Aleks: [00:00:00] Welcome Digital Pathology Trailblazers. In today’s episode, my guest is a pathologist, Monika Lamba, who is working for Q Square Solutions, the lab division of IQVIA. And we are going to be talking about digital pathology in clinical trials today. Clinical trials is actually the reason why digital pathology exists today.
In the late 1980s, Dr. Weinstein invented the telepathology solution to be able to get a second opinion for bladder cancer cases in a clinical trial that was not going so well because of discrepancies in diagnostics. And so welcome Monica to the podcast. How are you today?
Monika: I’m good Aleksandra. Thank you so much for the invitation to the podcast and I look forward to speaking to you here.
Aleks: I am so honored to have you here. Let’s start with you. Let’s start with. Telling the listeners about your background and your involvement in a [00:01:00] clinical trials. And then we can dive into the topic of what digital pathology does for clinical trials.
Monika: I am presently working at, I’m a pathologist scientist by training and I am presently working for Q Square solutions which is of IQVIA.
Now IQVIA, as is one of the largest clinical trial research organizations in the world and offers a range of clinical services for research. And it has a network footprint all over the globe. So I work at their Edinburgh site as the scientific director of pathology. I oversee clinical trials, provide pathology input for acid development, and importantly right now I’m in the process of integrating digital pathology and image analysis rates for the clinical trials.
So that is what I’m doing right now and have been working in the clinical trial space for quite some time now. Previously with Selkarta in [00:02:00] Belgium and now with Q Square Solutions here at Edinburgh. As far as your question regarding, how I joined this this space of clinical trials or how I’m working as a pathologist in clinical trials and how did this come about?
I think after finishing my residency in pathology, I was interested in oncopathology and oncopathology research. So that led me to, move from India to Belgium and where I did my PhD in molecular pathology. Working in different hospitals, tertiary cancer centers, universities, research centers, I think clinical trials.
It provided a perfect platform for the culmination of my diagnostic skills, as well as my research experience. So that’s how I moved from, let’s say, a university teaching hospital to this clinical trial space. And it’s been [00:03:00] quite some years for me now, and I enjoy what the space brings to a pathologist.
Aleks: So I think everybody knows what clinical trials are, but I, when I was reading up a I also learned about this while in the pharma industry and it’s a lot more complicated than just, giving the drug to people who have a certain disease and maybe you could give us an intro, what clinical trials are and how they are being organized and how this matching of patients to the trial happens.
Basically, give us an intro to what you do, which, what the company does that you’re working for.
Monika: Alcubierre typically has a lot of offerings, but as far as, clinical trial space is concerned and how they are organized and what exactly do we look into it. I think they are a very good and important tool to evaluate the efficacy and the safety of [00:04:00] any new drug or biomarker or let’s say any medical device or intervention.
So they act like a quality funnel for implementation and for development and implementation of any drug or any biomarker or any device or any, medical intervention.
Typically when we talk of clinical research, we can if you have to broadly divide it, it could be clinical trials and observational research or observational studies.
So clinical trials basically are, like interventional studies, where in the researchers recruit participants or patients for any medical intervention and try to see the effect of that medical intervention on that particular participant or the patient. Whereas in observational studies, what happens is there is no medical intervention as such during the study, but the researchers generally observe and collect data.
Now this data could be related to[00:05:00] your health, your personal habits, your, if there has been a medical intervention previously and the effects of that. So that is basically observation. And as far as how the clinical trials are organized or how they are conducted, usually what we typically call as a sponsor, the funding for running and executing the clinical trial comes from a sponsor.
Now, this sponsor could be a government organization. It could be a pharmaceutical or a biotech company. It could be non-governmental organizational or even research centers and medical hospitals or universities, but these are not the people running the trial. What we have to remember and know is that the trials are executed by a third party organization, which is completely independent of the funding is what we call as typically clinical research organization and that is what I q A or Q Square Solutions does.
So what happens is that [00:06:00] this third party organization usually has a team of health professionals, typically medical doctor. Is assigned to the title of principal investigator who oversees the research or who leads the research and is complemented by a group of health professionals, including other physicians, doctors, nurses, and also importantly, what happens is that especially in phase three clinical trials, wherein, the trial runs for a long time, there are also expert monitors which.
Aleks: What does it mean for a long time? What time, what kind of time span are we talking about?
Monika: It could Aleksandra, it could depend from trial to trial, sometimes it could be two years, three years, sometimes even more than that, five years has been. What we have to remember is that as far as any medical intervention or any medical drug, which has to be approved by these regulatory agencies, these are the most rigorous [00:07:00] scientific experiments which are conducted in any setting. The scientific integrity of the trial is very important.
Aleks: Many trials going at the same time, and it’s not that, Everybody for this trial comes to the same place at the same time and gets the medication and goes gets to be monitored. How do you match patients? to the trials and how do you coordinate it in the multi site and often multi national setting?
Monika: I think that’s quite a mammoth task to actually organize this.
Aleks: Yes.
Monika: And there could be, yes, it is. And there could be, operational efficiencies and if inefficiencies around it. But if I just to answer this question very broadly, I would like to say that researchers typically try to enroll participants in a trial.
Which identify with a certain set of criteria, what we call as eligibility criteria for that particular child. Now it’s [00:08:00] important that the researchers identify and understand the research question very well so that they are recruiting the correct or the right kind of participants to them to make sure that the eligibility criteria are met and the research question is answered properly.
So these eligibility criteria could be, the patient or the participant could be of a particular gender or of a particular age. They could have had some medical intervention in the past or not. They could also have a certain health condition or not. They could be exposed to certain environmental conditions or certain or they would have had certain personal habits.
So these are the different eligibility criteria. I have explained this very broadly so that, it’s more complex than this, than what it sounds like. So these are the eligibility criteria as which researchers usually try to define to the patient, to the participants. And the participants are, then they [00:09:00] are made to understand the research question.
They are made to understand what the benefits of the trial or the risks of the trial could be. They are also made to understand their particular health condition around it, how much time or how much the length of the clinical trial, what it would entail for the patient or the participant to be enrolled in the clinical trial.
So when all this is explained to them, we typically, the researchers typically then make them sign what we call as an informed consent. So once that particular participant signs the informed consent after making sure that all what is related to being enrolled in the clinical trial is understood by them, that is where, and those eligibility criteria aren’t then, fulfilled by those participants.
Then researchers then recruit these patients into or participants into the clinical trial.
Aleks: I think we could talk about the logistics for another 40 minutes. [00:10:00] Let’s move and it’s like beyond my comprehension, but let’s talk about pathology in clinical trials. What is the role of pathology in clinical trials and do all clinical trials require pathology?
What is the place of pathology and when do we need pathology? evaluation in clinical trials?
Monika: That’s a very, I would say that’s a very wide or a vast question Aleksandra. But I typically work in the field of oncology and immuno oncology as far as clinical trials is concerned. So what we know definitely is that cellular pathology really helps to stratify and to randomize patients depending upon pathology parameters.
So we understand that pathology plays a very crucial role in clinical trials because first of all, it is important that the pathologist identify the, or review the, [00:11:00] the disease and the stage of the disease correctly. So that is very important. Secondly, pathology parameters are then used to enroll, stratify, and randomize patients for the trial.
So that’s again a very important step. Then I would like to say that pathology parameters can be used as evaluate outcome measures and these outcome measures can be used just as standalone classifiers or could be combined with, let’s say, clinical data or molecular data. That again is very important.
Also lately I’ve seen that in the past few years we are typically looking at what we call pathologic complete response. This is being, part of the, this is more and more routinely incorporated in the study design of clinical trials where the pathologists look at any residual disease after that particular intervention or drug has been given to the participant.
So we typically then evaluate the biopsy of the patient and try to see how the [00:12:00] drug or the intervention has worked, whether there is minimum residual disease or not, or whether a complete pathologic response in terms of that very little tumor, very few malignant cells, or absolutely no tumors found.
So these, I think, are very important considerations as well as pathology in clinical trials is concerned. Apart from this, as we know that we are moving into an era of, let’s say, precision medicine and targeted therapies. So I guess pathologists are in a very unique position that they understand that they can help in this targeted medicine or this precision medicine because they understand the laboratory diagnosis and the pathologic, evaluation of the tissue or the slide, but they also understand the molecular data.
So that is very important as far as as far as, cancer therapy or when we move towards targeted therapy. When I evaluate a slide, I know that what I’m evaluating and contributing is that it will [00:13:00] also enhance the quality of the data for cancer research. So I think For me, that’s very important that we are contributing towards this era of precision medicine or targeted therapy as far as cancer is concerned.
Aleks: I think it just may be a little bit of a naive question on my part of course, there are millions of diseases, and basically what I’m hearing here is whenever pathology evaluation is part of the diagnostic workup to diagnose. This is when pathology is gonna be incorporated in a clinical trial as well. Am I correct?
Monika: To diagnose also and I would also say to review slides.
Aleks: Okay.
Monika: To also to enroll and to stratify patients as well when we are looking at those pathologic parameters. Also, the results when we get from, as I mentioned, I give you an example of the pathologic response of the residual disease when we are seeing that after the intervention what has happened to the patient?
So we [00:14:00] are also looking and reporting that aspect of the clinical trial too. Apart from that, I think very importantly, as we see that more and more, in terms of oncology, we, the last few years we have focused on immuno oncology and quantification of immune biomarkers. So I think pathology is playing a very important role in quantification of those biomarkers and then enrolling the patients for a particular trial or not.
Aleks: So with classical pathology, what are the limitations that we’re facing in clinical trials?
Monika: Ah, that’s a very interesting question because typically what is happening is, what genomic approaches are now transforming these studies into, as you said, multinational, multi centered trials. And we are seeing the importance of let’s say, standardized reporting and very, robust reporting of pathology slides.
So here comes the play of central review of pathology slides. The central review of pathology [00:15:00] slides is very important, not only let’s say when we are studying a new parameter or the novel, parameter is concerned, but also to validate What has been previously reported. So central review of pathology slides, I think, is very important as far as pathology is concerned.
And this can very well be aided by, as we mentioned, digital pathology. Because what typically happens is that, when we are looking at central review of pathology slides, the entire idea of transportation of those glass slides and blocks can be very laborious. Sometimes it is time consuming, sometimes there can be breakage or damage associated with it.
All these logistical questions can be answered by digital pathology, wherein the centers can directly, scan and send the slides to the particular expert pathologist. Now, why central review is important is sometimes we are looking at a novel parameter, wherein, the pathologist who is expert or who is Really, the key opinion later on [00:16:00] that reviews this so that it helps to standardize the inclusion criteria or the outcome measures.
So that’s very important. Also, it becomes important to get second opinion or expert opinion when we are looking at something which is very rare disease. Especially let’s say in cases of neurodegenerative disorders, wherein we see a lot of clinical trials which are coming in terms of neurodegenerative disorders.
So we do see that expert opinion for these disorders should be taken and central review of pathology slides is becoming more and more important and is being incorporated in clinical trials. Now the advantage with digital pathology is definitely, I don’t have to explain it to you. There’s a defining logistical advantage.
As far as digital pathology is concerned. Also, I guess training of the pathologist is very important for, let’s say, any trial. For each trial, there is usually the training of a pathologist and routinely trained and then evaluated for the assessment of whatever [00:17:00] that trial is looking at. And this training, I remember in the pre pandemic days.
It used to be, typically the expert pathologist would have to travel to different centers and, then they would obviously this is time consuming and it is also hard for the expert pathologist to, move from one center to another. And after the pandemic hit us, I think this training has pretty much moved online.
And now we see more and more training of pathologists for the clinical trial, which is happening online. Also, let me give you an example of tumor inflammatory cells, or TILs, which we typically see in breast cancer. We know that they have a predictive response for new adjuvant chemotherapy for breast cancer.
And for TILs, what we have is like a, feedback aided software wherein the pathologists can feed in their answers. So this has really helped to train the pathologists for assessing TILs, and this can be done and is being done for quantification of other biomarkers and immune biomarkers. So again, training of the pathologists [00:18:00] as far as clinical trials is concerned digitally is also very important, another feature of clinical trials, which I see is, I think we will touch base upon that is also the integration of image analysis as part of clinical trials.
Aleks: Yes, I definitely want to hear about that because the telepathology, this is where digital pathology originated and this was exactly the use case, right?
So if I understand correctly, you have the place or at the point where the patient enters the clinical trial, there is like a primary diagnosis by a different pathologist than the central reviewing pathologist in the clinical trial. Okay, so that reminds me what I do in the preclinical space where there’s always a peer review of the slides that I read as the study pathologist.
So I would be like the first pathologist and there is another one that reviews what I’m doing. And I hear this is an integral part of every clinical trial that has pathology as one of the informational points, right?
Monika: I think that’s a very important parameter if it is designed around [00:19:00] that.
Aleks: What about image analysis? Could you give examples where image analysis is an integral part of evaluation and how is it integrated into their pathologist workflow?
Monika: The thing is for image analysis in clinical trials, or let’s say image analysis in pathology per se. Now in Europe and also there have been certain, let’s say AI apps around, let’s say quantification of ER, PR, PDL1.
Chi 67 and also a prostate grading or looking at lymph node metastasis. So some of these apps have already received the CE IVD mark, which we typically, use in Europe for clinical use. So these apps are already in place and they have received the regulatory approval for clinical and diagnostic.
So that is one thing. Now we also see that there has been a lot of interest recently by the sponsors for integrating image analysis into clinical trials. Now this is [00:20:00] important because the integration of image analysis in clinical trials helps for a reproducible quantification of immunohistochemical biomarkers.
Also it helps in standardization of the outcomes and the So that’s important too. Now in my opinion because I am right now working on something similar. It’s important that, the quality checks are put in place right from the time we are doing the validation or the asset validation for that particular trial.
What is important is those quality checks are being put in place. The algorithm development can be path pathologist driven. It is important that there is concordance between the AI and the pathologist. That kind of correlation should help as well. Importantly, if you can get two pathologists or more than one pathologist for that correlation, that is very important.
It’s also important for the inter pathologist concordance or correlation as well. So all these should be [00:21:00] clearly outlined and detailed in the validation report. So this will The help in, understanding how this has been developed and has been led by the pathologist. Secondly, then it has to be incorporated in the study design right from the onset.
So that’s important as well. So we know that AI analysis or image analysis reads, as we say, are, that’s an area of interest, which is there presently.
Seems that it will continue to grow. We need to have, certain, I would say there is a lot of debate right now about how do we regulate it?
How do we standardize this criteria? Because anytime a scanner, or let’s say an algorithm is used for any medical opinion or a diagnostic decision, it comes under the perview of the regulatory authority to, regulate around it or to structure it better. That’s happening as well because there’s a lot of debate around it.
And I was recently reading that, the Colleges for Medical Pathologists now they are looking at what they are [00:22:00] calling as a pre cert model to assess like a pre market review and experience around that particular platform or application. So that’s happening as well, as far as clinical trials have been sent.
Aleks: So in general, where is there potential for more support from digital pathology for clinical trials? So you mentioned areas where it’s already being used. Is it more of what’s already being used or is there potential for other areas where something else can be used? What’s your opinion on that?
Monika: I think right now, as far as in my opinion, decision pathology is important as we discussed for the central review. So that definitely the training is very important of the pathologist. So that is also very important, not only of, pathology parameters, but also not only to assess a pathology parameter, but also to standardize the assessment.
So that is very important. So that training of a digital pathology would really help. Also [00:23:00] as we discussed image analysis is what we are seeing that it will help with reproducible data. It will help with reproducible quantification of those pathology parameters. It would also help in standardizing and validating the criteria.
So I think these are the present applications of digital pathology and image analysis reads. Also, I’m seeing that more and more this, I think you will know better than what I do is that, not only Algorithm development for reading a particular pathology parameter in terms of morphology or in terms of I H C.
But also we see now that there is more deep neural network intelligence, which is recording these parameters. Whether you say, TILs or whether you say grading of a particular stage of the tumor, or you say, looking at mitosis or you say looking at assessment of biomarkers. So I think we are seeing more and more involvement of image analysis around pathology as such [00:24:00] for diagnostic use and also in the development of and assessment of clinical trial, yeah, research data.
Aleks: Is the central review always on digital right now or it depends on the organization or in the country?
Monika: No, it still depends on the organization. It still depends on the organization in the countries because As we discussed, there is still a lot of regulation which needs to be, around it.
Also, there are, considerations, I would say, regarding there could be difference in the scanner resolution or in the platform resolution between where it is being scan where it is being read. So till all those criterias are more standardized and also I would like to say that, till those, let’s say, pathology parameters or the scanner parameters are more standardized to be accepted and in a clinical trial study, I think those differences are going to remain.
Aleks: Wow. It’s amazing that it’s like this telepathology aspect for me is such a no [00:25:00] brainer and it’s amazing that there’s still so much debate on how to do it, whether it’s good enough, and I guess, I don’t know. I hope I’m gonna live to the day where this is gonna be normal everywhere.
Monika: And I believe so. The way we are moving now, I think, I was speaking to somebody else, I think couple of weeks earlier, and we saw that in pathology, Because let’s say the application of digital technologies in a diagnostic field like radiology, they have been used for a long time now, it started somewhere in early 90s.
But the application of digital means in pathology has taken its own time, also because, there are a lot more complexities around pathology. There have to be a lot more quality checks. How does my staining at my institute compare to your staining? How does my scanner can be validated to let’s see the scanner at the central, the place of central view is still not validated to the scanner at the site.
So these things are becoming more and more [00:26:00] valid. They are becoming more topics of interest and also topics of debate. And I see that slowly regulatory authorities are trying to structure their guidelines.
around these very important topics, which are definitely we are speaking about it today, but I guess, and I’m hopeful that in the years to come, this would be part of, I would say, routine clinical diagnostic use or for use at clinical trials.
Aleks: Yeah, mine as well, I think, I know it’s going to happen, but then I’m annoyed that it didn’t happen yet so.
Monika: It’s taking its own time and I guess, we have to remain hopeful and optimistic around it.
Aleks: Definitely. Thank you so much for walking us through it. I think clinical trials in general are like such a logistically challenging thing that we could probably talk for longer. Like I would ask you questions like, how do you do everything there?
But the focus was digital pathology and thank you so much for walking us through what digital pathology is in clinical trials and I wish you a [00:27:00] fantastic day.
Monika: Thank you so much, Aleksandra. It was wonderful to speak to you and good luck. You’ve been working a lot to advance the cause of digital pathology. Good luck to you and good luck to all of us.
Aleks: Thank you so much. We are all the digital pathology trailblazers. So let’s keep trailblazing.
