DTRA’s Craig Lipset on Decentralized Trials and Accelerating Rare Disease Research
New technologies have always driven advances in clinical research, and that’s still true today. The Covid pandemic rapidly accelerated the adoption of decentralized trials, powered by emerging health tech, but in less dramatic times, life sciences must find ways to ensure continued innovation.
As an industry veteran and co-chair of the Digital Trials & Research Alliance (DTRA), Craig Lipset has a powerful perspective on the potential of emerging technologies, and how to successfully combat inertia and encourage adoption in clinical studies.
He joins Medidata CEO Anthony Costello to explore the origins of decentralized trials, the potential of Virtual Twins, and how the Buffalo Initiative is promoting research into understudied rare diseases.
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How are bold ideas born, and which ones survive to eventually shake up the status quo? We'll hear straight from our industry's greatest visionaries who are making waves and learn how they turned their dreams into disruptive reality. This is from Dreamers to Disruptors, a podcast powered by Medidata.
Imagine giving your time, your blood, your scans, and your data to a clinical trial, and then never seeing what your own participation helped create. For many patients, clinical research still asks a lot and gives back too little. And in rare diseases, the traditional path can be especially slow. Patients and families are often the ones pushing hardest to move research forward. Our guest today is Craig Lipset, a recognized leader in clinical trial innovation and medicine development. Craig is the founder of Clinical Innovation Partners and co-founder and co-chair of Decentralized Trials and Research Alliance, now Digital Trials and Research Alliance. Before that, he spent nearly a decade as head of clinical innovation at Pfizer, where he helped lead digital trial initiatives, patient engagement, and collaborations across therapeutic areas. Craig has helped move several important ideas closer to the mainstream, from decentralized trial models and remote participation to returning results and data to participants. He also brings the perspective of an advisor, board member, educator, and patient advocate with current work that includes the Buffalo Initiative and its mission to create new paths for ultra-rare disease development. In this episode, we talk about what happens when patients are not just participants in research but drivers of it. We discuss decentralized trials, the Buffalo Initiative's work in ultra-rare research, patient access to data, and how digital and Virtual Twin tools could change who gets to shape research in the future. This is a conversation about trust, access, and what it will take to move clinical research from talking about disruption to actually delivering it. Welcome to from Dreamers to Disruptors.
Hi everybody, thanks again for joining from Dreamers to Disruptors. I'm very pleased today to have my good friend Craig Lipset live in the Medidata studios. Craig, thanks so much for being here, and I know for we probably don't have anyone in this audience that doesn't already know who you are.
Well, maybe I don't know about that, but you know, I'm thrilled to be here with you. I've been waiting for my invitation to come down to the studio, and I just want to authenticate for your audience that the background is real. It's not a virtual background here.
It’s not AI-generated.
It's not. So I'm looking forward to rummaging through here, and you might want to check my bag on the way out.
We're going, we're sort of going for a Tiny Desk kind of feel back here, but I mean, I mean, there's a guitar if you want to play and sing something.
It's got Taylor Swift on it.
That's real Taylor Swift. That was my Halloween costume here at Medidata a couple years ago.
Not gonna shake that off.
Well, we've got a zillion topics to cover today
We do.
And these are the kind of podcast sessions that I love the most, because not only because you and I go back a ways, and we got a lot of shared blood, sweat, and tears over the years, and some successes maybe in there too, which we can talk about, but also really, you've been a mentor of mine for a long time. I would say all the way back to the beginning. We met in maybe 2009 I want to say 2008, 2009 when we started Mytrus. You were at Pfizer. I want you to tell that story in a second, but you came into this world of what we were trying to create in virtual trials, now decentralized trials, as really a strong voice from the pharma side that there was a need for this, and people like us that have tried for a long time to innovate in this industry. I think that we've learned along the way that you need, you need an innovation, and oftentimes I think that's a technology, but then you also need a market or a willing partner on the other side of the fence that wants to kind of take this into real time, and you were that person for us at Pfizer at the time, not by yourself, I mean, we had Andy Lee there, we had Briggs there, right. There was a crew of innovators that sort of partnered with the Mytrus team to create this, this new thing, and I think a lot of that had to do with you. Like, I remember you really being the driving force, and I've sort of looked up to that for a really long time.
You know, Anthony, what you're describing, though, reminds me of that TED Talk with the dancing man video, right, that like every one of these movements, you know, there is that that knucklehead that gets up first and starts dancing at the concert, and the rest of the crowd kind of looks at them like that person may be a little bit off, and the real ones who start the movement are the next two who follow them, who kind of make it safe for others to be able to go, and so you know, maybe for that scenario I was the dancing man, but it was really the others that then started to get up and dance that then turn it into something of a movement. But you're right, like we do have some history around this space, and it's kind of cool that we're both still here at a time when you see decentralized guidance documents from regulators around the world, it's, it's hardly like a mission accomplished banner on the deck of the aircraft carrier by a long shot, but the state of adoption is certainly very different, and, like, you were describing, like, you need a champion for these things, but, like, the Gartner hype cycle has on it, you need like a trigger, and in a lot of ways the pandemic was that trigger.
Yeah, and I was gonna say I think specifically with decentralized trials, I think it's been through a couple hype cycles, some of which driven by necessity, like during the COVID era, but anyway, we're getting ahead of ourselves. So let's go back, because I want you to talk a little bit about those days. You had a particular role at Pfizer. You were head of clinical innovation. It wasn't a time when every company had a head of innovation yet. Heads of digital, heads of innovation were still a newer concept at that time, especially, I think, in very large pharma. So, I just want... I think it'd be useful for the people here who may not know you so well to kind of talk about how you got started in that era, how you turned your career into a focus on not only new innovation, but really I would say you're focused on the game-changing innovations, the things that really move the needle the most, and it's some of the biggest companies.
You do… a little side note to that, that wasn't actually my title at the time we started doing the remote trial. My title at Pfizer, when I came in, was a director of molecular medicine. So, which you'd say feels like quite a stretch to say, hey, how about we try to like get a decentralized trial going for the first time. My, my origin story advisor, whether you consider this like a superhero, super villain origin story, you can tell me at the end. Look, like a lot of folks in our community, I started as a research coordinator in grad school, working primarily in stroke research at the VA Medical Center and at Columbia Presbyterian, and at the time we were doing a lot of innovative work looking at medical imaging as a way to try to measure the amount of salvageable tissue in the brain, and as much as I loved the clinical trial, I love this idea of new technology meeting new medicines, in this case, around a new endpoint, and so I doubled down on that, went to Parexel, helped to launch what became Perceptive Informatics. I was the first project manager, and then ran the medical imaging business there, and then went over to a small biotech, because I kind of felt like I didn't have ownership over a molecule, and I felt like I was kind of missing that. So I went to a young biotech company, I ran clinical and regulatory there, got an IND file. They were bought by a large pharma, and I was kind of looking around, saying, "What's what's missing on my resume? I'm a young guy, I didn't have like a big pharma logo, so I said maybe I'd do that for like two years, so I went to Pfizer, and two years turned to 13, 14 years very quickly, maybe because there was an org change every two years, so it always felt kind of fresh and new. When I was there, I joined the week that torcetrapib failed. Torcetrapib was the follow on to Lipitor. Lipitor, at the time, was the highest grossing molecule in the history of pharma, and so heres a company that had an $18 billion molecule, it was going generic, and the therapeutic that was supposed to fill that gap just failed. And I joined on Monday, and they announced it failed that Saturday, and so you know everything starts to get kicked up in the air. The company went out and bought Wyeth. There's reorgs happening. We are shaking up our whole development organization and shifting to like an outsourced model with two key CROs, like everything was kind of up in the air, and that's when I kind of pitched this idea to the leaders there, to time John Hubbard, running DevOps, Freda Lewis-Hall, who was the chief medical officer of kind of creative destruction. We're breaking down huge chunks of the organization, but we can't kind of outsource innovation in our future, and so let's create a small team to focus on just that. I already had a little bit of credibility with them, because we were able to get that remote trial up and running, you know. That remote trial, to me, to me was very personal. I had been diagnosed just before joining Pfizer with a rare pulmonary condition, sarcoidosis, and so I had my own journey of self-tracking my own health data, and how can I use my health data to better improve my own outcomes, and that got me kind of into this e-patient movement that was happening that I didn't know existed before then, and so I started to engage with this e-patient community leaders like Dave deBronkart and others at the time, and that kind of helped me to appreciate this possibility of shifting the epicenter of trials from research sites to the patients themselves, because of my own journey as a rare disease patient at the time, and so it was a fun opportunity for us to get to connect when we were, you know, kids with long heads of hair, high hopes and aspirations.
Yeah, I mean, I've clearly ripped my hair out over the years. You still look like you're doing all right.
Yeah, yeah, it's all it's all modern medicine.
Yeah, so let's tell people a little bit about the remote trial, for those that may not know.
Yeah, as you were mentioning, you know, getting that going required a lot of leadership buy-in, and at the time with leaders that are well known in this industry, like Briggs Morrison and Andy Lee, and others, having a great, you know, academic thought leader as a partner, like Steve Cummings, and then operators like yourselves to be able to bring that together. You know, at the time, the company was willing to take big bets, and for us this remote trial was just that. For those that aren't familiar, this was sort of predating a lot of decentralized trials. Really, the only prior art with industry in that space is some work that Lilly had done early on using virtual approaches for certain visits in trials, I think it was with one of their early erectile dysfunction medicines, and so you know it was kind of a new idea still to say, could we decentralize an entire trial under an IND. Uh, Steve Cummings had done some of that work with nutraceuticals, and so he had some operating experience around that, and so it was this journey of, could we take a molecule in the Pfizer portfolio, in this case Detrol, that was already approved for overactive bladder, and reproduce the registration trial using entirely decentralized elements that had never been put together before. The elements themselves weren't new. It was this art of can we put it together to create something radical and different. The idea of eco or video or eConsent, we didn't have to invent, but they had never been put together in this way. There are a lot of things that worked, a lot of things that didn't work. We did get through an IND, we got through FDA inspections, we got through a lot, but we didn't get through enrollment the way that we wanted. There's a lot that I'm sure we would do different today around our recruitment strategies or otherwise, but one thing that we did try to do was be really transparent about what worked and what didn't, and kind of embrace this idea of we're going to get this far down the field, we're going to place the ball here, we're going to be really open about how far the ball got and what we learned and didn't, and let's see if others can step in and keep moving that ball down field, and I think we started to see that with other companies like J&J doing work with the Chief Study, and so many others that then followed the work that you were able to do with the adaptable study here with Medi, you know, I think all of those kept moving the ball downfield, so that we could build enough know-how and experience that, quite honestly, when the pandemic hit, there were tools and methods we could pull off the shelf and use that we just weren't taking advantage of.
Yeah, and the regulatory approval side of that, I think, was really important at the time. So, it's... I'm glad you brought up your own health journey, because I think if you look at many of the things that you've done so far in your career, I think you can draw a line from this interest in transparency and autonomy, patients understanding what's happening to them, having access to their own data, being able to reduce burden by doing things in a decentralized way, and so on. You can sort of follow that thread through a lot of the innovations that you have personally tackled on behalf of a company you are working with, or on behalf of your own organizations that you have founded. In the meantime to kind of pursue those end goals, so you know, at Mytrus and Pfizer, we got approvals for things like eConsent. We had the first approval to run a decentralized trial under an IND. We got approval for remote capture of, you know, safety data. We got approval for doctors overseeing clinical trial patients across state lines like these things were never pieced together in that way before, and it really did lay the groundwork for a lot of what we saw happen in Covid being possible because there was prior art, and it laid the groundwork for a bunch of companies too, like Science 37 came after this, Medable came after this, a lot of the focus that you see, even in eCOA programs around the industry, I think we're heavily influenced by this push for decentralization, because there was a lot of space between a few eCOA instruments, which lots of people were doing, and a fully decentralized trial, which nobody had done yet, and we started to explore that space, and I think, to your point, we're still exploring it with maybe a couple blips, like Covid, along the way.
You know that that Covid example is an important one, as far as a triggering event, right? Because there was this unprecedented sense of urgency. How do we sustain our portfolio of medicines? How do we ensure that patients can keep access to medicines? We can continue to monitor them, we can continue to generate evidence of efficacy and safety in this unprecedented time. And fortunately, again, it didn't require people to invent anything new. All of these tools and methods were at our doorstep, and we knew how to navigate regulators around them. So kind of the next question for many would be, well, what happened after Covid? Then, right, the methods that people deployed aggressively during a pandemic are not methods that are sustainable in business as usual after a pandemic. And so, as the pandemic receded, the enthusiasm about using these tools remained, but the way that we were implementing them was not the way companies needed them for kind of business as usual in kind of steady state. That of course converged with a lot of economic sort of step backs, which brought a lot of portfolio reprioritization, a lot of reduced budgets in pharma, and so for a lot of companies there had to be this step back to reevaluate which methods are right for our portfolio. Who are the right partners for us going forward? So I think it was natural to see kind of this step back in adoption. The real question to me was, would industry be able to come back from that, or would they move on to other shiny objects and get excited about the next new digital innovation? I can say that, you know, in our community with DTRA, and we can talk a bit about what DTRA is. We have a community with pharma and tech CEOs and sites. The pharma companies are all present there because they remain committed. Adoption isn't easy, but some of them are really doubling down on making sure that these are enterprise tools available for study teams, and we'll see what kind of metrics, KPIs, and evidence we're able to generate now as a result.
Yeah, I think we should, I think we should cover DTRA for a second, because DTRA, you should tell the origin story of DTRA, but, but founded around the idea that decentralization could become mainstream, and it would take a village of companies, vendors, innovators, pharma CROs, kind of buying into that image to make it real. It's now pivoted a little bit more, I think, to be focused more on digital than just purely decentralization. But why don't you talk a little bit about why did you start DTRA, and what was the original vision versus kind of where it's ended up as it's gone through its natural kind of evolution to stay in step with where the market is at?
Just before the pandemic, Amir Kalali and I started discussing this idea of what could a consortium look like in this space? And for those of you that don't know, Amir, he curates an event called the CNS Summit, and like many other events, we found we were having these panels and conversations with you, with many other leaders in this space, and we would have these rich conversations about what is needed to improve adoption. The event would end. We'd scurry back to our day lives, and then maybe five or six months later, we'd regroup at the next conference and pick up the conversation where we left off. And so we started to talk about what can we do to fill that space in between, so we can actually get things done to improve adoption and make it easier. All of a sudden, we're having these conversations with leaders and pharma and other companies. The pandemic hits, people get a little distracted, rightfully so. But later that year, we're still able to get the Decentralized Trials and Research Alliance (DTRA) off the ground. DTRA is a nonprofit membership organization. Our members are most of the leading pharma companies, your clinical tech companies, your CROs, your big sites, health systems, government agencies, we're a public-private partner to the FDA, work closely with PMDA, with the authorities in the UK and across Europe, but in within DTRA, I'd say there's two things that we do. One is there's a set of initiatives our community work together on trying to ease the challenges around adoption through different work product that they create, maybe it's templates, maybe it's online tools and resources, and we make those all publicly available at dtra.org. We have this tube stop map that navigates the development process, and within that there are a plethora of resources for researchers. And then we create community, we create these places and spaces for people to share best practices and find the next partner that they may be in need of or looking for. But the people in our community don't just work on decentralized. Most of them are also responsible for other digital and innovation efforts within their pharma companies, their biotechs, their sites, their portfolio of solutions. And so it was kind of this scope creep that we've had over the last two years that our initiative started to take on real-world data and real-world evidence, started to take on other aspects of connected devices and digital health technologies, started to take on around AI. And so we had really one of two choices: either we prune back and we say, “Nope, we're just decentralized, these things are out of scope,” or we embrace it. And so we took that ladder, and now DTRA's first initial is ‘digital.’ ‘Decentralized’ is still a core resident of this house that was a commitment to our community. This is in no way meant to signal that we think we're done with progress in decentralized, but we can do more with the community that we've built, and I'm thrilled to take on that challenge now with our existing community and a number of new folks that have joined us,
I think it makes sense, and you know, decentralization is by definition digital, right? I mean, there is, there is no really useful tool in decentralization that you're not putting in front of a patient, and so I think that fits, and I like the fact that there's been an expansion to the remit of that organization to pull more constituents.
And even process innovations like home health or how we can leverage and work with healthcare providers and local communities, they may feel more processed than technical, but there's always that digital hook back to make them work and to make them operationalized and to make that and make that flow be transparent.
Yeah, so, and you mentioned a lot of things when you talk about DTRA. You kind of just glanced over a whole bunch of innovations throughout the years that have themselves spawned entire companies or strategic shifts on the part of pharma and regulators, and then there's international regulation, and kind of a very special lens that you have to put on all these things from an international standpoint, but I think a lot of those innovations go to something I know is passionate, you're passionate about, which is the hype cycle, and you and I have talked over the years a lot. You were actually the first person to introduce me to the Gartner hype cycle, because I hadn't heard of it before you showed it to me, and we've, we've dissected this thing together several times over the years, and argued about where things were, and looked for, looked for the right proof points about whether something was real or not, and you're kind of at the point now where I think you're literally owning your own version of the hype that's like from the brain of Craig Lipset, this is the way this is where things sit on the hype cycle, and you know, I say all of that to sort of introduce this idea that I really want to get your thoughts on today, and that is there is an enormous amount of new innovation technology, call it digital, whatever you want, that we throw into the top of the funnel, and it sits somewhere in a hype cycle, and we can debate where, but very few of these things ever get to steady state, and I don't care how many years you go back, if you want to look at the top of the funnel, the process of getting, you know, through the funnel over the hype cycle to regular adoption, it's very few technologies that make it all the way, and even though people like you have devoted your careers to like pushing to that point, because you're not a guy who's interested in just the latest shiny object so much as the needle-moving effect that that that innovation can have once it gets to steady state, but so few things do, so I want to hear your thoughts about why that is. What are we doing that we should be doing differently to sort of make more of these things not only real but make them worth the effort that goes into getting them through the first part of the funnel, which is not a cheap or easy experience, only to never realize the full potential further down where it really should be able to get to.
I have to say, I love this story about positioning of funnels, and in large part because it's how a lot of our industry operates. Obviously, for trials themselves, we talk about recruitment funnels, but within pharma companies, when we're talking about our medicine portfolio, we're talking about a portfolio, right, of early-phase bets that we navigate and shepherd through the development process, knowing that a certain number of those have to be realized, they have to come out the bottom and be able to scale often globally to be meaningful. It's almost, that's the definition of innovation, is an idea from which you are actually able to derive value and impact. Otherwise, they're just ideas. And if we take that image of the drug development funnel, and we say, now let's take the non-drug portfolio, let's take these innovation opportunities and treat them with the same rigor and discipline. Let's put them in a funnel. I think what we start to realize is we're really good at putting opportunities in the top of the funnel, we're really good at scouting them out, getting excited about them, and we don't see them through with anywhere near the same rigor and discipline that we do the molecules in our portfolio. Think about blockchain and decentralized and real-world data, and now generative AI and agentic AI, and all of these opportunities are kind of all sitting in this clogged, constipated process. So, why is that the case? Because if we don't get to this root cause of fixing the funnel, all we're going to keep doing is throwing more stuff at the top, more opportunities at the top, and I would argue that the last innovation, the last digital innovation that's made it out of this funnel and reached that enterprise scale globally is probably electronic data capture and everything else we talk about and get excited about, but then it loses momentum, it loses steam, because it falls into this morass that requires change and commitment, and those things don't just happen, they require investment, they require energy. If a pharma company were going to switch their platform to Rave tomorrow, they wouldn't just have a leader stand at a podium and say in 2027 we should be using Rave and walk away, but that's what they do for a lot of these other innovations, they would hire people and they would set targets and people would be accountable and if on December 31 the platform didn't switch over to Rave, somebody would be held accountable. We don't do that for these other innovations.
But why don't we do it? Because it's not like we don't understand these pieces, right? It's not like pharma doesn't have an appreciation for change management or the use of retraining their tools or the bringing in of SIs or whatever the pieces are that are necessary, it's not like they don't have the budgets, it's not like they don't have the vendor choices, it's not like they don't have the partnerships or the willingness on the part of companies like Medidata or CROs that want to help get them over that hump to steady state adoption, so what is the piece that you think is most responsible for us being in our own way, so much that a 26-year-old innovation like EDC is the last thing you can point to as an innovation that really moved the needle on an industry.
There's a couple of things that are conspiring against us here. One is, in this part, I can empathize with. Leaders of development organizations, you want your study teams to have ownership and accountability for the delivery of their molecules. The more that you centrally dictate how the study has to be run, you have to use this tool, I want you to use this approach, the less autonomy, control, and accountability that team ultimately has. It'll become easy for them to come back in two years and say, "Hey, boss, we missed enrollment, that's not on me, that was on you. You forced me to do these things that I never believed in, I never thought would work in the first place.” Development leaders want their teams to be accountable, and so the way you make them accountable is you give them more autonomy and control, which means you dictate less to them about how they run their study. Yes, you will dictate we're going to use this as our enterprise EDC platform. Here's our short list of eCOA solutions. It kind of narrows some of the playing field, but you put them in a fair amount of control to dictate how the game is going to get played. In parallel, we're in an ecosystem where it's really hard for leaders to invest in change beyond the short term. I would say change beyond 18 to 24 months is really hard for leaders of organizations. Honestly, they don't know if they're going to be there in 24 months, and so if I'm given the choice of 10 really small incremental things I could do tomorrow versus something that's much more ambitious and game changing for the enterprise, I'm probably going to do those small incremental things, because the big thing is going to take 24 to 36 months to drive through the organization and see a return on, and my leadership is going to lose patience. And we're seeing that play out today. Without naming names, there's a top 10 pharma right now that just turned over its CEO, just turned over its head of R&D. I think that's indicative of investors losing patience with change that was really good, but was just going to take too long for them to see the results of.
Yeah, I mean, it's interesting. I know this is maddening to you too, but those same companies that you're talking about still vesting power in lower levels of the organization to make study by study decisions, their stated goal is almost always beyond this time horizon that you're talking about. In fact, the company that I think you're referencing has specific 5 and 10 year innovation goals to move the entire industry, to move their entire pipeline, their entire clinical development program toward many of these new, innovative, faster, more efficient ways of doing things, so there's, you know, there's something clogged in the machinery there. If you have a 5, 10-year vision to do everything differently, that's going to take incremental steps all throughout that time, but you won't take the first step because of an empowerment challenge that you're having with the teams that run the trials. It seems like that's the place where the funnel clogs up in your view, and so my question is, like, what do we do about it, right? Because we can't go another 26 years on EDC and think that what we're all in this industry to do is bring faster therapies to patients, to say nothing of the fact that AI, which you've now mentioned a few times, is going to explode the discovery end of this funnel and throw a lot more things into the realm of possible clinical trials, which we will only be able to execute against if we're moving much, much faster. So I think you're making a strong case for the way things have been and why they've been that way. But my question is, How do we break this log jam once and for all? Because it's not sustainable.
Honestly, that to me is the grand challenge right now. And to be honest, I'm getting too old to worry about the incremental things in the funnel. I had a boss at Pfizer, Rob Goodwin, I used to work for in the day, and he used to say to me, “Craig, doesn't your head hurt from just banging it against the wall here all day long?” And when I was younger, it didn't really hurt that much.
It hurts now, and I think Rob's head might hurt a little bit more.
Maybe, maybe. But, like, okay, I'm just less patient and tolerant for the, for kind of, I'll call them the excuses, because we'll hear all the reasons why we can't do these things. The reasons why we say we can't innovate to me are the reasons why we must innovate. The reasons why we can't innovate that we'll hear is, “We're a highly regulated industry and data integrity is paramount, and patient safety has to be our number one priority.” Agreed. But if those are our three pillars, as an example, how can we tolerate the status quo? Why aren't we focusing on innovation to make those pillars tighter? Why aren't we electronically sourcing data for all of our studies when we know that's how we improve data quality, that's how we improve and monitor patient safety better and faster and in real time? And so it comes back to, okay, great. How do we fix this funnel? And to me, right now, I would say I'm leaned in on on two paths that I'm invested in. One is, how do we make the existing funnel more lubricated? How do we make it easier for these opportunities to have persistence and move through? And those are some of the things that we're doing together through DTRA. Whether that's de-risking, whether that's sharing evidence and examples, what else can we do with regulators or others to try to move those through? And then, in parallel, how do we build a new funnel, one with a group of stakeholders that maybe are a little more agile than traditional pharma, and that's not to say we're replacing pharma, but how do we leverage this other parallel funnel to de-risk and move these through in regulated trials, so that it makes it easier for pharma to do what they often do best, fast follow? And so that to me is, you know, this mix of how I split my time with DTRA on trying to fix the current funnel, and with the Buffalo Initiative as a place to say, how can we build a new funnel and de-risk digital twins, de-risk these innovative opportunities that we know we can implement it's just maybe too hard for pharma to make happen.
Yeah, well, I think it makes sense to parallel track those things. And let's come to the Buffalo Initiative in a second, because I want you to kind of talk about that, but I just want to push one more time on the current funnel and the current log jam and the lubrication, as you put it, to sort of fix that log.
Sometimes I think of it as a plumber, as a plumber with a little bit of good Drano, sometimes it's MiraLAX, whatever analogy your audience is most comfortable.
I’m not sure they're going to be comfortable with any of those, but they're out there now, so let's just stick with it. So, I think that you're, you're, you're framing this up now in the context of de-risking, and so I just want to ask you kind of one more point on this. When you think about the phenomenon of, and I know I'm oversimplifying it, but let's just, let's just say a simple view of the world is higher leadership in these organizations have long-term views, very open to spending money and changing the whole way clinical pipelines of the future will work to get drugs through faster, have have more years on patent, have better competitive advantage against competitors, and so on and so forth, but then in the lower levels the real like project teams that run the block and tackle mechanics of clinical research, there's less motivation to do that, right? It's like the old adage of, “You'll never get fired for picking IBM,” right? You'll never get fired in this industry for looking at 49 vendors, picking the point solution, and not trying to be too innovative on your trial until enough other people have done it that you're in the steady state hype curve with no risk. So, if you, if you can do things like de-risk that process, do you think that that de-risking ever touches those levels? Like, is there something that DTRA or these other de-risking ideas can do to help that study manager decide that they're going to be innovative, or are we just sort of stuck at that part of the funnel, because no one's willing to be first, or even 10th in a lot of these cases.
Nobody wants to be first, nobody wants to be last, but nobody wants to be first. And I think that, you know, there was a, my other favorite podcast would be, would be Freakonomics Radio, because I do buy into this belief that misaligned economic incentives are what drive all things in our ecosystem, including clinical trial success and failure, including the adoption curves around these. What's in it for that study team lead to say yes to this new and innovative approach? She's not getting paid more, she's not being given more time or capacity to consider the requirements and the reviews with legal and others. Quite honestly, like most of us, she wants to go home at the end of the day and have dinner with her kids and not be on calls late at night talking about requirements for the eConsent solution that's never been used in their company before. I don't blame her. Why would I say yes to that? Even though it might be good for my study, it's not just good for my sanity, and no one's rewarding me for that. So, what are the incentives that organizations should consider?
The top level corporate strategy? It should be the incentive that drives that.
Does that trickle down to my compensation, my recognition, or does it just stack up as risk for me and my compensation, that in the end of the day, if this delays my study by three weeks, I'm going to get dinged, not patted on the back for taking a chance with something new? So, there is certain incentive alignment that we need to certainly think about to give those people reasons to say yes, but through some of these collaborative efforts we can also make it less friction and less hard. They shouldn't have to stay late and miss dinner with their family to use that new eConsent solution. And so, how do we make the adoption easier, bring more fluid, less friction to that process, so that they can say yes without making compromises and sacrifices to their own personal lives and sanity?
Yep. Okay, I think I think it makes sense. It's, it's an interesting, I think it's a really interesting paradigm, because you've got to have top level corporate strategy, you've got to have top down leadership around innovation. It doesn't matter what industry you're talking about. I think there's... we would have you know, what did Henry Ford say? “If I asked the, if I asked the customers what they wanted, they'd say a faster horse,” right? So, if you're going to have top-down innovation, wide-sweeping, game-changing, revolutionary ways of doing things in a different way, there has to be top-down leadership. You're saying there also has to be bottom-up incentive structures that de-risk it for those people, and I think that makes sense. So, it's not so much about one of the things you've said to me in the past, is we lose interest in this funnel. It doesn't sound like you're saying so much that it's a loss of interest, it sounds like you're saying it's an incentive misalignment, or there's not enough choreography, maybe within these complex systems, in order to… You know, everyone's got to be rowing. See, how I got the Norway soccer game in there? So everyone's got to be rowing in the same direction, one way or the other, if we really want these big transformational things to happen in a timely way.
But the losing interest part to me is the way that manifests is we have leaders that get excited about these things, they'll talk them up at the town halls or the next investor conference, but are they making the long-term financial commitment to the change that's needed for that to actually drive meaningful adoption in their organization? I can think back to one particular flashback. Maybe it's a traumatic experience in my past. I'm not sure. A head of ClinOps at a major pharma had me come in. They had been workshopping and developing some capability to better integrate patient voice during planning design and planning a study and study design, and we did this session with all of their, you know, Clinops leadership, like sort of minus two in the org. It went great. We brought in patients, we talked about how feasible this was, and at the end he stood up, and I remember distinctly what he said. He turned to the group and he said we should be doing this for all the studies in our portfolio, and he sat down. And I said to him afterward, “You just killed this, because the only thing the people in this room heard was the word ‘should.’ That's not a mandate, that's a nice to have, it's a luxury, and if you really want to see that change happen, you say ‘we will.’” And ultimately years later in that organization they did, and the way that manifested is the protocol review committee that all studies had to go through began to systematically ask and signal to the org that they were going to do this. What insight did you receive from patients, and how did it affect the design of your trial? And that's how you drive enterprise change. You make those types of commitments, and you signal it.
Yeah, I think that's right. So, let's go to the Buffalo Initiative, because this is your other parallel track, and it's innovative, and you've done a lot of these things. Right, we didn't mention it yet, but you're an advisor to Every Cure, and the work that David Fajgenbaum is doing. You're also on the board of Circuit Clinical, a company, very innovative company that's looking at new ways of supporting clinical trials from the site side and bringing groups of sites together into consortiums that can do these things much faster, I would kind of put all of those in a, in an innovation bucket that, like you said earlier, is more, more of a process piece, this kind of site conduct piece, or in David Fajgenbaum's case, sort of reusing information for a different outcome or a different purpose. Buffalo, I think, fits into that in a way. So, can you kind of talk about those things as the other track of what you're doing around the edges of pharma to try to innovate?
And if anybody slipped into this episode without listening first to the David Fajgenbaum interview that you had, make sure you're clicking back in time and checking that one out, because…
That's a good one.
…most in our community probably have heard his story as a physician, as a patient in the Castleman community, and drug repurposing, and what they're using today with AI and smart, innovative pathways for evidence generation around how to repurpose these molecules. Right, so think about that. So, yes, they're using AI to develop this incredible map to figure out which molecules might also be able to serve other unmet needs, but then they're not budgeted and resourced to run big industry-grade clinical trials to answer the question of if they actually do. They're going to pioneer smarter ways to generate evidence, whether with real-world data leveraging registries or very smart designs for clinical trials, and that will de-risk smart ways to generate evidence for pharma to learn from. So that's great, and that's going to help us to leverage existing molecules, but we also have innovative molecules that are out there in indications that don't have an existing molecule that can be repurposed. In those areas, we need new models for how to move those molecules forward. Let me give you an example. We talk about rare diseases, and the industry that we're in embraces rare diseases. There are over 10,000 rare and ultra-rare diseases. Our industry will cross off the first few 100 at best. There are 1000s of these indications that will persist with unmet medical needs. Children with neurogenetic diagnoses that are alphabet soups of letters, right? Your child is diagnosed with a CACNA1A mutation, a FOXG1 mutation, and what does that mean? You're, you've got a child now who is having chronic seizures, they're they're not communicating, their cognition is impacted, their movement is impacted. Who's coming to help you? And so very often these parents have come together to create communities, finding those other needles in haystacks using social and other vehicles, and they create nonprofits, and they raise money, and they say maybe we could invest in research, and maybe if we could identify a molecule with an academic group and a CRO, maybe a gene therapy, maybe pharma is going to come and pick it up, maybe if we can even get it to the stage of an IND, it'll be de-risked enough that pharma will come. And what these families are learning is no one's coming. The indication is just too small. It's just never going to be commercially sustainable for our traditional biopharmaceutical ecosystem. So, you either beg pharma to care, or you do what these families do, which is you troubleshoot and you problem solve and you figure it out. And what we're seeing today are a number of these patient groups moving their own molecules into phase one, where they are the sponsors of those molecules, groups like the FOXG1 Foundation, the TESS Foundation, and others aren't waiting, and they're not bemoaning the lack of interest from industry, they're doing what these parents in the rare disease community do, which they figure it out, and they do it. And so, the Buffalo Initiative was launched by one of these rare disease mothers, Sunitha Malepati, who, whose daughter has a CACNA1A mutation, who helped co-found the CACNA1A Foundation in that space. But, she saw this emergence of this new ecosystem of sponsors, of drug development patient groups with their own molecules that they're holding on to, but each one was trying to figure this out on their own. They were bake sailing their way to fund INDs. They were kind of hacking and learning how to be drug developers. And so, the Buffalo Initiative was created as a nonprofit to have a fund as well as some development capability to be able to share with those patient groups to move their molecules forward. It's a fund that's blended capital, so it's a bit of philanthropy, but also can generate a modest venture return for for stakeholders. It's back today with the Chan Zuckerberg Initiative, the Biohub, as well as Renaissance Philanthropy. And… and that's moving forward to support that community. Okay, that's a great story. Right, patients are rising up, they're not just taking seats at pharma’s table, they are setting their own table and their own destiny. Cool. What does that have to do with the funnel? As I mentioned, these parents, they don't wait, they're not waiting for invitations, they're figuring things out. They have a sense of urgency like no other sponsor, and they're agile and have to be resourceful with their limited capital. If you introduce a digital innovation strategy to them that can help them move their molecule forward, they'll want it twice as fast. And so, what an interesting opportunity for pharma. This isn't competitive to pharma, they're not taking the molecules that pharma wants, they're going after the gaps, but they're going to do it in very agile and smart ways. How does that create this digital innovation sandbox for pharma, this parallel funnel where we can take digital twin strategies or others that we all aspire to, and maybe believe in, but how can these groups deploy them in INDs with regulators in the US, with regulators around the world? And look, they don't want to own these technologies, they don't want to own exclusivity in a process. We'll put everything in a wiki space, we'll share it all, and so what an interesting opportunity for pharma to have a seat at their table to be able to learn how.
It’s like a proof of concept training ground, almost for what's possible.
And just make it all open. All the feedback with regulators, all the concerns, and how they were addressed with research sites with other stakeholders, put it all out there and let pharma learn and let it be de-risked, and how can that help our funnel to unclog?
Yeah, amazing. Is there a place that you want to talk about for a second that people can go find more? Find out more about the Buffalo Initiative?
Yeah, check out buffaloinitiative.org We actually have a really cool portion of the website where we've created a, the first of its kind, this is a tracking tool for the molecules that patient groups are developing, where they are in their portfolio. What we found is in our industry, you can subscribe and get access to lots of data on which companies are developing what molecules and what indications and where they are in development, but here we have nonprofits that are developing molecules, and there was no central place to see that. We now are tracking over 50 molecules that patient groups are the holders of that are in various stages of development, whether preclinical and peri-IND, straight through IND, and into the clinic.
Yep, and you've mentioned in that, in the context of that story, you mentioned Virtual Twins a couple times, which is another area I know you and I are interested in. I think you know Dassault Systèmes and our life sciences team here are very focused on the creation of more and more Virtual Twins, digital twins. And we've done that for lots of process pieces of clinical research, twins of sites, of protocols, of budgets, of enrollment curves, and so on and so forth, that we use to help simulate a next trial design that's really fit to work, that's really set up to be low burden on patients and successful scientifically. But these stories about some of the things that you're doing, and David Fajgenbaum as well, seem like a perfect match for a Virtual Twin scenario of the future, where patients having more and more of their own data about their own health journey, their EHR records, their continuous health monitoring data over years and years from wearing devices, and what have you, those things will become a better and better digital Virtual Twin of the patient. Is there a place in these initiatives for those data to be volunteered into a research process, so that you can accelerate it, especially in areas like rare, where there just isn't a big enough population to get some of the traditional kind of statistical power that you're looking for when you set up these protocols?
I love how you set up this digital twin, Virtual Twin story, because I think for a lot of folks in the community, many maybe in your audience, when they hear that term, like a lot of jargon in our space, they might think of one example. I think you know when we talk about eSource or decentralized, it's a lot the same. Like, I hear eSource, and I think each are the EDC, but of course it's such a wider ecosystem, and the same is true as we think about Virtual Twins. And I think you set that up so well to think about all of the things we can twin in this process to help us with portfolio prioritization and being able to twin the molecules trajectory study design, and being able to twin and run scenarios of dozens or hundreds of possible futures for different study designs, all the way through to digital twins of me using the diverse data that I have about me, as we shared earlier, my own e-patient journey sets me up well, like so many other patients who are connecting my health data, I have access to all of my data from wherever it lives, whether it was self-tracked or EHR or diagnostic tests. And so, how does that set up this possibility for a twin of me? And what does that start to mean and look like? Well, you can use a twin of me in my indication, and maybe I'm going to that twin can help us to design the study better. Maybe it means that some of the control arm patients in the trial could be reduced because you could propagate some additional digital twins to help round out that control arm. Maybe over time you don't need a control arm. Maybe over time your need for an active arm is even reduced. You know, there are initiatives out there today using AI to make scientific research, bench research, incredibly predictable, creating virtual cells and virtual tissues, so that when you run a science experiment at the bench, you kind of know the outcome beforehand, and we can do the same going forward with our clinical trials. And shouldn't we? This is another one of these examples of if patient safety is our top priority, then we should be sparing people being in studies, unless we really have high confidence in what the outcome is going to be. And so, how do we start to envision what these trials look like in silico before we start to put them, you know, in vivo and start to put this into my body? Now, what is the connection with that to this kind of rare disease, ultra-rare space? In rare disease, the feasibility of control arms is very often questionable, and the regulators have been very clear that in some cases the concept of a self-controlled study is actually the best way to develop your ultra-rare therapeutic. What do we mean by a self-controlled study? We mean that you have enough natural history data about me as a patient to understand kind of my run-in, and that the nature and course of my disease, it's not lumpy, it's not episodic, it's kind of just steady and progressive. And so if I have enough natural history data, say from registries or other ways that I'm sharing data, can I be my own control in a trial? If a regulator is cool with the idea of a self-controlled study, a digital twin isn't a compromise, it's an upskill, right? So we're not going to regulators saying, embrace digital twins instead of a control arm, here you've already said instead of a control arm, we're cool with historical controls. Digital twins kind of one up that. They kind of are an improvement over the status quo. And so I think there's a really interesting opportunity for us to use that as our as our wedge to build more comfort and confidence with regulators in the US and overseas around how we use digital twins as control arm replacements in our trials, and how does that then start to create more confidence in larger populations?
Yep, yeah, and I think you hit on it exactly. I mean, those of us that are working in the area of Synthetic Control Arms, or digital twins for control arms, are doing exactly this. And it's not just areas like rare, which, of course, is important, because you just simply, you can't put enough people together to create a control arm and an active arm, but it's not ethically appropriate to do that anyway, in many disease areas, even if the population exists. There are many disease areas where it just simply is unethical to give someone a standard of care by a coin toss, essentially, when they're hoping and counting on a new therapeutic intervention for a completely unserved population, where the clinical trial is sometimes the only hope. So, I think you're right. Synthetic Control Arms provide an early use case for the value of digital twins, because in those cases they just represent the standard of care or the natural history control, but as we go…
And you’re right in thinking about these areas where standard of care is palliative at best, right? right, it's one thing if we say there's a standard of care that was drug approved last year and it's really good and we're trying to do one better than that, but we have a number of these indications where those patients aren't so lucky, right, and at best they're receiving something that is comforting, barely, but not therapeutic.
Yeah, but the, but I think the real holy grail for Virtual Twins, digital twins in this industry would be for the active arm right at the point, and what excites me, and this is why I'm kind of, I'm kind of bringing this up in the context of the work that you've done with so many organizations that are just sort of right around the edges of seeing a humongous benefit from the perfection of this technology. If you can create an active arm, if you can create a Virtual Twin, in order to at least simulate the trial, if not like skirt around the need for the trial altogether, obviously, you've moved the needle and changed the whole industry. But I think what's most exciting about that is that we're now at the point, because of the way we capture data, the way that continuous data is more and more, a part, an affordable part of many patients' healthcare journey, whether they're on a clinical trial or not. Like this ring on my finger, and this watch, know the last seven years of everything I've done, better than my EHR, better than my doctor, better than me, certainly better than any clinical trial site that I just drop in on next year because I join a clinical trial and they sort of see me from scratch on day one, right? So these tools and the legislation around my right to have access to those tools and companies' responsibility to share those data with me, these are sort of, I think, the holy grail of making Virtual Twins a possible reality, because we simply have the interest on the part of healthcare, you know, normal everyday patient consumers, and we have the access to the information to do it.
You know, you bring up so many great points here, and if we say that that's our holy grail, this opportunity to eliminate the need for certain studies or eliminate the number of patients that need to be exposed to an active arm of an investigational medicine, because our predictive power is so good. These digital twins are going to be powered by your EHR data, the center data, and all these other sources, but if we're talking about investigational medicines that have not been introduced in a human before, it's also going to be powered by a deep understanding of systems biology and the underlying science, and that where, like, this… I went to your NEXT meeting earlier this year, and you know, hearing some of that convergence with 3DS and seeing the the Virtual Twin of the heart that I know that Dassault folks had really been pioneers in working with the regulators around, I really think it's going to be the convergence of being able to understand the scientific data as well as this clinical data. To be able to put these threads together is part of how we're going to understand not just how will I respond to atorvastatin, because there's millions of people that have taken atorvastatin that may look like me, but how will I respond to this investigational medicine that's not been introduced into a human system before, and that has to be our holy grail. And I think that with these pieces, like we're seeing deep understanding of EHR and connected data, phenotypic data, deep understanding of the scientific data, so that we can really get to the cellular level of simulation. I think that's where these threads are going to get really powerful.
Yeah, all right. Well, we covered Buffalo, we covered DTRA, we covered digital twins, we covered the funnel and the hype curve. I mean, we've sort of been all over the place. Let's, let's land the plane here. So, I don't know how many times you've watched the podcast, you don't have to tell me, but we always end the same way, which is we ask the experts a couple different things. If you had a crystal ball, where do you think the industry goes, and I'm going to give you a pretty tight time horizon. I'm going to say five years max. Where do you think the industry goes? And then sort of the second piece of that is, can you frame that somehow into a call to action, because what we ultimately want the audience to leave the podcast with is some motivation from what they hopefully have, have learned a lot from in these conversations, some motivation to go do something that is, that's that's that, that's connected to this sort of transformation agenda that I know we both share, but that is clearly so hard to achieve in this industry. So, five-year prediction, and what should all the listeners wake up tomorrow morning and go do to help you realize that dream?
I think that over the coming five years we will continue to see incremental innovations that kind of pop, especially in these kind of very discreet, doable examples. I'm going to pick on, like generative AI for medical writing, like that's a very doable use case. You don't have to change things at sites, you don't have to try to change things with patients. It's, it's a part of a daisy chain of process where you know there's still a review process that continues, it's just this one box in the process of now a writer is going to sit in Microsoft Word, is kind of getting replaced in upskilled. Okay, the rest of the process is intact, it's discrete, doable. I think we'll see more discrete examples like that, whether it's with agentic, whether it's with other solutions, and that's good. And I think for many of us in our jobs will have opportunities to say yes or no to either be embracing some of those more incremental opportunities or poo pooing them and saying that just seems hard, and I think the challenge for many of us is how do we find a way to say yes without losing our minds without losing our hair, without missing dinner with the kids, right? And so I think that's like the challenge that everyone in the community can try to find a way to get to yes to articulate what the real pain points are that stand in the way of them being able to say yes, but I'm optimistic that in the coming five years we will see some of these much more meaningful examples start to manifest. These much more meaningful, game-changing examples that I think are going to be heavily powered by a lot of the Virtual Twin conversations we're having. Maybe some may happen in pharma, maybe some are going to happen in some other pockets that we can't even anticipate yet, because one of the great powers of AI in our space right now is around democratization of drug development. Patient groups can be drug developers. Who else will academic groups start to license out less molecules and develop more on their own? And as we start to see this ecosystem widen, you know, I think we'll start to see others that maybe are a little more agile, and that's a good thing, we kind of need all hands on deck, and so I think in the coming five years we will see some really exciting examples, say around Virtual Twins, but they may not be with the brands that we're most used to hearing from.
Yep, I think that's right. And so your call to action there is… I just want to make sure I got this. So, your call to action sounds like that…
Here's my call to action for you.
That that lower-level person we talked about before, you're saying a call to action for them is to go ahead and say yes to the little box around medical writing, because it's something, and maybe it kickstarts…
Maybe we learn from that. I know it's hard for many of us to find ways to say yes, but I think that's kind of the grand challenge that many of us have to upskill ourselves and get more comfortable and confident with. But I think that for those maybe in more enterprise roles, I think we're used to those of us being in big pharma, being in the left lane on the highway, that like we're leading the pack, and everyone else is going to follow, and I think right now it's going to be an interesting time where some of us in the left lane need to pull over and let some others take the lead, and maybe we tuck in and follow behind from pharma, draft off of them, support them, kind of clear the way for them, so that they can do that, and I think the industry will benefit as a result.
Interesting. All right, Craig. Well, it's been great. I appreciate you being here today. Thanks for the conversation. We'll talk more about Buffalo Initiative as the time goes on, but I'm really glad that you're involved in that, and looks, seems like it could be a game changer.
I'm so glad to be here, Anthony. Thanks so much for having me. Thanks so much to the community here, and I'm telling you, keep an eye on some of your swag back here. It might…
No, no, no, we got.. we got cameras on.
Yeah, good idea.
Thanks, everyone.
Thank you for tuning in to today’s conversation. If you've been enjoying this podcast, please subscribe to our YouTube channel and follow us on Spotify, Apple, or wherever you get your podcasts. If you have questions for me or thoughts about the episode, drop them in the comments. I do read them. Thanks again for listening to from Dreamers to Disruptors, and we'll see you again next time.