Clinical research is conducted according to an action plan known as a Clinical Trial PROTOCOL. Clinical investigation begins with the development of a clinical protocol and writing a research proposal is one of the most challenging and difficult in clinical trials.
What is a protocol?
The protocol is a document that describes the action plan of how a researcher performs a clinical trial. The protocol contains (the objectives, design, methodology, statistical considerations, and organization of a clinical trial), and ensures the safety of the trial subjects and the integrity of the data collected.
- The protocol demonstrates the guidelines to conduct a trial.
- It represents what will be made in the study by explaining each essential part of it and how it is carried out.
- It also describes the eligibility of the participants, the study duration, the medications, and the related tests.
The protocol contains complex details for trials evaluating pharmacological drugs, medical devices, and surgical instruments, which describe the ethical, medical, and regulatory functions of the clinical trial. A chief researcher governs the protocol.
What does a clinical trial protocol contain?
A clinical research protocol is a document that describes the
- study objectives,
- assessment types,
- collection schedules, and
- statistical considerations for analyzing the data.
- the protocol also outlines steps for protecting subjects and obtaining quality data.
Purpose of a clinical trial protocol
- It formulates hypothesis and objectives.
- Protocol raises the research question and defines its importance.
- It collects existing knowledge and discuss the efforts of other researchers who have worked on the related questions (known as literature review).
- Protocol clarifies ethical considerations.
- It suggests the methodology necessary to solve the question and achieve the objectives.
- It helps to discuss the requirements and limitations to achieve these objectives.
Advantages of a protocol in a clinical trial
- Protocol serves as a guide throughout the research.
- Allows the researcher to plan and review the project’s steps.
- It provides time and budget estimates.
A Protocol Review
Before initiating a study, the researchers submit the protocol to both an Institutional Review Board (IRB) and to regulatory authorities (e.g., FDA, EMA, PMDA, TGA, etc) for rigorous review in order to ensure compliance with subject protection standards and statutory requirements.
Institutional Review Board approves the clinical trials to ensure that the risks of conducting research are negligible and have any potential benefits. It is an independent committee that consists of physicians, dentists, statisticians, and members of the community.
The committee ensures that clinical trials are ethical and that the rights of all participants are protected. The board initially approves the research and periodically reviews it.
Contents of a clinical trial protocol
A general protocol includes the following contents
- Title of the study
- Administrative details
- Project summary
- Introduction to the research topic, background (Literature review)
- Preliminary studies
- Study objectives and/or questions. Statement of the problem.
- Methodology: Study design, study population, and methods of recruitment, variables list, sample size, methods of data collection, data collection tools, plan of analysis (analysis of data)
- Project management: Work plan (Timeline – proposed schedule)
- Strengths and limitations of the study
- Issues for ethical review and approvals
However, according to the ICH Good Clinical Practice guidelines, a protocol should include the following topics as below
- Title page (General Information)
- Background Information
- Study design
- Selection and exclusion of subjects
- Treatment of subjects
- Assessment of efficacy
- Assessment of safety
- Adverse events
- Discontinuation of the study
- Quality control and assurance
- Data handling and recordkeeping
- Publication Policy
- Project timetable/flowchart
Protocol writing is challenging and a skilled job. In protocol writing, the researcher reviews and critically evaluates the published literature on the interesting topic, plans and reviews the project steps, and serves as a guide throughout the investigation.
Impact of a poor protocol
Poor protocol designs leads to consequences that are costly and delay timelines. In the worst-case scenarios, poorly written protocols can jeopardize patient safety or result in data that do not support regulatory approval.
- The regulatory authorities and the IRB requires protocol rewrites and updates.
- Poor protocol may cause site staff misinterpret aspects of the protocol, compromising conclusions or data integrity.
- The results may not support conclusions to move forward with drug development.
- Cause time delays when the Sponsor cannot run the study (or at least certain aspects of it) until all issues are resolved.
To decrease these risks, one needs to follow the best practices to help create clear, well-written protocols that are operationally feasible, generate quality data, and are compliant with regulatory guidelines.
Challenges in protocol writing
The clinical trial protocol is a precise procedure of the study, and it must provide a clear picture and concise design to meet the aim and objectives of the study. While developing a protocol design, there should be a great coordination with medical experts, regulatory experts, statisticians, pharmacokineticists and operational experts.
How to write a protocol?
Drafting the protocol correctly will increase the likelihood that the conclusions drawn from the research are scientifically sound. once the study is launched, the protocol should not be altered during the progression of the study or trials.
International Council for Harmonisation Good Clinical Practice provided certain recommendation like what needs to be included in the protocol, structure of clinical study protocol and the standards. Adding an expertise to this would help in creating a great protocol design.
Tips to write a best protocol
Since the clinical trial protocol is the single most crucial document that ensures critical aspects of the trial, one needs to allot sufficient time in its development. Special attention shall be given 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, manuscripts, presentations, etc.
Here are some tips to write an ideal protocol for research.
- It is always important to follow guidelines for protocol content and address all essential points in the guidelines.
- The protocol shall contain all the research-related in the protocol and the informed consent form. Both these documents shall maintain the consistency.
- Include all relevant preclinical and clinical data, including published and unpublished data.
- Protocol shall contain all the study activities that participants will undergo.
- Taking review of protocol form people who are not directly involved in the research will be very helpful. This helps to identify unclear aspects, where regulatory agencies and the IRB may have difficulties as well.
- You need to consider the perspectives of the regulatory agencies and the IRB. Both perspectives are complementary but distinct. Invasive procedures or treatments should be minimized.
- Consider risk minimization which is particularly important in children and other vulnerable populations.
- In some cases, if necessary, you may need to seek advice from an IRB regulatory consultant.
Sample protocol templates
Here are some sample protocol from various sources.
- DMID- Greater Than Minimal Risk Template
- DMID- Interventional Template
- NIAID Clinical Research Toolkit- Clinical Trials Protocol Templates
- UCSF Protocol Template
- MOP Template
- DMID-Minimal Risk Template
- NIDCR-Interventional Protocol Template (Drug, Device, Behavioral)
- NCI-CTEP Protocol Development Templates and Guidelines
- Patient Care Manager Support Letter for Research
Here are few more examples of templates that complies with ICH GCP requirements.
- Protocol Template (simple)
- Protocol Template (complex)
- NIH Templates for Clinical Trials and Social Behavior Trials
- NIH e-Protocol Writing Tool
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