The issue of protocol complexity is receiving increased attention with the release of new data that show dramatic growth in the number of trial endpoints, data points and amendments, and industry stakeholders are mobilizing to adapt management and metrics tools to keep up.

With this data in mind — as well as the imminent release of the International Council on Harmonization’s (ICH) revised quality management guideline, ICH E8 — industry groups have begun the hard work of revising their quality metrics standards.

“We’re going to have to change the way we look at, measure and define many of our metrics moving forward,” says Ken Getz, director of the Tufts Center for the Study of Drug Development (CSDD). “It’s really keeping us on our toes as we continue to adapt our designs and the development pathway.” Getz presented data from CSDD’s most recent analysis of protocol complexity metrics last week to members of the WCG Metrics Champion Consortium (MCC) working group on risk management and quality improvement.

The time is right to update our approach to managing protocol complexity, says MCC founder and CEO Linda Sullivan. MCC is working on revising its protocol complexity and cost evaluation tools, which help sites cope with the extra burden unwieldy protocols and amendments create.

The number of trial objectives, endpoints and eligibility criteria has been growing across all three trial phases since 2013, CSDD’s data show. From 2013 to 2020, trial objectives increased by 15.9 percent in phase 1, 11.6 percent in phase 2 and 17.6 percent in phase 3. And the number of data points collected in phase 3 trials increased threefold in the past decade (CenterWatch Weekly, Jan. 17). Getz says there is little evidence that the growing complexity of clinical trials will abate or recede.

“The timing of CSDD’s results is important,” Sullivan told CenterWatch Weekly. MCC’s operating model is to look at work done on specific issues by a variety of different groups and develop practical tools that take the ideas to the next level. “MCC tries to build on the work that other groups have done,” she said, “and move it forward.”

“Why would we try to redo what CSDD has done?” she asks.

The consortium’s Protocol Operational Complexity Scoring Tool, first released in 2017, helps sites evaluate the amount of patient, site and study burden involved in a particular trial’s protocol by looking at 20 trial elements, such as use of vendors, patient population and number of site visits. The complexity elements align with TransCelerate’s Risk Assessment and Categorization Tool (RACT). RACT is built around a library of more than 100 risk indicators.

One particularly useful aspect of CSDD’s data was the way it broke down trends by therapeutic area, an approach MCC has been considering taking in development of new tools and metrics. For example, CSDD reports that oncology trials have an average of four protocol amendments in phase 2/3 trials, while nononcology trials have an average of 2.7 amendments. “It was exciting for us to see those kinds of breakdowns,” she says.

Another aspect of growing protocol complexity that MCC’s working group is planning to tackle is its financial impact. More patients, more data points and more deviations all represent additional costs in terms of lengthening studies’ timelines, complicating recruitment and retention, and reducing the overall quality of trials, factors the group will consider as it also updates MCC’s Cost of Poor Quality Estimator Tool. The tool, which MCC first released in 2017, assesses direct and operational trial costs, extra costs presented by trial extension and the cost of delaying a product’s entry into the market.

The MCC working group plans to meet again on May 12 to begin revising the protocol complexity and cost of poor quality tools.

To learn more about MCC’s quality improvement working group, click here: https://bit.ly/3eBoWM4.