P4C—Adaptive Trials, Platform Trials, Master Protocols and Beyond: Pathways to Transformation—or Not?
There has been much interest in and excitement about the potential of innovative trial designs, such as adaptive trials and platform trials, to make the long and expensive clinical trial process more efficient and effective. In a panel discussion at Partnering for Cures, some of the most highly regarded leaders in the field provided the audience with a tutorial about these new models and what is needed to make them the rule rather than the exception.
Moderator Anna Barker, a professor at Arizona State University and FasterCures senior fellow, kicked off the workshop by providing some context for the need for new approaches. Clinical trials, she said, are “the weakest part of drug development,” costing too much and taking too much time. The failure rate is very high, 50 percent or more, and many trials never enroll enough patients to get off the ground. This problem will likely get worse as we unwind biology and begin to identify and treat ever smaller groups of people—“one size never fits all anymore.” “Is there a problem with clinical trials?” Barker asked. “You bet there is. Can we do something about it? Yes, we can.”
Ronit Simantov, vice president of Global Medical Affairs, Pfizer Oncology
Don Berry, professor of biostatistics at MD Anderson Cancer Center and a driving force behind clinical trial innovation, declared it high time to think differently. “We haven’t changed what we’re doing much in 70 years. Name another modern technology that hasn’t changed in 70 years.” For the nonstatisticians in the audience, he described the meaning of a Bayesian approach to statistics and trial design, which underlies the new adaptive trials. Traditional randomized controlled trials are set up to answer one question—is A better than B? With a Bayesian approach, “you look at the data and adapt to the data, modify the trial. It leads to asking many more questions—is A better than B in this patient population? How about C? How about putting A and B together? The way people think is Bayesian. In the clinical trial realm, we try to make you think differently.”
Lisa LaVange, director of the Office of Biostatistics at the FDA’s Center for Drug Evaluation and Research, encouraged the audience members to share their ideas for conducting innovative trials with FDA. She explained that FDA likes several things about such trials, first and foremost, their patient focus, ability to screen patients by their genomic profile and ability to make trials more accessible to patients. It also likes the opportunities to ask multiple questions and to test multiple treatments in the same trial. She acknowledged that a lot of up-front planning is needed to conduct these trials but was emphatic that they can result in better quality.
LaVange noted that FDA issued a guidance on adaptive designs in 2010 but is in the process of replacing it with new, clarified guidance. “We are trying to keep up with the science and not stay in the past.”
Brian Alexander, the disease center lead for neuro-oncology at Dana-Farber Cancer Institute, related his experience with the planning of the new AGILE trial in glioblastoma multiforme. Frustrated that “patients would come in and there wouldn’t be a trial available” for them, the team that designed AGILE set out to “create a system where we can learn more and patients could get the best treatment.” “We didn’t go into it with lots of preconceived notions about what we wanted to do. It was very patient-centric,” as patients were involved together with clinicians, statisticians and imagers in identifying the important treatment issues to address. “Learning and being patient-centric aren’t at odds with each other, you can design a trial around patients with a disease and not around a specific product.”
Brian Alexander, the disease center lead for neuro-oncology at Dana-Farber Cancer Institute
Jeff Allen, president and CEO of Friends of Cancer Research, described another type of innovative trial, the LungMAP platform. He touted the advantages of this standing network of more than 700 sites (with half the patients enrolled at nonacademic medical centers) studying multiple drugs in multiple sub-studies, over a single trial meant to answer a single question. Allen noted some of the challenges in standing up the effort, which included accounting for all stakeholder perspectives. The clear message from the industry partners, he said, is that the trial had to result in statistical significance that would fulfill regulatory requirements. FDA was critical in providing counsel on that score and laying out the path forward.
Ronit Simantov, vice president for global medical affairs at Pfizer Oncology, addressed the advantages of these types of trials for product developers. “The state of science and the need for combination therapies is driving us to work together in a pre-competitive fashion. We can’t develop everything ourselves, for every single type of cancer with a particular biomarker. They also allow us to combine drugs” in a trial, often with other companies’ drugs. “And they allow us to fail faster. We need to find out quickly whether something is likely to work or not. It’s the best thing for patients.”
In closing, Barker asked each speaker to recommend a required action to move this paradigm shift forward. The group recommended:
- Question your assumptions from the start.
- Involve patients in the design from the beginning.
- Look for new sources of data, from electronic health records and other real-world evidence.
- Use common control groups.
- Allow FDA the opportunity to be open to innovation.