Clinical Researcher—April 2019 (Volume 33, Issue 4)

CLIN OPS INSIGHTS

Priti Sahai, MBBS, MS

The clinical research protocol is the blueprint that determines a study’s downstream activities, and it has an impact on all stages of the study—from design and planning to analysis and submission. The protocol describes the rationale for the research and how the study will be conducted. It provides important details such as background, objective, endpoints, schedule, statistical considerations, and other elements that offer clarity to all parties involved on what the study entails.

In other words, this critical document ensures that the investigators, study teams, institutional review board (IRB), and other administrative and regulatory bodies are all on the same page with respect to the study’s concept, activities, and conduct. Therefore, getting the foundation right from the start and having a detailed and clearly written protocol provides a big boost toward ensuring that the study is completed on time, within budget, and in a safe and compliant manner.

Shedding Light on Protocol Development

Even though the importance of protocol authoring is widely acknowledged, many challenges that show up in clinical research projects can be traced back to issues with the protocol document. Common examples of such issues include lack of clarity, inconsistency, and missing information. These issues are generally addressable in the protocol authoring process, and would not only prevent costly errors and delays, but also ensure a safe and effective process with fewer protocol violations. When such omissions or errors are discovered in the protocol, amendments are introduced leading to increased administrative burdens, expectations for retraining, and manual rework at levels which are detrimental to the overall study process.

A study conducted in 2010 by the Tufts Center for the Study of Drug Development examined protocol amendment data from more than 3,400 protocols from multiple phases and therapeutic areas. Nearly all protocols had at least one amendment, and more than a third of the amendments were categorized as being partially or completely avoidable. This excludes amendments that were made as a result of new safety information, regulatory requests, or changes in standard of care, but rather were due to flaws in the design and/or document.

Correlating this information with other data provided by the survey participants, it was observed that the direct cost resulting from a single protocol amendment was nearly $500,000, along with the addition of 61 days to the overall study duration. It is important to note that such unplanned expenses and delays come in addition to other challenges not as easily quantified (e.g., extra effort required by study teams, resubmissions, and other problems for the participating sites). Overall, the study estimated that in 2014 there was a cost of approximately $2 billion that could be attributed to avoidable protocol amendments for all active global U.S. Food and Drug Administration–regulated trials in that single year.

A Stitch in Time Saves Nine

The good news is that there are some simple yet concrete steps that can be taken to prevent such costly and time-consuming issues. Below are six points that can be incorporated easily into any research team’s protocol authoring process to ensure a greater chance of success:

• Begin with a structured approach—When getting started, seek out content libraries, guidelines, and structured protocol templates that centralize and build upon knowledge bases available from prior studies and shared best practices. Templates and prior examples provide a helpful boilerplate for information that must be included in the protocol, ensuring that you don’t miss key components. It’s a good policy to begin with the end in mind—the objective, the endpoints, etc.—and work your way through all the steps and processes needed to get you successfully to that point.
• Save your homework—During your explorations, it is important to keep records of references to all relevant background and supporting information, so that others reviewing and referring to the document are equally well informed about the research being undertaken. This also comes in handy when the researcher is looking at publishing an article.
• Adopt a collaborative approach—This has always been critical to research, but is even more important in current times, as research becomes increasingly complex and requires iterative review and input from an interdisciplinary team of experts. Collaboration is not just about the clinical, regulatory, safety, and statistical input that we seek, but also about insights from independent scientific reviewers, patient advocates, and peers, all of whom can provide important perspectives on matters not directly related to the specific research topic.
• Document the authoring process, too—Obviously, a key objective of this process is to have a final set of well-documented protocol material. However, remember that tracking the process and keeping a record of all key decisions made is extremely helpful—not just for future projects, but also should the need arise to review decisions or revisit issues in the current project.
• Keep it simple—Although it is important to keep detailed records of information gathered during the authoring phase, the protocol document should be kept as simple and devoid of inessential components as possible. The more complex the study’s design and documents, the greater are the chances for misunderstandings, errors, and complications. Detailed information that isn’t included in the protocol may be better served by being included in other material, such as the operations manual.
• Ensure consistency—While the above sections primarily address the protocol document, one should remain cognizant of other trial-related documents that require similar diligence and review (e.g., the consent form, the operations manual, and others). Sponsors and sites should work together to ensure consistency across the entire packet of documents being utilized in the study. Keeping this in mind at the authoring stage improves timelines for regulatory approvals and minimizes downstream issues.

Conclusion

Ultimately, it is a question of having a well-thought out plan early in the protocol authoring process and ensuring that a little more time and attention is spent upfront on key details. This decreases the likelihood of errors downstream due to omissions or misunderstandings, and increases the likelihood of success through a well-written, detailed, and clear blueprint for your research project.

Priti Sahai, MBBS, MS, (psahai@plexome.com) is CEO of Plexome Inc., a company based in Fremont, Calif., which helps stakeholders involved in clinical and translational research connect, share, and advance their research and clinical needs via a cloud platform.