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Webinar - Draft Guidance on “Principles for Codevelopment of an In Vitro Companion 

Diagnostic Device with a Therapeutic Product" 

Moderator: Irene Aihie

August 18, 2016

1:00 pm ET

Coordinator: Welcome and thank you for standing by. All participants will be in listen only 

mode until the question and answer session of today's conference. At that 

time, you may ask a question by pressing star one. Today's conference is 

being recorded. If you have any objections, you may disconnect at this time. I 

would now like the turn the meeting 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 July 14, 2016, the U.S. Food and 

Drug Administration issued the draft guidance principals for co-development 

of an in vitro companion diagnostic device with a therapeutic product. This 

draft guidance is intended to assist with the co-development of a therapeutic 

product and in an accompanying IVD companion diagnostic. This guidance is 

also intended to assist FDA staff with reviewing companion diagnostics or 

their associated therapeutic products.

The focus of today's webinar is to share information and answer questions 

about the draft guidance document. Your presenters will be Christopher 

Leptak from the Office of New Drugs and the Center for Drug Evaluation and 
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Research, and Pamela Bradley from the Office of In Vitro Diagnostics and 

Radiological Health in CDRH. Following the presentation, we will open the 

line for your questions related to topics in this draft guidance only.

Additionally, there are other central subject matter experts available to assist 

with the Q&A portion of this webinar. Now, I give you Chris.

Christopher Leptak: Hello everyone. We welcome you to today's webinar and I wish to extend 

my sincere apologies for the technical difficulties and certainly appreciate 

your patience for holding on on the line for the last 20 minutes or so.

Unfortunately as with most things with computers, the problems arise when 

you least expect them. So again we appreciate your patience.

As was said, we're going to start this presentation with a more formal 

discussion of what is in the guidance and that will be followed by a Q&A. So 

I'll be kicking us off for the first couple of slides and then Pam will be 

finishing the presentation. We'd very much appreciate if you could please hold 

your questions until the Q&A session and that'll be an opportunity to have a 

more general discussion.

So just to begin, the co-development guidance was a tri-center effort here at 

the FDA between CDR, the Center for Drugs, CDRH, the Center for Devices, 

and also for CBER, the Center for Biologics. There was a working group that 

convened to draft the guidance and ultimately the subject content for the 

guidance affects all three product centers. As was mentioned, the guidance has 

been published in draft from last month and the open comment period is 

through the middle of October.

So the purpose of today's webinar is to orient you to the guidance and also to 

hopefully facilitate your input onto the guidance as part of the public comment 

period. The webinar is such that given the time constraints, Pam and I will try 
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to limit the formal presentation initially as we - 40 minutes we'll try to gain 

some time there so that we can open up and still retain the full 20 minutes for 

the Q&A as much as possible. So with that, I'll kick us off.

The co-development guidance is the second in a series of guidances in the 

space where both a drug and a diagnostic are being developed together as part 

of a development program. For the purposes of our conversation, we'll likely 

be referring to drug which means both drugs and biologics and then we may 

say test or device which would be in the CDRH realm of the in vitro 

diagnostics. The first in this series was the companion diagnostics guidance,

which was published in final form back in August of 2014, which defines 

ultimately what the definition for companion diagnostic was and when it 

would be appropriate for that guidance to be invoked. Ultimately, it was more 

of a definitional guidance rather than a process one in that it defined what a 

companion diagnostic is, which is ultimately a device that is essential for the 

safety and effective use of the corresponding therapeutic product.

It described the uses of when companion diagnostics could be invoked, which 

is ultimately identifying populations most likely to benefit or most at risk for 

adverse reactions from a therapeutic, to monitor the response to adjust for 

treatment, and also to identify the population for whom the drug would be 

most taken effective for its use. Ultimately, the guidance describes the 

regulatory requirements around labeling as such, but it really was not a how 

to. And that's where the co-development guidance comes into play and that it's 

more of a how do you do a co-development program where both a drug and a 

test are in play. So for next slide.

I'm sorry. Right now we are on slide number six for the folks on the call. So 

for the draft guidance for co-development ultimately it's a how to guidance 

and in general the guidance that we'll walk through as part of the webinar
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presentation will cover the various components that are addressed as part of 

the guidance's content. So next slide, slide seven.

So first off, we're going to just focus on some of the general to orient 

everybody since this may be a new concept or topic area for you. And then 

we'll go through each of the different guidances topics in greater detail. Next 

slide, slide eight.

So ultimately as part of a co-development program what we've seen here at 

the FDA is that the role of the diagnostic as part of the drug development 

program can occur at many different points during that drug development 

paradigm. It could be an intended co-development program from the 

beginning, everything from the preclinical development, early clinical 

development, all the way through the program. But many times, depending on 

the analyte that the test is assessing or the biomarker, the role of that 

biomarker in terms of the product development cycle may not be appreciated 

until after some exploratory studies, especially in the early phases of that drug 

development program.

So as such, co-development is not necessarily intended to be a simultaneous 

development but rather that, once the co-development paradigm has been 

identified that at the time of approval of the drug and the therapeutic that there 

would be a co-approval or a contemporaneous approval such that once the 

therapeutic product and the drug product are then marketed, that both products 

are available to the public at the same time since it's important that they be 

available for healthcare decisions on the part of healthcare providers.

I should mention that the co-development guidance is focused on companion 

diagnostics. With that said, even if a diagnostic doesn't reach this essential 

definition to be called a companion diagnostic, the principles of co-
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development are - would apply even in scenarios where that essential 

threshold has not been met. So it's very much important that as part of a 

therapeutic program that the device is in play that you sort of plan ahead and 

plan in advance even if you're not sure of what the role that biomarker or 

diagnostic is going to ultimately be. Next slide, slide nine.

So let's talk a little bit about some of the co-development clinical trials at a 

very high level. So on slide number ten, when you're doing a co-development 

program not only are you developing the drug and the device, but many times 

the data to support both the drug and the device are occurring from data that's 

gathered as part of a single clinical trial design. Sometimes there's aspects of 

the therapeutic program or for the device program that necessitates sort of 

separate studies that are focused on only one of the two products. So many 

times the data that is collected can be supportive of both the drug and the 

device sort of in tandem.

The considerations as part of the clinical trial design are fairly complex and 

then also dependent upon the nature of the disease and the mechanisms of 

action, etcetera. So there's really no one-size-fits-all, but some of the things

that the product developers would like to consider are the mechanistic 

rationale for selecting the marker that's in play, the nature of the disease and 

whether or not there are other therapeutics that are available, whether or not 

you're moving people away from standard of care, the level of characterization 

and the test negative population and also some prospective retrospective 

analyses. Slide number 11 please.

So ultimately the guidance talks about the process by which a drug and 

diagnostic are co-developed, but it's not a prescription of how to design your 

clinical trial in any great detail. Certainly there are many different trial designs 

that are feasible. Two are listed here. And honestly, there's another guidance 
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in this space called the enrichment strategies guidance that I'll talk about in a 

moment where these different trial designs are discussed in much greater 

detail.

Ultimately when it comes to which trial design best fits your particular 

program is in large part depending upon the knowledge of pathogenesis of the 

disease, the strength of evidence for the biomarker, the biologic plausibility 

and ultimately what the results of that biomarker are leading to, whether it's 

identifying the patient population of interest, adjusting dose, trying to move 

people away from a potential adverse outcome, etcetera. So these are just two 

examples of what a program may look like that's incorporating both a 

therapeutic and a device product. Next slide, slide number 12.

So the enrichment strategies guidance is a draft guidance that's in the process 

of going to final. It was published as draft back in 2012 and we certainly list 

the reference here for your perusal. The purposes of today's seminar is not to 

discuss the enrichment trial guidance in detail but certainly there is content 

there that is very much supportive of what's covered in the co-development 

guidance. Slide number 13.

In terms of retrospective - sorry prospective-retrospective approaches, as part 

of a development program, as I mentioned earlier the role of the biomarker 

may not be fully understood, especially in early phase development. As such, 

it's beneficial if the drug developers at that time end up storing samples or 

tissue that ultimately later could be studied as the role of that marker is further 

elucidated. And as such if you have this - the stored material, you could then 

prospectively design a study to look at that collective information and then see 

what information might be gathered from that, both for the drug and the 

device as that product's co-development continues forward. Next slide 14.
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In terms of trying to identify your patient populations, ultimately you want to 

ensure, to the best extent and that is feasible, that you have an adequate 

representation of the biomarkers within that patient population as part of that 

drug development program. Depending on the mechanism action of the drug 

and the strength of evidence of the biomarker, as we talked about at some of 

the clinical trial designs, you may end up focusing only on marker positive 

patients to a large degree or it may be more prudent to actually look at all 

marker status as part of the trial. And again it's very much context specific. If 

you are going to differentiate based on marker status, determining what the 

cutoff values are between the marker positive and marker negative are going 

to be essential for the interpretation of the clinical trial results, especially from 

the device perspective. Next slide, slide 15. And at this point, I'm going to 

turn it over to Pam who is going to be discussing the aspects of the codevelopment guidance that are more in the device space.

Pamela Bradley: Great. Thank you Chris. I hope everyone can hear me. I'm assuming someone 

will let me know if you can't. Okay so thanks everyone for tuning in today and 

now we'll move on to requirements for investigational products. Okay so in 

co-development programs it's often the case that you have both a therapeutic 

product and IVD that are investigational. And both of these products have 

their distinct requirements so that investigational new drug regulation, at

21CFR312 and the investigational device regulation at 21CFR812. These are 

separate regulations. They're intended to address separate products and 

compliance with one regulation doesn't mean that the other regulation is 

fulfilled. So each regulation needs to be considered in the context of each 

separate product.

And as we've sort of continued down this path towards precision medicine, 

we're seeing more and more of these therapeutic product trials that use 

investigational tests. And so we're hoping that this guidance will help to 
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answer the questions that we're getting frequently. And since these questions 

tend to be about the IVD side of the equation, much of the section of the draft 

guidance is focused on the IVD issues.

So first, what do we mean by investigational IVDs? Well in this context of codevelopment where a therapeutic product or a drug clinical trial uses a test, the 

test would be considered investigational if it was used for a purpose and has 

not already received FDA marketing authorizations for that specific intended 

use. And just so we're all on the same page, I'll point out that the term 

marketing authorization is just an inclusive way of saying that it's been 

approved, clear, or granted a de novo request by FDA.

Okay so you have this investigational test. Now what? Well then the IDE 

requirements would apply. That the regulatory requirements depend on the 

level of risk that investigational IVD presents to study subject. So an 

investigational test can be exempt from IDA regulation or if they're not 

exempt then they fall into one of two categories, either significant risk or nonsignificant risk. And this slide provides an overview of - a very broad 

overview of risk determination. And the first question is: is the test exempt?

And the full criteria for exemption is spelled out in 812.2 but, in short and in 

this context for co-development programs, an investigational IVD would be 

exempt in situations where the testing is not used as a diagnostic procedure 

without confirmation of diagnosis by another medically established diagnostic 

product or procedure. And also to be in this category of exempt, it would have 

to be a non-invasive sampling procedure. So for example, if the test is used for 

exploratory purposes or retrospective analyses using tissue from a routine 

biopsy, that could fall into this exempt category.
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So if the test is not exempt. The next question is, is - does the use of the test in 

the trial pose significant risk to the trial subjects? So again it's spelled out 

fully in 812.3 and the most relevant provision of 812.3 is for co-development 

programs is the quote "is it for use of substantial importance in diagnosing, 

curing, mitigating, or treating disease or otherwise preventing impairment of 

human health and present the potential for serious risks to the health, safety, 

or welfare of a subject." Since you can't see my air quotes.

So the risk comes from using the investigational test for critical medical 

decisions in these trials, decisions like enrolling subject, assigning subjects in 

a trial to a different treatment arm or selecting a particular therapeutic dose for 

a subject. These uses are the ones that could provide - may pose serious risk to 

the health, safety, or welfare of subjects if the test result is incorrect. On the 

other hand, something like balancing the marker across treatment arms based 

on the test result would not be expected to pose significant risk to the study 

subjects. And this is what we call non-significant risk.

I'll just note that risk determination takes into account many other factors 

beyond this simple what is it used for in the trial and may look at disease or 

other aspects, other treatments that are available. And so it's not always a 

straightforward process. And FDA, in attempt to provide more clarity on this,

is intending to put out a draft guidance to explain further this risk 

determination process. But it's not elaborated to very much extent in the codevelopment guidance.

Okay so if an investigational test is significant risk, the sponsor has to comply 

with the IDE requirements again spelled out in 812 and in the guidance. But 

this includes having to submit to the agency an IDE submission. And FDA 

approval is required before the trial can proceed. On the other hand, if it's not 

significant risk, sponsors still have to apply with abbreviated requirements,
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which includes providing the IRB with an explanation for why it's not 

significant risk. But it doesn't - there's no IDE submission in this case.

Okay so co-development trials, they raise unique issues because often you 

have an IVD that's important for meeting the objectives of the trial as it relates 

to the therapeutic product but it's also an investigational IVD. So sometimes 

the information about the IVD is also needed by the therapeutic product 

center. And we've gotten a lot of questions over the years about where should 

the information go and we've tried to clarify that in this draft guidance. So as I 

mentioned, if the investigational IVD is significant risk you need to send FDA 

and IDE submission and that's where the information about the IVD will go.

Putting significant risk IVD information in an IND will not suffice for the IDE 

requirement. So it has to be done in its own IDE. But if the information is also 

necessary - if the IVD information is necessary to determine - for the 

therapeutic product center to determine whether the trial can meet its 

objectives, it may be sufficient for the IND to cross reference the IDE.

And then in the case of non-significant risk, an IDE isn't submitted. So if the 

therapeutic product center needs the IVD information then it may - it will go 

into the IND and there will be a discussion about this with the therapeutic 

product center.

Okay so what information actually goes into this IDE? And here's some of the 

things that we think are generally useful for assessing investigational IVDs in 

co-development programs. You know, obviously these would only be 

included in the IDE if they're relevant for the use of the IVD in the particular 

trial. So we're looking for a description of the IVD cutoff value, a description 

of the pre-analytical and analytical studies that demonstrate the reliability of 
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the assay particularly around the cutoff value. And we're looking for the 

results of these studies as well. 

A description and the results from other analytical studies that support the 

conclusion that the use of the IVD doesn't expose the subjects to unreasonable 

risk of harm. These other studies could be precision or limits of detection or 

specificity, things like that.

And the clinical trial protocol should be included, and this can be done either 

through direct submission or by referencing the appropriate IND. If you're 

referencing an IND, a letter of authorization to cross reference should be 

provided by the therapeutic product sponsor. And examples of letter - of these 

letters are in the appendix.

Okay so moving onto IVD considerations in co-development programs. There 

are two sections, two pretty meaty sections, about this in the draft guidance.

One, the first one is essentially about what to do when you're getting started 

and the major theme here is plan ahead. And the second is about things that 

happen in later stages of co-development programs and how to deal with some 

of the issues that emerge. Okay.

So I'll start by saying what I hope is really obvious and that is, the test is 

important. So if the test isn't reliable or accurate it could compromise the 

ability of the trial to demonstrate an effect on the treatment. It could also 

compromise the ability to determine whether the test can appropriately 

identify the subjects for whom the therapeutic product is intended to provide 

benefit. And we've seen cases of this where the testing was inconsistent and 

the drug was not able to be approved. These are situations we'd like to avoid.

So we provided recommendations in this draft guidance for how to approach 
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co-development programs from an IVD perspective to help avoid some of the 

common problems that we have seen.

Okay so what are these common problems that we've seen? And we've been 

looking at multiple many, many co-development programs over the past 15 

plus years. And here are some of the problems. So the tests are not adequately 

validated prior to use in the trial such that, you know, the test performance is 

not robust enough for the needs of the therapeutic product sponsor. It's also a 

problem when multiple tests with different performance are used in the trials.

This makes it really hard to know how the tests are comparable and whether 

they would identify the same population.

It's also usually a problem when changes are made to the test during trials.

And again here it's hard to know if the changed test would identify the same 

population as the test before it was changed. And then there's a possibility of 

introducing bias from prescreening. So prescreening is what we refer to as the 

practice of using local tests to funnel patients into marker based clinical trials.

One problem is that there's no assurance that local tests are interchangeable or 

standardized. And another problem is that prescreening could result in a 

biased clinical trial population that doesn't actually represent the population 

that would be selected in real world testing. Okay so lots of problems and here 

are some solutions.

Coordinator: This is the operator. Please stand by for today's conference. Pam will be 

rejoining us momentarily. Please continue standing by.

Pamela Bradley: Hello operator?
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Coordinator: And once again this is the operator. We appreciate your patience. We're just 

experiencing some technical difficulties. Please hold on the line. Pam will be 

joining us momentarily. Thank you. You may begin.

Pamela Bradley: Great. Thanks everyone. Sorry. I'm not sure what happened. I hope you can 

hear me now. I think we were just getting to some solutions. So that's the 

important part, not the problem. Okay so an overarching theme here is that the 

test - let's see. Okay everyone can hear me. Great. Overarching theme - the 

test should be analytically validated and it should be locked down before 

using in a clinical trial. It shouldn't be changed during the course of the trial. It 

should be sufficiently analytically robust, particularly around that clinical 

decision point or the cutoff.

And when you're using a test in a trial that's intended to provide the clinical 

validation, it's really important to have completed the analytical validation 

studies that are evaluating those critical performance parameters. And in 

pivotal trials, you should really be using a test with market ready performance.

And in the guidance, we define market ready as a test that's completely 

specified with complete analytical validation and one that meets the 

therapeutic product sponsor's expectations for performance.

So on the next slide, we're listing some additional general recommendations 

for helping to reduce variability and test performance. So all clinical trial 

assays, or CTAs, should be fully specified including all the components, all 

the protocols, all the instrumentation. It's really important to implement a 

single testing protocol at all sites that are involved in the trial. Also, the 

sponsor should evaluate comparability of test results among the potential sites 

prior to initiating testing at those sites.
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And the pre-analytical reagents and instrumentation should be considered to 

be part of the test system and these should be validated along with the IVD.

So, for example, tools or reagents for a DNA extraction should be considered 

to be part of that test and they should be validated as such. Also for all the 

steps of the pre-analytical specimen handling and preparation, there should be 

detailed SOPs or protocols that are followed at each of those sites that perform 

any of these steps so that everybody who is getting you the specimen has

analyzed it in the way that you need it so it's very comparable.

Okay this slide is listing recommendations for how to address that 

prescreening bias, which as I mentioned, it can happen when local screening is 

effectively a prescreen for identifying patients eligible for clinical trials,

where they're only sending forward those patients who are eligible according 

to a local test, and you may be missing patients who would be negative 

according to that local test but have - or might be positive according to the test 

use in the trial. So recommendations: One, avoid enrolling subjects into a trial 

based on confirmation of local test results, if you can.

Two, ask the participating clinical sites to send forth specimens from all 

potential enrollees, not just the ones that were positive by their test. And three, 

when it's unavoidable, which is the case in certain situations and particularly 

in oncology, it's important to be aware of the potential for bias and evaluate 

whether the expected prevalence of the marker is being skewed by 

prescreening and then to develop approaches to address this selection bias.

Okay so the draft guidance also makes the point that it's important to know 

what analytical studies are likely to be necessary to support the IVD 

premarket submission and to plan ahead for those studies. Again: plan ahead, 

plan ahead, plan ahead. So, for example, if the analyte is potentially unstable,

it might be necessary to take several samples. It can be from a small number 
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of clinical trial subjects but that will help you assess the stability. In general 

sponsors should collect and bank adequate samples from the clinical trial to be 

able to complete this full range of analytical studies that they anticipate having 

to do.

But it should be noted that not all analytical validation studies need to be done 

with the clinical trial specimens. But if you are going to do these, you know, 

with non-clinical trial specimens, it's important that the samples are from the 

same target population so we can reduce the chance for variability. And I'll 

also note that for some validation studies, it's possible to do them with 

contrived samples. And this is in cases when it's not possible to obtain the 

specimens for the particular marker, or something like that.

Okay so clearly banking specimens is really critical to being able to fully 

validate this IVD. And sponsors of the therapeutic trial, and Chris mentioned 

this in the beginning, that if you believe there's a need for a companion 

diagnostic or there may be need, then you should have a plan in place for 

banking the samples for future studies. Appendix two in the draft guidance 

goes into a lot of detail about specimen handling and this also includes a lot of 

information about banking specimens.

So here on this slide are just some of the highlights from the appendix. In the 

interest of time, I'll kind of run through these pretty quickly. Bank samples 

from the intent-to-diagnose population, not just the subjects who are enrolled.

Make sure to consider accessibility to samples in foreign countries. It's also 

important to consider the informed consent policies for all uses of the 

samples, for example, making sure that retesting is covered. Thorough 

specimen annotation is needed and it's important to consider how stable the 

analyte is when you're storing those specimens because you may be better off 

storing a purified or extracted analyte.
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Okay so another component that's really critical to successful companion 

diagnostic development is this issue of training versus validation set. Okay so 

the set of clinical samples used to design the IVD and establish that clinical 

decision point or cutoff is referred to as the training set. So testing should be 

conducted with the second set of independent clinical samples to validate that 

the chosen cutoff is the right one. This set is called the validation set. So for 

companion diagnostics, the validation set is generally made up of samples 

from the subjects who were screened for enrollment into that major efficacy 

trial. And for this reason, you really want to have your IVD design and assay 

cutoff established before the IVD is applied to these samples.

Sometimes after seeing the data, the sponsor will want to change the cutoff.

So, for example, they may want to change it to include all of the responders.

The changes are made based on the results from the validation set. Then 

effectively this becomes a new training set for the modified IVD and then the 

new cutoff should be validated with a different independent set of clinical 

samples. So okay.

And we also know that other types of changes might happen as well. They 

could be changes in reagent configurations or instruments or platforms and 

they can also happen pretty late in the IVD development or in the codevelopment program. And so in these cases, to determine whether this new 

test has a very similar performance to the previous test, the sponsor might 

need to do what's called - or typically will need to do what's called a bridging 

study.

So a bridging study is a statistical plan to assess concordance and discordance 

between two tests using the same samples from the clinical trial. So an 

analysis study takes into account discordance, missing samples, and effect on 
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drug efficacy. The retest population really needs to be representative of the 

intended use population for the IVD and it should adequately reflect the 

characteristics that could affect the test performance because reanalysis of the 

trial is potentially biased if this retest population isn't representative. So there 

should be a plan to analyze the worst case scenario for missing data with a 

sensitivity analysis.

Okay so that's lots of general advice and many of you may be wondering how 

to implement this advice in your specific codevelopment program because 

there's always going to be product specific considerations that feed into the 

plan. So our advice is basically: as soon as you know that there is codevelopment intent, use the pre-submission program for feedback about 

specific IVD issues.

So a pre-sub is a formal written request from the sponsor to FDA requesting 

FDA feedback. And it's an opportunity to ask questions and have discussions 

with the IVD review teams about the product development. Questions could 

be related to clinical protocols or analytical studies or the appropriate 

regulatory pathway for the IVD. The co-development draft guidance provides 

some links and additional information about the pre-sub program. And again 

please use this process to come talk to us as early as possible. The goal is 

really for IVD development to be as efficient as possible and not slow down 

the development of the therapeutic product, which is usually further along at 

the point where the IVD gets involved.

Okay so now we're switching gears to go over the recommendations for 

coordinating the review of the IVD and the therapeutic product again with the 

goal of contemporaneous approval. Okay so here are the different submission 

types. You have the new drug application for the drugs, the NDA, the 

biologics license application for the biologics and the companion diagnostic 
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will likely be class three and require a premarket application. But we do have 

information in there about other potential pathways.

The statutory timelines differ for the therapeutic products and the IVDs, but in 

practice the IVD review is going to be kept on track with the therapeutic 

product review timeline so that both products can then come into the market at 

the same time. And in some cases, those therapeutic product timelines are 

shortened even further such as for expedited review or accelerated approval 

and that can create a real crunch on the IVD side of things. But there are some 

things that we do and that the sponsors can do to help out in those cases.

One is IVD priority review. So generally FDA has granted priority review 

status to the companion diagnostic submissions and this is particularly true 

when the companion diagnostic is the first-of-a-kind. Another thing that helps 

is the modular PMA process where - so this is where modules are submitted as 

they are completed and not waiting until all the clinical data is there to submit 

everything as a complete package. So this process basically gives FDA a head 

start in reviewing the IVD and this allows any issues that are found along the 

way to be identified and addressed. The last module that comes in is the 

clinical data and that's basically timed with the start of the review of the drug 

as well.

Okay so with respect to the manufacturing inspection, FDA tries to schedule 

this as early as possible for companion diagnostics so they have time to 

address any findings from those inspections before the deadline. It's really 

helpful for FDA to have this module as early as possible so that all the 

necessary documentation can be in place ahead of the inspection. Okay so 

there's also the BIMO, or bioresearch monitoring, inspections and these are 

the inspections of the clinical investigations. It's extremely helpful for us for 

the FDA if the BIMO information is organized in the PMA either in its own 
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section or somehow identified as BIMO information. And the types of BIMO 

information are detailed in the guidance.

It may also be necessary to set up a master file. For example, maybe the 

therapeutic product company has proprietary information but this information 

is relevant to the IVD review. So in the IVD application, it can reference this 

master file to get to this information. So if you think this is going to be the 

case, it's good to set those up. Likewise, it's good to set up these letters of 

authorization ahead of time or as the products come in so that each one can 

refer to the other. So it's authorizing basically the other applicants to refer to 

the NDA or the BLA or the PMA in support of the other applicant's product.

So again there's some letters examples provided in the appendix.

All right so moving on to labeling. Okay so the draft guidance it reiterates the 

point that was made in the companion diagnostic final guidance that Chris 

mentioned in the beginning and that is that the two labels need to be consistent 

with each other. So as an example, if a drug's indicated for a population that 

has a particular spectrum of gene variants, the companion diagnostic should 

generally be indicated for the detection of all those variants in that spectrum.

The guidance also discusses that there are several types of claims that could 

be generated for a companion diagnostic and that the claims - these claims are 

usually based on how the IVD was used in the major efficacy trial.

First, prediction claims. So a prediction claim would be supported by evidence 

that the benefit accrues to, only to, or primarily to a population that's defined 

by that IVD result, or evidence that serious adverse reactions are confined to 

that population defined by the IVD result. So prediction claims, they require 

information about both test positive and test negative. And so it's not possible 

to support a prediction claim for the IVD if you've only tested the test positive 

- or sorry, if you've only enrolled the test positive or the test negative because 
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you - in these cases you just don't have information about the safety and 

efficacy of the population that's not treated.

So trial designs like that, where only the test positive subjects or only the test 

negative subjects are selected for enrollment in a trial, they typically support 

companion diagnostic claims for patient selection. And then the final category 

of monitoring claims, the guidance really doesn't go into the trial designs 

needed to support this. So you should discuss those types of claims with the 

agency directly.

Okay so the final topic before we open it up for Q&A is post marketing 

considerations and this is short and sweet. The first point I want to make is 

that we recommend that sponsors - therapeutic product sponsors consult with 

FDA when they're designing their post marketing studies that might involve 

companion diagnostics. And then the next point is pretty straightforward,

hopefully. If you - for adverse event reporting, so, report IVD reportable 

events to the IVD center; therapeutic product reportable events to the 

therapeutic product center. And if it's not clear or if both products could have 

contributed to the reportable event, report it to both centers.

Okay so let's sum up here with some key points. Use a clinical trial strategy 

that provides evidence for both the therapeutic product and the IVD. Read the 

enrichment guidance because it goes into much more depth on the trial 

designs that are appropriate for these studies. Interact with the FDA early and 

often. IVD sponsors can use the pre-sub program at any time in the process.

Plan ahead. Collect clinical trial specimens and annotate and store them well

because they will be needed for additional analytical validation studies and 

bridging studies or in the cases of when you're just learning about the 

biomarker, retrospective - perspective retrospective studies as well.
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So the therapeutic product sponsors are encouraged to engage with the IVD 

partner as soon as possible in this process. The trial sponsor should determine 

what the IDE requirements are that apply to the investigational IVD that 

they're using in their trial and fulfill them. It's really important to complete the 

analytical validation studies before using the test in the trial. And it's 

recommended to use the test with market ready performance in the pivotal 

trials.

Okay so I'll end with this complex slide. So even a simplified view of codevelopment, it's really a complex to figure. And I think that's the nature of 

this co-development process because you're trying to weave these two distinct 

processes into one and get across the same finish line. So for IVDs, you need 

to think about whether you need an IDE submission, completing your 

analytical studies before using the test in the trial. You need to validate a new 

version of the test and lock it down again before continuing on. So it’s these 

arrows that are going in and out of this analytical validation studies. And you 

may need a bridging study if the final version that you're putting before the 

FDA is not the same as what was used in the study.

So again use the pre-submission process at any point along this continuum to 

engage with the agency. On the therapeutic product side, it's much more 

linear, at least as compared to IVD development. So there are more regular 

meetings between FDA and the sponsor at the different phases. And these 

meetings are a great time to discuss incorporating the companion diagnostic 

strategy into the therapeutic product development.

Okay so with that, I will remind you that the docket's open until mid-October.

We hope that you'll submit comments and help us finalize this draft. I want to 

point that - point out that although we did a pretty deep - a pretty 

comprehensive walkthrough today that the draft guidance contains a lot of 
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other points that we haven't raised that are also important for successful codevelopment. And so we encourage you to take a deep dive and give us your 

comments on all aspects of the draft guidance that are important to you. Okay 

so thank you for your attention. We'll now turn it over to Q&A and I - we 

have colleagues from the - from all three centers that have been involved in 

this. Other people were involved as well. It was a great group effort. I think 

we can open it up for questions now.

Coordinator: Thank you and to ask a question...

Irene Aihie: Thanks Pamela.

Coordinator: ...at this time please press star one. Please unmute your phone and clearly 

record your name at the prompt. To withdraw your question, please press star 

two. Once again at this time, please press star one to ask a question. One 

moment please for the first question. And we do have questions coming 

through. One moment please. The first question is from (David Rim). Sir your 

line is open.

(David Rimm): Thank you. I have a question. I didn't hear anything about absolute 

measurements. You talked about pre-specified cutoffs but are those cutoff 

values equal to any absolute measurement or is there any stipulation for 

comparison of a pre-specified cutoff to a universal standard?

(Liz): Pam did you hear that one?

Pamela Bradley: (Liz) I was going to let you take that one. Sorry for the silence...
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(Liz): Okay. In that case, I'm not sure I exactly understand the question. So in terms 

of the cutoff, he wants to know how that corresponds with (unintelligible). I'm 

sorry is the questioner still there?

(David Rim): Yes I'm still here. The - I didn't realize the line was open. My - what I mean 

by a standard that is a cutoff could be a plus one or a plus two whereas a 

standard is a micrograms per ml or nanograms per ml, or microgram total 

protein. Some standard that could be reproduced by other sources or 

orthogonal methods, as opposed to an internally agreed upon and arbitrary 

cutoff.

(Liz): Yes so we would expect a cutoff, like plus one or plus two, if it was 

adequately explained how you got to that score. As you probably know, there 

are multiple ways to get to certain scores. We would also assess a cutoff that 

was a quantitative measurement or even a qualitative measurement of positive 

or negative if you had some kind of internal standard for understanding what 

positive and negative was. Does that answer your question?

(David Rim): So there's no reference standard to which these are required. That is, I'm 

concerned then that essentially a test could be analytically validated for 

reproducibility but not for so for precision but not for accuracy.

(Liz): So we would look for validations of accuracy as well as precision around the 

cutoff that you establish.

(David Rim): But accuracy infers that you can obtain the same result by an orthogonal 

method.

(Liz): So for us, accuracy would be in most cases comparisons to a truth, a reference 

method, a clinical manifestation. So we've done a number of these now and 
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this is - has not been an issue. In general, the accuracy ultimately pans out 

clinically by assessing what are the patients be selected actually pass the 

benefit intended. And the accuracy analytically is generally demonstrated 

against samples with a known value, whether that's a qualitative or a 

quantitative value or semi- quantitative.

Irene Aihie: We'll take our next question.

Coordinator: (Mark McCarthy) your line is open.

(Mark McCarthy):Hi. Thanks very much for taking the question. I'm not entirely certain that I 

understand some of the elements of timing and what appears to be an 

involvement of the question regarding the use of a clinical trial assay. The 

agency seems to be saying that the PMA or most of the time it'll be a PMA 

filing for a companion diagnostic will have to be completed but not 

necessarily approved prior to the commencement of the pivotal study for the

therapeutic article. Assuming I've got that right, I'm trying to sort of square 

that with the idea of a clinical trial assay and I’m not aware of any stipulations 

that a CTA cannot be used during the clinical trial. I mean and I don't know if 

the bridging study is how you take the CTA, you know, out to approval. But 

can you at least say a little bit about the question of, you know, having the 

entire PMA file versus having the PMA approved before the commencement 

of the pivotal study and assuming that's the case, where the clinical trial assay 

fits into all this?

Pamela Bradley: Sure. This is Pam. I'll take a first crack and then turn it over to the room. So 

maybe I misspoke but the - you do not have to have a PMA file before you 

start the pivotal study. You - what we hope is that the test that's used in the 

pivotal study has market ready characteristics so that you really understand 

how that test performs. And you mentioned that going from the CTA to the 
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IVD that would be filed as a PMA. That process can be done using the 

bridging study to get from that CTA to the IVD. Does this answer your 

question?

(Mark McCarthy):Okay thank you. Appreciate it.

Christopher Leptak: Operator next question.

Coordinator: Thank you and before we take the next question, as a reminder questions are 

only taken over the phone today. If you'll please press star one to ask a 

question at this time. Our next question is from (Abdel Halene). Your line is 

open.

(Abdel Halene): Sure. Thank you. Actually I have four questions. Do I share all of them at 

once or one by one?

Christopher Leptak: How about prioritize them?

(Abdel Halene): Sure prioritize. All right so for my question slide number four and slide 

number 14, I believe the question is the two points are related. It was 

mentioned that you can enroll marker positive subjects only if the biomarker 

is known to be a predictable prognostic. So does this mean that the biomarker 

clinical qualification has to be done in a prior clinical trial where the clinical 

value is the biomarker can be elucidated and the cutoff can be established?

Mike Pacanowski:Hi. This is Mike Pacanowski. The confidence that a clinical trial can be 

conducted in a marker positive subset locations depends on a number of 

factors. There may be experimental evidence that would suggest only a certain 

subset of patients respond. There may be preliminary evidence from early 

phase clinical trials that suggest differential responses based on biomarker 
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status. So there's a number of different approaches to determine whether or 

not a marker positive trial should be conducted. So it doesn't necessarily rely 

only upon clinical evidence necessarily.

Christopher Leptak: And just to be clear, you had mentioned as part of your question 

qualification. So qualification has a very distinct meaning here at the FDA.

And it involves biomarkers that are developed in a drug independent context 

through the formal biomarker qualification program. And just I'm not sure 

how you're using that term as part of the question but I just wanted to make 

that clarity.

(Abdel Halene): Yes I meant to prove that the biomarker is a predictable prognostic.

Christopher Leptak: So the biomarker development can occur within the IND context or 

through qualification. It wouldn’t have to be qualified in a formal sense for it 

to be used in an IND setting in clinical trial.

(Abdel Halene): All right. So my next high priority question is about the bridging study. So 

there was not too much details but my question is I know it can be case by 

case from FDA perspective. But and as (unintelligible) figure when we do 

bridging study with CTA again this is to be marketed for IVD against the 

CTA, do we reanalyze samples with the CTA also at the time of bridging or 

we consider the initial data? And if we need to re-analyze because probably 

the samples have been aged and we established it can be an issue, what about 

if reanalysis with CTA results can be discarded from the initial results?

Christopher Leptak: Pam do you want to start?

Pamela Bradley: I was going to let (Liz) answer this one.
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Elizabeth Mansfield: So I'm sorry the question was when do you need to the bridging study 

between...

(Abdel Halene): No. The question was if we - in your slide number 30, you mentioned the 

bridging study and I'm assuming you meant bridging of CTA clinical trial and 

assay which is to be marketed IVD. So and it happens most of the time now in 

pharmaceutical (unintelligible). So I’m asking as the final bridging do we test 

- do we need to reanalyze the samples with the CTA or we use the initial

results from the CTA? Because reanalysis sometimes is needed if in the 

stability of the biomarker can be an issue. So the question is do we need to 

reanalyze and fully analyze and the results from reanalysis can be 

(unintelligible) from initial results which is set of samples we use - set of 

results.

Elizabeth Mansfield: Okay. I think I understand your question is do you need to rerun the CTA 

in the bridging assay...

(Abdel Halene): Yes.

(Liz): ...when you're doing the bridging.

(Abdel Halene): Yes.

(Liz): I think it would generally be helpful if you did, but if you didn't have the 

samples or whatever, we can probably work with the original results.

(Abdel Halene): If we prefer to do actually reanalysis because of sample instability, especially 

if the study can take two or more years. So I’m asking - again my second part 

of question, if we reanalyze and we found the reanalysis data is not 

concordant with the initial results, which is it of the CTA results we'll use?
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Elizabeth Mansfield: Well I suspect that would be an internal discussion with the FDA, and I -

generally I think you probably want to use the results from when the samples 

were stable. But often when there's a stability issue, we have other ways to 

deal with bridging studies that don't necessarily use all of the original clinical 

samples.

Christopher Leptak: So we fully acknowledge that depending on when the co-development 

paradigm begins, especially if it's in the early phase, we expect, much like in 

the clinical program, that there's a maturation as you gather information and 

there's more scientific understanding. The same would be true under the buy 

site. So certainly we, you know, as the program moves forward, as it's 

successful and goes into phase three trials, also what we would like at the time 

of the phase three development is that the performance characteristics for the 

device are set and that there as Pam described sort of market ready. How you 

get there I think is a bit of a - there's a flexibility as the assay evolves and if 

there's any issues with stored samples.

(Abdel Halene): All right. Actually my question was for using CR. I’m asking about the 

clinical trial period of clinical trial with where CTT - CTA as (unintelligible) 

of this can be used for it.

Christopher Leptak: Right. So I know you had more questions but we have three other folks 

that are waiting to answer their questions. So if you don't mind, we'll move on

to them. And just so folks know we were originally scheduled to stop at 2:00 

but we're extending it given the technical difficulties earlier. But we do have a 

hard stop at 2:30.

(Abdel Halene): Sure.
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Christopher Leptak: So I guess the next questioner.

Coordinator: Next question from (Eric Thomas). Your line is open.

(Eric Thomas): Hi. I have two questions. One, do you think you could expand a little bit about 

situations when you have a device that's considered non-significant risk and 

information needs to be submitted to the IND instead of an IDE? That's an 

area where it seems to be unclear what's in our company about what level of 

information is really necessary. Often we've submitted and we don't receive a 

response. So we're not entirely sure what the division is looking for there.

That's the first question and then I can ask the second.

Christopher Leptak: Yes that one's hard to discuss in a very - in a general sense. Certainly if the 

device is initially considered to be a non-significant risk device, there are 

circumstances where the drug division would still like to know certain aspects 

about the device's performance in order to be able to interpret the trial from a 

drug perspective. What those characteristics are and when they would be 

required is very much context and case specific. But that information at least 

the way we work it out between the two product centers is that that device 

information could then come in under the IND at the request of the drug 

division and then we can consult with our device colleagues on whatever the 

information is that was submitted.

(Eric Thomas): So if I'm understanding the answer correctly it's really on only if the drug 

division requests that information. So say a risk determination request was put 

in and it comes back NSR. It's then usually generally acceptable then for the 

sponsor just to submit the protocol as per a typical study not including the 

device and just go forward?
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Christopher Leptak: Yes it's hard because an initial qualification for the device may be nonsignificant risk but then as that program development matures something may 

change that classification to a significant risk or potentially. So the important 

thing is to make sure that you capture all the information so that if you do 

require it for the IDE in the future, you have it available. But in the interim, 

submitting it at the request of the direct division to the IND is probably the 

best approach.

(Liz): But if the IND - if they don't request it, you're not required to send it. It's only 

when...

Christopher Leptak: Right...

(Liz): ...the drug division requests it and puts something in the IND (unintelligible).

Christopher Leptak: And maybe (unintelligible)...

(Eric Thomas): (Unintelligible) voluntarily ahead of time and weren't - it's ranged in terms of 

just having a few pages describing the general context of use to actually 

having like full validation. So okay.

Christopher Leptak: Right.

(Eric Thomas): That's really helpful. Thank you. And then my second question is regarding I 

know that the guidance, you know, promulgates using the market ready test in 

the phase three. Some cases - in some cases a test may be implemented in the 

phase three trial and then there are some improvements. Is the agency more 

open now to allowing concordance between two versions of the test if samples 

are being - can - shown to have concordance if they had to make some 

changes between the test employed in the phase three trial initially. Either it's 
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either done all retrospectively in terms of basically bridging between the two 

or having one portion run with one version of the test and the second run with 

the second version.

Pamela Bradley: So I'll start with just clarifying. We don't necessarily mean market ready test 

so much as market ready performance characteristics. And we understand that 

there are changes that happen after the trial is done to go to market.

(Eric Thomas): Okay.

Pamela Bradley: So maybe reagent configurations or things. So you don’t have to have the test 

- the exact test that comes before the agencies and that's so when we say 

market ready I just want to clarify that that doesn't mean market ready test 

packaged up ready to go out.

(Eric Thomas): Okay.

Pamela Bradley: And then for the second part of your question, it's that bridging study. So if 

you do make changes then it's important to just show that the changes haven't 

affected the performance.

(Eric Thomas): Okay.

Pamela Bradley: In the sense of concordance and discordance, you're still very similar in that 

performance.

Christopher Leptak: I mean if you think about the post-marketing setting, we realize 

technology changes and nothing is static that's one of the reasons for the drug 

label that we refer to the device as a FDA approved or a cleared test. We don't 
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list the specific test or model so that that way there is this opportunity for 

innovation improvement in the future.

(Eric Thomas): Okay. And well thank you very much both of you answers are really helpful.

If - well I don't - I know there's another speaker. If also if you had any 

information to clarify about differences between complementary and 

companion diagnostics because complementary is a relatively new 

classification I'd appreciate hearing anything you guys have to offer on that.

But I don't want to take the rest of the time as well. So thank you.

Christopher Leptak: Yes I think in the interest of time since that's a little bit off topic let's move 

onto the next questioner please.

Coordinator: The next question from (George Popper). Your line is open.

(George Popper): Thank you very much. So I have a question with respect to the next generation 

sequencing based IVDs. The recent draft guidance on the use of standards for 

the NGS based IVDs is restricted only to germ line diseases or variance. And 

I’m wondering for those cases where IVD devices are intended as a 

companion diagnostic for a somatic disease, what kind of guidance can CDRH

do with respect to data standards?

Pamela Bradley: (Liz) do you want to take this one since it's NGS...

(Liz): Yes. This is (Liz). At the moment we have not published any guidance or draft 

guidance on that. We have held a public meeting on it where I think a lot of 

principles were elucidated. At this time, I would suggest that the test 

developer would talk with OIR through the pre-submission process to get that 

information.
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(George Popper): Okay great.

(Liz): You can do that. Okay.

(George Popper): Thanks.

Christopher Leptak: And operator last question I guess.

Coordinator: Last question from (Julie Engel). Your line is open.

(Julie Engel): Hi. Thank you for taking my question. I just had a question about the use of 

RUOs in the clinical program. It sounds like there's flexibility in using those if 

they are labeled properly and if they are - if you plan to commercialize them 

then you would have to under - they would have to undergo the design control 

process. What about the use of class one assays in this same context? Would 

the same issues of labeling and validation apply or can they not be used in a 

clinical program?

(Liz): So this is (Liz). I don't think there would be any issue with using a class one 

device in a co-development context. Unfortunately, we haven't identified any 

case of - or maybe fortunately we haven't identified any cases in codevelopment where the device would have been considered class one. If such 

a thing were to happen, if we had not already classified the test I think we 

would have to go through the de novo classification process. In order to 

classify it as class one if we had already classified the test and then 

(unintelligible) class one, well I think we'd have to think about what we would 

do then in terms of how we would be able to refer to that test in labeling.

(Julie Engel): Okay thank you. I also had a second part of that question. We talk about if the 

possibility of a 510(k) or a de novo and the labeling of that would that also 
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include the therapeutic in those labels or just the device in the therapeutic 

label but not the therapeutic in the device label?

(Liz): Generally it's our intent for a companion diagnostic to mention the therapeutic 

name in the device label as well as the device name in the therapeutic...

(Julie Engel): Okay. That makes sense.

(Liz): ...or for the existence of the device in the therapeutic one.

(Julie Engel): Okay thank you which makes sense. It just wasn't clear in the guidance. Thank 

you.

Christopher Leptak: All right well thank you everyone for sticking with us especially with the 

technical difficulties early on. Hopefully this was helpful to you. And again 

just to echo Pam's earlier comments, please if you have any comments please 

upload them into the public docket and those comments will be considered as 

we move the guidance to final in the future.

Coordinator: And we will now turn the meeting back over to Irene Aihie for closing 

remarks at this time.

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 line web page at www.fda.gov/training/cdrhlearn by 

Friday, August 26. Please submit draft guidance related comments to docket 

number FDA-2016-D-1703 by October 13, 2016. The docket can be found at 

www.federalregister.gov/A/2016-16735. If you have additional questions 

about the draft guidance document, please use the contact information 
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provided at the end of the slide presentation. As always, we appreciate your 

feedback and this concludes today's webinar.

Coordinator: Thank you for attending today's presentation. This does conclude the 

conference. You may disconnect at this time.

END