Drug development innovations that work: Adaptive trial design
Many experts agree that the pharmaceutical drug development industry is on an unsustainable path. Drug development has become slower, more difficult, and more expensive. The average time to market has stagnated for decades, at approximately 12 years. Research and development costs have doubled, and are expected to continue to rise. And still, failure rates are as high as 90%.
Experts also agree that innovations in clinical development have the potential to drive better returns and greater efficiency. But what kind of innovations and what works? What doesn't work? Digging even deeper, why are existing innovations that have been around for many years, such as adaptive trial designs that allow researchers to alter a protocol based on interim data, not being widely adopted?
To get some quantitative answers on adaptive trials and three other innovations – patient-centricity, real-world data and precision medicine trials – PAREXEL asked the Economist Intelligence Unit (EIU) to assess these clinical trial innovations to better understand which ones can increase the likelihood of a successful drug launch, as well as stimulate discussion on how innovation can improve efficiency, productivity, and sustainability.
The results were eye-opening. As detailed in The Innovation Imperative: The Future of Drug Development, drugs developed using any of the innovations were much more likely to be successfully launched. They showed a 10 to 21 percentage point increase in that arena compared to drugs developed without these approaches. Specifically, adaptive trials increased drug launch potential by 13%, yet like the other innovations studied, are under-utilized by the industry. Innovative trial designs also led to more efficient trials, with patient recruitment time savings as high as 40%.
The study "makes a compelling, data-driven case for accelerating the adoption of new market access processes for drugs," wrote the authors. Moreover, added David Humphreys, head of Health Policy & Clinical Evidence Practice, EIU Healthcare, "these tools already exist but are not utilized to their potential."
So why are none of the innovations widely used today?
Adaptive trials in particular have a very low adoption rate – less than 1% across Phase II and Phase III trials – even though the study found that this innovation alone significantly decreased patient recruitment time and increased the likelihood of launch.
Low adoption rates are due to a variety of systemic and cultural barriers, the study found, including the newness and perceived complexity of some innovations, lack of workforce expertise, and an entrenched resistance to change.
"Some find adaptive trials too complicated," says Martin Roessner, Corporate Vice President, Biostatistics, PAREXEL. "But that doesn't have to be the case," he explains. "In adaptive trials, researchers simply have the ability to specify up front a set of criteria for adaptations to a study protocol that can be implemented as the trial progresses depending on the results observed at an interim analysis."
"This approach allows you to be more conscious of what you are doing," he says. "By evaluating the data in real-time, you are able to make informed decisions to change the direction of the study."
"Think of it in terms of building a house. The construction workers go to the site every day and see how it is progressing. If something goes wrong, they figure out how to take action to make it right. Why not do the same with a clinical trial," Roessner asks.
"Why spend millions on a protocol and wait until the end of the trial for a negative result, when we could have known earlier that the assumptions were not totally right? In every other industry, you look at your data on an ongoing basis and you make decisions based on what's coming in. That is the advantage of an adaptive trial. It allows you to react to the data, which triggers an adaptation to the protocol, so the trial has the best chance of being successful."
Workforce expertise limitations – a lack of staff with the skills needed to design or analyze the data from such trials – are a common barrier to implementing adaptive clinical trials, according to the study.
Partnering with a company like PAREXEL on adaptive trial designs can help overcome those limitations. In particular, sponsors can benefit from PAREXEL's advance planning capabilities as well as the experienced multidisciplinary team that is brought to the table.
"When we engage with a company on such a design, we are involved in every stage," says Jason Martin, Corporate Vice President, Global Data Operations, PAREXEL. "We develop the entire plan, bringing in all the disciplines: scientists, statisticians, medical experts, regulatory experts, technology experts. They are all there to provide their input into the design and execution of the trial."
"Adaptive trials need much more discussion early in the process. What implications will the adaptations have? If I want to change the patient population a bit, what impact will that have? You need to think through all of that up front, not while the trial is running," Martin adds.
"Partnering with PAREXEL can also ease concerns about complicated technological considerations," continued Martin. "Technology facilitates the real-time availability of data for decision making, supports tracking of the status of a study and the data and provides tools for logistics and drug supply."
"Organizational resistance to change, another barrier cited by the study, is also common," notes Roessner. "Many sponsors don't want to try anything new with a big investment at risk,” he says. “They often are particularly concerned that the Food and Drug Administration (FDA) will not approve their trial design."
"That's not a challenge, it's an opportunity,” says Roessner. "It's an opportunity for sponsors to get in touch with the agencies and work out a plan that is ultimately successful."
The FDA, he notes, recently released guidance that clarifies the current state and regulatory framework of adaptive trial designs, and guides sponsors on key design factors. "Overall, the FDA guidance encourages the use of these designs," says Roessner. "But it clearly emphasizes the need for rigorous planning, careful implementation, and comprehensive documentation of approaches taken to maintain confidentiality of interim results to ensure study integrity."
"Adaptive designs can provide a variety of advantages over non-adaptive designs," the FDA notes.
The EIU research authors concur: If adaptive trial designs were adopted more widely, they wrote, "The future growth and viability of the industry could be more sustainable."