I recently worked with a client on their clinical trial protocol for a huge study involving thousands of patients and hundreds of independent clinical investigators across the country. The study's protocol—the detailed plans and regimens that investigators must follow to test a drug in clinical development—was precise. Not only did it have lots of tests to determine the efficacy of the drug, but the protocol included a raft of criteria to ensure that only patients with a precisely defined set of health characteristics would participate in the study.
However, the company felt that such a rigorous design would create some problems. By creating such careful screening criteria, it would be difficult to find enough patients to fill the trial.
Because the tests to be administered were burdensome (such as multiple blood draws, 24-hour ambulatory blood-pressure monitoring), they might deter qualified patients from participating.The length and complexity of the protocol were bound to cause difficulties with patient drop-outs, driving up the time and cost to run the trial.
The company's worries were well-founded—and they're not alone. Pharma manufacturers of every size are running into problems operationalizing the protocols they set forth for their clinical trials.
Every R&D professional has a host of horror stories about protocols that went wildly awry: multiple amendments to the protocol, enrollment delays, and poor data quality, to name a few. But when asked, most people believe that the protocols are just fine—they see the science as generally strong, and the methodologies have a high likelihood of successfully determining the efficacy of the drug.
This disconnect between people's perception of protocol quality (high) and actual protocol quality (low) has led us to believe that there are actually two different kinds of protocol quality. Through our conversations with heads of R&D, medical management, and clinical operations at a dozen large and medium-size pharmas, we've seen that R&D organizations are set up to focus on only one of them. This organizational stumbling block thwarts effective execution of the protocol, and costs the typical R&D organization millions of dollars a year in lost productivity and months or years in lost cycle time.
This article explores these two types of protocol qualities. It offers some solutions to companies that want to improve protocol quality—based around execution and clinical trial operations—and in the process, bring their clinical trials under control, completing them on budget and on schedule.
Protocol Quality, Defined
During the development of a clinical trial protocol, most pharma R&D organizations focus on "scientific" protocol quality—that is, making sure that the scientific goals of the protocol are sound and that there is a reasonable chance the protocol will achieve study goals. Questions such as, "What tests do we need to determine whether our drug is effective?" or "How many patients are necessary to assure statistical accuracy of our results?" receive well-deserved and careful attention.
Protocol development teams often bring in medical consultants to help hone the scientific aspects of the protocol. But in their efforts, they often overdesign it, such as when they create too-stringent criteria for patient enrollment, making the protocol nearly impossible to execute. Protocol Review Committees tend to focus on the scientific aspects as well, poking and prodding the protocol to ensure it has a high probability of meeting its scientific goals. As a result, the team often amends the protocol, which then must be approved by FDA. Given that the average Phase III protocol has five amendments, costing almost $200,000 a piece in out-of-pocket costs, companies are spending nearly a million dollars on amendments per protocol. But when all is said and done, the scientific quality of a protocol tends to be reasonably good.