Protocols are the foundation of effective clinical trials — targeting potential recruits, dosages, end points and much more. Human studies must have practically doable, well-thought-out protocols, but the complexities of bringing new drugs to market make it extremely difficult for protocols to anticipate all the ways a trial can go astray.
Indeed, many protocols need to be amended in mid-study, with expensive consequences. For instance, a study by the Tufts University Center for the Study of Drug Development found that a substantial protocol amendment in a Phase II/III study on average adds more than $500,000 in costs and typically triggers a three-month delay. And nearly two-thirds (66%) of Phase II/III study protocols require at least one substantial amendment.1
Even more concerning is the fact that almost half of Phase III trials fail to meet their primary endpoints. These failures are costly to pharma companies, but a tragedy for patients. Often, a protocol design flaw is to blame.2
The Tufts study notes that many protocol amendments can be anticipated and potentially avoided. This helps explain the rise of protocol optimization — using data science and advanced algorithms to compare and contrast various protocol variables to find potential problems on a computer before they can cause costly trial delays.
How Does Protocol Optimization Work?
One of the leading proponents of protocol optimization is Sy Pretorius, chief scientific officer at PAREXEL International, a leading biopharmaceutical services company. Pretorius offers a new framework for protocol optimization, one that considers the approach in terms of building blocks and lenses. Building blocks are the key components of a protocol, and lenses are various ways to view each of the building blocks.
“By carefully evaluating and challenging each of these building blocks via the different lenses, we compile and model different scenarios for running the exact same study,” Pretorius says.
In doing so, we are able to identify the trade-off decisions that are inherent to study design and to drug development in general.
“Once these different scenarios are compiled, they are mapped out to assess their impact on project time,” Pretorius says. “We’ll also cost these out to assess the impact on project budget.”
What’s the Best Phase for Deploying Protocol Optimization?
Protocol amendments are much less costly in the earlier phases of a trial. The Tufts study found that median costs of substantial Phase II protocol amendments were 74% lower than substantial Phase III amendments.
In theory, Pretorius says, protocol optimization could work well at any juncture in the development process.
“However, what we see in practice and given the amount of work involved, the impact and associated return on investment in larger Phase III studies make these ideally suited,” Pretorius says.
How Does Protocol Optimization Streamline Clinical Trials?
Optimizing protocols ultimately means using data science and computer algorithms to discover inefficiencies that would be almost impossible to discover with traditional research methods.
Pretorius notes that the Tufts Center for the Study of Drug Development found that, on average, one-fifth of Phase II protocols and one-third of Phase III protocols collect non-core data that’s irrelevant to the study’s goals and requirements.
“Eliminating these non-core procedures has a tremendous impact on both the cost associated with a study as well as the time that it takes to complete the study.” Pretorius says. “Changing the design or one of the other building blocks often results in similar cost and time savings.”
How Does Protocol Optimization Affect Regulatory Issues?
PAREXEL started out in regulatory consulting more than three decades ago. Today the company employs about 800 regulatory-affairs experts, many of whom are former government regulators for the Food and Drug Administration and other agencies.
“The regulatory perspective is one of the lenses that we use to systematically evaluate every building block in a given protocol,” Pretorius says. “If there is a better and faster route to approval, this process and our resident experts will identify and suggest it proactively.”
How Do Patients Benefit From Protocol Optimization?
“The patient or patient-centric perspective is another important lens that we use to systematically evaluate every building block in a given protocol,” Pretorius says.
PAREXEL’s approach is to deploy tools that pull data from social media, focus groups, patient-advocacy groups, disease foundations and other areas to make sure the patient remains central throughout the entire process.
“The direct patient benefits that stem from this approach include protocols that are practically doable from a patient perspective, protocols that focus on issues that are critical to patients and many more,” Pretorius says.
 Tufts Center for the Study of Drug Development. 2016. “Protocol Amendments Improve Elements of Clinical Trial Feasibility, But at High Economic and Cycle Time Cost.” http://csdd.tufts.edu/news/complete_story/pr_ir_jan_feb_2016
2 Applied Clinical Trials, August/September 2016, Volume 25, Issue 8,“Phase III Trial Failures, Costly But Preventable,” Alberto Grignolo, Sy Pretorius, MD