Designing For Success: Your Guide Through Early Phase Translational Studies

Good afternoon everyone.

Thank you for the lovely introduction.

I am Bethany Montgomery, a technology lead from ARC Regulatory and today I'm going to be giving a presentation on designing for success navigating early phase translational medicine studies.

So for those who are not familiar with ARC, here's just a brief introduction.

We are Belfast based consultancy that supports the development of precision medicine through regulatory expertise and clinical evidence generation.

We specialise in vitro and companion diagnostics, helping developers design, validate assays, navigate regularity pathways and generate data for approval.

And you can see here we have our bespoke lab facility and it's basically there to care to anyone's needs.

We have a range of technologies which I'll go through later.

So imagine this scenario, you've got your drug developed, you've got your clinical plan in place, so you know the patient population that you're going to treat, you know the treatment duration, how many patients, etcetera.

And also you've got your biomarker selected.

So you know what the biomarker is for treatment enrolment or for treatment efficacy, for example.

But what's the next step?

Where do we go from here?

Well, the next step is planning your IBD study and the first step of that is your lab selection.

So we conducted primary market research, talking to all our sponsors and clients trying to see where the pitfalls were when they were coming to select their labs.

And these are just some of the common pinpoints that we identified.

The some of the labs just had a lack of understanding when it came to regulated design control and ISO13485 compliance.

Some of them maybe had limited experience with IVDR, so they were unwilling to support and study monitoring, or they had inconsistent project management, misleading timelines poor communications, and that all led to deviations or delays in timelines.

Not only that, one of the most surprising things we found was a lot of central testing labs just weren't interested in the early phase studies.

And that's because patient populations were low and often enrolment was slow.

So they're only really interested when it came to the commercialization at the end.

Not only that, but there are a lot of technology gaps.

So a lot of labs didn't offer a lot of assays which people needed, such as immune histochemistry, ELISA, or NGS.

So when it comes to your lab selection, you really got 2 routes to go.

You have your local testing, which is usually at the point of care.

So your hospitals or clinics or you've got your central testing and that can either be a health institution or CRO.

When it comes to local testing, although they may have faster timelines when it comes to generating data, they often risk variability when it comes to methods and data quality.

Your central testing, it's it has consistency in regularity conformance, but that usually comes at a higher cost.

When it comes to central testing, well, you pick a health institution or CRO.

They both need to conform to the following requirements.

They all need to have a QMS in place to ensure documentation and traceability purposes.

They need to have technical expertise.

They need people in the lab who know how to perform the assay correctly.

They need the capacity and resources.

So they need to be able to meet your demands when it comes to project timelines and patient numbers.

Also regulatory expertise, ensuring that they adhere to IVDR and GCP and also a willingness to support monitoring.

One of our top tips when it comes to selecting a lab is actually go and visit your site.

Make sure they've got all these requirements in place because the last thing you want to do is start your study, realise there's gaps and then have to restart by selecting another lab.

This all leads to delays in getting your drug to market.

Before I move on, I just want to talk about the health institution exemption.

Now IVDR was brought in especially to help with patients to make sure that they their safety was paramount when it came to performing tests which were to be used with the diagnostics or for treatment plans.

And under IVDR Article 5(5), a health institution, which is really an institution which is involved in the diagnostics or treatment of a patient, is able to manufacture or use a device which is not CE marked.

So essentially, they can bypass the IVDR submission and just go straight to the study.

What that means for pharma is that you can get accelerated project timelines.

So it means you don't have to go through the laborious process of submitting your PSA or performance study application.

And that leads to reduced cost because that means you can get your drug to market much faster, and the timeline is much shorter.

It also leads to enhanced flexibility, meaning you're able to adapt your test throughout for specific client or patient needs and also greater innovation through internal development and novel diagnostics.

Now for gold standard of a health institution lab, there's lots of labs out there, but not every lab can be considered a health institution.

For a lab be considered a health institution, they must meet the requirements under Article 5(5).

So they need to have things like QMS in place, document traceability, et cetera.

And they also need to be considered a health institution under the national competent authority.

They also need to have maintained rigorous quality and regulatory standards, including your ISO13485 for your quality, your 14971 and 15189 or for CAP CLIA if you’re in America.

What's interesting about this is that if you go for the health institution route, the way we sort of work it is we've, we make sure that we've got our documentation in place so that should the health institution exemption change in the coming years, you're easily able to pivot to a performance study application should you require it.

So what we find with performance study applications, it is quite a laborious process and time consuming process.

And what we've seen is it can take up to 14 months to get your study application approved.

We've been looking at ways to try and minimise this timeline so ways we can improve this.

And one of the ways we find is launching our ARC 360 Copilot, which is a Copilot which assists in all the regulatory documentation you may require for your submissions.

And what we find is we're able to reduce timelines, accelerate time for approval and reduce burden for pharma companies.

Not only that equates to lots of savings when it comes to getting your drug to market much faster.

Now the bit that I enjoy your assay validation is your next part.

So when it comes to planning your assay validation again a lot of documentation is still required.

So whether you're going for your pre-market approval or your IVDR submission, the validation is has to be very rigorous.

You need up to a 13 point validation.

The current CLIA framework, which is a four point validation process just fall shorts of that.

So what we think is that the CLSI guidelines which offers a much more structured approach to your validation process because it actually helps with your study design depending on what assay you're wanting to validate, your statistical rigour and acceptance criteria.

And what that essentially means is the comprehensive validation package that you develop will minimise your duplication and accelerate your regulatory compliance.

But the gold standard approach to your assay validation, it's important to make your validation customizable to your assay type.

So whether it's qualitative or quantitative depends on what validation points you select.

Actually designating a technology lead to see the product through from start to finish.

Making sure that your client has input across the full validation piece, as well as making sure you're compliant with clear IVDR and your CLSI guidelines and making sure your documentation is robust.

That is one key things when it comes to having this and because that again makes a seamless transition should you have to go to your performance study approval.

And again here we've got listed all the technological documentation that you may require for your submission, but this list is not extensive.

Again, this depends on your assay type.

So as I mentioned CLIA have got a four point validation process.

So you've got your precision, your accuracy, your reference interval and your reporting range.

But when it comes to science, there's a lot more parameters that can actually affect your study design.

Some of them are just listed here, which we find to be quite, you know, non-negotiable.

So you've got things like robustness, ruggedness, specificity, sample preparation.

All these parameters have an impact when it comes to how well your assay performs.

And so when it comes to the gold standard verification or validation, we make sure that we include all of these.

So just to put this into practise, I just want to demonstrate how we recently performed a Claudin18 validation study.

So the first part of this was actually choosing the marker.

So what was the actual need for demonstrating Claudin18 within our lab?

So Claudin18 is expressed AS2 isoforms.

You have your Claudin18.1 or 18.2. 18.2 is expressed in gastric cancer and it's also emerging as the second most important marker in gastric cancer next to HER2.

It's also gone unmet need.

So this disease area is classified as a rare disease in the US, and it's often diagnosed due to nonspecific symptoms.

So symptoms that are being recognised for maybe other more common disease areas and being investigated first.

And therefore there's a delay in diagnosis.

And we see here that 62% of people here are diagnosed are at an advanced stage with a 6% survival after five years.

And what's interesting is that 70% of people who have advanced stage cancer express the Claudin18.2 marker.

So when Ventana released this Claudin18 assay, which is the first FDA approved IHC companion diagnostic, we jumped at it.

We were going, we're getting this into our lab.

And the real purpose of this is to identify patients who are likely to benefit from Claudin18.2 targeted therapies, therefore improving their survival.

We then went on to our experimental design.

So we wanted to plan this as robustly as possible.

We first identified our sample type, so we wanted to get a representative population.

Therefore we got our gastric carcinoma slides.

We also needed a negative, a known negative expressor.

So we got our healthy tonsil tissue in.

We also got in a tissue microarray.

So that was for a specific study, which is essentially a microarray, which is a slide that has tissues of either healthy from various parts of the body or from different cancer types.

We then set our instrumentation.

So we got in the Ventana Benchmark Ultra Plus, an automated staining platform, which is supported by our DP200 digital pathology scanner.

We also got two of those in because we wanted to make sure that it didn't matter which machine was being used.

We could do that in our instrument variability study.

When it came to the reagents, we wanted to ensure that there was no difference between different antibodies lots.

So we at least tested 2 antibody lots.

And we ensured that all the bulk fluids and detection kits, hemotoxin and bluing agents were all qualified prior to use.

We wanted to do interoperator variability, so we got at least two trained scientists who were trained on both instrumentation as well as the acid procedure.

And we onboarded 2 qualified pathologists to interpret the data to ensure there was no bias when it came to sending the slides off for interpretation.

So these are the results.

I'm only going to be talking about a few of these things.

There's quite a lot to go through, but we can pick out accuracy.

So for accuracy and precision, we did three different studies.

We did a between day study, a between instrument study and an interoperator study.

And you can see here the results on figure one for inter day and inter instrument.

And you can see here that it didn't matter on what day the assay performed or on what instrument, the results were the same.

It was almost identical staining patterns and the interoperator assessments was also it was also factored in.

So we got 2 scientists to perform the exact same assay, and we got the same results.

The next one was specimen specificity, which we can see here in Figure 2.

And that was our TMA slide, which has all the different various tissue types.

And it passed because we got no unexpected staining.

So all the slides we expected to be positive were positive and all the ones that were expected to be negative were negative.

The final one is inner observer variability.

So again, we've got our two pathologists to assess the exact same sides, and we found that they gave the exact same reporting for both sides.

And I'm pleased to say that assay has been fully validated and is ready for use within our labs.

So what's next?

So we again want to look at markers which are really new, really relevant to the market.

So C-Met is a newly approved, you know, May 2025 and it is used to support treatment decisions for non small cell lung cancer patients with high C-Met expression.

We brought in HER2 as well.

So HER2, although it's not a new marker, the FDA label expansion now includes a previously unmet population of HER2 ultra-low expression.

So again, opening the door for new treatment opportunities as well as PD-L1, which is another marker for non-small cell lung cancer, again, which is used to aid in the treatment for or detecting ones for treatment.

And our bespoke facility is equipped for other clients’ specific assets and platforms should it be required.

And just a final bit about the ARC Labs and the services we offer.

So our core technologies, as I mentioned, we've got immunohistochemistry, which I've just gone through for gold standard platform with Ventana Ultra Plus and again, supported by our DP200 digital pathology scanner.

We also have qPCR.

Again, we've got multiple manufacturer platforms available.

And we've also got our automated DNA and RNA extraction platforms.

We do ELISA, so single Multiplex platforms.

And we are now introducing our NGS, which will be available in November 2025.

And again, we've got our lab capacity to introduce any other assays should the client require a specific one.

And again, I just wanted to highlight about the health institution.

So we've been designated a health institution under Article 5(5), which basically means that we are able to offer faster project timelines at reduced cost, enhanced flexibility to adapt tests and therefore greater innovation for our clients.

But just because we operate as a health institution doesn't mean we make our quality any less rigorous.

We've still conformed to our GCP and GLP.

We are ISO 2916 and CAP CLIA.

We also conformed all these other ISOs which are compliant for assay development validation as well as ISO 13485 for our quality management.

So we've got a booth here, Booth 28.

So if anyone is of interest and would like to come to us, the invitation is there.

And I'm here with some of my colleagues today.

So I just wanted to say thank you very much for listening and open to any questions.