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Understanding the Nuances of a Clinical Study Protocol

Understanding the Nuances of a Clinical Study Protocol

11 Jun 2024

One of the first recommendations that I received as an entry-level medical writer when I started writing clinical study protocols (or simply called protocols) was “not all protocols are created equally”. This may seem obvious, but as I gained more experience with this document type, I realized that this was a great piece of advice.

Writing a protocol may seem straightforward. But there are often unexpected hurdles in the design and development of a clinical trial, which can cause delays in the protocol-writing process. At the same time, there is frequently a sense of urgency to complete the protocol, either because it’s necessary for the submission of an Investigational New Drug (IND) application or because there’s a rush to initiate the clinical trial.

Before we look at some ways to develop a strong protocol, let’s make sure that we have a clear understanding of its purpose and framework.

So, how is a protocol born? Not surprisingly, a protocol starts from a good idea with one or more goals. Examples of “a good idea” can include fulfilling an unmet medical need within a disease population or bridging a “knowledge gap”. The basic structure and content of a protocol are described in the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) E6 guideline. The type of information includes background information, clinical trial objectives and assessments, clinical trial design, study participant selection and treatment, and a brief overview of the planned statistical analyses. 

With this in mind, the protocol can be conceptualized as a “road map”, describing everything from a clinical trial’s methodology to statistical considerations during the clinical trial process, including detailed guidelines and participant safety measures intended for personnel (eg, investigators, physicians, healthcare professionals) and other stakeholders (eg, Institutional Review Boards [IRBs]). The protocol should be a complete and consistent document to fulfill its ultimate purpose of finding a safe and effective investigational medicinal product (IMP) for a specific indication. Ideally, it should leave very little room for error and most importantly include instructions on what to do if such an error occurs. 

So, how can we achieve a strong protocol, which in my opinion, is a rigorous and challenging assignment? Success requires a careful attention to detail, and a commitment to ongoing learning, integrity, and precision. As you will see, the protocol must be written in a clear and consistent way to minimize the chance of error. Quality and accuracy are incredibly important in protocol authoring.

Here are a few tips to make writing a protocol a bit easier.

Understand where your study fits in and begin with the end in mind

It is important to understand where your study stands in terms of the overall drug program. Will your study be included in an upcoming submission? Will your study rely on the results of earlier studies? Addressing these types of questions can help determine the timeline for your project and keep the team focused on “big picture” issues without getting lost in all the details.

Assemble a team and agree on study goals

It is crucial to assemble a team that can address all aspects of a protocol, from drug formulation to regulatory requirements to analysis of data. As you’re putting your team together, remember to identify individuals who are key decision makers or who can help resolve potential disagreements within the team. Input from various team members is what ultimately determines how a protocol is written, and forgetting or neglecting a given area of expertise is understandably problematic and often translates to a delay in the timeline.

Once your team is assembled, it is important to make sure that everyone agrees on the same study goals. These questions may seem obvious, but different team members often have different opinions on what information should ultimately be derived from a study. Getting everyone on the same page early in protocol development can prevent confusion and extra drafts.

Be realistic with your project timeline

Not surprisingly, each protocol timeline will be slightly different; however, a realistic timeline which accounts for multiple reviews and yields a high-quality document in the shortest amount of time is generally the preferred approach. It is also useful to set up a granular timeline, so it is immediately apparent when the document is unlikely to meet key deadlines. By designing a robust timeline at the beginning, you can avoid frustration and disappointment toward the end of the protocol writing process.

Delays are common but the best way to stay on track is to maintain continuous communication with the team. As Regulatory Medical Writers, it is our job to ensure that the team makes a unilateral decision. In other words, we are acting as the glue that brings different pieces together into one comprehensive and cohesive protocol.

Create a protocol concept

Another excellent way to prevent re-writing and to simplify timelines is to create a protocol concept. A protocol concept is a short document (<15 pages) that briefly outlines key study aspects, such as clinical study design, participant inclusion and exclusion criteria, clinical trial objectives and assessments. This is not a regulatory document and there is no standard format.

A protocol concept should be reviewed and/or approved by the team before formal protocol writing begins. This allows the team to review the “big picture” issues in a small, condensed format, which is typically more efficient than asking the team to review a full-length protocol. Obtaining team agreement on the protocol concept then streamlines protocol writing and minimizes the risk of needing large scale edits.

Carefully consider your study design

The study design, which is the essence of the document, can have a surprising number of factors to consider. For instance, do you need a placebo or an active comparator for your study? Should you examine more than one dose level of your IMP? It can be tempting to try to answer as many questions as possible in a single study. But unnecessarily complicating a study can be problematic.

This is one area where a protocol concept is especially useful. Clinical trials can get more complex at the later stages of development, which makes it even more important to get the entire team on the same page as early as possible. It may also be useful to have a designated party review the protocol for feasibility such as a clinical expert or the Clinical Research Organization (CRO) responsible for conducting the study (if applicable).

Remember your writing considerations

It’s always helpful to begin writing a protocol using a company template, or a model protocol from the same (or similar) clinical program. A consistent template is a beneficial tool in submissions because it ensures “mapping” between the protocol and the expected data presentation, as well as enhances consistency and readability for regulatory agency reviewers. However, sometimes it can be challenging to convince teams that the best approach is to follow the template and only introduce changes related to the study design. This is where close communication with the team is critical. As Regulatory Medical Writers, we provide the team with constructive feedback and all the necessary information to make an informed decision.

Another issue that we often see is the desire to write two protocols in parallel (especially for one IMP that will be used for multiple indications). However, this approach makes it hard to generate consistency between documents. In our experience, parallel authoring, while it may seem like a good idea, increases the overall workload and can necessitate substantial edits (and potential delays) in later writing stages.

Instead, we suggest staggering protocol writing. That way, the overall structure and messaging of the first protocol can be pulled directly into the second protocol, and the team can focus on one document at a time. This staggered process typically allows the second protocol to be written much more quickly than the first, and we’ve found that staggering protocol writing doesn’t necessarily delay document finalization.

Consider planned amendments

Understandably, many teams want to minimize protocol amendments. But occasionally, pre-planning amendments can be a very helpful tool to increase the amount of useful data obtained in a study and to streamline the clinical development program. Pre-planning an amendment can be done informally, but it is crucial to determine what criteria must be met to trigger the filing of a specific amendment. A straightforward example may be to add dose cohorts if a maximum tolerated dose is not reached.

These are just a few considerations on how to start thinking about your protocol and take steps to streamline the authoring process. As you plan and write the protocol, remember to keep the document’s end purpose(s) in mind, as well as the recommendation that “not all protocols are created equally”.

If you are planning to author a protocol but have questions or are struggling on how to develop your study concept document into a cohesive protocol, please contact us. We would be delighted to discuss unique approaches on how to prepare your protocol by using your study design as a starting point. You can also find us on LinkedIn.

About The Authors

Maria N Fairbank, PhD, MSc

Maria Fairbank, PhD, MSc, is a Senior Clinical Research Scientist at Syner-G BioPharma Group. Prior to joining Syner-G BioPharma Group, Maria was a Senior Program Manager/Medical Writer II at Technical Resources International Inc, in Bethesda, MD.

Dr. Fairbank has medical writing experience supporting the National Institute of Allergy and Infectious Diseases (the Division of Microbiology and Infectious Diseases) and the National Cancer Institute (NCI, Cancer Therapy Evaluation Program), most recently as the Senior Program Manager for the NCI Centralized Protocol Writing Support Program for trials conducted by the Experimental Therapeutics Clinical Trials Network. With over 6 years of experience as a medical/regulatory writer, her therapeutic areas of interest and experience include oncology (immunotherapy), psychiatric disorders, and neurology. Overall, her work encompasses a number of submission level and study level documents, including Protocols and Amendments (Phase I through IV), Clinical Study Reports (Phase I through III), Investigational Brochures, Investigational New Drug (IND) Applications (ie, Module 2 documents), Clinical Overview Addendums (Module 2.5), IND Annual Reports, Developmental Safety Update Reports, IND patient safety reports and narratives, Informed Consent Documents, and Central Institutional Review Board Applications. Additionally, Dr. Fairbank has over 10 years of experience in academia either as a basic research scientist or as an instructor/mentor. Maria has a strong background in oncology, pharmacology, toxicology, physiology, molecular biology, and biochemistry.

Dr. Fairbank earned a MSc in Pharmacology and Toxicology from the University of Western Ontario (London, Ontario) in 2006 and a PhD in Cell and Developmental Biology from the University of British Columbia (Vancouver, British Columbia) in 2012.