What is a clinical trial protocol?
If you are involved in clinical investigation, you may need to contribute to the preparation of a clinical trial protocol. A clinical trial protocol is a document describing how a clinical trial will be conducted, including the objective(s), design, methodology, statistical considerations, and organization of the trial to guarantee the safety of the participants and the integrity of the collected data. The protocol also provides the background and rationale for conducting the study and the research questions that it addresses, as well as considerations on ethical issues. The format and content of clinical trial protocols are standardized and follow the guidelines for Good Clinical Practice (GCP) (first published in 1995, last updated in 2016) according to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
Why is the clinical trial protocol needed?
The protocol is a key quality control tool for all aspects of a clinical trial, being necessary for several reasons:
- It ensures the health and safety of all the study participants
- It provides a precise study plan
- It defines and manages the trial, and therefore it should be strictly followed by all the study investigators
- It guarantees the integrity of data, allowing the combination and comparison of data across all investigators and/or study sites
- It informs the study administrators, which frequently are a contract research organization (CRO)
- It is required to obtain ethical approval from a Research Ethics Committee or Institutional Review Board (IRB)
Preparing the clinical trial protocol
The protocol synopsis is the basis to write the complete clinical trial protocol, being usually developed by the sponsor or the sponsor together with the CRO. The synopsis is a short document listing the primary and secondary objectives of the clinical study and providing an overview of the study design and details about treatment(s). You can find an example of protocol synopsis from the World Health Organization in this link.
The protocol synopsis and the complete protocol document should be prepared following ICH E6 compliant templates to ensure consistency and the inclusion of all key elements. The protocol synopsis includes the following information: study title, product, clinical phase, protocol number, disease indication, trial identification number, information about sponsor and investigator, and information about clinical sites. Moreover, the synopsis describes the objectives, study design, study population, sample size, eligibility criteria (for inclusion and exclusion), treatment, and type and timing of assessment based on objectives (with a clear schedule or flowchart). A precise definition of the objectives and the study design increases the efficiency of writing and avoids inconsistencies. Sample size calculation should be based on the primary objective, with additional objectives categorized as secondary.
After preparing the protocol synopsis, the whole protocol can be developed. The complete protocol includes additional elements (listed below), such as the introduction (including clinical and non-clinical data), the rationale, a more detailed description of the assessments, the description of statistical methods, prior or concomitant treatments, and the conditions under which the study needs to be suspended or cancelled.
Topics included in a clinical trial protocol
The ICH website reports the full list of topics that should be included in the protocol. Note that site-specific information may be provided in a separate agreement, and some of the information listed below can be contained in other protocol referenced documents, such as an investigator’s brochure. Different specific guidelines have been developed depending on the anticipated study design, most of them containing a full list of items to be covered. As an example, you can download a generic protocol template from the Cancer Therapy Evaluation Program from the US National Cancer Institute here.
- Title page (general information)
Including protocol title; protocol identification number; date; potential amendments (more information about amendments in a following section); name and contact details of the sponsor, monitor, medical expert, investigator, and other institutions involved.
- Background information
Including name and description of the investigational product(s); a summary of findings from non-clinical and other clinical studies; known and potential risks and benefits; description of route of administration and dosage; statement ensuring compliance with protocol, GCP and regulatory requirements; description of the population; references to relevant literature.
A detailed description of the objectives and the purpose of the trial.
- Study design
Including information on the primary and secondary endpoints, description of the trial design, description of measures to minimize bias (including randomization and blinding), description of treatment and dosage regimen, expected duration of subject participation, description of discontinuation criteria, accountability procedures, etc.
- Selection and exclusion of subjects
Explanation of inclusion, exclusion, and withdrawal criteria, as well as withdrawal procedures.
- Treatment of subjects
Information about treatment (product name, dose, dosing schedule, route, treatment period, follow-up), other permitted or not permitted medications/treatments, procedures for monitoring compliance.
- Assessment of efficacy
Specification of efficacy parameters, as well as methods and timing for their assessment, recording, and analysis.
- Assessment of safety
Specification of safety parameters; methods and timing for assessment, recording, and analysis of safety parameters; reporting and follow-up after adverse events.
Description of statistical methods to be employed; sample size; termination criteria; procedures for accounting for missing, unused, and spurious data; procedures for reporting any deviation; selection of subjects to be included in the analyses.
- Direct access to source data/documents
The sponsor should ensure that it is specified in the protocol (or in other written agreement) that the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB review, and regulatory inspection(s), providing direct access to source data and documents.
- Quality control and assurance
Description of the quality assurance and quality control systems implemented to assure the quality of the data (including any training session, monitoring of investigators, instructions manuals, use of independent internal or external auditing procedures, etc.).
Description of ethical considerations relating to the trial, explaining compliance with ethical standards. You should explain, for example, how you are adequately addressing relevant ethical concerns and meeting applicable regulatory requirements for the trial in an emergency situation (such as when the prior consent of the participant is not possible). You can read the EU document about ethical considerations for trials on medicinal products conducted with the paediatric population in this link.
- Data handling and recordkeeping
This section ensures that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance. It should mention whether an independent data-monitoring committee has been established to assess the progress of the trial.
- Financing and insurance
Details about the trial financing and the clinical trial participant’s insurance that is compulsory in many countries.
- Publication policy
Description of the policies on the publication of clinical data (for example manuscripts, abstracts, posters, oral presentations, and review articles published by peer-reviewed scientific journals or presented at scientific meetings and congresses), declaring adherence to GCP and to applicable guidelines. (Note: topics 13-15 should be included in the protocol if not addressed in a separate agreement.)
- Project timetable/flowchart
Timeline description, including the planed start and end of the trial.
A team effort
Clinical trial protocols are not usually prepared by a single person. Instead, they are written by a multi-disciplinary team that frequently includes a medical expert, a statistician, a pharmacokinetics expert, the clinical research coordinator, the project manager, and a medical writer that includes all inputs in a final document, among other experts.
- The medical expert plays a prominent role in the preparation of the document, contributing to sections such as the design of the study, the objectives and endpoints, the selection criteria, and assessment procedures. The medical expert also provides input regarding the use of concomitant therapies or the stopping rules to be applied in dose escalation studies. The role of the medical expert is not normally outsourced.
- The statistician performs calculations for the sample size and power of the study (key to determine clinically meaningful differences between treatment groups) and contributes to the establishment of the objectives and endpoints. The statistician is responsible for the implementation of all the statistical procedures and ensures the minimization of potential variability in the study. The role of the statistician can be outsourced to a freelance statistician or biostatistics consultant.
- The pharmacokinetic expert contributes to the determination of objectives and endpoints, as well as dosing procedures, specifying the essential pharmacokinetic requirements of the drug. This expert also participants in the establishment of statistical procedures for the evaluation of pharmacokinetic data and in the determination of dosing frequencies from single to multiple ascending dose studies. The role of the pharmacokinetic expert can be outsourced.
- The clinical research coordinator contributes to the management and logistics of the clinical trial, including laboratory safety and sample logistics. Moreover, the coordinator is also in charge of determining the feasibility of the different assessments, preparing their schedule and description. The role of the clinical research coordinator is not normally outsourced.
- The project manager is in charge of developing detailed timelines for the protocol and the requirements for study set-up, in addition to overseeing data management. The project manager should also identify the sponsor’s expectations. The role of the project manager can be outsourced.
- Other people contributing to the clinical trial protocol include regulatory affairs specialists (that guarantee the adoption of all regulatory guidances, liaise with health authorities, and submit the Investigational Medicinal Product Dossier); laboratory staff (that handles samples and performs laboratory procedures); and the medical affairs/pharmacovigilance experts that manage the reporting of adverse events. Some of these roles can be outsourced.
- The medical writer, using inputs from the rest of the team, compiles the clinical trial protocol, ensuring the consistency of the information along the whole document. The role of the medical writer can be outsourced.
The SPIRIT Statement
To improve the content and quality of protocols, an international group of experts developed the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement. The SPIRIT Statement provides guidance in the form of a checklist of recommended items to include in a clinical trial protocol and related documents. The use of this guideline to write the study protocol optimizes the quality of reporting and facilitates the peer review process. SPIRIT has created an electronic tool (SPIRIT Electronic Protocol Tool & Resource, SEPTRE) to help researchers to produce high-quality clinical trial protocols using SPIRIT guidance.
Protocol deviations, violations and/or amendments
Protocol deviations are defined as accidental or unintentional changes to the protocol, or non-compliance with the research protocol, which do not increase the risk or decrease the benefit, or do not have a significant effect on the subject’s rights, safety or welfare, and/or on the integrity of the data. Protocol deviations result from the action of the subject or research staff. Examples of protocol deviations include a rescheduled study visit or failure to collect an ancillary self-report questionnaire. An example of protocol deviation is measuring vital signs prior to obtaining informed consent.
Protocol deviations should be distinguished from protocol violations, which are accidental or unintentional changes to the protocol, or non-compliance with the IRB approved protocol, without prior sponsor and IRB approval. Violations generally increase the risk or decrease the benefit, affect the subject’s rights, safety, or welfare, or data integrity. Examples of protocol violations include the use of an inadequate informed consent, the enrollment of subjects not meeting the inclusion and/or exclusion criteria, the use of prohibited medication, etc.
Protocol modifications that potentially impact the development of the study, the potential patient’s benefit, or may affect patient’s safety (including changes to study objectives, study design, patient population, eligibility criteria, sample sizes, study procedures, or significant administrative aspects) require a formal amendment to the protocol. Examples of protocol changes that must be reported include any increase in drug dosage or duration of drug exposure, any significant increase in the number of subjects to be enrolled, new test procedures, or the inclusion of a new investigator in multi-centric studies. As an example, the Substantial Amendment Notification Form in the EU can be found here.
On the other hand, minor corrections and/or clarifications that do not affect the way the study is conducted are considered administrative changes and should be documented in a memorandum.
Tips for writing a clinical trial protocol
Since the clinical trial protocol is the single most important document ensuring that critical aspects of the trial are communicated to all stakeholders, you will need to invest sufficient time in its development. Moreover, you need to pay special attention to study objective(s), design, and type and timing of assessments, avoiding potential inconsistencies in the final document. A well-written and detailed protocol increases the likelihood of obtaining high-fidelity data, minimizes the need for protocol amendments, and facilitates the preparation of other documents such as research protocols, manuscript writing, presentations, etc.
- Always follow protocol content guidelines and address all items included in the guideline.
- The background of the protocol should mention all relevant preclinical and clinical data, including published and unpublished data.
- All research-related activities should be detailed in the protocol and the consent form. It is important to ensure the consistency of both documents. Moreover, research-related activities must be linked to a research aim.
- Describe in detail all study activities that participants will undergo.
- Getting an independent review of the protocol from colleagues that are not directly involved in the research plan can be very useful. It can help to identify potentially ‘unclear’ aspects, where regulatory agencies and the IRB may have difficulties as well.
- Consider the perspectives of the regulatory agencies (mainly focused on the ‘public good’) and the IRB (concerned with the rights and welfare of the individual subjects). Both perspectives are complementary but distinct. Invasive procedures or treatments should be minimized. The minimization of risks is particularly important in children and other vulnerable populations. In some cases, you may need to seek advice from an IRB regulatory consultant.
The importance of public availability of clinical trial protocols
Protocol sharing can facilitate the critical appraisal of clinical trials (both the internal and external validity) and help to identify and prevent a selective reporting of outcomes and analyses. Making protocols publicly available increases the transparency of research while enabling scientists and prospective participants to learn about ongoing clinical trials. However, protocol sharing remains relatively rare (you can read more about the challenges here). Several open-access journals encourage the submission and publication of protocols, such as Trials (where more than half of publicly available trial protocols have been published. Trials also promotes the use of a structured protocol template for randomized trials), BMJ Open, and JMIR Research Protocols. Take into account that several medical journals -such as The Lancet and PLOS Medicine– require the inclusion of clinical trial protocols when submitting a clinical research article.
Accurately writing your clinical trial protocol and making it publicly available will greatly benefit patients and other users of evidence from clinical trials.
Need to hire a freelance clinical trial protocol writer? Post your project on Kolabtree and get quotes from experts for free.
Additional references and resources:
- Al-Jundi A. and Sakka S. Protocol Writing in Clinical Research. J Clin Diagn Res. 2016 Nov; 10(11): ZE10–ZE13.
- Chan AW. and Hróbjartsson A. Promoting public access to clinical trial protocols: challenges and recommendations. Trials. 2018; 19: 116.
- Chen AW., et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013 Feb 5;158(3):200-7.
- Chen AW., et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013 Jan 8;346:e7586
- Cipriani A. and Barbui C. What is a clinical trial protocol? Epidemiol Psichiatr Soc. 2010 Apr-Jun;19(2):116-7.
- Clinical Trial Protocol Development (last revised 2017). Clinical Research Resource HUB, UCSF.
- Guidelines for designing a clinical study protocol. Clinical Research Resource HUB, UCSF.
- van Bavel E. Multidisciplinary Approach to Protocol Writing. Applied Clinical Trials, 2016
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