Laurel: So mentioning the pandemic, it really has shown us how critical and fraught the race is to provide new treatments and vaccines to patients. Could you explain what evidence generation is and then how it fits into drug development?
Arnaub: Sure. So as a concept, generating evidence in drug development is nothing new. It’s the art of putting together data and analyses that successfully demonstrate the safety and the efficacy and the value of your product to a bunch of different stakeholders, regulators, payers, providers, and ultimately, and most importantly, patients. And to date, I’d say evidence generation consists of not only the trial readout itself, but there are now different types of studies that pharmaceutical or medical device companies conduct, and these could be studies like literature reviews or observational data studies or analyses that demonstrate the burden of illness or even treatment patterns. And if you look at how most companies are designed, clinical development teams focus on designing a protocol, executing the trial, and they’re responsible for a successful readout in the trial. And most of that work happens within clinical dev. But as a drug gets closer to launch, health economics, outcomes research, epidemiology teams are the ones that are helping paint what is the value and how do we understand the disease more effectively?
So I think we’re at a pretty interesting inflection point in the industry right now. Generating evidence is a multi-year activity, both during the trial and in many cases long after the trial. And we saw this as especially true for vaccine trials, but also for oncology or other therapeutic areas. In covid, the vaccine companies put together their evidence packages in record time, and it was an incredible effort. And now I think what’s happening is the FDA’s navigating a tricky balance where they want to promote the innovation that we were talking about, the advancements of new therapies to patients. They’ve built in vehicles to expedite therapies such as accelerated approvals, but we need confirmatory trials or long-term follow up to really understand the evidence and to understand the safety and the efficacy of these drugs. And that’s why that concept that we’re talking about today is so important, is how do we do this more expeditiously?
Laurel: It’s certainly important when you’re talking about something that is life-saving innovations, but as you mentioned earlier, with the coming together of both the rapid pace of technology innovation as well as the data being generated and reviewed, we’re at a special inflection point here. So, how has data and evidence generation evolved in the last couple years, and then how different would this ability to create a vaccine and all the evidence packets now be possible five or 10 years ago?
Arnaub: It’s important to set the distinction here between clinical trial data and what’s called real-world data. The randomized controlled trial is, and has remained, the gold standard for evidence generation and submission. And we know within clinical trials, we have a really tightly controlled set of parameters and a focus on a subset of patients. And there’s a lot of specificity and granularity in what’s being captured. There’s a regular interval of assessment, but we also know the trial environment is not necessarily representative of how patients end up performing in the real world. And that term, “real world,” is kind of a wild west of a bunch of different things. It’s claims data or billing records from insurance companies. It’s electronic medical records that emerge out of providers and hospital systems and labs, and even increasingly new forms of data that you might see from devices or even patient-reported data. And RWD, or real-world data, is a large and diverse set of different sources that can capture patient performance as patients go in and out of different healthcare systems and environments.
Ten years ago, when I was first working in this space, the term “real-world data” didn’t even exist. It was like a swear word, and it was basically one that was created in recent years by the pharmaceutical and the regulatory sectors. So, I think what we’re seeing now, the other important piece or dimension is that the regulatory agencies, through very important pieces of legislation like the 21st Century Cures Act, have jump-started and propelled how real-world data can be used and incorporated to augment our understanding of treatments and of disease. So, there’s a lot of momentum here. Real-world data is used in 85%, 90% of FDA-approved new drug applications. So, this is a world we have to navigate.
How do we keep the rigor of the clinical trial and tell the entire story, and then how do we bring in the real-world data to kind of complete that picture? It’s a problem we’ve been focusing on for the last two years, and we’ve even built a solution around this during covid called Medidata Link that actually ties together patient-level data in the clinical trial to all the non-trial data that exists in the world for the individual patient. And as you can imagine, the reason this made a lot of sense during covid, and we actually started this with a covid vaccine manufacturer, was so that we could study long-term outcomes, so that we could tie together that trial data to what we’re seeing post-trial. And does the vaccine make sense over the long term? Is it safe? Is it efficacious? And this is, I think, something that’s going to emerge and has been a big part of our evolution over the last couple years in terms of how we collect data.
Laurel: That collecting data story is certainly part of maybe the challenges in generating this high-quality evidence. What are some other gaps in the industry that you have seen?
Arnaub: I think the elephant in the room for development in the pharmaceutical industry is that despite all the data and all of the advances in analytics, the probability of technical success, or regulatory success as it’s called for drugs, moving forward is still really low. The overall likelihood of approval from phase one consistently sits under 10% for a number of different therapeutic areas. It’s sub 5% in cardiovascular, it’s a little bit over 5% in oncology and neurology, and I think what underlies these failures is a lack of data to demonstrate efficacy. It’s where a lot of companies submit or include what the regulatory bodies call a flawed study design, an inappropriate statistical endpoint, or in many cases, trials are underpowered, meaning the sample size was too small to reject the null hypothesis. So what that means is you’re grappling with a number of key decisions if you look at just the trial itself and some of the gaps where data should be more involved and more influential in decision making.
So, when you’re designing a trial, you’re evaluating, “What are my primary and my secondary endpoints? What inclusion or exclusion criteria do I select? What’s my comparator? What’s my use of a biomarker? And then how do I understand outcomes? How do I understand the mechanism of action?” It’s a myriad of different choices and a permutation of different decisions that have to be made in parallel, all of this data and information coming from the real world; we talked about the momentum in how valuable an electronic health record could be. But the gap here, the problem is, how is the data collected? How do you verify where it came from? Can it be trusted?
So, while volume is good, the gaps actually contribute and there’s a significant chance of bias in a variety of different areas. Selection bias, meaning there’s differences in the types of patients who you select for treatment. There’s performance bias, detection, a number of issues with the data itself. So, I think what we’re trying to navigate here is how can you do this in a robust way where you’re putting these data sets together, addressing some of those key issues around drug failure that I was referencing earlier? Our personal approach has been using a curated historical clinical trial data set that sits on our platform and use that to contextualize what we’re seeing in the real world and to better understand how patients are responding to therapy. And that should, in theory, and what we’ve seen with our work, is help clinical development teams use a novel way to use data to design a trial protocol, or to improve some of the statistical analysis work that they do.