Project-Protocol Writing in Clinical Research

WORKSHOP ONPROTOCOL WRITING IN CLINICAL RESEARCH

27.01.2015

Organized By

Bandaranaike Memorial Ayurvedic Research Institute (BMARI)

Collaboration with World Health Organization (WHO)

Dr. Pathirage Kamal PereraPhD in Pharmacology (P.R.China) , MSc (USJ), BAMS (Hons.), CTHE (SL), SEDA accredited in UK,

Dip in Research and Development of Products to Meet Public Health Needs (Japan) , M.Biol

Senior Lecturer Department of Ayurveda Pharmacology and Pharmaceutics

Head of the Department of Allied SciencesInstitute of Indigenous Medicine, University of Colombo, Rajagiriya, Sri Lanka

Learning outcomes

• Develop clinical trial protocol 2.

• Analyze ER issues in clinical trial3.

• Develop research project proposal4.

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Categories of health research

• Biomedical sciences: These include all biological, medical and clinical research, and biomedical product development and evaluation.

• Population sciences: These include epidemiology, demography and the sociobehavioural sciences.

• Health policy sciences: These include health policy research, health systems research and health services research. Economic analysis studies are now an important subcategory of health policy research.

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Clinical trials

• Considered the “true” experimental study

• “Gold Standard”

• Often a prospective study

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Clinical Trials

• Investigation of Treatment/Condition

• Drug Trials

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Core Components of Clinical Trials

• Involve human subjects

• Move forward in time

• Most have a comparison CONTROL group

• Must have method to measure intervention

• Focus on unknowns: effect of medication

• Must be done before medication is part of standard of care

• Conducted early in the development of therapies

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• Must review existing scientific data & build on that knowledge

• Test a certain hypothesis

• Study protocol must be built on sound & ethical science

• Control for any potential biases

• Most study medications, procedures, and/or other interventions

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Core Components of Clinical Trials

New initiatives for expanding access to the Scientific Literature

1. Open accesshttp://www.biomedcentral.com/openaccess,

2. Health InterNetwork Access to Research Initiative (HINARI)http://www.healthinternetwork.net

3. PubMed CentralThis initiative of the United States National Library of Medicine (NLM) provides free online access to the full text of life science research articles (http://pubmedcentral.nih.gov).

MEDLINE, is funded by the US National Institutes of Health.

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Criteria for a good research topic

• A good research topic should be:

feasible (can be done),

interesting,

novel,

Ethical,

relevant (has an implication).

These criteria have been collectively called the FINER formula (Hulley et al., 2001).

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Writing the research protocol

The protocol is the detailed plan of the study.

The written protocol:

• forces the investigators to clarify their thoughts and to think about all aspects of the study;

• is a necessary guide if a team (not a single investigator) is working on the research;

• Need to get the institution’s ethical approval;

• is an essential component of a research proposal submitted for funding.

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Format for the protocol / project proposal

1. Project title1.1 Title page

2. Project summary3. Project description:

3.1 − Rationale3.2 − Objectives3.3 − Methodology3.4 − Data management and analysis

4. Ethical considerations5. Gender issues6. Timetable7. Problems anticipated8. Budget9. References10. Curriculum vitae of the investigator(s)

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1. Project title

• The title should be descriptive and concise.

• It may need to be revised after completion of the writing of the protocol to reflect more closely the sense of the study.

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1.1 Title page

• This page should provide information on:

• Project title

• Principal investigator(s)

• Institution

• Duration of the project

• Funding requested

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2. Project summary

• The summary should be concise, and should summarize all the elements of the

• protocol. It should stand on its own, and not refer the reader to points in the project description.

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3. Project description

3.1 RationaleThis is equivalent to the introduction in a

research paper. It puts the proposal in context. It should answer the question of why and what:

(why the research needs to be done and what will be its relevance).

A brief description of the most relevant studies published on the subject should be provided to support the rationale for the study.

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3.2 Objective(s)

Specific objectives are statements of the research question(s).

Objectives should be simple (not complex), specific (not vague), and stated in advance (not after the research is done).

After statement of the primary objective, secondary objectives may be mentioned.

Young investigators are advised to resist the temptation to put too many objectives or over-ambitious objectives that cannot be adequately achieved by the implementation of the protocol.

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3.3 Methodology

Note: The methodology section has to be thought out carefully and written in full detail. Itis the most important part of the protocol. It should include information on the research design, the research subjects, interventions introduced, observations to be made and sample size.

• Research design: The choice of the design should be explained in relation to the study objectives.

• Research subjects or participants: Depending on the type of the study, the following questions should be answered:

– What are the criteria for inclusion or selection?– What are the criteria for exclusion?– In intervention studies, how will subjects be allocated to

index and comparison groups?– What are the criteria for discontinuation?

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3.4 Data management and analysis

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4. Ethical considerations

4.1 Ethical considerations

Approval by ethics review committees

For studies in humans (or involving human biological materials), the protocol must be approved by the local, institutional or equivalent ethics committee and/or national ethics committee.

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4.2 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 hast wo parts:

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

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.

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4.3 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.

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4.4 Ethical requirement

1. Collaborative partnership

2. Social value

3. Scientific validity

4. Fair subject selection

5. Favourable risk–benefit ratio

6. Independent review

7. Informed consent

8. Respect for subjects

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Ethical requirement Definition

Collaborative partnership Research leadership must include bilateral representation based on mutual respect between equal partners with community advice. It includes a responsibility to invest in the scientific training and capacity-building for ongoing research in a host country where such resources are not well developed.

Social value Knowledge gained from the research should have the potential to lead to new generalizable knowledge or improvements in health. Partners should specify in advance to whom benefits will accrue and in what way.

Scientific validity Research should be designed to produce beneficial and generalizable knowledge. This includes designing research so that it can be feasibly implemented in the settings where it will be conducted.

Fair subject selection Subjects should be selected on the basis of scientific importance, not based on convenience, vulnerability or bias.

Favourable risk–benefit ratio The potential benefits of individual participation should outweigh the risks of participation. Benefits to the community or population being studied should also be optimized. Compelling societal benefit can justify risks to individuals in certain circumstances.

Independent review To maintain the integrity of the research, bodies not tied to the investigators must agree that the risks and potential benefits of the research are justified.

Informed consent Investigators must obtain valid permission for study participation from subjects in a manner that is sensitive to the cultural context in which the study is conducted.

Respect for subjects Researchers should have a plan for how the research results will be disseminated; ensuring participants know their right to withdraw, and monitoring the research for relevant adverse events.

Table 1. A comprehensive framework for research ethics

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4.5 Experimental studies – Toxicity studies

Category 1: Indigenous herbal medicines

•These can be used freely by the local community or region•No safety data would be required.• If the medicines in this category are introduced into the market or moved beyond the local community or region, their safety has to be reviewed by the established national drug control agency.

Category 2: Herbal medicines in systems

•Used for a long time and have been officially documented.•Review of the safety category is necessary. •If the medicines are in safety categories safety data would not be needed.

Category 3: Modified herbal medicines

•Modified in any way including dose, dosage form, mode of administration, herbal medicinal ingredients, methods of preparation, or medical indications base on categories 1 and 2.•Have to meet the requirements of safety of herbal medicines or requirements for the safety of ‘herbal medicines of uncertainsafety’

Category 4.Imported/exported products with a herbal medicine base

•Require safety data, which have to meet the requirements for safety of herbal medicines or requirements for safety of ‘herbal medicines of uncertain safety’, depending on the safety requirement of the importing/recipient countries.

Ref: Guidelines for the Regulation of Herbal Medicines in the South-East Asia Region, World Health

Organization (WHO), 2004

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5. Gender issuesNote: • It was only recently that attention was drawn to the importance of addressing

gender issues in research protocols. 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 analysed for sex and gender differences.“

• Women were often excluded from clinical 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 sometimes tested on them without their proper informed consent, particularly in poor resource settings.

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

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6. Timetable (Gantt Chart )

• The investigators should commit themselves to a timetable. • This may include a preparatory phase to train research

workers, to procure equipment/supplies, or to complete a pilot phase.

• The timetable should then estimate the duration for collection of data, final analysis of data and writing up the report.

• In project proposals of a long duration (more than one year), the timetable should set milestones to be reached.

• These are taken into consideration when progress reports are reviewed by the funding agency.

• Funding is often released on the basis of these progress reports.

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TIME WORK PLAN- Example

Targets Time/Months

Apr May Jun Jul Aug Sep Oc t Nov Dec

Literature Survey

Development of Protocol

Clinical trial phase with ethical

approval

Data Analysis

Writing of data

Submission of data

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7. Problems anticipated

• Should demonstrate awareness of obstacles and difficulties, which may interfere with the successful completion of the project within the timeframe and cost proposed.

• Should explain how these obstacles and difficulties would be dealt with.

• An investigator who does not anticipate any problem probably has not thought out the details of the project carefully.

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8. Budget

The budget request should be itemized and each item should be justified.Budget itemizationThe following are examples of categories of expenses:• Personnel (names, positions, percentage of time spent on the project,

salary, fringe benefits)• Equipment• Supplies• Patient care costs• Travel• Data processing• Communications• Secretarial expenses• Publication/dissemination of information about the outcome of the

project.

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9. References

• The protocol should end with relevant references on the subject.

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10. Curriculum vitae (CVs) of the investigator(s)

• The ability of the investigators to carry out the project is an important consideration.

• Biographical sketches of the investigators or CVs should be attached.

• The track record of the investigators is important.

• Preliminary studies or other work done by the investigators on the subject should be included.

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References

1. Mahmoud F. Fathalla. WHO Regional Publications Eastern Mediterranean Series 30, A Practical Guide for Health Researchers, 2004.

2. WHO Guide for writing a Research Protocol for research involving human participation: http://www.who.int/rpc/research_ethics/guide_rp/en/, accessed on 02.01.2015.

3. Perera PK. Ethical Issues in Traditional and Alternative Medicine (TAM) , for Human Subject Protection Course (ER) Colombo , Forum for Ethical Review Committees in Asia and the Western Pacific In Collaboration with the Sri Lankan Medical Association and the National Science Foundation of Sri Lanka, 4-6 August 2014.

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Thank you!

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