FDA Webinar

Moderator: Irene Aihie

05-24-18/2:00 pm ET

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FDA NGS Webinar

Moderator: Irene Aihie

May 24, 2018

2:00 pm ET

Coordinator: Welcome and thank you for standing by. All lines have been placed in listenonly mode until the question and answer session at the end of today's 

presentation. To ask a question, please press star one on your touch tone 

phone. 

Today's call is being recorded. If anyone has any objections, you may 

disconnect at this time. I would now like to turn the call over to Irene Aihie. 

Thank you, you may begin.

Irene Aihie: Hello. And welcome to today's FDA webinar. I am Irene Aihie, of CDRH's 

Office of Communication and Education. On April 13, the FDA issued two 

final guidances related to precision medicine. 

The first guidance -- titled Considerations for Design, Development, and 

Analytical Validation of Next-Generation Sequencing-Based In-Vitro 

Diagnostics Intended to Aid in the Diagnosis of Suspected Germline Diseases 

-- provides recommendations for designing, developing, and validating NGSbased tests used to diagnose individuals with suspected genetic diseases. 
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The second guidance -- titled Use of Public Human Genetic Variant Databases 

to Support Clinical Validity for Genetic and Genomic-Based In-Vitro 

Diagnostics -- described an approach where the test developers may rely on 

clinical evidence from FDA-recognized public databases to support clinical

claims for those tests and provide assurance of the accurate clinical evaluation 

of genomic test results. 

Today Adam Berger, Zivana Tezak, and Laura Koontz will discuss and 

answer questions about the final guidances. Following the presentation, we 

will open the lines for your questions related to information provided during 

the presentations. Now I give you Adam.

Dr. Adam Berger: Thank you Irene. And thanks to all of you for joining us today. My name is

Dr. Adam Berger and I am part of the Personalized Medicine Staff here at 

FDA. As Irene mentioned I'm joined today by my colleagues, Dr. Zivana 

Tezak and Dr. Laura Koontz, also of the Personalized Medicine staff and we

will be discussing the two next generation sequencing guidances that were 

finalized on April 13 of 2018. In terms of an agenda for today's webinar, we 

will be going over the background for why FDA has developed these 

guidances as well as highlighting the major differences between the draft 

versions and the final versions. 

And -- as Irene mentioned -- at the end of the presentation we will go ahead 

and take any questions you might have. So, we'll go ahead and start with the 

background for why FDA developed these guidances and what are the 

agency's goals in doing so. 

Precision medicine is an approach to disease treatment and prevention that 

takes into account individual variability in lifestyle, environment, and genes 

with a focus on getting the right treatment to the right person at the right time. 
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New technologies have been developed over the last several years that have 

enabled greater identification of these characteristics, including in genome 

sequencing with the advent of next-generation sequencing -- or NGS. 

NGS itself is a technology that can rapidly and cheaply determine nearly the 

entire sequence of an individual's genome. This technology plays a critical 

role in advancing precision medicine precisely because of its unprecedented 

ability to identify that individual variation. However, NGS presents 

challenges for our traditional regulatory paradigm. 

In traditional testing -- where one test yields one result -- FDA would require 

validation of the analyte that the test detected. However, with NGS, one test 

can provide volumes of data, which often in the germline space cannot be 

predefined or the disease identified until after the test is actually performed. 

The agency recognizes that requiring validation of each variant that could 

potentially be detected can be infeasible when this can be up to millions of 

variants. Regulating these tests in a way that enables innovation required us 

to develop a nimble regulatory approach that could keep pace with the 

technological and scientific advancements in the field. 

Our vision was to implement new regulatory policies that promote research 

and accelerate the translation of precision medicine technologies into 

treatments that benefit patients. Overall we are trying to provide clarity to and

an efficient path to market for these technologies while making sure that 

patients receive accurate and meaningful information. 

In developing this regulatory approach, FDA sought to engage the public. We 

held five workshops -- from 2015 to 2016 -- to garner input on the overall 
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vision and technical details for analytical performance and clinical 

interpretation and to understand patient and provider perspectives. 

Some of the key things we heard from the public were that analytical 

standards should be a combination of design processes and performance 

standards; that there's a need for clarity and transparency about a test’s

performance and its limitations; and that there is a need to incentivize data 

sharing. 

After taking into account the feedback and insight we received from the 

public, we issued two draft guidances in July of 2016 that described a

regulatory pathway for NGS-based tests for certain uses. In doing so FDA 

was trying to anticipate and support the needs of a rapidly-evolving 

technology while ensuring that patients - while ensuring patient safety and 

assuring the quality and reliability of NGS-based tests. 

FDA feels that tests developed according to these guidances would be 

anticipated to have an efficient pathway to market. The draft guidances lay

out a two-pronged regulatory strategy for NGS-based IVDs for diagnosing 

germline diseases. 

The first approach details technical standards for NGS-based tests. Test 

developers that meet these standards may not have to submit a pre-market 

submission to FDA. We envision that these standards would be developed 

with the scientific community and can be updated as science and technology 

advance. 

Zivana will go into further detail on these technical standards later in the talk. 

The second approach outlines a process whereby a public database of human 

genetic variants could apply for and potentially receive FDA recognition as a 
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source of valid scientific evidence that test developers may be able to use to 

support the clinical validation of their test. Laura will delve into the details on 

this concept later in this webinar as well. 

So, moving to the guidances section of the webinar, let's go ahead and dive 

into the guidance on Design, Development, and Analytical Validation of Next 

Gen Sequencing-based IVDs. The scope of the draft guidance was specific to 

targeted or whole exome sequencing NGS-based tests intended to aid in the 

diagnosis of individuals with suspected germline diseases or other germline 

conditions. 

This scope was clarified in the final document in response to comments that 

indicate that the guidance only specifically applies to NGS-based tests 

intended to aid clinicians in the diagnosis of symptomatic individuals with 

suspected germline diseases. 

The draft guidance also laid out recommendations for the design, 

development, and analytical validation of NGS-based tests that FDA 

continues to believe could form the basis of future FDA-recognized standards 

and/or special controls that could reasonably assure the safety and 

effectiveness of these tests. 

The guidance also laid out a potential pathway whereby NGS-based tests 

intended to aid in the diagnosis of suspected germline diseases could be 

considered as candidates for down classification to Class II devices, since all 

novel tests -- including those with the intended use described in the guidance -

- are Class III by default. 

FDA continues to believe that this may be possible in the future as we gain 

more experience with these devices and develop special controls that could 
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provide a reasonable assurance of the safety and effectiveness NGS-based 

tests intended to aid in the diagnosis of suspected germline disease -- possibly 

under certain conditions of exemption -- without the need for 510(k) premarket review. 

I've already mentioned that we made revisions to the draft document in 

response to comments. Overall we received comments on the draft guidance 

from 38 organizations and individuals. 

Commenters were generally supportive of the proposed regulatory approach, 

and provided comments asking for clarification of the background, scope, and 

certain technical recommendations, including requests for the removal of 

specific thresholds for analytical performance. To go ahead and highlight 

some of the major changes from the draft to final in response to comments 

received, the title was revised to better reflect the scope and content of the 

guidance, to acknowledge that currently there are no applicable standards that 

FDA can recognize, and to support community engagement in developing 

standards by standards-developing organizations. The scope was clarified as I 

mentioned earlier. 

The analytical performance thresholds that were - that were included in the 

draft have been removed in the final guidance, which now recommends that 

test developers pre-define, justify, and report minimum acceptable overall and 

target threshold metrics such as accuracy, precision, and coverage. Finally, 

clarifications to accuracy metrics, performance evaluation studies, and other 

technical recommendations were made in the guidance. 

I'm now going to go ahead and turn the presentation over to Dr. Zivana Tezak, 

who will describe in more detail the analytical validation sections of the final 

guidance, including further details about the changes I've just highlighted.
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Dr. Zivana Tezak: Thank you Adam. Like Adam, I'm very happy to be with you today. And I 

will now try to take a bit deeper dive into the first of the two final guidances 

that Adam started to talk about. 

So, Adam has already provided a high-level description of the major changes 

from draft to final guidance. And that was in response to a number of public 

comments we received after issuing a draft. In the next few slides I will 

provide an overview of the major sections in the final guidance. And -- as you 

can see on this slide -- I'm starting with recommendations for design, 

development, and validation. 

Now, this section covers test design, performance characteristics, run quality 

metrics, and performance evaluation studies. The design section describes the 

test design approach, starting from the purpose for testing, steps to follow, 

what is needed, what is available. 

You will note that the recommendations on how to design the test are very 

flexible. They can accommodate different test designs, different indications. 

Something to pay some attention to are the recommendations on the 

interrogated regions of the genomes are designed to ensure that test 

developers can provide transparency in what genes their test can and cannot 

detect. 

Now about the performance characteristics. In the next couple of slides, I will 

dig a bit deeper into major test performance characteristics since these can be 

very challenging for NGS tests. Of course, performance characteristics 

include accuracy, precision, LOD, and analytical specificity. 
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The bullet point on test run quality metrics. Probably many people on this call 

are very familiar that this is the very NGS-technology-specific part. So, it's 

technology-specific in the guidance too. And these quality metrics are useful 

for assessment whether a test run or variant call should be accepted. 

They include metrics such as coverage depth, coverage completeness, as well 

as select metrics -- for various steps of the test -- such as specimen quality, 

base calling, or mapping. And -- as in the draft guidance -- ultimately the 

recommendations outlined in the guidance can form the basis of future FDArecognized standards or FDA special controls. So - and I will go into 

performance evaluation studies in the next few slides. 

So here I will highlight some parts mentioned on the previous slide. As Adam 

already mentioned one of the major changes from draft to final guidance is 

that -- in response to numerous, numerous comments, against providing 

specific thresholds -- the Test Performance Characteristics section was edited 

to remove those. 

So, we removed these specified minimum numeric thresholds. Instead, the 

final guidance recommends that test developers pre-define, justify, and report 

minimum acceptable overall and target threshold metrics. These thresholds 

will of course depend on technology, indications for use, and different 

variables such as types of variants that are detected and reported by the test. 

We do expect that specific numeric thresholds will be defined and specified in 

either upcoming consensus standards or special controls developed by the 

FDA. But those will be appropriate for a specific test or specific indications

for use. 
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The accuracy part. So NGS test accuracy should be calculated for each 

variant type in the context in which the test can detect them as well as for 

clinically relevant variants. The accuracy metrics section has added clarity 

and it's reflecting the importance and definition of metrics such as PPA, NPA, 

and TPPV.

We have added a new subsection that's illustrating accuracy metrics 

calculations. And we have also added the appendix in the final guidance, 

which was a very, very simplified example of such calculations. And that was 

all added in response to comments that were encouraging us to provide more 

details and sample tables and templates that demonstrate how to address, 

present, and calculate different accuracy metrics. 

And I will go in the next slide now into performance evaluation studies. So,

this section was expanded significantly in response to comments asking for 

clarification on types of samples and types of studies that can be used to 

evaluate test performance. And I will mostly highlight the accuracy part. 

So, accuracy is generally evaluated by comparison to a method identified as 

appropriate comparator. And in the past or for sequencing that has been 

mainly bidirectional sequencing. We have been however accepting other wellvalidated methods. 

For example -- and as appropriate -- accuracy can be evaluated by comparing 

to the sequence generated by - comparing sequence generated by a new test to 

a well-characterized -- so called gold standard -- reference sequence or a 

consensus sequence of agreed-upon well-characterized samples. This will of 

course depend on the availability of such samples. 
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Study samples. They should reflect the specimen types tested. And they can 

include a mix of well-characterized reference samples, they can include 

clinical samples that are relevant for the test, and appropriate surrogate 

samples. This section also includes recommendations for when to use in 

silico samples.

For variant types, it may be helpful to use the results of studies conducted 

with -- again -- well-characterized reference materials or some agreed-upon 

samples with high confidence calls. For clinically-relevant variants the 

accuracy calculation should use the results of studies conducted with clinical 

samples pertinent to test indications. 

As far as the number and type of samples that are required to demonstrate that 

performance has been met and the thresholds have been met with confidence 

for relevant metrics and the indications for use. That will depend on, again, 

indications for use and purpose of the test. And the number and types of 

variants. What are the number and types of variants claimed to be detected 

and reported by the test, and the other critical performance parameters that 

must be met to support that use? Additional sections of the guidance are 

listed on this slide and include supplemental procedures, variant annotation, 

filtering, and test labeling. Recommendations for what to present in test 

labeling include identification of genomic regions, sequence variants, or 

maybe variant types the test can and cannot detect and report. 

If part of an interrogated genomic region is difficult to sequence and cannot 

meet appropriate performance specifications, this should be reported as a test 

limitation. So, transparency is very big and important. Test labeling needs to 

include any limitations of the test. 
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For example, if the test cannot detect certain genes, certain types of sequence 

variants, certain allele frequencies, genomic context, certain rearrangements, 

insertions or deletions that are larger than a certain size or not detecting parts 

of specific genes relevant for test indications for use.

So, to wrap up with the significance of this guidance. It provides technical 

recommendations for designing, developing, and validating NGS-based tests 

for patients basically with either signs and symptoms or suspected of genetic 

disease. We believe these recommendations if followed can provide a 

reasonable assurance of the analytical validity of these tests. 

We also believe that recommendations in this guidance can be taken on by 

maybe standard development organizations -- or SDOs -- and that they can 

form the basis for consensus standards that can be developed by relevant 

stakeholders and experts. Standards developed by accredited consensus 

standards bodies are regularly recognized by the FDA. 

And of course, the advantage of standards is that they can be updated as 

technology and knowledge advance. Conformance with FDA-recognized 

consensus standards can be used to support a reasonable assurance of safety 

and/or effectiveness for many applicable aspects of these tests, we think. 

We envision relying on compliance with FDA-recognized standards that 

would guide the development and validation of NGS-based tests and can 

replace some of the pre-market review to provide a reasonable assurance of 

test validity. Now, in the absence of consensus standards -- or while we are 

waiting for such standards to be developed by the community -- we can use 

the recommendations in this guidance as a basis to develop specific special 

controls. And that can allow the down-classification, potentially, of these 

tests or even maybe potentially exemption of pre-market purview. 
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We believe that recommendations in this guidance benefit all types of

stakeholders that are involved with NGS. So, test developers we think can 

have a clear and transparent path to market. And in certain cases, may be 

even exempt from FDA premarket review. Patients and providers can get 

faster access to more accurate tests with well-validated, transparent 

performance. And FDA's mission of protecting and improving public health 

can be fulfilled in a more streamlined and a more rapid manner. 

So, I will now turn the presentation over to Dr. - my colleague Dr. Laura 

Koontz to go over the database guidance. 

Dr. Laura Koontz:Thank you Zivana. So, I will now spend the new few minutes discussing the 

second of our two final guidances, The Use of Public Human Genetic Variant 

Databases to Support Clinical Validity for Genetic and Genomic-Based InVitro Diagnostics. 

This guidance outlines the agency's thinking about how genetic databases can 

be use in the regulatory review of these tests. Specifically, how public genetic 

databases that follow certain quality specifications can be sources of valid 

scientific evidence to demonstrate clinical validity. 

So, first, I want to take just a second to define what we mean by human 

genetic variant databases. For this guidance, a genetic database is both a 

collection of assertions about the link between a genetic variant and a disease 

or condition. The way that these collections are structured can vary and 

assertions can be things like pathogenic, clinical significant, or even variant of 

uncertain significance. 
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Genetic databases are also publicly accessible. By that we mean that the 

assertions and the underlying data and SOPs used to arrive at those assertions 

are transparent and available to all users. As a best principle, publicly 

accessible databases would be open access. But some databases that operate 

with licensing models for commercial use could also be in scope of this 

guidance. 

So how does the ability to tap into publicly available genetic databases to 

support clinical claims benefit patients? Databases of genetic variants have 

the potential to speed evidence development for genomic tests since the 

evidence housed in these databases is typically generated by many people all 

over the world. 

Collectively, we can obtain evidence for the clinical interpretation of a greater 

portion of the genome than we can individually. Aggregated data could also 

provide a stronger evidence base for genetic and genomic based tests than any 

single test developer could amass on their own. 

Tests that use these databases would be connected with the current state of 

clinical knowledge regarding a genetic variant and its relationship to a disease 

or condition. Finally, FDA believes that as more evidence is gathered, new 

assertions could be supported by that evidence and be made by databases.

FDA has been able to leverage databases twice before in our regulatory 

review of submissions. And I'd like to take just a second to highlight these, 

but will note that more information about each is available publicly in publicly 

available decision summaries on our website. First, Illumina was able to 

leverage the publicly accessible CFTR2 database of Cystic Fibrosis variants in 

their submission for the MiSeq CF 139 variant assay. 
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Second, Myriad used their own proprietary database to support the submission 

of their BRACAnalysis companion diagnostic. Notably, Myriad provided us 

with the SOPs for how they make assertions about never-before-seen variants. 

And in doing so, were allowed to report out these new calls to physicians as 

part of their approval. 

These experiences helped the agency formulate and build upon the 

recommendations laid out in the final guidance, which we will now discuss. 

As mentioned, in July 2016 we released the draft guidance with the goal of 

allowing NGS-based test developers to leverage genetic databases as done in 

those two submissions. The guidance proposed how genetic variant databases 

could be used as sources of valid scientific evidence to support the regulatory 

review of NGS-based tests. 

Specifically, the guidance laid out a series of recommendations that FDA 

believes, when followed, would allow the database to be considered a source 

of valid scientific evidence, which can support the clinical validity of an NGSbased test. 

The draft guidance also proposed that NGS - or that database administrators 

that run databases that meet these recommendations could voluntarily apply to 

the FDA for recognition. They would need to submit an application to the 

FDA demonstrating that their database meets the recommendations set forth in 

this guidance. 

The FDA received over 250 public comments on the draft guidance from 38 

different stakeholders spanning the genomic community. We've heard from 

industry groups, scientific societies, patient advocacy organizations, and 

others. On the whole, commenters were generally supportive of the proposal 
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outlined in the draft guidance, but requested that the scope be expanded to 

incorporate additional uses of genetic variant databases. 

While the draft guidance was agnostic in terms of germline versus somatic

indications, we heard that commenters wanted it to explicitly include somatic. 

Commenters also asked for technical clarifications on various points in the 

guidance, and clarification on the definition of publicly acceptable. FDA took 

all of these comments into consideration and opted - ultimately opted to 

expand the scope consistent with stakeholder suggestions and added 

clarification where necessary. 

Next, we will talk about the specific changes we made from draft to final and 

we'll then summarize the final guidance. As I mentioned, we received 

numerous comments asking us to expand the scope to encompass all genetic 

and genomic based tests regardless of technology. For example, tests that rely 

on PCR or SNPchips should be able to leverage FDA-recognized databases to 

support their clinical validity. 

We agreed. And in the final guidance you will see that we have expanded the 

scope and the title to reflect this. Regarding publicly - regarding the definition 

of publicly accessible. As a best practice, we believe that databases should 

follow an open access model. That is, that the information about an assertion 

and the evidence underlying is available to anyone at no charge. 

We believe this will foster greater accuracy, understanding, and use of these 

databases. However, databases that use licensing models or charge fees for 

commercial access -- provided that all of that data is still publicly accessible --

may also fall within the scope of this guidance. 
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While out of scope of the guidance, proprietary databases -- or ones that 

charge fees for access -- may also be sources of valid scientific evidence that 

could be used to support the clinical validity of tests. Test developers that rely 

on these types of databases may find a database - may find the 

recommendation within this guidance useful when preparing pre-market 

submission for those IVDs. 

Any database administrator who has questions about whether or not their 

database is eligible for recognition -- or the evidence within could be relied 

upon as valid scientific evidence -- is encouraged to contact us. 

Also in response to comment, we clarified that somatic variant databases were 

in-scope for this guidance, and added metadata recommendations for these 

types of variants. And finally, we expanded details about the voluntary 

database recognition program, including information on how interested parties 

can submit information to the FDA to apply. We will discuss this in more 

detail later in this webinar. 

Next, I'd like to take just a couple of minutes to discuss the recommendations 

from the final guidance. These recommendations are geared towards 

administrators of the database, not a test developer. Databases that meet the 

recommendations outlined in this final guidance could be considered a source 

of valid scientific evidence and could be used to support the clinical validity 

of tests. These recommendations fall broadly into five different buckets. 

The first, transparency. Transparency is the cornerstone of this final guidance 

document. Because the FDA is proposing to rely upon assertions from 

databases and review their policies and procedures, but not each individual 

assertion, transparency is critically important. 
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Databases should provide transparency regarding its data sources, its 

operations, and including the use of publicly available SOPs. Further, the 

SOPs and assertions should be versioned so it's clear to the user not only how 

an assertion was arrived at, but when it was made, and how it may have 

changed from previous versions. Finally, data should be presented in 

standardized formats and the format used should be disclosed.

The second is data quality. Databases should provide sufficient assurances 

regarding the quality of their source data, including the use of accepted 

nomenclature and clear documentation of the evidence used to make variant

assertions. We would like to see sufficient metadata regarding variant 

assertion and the underlying data used to make those calls. 

Three, SOPs. Databases should have SOPs that define how variants are 

evaluated in order to arrive at an assertion about that variant's clinical 

significance, pathogenicity, and so on. Further, the SOPs that outline how 

those assertions are made should be supported by validation studies. 

Four, the use of qualified experts. Variant assertions should be made by a 

qualified expert. And these experts should adhere to a database's conflict of 

interest policies and publicly disclose any conflicts. The guidance also 

discusses the need for adequate training of database personnel and the need 

for methodology to ensure that individuals undertaking variant evaluation 

meet and maintain high quality standards over time. 

And five -- finally -- database hygiene. Data should be collected, stored, and 

reported in compliance with all applicable requirements regarding protected 

health information, patient privacy, research subject protections, and data 

security. The final guidance does not spell out each of these requirements, as 

they may differ on a case by case basis, but states that the database 
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administrator should know which laws and regulations are applicable and 

follow them. Of course, I briefly summarized these recommendations for the 

sake of time, but the final guidance contains more granularity on each of 

these. 

If a genetic database meets the recommendations laid out in the final guidance 

and would like to be recognized by the FDA, there is a voluntary pathway for 

them to seek recognition. And again, I will just emphasize that this pathway 

is voluntary. 

If so, recognition would occur in three steps. First, a database would 

voluntarily submit an application to the FDA for recognition. Again, this is a 

voluntary process and at the discretion of a database administrator, and the 

FDA is not compelling any database to seek recognition. Second, the FDA 

would assess the genetic variant database to ensure that all recommendations 

from the guidance have been met, if applicable. 

This would include FDA evaluation of the types of documentation listed here. 

FDA may also -- as part of the recognition process -- spot check variant

assertions to ensure that they are made in accordance with the database's SOPs 

and reflect the current state of scientific knowledge. 

Now finally, once a database has been FDA-recognized, the third step is 

maintenance of database recognition. The database guidance lays out a 

process for maintenance of recognition of a database through periodic 

reassessment of the database, its SOPs, and its assertions. 

FDA believes that if a database is recognized, the evidence contained within it 

could generally constitute valid scientific evidence and could be used to 

support the clinical validity of genetic and genomic based tests. 
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The assertions that a database could make about genetic variants could include 

a variety of statements such as relating to the pathogenicity of a variant. Or 

whether a somatic variant may be clinically significant. 

At our public workshops, we heard that it was important for patients and 

providers to receive information regarding variants of uncertain significance, 

as this may be medically useful information for an individual patient now or 

in the future. Therefore, we have clarified that it would also be permissible to 

report these types of assertions too. 

Finally, I want to take just the next couple of minutes outlining -- at a high 

level -- how administrators of databases who are interested in seeking 

recognition should go about contacting the FDA. We recommend that as a 

first step, before even submitting and application -- a database administrator 

should reach out to a member of the Personalized Medicine Staff -- such as 

myself -- to discuss their pending application. 

We can provide advice to the database administrators to help ensure it's a 

smooth process. Additionally, we can help database administrators target 

their application to the appropriate review division within FDA. Second, 

databases - database administrators should compile information demonstrating 

that they have met all of the recommendations laid out in the guidance -- as 

they are applicable -- and submit that to the agency using the informational Q 

Sub process. Excuse me, just to correct. The informational meeting Q Sub 

process. 

Detailed information about the submission process -- including how to format 

and submit a Q sub -- can be found on our website. And -- as always -- by 

reaching out to a member of the Personalized Medicine Staff. 
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So, after FDA receives an application for recognition, FDA staff will review 

and make a determination about whether or not to grant a database 

recognition. One question that we get a lot about the recognition process is 

whether there are any user fees for database recognition. The answer is no. 

The FDA does not plan to assess user fees for database recognition requests at 

this time. 

You may also ask, well then what are the timelines that FDA will use for 

reviewing recognition requests? We aim to review database recognition 

requests within the same timeframe as feedback is typically given during the 

informational Q Sub submissions. Or -- for those of you who aren't familiar 

with that -- 90 days. 

Finally, if recognition is granted, FDA will alert the database administrator 

and post this information on our website at the link noted at the bottom of this 

slide. And there we will also post a summary of our recognition decision. 

So now I want to take just a minute to shift into a summary of our key 

takeaways, and then we'll turn it over for question and answer. So, taken 

together, these guidance documents discuss the possible future down 

classification and exemption from pre-market review of NGS-based tests that 

demonstrate conformity with the standards outlined in this guidance, and that 

use assertions from FDA-recognized databases. 

We believe that this approach offers speed, scalability, and safety. 

So, speed. This approach provides test developers with an efficient path to 

market and connects patients with the current state of clinical knowledge 

regarding genetic assertions. 
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Scalability. We believe that test developers both large and small can benefit 

from this approach because it is based on standards and evidence that 

everyone can access. 

And finally, safety. This approach encourage innovation while still assuring 

patients and health care providers that NGS-based tests provide accurate and 

meaningful results. And now that these guidances are final we look forward 

to working with the community to implement them and realize their full 

vision. 

To do that we encourage the development of standards that can be used to 

support the regulatory framework for these tests and the submission of 

genomic databases for recognition to use to support regulatory decision 

making. And with that I'll turn it back over to Irene.

Irene Aihie: Operator, we'll now take questions.

Coordinator: Thank you. At this time if you'd like to ask a question please press star one 

and please record your name when prompted. If you'd like to withdraw the 

question you may press star two. Again, to ask a question please press star 

one. One moment please while we wait for the first question.

Dr. Adam Berger: And while we're waiting for those questions, maybe we can go ahead and pose 

a question ourselves. And, you know, I'll direct one over to Laura. 

You mentioned about the database guidance being specific to public 

databases. Could you comment on whether proprietary databases are eligible 

for recognition?
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Dr. Laura Koontz: So, proprietary databases -- or ones that charge fee for access -- are out of 

scope of the guidance and would not be eligible for recognition through this 

guidance. However, these databases -- as I mentioned -- may be sources of 

valid scientific evidence and could be used to support the clinical validity of a 

test. 

So, individual test developers that rely upon proprietary databases to support 

their IVDs may need to include supporting information regarding this 

database in their individual pre-market submissions. And to that end, they 

might find that the recommendations in this guidance are useful in preparing 

those pre-market submissions.

Dr. Adam Berger: Great. While we're still waiting for folks to come on with questions maybe 

we'll just continue an open discussion amongst ourselves a little bit. You 

know, one thing we've heard from various feedback is that the scope for the 

guidance on considerations for design, development, and analytical validation 

of NGS has changed. 

And you know, we thought we would go ahead and maybe comment on that a 

little bit. I'll go ahead and start and maybe then turn it over to Zivana. But 

you know, I think FDA does not view that the scope of the final guidance has 

actually changed from the draft. 

Both versions actually provide recommendations for designing, developing, 

and validating NGS-based tests intended to aid clinicians in the diagnosis of 

symptomatic individuals with suspected germline diseases. However, we did 

rearrange the scope section a bit in response to some of the comments asking 

for clarification of what had been perceived as potentially vague language in 

the draft. 
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The bulleted list of what is and is not in scope should actually help 

stakeholders in understanding which tests fall within the scope of the 

guidance. While the scope is focused, we've noted that the principles may be 

applicable in some circumstances to tests for some of the uses listed as out of 

scope and we are actually very happy to have these conversations with 

individual sponsors. A major reason why these are out of scope is that these 

tests may have other performance characteristics and/or risk considerations 

that are not addressed by the recommendations presented in the final 

guidance.

Dr. Zivana Tezak: Also, we want to add -- because we had heard some feedback that the scope is 

relatively narrow -- so we want to emphasize that we are well aware that the 

clinical demand for broader applications of NGS-based diagnostics is 

increasing. 

And we have actually started working with some standards-developing 

organizations on expanding the potential applicability of the concept - of what 

the concepts are in the current guidance to maybe have a larger scope. And to 

that end, CLSI -- or Clinical Laboratory Standards Institute -- has taken on the 

revision of their sequencing guideline, which is called MM09. And that is 

about to start in about a month. And from what I understand it's not going to 

include only germline applications, but probably also somatic and maybe 

some additional applications. So, we are looking forward to working with the 

community and seeing what the community and standards organizations can 

come up with for the scopes that are beyond the current guidance. 

But we think that what's laid out in the guidance can be a really good 

foundation for people to see what we are thinking. And maybe start from 

there and layer on to that.
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Irene Aihie: Okay, we'll go ahead and take our first question.

Coordinator: Thank you. Our first question comes from Lauren Davis. Your line is open.

(Lauren Davis): Oh hi. Yes, Lauren Davis here. And Russell Garlick. The question is 

probably for Zivana). We have shown -- and others have shown -- that in 

cancer-associated genes like MSH2, PMS2, BRCA1, BRCA2, there are 

regions where the insertions and deletions are very hard to detect.

So, my question is, do manufacturers have to demonstrate they can detect 

these hard-to-detect insertions and deletions in these pathogenic variant types 

prior to launching their assay?

Dr. Zivana Tezak: So, I think that - and I've - I think I may sound like a broken record. But it 

will depend on the purpose of the test and on the indications for use, as I think 

you know. 

So, if they are - if the test manufacturer is - manufacturer is claiming that 

they're detecting certain insertions -- or certain huge either rearrangements in 

certain genes -- then yes, they should detect - they should have a way to figure 

out how to prove that they can actually detect those. 

Now that goes back to what I was talking about if you have the way to 

analytically detect certain insertions of certain sizes. But then there are some 

clinically important ones and that's what I think you are - where you are going 

with your question. 

Which -- for some diseases -- there are some rearrangements or insertions or 

whatever it is that needs to be detected for that disease. So, you have 

CFΔ508. You want to detect that. You want to know that you're detecting 
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that. No matter whether you can detect similar deletions in different parts of 

the genes. 

So, I think the answer to your question is yes. And I think that the follow up 

answer to that is if we cannot find the clinical samples then samples that are -

the reference samples will be probably a good approximation for some of 

those.

Lauren Davis: Thank you.

Dr. Zivana Tezak: Thank you for the question.

Coordinator: Thank you. And our next question comes from Vera Diaz.

Vera Diaz: Yes, hi. My question's simple. And it's just, on Page Four of the guidance --

Consideration for Design and Development -- is there another document that 

further expresses what these types of tests might be? So specifically I don't 

know what type - standalone diagnostic purposes. What type of test would 

that be?

Dr. Zivana Tezak: So, this guidance is just for aid in diagnosis. Not for standalone. So, you're 

talking about scope. I can't log into my computer right now to look at what's 

on Page Four, but I'm thinking you are talking about the scope and what's in 

and out of the scope?

Vera Diaz: Correct.

Dr. Zivana Tezak: Right. So, this is the only guidance that we right now have for NGS tests.

Vera Diaz: Okay...
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Dr. Zivana Tezak: Like I said though, we can build on that. Or community can build on that. 

And propose and maybe work on some standards for different indications.

Dr. Adam Berger: Hey Zivana, let me just follow up real quick on that as well and just ask you 

an additional question on that. You know, we've had a lot of discussion 

around standards and their development. 

I was wondering if you might kind of give -- for those that may not be as 

familiar with it -- our, you know, how we actually recognize standards and the 

process that standards development organizations actually go through to 

develop those.

Dr. Zivana Tezak: So, the CDRH at FDA actually has established standards program. And that 

has been established under FDAMA back in 97. And this program is 

responsible for facilitating the recognition of both national and international 

consensus standards. 

And then we can use those standards in regulatory review. So - but we can 

only recognize standards and guidelines that are created by these certified

SDOs, or Standard Development Organizations. So, we can't really use the 

guidelines from professional organizations, even if they might be really, really

great. 

So, we need standards from SDOs to recognize. And then we can publish in 

federal register what standards are recognized. And they would be added to 

the list of recognized consensus standards which can be then found online and 

you can do the search of FDA-recognized standards and that should pull up 

the database -- this database of the recognition -- as the first hit. 
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And there is also -- since the 21st Century Cures -- any interested party may 

submit a request for recognition of their standard that is established by a 

nationally or internationally-recognized standard organization. So, in cases of 

NGS probably it would be something like CLSI or ISO.

Dr. Adam Berger: Okay. Thank you.

Irene Aihie: We'll take our next question.

Coordinator: Thank you. Our next question comes from Ryan Woodhouse. Your line is 

open.

Ryan Woodhouse:Hello. So, one question I have is that this is targeted towards germline 

diseases. And so, I was wondering if you would be releasing something 

similar for tests targeting somatic mutations?

Dr. Zivana Tezak: So yes. So right now, we kind of figured we would start relatively narrow. 

Because we are -- as you probably noticed -- we are talking not just about the 

review but we are also talking about down classification and also eventually 

exemption. 

So, we wanted to make sure that we have very narrow intended use. That we 

can eventually do all that with. Now for somatic, you may be familiar with 

the recent approvals and even de novo authorizations of several somatic NGS 

tests that we had. So, we don't anticipate issuing the guidance. 

But what you can do is look at the device summaries or summaries of safety 

and effectiveness of those tests to get some idea of what we are thinking there. 

And I want to hand it over to Laura to give a little bit more details on that.
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Dr. Laura Koontz: Sure. Thanks, Zivana. So, I will mention -- before jumping into the specifics 

-- that on our website -- on the In-Vitro Diagnostics portion of the CDRH 

website -- we do have a one-pager that outlines our approach for how we think 

about the analytical and clinical validation of somatic gene panels or 

oncopanels. 

So, some of the concepts that we have put forward in that white paper -- or not 

white paper, excuse me, one-pager -- are concepts that, you know, are in line 

with some of the things in the analytical guidance that Adam and Zivana

discussed. 

So, for example, for claims outside of companion diagnostic claims. So, for 

example, Foundation Medicine has 15 different companion diagnostic 

biomarkers in their test but report back information on 324 different genes as 

well as two different gene signatures. And MSK -- in their oncopanel, which 

was authorized last year -- report back information on 468 genes. 

For those biomarkers that are not companion diagnostics in both of those 

authorizations they were able to - the companies were able to leverage a 

representative approach to validate those biomarkers. So, that's a concept 

that's really in-line with what we've proposed in the - or what we've put in the 

final analytical guidance. 

And so again -- as Zivana mentioned -- I'd encourage you to take a look at the 

publicly available decision summaries for both of those documents, which 

have quite a bit of information about the specific analytical and clinical 

validation that both - that companies have been doing for somatic oncopanels 

to date. 
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And of course, if you have trouble finding that on our website feel free to 

reach out to us. We can always point you in the right direction.

Ryan Woodhouse:Thank you.

Irene Aihie: Operator, do we have any more questions?

Coordinator: We have no further questions. And again -- as a reminder -- if you'd like to 

ask a question, please press star one and please record your name when 

prompted.

Dr. Adam Berger: Well, I'll go ahead and ask one more while we're waiting for others to, you 

know, join in on the line. I've been - this is for either of you actually. Are test 

developers required to follow these guidances?

Dr. Zivana Tezak: So, I'll reiterate what Laura said several times. It's that no, these guidances 

offer one voluntary pathway to the develop and validate NGS-based tests for 

those who choose to use this pathway. 

But -- as usual -- test developers are always free to demonstrate analytical and 

clinical validity by other means. And they can all always come to us and - in 

different ways -- like the pre-submissions -- and discuss what those other 

means they would like to use.

Dr. Adam Berger: It looks like we have one in queue for a question. If we can go ahead and take 

that.

Coordinator: Thank you. Our next question comes from Marlee Gallant. Your line is open.
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Marlee Gallantt: Hi. I just wanted to get back to what you were talking about a moment ago 

with the test developers that had already gone through the process and used a 

representative approach to obtain their indications. 

And if -- for example -- a test developer has a companion diagnostic 

indication for a set number of genes, what would the process be for them to 

have additional genes added to that indication? Would they need to explicitly 

expand their labeling and could they continue to use that representative 

process?

Dr. Laura Koontz: So -- oh sorry, that's a loud mic -- so that's a great question. It depends on 

what types of claims you want to make about those additional variants that 

you're adding. 

If you do want to make a companion diagnostic claim about them then you 

would need to undergo variant-specific or signature-specific -- whatever the 

biomarker is -- specific analytical and clinical validation. Like you would for 

any, you know, first of a kind or follow on companion diagnostic. 

For adding additional variants to your panel -- if they are just sort of in this - if 

they're not those companion diagnostic biomarkers -- you would need to - it 

would depend on whether or not you had analytically validated them in the 

original submission whether or not you're able to add them. Or set reporting 

out on them without an additional submission to the FDA. 

So again, I would encourage folks to take a look at that one-pager on our 

website as well as contact us with any specific questions. Because it's a little 

bit out of scope for today's webinar, but I think that one-pager has quite a bit 

of information about in which cases an additional submission would be 

required or when you can leverage a representative approach.
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Marlee Gallant: Thank you.

Coordinator: Thank you. And at this time I show no further questions.

Irene Aihie: Thank you. This is Irene Aihie. We appreciate your participation and 

thoughtful questions. 

Today's presentation and transcript will be made available on the CDRH 

Learn web page at www.gov/training/cdrhlearn by Tuesday, June 5. If you 

have additional questions about today's presentation, please use the contact 

information provided at the end of the slide presentation. 

As always we appreciate your feedback. Following the conclusion of the 

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immediately following the conclusion of today's live webinar. 

Again, thank you for participating. This concludes today's webinar.

Coordinator: Thank you. This concludes today's conference. You may disconnect at this 

time. Thank you.

END