In Part II of Kevin Davies' interview with Wyeth's Michael Krams, the adaptive trial specialist discusses the criteria and challenges involved in going the adaptive trial route.
What determines whether you will employ an adaptive trial design for a new drug candidate entering the clinic?
Krams: We have a well-structured process called opportunity review.... We go through the portfolio, and wherever there appears to be an opportunity to deploy our thinking, we engage in a discussion with the Learn teams.
There are three steps. First, we put a concept sheet together, where we assemble initial information about the decision problems we have to work on. Then we develop different scenarios that might address these problems and translate them into research questions. We collect relevant information about endpoints, biomarkers, patient population, decision rules, etc. We call that a scenario analysis. We compare different options and potential approaches to answer the research question.
Then we assess the value of each of these scenarios in terms of three dimensions: First, what is the information value -- how much information do we get out of a given amount of resources? Second, how [much impact does] this design [have] on the business case? Ideally, we want to work as efficiently as possible in terms of dollars, resources, and getting the correct decision made at the earliest time. The third logistical aspect is: What are the implications of doing what we want to do on drug supply management? How can we ensure that from this perspective, we can optimize the approach we want to argue for?
So what are your options then?
Krams: So at the end of this scenario analysis, we have different options, one of which may well be the traditional approach. We can compare whether another scenario may have advantages against that traditional approach or not. If there are advantages, they will be quantified in terms of information value. For instance, what is the probability of identifying the correct dose to take into Phase III in scenario A, B, and C? Do we have a more efficient way of getting the answer? Do we get the answer earlier perhaps?
The final step is to translate this scenario analysis into a simulation exercise, where we take the scenario most acceptable to the Learn team and run large-scale simulations against it. That simulation report is the basis for the final decision made by our governance body.
Are you the chief architect of these simulation studies?
Krams: In any engineering environment, the actual build of a system is preceded by computer simulation -- think of cars, planes, other things. Simulation-guided clinical-trial design was established many years ago by Lew Sheiner, Carl Peck, Don Rubin, and others. My mentor has been and is Don Berry -- he heads the biostatistics unit at M.D. Anderson, and works with Peter Mueller, (his son) Scott Berry, and Peter Thall. The adaptive trials as we now build them are the product of a joint effort of many: statisticians, clinicians, programmers.... The architects? Our statisticians are the architects.
What kind of drug candidate or therapeutic area is best suited for adaptive trial design?
Krams: There needs to be a research question with sufficient uncertainty around it. If we already know the answer and just have to confirm it, we can build a very efficient traditional design. But if we are not quite sure what dose to take into Phase III or which subset of the population would benefit most, then it pays to run an experiment to hone in where the answer lies....
In many drug development programs, there is insufficient effort in exploring the dose response relationship.... We've taken the decision to initially apply the concept of adaptive trials to the Learn paradigm, particularly around exploring the dose response. The hierarchy of questions is: First, do we have a viable product? We do want to know whether we have proof of pharmacology, proof of concept. If so, then second, what is the correct dose to take into Phase III?
At what point in drug development should adaptive trial designs be deployed?
Krams: Adaptive trial designs can be deployed from the very beginning of clinical drug development: Phase I -- continuous reassessment -- across Phase II -- response adaptive dose-ranging studies -- to confirmatory Phase III trials -- e.g., blinded sample size re-estimation, group sequential designs, maybe even seamless Phase II/III.
Your final thoughts?
Krams: We are doing adaptive designs! It's happening, big time. Adaptive trials in Learn clearly are in line with the philosophy of the FDA's Critical Path Initiative. It's fun to plan and implement these designs and observe the impact on the efficiency of the clinical drug development process. And it's fun to be part of a Ferrari team. We can already feel the impact. Just imagine when we will have a dozen case studies or more under our belt. I am convinced that we will be able to show how these designs added value to what we do. And it will be great to share how we managed to deal with the challenges on our way. Challenges are there to be overcome.
Editor's note: In the May 7 issue of eCliniqua, contributing editor Deborah Borfitz will examine the technical challenges of implementing adaptive trials in an interview with George Lazslo, founder of life sciences strategic consulting firm Laszlo Consulting.
Read Part I of Biting the Adaptive Trials Bullet.
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