Oncology drug development is becoming more complex, and bioanalysis can no longer be treated as simple drug measurement.

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In this episode of BioTalk Unzipped, Gregory Austin and Dr. Chad Briscoe speak with Dr. Lakshmi Amaravadi, Head of Oncology Bioanalysis at AstraZeneca, live from AAPS PharmSci 360 in San Antonio.

Dr. Amaravadi unpacks why biomarker validation is not one-size-fits-all, how context of use should guide scientific decision making, and why fit-for-purpose validation matters in modern oncology drug development.

The conversation explores:

00:00 Why oncology bioanalysis is becoming more complex

02:12 FDA biomarker validation guidance and industry response

04:27 What “fit for purpose” means in practice

06:38 PK assay validation vs biomarker assay validation

07:52 What drives Dr. Amaravadi’s work in translational science

10:48 Why validation is not a checkbox exercise

12:19 Advice for young scientists entering bioanalysis

15:12 Why oncology drug development is uniquely complex

18:17 ADCs, bispecifics, T-cell engagers, and conditional T-cell engagers

19:38 Why bioanalysis now requires understanding biology

20:46 Dr. Amaravadi’s path from molecular biology to bioanalysis

24:34 Critical reagent management in complex oncology assays

26:42 Validation, qualification, and context of use

29:03 Final thoughts from AAPS PharmSci 360

This episode is especially relevant for scientists, bioanalytical leaders, translational researchers, clinical pharmacologists, oncology development teams, biomarker scientists, and anyone working at the intersection of drug development, assay validation, and precision medicine.

Dr. Amaravadi discusses how oncology programs now involve ADCs, bispecifics, T-cell engagers, conditional T-cell engagers, complex linkers, multiple measurable species, immunogenicity considerations, and biomarker strategies that require deeper biological understanding. As she explains in the episode, the future of oncology bioanalysis is not simply measuring what is present. It is understanding what the measurement means in the context of the biology and the development decision.

Follow BioTalk Unzipped for conversations with leaders in biotech, pharma, bioanalysis, clinical development, translational science, regulatory strategy, and the future of medicine.

Guest

Dr. Lakshmi Amaravadi

https://www.linkedin.com/in/lakshmi-amaravadi/

Hosts

Gregory Austin

https://www.linkedin.com/in/gregoryaustin1/

Dr. Chad Briscoe

https://www.linkedin.com/in/chadbriscoe/

Sponsor: Leucentra

Related Links

Celerion

https://www.celerion.com/

There's unprecedented complexity in the oncology drug development space. You're administering a drug, multiple linkers, four or five different species possible that you can measure, inactive, active. That's why the bioanalysis is now not just simply you put this drug and you measure. You really need to understand the biology.

Dr. Lakshmi Amaravati, the head of oncology and bioanalysis at AstraZeneca. She authors recent papers that were AAPS on how we think about biomarker and ADA validation. We need to go with what science tells us. Fit for purpose, there's no one size fits all. The crux of the issue is really that. When it comes to biomarkers, 99 % of the time you do not have the same.

reference standard that you can use that behaves like an endogenous biomarker. What does fit for purpose kind of mean in practice? Validation itself means to ensure the method is performing as appropriate for the purpose while the guidance documents are there to guide you to how to go about validating an asset. But that doesn't mean it's a checkbox. You still have to think about why am I doing this? As a scientist, how do I measure biomarkers? How do I

efficiently use my scientific knowledge to enable decisions quickly to move drugs through and I've been fortunate being parts of project teams where we brought multiple drugs to market. What personally drives you on this topic? A couple of things I think worth saying. One is

Welcome to BioTalk Unzipped, where we unzip, unlock, and uncover the stories behind medical progress. I'm your host, Gregory Austin. I'm joined together with Chad Briscoe, and we're here at AAPS, FarmSci 360 in beautiful San Antonio, Texas, just right off the River Walk. And today with me, I'm joined by someone who shows up very often when we talk about biomarker or ADA validations, Dr. Lakshmi Amaravati. And she's the head of oncology and bioanalysis at AstraZeneca.

She authors also a couple of recent papers that were the APS on how we think about biomarker and ADA validation. So thank you for being here. Thank you, Gregory. Thanks for having me. Absolutely. So Lakshmi, you're part of today's hot topic, right, on the FDA new biomarker validation that came out this year. For those who aren't maybe as familiar with that guidance, what's the essence of the guidance and why is it significant?

Yeah, you know, when this guidance came out in January this year, it caused a lot of commotion, I have to say, within the pharmaceutical, bioanalytical community, both in the US and in Europe. Those of us in the biomicrosyn precision medicine community, where it's most relevant, we got together, really poured over it, as we always do with guidance documents. And it turns out it's a level two guidance. What that means...

for the FDA standards is that there's not a substantive change in the practice or the specific way of you apply the existing guidance, meaning the previous guidance. So that is why there's no common period. It's more of the way we interpreted that is more of an administrative change because the section on the biomarkers was included in the prior guidance, which was called

Some trepidation, were they excited? Was it business as usual? How did they respond? Yeah, I think it's fair to say it caused some confusion. There was a lot of apprehension depending on who you talk to, different ways of interpreting it. Some folks felt like the biomarkers now have to follow ICHM10. That's one way of interpreting it. Another way of interpreting it is we need to go with what science tells us. If it's for purpose, there's no one size fits all.

So we've actually critically evaluated and that's what we'll be talking about later today. Very good. You mentioned fit for purpose. That's a vernacular that's been around for a while, but it seems like it's becoming more front and center again. In your opinion and in your professional opinion, what does fit for purpose kind of mean in practice? Yeah, a good question. And the other term that you might be hearing a lot more lately is context of views.

I have that on my list as well. Yeah, let's talk about it. Yeah, sure. You know, we believe they're synonymous with each other, for purpose and context of use. Basically what that means, and actually it's funny, you go back to the ICHM-10 guidance, you also see for the drug concentration assays, which we commonly refer to as PK assays, they also talk about validation itself means to ensure the method is

performing as appropriate for the purpose that you're using or for the context you're using. The difference between PK assays and biomarker assays is that for PK you have one context, which is to measure, is, you're measuring the drug concentration, you're administering the drug to the patients, you're measuring exactly the same drug in the blood, right, for the most part. Whereas,

when it comes to biomarker, that's where the differences come in. And we're trying to, we'll have to go deeper into the science of it to really define what the context of use is. Because the context of use encompasses prognostic biomarkers, diagnostic biomarkers, pharmacodynamic biomarkers, efficacy biomarkers that actually enable approval. So there's a number of different contexts of use.

That's one way to think about it. The other way is early expiratory biomarkers versus phase one, phase two dose decision enabling biomarkers versus finally all the way up to companion diagnostic. So the context vary as you, how you apply the biomarkers as well. That makes sense, yeah, of course. So no one size fits all obviously. Absolutely, yeah, exactly.

So what are some the biggest differences between a PK assay validation and a biomarker assay validation that maybe some people still misunderstand? Yeah, I think it's very tempting, especially folks who are used to using ligand-binding assay formats and mass spec assay formats. It's something to think they're essentially the same, and you can apply the same philosophy. But the biggest difference in practice, and then you asked that before,

What happens is it senses the reference standard where you have a PK assay, has a reference standard material, and you're essentially using that to calibrate and ensure your method is performing because you're measuring the same molecule in your patient samples. Whereas when it comes to biomarkers, on the other hand, you do not have, for the most part, 99 % of the time, you do not have the same

reference standard that you can use that behaves like an endogenous biomarker. So that crux of the issue is really that. Okay. Now, thank you for splitting that apart and helping clarify that. What personally drives you in this space and on this topic? On this particular topic? I guess personally for me,

You know, my career started off in early discovery. I was doing target validation, you know, really basic science in a way, but also in pharma industry. You know, I went to Eli Lilly early on as a postdoc and wanted to learn about what it is to develop drugs, going from academia into industry, and I loved it. I loved the cross-functional, translational aspect of how you think about science.

So that's what made me realize, okay, I want to stay in industry. And then I continued, I worked in basic discovery for five years or so. Then I moved into translational space because I realized, okay, can, that science is exciting and there's no right or wrong. But you may do basic science even in a pharma setting, probably never get to bring a drug to the market just because it takes so long to get there.

Yeah, so I wanted to really see what it is like to go. So I moved into this translational space where, you know, over the course of my career, I built teams where we were focused on developing biomarker and bioanalytical strategies and assays to understand how, you know, when you administer a drug, what happens to the drug? That's your PK.

And then how does the body respond to that drug, which is the biomarkers and immunogenicity, those are all responses to drug treatment. And that's fundamental to understanding or informing drug development along the way of clinical development. And then you bring the drug to the market. So what drives me really is, as a scientist, being able to understand the importance of what we just talked about, right? How do I measure biomarkers? How do I efficiently

use my scientific knowledge to enable decisions quickly, to move drugs through. And I've been fortunate in my career, having been able to bring multiple, being parts of project teams where we brought multiple drugs to market. That's gratifying. Yeah, it has been really gratifying. That's good. Yeah, I know you mentioned two things. One, on the discovery side, I think those folks have to have extreme delayed gratification.

It's gonna take a long time before you actually see that get applied in a meaningful way. And quick decision making, especially in industry, is extremely key. Even though it can be scary to make those fast decisions, You know, wanna have everything, but I think fast decisions, know, fail fast and recover faster is also important. Right, exactly. mean, fail fast also makes fast and smart decisions, right? So I think that's where I see, you know, within the industry we have a

an opportunity to really optimize by working cross-functionally because not everybody knows everything. And in a drug division, it's a team sport. And you kind of have to really ask always, thinking head on, to say, what is the question that I'm trying to answer? Now that we're talking about our AAPS organization, validations, my experience with regulators has always been, while the guidance documents are there,

they're to guide you truly to think about how to go about validating an assay, let's say. But that doesn't mean it's a checkbox. Exercise, you still have to think about why am I doing this? Accuracy, precision, or whatever the parameter might be. And if your context or if your particular problem warrants a different approach, you can scientifically justify it. And that's in the guidance.

That's in ICHM 10, that's in the FDA. And that's been my experience as well, where we have been able to go to the agency and say, here's why I did what I did. And if you're able to articulate that position, it's never been not successful. good. Yeah, yeah. Congratulations on that. Thank you. That's excellent. Thank you. You've had the opportunity to mentor a lot of scientists and young scientists across your career.

What is one thing that you would share with a young scientist today as they're getting started in their scientific career? Yeah, one thing. I think it is don't fear is what I would say. Stay curious, reach out. And for me, probably would, at one point in my career, I would say I was an introvert.

I have to say when I started coming to AAPS about 20 years ago, folks before me who were very engaged in the community have allowed me to come in and welcomed. I think for young scientists, I think take advantage of all the opportunities that you have. Of course, compared to 20 years ago, the landscape has changed a lot, both in information that's available to you, various social media,

various conferences actually. We didn't have this many bio-analytical conferences back then. But then now also the drug modalities are changing. The regulation is changing, the landscape is changing. So I think there's also a lot of opportunities. We don't have to be intimidated by that. But my suggestion is go for it.

especially how things have changed just I think socially for young people. There's so much in their devices. It's like put your phone down, get away from your desk, meet people in real space in real time because there are so many people like yourself who willing to help, mentor, offer helpful information if you just ask. Yes, absolutely, absolutely. Yeah, and those networking connections, immensely valuable. They're more valuable than gold.

They really are. absolutely. Yeah. And not just when you're in school, you know, forever. Yeah, no, you should always be networking and keeping up with people. It's critically important to your career. Yeah. And you enrich yourself. Absolutely. Good deal. All right. Well, Chad is going to ask you some questions now. thank you very much for talking to me. Thank you. Thanks, Gregory. Yeah, my pleasure.

Just a quick one. We are very excited to share that this episode is brought to you by our founding sponsor, Lucentra. Inspired by science, empowered by IT, Lucentra works with life science and healthcare organizations to make technology the way it should. They help teams evaluate, implement, and get real value from IT solutions that support innovation, not slow it down. So if you're unsure about your current technology or want a second opinion, Lucentra is just a call away.

I know John Lord, he's the founder of Lucentra, great guy, very experienced, very authentic professional, just a good guy to work with and someone you can count on. So thank you, Lucentra, for sponsoring this episode. All right, Lakshmi, delighted to be here with you today. Good to be here again, Chad. Somebody I've known for a long time in the bioanalytical industry, so delighted to have you as a guest, finally, on Biotalk on Z. My pleasure.

I wanted to dive a little bit deeper just into oncology drug development with you. So that's an area of your focus right now, I believe, within AstraZeneca. So talk to me just in general about what drives you in oncology drug development and a little bit of how oncology drug development is different from other modalities and other therapeutic areas rather. Yeah, yeah, thanks for asking that.

I've, over my career, I've worked in multiple therapeutic areas as I was leading the teams in other organizations, worked across many therapeutic areas and came back in a way when I went to AstraZeneca to oncology. I guess a couple of things I think worth saying. One is, personally for me, and I'm sure many in your audience, somebody has been touched in your family, friends, circle.

Same thing happened to me as well. That really keeps you motivated. It's still a devastating disease, although of course we should acknowledge significant progress that's been made with immunocollegy in the last decade or so. So that to me is very rewarding. I think it's also fair to say, as Gregory and I were talking earlier, it is one of those drug development paths you can bring

your drugs faster to the market. And then coming back to the science of it, it is complex. And one thing I am still learning now is it has mushroomed, know, the oncology clinical trials in particular. Once you see a signal in your face, one study, pharma companies tend to expand, you know, going to number of different indications, right? In a way, almost signal-seeking.

So the clinical trial complexity, unlike I have seen in any other indication, and as well as combinations trials, And especially since we are in the pharma and bioanalytical community, that really brings a lot of complexity to what we do. know, interferences, selectivity in the presence of ADCs, ADCs with prodrugs, you know, or.

a bispecific antibody with an ADC. knows? I the engineering of these molecules has become so complex. So I think to me, unprecedented complexity in the oncology drug development space brings both challenges and opportunities. And then of course, cell therapy nowadays, that has a whole other dimension of complexity too. Absolutely, absolutely.

Yeah, so I misspoke when I was talking about therapeutic areas and I said modalities because I was thinking in oncology there are so many modalities now. So can you talk about maybe a couple of those and ones that are surprising or amazing to you, right? That it's like, wow, I can't believe we can engineer these sorts of molecules now. Yeah, yeah. You know, it's relatively new to me, I would say. We are getting into not just T cell engagers but also conditional T cell engagers.

So what that means is these molecules, I don't know if you've seen one of those structures. I don't think so. They look, you know, we used to call some of these bispecific, trispecific, know, Frankenstein-type molecules. Now these are truly Frankenstein-like. It's the complex molecules where you are conjugating essentially not an ADC, but a biologic, but still with linkers. And you might have two different types of linkers that are...

that can be cleaved in the tumor microenvironment. So you're administering a drug with multiple linkers. So there's maybe four or five different species possible that you can measure, partially cleaved, inactive, a number of different moieties that it causes the complexity of understanding your mechanism. So that's why the bioanalysis is now not just simply

you put this drug and you measure, you really need to understand the biology. So that's been amazing to me, conditionally cell engagers. So that's interesting, the comment that you don't just need to understand the assay, you have to understand the biology. So has that changed how you train and develop bioanalytical scientists within the organizations that you're from? Yeah, I'm glad you asked. I was thinking about it the other day coming to this conference, actually.

It's changing so much, know, bioanalysis. I wonder, honestly thinking out loud, if down the road should we have a different name for a bioanalysis? Because it's not, you have to know the biology, you have to know the mechanism, and only then you are able to really develop the right asses.

And as we were talking about earlier, the context of use and how you apply it is going to become a lot more applicable even for PK assays as well. So absolutely, I think it's going to definitely change how we train our scientists. It's building a lot more into clinical pharmacology space, what used to be called clinical pharmacology or translational.

Yeah, so my path was I thought instruments were really cool and I was really, you very techie and so I kind of came into bioanalysis through the instrumentation and that and now there's all the biology and all that that I feel like I'm still learning and trying to come up to speed. What was your path into bioanalysis through education and? yeah, Honestly, I had no education in bioanalysis, right?

I was trained as a cell molecular biologist, developmental biologist actually. And then I went to, as I was saying earlier, I worked in discovery research early on in my career. Then I made the, I wanted to kind of get to know translational, what does it take to bring a drug to a patient? That's what motivated me into translational space. I have to say, maybe two things come to mind. The first,

Couple of months I was in a lab at Biogen and drug tolerance in immunogenicity assays was a relatively new concept. I actually went to conferences like this to learn. It was a relatively small community and FDA folks were there too. And everybody was learning from each other for the first time. I go back and we realize, oh, we have not looked at drug tolerance in this assay. How do we do this? Then there was no set way of doing it. So I was challenged with

I was asked to go figure it out. So I was in the lab at the time and I figured out how to do it. I was very proud of what I had done, which was good. And then I go to my regulatory lab counterpart and I said, hey, I have this assay now that I've developed. Now you can take it and run the samples, right? And I had no idea what a bioanalysis was. And she was like, Lakshmi, I need a protocol, an SOP.

and we have to write a validation, you know. I was like, what is, it felt like to me Greek and Latin. I was like, what is all this? You know, I'm a research scientist, does she not trust me? I have developed this assay and that should work, right? And then she showed me what a validation report looks like. It's like, wow, okay. That was eye opening to me. And from then on, you when I hire people too, I tell them, when they come from a research setting, hey, there's no right or wrong.

This does require wearing a different hat and thinking about the details. But at the end of the day, you're still answering a bigger picture scientific question. If you like it, this is for you. But if you don't want to be in those details, then maybe elsewhere. that was my first exposure to bioanalysis. And I loved it. And the reason probably I really became passionate about it was my first drug. So after I went to Biogen within an year,

The drug that I worked on, I just told you about the drug tolerance. In fact, FDA came back with a question. We submitted the data that I had generated. Oh, beautiful. Right. I mean, obviously, this is 0.1 % of the whole. But it was everything to you. Yes, exactly. And that was my first time. And then they approved the drug, and patients were taking it. It was announced. So I had only been there for one year, and I contributed small.

I was like, wow, I felt to this day, it still feels like that experience is still fresh in my mind, something I contributed to, and now a patient is taking the drug. I have to say from then on, I kind of got hooked in a way to drug development. I've been fortunate to have been part of many teams where multiple drugs that I worked on got approved. Yeah. That's fantastic. That's fantastic.

changing gears a little bit, another hot topic in bioanalysis, of course, and we can't talk about it enough, is critical reagents. And so I wanted to get your thoughts in the context, again, of this very complex and increasingly complex oncology drug development and increasingly complex assays about, talk a little bit about the criticality of critical reagent management, but also how you're managing that increase in complexity. Yeah, yeah.

It doesn't get noticed, it's everything, right? It's the parts of your engine. You know, to run the car. You don't run a car without a carburetor. Yeah, exactly. Yeah. And I think, you know, gets, you know, it doesn't get the attention that it deserves, but absolutely. that is, you know, every, you know, in my teams, what I've done always is to kind of dedicate some resources.

to focus on critical reagent characterization, critical reagent generation, and AstraZeneca, we've been fortunate that we can work with some of our counterparts in a different department to be able to work with them to generate and to be able to antibodies and things like that. But you know, even for diesel engagers we were talking about, Even mass spec is also being used now to be able to, especially,

specifically measure different moieties, right? But it all is on immunocapture, right? So you still depend on those reagents, right? Yeah, I think it can be understated, the importance of it. do think we are, speaking of educating, bringing a new generation, I almost feel like we could even have courses about that and train people.

even maybe business start, where people can actually supply the reagents. I mean, we now go- Yeah, manage, warehouse, the critical reagents, yeah, because it's getting more and more challenging for sure. absolutely. That's fantastic. So one other thing I want to ask you about, and it goes back to some of the discussion with Gregory about the biomarkers in context of use. So one of my-

sort of, I don't know if it's a soapbox, but things that I've been thinking about a lot is we've been trying to come up with different words for validating, qualifying, all sorts of different terms or like just implement or out of the box, right? All these words for anything from biomarkers to PK. For me, what I've been thinking is we're working too hard trying to come up with these new words. I think there's two. I think there's context of use and validating appropriate for that context of use, right?

It's all validation. That just means that you're doing it for the, you're testing it for the right context of use. So am I crazy? Is this something that we should try and push? Everything's a validation? Absolutely. Definitely when it comes to biomarkers, no question. In fact, we are going to talk about this at the Art Topic Session as well. Everything is a validation for that context of use.

instead of qualification, partial validation, full validation. Honestly, feel like I think more about it. We kind of are shooting ourselves in the foot by making it so complex. Biomarkers are complex enough to now add onto it in all these terminologies. And it means different things to different people. no, absolutely. we should go for it. Because even PK assays that we do know the context to use.

every validation is a little different. They have different nuances. A PK validation for an ADC is different from a PK assay for a small molecule, even if we're using mass spec for all of them. So, I'm on the right track on that one then. Absolutely. No, I agree with you. I didn't mention PK assays. I will say I kind of held myself back because we have regulatory documents about.

Partial validation, things like that, right? But we should address that as well. agree. Yeah, everything is a validation. Well, Lakshmi, it's a pleasure to be a part of this amazing part of the pharmaceutical industry to see at these meetings, to have these conversations. Thank you so much for being a guest on Biotalk on Zipf. Thank you, Chad. My pleasure. My pleasure. Enjoy the rest of the meeting. And yeah, thanks again. Thank you. Thanks. Appreciate it.

Thank you so much for joining us on this episode, Dr. Lakshmi Amaravati. And we also want to give a great thank you to AAPS for hosting us here, for allowing us to be in this space, and for all the support, especially from Rebecca Stofer and across the organization with BioTalk Unzipped. Thanks, and we'll see you soon.