Paper presented at a seminar on 'Evaluation of Research Proposals' organized by the Research Directorate of the Ministry of Health at Dammam 2-5 July 2010 by Professor Omar Hasan Kasule Sr MB ChB (MUK), MPH (Harvard), DrPH (Harvard)

1.0 CONTENTS OF A CLINICAL RESEARCH PROPOSAL

1.1 Identifying information

Title of the research project
Information on each of the principal investigators: name, address, professional title, qualifications, name and address of employer, experience in clinical research, and recent research projects involved in
Information on the person completing the application form: name. Qualifications, address, professional status
Name, address, and telephone of person to be contacted about the project in urgent and non-urgent matters
Sponsor of the research: name, contact person, address, level of support, conditions attached to the sponsorship, equipment and staff provided by the sponsor, payments to research subjects, restrictions if any on the publication of research results.

1.2 Description of research

Description of the research: type of research subjects (healthy volunteers, inpatients, outpatients), scale of the research (single center, national multi-center, international multicenter), Sponsor (commercial or academic institution), commercial research (drug development, testing devices of equipment), academic and non-commercial research (therapeutic study, non-therapeutic study, laboratory research, epidemiological research)

1.3 Protocol and dates

Study protocol: existing protocol, new protocol submitted with application
Dates: starting date, closing date, duration
Chapters of the protocol: Title page, background and Introduction; Objectives of the trial; Patient Selection Criteria; Trial design; Therapeutic regimen: dose and toxicity; required evaluations: clinical, laboratory, and follow-up; criteria of evaluation; registration and randomization of patients; forms and procedure for data collection; statistical procedures; administrative responsibilities; informed consent; references; regulatory regulations, drug ordering, appendices (consent form etc).
Definition of objectives: A clinical trial is a serious and expensive undertaking that must not be started before defining clear, specific, and attainable objectives.
Literature review: Once objectives are set, literature review is carried out for similar studies or similar outcomes.
Definition of patients: method of randomization, inclusion and exclusion criteria, treatment allocation, and withdrawals. The criteria should not be too rigid to ensure a homogenous population. Registration procedures must be defined explicitly. Rigorous enrollment procedures should ensure that the subject does not have the outcome at the time of enrollment.
Description of treatment: treatments, response assessment (single-blind & double-blind), protocol departures, definition of end-points and criteria of efficacy, duration and frequency of treatment. Treatments may be single agent, combined modality, or adjuvant therapy. Description of treatment administration includes what to do in case of side effects or adverse drug reactions. A schema is a treatment plan in graphic form.
Sample size: The sample size is fixed in advance in fixed sample studies. In sequential sample trial…. What really matters is the number of events and not number of subjects. A study of 1000 patients with 5 events is a weak study.
Data Collection: The exact methods of data collection must be described in such detail that any knowledgeable person will be able to carry out the protocol without further instructions. Measurement of effects and end-points must be defined. The data collection section must define the items of data to be collected.
Data-base: The design of the study data-base including details of data retrieval and security features. The database should be designed such that automatic editing checks are made for eligibility criteria and data inaccuracies as data is entered.
Regulatory measures: Information must be obtained on whether the institution where the research is undertaken is in good standing. Is the investigator authorized? Are regulatory requirements met? Are patients eligible? Demographic data. Measures to ensure protocol compliance.
Quality control: Quality control measures must be put in place. The local clinical site is responsible for ensuring timeliness, completeness, and consistency of data. It must also make sure that patient identifiers are correct and that the necessary privacy measures have been taken. The coordination center is responsible for systematic review of the data and making sure it is complete.
GCP responsibilities of the local participating site: ethics committee approval, patient recruitment, patient informed consent, collection and record of data required by the protocol, reporting of adverse effects, ensuring protocol compliance, ordering and storing study drugs.
GCP responsibilities of the study coordination center: confirmation of the ethics committee approval, confirming informed consent, confirming the accuracy of the data by regular visits to the study site, screening qualifications of study personnel, quality control of CRF, monitoring adverse effects, analysis of the trial and report of results.

1.4 Ethico-legal issues

Informed consent: patient/volunteer information sheet, use of a standard consent form, who will seek consent? method of approaching potential research subjects, time given to respondents to make up their mind about participation,
Potential benefits
Potential hazards and discomforts
Methods of assuring confidentiality
Insurance
Signed declaration

1.5 Patient/volunteer information sheet

Invitation to participate
Full title of the proposed research that is self explanatory to lay readers
Purposes of the research
Procedures and duration of the research
Description of foreseeable risks and side effects
Description of benefits of the research
Description of alternative treatments
Statement on confidentiality
Compensation for research subjects in case of injuries
Statement that participation is voluntary
Contact person for further information

Have you read and understood the patient information sheet?
Have you received enough information about the study?
Do you understand that participation is voluntary?
Do you agree to participate in this study?
Do you understand that you are free to withdraw from the study at any time and without having to give any reasons and that such withdrawal will not affect your medical care?

2.0 ETHICAL REVIEW

2.1 The ethics committee will use the following criteria in assessing a submission. To make assessment easier the application is submitted in a standard format. Documentation showing informed consent must be submitted.

2.2 The committee will look to see whether the research subjects were informed of the objectives of the study and of their rights to participate, abstain, or withdraw from the study. Special scrutiny of proxy consent will be made to ensure there is no abuse. The investigator must submit reasons in writing in cases in which full disclosure is deemed inappropriate.

2.3 The committee will look to make sure that the objectives are clearly stated and are attainable.

2.4 The research design and statistical methods must be judged adequate to produce clinically and scientifically useful results. The committee will compare the scientific merit and benefit of the research against risks and costs to patients.

2.5 The submission must have detailed resumes of the investigators to enable the committee assess their competence to undertake the research successfully.

2.6 The adequacy of research facilities is also assessed. The proposal must provide details on how confidentiality and security of the data will be assured.

EXERCISE #1: SURGICAL PROPHYLLAXIS FOR ACUTE APPENDICITIS – SINGLE ANTIBIOTIC (CEFOPERAZONE or METRONIDAZOLE) VERSUS A COMBINATION OF CEFOPERAZONE and METRONIDAZOLE

I. PROJECT IDENTIFICATION

A. Project number (Please refer to the Guidelines)

B. Project title (Please indicate the title of the project; the title should be short and concise)

SURGICAL PROPHYLLAXIS FOR ACUTE APPENDICITIS – SINGLE ANTIBIOTIC (CEFOPERAZONE or METRONIDAZOLE) VERSUS A COMBINATION OF CEFOPERAZONE and METRONIDAZOLE

C. Project leader (Please indicate the name and identification number of the project leader)

D. Organisation (Please indicate the name, address, telephone and fax of the organisation in which the project leader is
based)

E. Key words (Please provide a maximum of 5 key words that describe the research of the project. The key words will be incorporated in a database on Malaysian research)

Appendicitis

Antibiotic prophylaxis

II. OBJECTIVES OF THE PROJECT

-A. Specific objective of the project (Please describe the measurable objectives of the project and define the expected results. Use results-oriented wording with verbs such as "to define ...", "to determine ...", "to identify ...")

OBJECTIVES:

1. To study the efficacy of cefoperazone or metronidazole use as a single antibiotic for surgical prophylaxis in patients with acute appendicitis for appendicectomy in comparison to a combination of cefoperazone and metronidazole.

2. To compare the efficacy between cefoperazone and metronidazole use as a single antibiotic for surgical prophylaxis in patients with acute appendicitis.

3. To identify the bacteria that are involved in the occurrence of acute appendicitis in this hospital.

4. To study the sensitivity pattern of the bacteria identified to the antibiotic administered to these patients as surgical prophylaxis.

B. Research background of the project (Please indicate if the project is new, modified or extended. Give a summary of your literature review to indicate the originality of the proposed research, and describe related research to assist in assessing the research rationale and the potential for success)
	Project status (please indicate)				X	New	Modification to	Extension of
							previous project	existing project

		Literature review summary A se Search on medline did not turn up any titles of clinical trials of antibiotic prophylaxis in appendicitis using cefoperazone or metronidazole singly versus combination. Related research There is no related research in the faculty at the moment. No similar study to our knowledge is being carried out anywhere in Malaysia at the moment
C. Type of research (Please indicate the type of research, one only; see definition of terms in the Guidelines)
		x	1.	Scientific research (fundamental research)

			2.	Technology development (applied research)

			3.	Product/process development (design end engineering)

			4.	Social/policy research

III. BENEFITS OF THE PROJECT

A. Direct customers/beneficiaries of the project (Please identify clearly the potential customers/beneficiaries of the research results and provide details of their relevance, eg, size, economic contribution, etc)

Surgeons and anesthetists at the hospital

Hospital business managers will be interested in the cost-savings that the study results may suggest

B. Outputs expected from the project (Please refer to the list of outputs in the Guidelines and give further details)

A research report on the best prophylaxis for acute appendicitis

C. Technology transfer/diffusion approach (Please describe how the outputs of the project will be transferred to the direct beneficiaries/customers. Please also state if the project outputs are sustainable, ie, if they can be utilised without further external assistance)

No technology transfer is involved

D. Organisational outcomes expected (Please refer to the list of outcomes in the Guidelines and give further details)

Research skills in clinical trials

E. Sectoral/national impacts expected (Please refer to the list of impacts in the Guidelines and give further details)

Better and cheaper management of appendicitis

IV. PROJECT STRUCTURE

A. Research organizations involved in the project (Please identify all research organisations collaborating in the project, and describe their role/contribution to the project)

B. Industry linkages (Please identify any industry or end-user group involved in the project, and describe its role/contribution to the project)

C. Project Team

Name

Organisation

Man-months on project

Project Leader (Please provide name):

Programme Head (Please provide name)

Support Staff (Please indicate how many)

Total

109

A. Research methodology (Please describe the research methodology to be followed. Identify specialised
equipment, facilities and infrastructure which are required for the project, and indicate which are new)

STUDY DESIGN: This is a standard randomized multi-center clinical trial with two arms. Subjects recruited into the study will be randomized to two groups. The first group will receive one antibiotic as prophylaxis prior to surgery for appendicitis. The second group will receive two antibiotics as prophylaxis prior to surgery. The physicians, pathologists, and laboratory personnel involved in post operative assessment will be blinded as to the type of prophylaxis regimen administered.

PARTICIPANTS IN THE STUDY: Both male and female patients of any age admitted to a participating hospital with a provisional diagnosis of acute appendicitis will be included in the study provided they or their guardians give consent to participation in the study. The aim will be to accrue about 300 patients in each arm of the study

EXCLUSION CRITERIA: Patients will be excluded if they have underlying medical or surgical problems such as diabetes mellitus, renal failure, coagulopathies, chronic obstructive airway disease, and auto-immune disease that may put them at risk of post-operative wound infection. Patients who are found to have perforated appendices at surgery will be put on a regimen of combination of cefoperazone and metronidazole and will be excluded from further participation in the study.

METHOD OF RANDOMIZATION: Assignment to either arm of the study will be based on the time of hospital admission. The first patient will be assigned to one arm. The next one to the other arm. This alternation will be carried out until the right number of patients accrues in each arm.

TREATMENTS ADMINISTERED: One group of patients will be given either cefoperazone or metronidazole as prophylactic in roughly equal proportions. The other group will be given both cefoperazone and metronidazole. The antibiotic will be administered intravenously in the operation theater before induction of anesthesia. The dosage for metronidazole will be 500 mg and for cefoperazone will be 1 gram.

MICROBIOLOGICAL ASSAY: During surgery, a swab will be taken from the appendix stump for culture and sensitivity for both aerobic and anaerobic bacteria.

PATHOLOGICAL EXAMINATION: Biopsy specimens from the appendix will be sent for pathological examination

POST-OPERATIVE FOLLOW-UP: During the post-operative period, patients will be monitored for the following: pain, fever, and condition of the wound. Blood culture and sensitivity will be carried out every 3^rd day to detect any infection. Patients will be discharged from the ward once temperature falls and there is no evidence of wound infection. They will be seen again in follow-up clinic one week after discharge for wound inspection and review of the histology and microbiology report.

OUTCOME MEASURES: Indicators of post-operative infection: fever, blood C&S, wound infection, Type and nature of bacteria found pre and post operation

STATISTICAL ANALYSIS: Standard techniques for RCT will be used.

B. Project activities (Please list and describe the main project activities, including those associated with the transfer of the research results to customers/beneficiaries. The timing and duration of these activities are to be shown in the Gantt chart
in Form VI)

Completion of literature review

Personal consultations with physicians in hospitals

Clinical trials protocol

Pre-test

Patient recruitment and randomization

Monthly project review meeting

Project closure and data analysis

Report writing

C. Key milestones (Please list and describe the principal milestones of the project. The timing of milestones is to be shown in the Gantt chart on Form VI. A key milestone is reached when a significant phase in the project is concluded, e.g. completion of
test, review, commissioning of equipment, etc)

Clinical trials protocol

Pre-test

Patient recruitment and randomization

Project closure and data analysis

Report writing

D. Risks of the project (Please describe factors the that may cause delays in, or prevent implementation of, the project as proposed above; estimate the degree of risk)

Factors:

Patient recruitment

Low Medium High

Technical risk:

Timing risk:

Budget risk:

E. Duration (State the planned starting date of the project and the elapsed time, in months, to complete this project; technology transfer activities should be excluded from elapsed time)

.Starting date: July 1, 2000

.Duration/elapsed time: 24 months

VI. PROJECT SCHEDULE

2000

2001

199_

Research Activities

Completion of literature review

Personal consultations with physicians

Clinical trials protocol

Pre-test

Patient recruitment and randomization

Monthly project review meeting

Project closure and data analysis

Report writing

Technology Transfer Activities

 Planned milestone

S1: First Semester( January - June)

S2: Second Semester (July - December)

VII. PROJECT COSTS

A. Staff costs (Please include the yearly staff costs of the project. For computation, use the Staff Cost Estimation Form in Appendix D. Numbers in parentheses refer to expense codes)
	Staff Category	Total RM	2000 RM	2001RM	2002 RM
	Salaried personnel (11100 ) Temporary and contract personnel (J 400)	219,500 19,050	130,000 11,550	89,500 7,500
	Sub-total staff costs	238,550	141,550	97,000

B. Direct project expenses (Please include the yearly direct expenses of the project. For computation, use the Direct Expenses Estimation Form in Appendix E. Numbers in parentheses refer to expense codes)
	Expense Category	Total RM	2000RM	2001RM	2002RM
	Travel and transportation (J 500) Rentals (J 600) Research materials and supplies (J 700) Minor modifications and repairs (J 800) Special services (J 900) Special equipment and accessories (J 1000)	12,000 0 11,000 0 0 0	6,000 0 7,000 0 0 0	6,000 0 4,000 0 0 0
	Sub-total direct expenses	23,000	13,000	10,000

C. Total cost (Please add the sub-totals of A and B)
		Total RM	2000RM	2001RM	2002RM
		261,550	154,550	107,000

VIII. PROJECT FUNDING

A. Funding sources (Please indicate funding sources for the project; see list of funding sources in the Guidelines)

Funding Sources

% of Total Funding

- External Grant

- Internal Funds

- Other Sources (please specify)

Total

B. Disbursement schedule for IRPA funds, by participating research organisation (Please indicate how IRPA funding for the project will be allocated)

Organisation

Total RM

2000 RM

2001RM

2002RM

IX. CONTRACTRUAL MATTERS

. Contractual obligations under this project (Please indicate any contractual obligations with third parties that will be entered in for this project) None
B. Ownership of intellectual property rights (Please indicate the organisation(s) that will own the intellectual property rights that may arise from this project) Not relevant
C. Approving Officer (of the organisation in which the Project Leader is based)
Name	:

Designation	:

Date	:	Signature	:

Please follow the following format when submitting the curriculum vitae of key research personnel
A. Personal Data
1.	Name	:
2.	IC No	:
3.	Date and Place of Birth	:
4.	Sex	:
5.	Nationality	:
6.	Name of Current Employer	:
7.	Address	:
8.	Telephone No	:
9.	Fax No	:
10.	Title of Position Held	:
11	Signature of Researcher	:
12.	Date	:
B. Educational Qualifications
1.	Academic Qualification Degree Field Year Name and Place of Institution Degree Field Year Name and Place of Institution Degree Field Year Name and Place of Institution (Repeat as necessary)	: : : :
2.	Other Professional Courses Completed Field Year Field Year (Repeat as necessary)	: :

C. Research Experience
1.	Number of Years of Experience in the Field Related to the Proposed Project	:
2.	Fields of Specialisation	:
3.	Major Research Programmes/Projects Completed Title From To Position held Major output Title From To Position held Major output Title From To Position held Major output Title From To Position held Major output (Repeat as necessary)	: : : : :
D. Research Achievements
1.	Honours and Awards	:
2.	Major Publications	:
3.	Number of Patents	:
4.	Major Commercial Achievements

A. Project title
B. Relevance to proposed project
C. Organisation(s) that were involved in the project (Please indicate the organisation that led the project)
D. Names of senior staff
. Programme head:
. Project leader:
. Key researchers:
E. Description of the project(Please indicate project customers/beneficiaries,research approach adopted and outputs)

A. Project title
B. Relevance to proposed project
C. Organisation(s) that were involved in the project (Please indicate the organisation that led the project)
D. Names of senior staff
. Programme head:
. Project leader:
. Key researchers:
E. Description of the project(Please indicate project customers/beneficiaries,research approach adopted and outputs)

A. Project title
B. Relevance to proposed project
C. Organisation(s) that were involved in the project (Please indicate the organisation that led the project)
D. Names of senior staff
. Programme head:
. Project leader:
. Key researchers:
E. Description of the project(Please indicate project customers/beneficiaries,research approach adopted and outputs)

Role in Project	Total	Project Leader	Researchers	Contract Staff	Support Staff
Daily Rate (RM)		100	100	0	30
Research Activities	Man-Days1
Completion of lit. review Consultations with physicians Clinical trials protocol Pre-test Recruitment & randomization Data collection Monthly review meeting	5 20 50 200 500 750 50	5 10 30 30 50 50 10	0 10 20 150 500 400 35	0 0 0 0 0 0 0	0 0 0 30 50 300 5
Total Year 1 (2000_) Man-days	1685	185	1115	0	385
Total Year 1 (2001) Cost (RM)2	141,550	18,500	111,500	0	11,550
		(11100)	(11100)	(11100)	(J 400)
Recruitment & randomization Data collection Monthly review meeting Data Analysis Report writing	400 600 50 150 50	40 40 10 30 30	300 300 35 100 15	0 0 0 0 0	60 160 5 20 5
Total Year 2 (1997_) Man-days	1145	150	745	0	250
Total Year 2 (1997_) Cost (RM)2	97,000	15,000	74,500	0	7,500
		(11100)	(11100)	(11100)	(J 400)
Total Man-months3	109	13	72	0	24

Notes

1. For each research activity, estimate the man-days required by each staff category.

2. Compute the staff cost for each year by multiplying the total man-day by the daily rate of the corresponding staff category. For daily rate computation, refer to the Guidelines.

3. Compute the total man-months required for the project by dividing the total project man-days by 24.

Numbers in parentheses are expense codes as shown in Form VII.

Expense Categories and Items	Total RM	2000 RM	2001 RM	2002
Travel and transportation (J 500)	12,000	6,000	6000
Project meetings	12,000	6000	6000
Rentals (J 600)	0	0	0	0

Research materials and supplies (J 700)	11,000	7.000	4,000
Laboratory supplies and reagents	11,000	7000	4000
Minor modifications and repairs (J 800)	0	0	0	0

Special services (J 900)	0	0

Special equipment, accessories* (J 1000)	0	0

Total direct expenses	23,000	13,000	10,000
Special Equipment and Accessories (Please describe and provide justification for major purchases) 1. Description 2. Justification 3. Estimated Cost
Special Equipment and Accessories (Please describe and provide justification for major purchases ) 1. Description 2. Justification 3. Estimated Cost
Special Equipment and Accessories (Please describe and provide justification for major purchases) 1. Description 2. Justification 3. Estimated Cost

* If major equipment, please provide description on page 2 of this appendix

Numbers in parentheses are expense codes as shown in Form VII

Integrated Medical Education Resources

1007P- EVALUATION OF A CLINICAL RESEARCH PROPOSAL

1.5 Patient/volunteer information sheet

II. OBJECTIVES OF THE PROJECT

IV. PROJECT STRUCTURE

VI. PROJECT SCHEDULE

IX. CONTRACTRUAL MATTERS