January 2016 – by Stephanie De Masi
Writing a clinical research protocol is a complex and time consuming process. Even before the protocol is written, the study team must frame and refine their research question, and then determine the protocol’s level of pragmatic constraints. The PICOT1 and PRECIS2 tools, respectively, are excellent resources to utilize in these initial crucial stages of protocol preparation.
Each study protocol will be reviewed by a variety of stakeholders including, but not limited to, other investigators, committee members (e.g. steering, safety, ethics), research staff, and regulatory bodies (e.g. Health Canada, FDA). A well thought-out, thorough, and concisely phrased protocol will encourage buy-in from collaborators, promote compliance to study procedures, and facilitate the regulatory review process. Keeping this in mind, the following are a few general items to consider during protocol writing:
Introduction: Information from the grant application (if applicable) is useful in the introduction. Background, rationale, and previous studies can be discussed to provide justification for conducting the study. The study’s purpose should be clear. For example, the purpose may be to gain scientific knowledge in an understudied therapeutic area, or it may be to conduct a pivotal clinical trial with the goal of market approval for a drug product.
Choose Only One Primary Outcome: The primary outcome is the measure by which your research question will be answered. The primary outcome also dictates the sample size. Secondary and exploratory outcomes can also be added, but should be focused and limited in number. Avoid trying to “do it all” and concentrate on a small number of well-defined key questions.
Statistical Plan: Describe statistical methods, sample size and a plan for data analyses (i.e. when, how, and how often). It is advisable to involve a trained statistician early on in protocol development.
Eligibility Criteria: Inclusion criteria are intended to define the study population. Exclusion criteria further refine the study population and usually include relevant contraindications. If a criterion is stated in the inclusion criteria (e.g. presence of X condition), there is no need to re-address the same item in the exclusion criteria (e.g. absence of X condition). Eligibility criteria should be kept as simple as possible; the more there are, or the more complex, the more difficult enrolment becomes, and the less generalizable the results. Mitigate potential confusion by simplifying language and avoiding complex double negatives, which will also facilitate enrollment by the study team. This is especially true in trials with hyper-acute patient populations, when enrollment is time sensitive and a few minutes of delay may result in a missed opportunity.
Operational Details: Describe the study methods and include a schedule of events, or list the study assessments. If possible, specify who should perform each assessment or administer the trial intervention (e.g. does the assessment need to be conducted by a physician, or can it be performed by a trained study staff member?). It is useful to include a diagram or visual algorithm to clarify the steps required during enrolment and follow up procedures.
Expectations of the study team should also be outlined (i.e. who will have access to study data, how the data will be reported, and what type of database will be used). Address the security features in place to protect participant identity and personal health information. You can also decide to allow the study team to interpret sections of the protocol using their discretion, or alternatively, implement constraints (e.g. define what is considered a deviation from the protocol).
Safety Reporting: It is valuable to state what is (and what is not) a reportable adverse event, who is responsible for reporting adverse events, and when and to whom they will be reported. In some patient populations, such as the critically ill, it is often advisable to avoid template definitions of adverse events, and instead tailor the phrasing to the research study. In a critically ill population, many adverse events are expected, and therefore reporting all events could dilute a true safety signal. Furthermore, over-reporting places a large administrative burden on the study team.
For studies that involve high-risk interventions or a very vulnerable patient population, it is beneficial to include a risk/benefit analysis and specify any conditions under which the study will be stopped and/or a patient withdrawn.
Appendices: Will there be multiple research teams working from the same protocol? If so, include appendices, such as any validated scales used to measure study outcomes, which will ensure that all research teams are using the correct version.
Summary Page: Research teams frequently work on multiple studies. A summary sheet or protocol synopsis is valuable as a quick reminder of essential information, such as key study contacts (principal investigator, regulatory sponsor, funding agency) and the main goals and details of the study.
Regulatory Oversight: Assess the potential requirement to submit the study to Health Canada (or FDA). Does the protocol include testing a new/unapproved drug or device, or an approved drug or device outside of its intended use, or outside of its intended patient population? If yes, oversight by Health Canada is mandated in Canada, and submission of a Clinical Trial Application (for drug or biological product testing) or an Investigational Testing Authorization (device) will be required. If Health Canada oversight is not necessary, it is recommended to state the reason(s) for exemption within the protocol.
Registration: Clinical trial registration (typically via ClinicalTrials.gov) is mandatory for many granting agencies, private/industry funded research, and for publication. The International Committee of Medical Journal Editors (ICMJE) provides helpful guidelines to determine when registration is appropriate.
As you can see, there are many things to consider when writing a clinical research protocol and this is by no means an exhaustive list. Be sure to consult your local ethics board guidelines and checklists, as well as the CONSORT3 and SPIRIT4 guidelines for a more comprehensive overview of what to collect and what to report in your clinical trial protocol. Good luck!