Do the Complexities of Clinical Trials Demand CRO Support?

Interview with Dr. Gwyn Bebb

[00:00:05]

John Marshall, MD: As we promise for Oncology Unscripted we bring the best voices, the brightest minds on all of our subjects. And so, we are very, very lucky to have Dr. Gwyn Bebb join us today. He's the Senior Vice President and Franchise Head and Global Therapeutic Area Head for Oncology from Parexel International, one of our world's greatest organizations CRO institutions. And he's nice enough to join us early in the morning from the West Coast to talk a bit about CROs today. So, Dr. Bebb, welcome and thank you for joining.

Let me start right in by. So, you're saying, where are we today with CROs? You know, a little bit about the evolution of that, and maybe even wax poetic a little bit about where we go in the future. I know I've just asked a lot, but. Fire away. Tell us what you're thinking. Okay.

[00:00:57]

Gwyn Bebb, MD, BM, BCh, PhD: Well, John, first of all, I want to say thank you very much for inviting me to this forum.

I was just chatting to one of my colleagues recently, and we were commenting on how protocols for clinical trials have evolved from being fairly simple, you know, maybe three or four page documents to being the kind of encyclopedic tomes that we see today with many hundreds of pages, and I think that sums up some of the aspects of the evolution of clinical trials in general. Which essentially, is an increase in the need to be precise about the endpoints, to be precise about the design of the clinical trial, to understand the regulatory bodies perspective, to understand the nuances of the endpoints and the measurements that we take in trying to prove that these new treatments are better than what we have. And as a result, I think, however innovative and exciting your new molecule or your new therapeutic approach is, and however motivated we are to get these promising new things into the clinic for our patients, there is a very, very important need of maintaining the rigor required to demonstrate that what we are proposing is safe and is going to be better than what we have. And in there, I think, lies all the complexities. And for, say, a small team from an academic institution that has promising data who now want to bring it to the clinic. It is a very daunting prospect to try to conduct a clinical trial in today's environment. So therein, there is an immediate need, if you see, for somebody who has the expertise to run clinical trials, and that in some ways is where the clinical research organizations come in.

John Marshall, MD: Let me jump in there. You know, you and I have watched this evolution occur. So, I remember one of my first protocols is, as you say, maybe a four-page document. And, and now they're, they're incredibly long. I'm thinking about the escalation of that complexity. It's, it's multifactorial.

The way I think about it is that cancer has gotten more complicated. There's more and more subtypes of patients and the like. Okay. The drugs have gotten more specific, so I get an element of complexity there. But we've also started to measure more and more things in order to prove that safety that you talk about. You have that you have the sponsor wanting to get to the patient. Before that was just through the physician, and now the CRO, because this is this middleman kind of discussion we've been having, the CRO has joined in on this to identify and train and oversee the clinical site. Can you talk a little bit about that piece of it, and the importance of that in in the overall flow of things?

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Gwyn Bebb, MD, BM, BCh, PhD: So, that kind of sums up a lot of the challenges we have. There's many paradoxes in here. I think. The world of clinical trials is so exciting and so promising, seeing the new ideas that are coming through. Gosh, you know, everybody gets very excited and very motivated to bring these to the patient as quickly as possible. But as you say, cancer as an example has evolved very much. We have a very specific slivers of classification of patients with, for example, lung cancer. It wasn't just used to be maybe just lung cancer. We have small cell, non-small cell, and then we have all these molecularly defined categories of lung cancer, each with a potential molecular marker that can be targeted for benefit. Now, if you have an agent that, it targets one agent. But if those patients don't have a, that marker in their tumor, then we're not going to have an effect. And so, including too many patients in the clinical trial that are unlikely to benefit will mask the positive effect. On the other hand, trying to get too specific, maybe it limits your, the number of patients that you have accruing the right number of the required for the statistical design may be challenging. And so, these are all components where it is very important. to invoke the help of a body of expertise that can help you through the clinical trial trajectory. And that's essentially what clinical research organizations are. When I was a physician, when I ran my own lab, my expertise was very limited to those particular areas. And if I had been lucky enough to bring something to the clinic from my own lab, I would not have been able to do everything that was required to conduct that clinical trial. And that need, you know, I’ve said it's particularly required for small Innovative teams from academia, but the same applies for innovation anywhere and the same applies for big pharma they have a lot of internal capabilities, but sometimes, whether they're overloaded with their current, requirements, whether they're pivoting to a new area, where they're doing something completely different. Sometimes the expertise provided by a clinical research organization, such as Parexel, is exactly the expertise they need to invoke to move things forward. Everything included in that package, from the identification of the biomarker, all the testing that's required to do that, the clear delineation of which patients is the investigator in the trial going to bring into the trial. How do we meet the regulatory body requirements to make sure that the test we use to identify the patients is a valid and reliable and reproducible one? How can we help design a trial in such a way that it can run uniformly across many countries? How can we make sure that the statistical design is going to meet the criteria required of the regulatory bodies to demonstrate that what we have is better than what we had? And so, these are not, this is not a range of expertise that you can just pluck out of the air. And, you know, I think that's one of the things that makes me very excited about working for Parexel is that we have this expertise that can slot into this critical area to drive innovation forward while maintaining the academic rigor required, and of course, most importantly, protecting the interests of the patients who are kind enough to volunteer their time and their bodies in a way to take part in what is a scientific experiment.

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John Marshall, MD: I think that's great. I was going to ask, and you just answered was sort of your perspective on the value of what the CRO brings to the table. And I think you did a great job of describing that. as you were going to, I want to kind of go to the patient side of things. So one of the worries we have in the clinical side is that the patient who now is eligible for that trial in the end is so perfect is so squared off at the corners to fit, that that doesn't end up representing the ultimate patient who will be treated with this therapy because there's, you know, patients are not that clean in general, if you will, so, you know, softening the edges around eligibility for us would be good to increase accrual and also therefore represent that patient at the end.

And one other angle on this is, you know, the patient is volunteering. A lot of clinical trials, that are not so cancer therapeutic, we've actually ethically understand it's okay to incentivize a patient to go into a clinical trial. We do ask a lot of them. It is extra visits. It is extra time, extra biopsies, sometimes, things like that. So, they are volunteering their bodies at a sacrifice of some quality-of-life component. And I wonder what your thoughts are. Ultimately, could we get to a place where we are incentivizing that patient? So, softening the edges of eligibility, is there a role for incentivization of patients?

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Gwyn Bebb, MD, BM, BCh, PhD: Well, thank you very much for bringing that up because the patient centricity of clinical trials is a very important theme. It is something that we at Parexel are very, very aware of. We have a patient officer who is part of our company whose task is to maintain a focus on the patient as we look at the design of clinical trial. And as you say, these patients are volunteers. A very important part of clinical trials is the moral and ethical framework for essentially conducting experiments on our fellow human beings. And this is, this is a very, very important area. I have a lot of passion for that. And, you know, the history of experimentation of fellow humans is a terrible one. And so that's just why we have international agreements, we have ethical review. An awful lot of regulatory input on how to go about attracting patients to clinical trials.

Let's address the inclusivity to start with. I think this is an important point. One of the things I like about clinical trials is the, the tension that we get when we, when we have slightly opposing forces trying to drive us forward.

So, as you say, on the one hand, we do want to create the biggest possible chance of deriving the positive signal that we're looking for and so we have to be very rigorous about the patients that we put in a clinical trial. Otherwise, we will lose the positive signal that may be there in a very, very important, new, therapeutic, agent. On the other hand, as you say, we don't want to be too restrictive. There's many, many examples of this, you know, performance status, for example, clinical trials have always honed in on performance status 0 or 1. Because the outcome that we associate with performance status 2 and 3 can actually compromise the signal that we're looking for. So, trying to soften those edges is something that many of the regulatory bodies are trying to drive us forward in doing. Another example, for example, is the inclusion of brain metastases in our clinical trials. Very often it has been the case that patients with brain metastases from their primary cancer were excluded from clinical trials and we know that that is a very unfortunate paradigm, and I think that too is now evolving and changing. But as we said at the beginning, you know If you're looking at a new agent that targets a particular therapeutic target including patients in whom that therapeutic target is not present is not going to be useful for anybody. It's not going to be useful for that patient and it's not going to be useful for that clinical trial.

Now let's turn to the incentivization of patients. I think this is a very difficult area to navigate very often, and, as you say, incentivizing patients is not the main theme of our approach to clinical trials. Many patients, when I was in clinical practice would ask me, you know, why would I, why would I join this clinical trial? And I would say, broadly speaking, there are three reasons for, for a patient to take part in a clinical trial. One of them is for the opportunity of getting a new, exciting, innovative therapy. That is a very, very good motivation. Another one I think is overall, there is a body of literature that suggests that patients participating in a clinical trial. generally, do better than those who don't. And there's lots of reasons for that. And that is possibly, as you said, the more intense follow up, the more supervision of their whole clinical experience probably helps drive those, those data of survival forward. And then the third reason, this is very altruistic indeed, there are some patients who just want to contribute to the general body of knowledge about their disease for those who, as I say, come after them.

Now you know a very important part of this having made having looked into their heart and realized what motivates them, the next thing is if we are patient centric we have to make the burden of the clinical trial as minimal as possible. And I think one of the major things that we see happening is that the increased visits the increased procedures they Don't make your quality of life better, right? They take a lot of time and a lot of energy for the patients. And when it gets to the point where you're missing work, you're missing the opportunity of giving care to those who depend on you, then that is a significant detriment. And so, making sure that there is what we have termed fiscal neutrality, for example, in participating in a clinical trial is very important. So, there is a drive to make sure that the costs incurred by patients, whether it's food, travel, care costs, those such things are very much part of, of what we provide to, to make sure that it is not too much of a detriment to the quality of life. I think those things are probably slightly different from actually incentivizing patients to take part in a cancer clinical trial.

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John Marshall, MD: Thank you very much, Dr Gwen Bebb for sharing all of your experience and knowledge around the world of clinical research and in the role of a clinical research organization in making sure that we do it right. And we do see the clearer value, but as we've talked about, there are still lots of issues that we need to address as we evolve this relationship further.

So, again, thank you very, very much for joining us on Oncology Unscripted.

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Gwyn Bebb, MD, BM, BCh, PhD: Absolute pleasure, John. Thank you for hosting so gracefully.​

Are There Alternatives to Traditional CROs?

Interview with James Palazzolo

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John Marshall, MD: As I promised you, I have experts in the world of CRO and clinical research, and not just experts, really visionaries about the problem and about how we can move forward. And I'm honored to be joined today by what is becoming a pretty good acquaintance in this world of clinical research.

So, James, James Palazzolo, is out on the West Coast right now and he has joined us from Quantum Leap Healthcare Collaborative, and I'm going to really leave it to James to describe, to us, the CRO, in a sense, that he and his team has created in large part response to the problems we have been talking about with CROs. So, James, welcome.

So, you get to tell us whatever you want to say about CROs. Tell us a story in the background of what you've created.

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James Palazzolo: Yeah, thank you, John. So, it's an interesting world, right? We all want our medical decisions to be made based on data. And the ultimate way to do that is with a randomized control clinical trial, an RCT. And as the practice of medicine became more and more data driven, of course, more and more trials are needed to be conducted. RCTs by themselves are the pinnacle of how this data is collected and the results are generated, but there are some downsides. The downside is it requires extreme precision. Data collection needs to be done in a way that's meticulous. And it creates also a form of a Hide-Bound system where we can only do things one way. And frankly, I think there are alternatives. Alternatives can include things like using game theory, Bayesian statistics, platform trials, master protocols, and the list goes on...decentralized trials. We can make a long list. Of innovations, but these new innovations haven't always penetrated the traditional world of the RCT. The RCT is driven heavily by government regulation, but also by the routine of practice. So, the people or organizations that conduct these are usually called CROs. They're professional data collectors and can put that data together for people who wish to have an R C. T. conducted. The downside, though, is that it really doesn't benefit to have all these innovations over and above what we can provide to RCTs. And so maybe we need a new form of an organization to make that happen. And that's what we've done at quantum.

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John Marshall, MD: Yeah, tell us a little bit about that. I mean, you know, part of what the concern is, is that there's this ever-ending escalation of precision. If we can look for more data. If a CRO came and audited us here and found no problems, then that would put them out of a job. Right? So, part of their essence has to be to find some problems to justify their existence. So maybe tell us a little bit about how you've evolved this for your team.

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James Palazzolo: There's no doubt that misplaced precision is everywhere, right? We could focus on all the wrong things, but we tried to apply a bunch of newer tools to make this better. So, one is we set up a platform clinical trial that once it starts continues to run. So, it'd be like, if you brought the Olympics to the same city, every 4 years, you wouldn't need to build more stadiums. And some people would love that because the public would have access to these things. Other people would hate it. Like if you're in the stadium building job, it would be bad for you. So, it's going to depend on where you sit on this issue. In our case, with a platform clinical trial, we can run cancer trials over and over again with the same infrastructure, but that's not all we can do. Right? We're also going to listen to, veteran clinicians like yourself, who guide us into what is the most important. We no longer use misplaced precision focused on the. Parameters that are most important, but we're also going to provide these results to patients in in plain English in digestible form. So, whether you participate in the trial, or you're curious about the results, we're going to make them available to everyone.

Another thing we've done is put this in not in a not-for-profit company, so that the company itself isn't doing this. We don't have a vested stake and who wins or loses. We're not looking for the next contract from the next pharmaceutical company. Frankly, we're working with groups of very curious, but also very experienced investigators who want to learn more about. their particular, area of oncology, and then we're going to grind on that, not just for two or three years in a trial, but maybe decades until we find real lasting solutions that make the problem better for the patients who suffer from it.

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 John Marshall, MD: I want to kind of come back to a couple of things you said so this idea of having experts be part of the decision-making. So, I remember back when we were involved in decision-making and design of clinical trials and running them. And then something happened where Industry actually hired the physicians.

So now instead of borrowing us when it was time to design a trial, everybody went in house. And so, they had their internal experts. And so we no longer were really being asked what our opinion was about a trial or a trial design. But we were being asked just would we do the trial that's being handed to us? Are we okay with that? I do think that's driven a further wedge between the reality of patient care and this sort of mystical   of precision, you know, data from the randomized controlled trial. So that's one. The second, and I can't help but have this vision of the London underground and this platform clinical trial, like, you know, you could be on the London underground sitting next to Paul McCartney, right?

So Paul McCartney would ride the London underground, everybody uses the public transportation there in order to get around. It's the most efficient way to do it. You've built, in essence, the, you know, the Piccadilly line for clinical research that everybody can get on and use if they want to try and lower costs and to improve speed of accrual. Is that a fair analogy?

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 James Palazzolo: I think that's absolutely fair. And, you know, if we're going to improve things like racial disparities and medicine, we need a more uniform tool platform trial where everyone can participate that, of course, includes the high-end academic centers. We're going to provide very useful information, but also safety net and community hospitals where everyone has a chance to participate. Of course, it's up there choosing. But, if they choose to participate, their data will be included, and we'll get more information that allows us to do a better job for everybody.

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John Marshall, MD: And so, it's just so our audience knows your, your basic group is supporting as a CRO in a way for this platform trial and its relatives. Right?

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 James Palazzolo: That's right. So, our organization provides the same functions to conduct a clinical trial that a CRO would have. If an industry company, a medical device company, a pharma company did some of their trials in house. They would have these same functions. We have them. But rather than going out and seeking new projects to work on, we built the project with people like you to make sure that it was relevant in reflective current clinical practice and then continuously improved it over time, so that we could enroll patients in trials that more closely reflected their actual routine care and didn't get hidebound in the routine or the tradition of an RCT. It is an RCT. But it is more flexible. And then it collects the appropriate information at the right time.

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John Marshall, MD: And we know you guys have been at it a while, and you guys have produced FDA approvals and innovation in how we treat patients in general. You've broken the mold in a way that's allowed us to accelerate our innovation instead of sort of plodding along as we've been doing. So, James, I can't thank you enough for joining us. I know everyone will be interested in hearing more about it your success, so be careful. You might get some phone calls after this. James, thanks for joining us.

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James Palazzolo: Thank you, John.

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 John Marshall, MD: I can't thank our experts enough for sharing their thoughts about clinical research, CROs, and maybe some thoughts about how we move forward going ahead, because we need to move forward and we need to make it more efficient so that we can provide better cancer care for people all around the world.

And I hope you have found this episode seven of Oncology Unscripted useful, maybe a little enjoyable, but certainly thought-provoking as you go forward in your week ahead. John Marshall, thanks for joining.

This transcript has been edited for clarity.