An investigator-initiated trial (IIT) protocol for a clinical trial outlines how the study will be conducted. Depending on the sponsor, IIT protocols can vary significantly in requirements and depth, so it is always a good idea to first check with the sponsor. In fact, most sponsors will have their own specific protocol templates. In this article, we’ll outline some of the standard criteria that need to be included in most IIT protocols.
The International Council for Harmonization (ICH) has put together a very comprehensive guide for developing an IIT protocol (link) that complies with good clinical practice. Based on their recommendation, a complete comprehensive protocol includes the following sections:
- Title page (General information)
- Background information
- Trial rationale and objectives
- Trial design
- Selection and withdrawal of subjects
- Treatment of subjects
- Assessment of efficacy
- Assessment of safety
- Direct access to source data/documents
- Quality control and quality assurance
- Data handling and record-keeping
- Financing and insurance
- Publication policy
- Other supplementary information
The overall aim is to ensure that both the researchers and the sponsor are completely transparent on how the study will be conducted, including how to deal with potential problems. It is, therefore, important to provide as much detail as possible for each of the required sections.
The background section should provide a snapshot of all the work pertinent to the proposed study. This includes an overview of both non-clinical and clinical studies that have been published. The goal of this section, however, is not to write a comprehensive literature review, but rather provide enough evidence as to why the study should be conducted. Remember that not everyone has time to read a long introduction, so be concise and persuasive.
Trial Rationale and Objectives
The study rationale should explain “why” you are conducting the study by comparing the benefits versus the potential risks of conducting the study. Although many researchers shy away from mentioning any risk factors in their protocol, for fear of rejection, this is not good practice. Remember that a study protocol should be transparent, so acknowledging the risks in the protocol will reduce your liability later on, especially if something goes wrong in the study. Additionally, any study that has minimal risks also tends to have very little rewards. That being said, draft your rationale in such a way that the positive impacts of the study far outweigh the risks.
The objectives of the study should exactly describe “what” the study is trying to assess. For instance, a study objective could be to evaluate the clinical efficacy of a new eye drop formulation over a 3-month treatment period. Remember that the study objective is the heart and soul of the protocol, so all the other sections should be written with this purpose in mind.
The study design describes “how” the study will be conducted, and typically contains a short description of the overall methodology or approach. It does not need to be creative, but it does need to answer all of the following questions:
- How many centres will be involved in the study?
- What are the blinding requirements?
- How will the subjects be screened and selected (inclusion/exclusion criteria)?
- How will they be assigned to the treatment conditions?
- How is the efficacy of the treatment being evaluated (including baseline)?
- What is the duration of the study?
Selection and Exclusion of Subjects
For clinical studies, the inclusion and exclusion criteria for participants ensures that the sample represents the population of interest. Inclusion criteria typically include gender, age, ethnicity, and a particular diagnosis of a condition or disease. Exclusion criteria include conditions or abnormality that may affect the safety of the subject or the quality of the collected information. It’s important to remember that even with the right selection criteria, the final sample may not actually represent the population. For example, in developing a vaccine for COVID-19, pharmaceutical companies found that it was mostly Caucasians that volunteered in their clinical trials. It was not because other ethnicities were excluded in the selection process, but rather it was because other ethnic groups were less likely to volunteer for these trials. Therefore, when developing your selection criteria, you should ensure that everyone has an equal opportunity to participate.
Treatment of Subjects
In this section, you will need to describe the blinding criteria (single-blind, double-blind, or triple-blind) for the study. In addition, you will also need to decide how you will randomize your sample into the control and treatment groups. For certain IIT protocols, the sponsors may also request information on how the test product is acquired or formulated, and how it will be administered d to the participants. For example, in a study evaluating a new eye drop, a researcher will need to include information relating to the dosage, dispensing, administration, storage, and disposal of the eye drop.
Assessment of Efficacy
To assess the efficacy of a treatment, you will need to define measurable outcomes, also known as clinical endpoints. A primary endpoint is defined as the main measurable outcome for which the study was statistically powered. For example, a primary endpoint for a study evaluating a new eye drop could be an improvement in tear break-up time. Secondary endpoints are additional outcome measures that are analyzed statistically post-hoc, and therefore have not been randomized or powered. They lack statistical power and should be interpreted with caution. In the previous, a secondary outcome could be a measure of whether the participants’ comfort has increased following the study.
In the initial protocol, the role of statistics is to determine the correct sample size using a power analysis. If you’re unsure of how to calculate sample size, read our previous blog on statistical power. This section should also outline the type of statistical tests that will be performed once the data has been collected.
Pace Yourself until Completion
You’ll soon realize that preparing an IIT protocol is a marathon, not a sprint, so it’s important to pace yourself. Set aside a bit of time each day to complete a few sections at a time. Give yourself deadlines to stay motivated and on-track. If you need help, ask your team or a colleague for their input. Fortunately, many sections in an IIT protocol can be re-used and re-worded for future IIT applications. So, once you’ve completed your first IIT, use it as a template for other submissions. It does get easier and faster each time! For more help with preparing or revising your IIT protocols, please contact Sengi.