Overcoming the Protocol Intimidation Factor

Rehearsal of skills and procedures is important to many operations, particularly those that require various individuals and departments to work together as a cohesive whole.  No Broadway play, for instance, would test how well all of its moving parts work together on opening night. Having all of the actors, musicians and crew show up for a live performance without first having practiced working together would guarantee a lousy show.

Similarly, no clinical trial should be testing how well the protocol is operationalized at each site during the first days of the actual study. Doing so could put patients at risk, as well as increasing the likelihood of deviations that can add time and cost to completion of the trial. But this type of practice is not typical in the industry.

In fact, it’s common for sponsors to expect different sites with different infrastructures, experience and staffing to go live with a complex protocol with no rehearsal beforehand.

Protocols have been growing in complexity over the last several years. And the more complex the protocol, the higher the protocol intimidation factor—the number of challenges faced in implementing it across varied sites—becomes. 

In January 2021, for instance, Tufts University’s Center for the Study of Drug Development (CSDD) noted that protocol complexity had been rising rapidly in recent years. That report indicated that Phase 2 and 3 clinical trials have an average of 20 endpoints, with 1.6 primary endpoints—that’s a 27% increase in 2021 over 2009. And in January of this year, another CSDD report indicated that 70% of research site staff think that clinical trials have become more difficult to conduct over the last five years.

Extra endpoints and procedures are just part of the picture. A variety of factors add to protocol complexity—from new technology to use of multiple systems to excessive demands on research staff time. And some of these are beyond any sponsor’s ability to change. For instance, new technology will continue to be utilized in clinical research and the requirement to use multiple systems is likely going to continue, as well.

Many things that impact the protocol intimidation factor, such as the technology used or complexity of enrollment criteria, cannot be removed from the equation. Rather, sites need to be efficiently brought up the learning curve via effective training to manage those factors.

But there is plenty that can be done to ensure that fewer stumbling blocks arise as sites strive to implement protocols, and to address those obstacles that do pop up much earlier in the process. Focusing on two factors—careful protocol analysis to identify potential obstacles or challenges and process for rehearsing proposed workflows at different sites—can greatly reduce the protocol intimidation factor.

For instance, protocols and associated documents—like operations manuals, patient instruction sheets, investigator brochures, etc.—often contain redundant information. And any time information is repeated, there is a chance for inconsistencies, which can cause confusion and lead to deviations down the road. Additionally, vendor instruction sheets may not jibe with the protocol or instruction manual if no one reviews these documents for consistency with the protocol.

Scheduling challenges are also common sources of problems when implementing a protocol. For instance, a protocol might have a patient visit lasting 20 minutes, but at some sites, that may be unrealistic if the patient must go to two different places to complete the tests or procedures required for that visit.

Cross-referencing all documents with the protocol early on to identify disparities and inconsistencies can avoid confusion—which can lead to deviations—after a trial kicks off.

And simply conducting a “day in the life” exercise to get a realistic sense of how long patient visits, procedures, investigational product preparation, delivery and administration, and other activities take can make a study run much more smoothly after enrollment starts.

The protocol provides the top-level overarching guidelines; instructions for administering an investigational drug, for instance, may state that the product is delivered as an infusion with a two-hour window to administer after preparation. But that simple instruction must be backed by guidelines, manuals or instructions for several different departments at a site, such as the pharmacy, lab and nursing staff. What may not be clear in the protocol is that preparation of the drug may require 27 steps conducted over four hours at the pharmacy, for instance.

If all of the steps aren’t mapped out, visualized and rehearsed in a safe way before patients are enrolled, the risk of deviations becomes much higher after a study begins. To achieve this, someone must cross-reference all the manuals and other documents associated with a protocol, look for pain points and obstacles and get those addressed.

Visualization and animation can help with this type of analysis, making clear any areas where discrepancies exist or could cause problems.

For example, Pro-ficiency’s Pro-active Protocol service offers animated walk-throughs of all of the steps required for a patient visit under a given protocol. This allows sites and sponsors to understand fully how protocol implementation will look in real life at different sites that would be enrolling patients. This approach can provide a rehearsal that illustrates what is—and what isn’t—possible for a given site.

Some sites are able to conduct their own internal rehearsals. They know their own infrastructures and can coordinate all relevant systems, such as those found in the pharmacy, imaging and laboratory departments. But even for these sites, sponsors can help accelerate the process by providing the basic workflows that sites can then adapt to their individual operations.

If a sponsor puts in the effort up front to operationalize its protocol, that can get the day-in-the-life rehearsal 80% of the way completed; sites can then tailor and adapt that plan to suit their specific needs and infrastructure.

It is important to bring vendors into the conversation, as well. The same process needs to be applied to vendor operations. For instance, a trial might call for use of a wearable continual glucose monitoring and e-diaries provided by vendors, both of which provide data inputs to determine whether a patient is randomized. A review of the protocol and vendor use instructions must be conducted to look at factors such as whether the data can automatically load into a site’s system or must be manually added. And the complexity factor is multiplied in cases where there are multiple interactions or dependencies.

In short, for a clinical trial to run effectively, all participating entities and systems must work in perfect sync. And that requires a director to ensure that every department understands not only exactly how its own workflow should run, but when and how that may impact other departments.

And the earlier this fine-tuning is done, the better. It is more efficient to evaluate the protocol for complexities and challenges before enrollment begins than to wait for sites to make mistakes and have to go through the protocol amendment process.

There are definite limits to steps that can be taken to reduce protocol complexity and lower the protocol intimidation factor. Some challenges—managing staff resources, applying new technologies and working in multiple systems—are likely to remain despite sponsors’ best efforts.

But while there are limits to how much protocol complexity may be influenced, there are options for better operationalization of the protocol. Identifying every step in every workflow required for a protocol-mandated task or procedure can help develop a realistic visualization of how day-to-day conduct of a study will look, whether from the perspective of the lab, imaging, pharmacy or other department.

This sort of effort will reduce site burden by requiring sites to spend less time figuring out how to implement the protocol. And visualization of all workflows can help to provide a dress rehearsal that lets all site staff practice their roles safely, with no undue impact on patients and no risk of deviations or unusable study data. Practice makes perfect, and spending time to conduct such a rehearsal will mitigate many challenges that occur in increasingly complex clinical trials.


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