People have been trying to find ways to make the processes applied in clinical development more efficient for decades. This has typically looked at finding ways to ship material faster and more reliably; better identifying participants for clinical studies; or cleaning and processing data more quickly. There are also many technical areas that can be improved on, and each of these can help speed things up. Every day makes a difference for someone suffering, and by identifying and eliminating the inefficiencies in the system, it is possible to shave time off the drug development cycle.
Yet, poorly written clinical study protocols sit as a root problem in clinical development, and little is being done to improve these. The protocol is the foundation of every clinical study. It informs investigators and study staff about the study’s intention and provides a recipe for what needs to be done and how. It ensures the clinical team at the sponsor and vendors are aligned on what the study purpose is and how the results will be analysed. Finally, it feeds into the clinical study reports and, ultimately, the clinical summaries for submission dossiers.
Poorly written protocols lead to inconsistencies in the collected data as a result of differences in the timing of collection, the methodology of collection or even the state of the participants during collection. If the objectives are not clear, incorrect statistical methodology might be applied, resulting in meaningless outcomes. Clinical studies have an ethical obligation to ensure they are contributing meaningful and relevant information; poorly run studies that produce meaningless outcomes are incompatible with a patient-centric approach to clinical research.
Fix it before it’s broken
A poorly written protocol can impede teams in multiple domains, from setting up and running the study to reporting on the study and applying for marketing approval. The combined knowledge gained from all the studies of a clinical development programme provides the necessary knowledge to determine the risk-benefit profile of a new drug product. If the data collected in those studies is inconsistent, has gaps or quality issues, then more studies will be needed to eliminate those problems.
In other words, having a clinical study protocol that communicates clearly and helps users find the exact information needed to make a decision or perform their task in a consistent way would kill many birds with one stone. It has the potential to effect transformative change by improving multiple, interdependent activities. It might not be a full panacea, but it certainly takes us in that direction. The question is, why is this so difficult to achieve?
There are many reasons that protocols do not end up as they should. One is that teams are often not aligned on what they want, and the protocol ends up trying to squeeze multiple agendas into a single study. Subject matter experts on teams can lose sight of the fact that studies are not academic excursions. The more complex a study becomes, the longer it will take to run and the greater the chance for people to become confused about its purpose. A significant increase in the complexity of study designs over the last 20 years has decreased the quality of clinical data and increased study costs.
In addition, many stakeholders involved in writing protocols have not been given sufficient training in what makes a good protocol and what to focus on. It is not enough to just grab the next physician who understands the therapeutic context and throw them into the foray, hoping they will design studies with a clear regulatory focus. The protocol-writing team requires people with sufficient understanding of the regulatory goals to provide a proper vision for the study design and content. They should be familiar with the SPIRIT guidelines and ensure they are applied effectively.
The value of the medical writer
With the increased complexity of studies, it has become even more important to have a good medical writer involved who ensures the protocol presents a cohesive description of the study concept, rather than a patchwork quilt of ideas. For all the reasons mentioned above, this document needs to be well crafted, with concise writing that leaves no room for misunderstandings. The medical writer must also understand how this document will ultimately feed into downstream documents such as the clinical study report and summary documents. This helps to produce a protocol that streamlines writing these other documents.
The medical writer is at the heart of the protocol writing process. As they pull together all the pieces, they are best placed to recognise inconsistencies in the design concept or other things that might be impractical. While each subject matter expert or functional area tends to review the protocol from their thematic perspective, the medical writer is often the only person who thinks about all the ideas holistically, considering how they all relate to each other.
The process of writing a protocol
Another problem rampant in the industry is, to quote John Bergman, “There is never enough time to do it right, but there is always enough time to do it over.” If companies want to prepare protocols that will actively reduce protocol deviations and the need for amendments, they need to give teams sufficient time to think about the protocols before they go live. Companies repeatedly request protocols be prepared in ridiculously short periods of time. This shows a complete lack of understanding of the complexity of the process to conceive a well-designed study and develop a well-written protocol.
If companies want to be sure that a study site can do all the things required for each visit, then they will need to ask. If they want to know how realistic it is to get blood samples from sites all over the globe to a centralised laboratory for analysis, they will need to talk to the people who do this daily. That means allocating time for conversations with those people and ideally for them to review the protocol draft. In addition, the core team developing the study outline should have time to let ideas settle. Humans craft thought through an iterative process. By discussing with each other and having the time to bounce ideas around, we come up with very good solutions to problems. But if that time is not available, then we will be stuck with the initial rough idea, warts and all, that never had the opportunity to be refined. A team of experts with the knowledge and skills to do great things should be given the breathing room to think things through. Forcing to deliver a final protocol in a matter of weeks from start to finish is a guarantee for much longer delays later on through amendments and deviations.
The process of writing a protocol requires several steps, underscoring the need for sufficient time to do it properly. It should start with creating an outline that is agreed on by a wide group of stakeholders, including sponsor management, site staff and vendors. It is important to get the concept in place before diving into the details. This is before it moves into drafting a fully populated protocol that will be circulated for review among those same stakeholders, so they can confirm it reflects their vision of the study.
In an industry striving to beat the clock, it is staggering how much time is spent on fixing clinical studies once they are running, rather than aiming to get them right from the start. The cost of activities not considered essential to study objectives and endpoints is estimated to be between $4–6bn each year. There are multi-fold efficiencies to be gained by helping teams produce well-crafted study protocols. Investing a little more time in preparing a robust study outline and communicating this clearly and effectively will not only reduce protocol deviations and the need for protocol amendments, but it will also reduce the time for writing study reports and clinical summaries and make the assessment of these documents more efficient for agency reviewers. If clinical studies are to become more efficient, it’s time to focus on getting the protocols right from the start.
