This article will detail what a study protocol is, how to develop one, and provide some insight on the best (and worst) practices for new study protocol developers.
According to ICH GCP guidelines, a study protocol is a document that describes the background, rationale, objectives, design, methodology, statistical considerations, and organization of a clinical research study. ICH is the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and GCP stands for Guideline for Good Clinical Practice. In short, a study protocol is a legal document that outlines a study plan for a clinical trial, which is designed to answer a key question.
While developing a study protocol it is important to keep your big picture goals in mind. These big picture goals can be things such as:
Before you start writing, you need to consider who your audience is, and write your study protocol based on that information. For example, if you are writing to individuals inside your organization you might want to focus on answering questions related to the product. While writing to individuals or groups outside your organization, such as an Institutional Review Board (IRB), you will want to write in a way that addresses some of the key problems that these groups or individuals might be concerned with.
🔬 Read More: Things to Consider When Working with an IRB
Understanding your audience early is important as it allows you to get feedback from these groups to learn what they need before you start writing. This allows you to cater your proposal to these groups while you're writing, as opposed to having to change your proposal halfway through the process. For example, the IRB will be most concerned with safety of subjects, a detailed device description, and risk analysis.
You should aim for the takeaway or big idea to be the same, no matter the reader. Each reader should be aware of the end game for your study, and how your study plays into your big picture goals. In short, knowing your audience before writing will help you avoid multiple changes after the protocol is written.
A study protocol should not be written in a vacuum. Throughout your development process you should be thinking about who you need to contact as early as possible. Possible contacts could include:
Many research organizations such as large universities have their own processes you need to adhere to. Knowing about and understanding these processes early on in development is key to a successful proposal with minimal edits.
This is also a good time to define roles with everyone you have involved in the project. For example, in some studies the monitors and the site staff have completely separate roles, in other studies they might need to overlap or communicate more often. Clearly defining these roles and responsibilities before the study commences is essential for a smooth-running clinical research study.
In addition to the “who” of your study, you also need to clearly define the “where”. Some key questions to ask include:
If you do have dueling IRBs it is important you create a reliance agreement which will divide responsibilities amongst the IRBs. These agreements are important because they clearly define roles and shift liability to a specific organization in case a certain task is not completed.
🔬Learn More About: How to Choose the Right CRO
Developing your protocol and brainstorming before writing is important. Again, thinking about the big picture is essential for a successful protocol. Start to think about the study in the context of product development, what your five year trajectory is, and what type of regulatory support you will need. You will also need to understand and define who your subject population needs to be. What is feasible within that population?
With that, you’ll need to understand who will be conducting the trial. What are the day to day activities of these people? How can your study work around or with their other duties? Is the primary function of the PI this study, or do they need to perform other tasks in addition to your study? These questions all need to be considered before a fully-fleshed out study protocol is created. Involving the key players in your decision making is essential because they likely have a unique perspective on possible best practices.
The most important thing to keep in mind while writing your protocol is to be consistent with your message. Make sure that you completely iron out the research question you are trying to answer, and have your protocol flow to answer that question. Along that same vein, try to only state information once if you can help it. This will help you with editing later because if something needs to be amended it only needs to be changed once. This reduces contracting information in the same document.
Another important thing to know before you start writing is where specific information needs to be placed. A great resource for templates and past protocols is clinicaltrials.gov. There are multiple names for the same things, such as Statistical Analysis and Statistical Plan. While on clinicaltrials.gov, try to look up templates from similar devices or predicates.
When writing, it is important to start with your objectives to make sure they are comprehensive and specific. Even if you are not the main author of your protocol, this is part of the process you want to be the most involved with as it sets the basis for your research.
At each step of the process you want to make sure to connect to a clear objective. An example of a poor objective could be: “we want to evaluate safety and efficacy of the product”. This is broad and tells you almost nothing. An example of a good objective could be: “to collect data from X population using Y device at Z location and compare device readings to the current standard of care (blood draw, measurement, etc)”. This clear objective helps write your step by step procedures later on in the protocol. Consult with your interdisciplinary team, a statistician, clinical staff, regulatory agents, scientists, and your PI to create your objective.
After creating your objective, you can create your Protocol Synopsis. The synopsis is essentially a summary for your study protocol. The synopsis should include:
After writing the synopsis, make sure to check in with your team to ensure everyone is on the same page. Doing this will help avoid creating a plan that some members don’t agree is feasible or practical.
Below is a list of the most common elements of a study protocol. These might differ slightly from time to time, but are all essentially the same, with only slight wording differences.
This article will choose a few of these elements to go in deeper detail into below.
The background section should define the product, mention the disease/condition, and why the product is relevant. It will also provide a summary of the background data, both clinical and non-clinical, that is of significance for why this product could be used.
The study rationale should answer the questions of why and what. Why does this research need to be done? What is its relevance? The study rationale should also include a brief description of the most relevant studies published on the subject in order to support the rationale. It also discusses the relevance of studying the product within your specific study population and why that population is the best choice for your study. In addition, this section includes the risk benefit assessment for your study and its participants. What is the risk associated with the study and why is it justifiable? How will these risks be mitigated? What are the benefits that can be seen from completing the study - both for the subject and for society as a whole?
The study objective is the section where you explain the research question. As noted before, this is a time to be simple yet specific in stating your purpose for conducting the research and collecting data.
Your desired research outcomes and study endpoints are connected. Your primary endpoint measures your outcomes which will answer the primary question in your protocol. Look at this as a big picture by including your primary endpoints in your study objectives above.
Your study design should also flow from your objectives. This section will describe how the study will be designed, the screening time period, your randomization plan, types of controls, number of centers, duration, etc.
Here is where you can give the specific or step by step details of the study design. It essentially explains how you will be collecting the data for your study. It includes detailed directions and descriptions of how you will be running the study. Here you should include the relevant clinical data you need to collect, such as:
This is a time to be specific, not broad. A bad example is just “vitals”. Instead you want to detail what specific vitals you want and the specific way to collect them. No one will collect an additional piece of data unless you ask for it! Another option is to create an additional study manual in order to add more specific details.
Your methodology section will transition well into your schedule of assessments. The schedule of assessments is a sequentially planned protocol of events in a table format. This is a section you want to make sure is easy to follow, hence the table format. See below for an example:
If there are clinical events that normally happen, such as a height check, still include them in your schedule of assessments.
The subject enrollment section gives details on the types of subjects that are included in the study. This is where you place the inclusion and exclusion criteria. The inclusion and exclusion criteria detail who should and should not be a part of the study. You need to detail any contraindications or unsafe populations for the study. Your exclusion criteria doesn't have to be individuals that need to be excluded for health reasons but also those that will not give you valuable data. Overall you want to make sure you are minimizing risks and bad data.
You also need to describe your randomization or blinding plan. Do you need a single blind, double blind, or no blinding? Oftentimes medical device trials are not blinded.
The protocol must also contain your plan for subject withdrawal. It needs to contain your criteria for withdrawal and your individual plan for replacing dropouts. This can not be decided after the study starts, so it is important to have a plan within your study protocol.
An adverse event is any untold medical occurrence associated with the use of a device or drug in humans. In this section you should list all of your anticipated adverse events, in addition to explaining what and when to report. If you have an unexpected adverse event it must be reported to the IRB within four days, and some specific adverse events must be reported to the FDA. The guidelines for reporting adverse events are included in the FDA’s Code of Federal Regulations (CFR) 21CFR 812.150. The PI must be aware of these adverse events and how to report them. This section is also where you can outline a set of rules for when you, as sponsor, need to be notified of an adverse event (whether it is anticipated or unanticipated).
This section should include what you intend to do with your data, which subjects are included in each analysis, and what data points will be used. In order to prevent cherry picking data, It is important to include your expectations for what data points you will be using before the study has commenced. You can also include how you will use demographics to analyze the data, such as a breakdown of the effects of your device on males versus females.
You should also include how you plan to analyze the data, such as a t-test. This is a great time to utilize what your predicate did, and draw information from their study protocol.
The data handling and monitoring section should give the reader an insight on how you plan to collect and manage your data. Below is a list of data-related issues you should have a plan for:
All of the above data-related problems should be addressed in the study protocol. This is another section where the statistical methods used for the analysis of the data need to be outlined and clearly identified.
This section will discuss how the study will comply with the rules outlined in GCP regulations. An example of a line from this section could be: “Research will be conducted in accordance with X regulations. Study staff will be trained to Y.”
Here are some other typical additions to this section:
This section should also include information on if and how publications will be handled. You need to answer questions such as:
This section is essential for readers, specifically your IRB, as it proves and outlines your commitment to following regulatory and ethical guidelines.
🔬Learn more: Regulatory Affairs for Life Science Startups
A great clinical protocol will help feed into other essential clinical documents such as your Informed Consent Form, Investigator’s Brochure, Clinical Study Reports, Case Report Form (CFR), and many more. Brainstorming is a large part of writing a study protocol, as it allows for fewer revisions after you have started writing, leading to fewer mistakes. Success of the study will depend on your ability to plan for all possibilities before they happen, and your ability to adapt when they inevitably come your way.
This information comes from a talk with Tala Harake, in partnership with University Lab Partners. Access the video here.
Tala Harake is a Managing Partner at Vigilant Clinical Trials Consulting. After completing her undergraduate studies in Biology and Mathematics, Tala went on to earn a graduate degree in Biochemistry. She then began her career at Masimo, where she headed their clinical research department. In 2020, Tala departed Masimo to start her consulting company Vigilant Clinical Trials Consulting, LLC. Since starting VCTC, her clients have included medical device start-ups, university research centers and medical societies. Throughout her career, Tala has been driven by a passion for medical devices and an underlying desire to help get these incredible devices to market and into the hands of healthcare workers.
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