At a symposium marking the Clinical Trials Transformation Initiative’s 10th anniversary, industry and regulatory discussed the progress made by its Quality by Design initiative and the additional work needed to encourage the research industry to be more focused on trial quality and efficiency.
Quality in clinical trials is defined as the absence of errors that matter, said Ann Meeker-O’Connell, head of bioresearch quality and compliance at Johnson & Johnson.
While inflexible, one-size-fits-all approaches to quality can undermine the development of specific strategies for a given study, Meeker-O’Connell said CTTI’s Quality by Design project recommended sponsors examine clinical trials prospectively and take early action to protect critical factors from affecting outcomes.
More than anything, the design of the trial should be streamlined wherever possible, she said, with the study’s planned activities and data collection narrowed down to those essential for the trial’s objective. But efforts to create a company culture that values and rewards critical thinking about clinical trials quality should go beyond reliance on checklists and other tools, Meeker-O’Connell said.
Implementing quality measures early into clinical trial design has not been an easy task for the research industry, said the FDA’s Robert Temple, CDER’s deputy director for clinical science. However, reducing costly protocol amendments — as well as the possibility of errors that may impact patient safety or the study’s final results — are worth the effort.
CTTI — founded in 2007 as a public-private partnership between the FDA and Duke University — developed a toolkit, including templates, guidelines, workshops and videos, to help companies implement the recommendations.
“People need to see examples of simplifications and design features that did or did not work as hoped,” alongside their ultimate effects on the trial and outcomes, to convince companies to adopt the quality measures, Temple said.
For instance, CTTI addressed on-site trial monitoring and error prevention because it is a main cost driver in conducting clinical studies, he said. Errors that mean amending the protocol in later stages can be incredibly expensive. According to the Tufts Center for the Study of Drug Development, the total cost of a single, substantial amendment to a Phase III protocol — such as changes on a global level that would require approval from a review board or regulatory authority — can reach over $500,000 each.
CTTI recommends sponsors institute electronic data collection systems that allow sponsors to monitor at a distance, with problems being detected centrally. The system can also reduce and target site visits to problematic locations and identify high-risk issues — such as misdefined endpoints, too many study dropouts or too little variability.
Sponsors should take the time to develop thought-out clinical trial protocols, with endpoints that can be measured well at each site, even with additional training, and potentially use real-world data to ease patient burdens and promote adherence, Temple said. Protocol adjustments could be site-specific as well, with a focus on sub-sites that are having problems.
Companies could consider using endpoints that are already collected as part of an electronic health record — and using past records to find concomitant treatments and previous health experiences, as well as ways to schedule patient visits or guide assessments, Temple said.
In addition, enrichment strategies could help identify high-risk patients, likely treatment responders, and those most likely to comply with a study protocol, he said.
Amgen Case Study
Julie Dietrich, director of Amgen’s Development Design Center, presented a case study to the symposium of how her company integrated CTTI’s recommendations into its trial design process.
To get departments focused on streamlining clinical trials, a popular metaphor Dietrich used was that of a new, fresh Christmas tree. As more and more people place their ornaments on it, it runs the risk of becoming a mess, or even falling over, she said.
“We would be meeting with large, cross-functional teams,” Dietrich said. “Medical, safety, economics… and they would all have pet interests that they wanted to learn from the study.”
But you have to keep your eye on how those additions are relevant to the final product, she said. “Adding things could add chances for errors that matter… In the end, delays don’t serve the patients or the stakeholders.”
Another challenge at Amgen was communicating the value of planning ahead. Everyone is focused on reducing time to first patient enrollment, but they may not see that thorough trial design can reduce the time to database lock and analysis — the time that really matters, Dietrich said.
For example, red flags were identified early in the trial design process when a study included over-reliance on a daily, patient-completed diary for the development of study data. It was unclear if enough patients would complete the tasks on schedule, she said.
Instead, Amgen adopted methods of obtaining data through usual care — to reduce the patient’s burden for data collection during study visits — and shortened the period of diary collection, she said.
“We have quite a wealth of information available to us,” Dietrich said. “The challenge is knitting together different data sources and having it tell some kind of story, so that decision makers known what to do with it.”