Not only do they create the plan, but clinical study protocols serve as a repository of knowledge for strategic intentions and are used for multiple down-stream activities. They are the basis for trial registration, provide guidance to those running the study, and are used to appraise the study. Yet, many protocols do not fully address important study elements, which impairs understanding and implementation, often leads to amendments, and reduces the efficiency in later stage activities. The importance of these documents is often not recognised and getting them wrong costs the industry billions and delays, or even hinders, drug development.
Clinical studies frequently falter because they try to do too much, and their design and intent is poorly communicated. The more complex a protocol becomes, the less likely it is to perform well. More complex protocols tend to have more amendments, longer cycle times, and poor recruitment and retention rates. A recent Tufts study on global protocol amendments found that protocols with global amendments were larger in scope and had longer patient recruitment and overall study durations, compared with those without. Notably, almost half (45%) of the amendments in these studies were considered to be avoidable.
Over the past 20 years, there’s been a significant increase in the complexity of study designs, resulting in lower quality clinical data and increased trial costs. Despite initiatives such as the SPIRIT 2013 checklist and guidelines and adaptive trial design techniques, intended to simplify protocol design and reduce unnecessary procedures in trials, companies continue to run unnecessarily complex studies. These complex study designs and poorly crafted study protocols are a key reason for increased costs. It has been estimated that the cost of activities included in studies not considered essential is between $4 and $6bn each year. In addition, the median cost of implementing a substantial amendment has been reported to be $141,000 for a phase 2 protocol and $535,000 for a phase 3 protocol. These are costs that could be avoided if teams are made to understand how to develop and write more effective study protocols.
What makes a study protocol effective?
There are four factors that are crucial to make a study protocol truly fit for purpose. It needs to be precise, simple, practical, and clear in terms of the study design and communication. Instead of trying to do a bit of everything, it should concentrate on a few precise questions. Many studies collect far too much extraneous data, which means that the investigators and sites are busy doing things that won’t actually contribute to the task at hand.
The practicality of running the study and the clarity with which the study is communicated is critical to its success. When writing a study protocol, teams need to consider how feasible it will be to do all the things planned. Many protocol amendments are needed because, after that study is up and running, it becomes clear that certain activities just can’t be done the way they were planned, or site staff misunderstand what they are meant to do. Protocols must present the ideas and activities in a clear and consistent way to make sure that everyone involved truly understands the intention of the study, what is meant to happen, and when. The user-friendliness of the protocol plays a huge role in ensuring that the same activities happen in the same way across all sites and will ultimately reflect on the consistency of the data collected across sites.
Appropriately accounting for all these factors contributes to a study protocol that is likely to avoid misunderstanding by investigators, is less expensive and more practical to run, and overall is more effective.
Common problems
The most common problems with study protocols are:
■ too many objectives (a lack of precision)
■ too many inclusion and exclusion criteria, and too many secondary variables (a lack of simplicity)
■ too many activities planned (a lack of practicality)
■ inconsistency and poor communication of the intentions (lack of clarity).
Study findings reported in 2012 by the Tufts Center for the Study of Drug Development found that a typical protocol has an average of seven objectives and 13 endpoints. If a study is trying to answer seven different key questions, that is probably five too many to truly answer any properly.
Often less is more and having too much tangential information can simply cloud the picture and distract from what could otherwise be a crisp, clean message. Teams also need to consider that drug development and the task of getting a drug approved is a different exercise than that of a scientific exploration of the many facets of a drug. They need to ask themselves what data are critical to demonstrate that the drug works and is safe in the particular indication being sought. If endpoints simply give the same answer in another way, a choice should be made to select the most relevant tests, and the others can be removed.
Even if the study design is simple and practical, inconsistent and confusing information will not aid usability of the protocol. The different sections of a protocol should fulfil their intended purpose with minimal repetition between sections. Study protocols often confuse study objectives with endpoints, such that endpoints are given in place of objectives, leaving the readers unclear about the fundamental aims of the study. Similarly, it is often difficult to find important information in protocols, such as the exact dosing regimen, details about dietary or other restrictions during the study, or the intended timing for activities.
Another common pitfall seen in protocols is a lack of consistency between key sections such as the study title, study objectives and the planned primary analysis. If these are not aligned, the investigators are left to assume the true intention and it is likely that different investigators will assume different things.
The importance of a good writer
An experienced medical writer increases the likelihood that the protocol will be practical and user-friendly. In addition, when writing a protocol, a medical writer is envisioning how the data collected will appear in the study report and can help teams to understand, and perhaps choose, which parameters are going to be the most meaningful when it comes to crystallising the take-home messages. They will help keep the team focused on these details and flagging up places that could be simplified, details that could be removed, and inconsistencies between sections.
The mistake many companies make is to assume that the content stakeholders (for example, clinical scientists, study manager, and statisticians) are also effective communicators. Out of convenience, many protocols are often written by teams at CROs who will be responsible for running the study, generally as part of a full-service contract. This may mean the sponsor has one less contract to organise, but it does not guarantee they will have a trained medical writer in place to craft a strong protocol. While those teams may be very good at the skills needed to run a study, they are not necessarily specialised in writing documents.
Conclusion
In today’s regulatory environment, many studies are too complex with protocols that are unclear and lacking important information. By consciously designing studies that are precise, simple, practical, and clearly communicated, companies can improve the consistency and quality of the data that will be obtained. With so much at stake, companies should do everything in their power to ensure that experienced medical writers are used to help the clinical teams craft protocols that communicate effectively. It may not be the only way to improve the design and quality of clinical studies, but having specialised medical writing companies involved in protocol writing can go a long way to improving clinical study protocols.
