Department of Medicine Research Protocol Template

Statement regarding the use of this document:

The general protocol format provided here is intended as a guide or starting point for generating your own research protocol. While preparing detailed and complete research protocols may appear extensive it will facilitate execution of the study, grant applications, ethics applications and preparation of manuscripts. The format outlined is by no means rigid and will vary depending on the complexity and extent of the individual research study. The format as presented follows the guidelines presented in Chapter 17: Writing a Research Protocol, in The Research Guide: A Primer for Residents, Other Health Care Trainees, and Practitioners1. Read the chapter for more in-depth discussion on each of the sections. Additional sources of information include the Tri-Council Policy Statement Ethical Conduct for Research Involving Humans (2nd edition)2, and the Canadian Institute for Health Research website3. This document was not created in conjunction with any of the UBC affiliated REBs and thus should not be considered an official REB template. The outline does not replace the specific guidance notes provided by each REB and these guidance notes should be consulted prior to submission.

Note that a study protocol should be considered a ‘version-controlled’ document. You should keep incremental dated versions, particularly following REB approval where any change (ANY change) must be reported to the REB in the form of a protocol Amendment or at the time of Annual Review (if administrative/editorial only). It should be clear to the entire study team what version of a research protocol is in effect at any given time – the protocol isn’t just something you need for approval, it should be a valuable reference during the conduct of the study and when you compiling manuscripts for publication.

Protocol Format Outline:

Project Title

Choose a title that adequately describes the core research objective and the population under investigation. Titles may include information about the type of intervention used in a randomized clinical trial.

Project Summary

Summaries are used to establish the scope and objectives of the research project. This should include a statement about the motivation behind the project, the proposed methodology, anticipated outcome and significance and potential impact to scientific community. Any pilot data obtained and progress should be included, in the context of framing the current proposal.

For larger complex studies the summary may take the form of an overview with specific headings outlining the critical details of the study. These details may include: objective, study design, sample size, selection criteria, interventions, outcomes and duration of study. For smaller studies this may simply a paragraph.

.Background and Scientific Justification

Within this section you want to clearly frame the research by providing an overview of the current state of knowledge/care and describe why there is need of change/improvement/research. A well-framed research question is crucial to study design.

The structure of this part of the protocol typically follows a well prescribed format including the following: narrative of the current state (standard of care, diagnostic test or practice under investigation), a description of problems associated with this current state (e.g., inconclusive knowledge, or poor outcome), or may suggest a reason as to why the current accepted theories may require revision.

Typically a survey of the current body of knowledge in the core research area, leading the reader to understand why the new study is being proposed. Pilot data, preliminary results and anticipated extensions of current work should be clearly outlined. The reader should clearly understand why the proposed approach, team and location are integral to answering the proposed question. The author should ensure that references are relevant and up to date, as this demonstrates due diligence and sufficient preparation.

Research Objectives

Succinct statement of the hypotheses and research objectives. The objective(s) should be listed as short statements of the scientific goals of the study.

In clinical/ interventional research studies you may include a hypothesis test statement. The statement should include a description of the suitable statistical test, the population under investigation and the probability of proving the null hypothesis. For correlation and comparison based studies a formal hypothesis test is typically replaced by a statement which outlines the variables of interest in the test population and the set confidence intervals.

A single primary objective should be provided as well as many additional secondary objectives as necessary. If not stated as a specific hypothesis, each objective (primary and secondary) should be accompanied by a statement of the relevant testable hypotheses or succinct research question. While reference to subject-specific outcomes/endpoints relevant to the hypotheses/research question should be made, details should be listed in the appropriate section under Methodology

Ensure the objectives are attainable within the given constraints of time, funding and team members. Minimize the number of objectives to ensure that the scope of the proposal is attainable.

Methodology

This is a critical component of a protocol, and should be as detailed as needed to ensure that any person who wishes to repeat the study could follow this and achieve the same outcome.

  1. Study design: You can describe your study design in the context of the evidence which will be used to draw your conclusions. Specifically, are you completing a retrospective chart review, a prospective observational study, a randomized control trial, or interventional study. Describe the number of participants, number of visits, duration of participation, and expected duration of the study.

How is the group under investigation defined, (ie. control vs. experimental group), control matching, and any methods for randomizing participants to groups. If not randomizing, describe how selection bias will be managed. If a comparative group study, describe who will be blinded and how the blind will be maintained, or justify why no blinding is necessary.

  1. Study Population: Define the criteria for inclusion, recruitment and any exclusion criteria. Bear in mind that when excluding certain groups from your research you must justify this choice and provide an ethical reason for doing so. This includes woman who may become pregnant, the elderly, and children. Refer to Chapter 4: Fairness and Equity in Research Participation in the TCPS_2 for more detailed instructions surrounding exclusion2.

Describe how participants will be recruited to the study, and how they will be approached and by whom. Include any recruitment materials (advertising, letters to participants, websites, etc).

Describe how potential participants will be approached and consented for eligibility screening.

  1. Outcomes/Endpoints: Outcomes and endpoints are what is actually being measured within the participant population. Clearly define primary and secondary outcomes/endpoints to be measured. Generally, there should just be one primary variable with evidence that it will provide a clinically relevant, valid and reliable measure of the primary objective (e. g. lab procedure, safety measure). Secondary outcome measures should be included whether or not they add information about the primary objective or address secondary objectives. Discuss their importance and role in the analysis and interpretation of study results
  1. Study Procedures: Describe, in chronological order where possible, the procedures that each participant will undergo, which are solely for research purposes and which may be done for evaluation or treatment of the participants condition. Include a schedule of visits and an approximate duration of the visit.
  1. Data collection and Management: Pursuant to UBC Policy #85, describe how data be recorded, verified, stored, secured and confidentiality maintained for the required 5 years following study completion. Be precise about both the methods and means used (essentially, who, when, where). Include details if using a standard procedure, standard method of care or a method thatwas validated previously within the research group.

Collection and storage of personally identifying health information must be justified, and if so, describe how the data will be stored, used and how you will maintain patient confidentiality. Who has access to study data and who will perform the analysis? How long will the data be kept, and how will it be destroyed? Will the data be de-identified? If yes, who will have access to the key?(Refer to Chapter 5 – Privacy and Confidentiality in the TCPS_2 for more detailed instructions surrounding confidentiality and de-identified or anonymized information2.)

  1. Specimen collection and storage: If specimens (eg: tissue, fluid or DNA) will be stored a list of specimens, locations and conditions of storage must be described. If specimens are to be used beyond the scope of the current study, participant consent must be obtained to do so, and the intent should be described in the protocol.

Statistical Considerations

  1. Sample Size Justification: The sample size is typically justified based on the primary objective of the study;restate the objective and relevant hypothesis and outcome/endpoints. Also, recapitulate the relevant portions of the background material that support what you might reasonably expect to observe in the present study. If you are unsure about what might be observed on the bases of the existing data or literature, provide a range of possibilities and select a sample size on the basis of situations you think are likely to occur and will support the Primary Objective.

State the final proposed sample size and the associated power to reject the null hypothesis (or the precision if this is an exploratory study with no comparator group); online calculators may be necessary to calculate power or sample size, or a statistician may be necessary for more complex situations.Examples of good power calculators include:

and

Power is typically at least 80%; Is the proposed sample size reasonable with respect to the time, funding and environment in which the study will be conducted? The Type I error rate (α) is typically set to 0.05 and 2-sided hypothesis tests / confidence intervals are the most common – both of these must be stated.

Remember that when describing the power you are also describing the risk that even if the study is run correctly it will still not be able to adequately answer the hypothesis. Specifically, if you have a study with 80% power you are stating that there is a 1/5 chance that it will fail. It is worth considering your patient population when considering the power level needed, particularly when working with vulnerable populations. Is it ethical to ask the population to participate if there is a 20% chance of failure? For vulnerable populations it may be worth increasing the number of participants to increase the power of the study and thus ensure a measurable outcome is possible.

A sample statement may look the like the following: “A study of N (sample size) patients will result in X% power to detect a minimum difference of Eff (effect size) increase in survival in patients treated with (drug1) compared to the standard treatment (drug2), using a 2-sided test with an  value of 0.05”

2. Primary Analysis:Specifically, what analysis methods will be performed to achieve the primary outcome. Also of critical importance is a description of what study participants will be included in the analysis and how those who leave the study will be included. Will the Intent-to-Treat principal be followed? If not, why not. Also, when will the analysis be performed – are you performing analyses prior to the completion of enrolment and follow-up? If so, how are you ensuring that the study-wide Type I error will be maintained. Also, if several hypothesis tests are included in the Primary Analysis, how are significance levels adjusted to preserve the Type I error rate? What contingencies (transformations or non-parametric methods) will you have if the assumptions of the proposed methods are not met. Will your primary analysis include adjustment by covariates? Why or why not?

It is important to define methods of analysis, and contingencies a priori to avoid bias. Exploratory analyses would typically be included in a separate section, and are encouraged to ensure the maximum information is obtained from any research project. Occasionally, preliminary research studies may leave the PrimaryAnalysis section somewhat more open ended, but the justification for this should be made clear.

  1. Secondary Analyses: Analyses supporting secondary objectives should be specified here and in a similar manner as the Primary Objective. This may include alternative analyses of the Primary Outcome, or analyses of subgroups, or simply testing of alternative hypotheses from the Secondary Outcomes. Correction of Type I error for multiple testing is not typically required for several Secondary Objectives.
  1. Exploratory Analyses: This section is not always required, but may be pertinent if there are additional, preliminary, investigations on subsets of participants or peripheral results that may be hypothesis generating for future studies.

Ethical Considerations

Describe any outstanding ethical issues not addressed in the Methods including recruitment, inclusion/exclusion criteria, burden, risks and privacy issues surrounding data collection and management. If consent is required how will consent be obtained? How will participants be contacted, and how long are they given to consent? How will participant confidentially be maintained?

Are you using a placebo or control arm for any portion of this work, if so you must clearly indicate why it is necessary to introduce this into the study in order to achieve the endpoint or measure the outcomes, and meet the objectives of the study. Include a statement about how the potential loss of trust will be mitigated by the research team, e.g., debriefing of participants. Will the participants in the control/placebo group be offered the other treatment option? How will the team manage questions about the treatment?

Are you administering a new treatment? Will this treatment option be available long term for participants and how will the cost be covered? How will care of adverse events which are not resolved during the course of the study be managed?

If you are conducting a clinical trial how will duty of care be upheld? What criteria will result in participants being withdrawn from the study? How will therapeutic misconceptions be managed? Under what conditions would unblinding occur?

Is there a potential conflict of interest of any study members? If so this should be identified clearly.

Statement of Risks and Benefits

Provide a statement about the level of risk of the proposed study. The TCPS_2 defines minimal risk as that which poses no greater potential for harm than the participant would expect in their everyday life, as it relates to the research2. Retrospective chart reviews are deemed minimal risk.

If your study involves any risks to the participant they should be outlined here. A statement on the magnitude and seriousness and probability (quantification) of each risk should be given.The details here should match what is written in the consent form and REB application. Risks include not those associated with experimental interventions, but also those associated with procedures required by the protocol. Breaches of confidential information (eg: images or genetic information) should also be considered as risks of participation.

Bear in mind that as a researcher you may also be exposed to risk during the course of the research. This is particularly important for trainee researchers. If there are any potential risks to the study team members collecting and carrying out the research it is good practice to acknowledge this risk, and state what measures will be taken to mitigate this risk. Will the trainees be supervised, and who will do the supervision?

Address any benefits that study participants may receive as a result of being in the study, this includes any and all remuneration, reimbursement, and draws.

Composition of Study Team

Describe the study team who will participate in all aspects of the research. This should include a description of who will have contact study participants, who will collect and analyse the data, and who is responsible for the overall governance of the project.

This section should be completed to ensure that it is clear to the REB that all team members are qualified to carry out the work. Indicate which members have undergone required TCPS 2: Core ethics training2,3.

Timeline of Study

While this section seems irrelevant to the process of ethics it is actually very important, in order to determine whether the study should be approved it is important that the REB is satisfied that the work being proposed can be accomplished within a reasonable time frame. This is critical when studies are supported by grants, is there enough money and time to allow this study to come to completion? It is not ethical to initiate a study which cannot be completed, because there would be no positive outcome, and the burden/risks taken on by the participants would outweigh the benefits to society.