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Our session and our first speaker is Alan Wookey, the Vice President's Companion Diagnostic and Oncology from IQVIA Laboratories and he is going to remind us of the role of the labs in precision medicine.
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Alan, please.
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OK, thanks.
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Thanks for the introduction.
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Want to thank Oxford Global for inviting us along here today.
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This really is the gold standard event for biomarkers and companion diagnostics.
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And part of a motivation for coming and speaking to you guys today is really around the role of the central lab in the companion diagnostic landscape often forgotten.
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We hear many presentations about partnership between pharmaceutical companies and diagnostic companies, but there's often a lab that provides all this testing and the landscape we work in now that it's often a global lab that requires testing in US, Europe and China as a minimum.
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And the other thing I'd say is a lot of sort of case examples I'm going to describe today are around immunohistochemistry.
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Some of the technologies will be discussed, but immunohistochemistry has sort of stood the test of time and companion diagnostics in part because it's a well tested technology.
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But when it's approved for reimbursements, it's reimbursed at a relatively low expense.
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So just two slides on the corporate.
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So who's IQVIA laboratory?
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So today's a big day for our company because we would we were Q2 Solutions which is a joint venture between Quest largest reference lab the United States and Quintiles the CRO.
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And over the course of time Q2 Solutions bought various companies including rules based medicine, which are here today.
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But as today we're rebranded as IQVIA Laboratories and we're part of the big IQVIA CRO with the big IQVIA data analytics company, more than 80,000 people globally.
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The lab piece we're about 5500 people and we probably have about 30 or 40 dedicated to companion diagnostics.
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In terms of global footprints, this is a footprint of all the labs.
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These aren't just the CDx labs.
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We don't have that many CDx labs, but these are the labs that we provide central safety testing, bioanalytical biomarker testing across the globe.
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The all sort of mission statements, it's you know, it's to be the best if we can.
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Companion diagnostic programmes are extremely complex and no two are the same.
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But the sort of the text on the right sort of describes some of the critical success factors or critical success criteria that we regard as being important to deliver these programmes successfully.
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So we talk really is just to provide a very brief landscape.
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I don't want to insult your intelligence by telling you what a companion diagnostic is.
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Talk through what our experiences, what we've seen, what works, what doesn't work.
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And it would be remissive me not to touch on some of the regulatory frameworks, particularly the final rule in the US and IVDR in Europe.
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Sort of key summarise those key success factors that we've had with successful CDx programmes and then think about the future in terms of CDx.
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A companion diagnostic very simply is an assay that's going to be required for before a therapy is given.
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And because companion diagnostics in clinical development are investigative, they're not approved until they are approved.
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They command the highest bar in terms of regulatory scrutiny and accordingly global central labs have had to build a structure to be able to adhere to that regulatory scrutiny.
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I go back 22 years and I'm probably older than most of you here.
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This was proper patients on the top there.
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And the question to the clinical development team when I was working in the pharmaceutical industry is what was the underlying reason that patient got a, you know, a favourable response to tyrosine kinase inhibitor at the time.
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And it was elucidated that it was EGFR mutation was a predictive mark of a response.
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And the two sentinel papers still in my mind today are the two most important papers to come out for precision medicine came out simultaneously in 2004, describing EGFR mutation as being predictive for response.
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We're a lot smarter as an industry now because we do plan and we're proactive.
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20 odd years ago we were a little bit reactive.
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So we're in a much better place than we were then.
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But it was a good example and part of the reason I got involved in this space in terms of what companion diagnostics are and what they're not.
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So many precision medicine biomarkers may go on and be a companion diagnostic, but many won't.
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Some of the historical biomarkers like ER and PR are on precision medicine markers, but they were never approved as companion diagnostics.
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So there's many markers that are and many that aren't.
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But precision medicine is sorry, companion diagnostic is just one way of enabling precision medicine.
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That's the point of that slide.
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And then in terms of just want to go through these slides in terms of what's really important from a central lab perspective.
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And some of the key things that we deem is really important is around partnership.
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And what we've done at our lab is to ensure that for all the major IVD partners that we have, they've qualified our laboratories so that when and CDx opportunity comes around, we're not starting from scratch.
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They're confident with the proficiency, the certification and qualifications of the personnel at those labs.
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And we've run over 180 companion diagnostic studies.
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Majority of them have been with those IVD partners and we've supported them in the US, Europe and China and our Singapore labs.
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And out of all those 180, there's a lot of attrition, but we did, we were part of seven successful approvals.
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And I'll talk about a couple of them shortly.
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In terms of our CDx footprint, we have 5 CDx labs and they're part of our central labs and they're in the West and East Coast of the US, Edinburgh, Scotland, Beijing and Singapore.
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And the capabilities we support are immunohistochemistry, FISH, NGS, et cetera.
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The normal things you'd expect the lab to support.
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Bottom left point is quite important around ISO13485 and how we addressed IVDR because we're not a healthcare institute.
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The lab is not in a hospital and it's not treating patients directly within the institute.
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So we had to circumvent a healthcare status by developing a quality management system to ISO13485.
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And that means as a lab in Europe now we're able to support clinical trial assays or lab developed tests of a terminology you want to use top right.
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Again, this is another really important piece around pathology.
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So in the space of oncology and the majority of precision medicines is oncology, but it's critical.
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I think one of the speakers mentioned it before about lack of pathologists.
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What we've done is really spent a lot of time and effort in building up a pathology set of individuals and we've, I think we've got probably 35 pathologists now and they're all on the company books.
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These aren't consultant pathologists and they are able to support companion diagnostic project from a reading down the microscope.
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The IHC, the FISH may be doing some digital pathology now, but also acting as principal investigators for the assay for many of their programmes.
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And we, you know, we've been part of some nice what it's what makes the job, you know, worth doing.
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We're part of some nice success stories and a couple of them with Keytruda and Regeneron's Libtayo, we've been part of.
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Just in terms of technology.
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And I mentioned AP is IHC, I should have highlighted that, but that circle on the left is changing and it's becoming more in from a central lab perspective, we're doing a lot more AP than we are genomics and molecular.
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And I think part of the reason that genomics is sort of tapered off a little bit from the central lab is that there's a lot of local testing done now.
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So the reliance on central lab is not as great.
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And also the turn around time for genomic assays are largely more than the five day sort of, you know, industry standard that's required at clinical sites to get patients in.
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So apologise for the acronyms at the bottom right on the X axis there.
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But basically Q Beijing is our China lab.
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And indeed a big portion of what we do as a US organisation, UK organisation is work in China to support companion diagnostics.
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And then it would be remiss of me not to mention PDL 1 testing.
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We've just recently reached a milestone of over 100,000 tested in clinical trials with the two dominant clones and all the indications in the in on the right hand side of the indications, we've either verified as a CDx or validated off from the IFU on the assay.
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So it covered most the tumour indications that we encounter in clinical development.
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And although historically a lot of these were, you know, Keytruda for example, was single agents, a lot of it's in combination now with other agents.
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So these tests are still happening time and time again in clinical trials and our organisation we see many of these over the course of time, but not just CDx.
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Just wanted to start with you on with PDL 1 and this is just this was a programme that we were involved with.
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It was the Merck Keytruda PDL 1 testing and although as a lab we don't have line of sight for commercial, what's going to happen in the commercial setting.
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But this is a tale of two very similar therapies.
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And indeed Opdivo was launched in non small cell before Keytruda.
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Keytruda sales were much greater than the than Opdivo’s.
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And in part, I'm not saying the whole reason, but in part he truly developed the therapy in companion with a companion diagnostic assay, whereas Opdivo was developed the complementary, not companion assay.
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So complementary path is exactly the same path as a companion, but it doesn't sit on the drug label as a mandatory testing requirements.
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So that was, you know, a nice example of a CDx helping drive therapeutic adoption case.
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This next case study was a partnership we had with Regeneron and an Agilent.
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So Agilent's the IPD company that made the assays.
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And we did a three-way relationship to enable successful companion diagnostic development.
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And I'll show you in a couple of slides the fruits of our labour.
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This was a tremendously complex study, but it demonstrates that central lab can work in not just one technology which was PDL 1 which was the CDx assay, but the standard of care assays, ROS, ALK, and EGFR were required.
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And it was testament to the pathology network we had and the net and the global labs that we got 1200 of these done in a year and 95% of them were in a five day turn around for the four assays.
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And that was a requirement, that was a specific requirement from the pharmaceutical sponsor that you had to have five day turn around.
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They were concerned that the at clinical sites there was competition for their therapy with other therapies.
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So as a lab, we had to turn that round in five days.
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And the majority of the time we do, if we don't tend to be 5 days turn around, it tends to be, the reason tends to be is because the sample's poor or there's incorrect labelling and we got to go have a project manager go back to site and chase that.
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But these next three slides very briefly describe when we sat out was on this programme, what were the key critical success factors for the pharmaceutical company, the lab and the IVD company.
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And they're all very different, but sitting around and appreciating each other's concerns.
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Let's go back.
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That's the lab and that's the that's that was Regeneron.
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These were aligned so that we worked as a team and worked as a, you know, a tripartite partnership to for, you know, for success.
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And I'll highlight one of them on there was one of the big things in pharma.
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And in my experience, one of the biggest weaknesses is regulatory knowledge and support.
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And that was one of the key things that the pharma sponsor asked of the lab was to, you know, to provide that.
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So that's, that was the sort of key success factors for the three companies.
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And at the end of it was a really nice story because at the end of it, on the same day the FDA approved the therapy and the assay that was a true co-development.
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And that assay is now it was 22C3 PDL 1.
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One clone from Agilent is now on the market.
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It's on the Regeneron therapeutic label as being a test required before that agency is prescribed in for non small cell lung cancer.
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Third case example I just wanted to highlight was the importance of a global anatomical pathology footprints and this references some work we did with the cloud in 18 IHC assay.
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Just one slide on this, but the bottom left in order to do these samples in the five days turn around and it and during the clinical trial, we used 17 in house pathologists to score those samples for nearly 2500 tissue samples we got in into our labs.
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And the other nice thing about this was the biomarker frequency which says 36% were positive.
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We were told at the start of the study to expect 35% positive.
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So it was a nice little QC that we've done a, you know, a good job on that and used for global testing labs in the US, Singapore, China and Europe to do that.
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And there last case example I wanted to just to mention was to show you that majority of CDxs are 1 assay.
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This is a 2 assay CDx that we were asked, we were tasked to do from a pharmaceutical company.
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And it put, the other complexity of this was it wasn't tissue, it was bone marrow aspirate.
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And so we had to do CD38 enrichments for the cells and then do the FISH 1116 assay and the BCL 2 molecular assay.
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So CDx is not just changing technology, but changing complexity in terms of the number of markers.
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Let's go just two slides on the people who deliver this work without a proper decent operational delivery group, this doesn't happen.
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And this is, you know, these are the activities that go into a into making sure first place first CDx patients in cannot afford that to miss or that's a slip.
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So there's two things that really make that work that time we have to have alignment with the IVD companies to come to the labs to train, provide proficiency and also from to provide the IUO reagents that are going to be used to support the CDx.
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If that doesn't happen, then that time will slip.
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And I think when you're doing your own CDx programmes, nothing else you've listened to me today that to me is they're critical.
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You've got to have alignment with your IVD companies.
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That's so that the lab is not the root cause of my first patients in my slip.
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And then the typical team members, you know, we have, I mentioned the principal investigators, we have study coordinators, they're responsible for the regulatory binder, they're responsible for liaison with the IVD partners when they come on site.
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Obviously project management and set up management to develop the database for the assays sort of in Europe.
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It would be remiss of me not to mention some of the regulations and I'll just give you, I've described them from a central lab perspective because regulatory is complicated enough.
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But without we know IVDR and the FDA final rule.
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And for those Europeans here that the FDA final rule is the FDA historically allowed the development of lab developed tests and they exhibited what was called enforcement discretion.
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So they didn't regulate the LDTs and that's going to change now under the final rule.
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So in essence what IVDR and what the FTA have done is if there's any sort of positivity from these changes is it should harmonise to a great deal.
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And what we've done at our organisation is provide the sort of most rudimentary regulatory services to support clinical trial assays or LDTs as they're described there.
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But more importantly, you know, this IVDR sort of thing that's been foisted upon us within our lab with IQVIA Labs.
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And we have the lab in Edinburgh, Scotland.
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In the last 12 months, we've had over 500 requests into the lab to ask about is the assay IVDR compliant, doesn't need to be IVDR compliant.
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How do we make it IVDR compliant and in on almost every question is different.
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So it's very difficult to template responses for IVDR requests.
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But what we've done at the organisation is we have a team behind the scenes that deal with IVDR requirements and hopefully they can sort of de risk some of the assays including CDx assays that go into these clinical development programmes.
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And the way we've approached it at the central lab is around difference between early and late stage.
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So early stage clinical trials, non-registrational trials, we can validate an assay and as long as we follow these criteria here, then we can under our quality management system, ISO 13485, we can perform CTA assays for patient selection and for patient management decisions.
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With regard to sort of late phase registration studies, our position and the position of our IVD partners is that the burden falls on the IVD partner, not the lab.
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And the IVD sponsor is responsible for ensuring IVD our compliance with the assay.
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And as a central lab, they are our, that's what we do.
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A big part of what we do is ensuring we have Ethics Committee approval for global studies in Singapore, China, Europe and US.
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But so the burden in no studies.
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And the majority of the studies I've described to you today are indeed, you know, registrational studies.
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And then just in terms of our regulatory directors, you just put this together just to say these are the tests used for medical decisions.
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These are the types, the classifications of tests that we've used.
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Anything from a CE marked assay, that's that can continue.
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It's use down to test for, you know, for performance studies.
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And indeed the one at #5 is probably the most common one that we see as a global central lab.
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And then just, I know we've run out of time.
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We've got just a couple of minutes on some of the IVDR challenges, and I'll leave these slides with you.
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But these are what we've seen as a central lab and what some of the mitigations we don't have answers for many of those issues and what the impacts are on particularly patients and study timelines that I think everybody would admit that IVDR has providers with challenges in terms of timelines and making sure patients get onto clinical trials at the right time.
22:02
And then just in terms of development path and often as a central lab, we get asked, well, what's the difference between an IVD CDx development and a lab developed test developments and what we tried to do there, they sort of list the sort of characteristics of an LDT or a clinical trial assay versus a traditional IVD CDx.
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And some development programmes will want a lab developed test.
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They might not want to make that big investment.
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I think it was described this morning, 5 to $20 million of investment for an IVD CDx a lab developed test can offer a significant attractive option from a business perspective.
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But the big limitation of the LDT is it's one lab and if you're going to distribute at the end of the day, you've got to have a plan to make that assay distributed.
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So just in terms of some sort of future predictions, we are expecting to use, and we do it our facility digital pathology, especially with the advent of the antibody drug conjugates where internalisation of the agents in the cells is key and having assays that are sensitive enough to pick up markers within cells, not just on cells.
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There's going to be key.
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There's been no flow cytometry CDx has approved to date.
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We have some nice relationships, especially one with Becton Dickinson to get CDx flow in into mainstream.
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I've sort of run out of time, but key success factors to me, big one is partnership at the bottom, anatomical pathologist globally and having a presence in China.
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Probably the three key ones for me and I'll finish them on that slide on partnership, which describes the central lab as a big part of a companion of diagnostics developments.
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Thanks for your time.