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The “Protocol” term is derived from the Greek Word “PROTOKOLLON” means a format procedure for carrying out scientific research. A Protocol is defined as the document that describes the background, rationale, objectives, study design, methodology, statistical considerations, and organization of a Clinical Research project.

Clinical Research is conducted as per protocol) or an action plan. The protocol demonstrates the guidelines for conducting the trial. It illustrates 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 duration of the study, the medications and the related tests.

Aims of the Protocol:

• To raise the question to be researched and clarify its importance.
• To formulate the trial design.
• To emphasize on existing knowledge and discuss the efforts of other researchers who have worked on the related questions (Literature Review).
• To formulate objectives and endpoints.
• To clarify ethical considerations.
• To suggest the methodology required for solving the question and achieving the objectives.
• To discuss the requirements and limitations in achieving the objectives.
• To uniform the practice across the stakeholders.
• To describe all the information related to clinical trials that are going to conduct.

  Benefits of the Protocol:

• Allows the researcher/scientist to plan and review the project’s steps.
• Serves as a guide throughout the research.
• Forces time and budget estimates.

Protocol Development Team:

• Medical Writers
• Medical Monitors
• Pharmaceutical Physician
• Clinical Research Manager
• Quality Assurance Manager
• Statistician
• Data Management Personnel
• Regulatory Authority Representative
• Safety Group Representative
• Investigators
• Legal Representative

Process of writing a protocol:

Literature review

Determine end points

Formulate hypothesis / research question

Draft a Protocol

Peer review        

Final version

Amendments

The Protocol language / the content should be understood by:

• Stakeholders, Investigators
• Other Physicians
• Nurses
• CRAs
• CRCs
• IRB Members
• Scientific Reviewers
• IC for a Layperson

Contents and Format of the Protocol:

The research protocol generally consists following format:

• Project Title
• Confidentiality Statement
• Protocol Synopsis
• Administrative Details
• Project description:
• Rationale
• Objectives
• Primary and Secondary endpoints
• Inclusion/Exclusion Criteria
• Methodology/Design
• Data Management and Analysis
• Ethical Considerations
• Gender Issues
• References
• Annexures

Project Title:

Title of the proposal should be accurate, short, concise, and identify WHAT is the study about, WHO are the targets, WHERE is the setting of the study, and WHEN it is launched, if applicable.

It should make the main objective clear, convey the main purpose of the research, and mention the target population. Carry maximum information about the topic; it is a good practice to keep the title to within 12-15 words. It should convey the idea about the area of research and what methods are going to be used in a compact, relevant, accurate, attractive, easy to understand, and informative way.

Administrative Details:

Administrative details or a protocol summary should follow:

• Contents page list of relevant sections/sub-sections with the corresponding page number.
• The signature page is signed by senior members of the research team and dated to confirm that the version concerned has been approved by them.
• Contact details of the research team members listing postal, e-mail addresses and telephone numbers.

Project Summary:

Project summary should be concise and summarize all the elements of the protocol. It should states own own and not refer the reader to points in the project description.

Project Description

Rationale

This is equivalent to the introduction in a research paper. It puts the proposal in context. It should be answering why and what: why the research needs to be done and what will be its relevance. A brief description of the relevant studies published on the subject should be provided to support the rationale for the study.

Study Objectives (Aims):

The aims should be explicitly stated. These should be confined to the intention of the project and they should arise from the literature review. State the goal you need to achieve.

The study aims or objectives emerge from the study questions/ hypothesis. They are answers to what are the possible responses to the research question or hypothesis under analysis and measure. Aims should be feasible, logical and coherent, concise, realistic, considering local conditions, phrased to clearly meet the purpose of the study, and related to what the specific research is intended to accomplish. For example, to evaluate knowledge level regarding dental caries in primary school children in KSA (this is not detailed). The following should be added: Causes, treatment, preventive measures, etc.

The objectives should be (SMART objective): Specific, Measurable, Achievable, Relevant and Time based.

Specific Aims:

Details of each objective that will finally lead to the achievement of the goal should be stated. Specific aims one by one should be listed concisely. It is good practice not to include too many aims in the study (2-5 best); too many objectives often lead to inaccurate and poorly defined results. Furthermore, aims should be achievable, realistic, and specific with no general and ambiguous statements. They should be stated in action verbs that illustrate their purpose: i.e., “to determine, to compare, to verify, to calculate, to reduce, to describe, etc.”

Secondary Objectives (Optional):

These are referred to as ancillary and minor objectives that could be studied during the course of the study.

The formulation of objectives helps to focus the study and to avoid the collection of any unnecessary data and hence organize the study in clear and distinct stages.

Inclusion/Exclusion Criteria

In a clinical preliminary, the examiners must indicate inclusion and exclusion measures for investment in the examination.

Inclusion and exclusion criteria are usually written in a positive way: if a participant has inclusion criteria, they are in; if they have exclusion criteria, they are out. Inclusion and exclusion criteria may include factors such as medical history, race, ethnicity, age, gender,  type and stage of the disease, the subject’s previous treatment history, and the presence or absence of other medical, psychosocial, or emotional conditions.

Inclusion and exclusion criteria are meant to ensure patients’ safety during the study, provide data (justification) of subject appropriateness for the study, to minimize withdrawal (also costs) and ensure that primary end-points of study are reached.

Methods and Materials:

It should describe in detail the ‘Where’, ‘Who’, ‘How’ the research will be conducted. It explains the study design and procedures and techniques used to achieve the proposed objectives. It defines the variables and demonstrates in detail how the variables will be measured. It details the proposed methodology for data gathering and processing.

Methodology composes an important part of the protocol. It assures that the hypothesis will be confirmed or rejected. It also refers to a thorough strategy to attain the objectives.

The methods and materials are divided into various subheadings

a) Study design (cross-sectional, case-control, intervention study, RCT, etc.):

The proper explanation should be given as to why a particular design was chosen (on the basis of proposed objectives and availability of resources).

A study design is in fact the researcher’s general plan to acquire the answer (s) to the hypothesis being tested. Here, strategies will be applied to develop a balanced, correct, objective, and meaningful information. It explains the methods that will be used to collect and analyze data. Proper selection of the study design is important to attain reliable and valid scientific results.

Logistic concerns, economic features, Ethics, and scientific thorough-ness will determine the design of the study. Here, a chief concern is given to the legality of the results including potential bias mystifying issues.

Randomized controlled clinical trial is the best to document a causal relationship between an exposure and its outcome [Table/Fig-1].

Purpose	Study Design
To determine frequency and burden of a disease	* Cross-sectional survey (Prevalence) * Cohort study (Incidence)
To identify the risk factors	* Cohort study * Case-Control study
To determine prognosis of a disease	* Cohort study
To determine efficacy/effectiveness of a new treatment	* Clinical trials * Community intervention
To evaluate community programs	* Evaluation

b) Study population (Study subjects):

Where are you going to do the research and who is the study population (why doing research in this place and why selecting this population?).

It describes in detail the study subjects, all aspects of the selection procedure, and sample size calculation. The proper definition of eligibility, inclusion, exclusion, and discontinuation criteria of the study subjects should be stated. Allocation of subjects to study arms should be explained and described in detail bearing in mind the concealment and randomization process.

Eligibility Criteria:

• Inclusion and exclusion criteria must be met in order to participate in a clinical trial.
• The important criteria used to determine appropriateness for trial participation include age, sex, the type and stage of a disease, treatment history, and other medical conditions.
• Eligibility criteria to enrol the patients are the largest barrier to clinical trials.
• There is no guideline to write these criteria.
• Poorly written or poorly conceived criteria may affect the scientific validity of clinical trials.
• Reasons for imposing eligibility criteria include scientific rationales, safety concerns, regulatory issues, and practical considerations.

The points to be considered to write a good eligibility criteria:

• The number of eligibility criteria should be kept to a minimum.
• Criteria should include only those absolutely necessary to ensure the scientific validity and patient safety.
• Eligibility criteria should be clearly defined and verifiable by an external auditor.
• Eligibility criteria should be straight forward and unambiguous. Which of these criteria is better understood?
• Pregnant and/or nursing women are not eligible.
• All the women of childbearing age are required to have a negative serum pregnancy test.
• Nursing women are not eligible for this study. All women of childbearing potential must have a negative serum pregnancy test within 2 weeks of study enrolment.

Failure to write eligibility criteria properly leads to:

• Failure to mimic clinical practice
• Increased study complexity
• Increased costs
• Less number of patients getting recruited.

c) Sample size:

Sample size calculation is recommended for ethical and economical reasons. The calculation of the sample size must be explained including the power of the sample. The sampling technique should be mentioned, e.g., randomization that will be used in order to obtain a representative sample for your target population. Each step involved in the recruitment of the study subjects should be described according to the selection criteria (inclusion and exclusion criteria).

 “Informed consent” should be captured.

d) Proposed intervention:

Full description of proposed intervention should be given. Here, all the activities and actions should be recorded and thoroughly explained in their order of occurrence.

• When using drugs, both scientific and brand name should be mentioned followed by the name of the manufacturing company, city, and country. Drug route of administration, dosage, frequency of administration, and total duration of treatment with the drug should be mentioned.

• When using equipment, its name should be given followed by the name of the manufacturer, city and country.

Involved personnel should precisely define:

• Who will be responsible for the interventions?

• What activities each delegated personnel will perform and with what frequency and intensity?

e) Data collection methods, instruments used:

Data collection tools are:

• Retrospective data (medical records)

• Questionnaires

• Interviews (Structured, Semi-Structured)

• Laboratory test (literature or therapeutic knowledge should be referenced, if established test or description should be provided in details, if not established)

• Clinical examinations

• Description of instruments, tools used for data collection, as well as the methods used to test the validity and reliability of the instrument should be provided.

Data management and analysis:

The protocol should provide details on how the data will be managed, including data coding for computer analysis, monitoring and verification. Details should also be provided on the available computer facility. The statistical methods e.g. ANOVA, program R or winlonlin used for the analysis of data should be clearly outlined.

Ethical considerations:

Ethical considerations apply to all clinical trials of health research. These include trials involving human experimentation, whether the trial is of therapeutic or diagnostic nature that is carried out on patients who may expect a potential benefit from their participation or is of a purely scientific nature for which subjects volunteer to advance medical science but will not draw any therapeutic or diagnostic benefit.

There are also ethical aspects for research on human subjects but not experiments. Epidemiology, field and qualitative studies fall into this category. Although no experiments are included, such studies can be equally interesting in individual privacy and communities. The ethics of research associated with experiments on animals has only recently been receiving appropriate and increasing attention.

This includes two

components:

1. The first is written approval of the independent or institutional ethics review committee, with a written form for informed consent, where appropriate.
2. The second is a special section or area, preferably in the format of a checklist, to address all possible or relevant ethical concerns. In a nutshell, getting ethical approval is not enough.

Approval by ethics review committees

For the clinical trial, the protocol must be approved by the local, institutional or equivalent ethics committee and/or national ethics committee.

For preclinical studies, approval is required from the animal welfare committee of the institute or its equivalent.

Principle Investigator(s) should indicate that the research will be carried out in accordance with ICG-GCP.

Informed decision-making:

A consent form, where appropriate, must be developed and attached to the protocol. It should be written in the prospective subjects’ mother tongue. The consent form has two parts:

 a) A statement describing the study and the nature of the subject’s involvement in it; and

 b) A certificate of consent attesting to the subject’s consent.

Both parts should be written in simple language so that the subject can easily understand the contents. As much as possible, the use of medical terminology in writing up the consent form should be avoided. Special care is needed when subjects are illiterate.

Ethics checklist:

The protocol must describe the measures that will be undertaken to ensure that the proposed research is carried out in accordance with the World Medical Association Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects.

A checklist must address ethical concerns that could be raised about the methodology, including the research design, selection of subjects, the interventions introduced, and the observations to be made.

• Is the research design adequate to provide answers to the research question? It is unethical to expose subjects to research that will have no value.

• Is the method of selection of research subjects justified? The use of vulnerable subjects as research participants needs special justification. Vulnerable subjects include those in prison, minors and persons with mental disablity. Particularly in international research, it is important to ensure that the population in which the study is conducted will benefit from any potential outcome of the research. They should not be doing it to the benefit of another population. Justification is needed for any inducement, financial or otherwise, for participants to be enrolled in the study.

• Are interventions justified, in terms of risks/benefits ratio? Risks are not limited to physical harm. Psychological and social risks must also be considered.

• For observations made, have measures been taken to ensure confidentiality?

Gender issues:

Attention was drawn to the importance of addressing gender issues in research protocols recently. The Commission on the Status of Women made the above statement. This was in response to several areas of concern. “Ensure, where indicated, that clinical trials of pharmaceuticals, medical devices, and other medical products include women with their full knowledge and consent and ensure that the resulting data is analyzed for sex and gender differences.”

• Women were often excluded from trials on disease conditions that affect both men and women, on the basis of biological variability, and/or vulnerability. But women were given the same drugs, which had not been tested on them, as men if the drugs proved safe and effective for men.

• Drugs and devices intended for use by women only were tested on them without their proper informed consent, particularly in poor resource arrangements.

• When women were included with men as research subjects, gender was not always taken into consideration when results were analysed.

It is well known that genetic and hormonal factors modify the prevalence, behaviour, and treatment of diseases of body systems in men and women. But what is less known is that culturally evolved gender-related differences in lifestyle behaviour are also powerful determinants of women’s health and account for major differences in the disease burden between males and females, probably more than genetic or hormonal factors. Both biological factors and gender-related differences can influence the outcome of the research for men and women.

Reference System:

Referencing is the regular method of recognizing information taken from other researchers’ work. A proper citation will enable the readers to follow-up any reference of interest. Plagiarism refers to claiming and acquiring someone else’s ideas, an action that is considered a criminal act.

Failure to reference an idea that you have found in your research, or to acknowledge the work of other team members in a team assignment falls under the category of plagiarism. Therefore referencing is an extremely important aspect of the research protocol. The two most commonly used citation systems in clinical writing are the Vancouver system and the Harvard system. The choice of referencing system is dependent upon the funding organizations where the research protocol is being submitted. These frequently identify their preferred system of referencing and this should be strictly adhered to. The most common style used in dental literature is the Vancouver style.

Annexure:

The following annexes are to be attached at the end of the protocol:

1. Informed consent form.

2. Letters from ethics committees.

3. Study questionnaire (copies of any questionnaires or draft questionnaires).

4. Case Record Forms (CRFs).

5. Schedule of events

6. Laboratory paramenters

7. Budget details.

8. Curriculum Vitae (CV) of the chief investigator and co-investigator and their role in the study. It will ensure that the role of each investigator is well defined.

Protocol Violation:

A protocol deviation occurs when the subject, investigator, or sponsor fails to adhere to significant protocol requirements affecting the inclusion, exclusion, subject safety, and primary endpoint criteria.

Protocol deviations of the study include –

• Failure to meet inclusion/exclusion criteria.
• Use of prohibited concomitant medication.
• Failure to follow good clinical practice.

Conclusion

The most difficult stage of conducting a research project is the preparation of a protocol that results in a short yet comprehensive document that clearly summarizes the project. Such a proposal is considered successful when it is clear, free of typographical errors, accurate, and easy to read.

It is important to analyse the steps in developing a protocol in order to perform an appropriate study and obtain reliable data/ results. Extra time spent to write a good protocol will save failures at a later stage besides helping analysis. If the protocol is poorly prepared and not adhered to, it is unlikely that the project will yield the information that was hope for and in all probability, the chances of selling your Inputs to the reviewers of a granting agency would be less.

Content: Dr. Likhitha Sri Barma