A clinical research protocol is one of the most vital components of any study.
It describes an overview of the research, including the main objectives, study design, and key considerations. It also ensures the safety of study participants and maintains the integrity of clinical data.
The protocol document must be reviewed and approved before the trial can proceed, so it’s important that it is accurate, submission-ready and compliant with regulatory standards
In this guide, we cover the most important steps to follow when writing a clinical research protocol, based on the recommended topics provided by the ICH Good Clinical Practice (GCP) guidelines.
What is a clinical research protocol?
A clinical research protocol is a document that outlines how a clinical trial will be conducted and the clinical trial management processes that will be in place throughout the study. It provides a detailed description of the research objectives, design, methodology, and key study considerations. It also describes the background and rationale behind the research.
As well as outlining the study plan, the research protocol also describes the safeguarding and safety measures that the study will follow.
The main purpose of the research protocol is to outline the study plan, with guidelines for the research to follow. The protocol is formulated around the main research question. As such, the guidelines provided in the study protocol ensure that the trial stays centred around the main aims and objectives of the research.
This is one of the most common types of clinical writing, and is integral to any kind of trial.
A study protocol can be likened to a cookbook recipe. It contains the precise ingredients, metrics, and methods to follow when cooking – or conducting a clinical trial.
Why a clinical trial protocol is necessary
Research protocols are important for a number of reasons. Mainly, the protocol document provides a definitive plan for how the study will be conducted.
This is developed to ensure that researchers remain consistent and compliant in their methodology and activities across the trial, resulting in smoother operations and more reliable clinical data.
Under Good Clinical Practice (GCP) regulations, a clinical research protocol is required in order for a trial to commence, and is also required for obtaining ethical approval. Furthermore, the research protocol ensures that the appropriate patient and participant health and safety measures are in place.
For instance, the protocol outlines the specific safety parameters that the trial will investigate throughout, and how these will be managed and followed up.
How to write a clinical research protocol
According to Good Clinical Practice guidelines, a clinical research protocol should include the following topics:
- Title page (general information)
- Background information
- Objectives/purpose
- Study design
- Selection and exclusion of subjects
- Treatment of subjects
- Assessment of efficacy
- Assessment of safety
- Discontinuation of the study
- Statistics
- Quality control and assurance
- Ethical considerations
- Publication policy
- References
- Supplements/appendices
Title page (general information)
The title page is the very front page of the clinical research protocol. This should provide an overview of the following key details:
- Protocol title
- Protocol identification number
- The date
- Name and contact details of the sponsor, investigator, monitor and medical expert
Background information
The first contents page of the protocol should contain introductory background information about the study. This provides the rationale behind why the study is being conducted, detailing information about what is already known about the treatment or condition.
This should open with the name and description of the investigational product, with an overview of the previous clinical or non-clinical findings that relate to the product. The known potential risks and benefits should be summarised here, alongside supplementary information about the population being studied.
Next, a description of how the treatment will be administered, dosed, regimented, and the length of time that patients will receive it. The background section will also provide a statement regarding how the trial will be conducted in compliance with the protocol; as well as Good Clinical Practice and any other regulatory standards.
Lastly, this section should include references to relevant literature that provide background information to the trial.
Study objectives and purpose
This section outlines the primary objective of the research. Whilst every trial has a primary objective, there may also be several secondary objectives to include here, depending on the nature of the study.
The research question should be referenced in this section, alongside the specific objectives that relate to the main question. The objectives should be clear and simple – these are usually listed in a bullet point format.
It’s important to make sure that objectives are achievable within the scope of the proposed study. Whilst it is tempting to cover a wide range of objectives, it’s vital to limit these to realistic, achievable aims.
Study design
The study design section provides a detailed description of the trial design, including how the trial will be conducted in order to meet the primary and secondary endpoints of the research. The study design must also support the main objectives outlined in the previous sections.
This section describes the type of trial design that will be used to conduct the study, for example, double-blinded, single-arm, placebo-controlled, or other study designs. Plan this section carefully, detailing all study activities that subjects will undergo. Not only should this outline the type of trial design, but should also explain every relevant detail involved with the design.
As an example, the trial might use a multi-arm study design. In this case, the protocol document should describe the number of arms, the number of subjects per arm, and the specific procedures involved. Similarly, for a biomarker-based study, describe which specific biomarkers will be used, and how these will be measured.
This should involve the types of observation or intervention that subjects will undergo, details about visits, timescales, data collection, and the sequence of study activities. It’s important to be specific here with the following points:
Observations – provide details of what exactly the research will observe, how the observations will be made, and how frequently.
Interventions – describe what the intervention is, whether it is in phase 1, 2 or 3 of research, how it will be administered, how frequently it will be administered, and in what dosages.
Visits – outline the time periods between visits, as well as the frequency, and what will happen at each visit.
Timescales – provide a timeline of when procedures will take place, and in what sequence.
Data collection procedures – describe the specific data collection procedures, and how the research will ensure data accuracy, compliance and subject anonymity.
Selection, exclusion and withdrawal criteria
Eligibility criteria are key in clinical trials. They define the patient population that is being investigated, and are often tailored to meet the aims and objectives of the research. In order to attain a well-defined population, the clinical research protocol outlines subject inclusion and exclusion criteria.
In this section, the specific characteristics of inclusion and exclusion criteria are covered to provide details on the requirements for study entry.
Inclusion criteria specifies the characteristics that will be accepted, and exclusion criteria specifies the characteristics that will not be accepted.
Inclusion and exclusion criteria could specify characteristics such as the stage of disease, age, history of disease(s), smoker status, or body mass index (BMI). It can also include more specific characteristics, such as the molecular profile of the disease – as is often the case in rare disease and oncology research.
Alongside inclusion and exclusion criteria, this section of the study protocol should describe the subject withdrawal criteria. Whilst subjects can withdraw at any point, there may be instances where the investigator or sponsor decide to withdraw subjects. This might be due to safety concerns or non-compliance with trial procedures.
The grounds for subject withdrawal should be outlined in this section. For example, these might include pregnancy during study duration, or intention to become pregnant, intolerable adverse effects, violation of study protocol, or an endangerment to the subject’s health.
Treatment of subjects
In this section, the protocol should cover key information about the treatment that will be administered to subjects. This should include:
- The name of the product(s) to be administered
- The dose(s) of the products
- Dosing schedules
- The route of administration
- Treatment periods
- Permitted and non-permitted medicines during the trial
- Follow-up periods and procedures
- Monitoring procedures
These details ensure that there is a clear understanding of how subjects are to receive treatment, not only ensuring consistency throughout the trial, but also keeping subjects safe.
Assessment of efficacy
Efficacy and safety are two of the most important considerations in clinical research. In order for a study drug to be successful, it must be proven efficacious and safe for use. As a result, the study protocol must clearly specify the efficacy and parameters, alongside supporting information.
Efficacy and safety are split into two sections in the clinical study protocol.
For efficacy, it is important to state the endpoints that would define efficacy. For example, the trial may want to develop a drug that:
- Eliminates specific symptoms (such as headaches, for instance)
- Prevents certain disease symptoms
- Cures a disease
- Delays the onset of symptoms
- Takes effect more quickly
In any case, it’s essential to be specific when defining efficacy parameters.
This section of the study protocol should also cover the procedures for assessing, reporting and analysing efficacy throughout the trial.
Assessment of safety
Similarly to the assessment of efficacy, it is essential to assess safety parameters in the study protocol. This section should include the primary safety endpoints to be measured, with details on how these will be assessed, reported and analysed.
Examples of safety parameters might include:
- Vital signs, such as blood pressure, pulse rate and ECGs.
- Physical signs, such as heart, lung, and weight measurement.
- Laboratory tests, such as toxicity indications, red blood cell count, and white blood cell count.
The clinical research protocol should also provide definitions of adverse events, defining adverse and serious adverse events separately. The intensity of adverse events should also be defined, with guidelines on how to judge mild, moderate and severe adverse reactions.
Finally, this section should describe how the study will follow up adverse events, including the type of follow up and duration.
Discontinuation of the study
Much of the research protocol will focus on what happens during the study, but there should also be a statement on what happens at the end of the study (often referred to as the ‘study close’).
Discontinuation procedures should describe the steps taken to bring the study to a close. For instance, patients will no longer receive investigational treatment, all databases will be locked for analysis and there will be checks to ensure that all data has been collected.
Statistics
This section of the research protocol provides a description of the statistical methods used in the study. This should cover all statistical considerations, such as methods, timings, number of subjects, and sample size.
This will also include the level of significance that will be used, and procedures for handling missing or unused data.
Quality Control and Assurance
This section of the research protocol outlines the quality control measures that will be put into place throughout the study.
For example, a description of the systems, clinical data management procedures, training, instruction manuals, and auditing procedures.
Ethical considerations
The research protocol should state ethical considerations of the study in line with Good Clinical Practice regulations, as well as any local regulations or laws.
This section commonly outlines subject confidentiality procedures, stating the rights of patients and participants in the trial. For instance, their right to withdraw at any point throughout the study, and how the trial will comply with this right.
Similarly, the study protocol’s ethical section should state the responsibility of the investigator to obtain signed informed consent from subjects prior to participation in the trial.
Publication policy
The protocol should outline the sponsor’s publication plans where necessary, describing what will happen following the study close. For instance, who will have the rights to publication, and where the data will be published. It may also indicate whether the raw data will be accessible all together.
The publication policy is sometimes addressed in a separate agreement to the research protocol document. If not, then it is usually included in the protocol.
References
References to all cited data and research sources should be included here. This should be numbered sequentially, attributing to numbered references cited in the text. This helps maintain the protocol’s validity with supporting background data or research.
Appendices
The clinical research protocol should end with an appendices section. This includes all documents that are to be submitted with the protocol for review. For example, subject consent forms, participant manuals, and any other documents referenced in the protocol.
Final thoughts
Writing a clinical research protocol is a challenging task. There are a large number of factors and steps to consider when describing the scope of the research. Though nonetheless, it’s essential to cover them in the protocol.
From study background, trial design, ethical considerations and key definitions, it’s important to provide a comprehensive overview of the research, and provide specific guidelines on study procedures.
Without the protocol, clinical trial procedures risk becoming inconsistent, unsafe, and noncompliant.
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