0:51
Thank you very much.
0:52
I'm going to skip through the legal slide here.
0:57
The way I've sort of organised this session is very practically.
1:01
So what I'm going to do is talk a little bit about CDx models with you.
1:05
I'm going to talk a little bit at a high level on the US and EU regulatory framework.
1:10
And then I'm going to talk about a little bit of the tools that we've developed within CellCarta to classify a number of assays as we think through what are the requirements for validation, what are the requirements for quality regulatory as we work through the process of clinical trials all the way through to a companion diagnostic.
1:27
And then I'm going to give you some very practical information around FDA and IVDR.
1:32
So we've been submitting things to health authorities in Europe for just over 2 years now as an organisation.
1:38
And so we have some practical learnings that I'll share with you and I'll present them a bit on the slide.
1:44
So you have a sense of what we've gone through.
1:47
So I know everybody knows this, so I'm not going to read you the definition here, but I'm going to spend the majority of my time today talking about clinical trial assays and the framework to get from a clinical trial assay to a CDx.
1:59
I'll spend less time on the approval process of a CDx and more time around how we actually work through that process.
2:07
I want to start with a framework for companion diagnostics and so on.
2:12
The top is a traditional pathway.
2:14
So think about a kitted IVD manufacturer like a Roche or a Ventana or Abbott.
2:21
They have instruments, they have kitted assays and those are deployed in a variety of different clinical trial settings.
2:29
We don't operate in that business.
2:31
We're a CellCarta lab based business.
2:32
So I want to talk about the bottom two a little bit with you.
2:36
The first is a single site.
2:37
So when we think about bringing an assay to the market, the traditional sense of putting it on a kitted instrument and distributing it is one path forward.
2:46
Perhaps a smaller more narrow path is the single site model, which is applicable to both Europe and the US and in that it may make more sense if you've got a rare disease, a small patient population where you're not going to have high volumes of assays being tested for patients.
3:02
It's another alternative.
3:03
It tends to be a little bit faster, a little bit less expensive because of some of the differences in the development processes between the top two.
3:11
I would say what's become most interesting recently as we've developed that model is this hybrid model where as you go through clinical development, you might have a series of clinical trial assays that have the potential to be a companion diagnostic, but you're uncertain.
3:25
And so there's risk associated with a full investment in a kitted assay.
3:30
And so often times we'll work with sponsors who come to us and say, I've got an assay.
3:34
I'm not exactly sure it's a valuable assay to take forward to a companion diagnostic.
3:39
We'd like to look at it in an exploratory sense.
3:41
And if it proves to be valuable, then we may take it to the market or it might be a candidate for a companion diagnostic.
3:48
So we spend a lot of time, I would say, in this hybrid model.
3:51
And I'll show you the sort of points of departure from that in just a moment.
3:56
But it's helpful if you think about this to sort of de risk your portfolio when you're uncertain about the number of assays that you might be taking forward in the value proposition as a companion diagnostic, very simplistic framework.
4:08
But here, what I'm just trying to illustrate is as we go through the development process and we start to deploy an assay, let's say we're using it for an exploratory purpose in a clinical trial and you're trying to develop this sense of would it be viable in let's say a patient selection or determining a risk profile for a patient.
4:24
Once that's determined and your patient population is large, we sort of have this different path we can take.
4:29
We can certainly take it all the way to a companion diagnostic.
4:32
But often times what clients want us to do is to transfer that assay to another diagnostic manufacturer because the patient population sort of demands that it's on an instrument and it's a kitted assay.
4:42
So we sort of provide both of these pathways.
4:45
We also have a number of circumstances where clients come to us and say for the first indication, I want it to be a single site assay.
4:51
But soon after as I look at follow on indications, the population will be so large, we won't be able to keep it in a single site model and we'll begin to transfer even post approval.
5:02
What do you need to make this happen?
5:04
You certainly need to have a very strong partnerships with manufacturers like Roche, like Ventana, many others, Agilent.
5:12
I need to have a team of people who can navigate the regulatory nuances as you work through this process from early stage development all the way through a companion diagnostic.
5:21
And what's been very helpful is to have a global footprint because trials are often run in the US, Europe and China.
5:26
And so having that global footprint is certainly very helpful in this process.
5:31
Another very high-level framework, but often times there are questions that come up around, you know, what are the FDA processes and what are some of the European processes from?
5:39
How do we classify an assay, whether it's a Class 2 or a Class 3 assay, which is really where we would fit for a companion diagnostic or a Class C under IVDR.
5:51
I'm going to spend the majority of my time today on those second two bullet points both on the US and Europe talking about how do we deal with the clinical trial assay as it progresses through development and how would we take it to the market.
6:04
And then I won't spend much time on post marketing surveillance and some of the things that happened post approval.
6:11
I put this model up because we developed this within CellCarta.
6:14
We often had many questions around how do we look at assays?
6:18
What are the requirements associated with those assays?
6:20
And so what you see from this is a perspective of the assay as it's used in the clinical trial.
6:26
So don't think of the clinical trial itself, but how is this assay used in a clinical trial?
6:30
And this is basically an intended use framework.
6:33
So off to the left.
6:34
I'll touch on this, but I'll spend most of my time on discovery through the CDX portion of it.
6:40
The first one is really what a manufacturer comes to us and says we need your help in developing data that's useful for their label as they bring an assay to the market.
6:48
And so we're not doing any of the regulatory work.
6:50
We're just simply serving as a laboratory in a larger study for a kitted assay manufacturer.
6:57
If you look at 2 through 7 from discovery through companion diagnostic, what we've put behind each one of these pillars is a sense of how do we validate the assay.
7:08
What are the quality control measurements or QA deliverables that go behind each one of these assays?
7:14
And what are the regulatory deliverables that go behind each one of these assays?
7:18
And that's really helpful as we sit down with sponsors and talk about, you know, what's the difference of what we deliver from an exploratory perspective all the way through to a companion diagnostic.
7:27
Below you have a sort of quality framework that we built within the company that addresses the sort of quality deliverables that you would need or the system that you would need for each one of those.
7:38
If I think about a companion diagnostic, in our experience as a company, often what you see is a lot of these assays are IHC or genomics-based assays.
7:46
They typically start out in an exploratory purpose in a sense.
7:50
So we might be deploying them in a as an exploratory purpose in a clinical trial for the sponsor to get familiar with the assay, the value proposition of that as a potential companion diagnostic.
8:00
And then it skips from exploratory into either 6 or 7, which is I either know it's not, but I need it for patient selection or I know it needs to be.
8:09
And then I need to pursue a path of companion diagnostic.
8:12
And what's behind six and seven are typically a lot more deliverables from a QA perspective.
8:17
Think about design control, think about how we qualify vendors, think about all the submissions that need to go in from an IVDR or an FDA perspective.
8:25
So this gives us a little bit of a framework that we can sit down with clients and talk about exactly what's necessary from a delivery perspective for that assay and what things we're going to do from a quality and regulatory point of view to deliver that assay.
8:41
Over the last two years, when we sort of set out on this journey of creating this framework within our company to support a companion diagnostic in a single site model, 1 of the things that we did that I thought might be helpful for you to know is we unified our entire quality system across the company.
8:57
And we did that through master control.
9:00
The reason I point this out on the slide is that as you think about your system going from early stage into a companion diagnostic, you need to have some sense of how the quality pieces integrate, whether it's an event, a Kappa, the things that you would normally incur as you move through development, how you qualify your suppliers, particularly if you're going into a companion diagnostic development is all the design and development deliverables.
9:22
So think about a model where either we have to take it to commercialisation as a single site model, or if we're in a situation where we need to transfer it to another manufacturer, they want to see that it was run under design control.
9:35
So we've built that framework in and then there are all the regulatory deliverables and I'll touch on some of those in just a moment.
9:41
But think of the IVDR submission, some of the submissions that need to go into FDA.
9:45
We built all of that within a about a two-year span and then qualify two of our sites to be companion diagnostic manufacturing sites, one in Europe in Antwerp and the second in the US near Chicago.
9:57
And our notified body in this case is BSI, so FDA investigational device exemption metrics.
10:08
So we as a company have submitted a number of risk determinations to FDA.
10:14
So I'm going to take the next couple of slides.
10:16
I'm going to talk a little bit about FDA and then I'm going to compare and contrast a little bit around IVDR.
10:22
So you may recognise that there are two ways to submit when you're going through clinical trials in the US, you need to determine especially if your assay has risk to patients.
10:31
So think about, you know, is there a decision that's being made on your result that will determine the therapy, whether they get it, whether they don't get it, what their dose exposure is.
10:39
All of those are risks that you have to clear with the FDA.
10:42
And there's two paths forward.
10:44
One is through an IRB and the second is through FDA directly either to do that risk determination or acceptable approaches.
10:51
I will tell you that over the last two years, I think we've made one IRB submission because most sponsors would prefer that we submit directly to FDA in part because if there's a risk associated, they just want to hear from FDA directly because then FDA has some of the data that will ultimately get leveraged in the later part of that application should it go for approval.
11:10
The majority of what we typically get and the diagnostic area are non-significant risk determination.
11:16
So you can see of the 21 submissions we've made over the last two years, 20 have been non-significant risk and one has been significant risk requiring us to file an IDE with FDA.
11:27
And I would say the last point on here is also really instrumental.
11:30
We rarely encounter this, but there are occasions where the sample for the diagnostic actually drives a risk determination.
11:37
So I think if a patient needed a bone marrow biopsy where otherwise it wouldn't be standard of care, it would drive a significant risk and FDA would require us to file an IDE.
11:48
I want to just highlight some FDA statistics here on accelerated approval.
11:54
Over the last several years, there have been 64 accelerated approvals for therapeutics requiring a companion diagnostic.
12:00
And then if you look at some of the stats related to single sites, you're seeing about 50 that have been approved over the last five or six years, which is pretty significant, not of course as big as the number of assays that are placed on kitted instruments.
12:15
However, it's a viable approach and it's certainly one that FDA is very familiar with and it's getting more attention again, and particularly in rare diseases or small patient population sample sizes.
12:29
I want to turn over a little bit to the EU and talk a little bit about what some of the deliverables are.
12:35
So again, think back to this clinical trial assay that you need to manage.
12:41
The criteria for whether IVDR applies or doesn't in Europe is related to whether or not there's a health decision that's made from that assay.
12:49
So if it's exploratory in nature and we're gathering data, IVDR doesn't apply.
12:54
If we are making a decision about whether a patient is enrolled in a trial or not enrolled or receives a certain dose or there's a dose escalation as a result of that, IVDR applies.
13:03
So the most simplistic way to think about it is the result of my assay driving a decision, a health decision during that clinical trial, IVDR that applies.
13:12
And these are some of the documents that we need to put together as an organisation to satisfy those requirements.
13:18
And we've done a number of these.
13:19
I'll talk about the stats in just a moment.
13:22
But whether it's an investigator brochure, the general safety performance requirements, the performance plan of that assay in the clinical trial, and you can see the list here, information for use, especially if it's an assay that we develop, we have to develop our own IFU as part of that application process.
13:43
I wanted to give you a sense of the timeline.
13:45
We're often asked, you know, what is the timeline associated with some of these submissions?
13:49
And of course, this is a general timeline.
13:52
Every project can vary a little bit.
13:54
So it's a bit of a general framework.
13:56
So we think about the left-hand side, how long does it take to validate the assay or generate that data?
14:01
Somewhere between three and four months on average, but I put some flags in there to for you to see what are some of the IVDR milestones and other milestones necessary to bring this thing forward and actually clear the IVDR process.
14:13
So you've got the application itself.
14:15
We talked about some of the documentation on the previous slide.
14:18
You've got Ethics Committee submissions that are required in Europe.
14:20
You've got IRB submissions perhaps that are required.
14:23
And then the package itself that needs to be submitted.
14:26
The first few pieces that usually the EC approval and the IRB approval happen relatively quickly, somewhere in the first 30 to 60 days and then the IVDR package is typically a four month process.
14:39
I would say, and I'll comment on this a little bit more later, but the metrics around the approval process have been improving over the last year.
14:46
I think the first year of IVDR was more of a challenge as health authorities and industry was preparing and getting used to the submission process.
14:55
I think a lot of that has been ironed out now and we're starting to see more accelerated timelines for some of the IVDR packages.
15:02
And of course, the status right now in Europe is that we have to submit these to every health authority.
15:06
So there's not a centralised way for us to submit.
15:09
So when we submit a package, we submit a country by country, wherever those clinical trial sites are being run.
15:16
This gives you a sense of just some of our submission activity over the last two years.
15:21
We put together a number of packages as you can see, and you can see on the chart where we've actually submitted to.
15:28
So we have a number of submissions across a variety of different countries.
15:32
We put together over 25 clinical performance packages.
15:36
And you can imagine depending on the scope of the study, that could be 1 country or 10 or 20 countries for each individual package.
15:42
So when you're looking at the stats, think about one package goes to many countries or one, it depends on the structure of the clinical trial by the sponsor, lessons learned.
15:56
What have we learned over the last two years with IVDR?
15:59
I think there was a very strong focus on the regulation, what we needed technically to submit in those packages, those core packages that go to regulatory authorities, lots of effort around that.
16:11
But the things that are maybe less documented are how does each agency receive those packages going to be by e-mail?
16:17
Does it have to be in paper?
16:18
Is there electronic portal?
16:20
Do they want the EC submission before the IVDR submission?
16:23
Can it be done simultaneously?
16:25
Some countries ask for paper certifications, so somebody has to sign a declaration.
16:30
In some cases that's got to be an ink.
16:32
I only raise these because every one of those little missteps causes a week, two- week, a three-week delay.
16:37
And you can imagine on the pharma side, they're looking at, you know, nobody gives regulatory extra time in the schedule.
16:43
So you've got to get to an end point very fast because the approval of that IVDR package is the gatekeeper for when that trial starts in a particular country.
16:55
So just a summary before I go to the last slide on FDA and the final rule.
17:01
The only thing I would say here is that there is a tremendous amount of collaboration between the manufacturer or the developer of that assay and the sponsor really understanding the clinical trial framework where they're going, what that means strategically country by country when those filings need to go in to hit the timelines for first patient in.
17:21
So it's not just about the core technical package, it's also about all the nuances and individual documents required for each individual country.
17:28
And I think that's the main point I would make here.
17:31
And the learnings aren't necessarily that I'm sharing well publicised.
17:34
So it's your own experience and collecting all of those data that really help you navigate.
17:39
My last slide before I open up to questions is just I wanted to spend a moment on this final rule by FDA.
17:45
We often get questions around, you know, what does it mean?
17:48
And for those of you who have followed this topic in the US, this started many years ago with the VALID Act.
17:54
And FDA was hoping that Congress would act at the end of 2022 and pass the VALID act and restructure the framework in the US similar to what's happened under IVDR that didn't occur.
18:04
And so FDA has long had a position on assays, commercial assays that exist in the US marketplace of enforcement discretion.
18:12
So they've allowed laboratories and hospitals and many other places to produce testing and then offer that commercially.
18:18
That era is now ending.
18:20
So people talk about LDTs, but really the LDT process in the US is coming to a close.
18:25
And really FDA's position is on this for a long time has been that those create a significant risk to the population.
18:31
So you might have some laboratories that have great quality systems, great scientists that are delivering great quality product and results to the marketplace, but you also have the other end of the spectrum and it wasn't being policed very well.
18:44
And so this was their answer to the lack of Congressional act was to remove the enforcement discretion and take these products off the market within a four year period of time based on a risk based approach.
18:55
Part of the reason we built the systems that we did is because we wanted to make sure we were prepared for this when FDA took action, which they did.
19:02
So the things that are on your quality systems, making sure you're compliant with FDA requirements Part 820 or the 13485 ISO requirements were absolutely essential for us to continue to not just develop things during development, but also to if we needed to launch something, it had to be launched in a way that was sanctioned by FDA, not in an LDT sort of fashion.
19:23
With that, I will open it up for questions.
19:25
Thank you.