We return to our discussion with Ken Getz of the Tufts CSDD for part 2 of our blog post on key challenges in clinical trial operations. You can find Part 1 of the interview here, or read on to gain his insights on the fundamental problem at the heart of clinical trial operations challenges, and his views on the initiatives and programs that he believes show the most promise for the future.
What role do protocol amendments play?
Protocol amendments are perhaps one of the strongest manifestations of a complex design. Amendments we often think of as a problem in themselves, but an amendment is actually a solution to an underlying problem. That problem relates specifically to the design of the study itself. Protocol amendments are incredibly disruptive. Amendments are highly associated with complexity; the more complex a protocol, on average, the higher the number of protocol amendments. The number one reason we amend a protocol is actually to relax our eligibility criteria because they were too demanding and too stringent to begin with, which is fascinating. It ties in with what we were talking about earlier. We amend our protocols often because we're having so much difficulty meeting our enrollment targets. Amendments also contribute to that doubling of the planned trial duration that I mentioned to you earlier.
Our research has shown that the typical amendment requires about three months of time and a half a million dollars in direct costs to implement. This is for a single amendment. These are not trivial expenses and they increase our cycle times dramatically. About 40% of all amendments are implemented before the first patient has even received the first dose. This means that we should have taken the time to challenge the feasibility of the protocol, instead of rushing to get sites signed up and the study underway and then deciding to implement a substantial amendment on a protocol.
"....we have to dig deeper and look at some of the fundamental causes of the problem..."
What are the areas that have the most potential for improvement? Are there any lower hanging fruit?
That's actually been at the heart of the problem. We have now more than two decades of time where we've been aware of these long cycle times, these rising costs and delays, and the very high failure rates. Typically, the approach is to look for the lower-hanging fruit. Let's develop an application that automates this particular process, or let's develop databases that make it easier to look up an investigative site that might qualify for our study – and many, many, others.
Many of the new solutions or practices that have been implemented, have the potential to correct a specific area within the cycle – point solutions. However, we have not seen broad-based sustainable improvement across the full development cycle. What it has suggested to us is that we have to dig deeper and look at some of the fundamental causes of the problem. We believe that the root of this is the scientific and operating complexity of our trials, which has to be addressed in order to simplify and make the execution of our protocols easier and more feasible.
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Do you feel regulators could play a role in helping with some of these inefficiencies, or is it purely the industry’s responsibility to improve their operations and planning?
That’s a very good question. I'm often asked whether regulatory agencies are to blame for the expanded scope of our protocols and the increasing demands. Our research suggests otherwise; it suggests that, more often than not, it has to do with our clinical teams having very ambitious objectives. In addition to targeting a primary and a couple of key secondary endpoints, we add all of these additional endpoints that we hope to measure. Many of them are what we would call tertiary and exploratory in nature. Those all add much more complexity and drive up the volume of data that we collect. In many cases, they increase the diversity of the applications that we're using to collect the data. We're using wearable devices, mobile technologies, electronic health information, social media, real-world data, patient-reported and electronic clinical outcomes assessments. The list goes on. So much of it is related to the clinical team's ambitions. That's really the first place we have to focus. How do we get the teams to realize that every additional procedure we add contributes to making the protocol less feasible? That has a huge impact on the investigative site's performance and, ultimately, on the patient's willingness to remain in the study and to complete their participation in the trial.
We've now got 15 years of research supporting our belief that protocol design and scientific and operating complexities, are challenging the performance of our programs from a scientific perspective, as well as even just from our measures of speed, efficiency, and cost. We believe very strongly that optimizing the design of our studies could really help to accelerate cycle times, lower costs, and drive higher levels of efficiency. Especially now we have so many clinical projects, that are being managed by a wide variety of both internal and external parties that interact with the development program.
"We're big advocates for adaptive trial designs, in large part because adaptive designs require so much upfront thinking and planning, including simulations, to really anticipate what types of changes and adaptations might be implemented while the protocol is underway."
We've talked a lot about "problems" or "inefficiencies" in the industry. What are some promising initiatives for tackling these?
We're very optimistic about the initiatives that we're seeing. Many companies today, especially at the largest and mid-sized pharma companies, are relying even more heavily on protocol review committees to challenge the feasibility of the protocol before it's finalized. We see a number of organizations that are using protocol design authoring templates. There are a couple that are gaining a lot of traction including the common protocol template that was developed by TransCelerate. There's also the SPIRIT template, which was developed by a global community of medical writers. We like a lot of the patient advisory boards- where you give patients a rough draft of the protocol, and you ask them to talk about what it would mean for them to be a volunteer in that specific trial. This provides a lot of insight into the inconveniences and burdens of their participation. In turn, that's helped to reduce the number of procedures and to simplify the design of the study.
We're big advocates for adaptive trial designs, in large part because adaptive designs require so much upfront thinking and planning, including simulations, to really anticipate what types of changes and adaptations might be implemented while the protocol is underway. Those changes, ultimately, are vetted by the ethical review committee, and clinical teams prepare themselves for them. As a result, it minimizes a lot of the sudden disruptions that you might face when you have an unexpected amendment that has to be implemented. The process of developing an adaptive design where you're spending so much time doing upfront planning and anticipating changes in advance, we think is also a very helpful way to optimize a protocol design going forward.
Thank you for painting an inspiring vision for the future.
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Getz, K. (2017) trends in clinical trial design complexity. Nature Review Drug Discovery, 16(5): page 307.
Getz, K. (2012). Enrollment Performance: Weighing the "Facts".
Lamberti, M., Wilkinson, M., Harper, B., Morgan, C. and Getz, K. (2018). Assessing Study Start-up Practices, Performance, and Perceptions Among Sponsors and Contract Research Organizations. Therapeutic Innovation & Regulatory Science, p.216847901775140.
Getz, K., Stergiopoulos, S., Short, M., Surgeon, L., Krauss, R., Pretorius, S., Desmond, J. and Dunn, D. (2016). The Impact of Protocol Amendments on Clinical Trial Performance and Cost. Therapeutic Innovation & Regulatory Science, 50(4), pp.436-441.
About Ken Getz
Ken Getz is an internationally recognized expert on R&D and clinical trial management practices and trends, the global investigative site landscape, site management and patient recruitment and retention practices, and the worldwide market for outsourcing clinical research functions. Mr. Getz’s research studies on protocol design complexity and clinical research efficiency and effectiveness, conducted over the past two decades, are considered by many in the research-based life sciences industry to be pioneering work. His 20+ years of original research benchmarking R&D management practices, global outsourcing and the investigative site landscape have contributed to industry-wide understanding of these critical markets and to improvements in management strategy and execution.