomic sequence entries that are near

complete high-quality draft genomes with metadata

requirements. For more information on proprietary

databases, see Sections VI(D) and VIII. FDA, in

collaboration with various federal agencies, has

developed a public database entitled ‘FDA-ARGOS:

FDA dAtabase for Regulatory Grade micrObial

Sequences; BioProject 231221.’ This database supplies

a set of validated regulatory-grade microbial genomic

sequence entries which is available at the National

Center for Biotechnology Information’s (NCBI) website

As written currently, this section focuses on the FDA-ARGOS

database and its use as an alternative comparator method to

clinical evaluation. However, as the FDA clarifies in Section VIII,

“genomic sequence depositions in the public domain or in

proprietary databases can be evaluated and qualified for

regulatory purposes.” In short, both public and proprietary

databases that use regulatory-grade genomic sequences may

be used as an alternative comparator for clinical evaluation. As

such, we recommend revising this section to account for this, as

its focal point should be that regulatory-grade databases,

whether public or proprietary, may be used as an alternative

comparator method for clinical evaluation.


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(http://www.ncbi.nlm.nih.gov/bioproject/231221

(update with FDA web portal link)). Regulatory-grade

microbial sequences are near complete high quality

draft genomes with metadata requirements. For more

information see Section VIII, Appendix.”

12. 226-229

Clarify the statement: “This database supplies a set of

validated regulatory-grade microbial genomic sequence

entries which is available at the National Center for

Biotechnology Information’s (NCBI) website

(http://www.ncbi.nlm.nih.gov/bioproject/231221 (update

with FDA web portal link)).”

The ID Guidance does not address how the FDA-ARGOS

database information was validated. Please include a reference

or detailed information on the FDA-ARGOS database validation

criteria and process.

13. 229-231 Clarify the statement: “Regulatory-grade microbial

sequences are near complete high-quality draft

genomes with metadata requirements.”

It is unclear what constituted near complete high-quality draft

genomes for the FDA-ARGOS database. It also is unclear what

constituted the metadata requirements.

14. 249-254

Revise as follows:

• “Targeted Infectious Disease NGS sequencing:

Targeted sequencing requires a priori knowledge of the

target sequence; thus, its scope is limited to specific

targets. For the purposes of this document, targeted

sequencing refers to preferential amplification of defined

regions that target a specific organism(s) or marker(s)

selected for analysis a priori by any laboratory or

bioinformatics method (e.g., amplicon sequencing,

whole genome sequencing or a k-mer signature

database) based on the diagnostic device’s intended

use.”

Whole genome sequencing (WGS) could be added in "targeted

sequencing approaches" for the purposes of the ID Guidance.

We are aware of WGS-based tests that use a priori knowledge

of sequence targets and database-driven algorithms to identify

defined infectious agent(s) or marker(s) of interest.

http://www.ncbi.nlm.nih.gov/bioproject/231221

http://www.ncbi.nlm.nih.gov/bioproject/231221


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15. 280

Address discovery of emerging or novel pathogens or

other research applications in a manner consistent with

human sequencing.

Currently, the ID Guidance explicitly states that it does not cover

discovery of emerging or novel pathogens or other research

applications. However, emerging and novel pathogens are akin

to germline or somatic variants of unknown significance. The

expectations for inclusion of these targets should be clarified and

should be similar to those for NGS for human sequences.

16. 318 – 319

Clarify the following statement: “We note that device

performance should be established prior to using this

alternative comparator.”

It is unclear what the FDA means by this statement. Based on

the discussion throughout the guidance, the FDA-ARGOS

database seems to be most useful as an alternative comparator

method in the clinical evaluation of Infectious Disease NGS Dx

devices. Therefore, it appears that “device performance” in this

context may refer to the analytical performance of the device,

but this needs to be clarified.

17. Section IV.

Re-title Section IV. to “Risk Management.” “Benefit-Risk Analysis” is terminology that, through guidance,

FDA has applied to PMA and De Novo submissions. Given that

the focus of this Draft Guidance is 510(k)s, PMA terminology

such as “Benefit-Risk Analysis” should avoid being used, and

this section should simply be re-titled to “Risk Management.”

18. 386 – 392

Revise as follows: “The guidance document entitled

‘Factors to Consider When Making Benefit-Risk

Determinations in Medical Device Premarket Approvals

and De Novo Classifications’ provides information on

FDA benefit-risk determinations. Premarket

submissions should include a discussion of the potential

benefits and risks associated with the device that is

being assessed, the hazards and consequences

associated with those risks, analytical strengths and

Given the focus on 510(k) products in this ID Guidance, the

wording should be modified to reflect the activities that take

place when a risk analysis is conducted following the principles

outlined in the FDA-recognized consensus standard ISO 14971

“Medical Devices – Application of Risk Management to Medical

Devices.” See also comment above.


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weaknesses of the technology, and the mitigations that

have been put in place to reduce the risks as much as

possible. ISO 14971 ‘Medical Devices – Application of

Risk Management to Medical Devices’ (FDA recognition

number 5-40) may be a useful resource when

conducting such a risk analysis. clinical information that

is available demonstrating device effectiveness.”

19. 422-461

Revise as follows: “You should describe in detail the

methodology used by your device. You should

describe, at a minimum, the following elements, as

applicable to the device:…

• Design inputs and outputs with a risk analysis

and traceability matrix”

Design inputs and outputs are not typically included in a 510(k),

and we do not believe that information is warranted here. See,

e.g., Federal Food, Drug, and Cosmetic Act (FDCA) §

513((i)(D)(i). FDA can assess this information as part of a post-

market inspection of the company’s compliance with the QSR.

21 C.F.R. § 820.30(c) (design input); 21 C.F.R. § 820.30(d)

(design output).

20. 463-469

Revise as follows: “When applicable, you should include

descriptions of design control specifications that address

or mitigate risks associated with Infectious Disease NGS

Dx devices. For example, design controls may be

needed:

• For manufacturing process procedures that may

affect quality. “

Information related to manufacturing process procedures is not

typically included in a 510(k), and we do not believe that

information is warranted here. See, e.g., FDCA § 513((i)(D)(i).

FDA can assess this information as part of a post-market

inspection of the company’s compliance with the QSR.

21. 513-533

Revise as follows: “A description of how you intend to

use your risk assessment to mitigate risks through

implementation of any necessary controls over ancillary

reagents should be addressed using your risk

assessment. These may include, where applicable:…

It is unclear how an infectious disease NGS device would have

an ancillary reagent that is lot-number controlled.

A company’s complaint-handling protocol or information related

to Corrective and Preventive Action (CAPA) should not be


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Identification of reagent lots that will allow

appropriate performance of your device.

• Complaint handling protocols.

• Corrective and preventive actions. “

required as part of a 510(k) submission. See, e.g., FDCA §

513((i)(D)(i). FDA can assess this information as part of a post-

market inspection of the company’s compliance with the QSR.

21 C.F.R. §§ 820.100; 820.198.

22. 543 – 544

Revise as follows: “This includes any positive and

negative controls intended for use with the assay as well

as the appropriate internal external controls

recommended, but not necessarily provided, for the

assay.”

Positive and negative controls are external controls, so the use

of “external” is redundant in this sentence. Furthermore, internal

controls are valid and actually control with each patient

specimen (i.e., more frequently than once daily). The ensuing

discussion includes, appropriately, “internal” controls as well as

“external” controls.

23. 781 - 793

Revise as follows: “You should submit your minimum

requirements and cutoffs used as quality control for your

material, including, for example, but not limited to the

following factors…

• Agarose gel or equivalent technologies that

separate DNA fragments based on size…”

• …A specific quantification of DNA versus RNA.

Lines 785 – 793 provide a list of quality control metrics that must

be included in infectious disease NGS submissions. However,

other than sample amount and sample volume, the remaining

QC metrics listed are very likely too low to be measured (for

example, viral RNA yield from a plasma specimen). In another

context, the target(s) to be sequenced is/are not likely to be

distinguishable from other nucleic acids present in the sample

prior to enrichment, so the value obtained from the QC metrics

would be meaningless. For example, a total nucleic acid

extraction from a whole blood sample will likely be >99% human

DNA with very good yield (>500 ng), but little to none of this is

likely to be microbial, so the values are meaningless for a

microbiome assay. Nevertheless, sequencing this sample will

still potentially yield a valid microbial profile. We, therefore,

recommend that these factors be provided as examples rather

than mandatory for inclusion in submissions.


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Capillary systems with special gels are widely used.

Depending on the target, the specific quantification of DNA

versus RNA may be needed.

24. 836-844

Clarify the statement: “The sequences of the multiple

DNA\RNA fragments that comprise the signal outputs of

the reaction should be stored in a suitable format that

allows subsequent bioinformatics analysis. There are a

number of data formats applied to Infectious Disease

NGS; however, the most common are the text-based

formats FASTA (stores the biological sequence format

used to search National Center for Biotechnology

Information BLAST database) and FASTQ (stores both

the biological sequence and its corresponding quality

scores).”

FASTQ and FASTA files are not signal outputs from the

sequencers but already processed results (by sequencer

provider base-calling programs embedded with the sequencer).

If FDA wants signal outputs stored, then FASTQ and FASTA

files are not the right formats for that storage. FDA should clarify

what data it wants stored, and modify the types of files

accordingly.

25. 999-1004

Revise as follows: “(9) Sample to Result Turn-Around

Instrument Run Time (TAT)

The sample-to-result turn-around instrument run time

should be provided for the Infectious Disease NGS Dx

device. Please include data demonstrating turn-around

times for “locked-down” Infectious Disease NGS Dx for

both: (1) laboratory workflow from clinical sample to

sequence, and (2) the subsequent computational

analysis of Infectious Disease NGS data from sequence

to actionable clinical result.”

In line 1003, FDA is asking for laboratory workflow from clinical

sample to sequence. Since the test is not cleared yet, there is

no way for the manufacturer to know how the test will actually be

implemented for pre- and post-analytical factors (i.e., timing of

results reporting). The only thing the manufacturer can control is

sample processing and instrument run time, and not how

specimens flow through the laboratory (especially if the test is

run on a “batched” system where laboratories wait to accumulate

a minimum number of specimens before running the test).

Likewise, before the test is marketed, there is no way of knowing

how long, on average, it takes laboratories to report out results.


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26. 1052-1055

Clarify the statement: “Limit of Detection (LoD) provides

a measure of assay analytical sensitivity for a particular

target, and is defined as the lowest concentration of a

target that can be sequenced reliably and distinguished

from negative specimens with consistent detection in

≥95% of the specimen replicates.”

It is unclear what FDA means by “can be sequenced reliably” in

this statement. It may mean “coverage at a minimum of 20X

over 95% of the core genome at Phred like quality score8 =>

Q30” or a lower level of coverage if adequate justification is

provided, as is indicated in lines 926-927, but clarification on this

point is warranted.

27. 1066-1068

Revise as follows: In brief, the LoD determination can be

performed with a pool of different claimed targets in

claimed specimen matrix. This pooled approach is also

applicable for inclusivity and reproducibility studies.

Since all NGS technologies have a limited capacity

within which all DNA molecules are competing to be

processed, the pooled approach should be carefully

designed to avoid the bias possibly introduced by a too

high level of multiplexing.

Added to help avoid potential for bias.

28. 1327

Revise as follows: “Please note that in the majority of

instances only one site may be located outside of the

United States. If additional sites are desired, please

contact the Agency.”

FDA should consider a manufacturer request to include more

than one site outside of the United States, particularly if an

infectious agent is at higher prevalence outside of the United

States, or if the study timing coincides with disease seasonality

(e.g., flu studies).

29. 1362 –

1365

Establish sample requirements more consistent with

prior Agency requests for NGS or PCR diagnostic

products or provide sound statistical rationale for

requiring 1500 prospective samples for the evaluation of

negative percent agreement.

The ID Guidance requests 1500 prospective samples for the

evaluation of negative percent agreement, which is inconsistent

with precedent; FDA required 500 samples to demonstrate

accuracy for NGS diagnostic devices in previous related

submissions and 755 samples were used in a prospective

clinical study to evaluate the performance of recently cleared

PCR assay intended as an aid for infection control in detecting


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and differentiating genetic markers of resistance. While the

Agency provides statistical rationale to support the need for at

least 50 positive specimens for the evaluation of positive percent

agreement (lines 1427 – 1436), FDA fails to provide a similar

statistical rationale for why this number of samples is needed for

infectious disease NGS diagnostic devices. We urge FDA to

establish sample requirements more consistent with previous

expectations.

30.

Section VI.

E. (1) and

(2)

Allow regulatory-grade genomic target sequence

databases to be used as alternative comparators for

both negative percent agreement and positive percent

agreement evaluations.

The ID Guidance indicates that the use of regulatory-grade

databases as an alternative comparator method in clinical

evaluations is only suitable for negative percent agreement and

not positive percent agreement evaluations. We disagree with

this approach and believe that regulatory-grade databases are

suitable for use as alternative comparator methods in both

negative percent agreement and positive percent agreement

evaluations. The choice of a comparator method for sequencing

applications can be very challenging, particularly for rare

variants. There are few FDA-cleared or approved technologies

from which to choose, and their technology is often inferior to

that of the submitted device. Use of a regulatory-grade

database as an alternative comparator alleviates these

challenges associated with the use of traditional comparator

methods.

31. 1548 –

1549

Revise as follows: “Furthermore, for Class II devices,

modification or an update of a library and bioinformatics

pipeline would require premarket review by the FDA if

the modification has the potential to significantly affect

the safety or effectiveness of the device, as determined

by the manufacturer according to 21 C.F.R. 807.81.”

In their current form, lines 1548 – 1549 indicate that all library

and bioinformatics pipeline updates or modifications should be

communicated to the FDA prior to their use and implementation.

For Class II devices (which are the main focus of this guidance),

this is contrary to the principles provided in the Federal Food,

Drug, and Cosmetic Act and the implementing regulations. In


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should be communicated to FDA prior to use and

implementation

particular, the regulations state that, for Class II devices,

changes or modifications to a device that could significantly

affect its safety or effectiveness would require premarket

notification. 21 C.F.R. § 807.81. Therefore, it should not be

necessary to submit all library and bioinformatics pipelines

updates or modifications to the FDA for premarket review but

only those that could significantly affect the device safety or

effectiveness. For example, a manufacturer may determine that

a modification to a single line of code in a bioinformatics pipeline

does not influence the device’s safety or effectiveness. Such a

modification should, therefore, not be submitted to the FDA for

premarket review or as a notification. The text should be revised

accordingly. Additionally, we encourage the FDA to consider a

more flexible approach to modifications of NGS tests to

encourage innovation while protecting public health.

32. 1590-1592

Clarify the statement: “Extracted gDNA should be of

high quality and purity, and at sufficient concentration to

achieve a suitable yield to assure adequate depth and

breadth of genomic coverage for the type of sequencing

method employed.”

We agree with this statement, but the statement is very

subjective. We recommend that FDA add criteria, for example,

of what constitutes “high quality”, what constitutes “high purity,”

and what is “adequate depth and breadth of genomic coverage”

that was used to establish the “regulatory-grade” database FDA-

ARGOS.

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