0:01
There's been some really wonderful talks over the last couple of days.
0:04
I was talking about emerging biomarkers and challenges that we face in relation to seeing those right through to use in clinical trials and hopefully right through to market and approval.
0:16
And what I hope to cover in the next 20 minutes or so are some considerations when it comes to deploying some of these assays into clinical testing.
0:26
And I want to share with you some of our experience of what we think are important things to plan ahead for your biomarker programmes.
0:33
So for those of you that may not be familiar with us Almac Diagnostics are a precision medicine company and we specialise in biomarker driven clinical trials.
0:46
So some of you may be familiar with us more for our kind of biomarker discovery type activity.
0:52
So we have three main kind of services that we'll offer.
0:55
The first would be genomic services.
0:56
So this is really high throughput data generation.
0:59
So I know a lot of colleagues that we've been speaking to today work closely with us in their biomarker discovery programmes, but maybe less familiar with us in relation to our clinical trial solutions offering.
1:11
I'm from the assay development and validation team.
1:13
So our team is responsible for the development of assays for use in clinical trials and taking those right through to CDx programmes.
1:22
As part of that we also have our cap and clia credited clinical test and laboratories and we'll work with our clinical testing team to transfer across all of the devices that we've been developing for deployment in global clinical trials.
1:35
So that gives a whistle stop tour of the different services that we offer.
1:40
This is the marketing side, but it basically highlights, I suppose the key values of what we think are important and when we're working with our clients.
1:47
So obviously there's the quality of the data and very much when we're working on these programmes, we really like to take a collaborative approach in relation to partnering with you, in relation to your biomarker development and validation.
2:00
But the bit I'm actually going to focus on is more the flexibility angle.
2:04
We've heard so much over the last day of emerging biomarkers, the challenges with technologies, regulatory pathways.
2:12
And I suppose for this, it's the ability to be flexible is really key in relation to making sure that we can provide solutions for clinical trials and adapt that evolving biomarker.
2:24
So with this in mind, this, I've just given it an overview of the many platforms that we offer in Almac diagnostics.
2:33
So we have the whole suite of NGS platforms, the same for qPCR, we have IHC from all of the major suppliers along with digital pathology and pathology services.
2:47
So really it's trying to cover the wide area that you would need to support your biomarker needs.
2:53
And if anything, this is something that we constantly evolve.
2:57
We would work with some of our partners that when they've got new technologies or biomarkers coming through, we'll work hand in hand with them to onboard new technologies and make sure that we can provide them with a solution of actually deploying them in a clinical trial setting.
3:11
So along with that, we've been doing interventional clinical trials for 15 years.
3:16
So we have all of the associated kind of accreditations that one would expect for clinical trial use.
3:20
So that would be clear CAP accreditations, ISO15189, our manufacturing certifications or permits.
3:27
So we're fully kind of laid out for actual delivery of global clinical trials.
3:34
But as I've mentioned, I'm from assay development & validation.
3:36
So I'm very much going to focus on this for today's talk, and I want to focus specifically on the custom assay development and validation.
3:45
Now we've been talking with some of the colleagues throughout the conference in relation to what type of assay can be used.
3:55
And we certainly can take the likes of an off the shelf assay, bring that into Almac and on board that under our quality management system and validate that for use in a clinical trial setting.
4:05
So that's something which we can offer kind of a standard, but we also have a custom assay development & validation.
4:11
And this is really for a scenario when the really isn't a product out there that you could use easily.
4:16
And in these instances we can build an assay for you from scratch.
4:21
There's a couple of reasons why would you want that?
4:24
So sometimes it'll be that maybe your gene of interest just does not represent it on a panel.
4:29
This is particularly relevant if you're not in the oncology space.
4:32
And we've seen an awful lot of adoption of precision medicine-based approaches more in the chronic disease area.
4:38
Or it could be that those panels have challenges in relation to operational delivery.
4:43
If you're only interested in one or two genes, why are you using all of that sequencing capacity just for exploratory purposes?
4:50
So maybe it's a case of us having an assay that we developed that has smaller content and we can deliver with a faster turnaround time or even it could be a driver from a technical perspective of you need an assay that's that bit more sensitive than what's on the market.
5:02
So in relation to your custom solutions, we'll do this across platforms.
5:08
You'll see we do brand ourselves as platform agnostic and very much pride ourselves on offering what is the most technically appropriate solution for our partners.
5:17
So when we're working at the very initial stages of scoping out an option, it'll be making sure that we offer to you what we think is most technically appropriate because that's what you need for your biomarker programmes.
5:28
So we're not biassed by particular platforms.
5:32
So we'll offer this flexibility.
5:34
And I think an important thing which we find because we deal with trials from very early stage, from phase one right through to phase three registrational trials, there can be a need even to adapt your platform choice and mature that assay as you move from phase one to phase two.
5:51
And because often the biomarkers in a phase one will hope to be refined to be smaller, to be able to be on a platform which has maybe a better install base, cheaper test perhaps.
6:03
So again, it's something that we can help navigate your assay to mature that from phase one through to phase three.
6:11
Obviously for this, if you're working in a clinical trial or even in a prototype CDX setting, we have all of the associated partnership agreements and supply agreements to make sure that you have continuity for all of your programmes.
6:23
And very much when it comes to the custom side of things, we're building a tailored solution to meet your biomarker needs.
6:29
And so it's not that you're having to adopt on and lend your biomarker to what is an existing, we'll build something for scratch for you, for your specific intended use.
6:38
So all of the assays that we develop which are investigational use or indeed prototypes, CDxs will all follow product development road map.
6:47
For those of you and that are familiar with this field, this is basically hanging off the structure of your design control and risk management process.
6:53
So you have your planning phase.
6:55
And this is really what I've just talked about is offering the most appropriate technical solution to meet your needs.
7:02
But as well, building this in relation to your regulatory strategy and making sure that those design features are coming into your product development.
7:11
We'll do all the development activities.
7:13
And again, when you would say assay development, I think a lot of people from my job title, a lot of people would assume the wet lab piece.
7:19
But when you're talking about an assay, it's not just the wet lab laboratory process.
7:23
It's tagging on to that, the manufacturer of controls, having those in a format that potentially is capable if we're into complex kind of genetics area, it's building a bioinformatics pipeline, validating that to the sufficient level and potentially kind of having that packaged in the form of a software that could be easily used in a clinical setting.
7:45
We do all of the analytical validation and again, all of this is done in compliance with design control and risk management procedures.
7:51
And then finally, we'll author all of the technical documentation for regulatory submissions and be responsible for all those interactions.
7:58
We like, I don't know if any of you attended the sessions on an IVDR, but we like all of the other providers have updated all of our technical documentation to make that IVDR compliant.
8:09
And then finally this assay then will get deployed.
8:12
And I suppose why there it's an IUO assay or a CDx, they have to follow the same fundamental principles.
8:17
It's just on a different scale really.
8:19
And in this instance we'll be deploying across into our clinical testing laboratories.
8:25
So the talk I was going to give was on how do you plan for success for clinical trials.
8:33
So what are the considerations when it comes to developing an investigational use clinical trial assay?
8:39
And I suppose for this, it's not just the building blocks of building an assay, it's really considering and working with in partnership with our clients for their programme needs because it can be dictated by things such as what phase of trial are you at?
8:56
Because the asset that I would build for a phase one trial may look radically different from an assay that I would intend to use in a phase three registrational trial.
9:04
Sometimes it can be the maturity of the biomarker.
9:07
So it can be.
9:08
And I think this is really key that for any of these programmes, it's important that the actual validity of your biomarker in its own right shouldn't be compromised.
9:15
So in a phase one trial, that might mean deploying something which is extremely complex and by no means without easily flow in relation to kind of marketing approval.
9:26
There may not be the install base, there may be challenges.
9:28
But if that's the most appropriate biomarker at the time, that's what you should be using in your phase one trial and not being afraid to kind of navigate the maturity of that biomarker assay to complement kind of the maturity of your biomarker in itself.
9:41
So sometimes we all have quite complex NGS based biomarkers, maybe with an AI component on them that we're deploying in phase one trials.
9:49
But with the idea that as more clinical evidence is generated that we're trying to refine that down into an assay that will really lend itself better for market access.
9:57
So that could be a smaller gene panel on a qPCR installed base that really would lend itself to kind of market approval and uptake can also be budget.
10:08
And I think this is really important.
10:10
We would work with a range of everyone from kind of small biotech companies to large pharma.
10:15
And the budget is a big consideration and it's very much linked to kind of appetite for risk in many ways as well.
10:23
So you could go into phase one trial with a prototype CDx assay, but that's going to cost you a lot of money.
10:30
Whereas it is perfectly acceptable to go into an early trial with a really robust assay, which has been validated to be compliant with IVDR and it's fit for its intended use.
10:41
And that you can defer that investment until later in your pipeline when you know if your drug is going to be successful because you can't invest that budget on every single biomarker programme from the beginning.
10:52
So it's not being afraid to navigate that and I think you can really only do that when you're working with a partner that will work and navigate that pathway with you.
10:59
And then finally this goes that leads to my point of regulatory strategy and having that in mind.
11:05
So take home message from the start of this is basically we've talked about, you know, the right biomarker for the right patients at the right time.
11:13
And for me the extension of that is the assay, having the right assay for your biomarker at the right time and not being afraid that may look different in a phase one versus a later stage in the programme.
11:23
So I'm going to go into some of the actual considerations of the building blocks.
11:27
So these are all of the things that we would have to consider when we're building an assay for my team, we can do everything.
11:34
We can provide every one of these pieces of the jigsaw.
11:37
So if you want, you can come to us with a biomarker without any assay developed and we'll build all of this from scratch for you and to meet your intended use.
11:45
Alternatively, sometimes we'll have where you have a decent assay that you've already been using maybe in a preclinical setting.
11:51
And those instances, we can also tech transfer that in and do those additional development pieces that are required to make that applicable for use in an investigational setting.
12:00
So I'm going to, I'll not go through these in great detail, but these are just some of the things that to consider.
12:05
So things just as your sample type and that could be even in relation to selecting the appropriate blood collection tubes and their availability in different jurisdictions and things or challenges in relation to logistics of a sample types, which are not particularly stable.
12:23
I talked a little bit about the custom assay design.
12:25
So again, we can develop these across all of our different platforms and these can be tailored to your needs.
12:30
And I suppose for that bit, this is an area which would allow you to have lock in early kind of continuity that you could potentially take the same design of the assay through to a later stage trial without having to reinvent the wheel.
12:44
We also do our control manufacturer and again, we can do custom design for these.
12:48
We can also take sometimes off the shelf solutions.
12:50
And again, it's something to be aware of that often in the early trials, if you've got a complex signature, sometimes the manufacturing of the control can be a challenge and there's a requirement you need a control span on that clinical decision point in clinical testing.
13:04
But you can't have that.
13:05
And it's maybe challenging to have that in a kitted format that you would have in a box that you're going to have for a distributed kit.
13:10
But if anything, we have kind of sometimes been used in like selling models in relation to manufacturing those for use in a clinical trial.
13:19
They're robustly kind of manufactured and they allow us to control for the assay during the trial.
13:23
But it's good, it allows us more time to be able to build a kitable control at a later stage.
13:29
And again, we have our manufacturing standards and to do all this.
13:32
A big one is the reagents.
13:34
And this is something that you do you select an RUO reagent or do you need a Dx or do we need to OEM reagent from a supplier and start to build you a prototype IVD kit.
13:44
And again, this is something that there's a big cost difference here and it's having an understanding of that investment and really being aware of what risks are you really mitigating.
13:55
So with all of our assays, we can take in an RUO assay.
14:00
We'll bring that under our quality management system.
14:02
We'll define the manufacturing release instructions and us Almac will take responsibility under our ISO1345 accreditation to test that and release that for use in the clinical labs.
14:12
So we can provide a fit for purpose solution for trial use using audible reagents and really the having the OEMDX version of those is something which arguably is only more important at a later stage.
14:26
And there's ways of even kind of having a combination approach where maybe you have custom assay design so that you know that will go with your biomarker programme from phase one to phase three.
14:36
But potentially some of the accessory parts of that process, maybe you're using RUO reagents initially and then moving across to Dx versions at a later stage.
14:46
We talked about the range of platforms we have and again we would make sure that we select the most technically appropriate platform for your intended use.
14:54
But obviously depends on what stage your biomarker programme is.
14:58
We do need to start looking at the commercial side of our team in relation to installed bases of those platforms and all of the different jurisdictions that you would intend to have and do market in your device and making sure that we tailor a solution to meet that.
15:13
But you can see that there's not a right solution.
15:15
It's about having the right solution for the at the right time of your biomarker life cycle.
15:21
We would have our own kind of bioinformatics and software development team as well.
15:25
So for some of these complex assays, why there they be AI algorithms or machine learning based techniques or us building something from scratch, we build all of these and we'll validate those for use in the clinical trial setting.
15:38
All of this for our trials, we usually deploy software which we would validate under IEC62304 for use in clinical trials.
15:47
And really this takes out any potential use of user error when it comes to delivering this in a trial setting.
15:53
Final bit is the analytical bit.
15:54
So obviously making sure that we do that analytical validation to support that intended use.
15:58
This is one that's become a little bit more of a hot topic with IVDR of it because as with a lot of the guidance, they don't tell you explicitly which AB studies you need to do.
16:08
And it's about making sure that you can justify the scale and scope of analytical validation based on the intended use.
16:13
So that could be anything from full CLSI compliance to something which is more in compliant to kind of your CAP type of requirements for analytical validation.
16:25
But we can take all of these pieces together and build them into your product for use in clinical trials.
16:31
And what I'm going to do is talk you through because this is all very theoretical.
16:35
And I wanted to talk you through kind of an example of a product that we've done this for.
16:39
In this instance, this was a product that was at a later stage, and it is for like a prototype IVD and we were using this in a clinical trial setting.
16:47
So some of those key factors we built that into the decision making of the pros of our product.
16:52
So the requirements that we got from our sponsor was that we wanted it was to be used in a phase two, phase 2B trial in MASH.
17:01
And this trial is going to have 150 global sites including sites going to be developing an assay for PNPLA3 germline mutation from peripheral blood.
17:15
And we also had an exploratory assay for buccal samples and they needed a turn around time of seven days.
17:22
So I'm not going to go through, I think we've discussed enough the different considerations.
17:26
I'm not going to go through these in detail, but I'll take out one or two that I think are important.
17:31
First one would be in relation to your custom designs.
17:34
And while it's, this is a very simplistic idea, you can't get much simpler than a germline genotype and assay, but it's making sure you do the small things right in relation to assay design.
17:43
So in this instance for this particular gene, there's a Novel-LINE-1 insertion, which if you don't take us into consideration when you're designing your assays that can impact the false results from your assay.
17:56
So again, for all of our custom designs, we made sure that we designed this to be downstream of this line 1 insertion and then performed all of the accuracy and development studies to prove that and that assay wasn't being impacted.
18:09
The next one I want to go on to is in relation to kind of selection of instrumentation.
18:14
Obviously we selected IVD collection tubes and extraction kits for this.
18:20
But when it came to the platform we selected the Quantstudio 5 Dx and we developed our own software.
18:27
But these are the exposed reasons why.
18:28
So they we chose the Quantstudio 5 Dx because it was globally registered instrument.
18:34
There was an intention that they would this was to seek market approval globally.
18:38
So it was important to have a platform that had that reach.
18:41
So this is US-IVD,CE-IVD and NMPA certified.
18:46
Interesting thing of anyone who's using the Quantstudio 5Dx will be said, but it has online genotype and call.
18:52
And why did you set up your own?
18:54
And I suppose this is a consideration for when you're dealing with a research based scenario versus a clinical trial.
18:59
So the algorithms that they would have on board the instrument work perfectly well when you're running kind of larger batches, but the algorithm struggles with single sample batches and you can get undetermined calls basically.
19:10
So and in a clinical trial setting, you have to make sure that assay is robust if you're running one sample or if you're running 20.
19:17
So for this, we developed our own off instrument custom software and we had fixed thresholds as you can see here for genotype calling.
19:27
And we set these thresholds to account for any instrument bias.
19:30
So we intend to deploy this across 3 clinical testing sites and also for reagent lot bias and all of the drivers that could potentially have an impact on performance.
19:38
And then we validated the software and deployed this across three sites.
19:42
We then performed the validation and again, this was across the three clinical testing sites.
19:47
So Almac has two CAP CLIA and ISO1589 accredited laboratories, one is based in Craigavon in Northern Ireland and the other is in Durham in North Carolina.
19:59
We were able to do all of the global clinical testing with the exception of China.
20:03
And for the client China testing, we partnered with an accredited lab to deliver the assay.
20:09
So we manufactured this assay was developed in a kit format.
20:14
So we manufactured our genotyping kits that are UK headquarters and then we shipped these to the US and China labs.
20:20
We did the training and tech transfer of these studies and then we performed the analytical validation under design control and in compliance risk management across each one of the sites.
20:30
And this is a really important factor is that we ensured that we had a single set of analytical performance claims across each of the labs.
20:36
It was really important that we took this overarching approach because what you don't want to have is that you have different analytical claims on each site.
20:43
So we did this to establish the assay robustness.
20:47
We also then went through all of the regulatory side of things IDE,CE marking, CPS applications under IVDR and Chinese ethics approval.
20:57
The one thing I wanted I suppose at the end because the proof of this is in the performance of the device.
21:02
I haven't invested in the design.
21:04
And for this we did monthly kind of lab director reviews of the KPIs for the trial.
21:09
We had quarterly on-site monitoring to every one of our clinical sites including China and US and the UK sites.
21:16
And of the 2,500 samples that we tested, 98.9% met CLIA turnaround time and 99.2 had a valid result.
21:26
So the performance in relation to the robustness of that assay speaks in relation to how well it ran in the clinical trial and that ultimately is what we're trying to do here.
21:34
So I know I'm just up on time.
21:36
I'm going to finish then up with just my summary of, I suppose what are the key considerations when you're developing an assay from my side, it's just plan ahead and really engage with your clinical trial solutions provider early.
21:48
Talk to them about budgets, timelines, risks, map them out and have all of those options so that you're going in with your eyes open in relation to the decisions you're making.
21:56
Make sure you adopt a fit for purpose solution and maybe don't invest too early if you don't have to and if need be, map out that road map if you're from IUO to credential IVD and make sure that aligns with that regulatory strategy.
22:10
So collaboration is the take home message.
22:13
So thank you so much for your time and I'm very happy to take any questions.