Shifa Clinical Research Center Policy Manual

SHIFA CLINICAL RESEARCH CENTER

Policies and Guidelines Manual

“Research is defined as any systematic investigation designed to develop or contribute to generalizable knowledge”.

"Research is to see what everybody else has seen, and to think what nobody else has thought."

- Albert Szent-Gyorgyi

Shifa International Hospital TABLE OF CONTENTS

___________________________________________ Research Policies

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MISSION and VISION STATEMENT

5

I. RESEARCH AND RESEARCH COMPLIANCE

1.1 Purpose of Policy 6

1.2 Scope of Policy 6

1.3 Glossary 6-11

2. OFFICE SUPPORTING RESEARCH

12

2.1 RO working: proposals, routing, communication with PI’s 12-15

2.2 IRB working: review criteria, time frame 16-19

3. Academic Policies Pertaining Research 20

3.1 Ethical Principles 20

3.2 Health professional-Pharmaceutical relationship 29

3.3 Conflict of Interest

30-33

3.4 Authorship 34-39

4. Financial Aspects of Research proposal 39

4.1 Budget 39

4.2 Funding Policy 39

4.3 Receipt and Disbursement of research Funds 40

4.4 Cost Estimation 40-41

4.5 Research Fund Management 41

4.6 Agreements /Contracts/MOU’s 41

5. Non-Faculty Research Appointments 42


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6. REGULATORY COMPLIANCE

43

6.1 Human subjects in research 43-48

6.2 Environment Health and Safety 49-57

6.3 Laboratory Animals in Research 58-92

6.4 Ministry of Health and Regulatory Authorities 93

6.5 Safety Events and Reporting 93

7. OTHERS 94

7.1 Informed Consent Form (ICF) and Guidelines 94-95

7.2 Checklist for Completion of Informed Consent Form (ICF) 96

7.3 Research involving pregnant women or fetuses 97

7.4 Research involving neonates 98-99

7.5 Research involving the placenta, the dead fetus or fetal material 99

7.6 Form-A: research application form 100-

107

7.7 Form-B: modifications/amendments to research proposal 108

7.8 Form-C: budget form (estimates for support requested) 109

7.9 Form-D: potential hazards and toxicity 110-

111

7.10 Regulatory compliance 112-113

8 GUIDELINES 114

9 REFERENCES


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فـال تـتـفـكـرونفـال تـتـفـكـرونفـال تـتـفـكـرونفـال تـتـفـكـرونأأأأ

MISSION STATEMENT

Facilitating an ethical, scientific and collaborative journey of reflection, inquiry, discovery and

innovation.

VISION STATEMENT


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Leading national and global collaborative efforts in clinical research, aiming for creation of

beneficial knowledge ("Ilman Nafian" )translating into healing (Shifa) for humanity.

I. RESEARCH AND RESEARCH COMPLIANCE

1.1 PURPOSE OF THE RESEARCH CENTER

To contribute to knowledge translation in health sciences through clinical outcomes based

research, capacity building and infrastructure development and to provide research opportunities

for health professionals at the clinician/faculty, postgraduate and undergraduate level at Shifa

International Hospital in liason with affliated institutions . The Research center will also review

proposals for submission to IRB or referred from IRB ; make recommendations for amendment

and/or approval.

1.2 SCOPE OF POLICY

This research governance policy applies to all individuals involved in the conduct of clinical

research taking place within or facilitated by SIH, SCM & SCN and administered hospitals and

clinics.

1.3 GLOSSARY

Research: Research may be defined as "a systematic investigation, including research

development, testing and evaluation, designed to develop or contribute to generalizable

knowledge”.

Researcher: The person conducting the study.

Principal Investigator: The person authorized to take overall responsibility for the research

being conducted.. If a team of researchers is conducting the research, the Principal Investigator is

the leader responsible for that team.

Co--Investigator: Any individual member of the research team designated and supervised by the

investigator to perform procedures and/or to make important decisions (e.g.,clinical research associates,

residents, research fellows). See also Investigator.


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Human Subjects: A “human subject” is a living individual about whom an investigator

(whether professional or trainee) conducting research obtains (1) data through intervention,

experimentation or interaction with the individual, or (2) involves identifiable private

information.


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Risk: Risk means that the probability and magnitude of harm or discomfort anticipated in the

research are not greater than those ordinarily encountered in daily life or during the performance

of routine physical or psychological examinations or tests

Benefit: A research benefit is considered to be something of health-related, psychosocial, or

other value to an individual, research subject, or something that will contribute to the acquisition

of generalizable knowledge.

Money or other compensation for participation in research is not considered to be a benefit, but

rather compensation for research-related inconveniences.

Protocol: A document that describes the objective(s), design, methodology, statistical

considerations, and organization of a study.

Institutional Review Board (IRB)/ Ethics committee (EC): An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a research study/trial by, among other things, reviewing, approving, and providing continuing review of research/trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the subjects.

Informed Consent: A process by which a subject voluntarily confirms his or her willingness to participate in a particular study, after having been informed of all aspects of the study that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.

Impartial Witness: A person, who is independent of the study, who cannot be unfairly influenced by people involved with the study, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.

Legally Acceptable Representative: An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical study.

Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)

Any untoward medical occurrence that at any dose:

� Results in death

� Is life-threatening

� Requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity.

� Is a congenital anomaly/birth defect.


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Regulatory Authorities: Bodies having the power to regulate. In the ICH GCP (?) guideline the expression Regulatory Authorities includes the authorities that review submitted clinical data and those that conduct inspections. These bodies are sometimes referred to as competent authorities.

Multicentre Study: A clinical study conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.

Vulnerable Subjects: Individuals whose willingness to volunteer in a clinical study may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

Well-being: The physical and mental integrity of the subjects participating in a clinical study.

Alternative hypothesis: The alternative hypothesis states that an association between predictor and outcome variables is present. It represents the possibility that the experientially observed effect is genuine. It cannot be tested directly. The classical approach is to calculate the probability that the observed effect will occur if the null hypothesis (aka random chance) is true. If this value (the “p-value”) is small, then the null hypothesis is rejected in favor of the alternative hypothesis.

Categorical variables: phenomena that cannot be quantified, thereby measured by classifying into categories. Example: blood type, gender.

Cluster sample: sampling technique where the entire population is divided into natural groupings, or clusters, and a random sample of these clusters is selected.

Continuous variable: rich in information; have quantified intervals on an infinite scale of values.

Confidence interval (CI): statistic calculated from the range of the lower confidence limit and the upper confidence limit. A 95% CI indicates, that if the study were replicated several times, there is a 95% chance that the same results would be obtained.

Correlation coefficient: measures strength and direction of the linear relationship between 2 variables.

Dependent variable: A dependent variable is what is measured as an endpoint in an experiment. The dependent variable responds to or is affected by the independent variable. It is called dependent because it "depends" on the independent variable.

Design: the way in which you conceptualize your research project.


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Exclusion criteria: defines the subset of population not eligible for study participation; if too excessive, then ability to generalize becomes compromised.

Hypothesis: version of research question that summarizes all of its elements: sample, design, predictor variables, outcome variables. Hypothesis establishes basis for tests of statistical significance.

Incidence: statistic obtained from a cohort study; proportion of variable over a period of time. Inclusion criteria: define the main characteristics of the subject population.

Independent variable: An independent variable is the variable a researcher can choose,

control and/or manipulate. It is presumed to affect or determine a dependent variable. one that comes before the outcome variable does not change. May be a qualifier, or descriptor of study population, Also known as, predictor variable.

Intervention: special predictor variable that the investigator manipulates. Measurement scales: describe phenomena that can be analyzed statistically; continuous or ordered discrete and categorical variables considered with methods.

Methods: detailed tasks, steps, stages and procedures you will use to conduct the study.

Null hypothesis: states that there is no association between the predictor and the outcome variable. It is the opposite of the alternative or research hypothesis. Ideally, you want the data to prove the null hypothesis is false, which makes your (“research”) hypothesis true.

Odds ratio: estimate of strength of association between each predictor variable and presence or absence of disease.

Ordered discrete: scale with a finite number of intervals.

Outcome variable: variable often being measured as endpoint, Also known as the dependent Variable

Power analysis: procedures and formulas that allow the researcher to determine the likelihood of achieving statistical significance with a particular sample size. Contains four variables in its calculation: 1. level of significance set by the researcher (identified as alpha, typically alpha is given the value of .05) 2. probability of obtaining a significant result (power desired computed as 1-beta, typically beta is given the value of 0.8) 3. population effect size, or the hypothesized effect on the groups 4. sample size

Predictor variable: one that comes before the outcome variable. Does not change. May be a


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qualifier, or descriptor of study population. Also known as, independent variable.

Prevalence: statistic obtained from a cross-sectional study; proportion of variable at one point in time. P-value: measures the strength of evidence in support of the null hypothesis. Since the null hypothesis is the opposite of the study hypothesis, naturally you would want your data to support your study hypothesis and not the null hypothesis. A p-value less than or equal to .01 is generally considered statistically significant. A p-value less than or equal to .005 or less than or equal to .001 is considered highly significant.

Research question: what outcomes the study addresses.

Sample size: number of subjects needed to observe the expected difference in outcome between study groups with a reasonable degree of probability or power.

Significance: in regards to the study question - why is the question important, how will it contribute to society, what benefit will it bring, any existing research around this topic that may have left unanswered questions, or questions you wish to challenge. In regards to statistics - a result is considered (statistically) significant if it is unlikely to have occurred by chance. The significance level is usually represented by the Greek symbol α (alpha).

Simple random sample: give numbers to qualifying sample population, then randomly select Participants

Stratified random sample: dividing the population into subgroups based on specific criteria, Then randomly selecting from each group, or “strata”

Study sample: subset of target population available for study.

Target population: defined by clinical, demographic, geographic population; who the results will be generalized to.

Type I error: incorrectly concluding that the null hypothesis is false, when it is actually true. The probability of committing a Type I error is equivalent to alpha, the significance level given to the study.

Type II error: occurs when the test fails to reject the null hypotheses as false when it is in fact False. Probability of this type of error decreases as the amount of data collected increases. The Probability of committing this type of error is equivalent to beta. The probability of not Committing a Type II error is equivalent to power.

Validity: how well the measurement represents the phenomenon of interest.


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2. OFFICE SUPPORTING RESEARCH

2.1 RESEARCH OFFICE:

The administrative office of the Research Center is responsible for processing, reviewing,

implementation and monitoring of research at the institution.

Procedures/Guidelines

Submission of a Research Proposal

2.1.1 A scientific research proposal may describe any one of the following biomedical research

activities in humans:

� Use Of Category I Drug: A Formulary drug for an unlabelled indication or in a

combination or dosage different from that recommended by the manufacturer.

� Use Of Category II Drug: A non-Formulary drug in a Phase II/III trial.

� Use of a device

� A procedure

� A clinical diagnostic problem

� A physiological function or effect

� The pathophysiology of a disease

� A research project in any area of health care/ sciences

2.1.2 All protocols shall be written according to the research proposal format of the Research

Center.

2.1.3 The Principal Investigator(s) shall submit the completed protocol, through their

Department Chairman/Section Head, to the Research Office for Full Review, Expedited

Review or for Exempt Status.

2.1.4 The Research Office shall take the following actions:

� Review the application for completeness and justified status review.

� Send the application for review to the IRB, if complete.

� take up to (maximum) 10 working days to review the application before sending it

to the IRB.


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� The status review (Full, Expedite or Exempt) recommendations shall be sent by

the Research Office to the IRB.

� Research application tracking system will be maintained by the RO for the

convenience of the applicants

2.1.5 The Institutional Review Board (IRB) approval will be documented before

commencement of any project.

IMPORTANT

Annual Reports on the progress of the study should be sent to the Research Office,

or more frequently if so specified by the RO. On completion/discontinuation of the

study, a Final Report should be sent to the Research Office which in turn will send

it to the IRB.

2.1.6 General Instructions for the Principal Investigator

� The research proposal should be carefully planned before commencing writing.

� Establishment of deadlines for the preparation of the proposal is important particularly in

collaborative investigations.

� When writing a research proposal, the following format should be followed:

� Use Basic English.

� Avoid jargon and spell out acronyms when used initially.

� Number ALL pages consecutively beginning with the first page of the proposal

and continuing to the last page.

� Whenever possible, research proposals should be reviewed and proofread by an objective

colleague. More often than not, the colleague will draw the attention to some minor

points in the proposal that may have been overlooked.


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� If an investigator wishes to participate in a multi-center study which has been initiated

and previously approved by an acknowledged academic, medical or research institution;

he/she must submit a copy of that proposal, together with the approval letter from the

associated institution. The Research Center shall review such proposals in an expedited

fashion.

� If an outside company is sponsoring any research a copy of agreement between the drug

company and the hospital must be attached with the application.

� Investigational drugs should be preferably kept in the hospital pharmacy. The hospital

pharmacy should inform the Research Office in writing once the drugs are received by

the hospital. The Pharmacy shall follow all procedures and protocols as outlined in the

protocol/sponsor’s guidelines for the appropriate storage of investigational product.

� The principal investigator should submit the proposal with all relevant forms completed,

and a covering memo; through the concerned department chairman or head, to the

Research Office.

� The proposal sent to the Research Office will be screened for compliance with

submission criteria.

� Completed proposals will receive a reference number (e.g., 2011.01) used for tracking

and future correspondences.

� The Research Office will arrange for the proposal to be forwarded to IRB for discussion.

� The Principal Investigator will be contacted by the Research Office if any clarifications

or recommendations are required.


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� The Principal Investigator will regularly update the Research Office, in writing, of the

progress of the research and any new information that comes up during the course of the

study (where applicable).

� IRB will approve, disapprove or require clarification.

� A deadline will be set by the Research Office for studies, which have exceeded the time

frame set by the Principal Investigator.

� For studies that have attained IRB approval and have not been initiated within one year of

approval, will be considered null and void and a detailed report to be submitted by the

concerned Principal Investigator to the Research Office(PI or Principal Investigator

should be consistent throughout the document)

� For Sponsored Research all possible hospital facilities may be utilized including but not

limited to Laboratory, Radiology and Pharmacy etc.

� Research Center intranet website will be established for information, queries, forms,

application tracking and approval status etc.

� CPSP Synopsis will be discussed within the individual departmental research forums and

reviewed by the Departmental Head or his designee besides the supervisor for that post

graduate trainee prior to IRB submission. Once approved by the IRB, synopsis can be

sent to CPSP.The Shifa Clinical research center shall help in capacity building with

scheduled workshops and seminars and for projects with IRB approval involving human

subject research at Shifa International Hospital

� A reprint of any publication arising from the research project should be sent to the

Research Office.


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� When a final report has been presented to the Research Office, the follow-up tracking

system will be closed.

� A closed file of any research proposal should be kept in the Research Office for 2 years.

� A separate space is to be allocated in the Hospital’s Medical Record Room /Clinical

research center for archiving study specific patients file for source document verification

and inspections/audits.

� The Research Office through appointed Monitors shall perform Periodic Monitoring

Visits to the project site for audits/inspections as and when appropriate by giving prior

written notification to the concerned P.I to ensure protocol compliance.

� All sponsored research will be brought to the Research Office which in turn will provide

full support to the P.I including but not limited to feasibility assessment, administrative

support, study staff, implementation processes, contract negotiations, IRB/EC

submission, Regulatory Authority submission/approval etc. to ensure timely initiation,

ethical conduct and successful completion of the projects.

2.2 INSTITUTIONAL REVIEW BOARD (IRB) & ETHICS COMMITTEE (EC)

FUNCTIONS

3. ACADEMIC POLICIES PERTAINING RESEARCH

3.1 ETHICAL PRINCIPLES

3.1.1 BELMONT REPORT

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

issued "The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of

Research." The report sets forth three principles underlying the ethical conduct of research: Respect for

persons, Beneficence, and Justice.


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Summary: On July 12, 1974, the National Research Act (Pub. L. 93-348) was signed into law, there-by creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. One of the charges to the Commission was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles. In carrying out the above, the Commission was directed to consider: (i) the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine, (ii) the role of assessment of risk-benefit criteria in the determination of the appropriateness of research involving human subjects, (iii) appropriate guidelines for the selection of human subjects for participation in such research and (iv) the nature and definition of informed consent in various research settings.

The Belmont Report attempts to summarize the basic ethical principles identified by the Commission in the course of its deliberations. It is the outgrowth of an intensive four-day period of discussions that were held in February 1976 at the Smithsonian Institution's Belmont Conference Center supplemented by the monthly deliberations of the Commission that were held over a period of nearly four years. It is a statement of basic ethical principles and guidelines that should assist in resolving the ethical problems that surround the conduct of research with human subjects. By publishing the Report in the Federal Register, and providing reprints upon request, the Secretary intends that it may be made readily available to scientists, members of Institutional Review Boards, and Federal employees. The two-volume Appendix, containing the lengthy reports of experts and specialists who assisted the Commission in fulfilling this part of its charge, is available as DHEW Publication No. (OS) 78-0013 and No. (OS) 78-0014, for sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402.

3.1.2 NUREMBERG CODE

Trials of War Criminals Before the Nuremberg Military Tribunals Under Control Council. Law No. 10, Vol 2, pp. 181-182. Washington, D.C.: U.S. Government Printing Office, 1949.

Developed in response to the Nuremberg Trials of Nazi doctors who performed unethical experimentation during World War II, the Code was the first major international document to provide guidelines on research ethics. It made voluntary consent a requirement in clinical research studies, emphasizing that consent can be voluntary only if participants are able to consent; they are free from coercion (i.e., outside pressure); and they comprehend the risks and benefits involved.

1. The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision. This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and


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hazards reasonable to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment. The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.

2. The experiment should be such as to yield fruitful results for the good of society,

unprocurable by other methods or means of study, and not random and unnecessary in nature.

3. The experiment should be so designed and based on the results of animal experimentation

and knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.

4. The experiment should be so conducted as to avoid all unnecessary physical and mental

suffering and injury.

5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

6. The degree of risk to be taken should never exceed that determined by the humanitarian

importance of the problem to be solved by the experiment.

7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.

8. The experiment should be conducted only by scientifically qualified persons. The highest

degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

9. During the course of the experiment the human subject should be at liberty to bring the

experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.

10. During the course of the experiment the scientist in charge must be prepared to terminate the

experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

3.1.2 WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI

Introduction


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1. The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects includes research on identifiable human material or identifiable data.

2. It is the duty of the physician to promote and safeguard the health of the people. The physician's knowledge and conscience are dedicated to the fulfillment of this duty.

3. The Declaration of Geneva of the World Medical Association binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient."

4. Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.

5. In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society.

6. The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality.

7. In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens.

8. Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care.

9. Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.

Basic Principles For All Medical Research

10. It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject.

11. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation.

12. Appropriate caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected.

13. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol. This protocol should be


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submitted for consideration, comment, guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be independent of the investigator, the sponsor or any other kind of undue influence. This independent committee should be in conformity with the laws and regulations of the country in which the research experiment is performed. The committee has the right to monitor ongoing trials. The researcher has the obligation to provide monitoring information to the committee, especially any serious adverse events. The researcher should also submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.

14. The research protocol should always contain a statement of the ethical considerations involved and should indicate that there is compliance with the principles enunciated in this Declaration.

15. Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given consent.

16. Every medical research project involving human subjects should be preceded by careful assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This does not preclude the participation of healthy volunteers in medical research. The design of all studies should be publicly available.

17. Physicians should abstain from engaging in research projects involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results.

18. Medical research involving human subjects should only be conducted if the importance of the objective outweighs the inherent risks and burdens to the subject. This is especially important when the human subjects are healthy volunteers.

19. Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research.

20. The subjects must be volunteers and informed participants in the research project. 21. The right of research subjects to safeguard their integrity must always be respected. Every

precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's information and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject.

22. In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal. After ensuring that the subject has understood the information, the physician should then obtain the subject's freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed.

23. When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship with the physician or may


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consent under duress. In that case the informed consent should be obtained by a well-informed physician who is not engaged in the investigation and who is completely independent of this relationship.

24. For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a legally incompetent minor, the investigator must obtain informed consent from the legally authorized representative in accordance with applicable law. These groups should not be included in research unless the research is necessary to promote the health of the population represented and this research cannot instead be performed on legally competent persons.

25. When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorized representative.

26. Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent, should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population. The specific reasons for involving research subjects with a condition that renders them unable to give informed consent should be stated in the experimental protocol for consideration and approval of the review committee.

The protocol should state that consent to remain in the research should be obtained as soon as possible from the individual or a legally authorized surrogate.

27. Both authors and publishers have ethical obligations. In publication of the results of research, the investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be published or otherwise publicly available. Sources of funding, institutional affiliations and any possible conflicts of interest should be declared in the publication. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.

Additional Principles For Medical Research Combined With Medical Care

28. The physician may combine medical research with medical care, only to the extent that the research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with medical care, additional standards apply to protect the patients who are research subjects.

29. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.1

30. At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.2

31. The physician should fully inform the patient which aspects of the care are related to the research. The refusal of a patient to participate in a study must never interfere with the patient-physician relationship.


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32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgment it offers hope of saving life, re-establishing health or alleviating suffering. Where possible, these measures should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded and, where appropriate, published. The other relevant guidelines of this Declaration should be followed.

INTERNATIONAL CONFERENCE on HARMONIZATION / GOOD CLINICAL

PRACTICES (ICH/GCP) GUIDELINES FOR CONDUCTION OF CLINICAL

RESEARCH

� Clinical Research should be conducted in accordance with the ethical principles that have

their origin in the Declaration of Helsinki, and that are consistent with GCP and the

applicable regulatory requirement(s).

� Before a research is initiated, foreseeable risks and inconveniences should be weighed

against the anticipated benefit for the individual study subject and society.

� Research should be initiated and continued only if the anticipated benefits justify the risks.

� The rights, safety, and well-being of the study subjects are the most important

considerations and should prevail over interests of science and society.

� The available nonclinical and clinical information on an investigational product should be

adequate to support the proposed clinical research (drug studies).

� Clinical research project should be scientifically sound, and described in a clear, detailed

protocol.

� A research project should be conducted in compliance with the protocol that has received

prior institutional review board (IRB)/independent ethics committee (IEC)

approval/favorable opinion.

� The medical care given to, and medical decisions made on behalf of, subjects should always

be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.

� Each individual involved in conducting a research project should be qualified by education,

training and experience to perform his or her respective task(s).

� Freely given informed consent should be obtained from every subject prior to clinical

research participation.


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� All clinical research project information should be recorded, handled, and stored in a way

that allows its accurate reporting, interpretation and verification.

� The confidentiality of records that could identify subjects should be protected, respecting

the privacy and confidentiality rules in accordance with the applicable regulatory

requirement(s).

� Any Investigational product/s should be used in accordance with the approved protocol.

INVESTIGATORS RESPONSIBILITY FOR PROTECTING HUMAN SUBJECTS

Who are Investigators?

� The term “Investigator” to refer to an individual performing various tasks related to

the conduct of human subjects research activities, such as obtaining informed consent

from subjects, interacting with subjects, and communicating with the IRB.

� Investigators can include physicians, scientists, nurses, administrative staff, teachers,

and students, among others.

� Some research studies are conducted by more than one investigator, and usually

one Investigator is designated the “principal investigator” with overall responsibilities

for the study.

What are Investigators responsible for?

� Protecting the rights and welfare of the human subjects who participate in their

research.

� They must also understand the ethical standards and regulatory requirements governing

their research activities

� To conduct research on the agreed protocol and in accordance with the legal requirement

and guidance


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� Obtaining IRB approval before beginning any human subject’s research.

� Obtaining and documenting informed consent of subjects or subjects’ legally authorized

representatives prior to the subjects’ participation in the research.

� Obtaining prior approval from the IRB for any modifications of the previously approved

research

� Ensuring that progress reports and requests for continuing review and approval are

submitted to the IRB.

� Providing to the IRB and Research center prompt reports of any unanticipated

problems involving risks to subjects or others

� Providing to the IRB and Research center prompt reports of serious or continuing

noncompliance with the regulations or the requirements or determinations of the IRB.

� To comply with internal and external audit requirements.

� Keeping certain required documents for at least three years after completion of study.

3.2 HEALTH PROFESSIONAL-PHARMACEUTICAL RELATIONSHIP

� Health professionals at SIH and STMU affiliated facilities who participate in industry

associated research will do so ONLY if that research meets accepted ethical, regulatory,

and scientific standards.

� Health professionals at Shifa International Hospitals Limited will not be involved in

research in which the sponsor imposes any obstacle to publication of the study results.

� Research whose primary purpose is promotion of a drug product or device is not legitimate

and does not hold patient welfare in the highest regard. As an example, the Health

professionals at SIH and STMU affiliates will not participate in studies for which the

primary purpose is to familiarize prescribers with specific drug products (i.e., marketing or

"seeding" studies).

� Payments to patients, subjects, or health professionals participating in studies should be

reasonable and represent appropriate reimbursement for time and expenses.

Disproportionate fees for collection of patient data in a research study should lead one to


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evaluate closely the purpose of the study, as excessive compensation for conducting a study

constitutes a gift

� If allowed by the funding agency, money that remains after all study expenses (such as

investigator and coordinator salaries and overhead) have been paid should be used to

support research training programs, enhance the educational or research mission of the

institution, or improve patient care directly.

� Reimbursement of expenses for attending clinical investigators' meetings should avoid

unnecessary extravagance and cover the expenses of the investigators for the time of the

meeting only.

3.3 CONFLICT OF INTEREST

Why Should You Care About Conflicts of Interest

Conflicts of interest are intrinsic to a researcher's enterprise. Not only can a conflict harm particular study participants but, on a larger scale, a conflict of interest can damage an entire research enterprise by reducing the trust and confidence that people generally have in research. Objectivity is fundamental to this trust

Definition of a Conflict of Interest

A conflict of interest involves the abuse -- actual, apparent, or potential -- of the trust that people have in professionals. The simplest working definition states: “A conflict of interest is a situation in which financial or other personal considerations have the potential to compromise or bias professional judgment and objectivity”.

An apparent conflict of interest is one in which a reasonable person would think that the professionals judgment is likely to be compromised. A potential conflict of interest involves a situation that may develop into an actual conflict of interest. It is important to note that a conflict of interest exists whether or not decisions are affected by a personal interest; a conflict of interest implies only the potential for bias, not a likelihood. It is also important to note that a conflict of interest is not considered misconduct in research, since the definition for misconduct is currently limited to fabrication, falsification, and plagiarism.

There are many varieties of conflicts of interest, and they appear in different settings and across all disciplines. While conflicts of interest apply to a "wide range of behaviors and circumstances," they all involve the use of a person's authority for personal and/or financial gain. Conflicts of interest may involve individuals as well as institutions. Furthermore, individuals, in


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certain circumstances, may have conflicts occurring on both an individual and an institutional level, as may be seen among members of an Institutional Review Board (IRB).

Conflicts of interest are broadly divided into two categories: intangible, i.e., those involving academic activities and scholarship; and tangible, i.e., those involving financial relationships.

Conflicts of Interest at the Individual Level

Objectivity is the sine qua non of scientific discovery. But bias in judgment is virtually impossible to eliminate. There are often subtle, and not so subtle, pressures that can influence how we perceive and how we act. All research professionals understand the pressures to publish, to get funding, appointments, promotions, and to earn respect from peers. In an effort to succeed, there are myriad areas where bias can influence judgment and diminish objectivity. A desire to validate a pet theory, overconfidence about a particular concept, overreliance on a belief held by a special group, ruling out data that don't support a hypothesis, and internal or external pressures to get a specific result are all influences that may lead to distortions in objectivity. Any of these biases or pressures may lead to what sociologists call selective inattendance. Your mind-set may cause you to overlook important data or to misperceive critical observations. Bias can be too subtle to recognize and too difficult to control. It can creep into how research questions are selected and framed, the choice of research design, the selection of research participants, and how the data are collected, analyzed, interpreted, and ultimately published. Whether you describe the glass as half empty or half full is influenced by what you want your results to look like. Bias can even influence the sharing of the results of the study.

Academic Conflicts of Interest or Intellectual Bias

Academic scientists have special responsibilities to disseminate knowledge, to maintain academic standards, to critique the current state of knowledge, to synthesize existing knowledge, and to apply knowledge to solve basic and applied problems. The peer-review system is the benchmark of the scientific process. An academic conflict of interest could occur if an individual interferes with the peer-review process for some type of intangible personal gain. For example, bias can cause a reviewer to respond positively to a manuscript because it presents results favoring a method or production in which the reviewer has a personal interest or a reviewer may act to delay the publication of a competitor's manuscript in order to strengthen his or her own chances for publication or funding.

These are intangible interests, and they are indigenous to every researcher. Indeed, the drive for recognition can be overwhelming, particularly when a future position or livelihood depends on these public achievements.

Other Types of Conflicts of Interest


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In addition to academic conflicts of interest, there are other intangible conflicts that can compromise objectivity. For example, conflicts of commitment, which may also be called conflicts of effort or conflicts of obligation, occur when the extent of time spent on a secondary activity competes with the time expected to be spent on teaching, research, or service by the primary employer.

A conflict of conscience occurs when personal beliefs influence objectivity in research. For example, a scientist may have a particular view on abortion that influences his or her view of the scientific merit of a study that uses human embryonic stem cells.

Clinical Research

Clinical researchers subscribe to three basic elements: scientific integrity, patient safety, and investigator objectivity. Yet these researchers are likely to experience conflicts of interest by virtue of their altruistic dedication to the pursuit of knowledge while striving to maintain the welfare of the human volunteers participating in their investigations. Bias and decreased objectivity are of particular concern in the clinical-research setting, where the rewards and risks are both potentially great. Here, bias in judgment might creep in not only to influence the questions pursued and the choice of research design but also to affect the selection and retention of research participants, the reporting and attribution of adverse events, and the collection, statistical analysis, interpretation, and reporting of the data. In assessing conflicts of interest, we need to consider the likelihood of bias as well as the consequences of the conflict of interest, because at times the consequences can be lethal.

Safeguards

The scientific method includes a series of steps to ensure that the results of any study are unprejudiced and repeatable. These steps include: identifying a problem through observation, formulating a hypothesis, testing the hypothesis through data collection and analysis, and deriving a conclusion that either confirms or fails to confirm the hypothesis.

Fortunately, there are safeguards that can be put into place to help reduce bias and improve objectivity. Conscientious application of the scientific method is one such safeguard. For clinical trials, randomized controlled trial designs ,a Data and Safety Monitoring Board (DSMB) may be required. Vigilance is always necessary.

The Commercialism of Clinical Research

The research community has long recognized academic conflicts of interest. Lately, however, there has been a sea change within the research enterprise, whereby the accelerating commercialization of biomedical research is of mounting concern. A few statistics are telling: research-and-development investments by pharmaceutical companies increased from $1.3 billion in 1977 to $32 billion in 2002, a 24-fold increase in just 25 years, and PhRMA companies alone spent more on pharmaceutical R. & D. than the total 2002 NIH (USA) operating budget of $24 billion.


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Clearly, commercialism is driving the scientific establishment, and this, indeed, can be beneficial. Yet the intertwining of academic research and commercial interests can lead to financial conflicts of interest. A financial conflict of interest involves some type of financial payment, such as a consulting fee, equity in a company, or other monetary reward, which influences an individual to prefer one outcome to another. Any of these can be problematic if they are related to the product under study or the sponsor of the research.

Financial conflicts of interest are considered tangible conflicts, because they can be seen and measured. While they appear easier to deal with than intangible conflicts of interest, they may not be. Financial arrangements with sponsors are affecting many areas of scientific life. A growing literature is documenting, with disturbing accounts, how the new entrepreneurial environment is altering the publication practices and prescribing patterns of investigators and clinicians.

Intangible conflicts of interest, as previously described, are problematic, but they are widely recognized and shared. What has captured the attention of the scientific community and the public are those conflicts caused by money and financial relationships, the tangible conflicts of interest. Many fear that the cost of these relationships could be the integrity of science itself.

Note: To resolve any conflict of interest including but not limited to Scientific Misconduct, Plagiarism, Fraud, Authorship issues, Data Ownership, Misconduct, Redundant Publications or any other dispute, IRB/EC will meet to resolve any outstanding issues.

3.4 AUTHORSHIP

Introduction

The goal of research and scholarly publication is the timely dissemination of information to

scholars, students, and the general public in order to engage them in the challenge of discovery,

enhancement of knowledge and the improvement of life. In turn, authorship to a scholarly and

research publication has come to serve the academic profession as a highly dependable

recognition of merit.

Academic success and promotions are judged by the number of quality publications in peer-

reviewed journals. These are considered to be the main determinants of academic grading in

higher education. Therefore, the pressure to publish is such that researchers are often tempted to

be co-authors in a paper without having made substantial intellectual and scientific contribution.

This issue is not unique to Pakistan. Groups of researchers and editors all over the world have

been suggesting mechanisms and defining criteria to resolve issues related to authorship. The

International Committee of Medical Journals Editors, (ICMJE, also known as the Vancouver

group) drew up guidelines based on the principal that each author should be able to define-the-

work and to defend-the-work publicly. These guidelines may be summarized as:


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Authorship should be based only on a substantial contribution to:

� Conception and design or analysis and interpretation of data.

� Drafting the article or revising it critically for important intellectual content and

� Final approval of the version to be published.

All the above criteria must be met. Participation solely in the collection of data, supervision of

study activity, or acquisition of funding does not constitute authorship.

ICMJE criteria (2000) require that ‘each author should have participated sufficiently in the work

to take public responsibility for appropriate portions of the content. One or more authors should

take responsibility for the integrity of the work as a whole, from inception to published article.

Fields like Nursing Research and Education have adopted very similar guidelines for authorship.

The American Psychological Association Manual (APA Manual) further clarifies that the order

of assigned authorship should reflect the relative contributions to the work and not the relative

status of the individuals.

Objectives and Principles:

The institution’s Authorship Guidelines seek to establish a clear and sound framework for the

encouragement of invention, innovation, creative work and technological development. It

provides a framework for managing the institution’s authorship policy objectives, which are:

I. Establish and enhance the climate for innovation and invention;

II. Foster a healthy environment for education, research and development;

III. Avoid disputes over attribution of academic credit;

IV. Recognize respective rights of faculty, students and research staff to

authorship of publishable material towards which they have made significant

contributions.

General principles regarding authorship

4.3.1 Authorship credit must be assigned only to those whose

contributions are substantial.

4.3.2 Each author should have participated in formulating the research

problem, designing and implementing the study, interpreting the

results, writing and reviewing the research paper, and should be

prepared to defend the publication against criticism. All authors are

publicly accountable for the content and conclusions of the paper.


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4.3.3 The order of authorship should reflect the relative contributions of

various participants in the project. The intellectual and substantive

contributions of research team members to the project should be

stated on all papers and presentations resulting from the project.

An editor may request written documentation of each author’s

contribution.

4.3.4 If participants of a research project have contributed equally, and

no one person can be identified as having a more significant role

than others, then the group may consider representing themselves

by a corporate (collective) title (if acceptable to the relevant

journal). The article should then carry a footnote containing the

names and contributions of individuals represented by the

collective title.

4.3.5 In the case of equal contributions to a publication, authorship may

also be assigned by listing names alphabetically, with a qualifying

statement that all contributions are equal.

4.3.6 In a project that may lead to multiple publications, each

investigator may take turns to be the first author on at least

one publication, provided his/her contribution to all

publications is equal. This may be determined based on the

level of individual involvement and interests in a particular

aspect of the study. Please refer to section 7.0 for further

guidance.

4.3.7 Individuals who make substantial contributions to a paper but are

not project team members may be recognized as an author.

4.3.8 Gift [1] and ghost [2] authorship are strictly not acceptable.

4.3.9 Contributions of those who are not co-authors (such as those

providing technical assistance or those involved in data

collection) must be acknowledged.

4.3.10 The investigative team and funding source must be acknowledged

on all papers and presentations resulting from the project.

4.3.11 Titles for papers and presentations must be discussed by the

research team to avoid overlaps, omissions and controversy.


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4.3.12 Before being submitted, the paper should be reviewed by the

Principal Investigator (PI) if this person is not an author on the

paper.

4.3.13 Authors should notify the editor if they have published or

submitted elsewhere for publication the same or a substantially

similar manuscript if a transfer of copyright is involved.

4.3.14 All authors should sign the letter of transmittal and copyright

release form. (It is not sufficient for one author to do so on behalf

of the others).

Gift authorship: is defined as co-authorship awarded to a person who has not contributed

significantly to the research project. Junior researchers often feel pressured to accept or assign

honorary authorship to their supervisors or senior co-workers who have substantial powers over

their future career. In addition, young investigators may feel the need to increase their

publication list quickly in order to secure their next job or they believe that including more

experienced colleagues as authors will increase their chances of publication. Senior researchers

assign gift authorship as repayment for favors or for encouraging collaboration and maintaining

good working relations. Regardless of the cause, gift authorship is an unacceptable practice for

academic publications.

Ghost authorship: is defined as the failure to award authorship to a person who has contributed

significantly to the research project. Ghost authorship may come about because of differences in

the criteria that junior and senior researchers use to define authorship, a decline in work ethics

during the course of the project or a change in the work environment. Contributors who leave the

project before its closure are often deprived of authorship. Regardless of the cause, ghost

authorship is an unacceptable practice for academic publications.

Co-authorship between Faculty and Students: General principles

Authorship is not presumed to be a right obtained by association with a research project, without

significant contribution. It is to everyone's benefit that there is a clear understanding about

potential joint authorship roles whenever there is research collaboration among faculty and

students, whether the latter are assigned as apprentices, students in a class, hired assistants, or

any other role. Initial arrangements can always be re-discussed should circumstances change; for

example, if the student contributes more to the project than originally anticipated.

1 Principal authorship and other publication credits must accurately reflect the

relative scientific or professional contributions of the individuals involved,

regardless of their relative status.


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2 Under no circumstance may a student at SCM publish data owned by SCM or

SCM faculty without permission from the relevant body or faculty member for the

relevant project.

3 The person who conceptualized the project, secured the funding, developed the

research instruments, etc., should review any publication or other public

presentation from the project and give his/her permission if something from the

project is to be published without his or her name on it.

4 A student is presumed to have authorship of his or her master’s thesis and/or

doctoral dissertation and is encouraged to publish any part or all of the approved

thesis or dissertation unless there have been some prior restrictions to which the

student has agreed (e.g. that authorship must be shared with others contributing to

the project or to wait for a jointly authored or edited book combining several

theses). However, students must inform the supervisors of their intention to

publish.

5. If a student expects to be sole author on publications based on all or part of his/her

thesis research, this should be discussed in advance with the supervisor and an

early agreement in writing must be reached.

6. When a significant amount of additional research is required to produce

publishable material, or when the student contributes little to the writing of the

paper, the supervisor may be the first author. Its up to the supervisor to make the

student write up his own work. In basic sciences the supervisor is ALWAYS the

last author known as the senior author and is usually the corresponding author.

7. When a group of students work together on a project and their relative

contributions are equal, they should consider representing themselves by a

collective title, or list the names alphabetically with a qualifying statement that

the contributions are equal. The requirements of the journal itself will determine

the relevant option.

8. Individuals who are not enrolled in a graduate program but are employed as

research assistants should not expect joint authorship of their supervisor's

publications, unless they have made a significant original contribution to the

research program.

9. Data gathered for a research project or a program of research under a PI (using a

grant or otherwise) may not be used by students or collaborators without the PI's

permission, unless they have been made part of a public archive. In either case,

proper acknowledgements are imperative.


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10. It is impossible to anticipate all potential problems. Mutual respect, trust and clear

communication forestall difficulties. Please refer to the ‘Dispute Resolution’

section below for further direction.

Dispute Resolution:

If a dispute or concern arises with respect to authorship, the student, researcher and his/her

supervisor should first try to resolve any differences amicably. If a discussion with the supervisor

does not resolve the problem, several avenues of dispute resolution within the student’s/

researcher’s section can be approached in the following order:

� Head of the section

� Research Center

� IRB/EC

Strategy for determining authorship

As scientific research becomes more multi-disciplinary in nature, individual contributions of all

authors must be specified and perhaps a strategy for assigning credit when publishing should be

adopted. The procedure developed by Digiusto, 1994, and Ahmed et al., 1997 can serve as

guidelines and details can be obtained from research and training center.


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4- FINANCIAL ASPECTS OF RESEARCH PROPOSAL

4.1 BUDGET

1 All research proposals incur (overhead) costs subject to the use of various hospital facilities

during the course of the project (It is very unusual for any research project that involves

human subjects requiring clinical care to carry Zero budget!).

2 These expenses are the consequence of using various hospital/college services needed over

and above that which are offered routinely to a patient with the same medical condition who

is not a study participant.

3 Identifying an estimated budget cost will enable companies supporting research to fund the

project appropriately. For this reason it is very important to get advice regarding the

overhead cost estimation, which should include also the various hospital services, used for

the study.

4.2 FUNDING SOURCES

The Research Department shall offer funding for the research projects if and when

appropriate.

The other potential sponsors are:

� Pharmaceutical Industry (profit institutions).

� National and International Granting bodies in Pakistan and abroad.

� Other donor/sponsorship sources (non-profit organizations).

� Individuals (e.g. private patients).

4.3 RECEIPT & DISBURSEMENT OF RESEARCH FUNDS

1 For self directed research with no contractual obligation for defined outcomes, grant money

should go to the Research Center account for disbursement to the PI and indirect costs be

charged at an agreed percentage and rest given on as needed basis to PI and the study team

but no direct remuneration to be paid to the PI by the Sponsoring organization.

2 If the grant is contractual (government, private sector) setting specific terms regarding

research outcomes and proprietary rights, then an agreed percentage overhead will be

charged and rest should be used for direct costs and remuneration to PI and the study related

staff at a predetermined rate.


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3 The revenue from overheads should be distributed to college/university administration,

research center, and department to which PI belong at an agreed rate.

4.4 COST ESTIMATION

(Please complete FORM-C for cost estimation)

In order to know ways how to handle overhead costs for a research project estimation of

overhead cost and subsequent management of generated funds for a research proposal should

include:

1 Pathology and laboratory investigations.

2 Other diagnostic studies (Cardiopulmonary, EEG, ECHO, etc.).

3 Medical imaging procedures.

4 Pharmacy-including drug dispensing costs.

5 Clinic visits.

6 Physician’s time and input.

7 Nursing Services.

8 SCMRC costs

9 Patient related costs (transportation, etc.).

10 Other costs.

11 An approved price list for the above will be available at the Research office. In addition the

list will be available for each section head.

12 The cost of various procedures relevant to the proposed research will be provided to the

principal investigator on request through the chairman or head of his/her section.

13 Research proposals not funded by external donor organizations should be charged at actual

cost of consumable and incurred cost born by the sponsor (see please next point).

4.5 RESEARCH FUND MANAGEMENT

To allow the Research center to monitor funds made available by funding agencies, the following policies and procedures should be considered:


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1 All funds generated through industry or other donor bodies should be received and accounted for by Research Office assigned budget/accounts office (financial audit).

2 A Research Cost Centre has been established for this reason.

3 All agreements/ contracts/MOU’s will be signed between the Research Office on behalf of the institution and the Sponsoring Organization. All payments/grants/funds will be received in the name of “Shifa Foundation” which will be deposited in the Research Fund and then disbursed as per section 5.3. The Agreements/Contracts/MOU’s should have the signatures of the concerned Principal Investigator along with the relevant departments approval involved in the services.

4 Generated funds from support services will be utilized to support the costs of such

services (future researchers and/or needs for the services i.e. equipment).

4.6 AGREEMENTS/CONTRACTS/MOU’s

1. All Agreements/Contracts/MOU’s shall be signed and negotiated by the Research Office and the Sponsoring Organizations.

2. Research Office shall mediate all correspondences between the P.I and the Sponsoring

Organizations. 3. An Agreement will be signed between the Research Office and the P.I for all sponsored

research outlining various financial heads.


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5. NON-FACULTY RESEARCH APPOINTMENTS

RESEARCH MEDICAL OFFICERS

All Medical Officers hired for Research activities and any other study related staff shall be appointed/hired directly by the Research Office. Functional and administrative reporting of all Research Medical Officers and other research related staff will also be to the Research Office. Projects/tasks will be assigned by the Research Office to the RMO’s who in turn will work in close collaboration with the concerned Consultants for successful initiation and timely completion of the proposed research studies. All RMO’s will be required to submit weekly reports of study progress to the Research Office Note: All study related appointments (when and if required after careful assessing the need by the Research Office) will be made by the Research Office in an open and transparent fashion after being approved by the Medical Director. ADMINISTRATIVE SUPPORT STAFF AND LOGISTICS/EQUIPMENT

The Research Office will formulate a competent team which will assist in day to day operations and functioning of the Research Office.


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6. REGULATORY COMPLIANCE

WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI

Introduction

1 The World Medical Association has developed the Declaration of Helsinki as a statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects includes research on identifiable human material or identifiable data.

2 It is the duty of the physician to promote and safeguard the health of the people. The physician's knowledge and conscience are dedicated to the fulfillment of this duty.

3 The Declaration of Geneva of the World Medical Association binds the physician with the words, "The health of my patient will be my first consideration," and the International Code of Medical Ethics declares that, "A physician shall act only in the patient's interest when providing medical care which might have the effect of weakening the physical and mental condition of the patient."

4 Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects.

5 In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society.

6 The primary purpose of medical research involving human subjects is to improve prophylactic, diagnostic and therapeutic procedures and the understanding of the etiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, and therapeutic methods must continuously be challenged through research for their effectiveness, efficiency, accessibility and quality.

7 In current medical practice and in medical research, most prophylactic, diagnostic and therapeutic procedures involve risks and burdens.

8 Medical research is subject to ethical standards that promote respect for all human beings and protect their health and rights. Some research populations are vulnerable and need special protection. The particular needs of the economically and medically disadvantaged must be recognized. Special attention is also required for those who cannot give or refuse consent for themselves, for those who may be subject to giving consent under duress, for those who will not benefit personally from the research and for those for whom the research is combined with care.

9 Research Investigators should be aware of the ethical, legal and regulatory requirements for research on human subjects in their own countries as well as applicable international requirements. No national ethical, legal or regulatory requirement should be allowed to reduce or eliminate any of the protections for human subjects set forth in this Declaration.

Basic Principles For All Medical Research

1 It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject.

2. Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant


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sources of information, and on adequate laboratory and, where appropriate, animal experimentation.

3. Appropriate caution must be exercised in the conduct of research which may affect the environment, and the welfare of animals used for research must be respected.

4. The design and performance of each experimental procedure involving human subjects should be clearly formulated in an experimental protocol. This protocol should be submitted for consideration, comment, guidance, and where appropriate, approval to a specially appointed ethical review committee, which must be independent of the investigator, the sponsor or any other kind of undue influence. This independent committee should be in conformity with the laws and regulations of the country in which the research experiment is performed. The committee has the right to monitor ongoing trials. The researcher has the obligation to provide monitoring information to the committee, especially any serious adverse events. The researcher should also submit to the committee, for review, information regarding funding, sponsors, institutional affiliations, other potential conflicts of interest and incentives for subjects.

5. The research protocol should always contain a statement of the ethical considerations involved and should indicate that there is compliance with the principles enunciated in this Declaration.

6. Medical research involving human subjects should be conducted only by scientifically qualified persons and under the supervision of a clinically competent medical person. The responsibility for the human subject must always rest with a medically qualified person and never rest on the subject of the research, even though the subject has given consent.

7. Every medical research project involving human subjects should be preceded by careful assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others. This does not preclude the participation of healthy volunteers in medical research. The design of all studies should be publicly available.

8. Physicians should abstain from engaging in research projects involving human subjects unless they are confident that the risks involved have been adequately assessed and can be satisfactorily managed. Physicians should cease any investigation if the risks are found to outweigh the potential benefits or if there is conclusive proof of positive and beneficial results.

9. Medical research involving human subjects should only be conducted if the importance of the objective outweighs the inherent risks and burdens to the subject. This is especially important when the human subjects are healthy volunteers.

10. Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research.

11. The subjects must be volunteers and informed participants in the research project. 12. The right of research subjects to safeguard their integrity must always be respected. Every

precaution should be taken to respect the privacy of the subject, the confidentiality of the patient's information and to minimize the impact of the study on the subject's physical and mental integrity and on the personality of the subject.

13. In any research on human beings, each potential subject must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the discomfort it may entail. The subject should be informed of the right to abstain from participation in the study or to withdraw consent to participate at any time without reprisal.


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After ensuring that the subject has understood the information, the physician should then obtain the subject's freely-given informed consent, preferably in writing. If the consent cannot be obtained in writing, the non-written consent must be formally documented and witnessed.

14. When obtaining informed consent for the research project the physician should be particularly cautious if the subject is in a dependent relationship with the physician or may consent under duress. In that case the informed consent should be obtained by a well-informed physician who is not engaged in the investigation and who is completely independent of this relationship.

15. For a research subject who is legally incompetent, physically or mentally incapable of giving consent or is a legally incompetent minor, the investigator must obtain informed consent from the legally authorized representative in accordance with applicable law. These groups should not be included in research unless the research is necessary to promote the health of the population represented and this research cannot instead be performed on legally competent persons.

16. When a subject deemed legally incompetent, such as a minor child, is able to give assent to decisions about participation in research, the investigator must obtain that assent in addition to the consent of the legally authorized representative.

17. Research on individuals from whom it is not possible to obtain consent, including proxy or advance consent, should be done only if the physical/mental condition that prevents obtaining informed consent is a necessary characteristic of the research population. The specific reasons for involving research subjects with a condition that renders them unable to give informed consent should be stated in the experimental protocol for consideration and approval of the review committee. The protocol should state that consent to remain in the research should be obtained as soon as possible from the individual or a legally authorized surrogate.

18. Both authors and publishers have ethical obligations. In publication of the results of research, the investigators are obliged to preserve the accuracy of the results. Negative as well as positive results should be published or otherwise publicly available. Sources of funding, institutional affiliations and any possible conflicts of interest should be declared in the publication. Reports of experimentation not in accordance with the principles laid down in this Declaration should not be accepted for publication.

Additional Principles For Medical Research Combined With Medical Care

1. The physician may combine medical research with medical care, only to the extent that the research is justified by its potential prophylactic, diagnostic or therapeutic value. When medical research is combined with medical care, additional standards apply to protect the patients who are research subjects.


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2. The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.1

3. At the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.2

4. The physician should fully inform the patient which aspects of the care are related to the research. The refusal of a patient to participate in a study must never interfere with the patient-physician relationship.

5. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic methods do not exist or have been ineffective, the physician, with informed consent from the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic measures, if in the physician's judgment it offers hope of saving life, re-establishing health or alleviating suffering. Where possible, these measures should be made the object of research, designed to evaluate their safety and efficacy. In all cases, new information should be recorded and, where appropriate, published. The other relevant guidelines of this Declaration should be followed.

6.2 ENVIORENMENTAL HEALTH AND SAFETY

Biohazard in Research

Introduction Research may involve biohazardous agents and may generate biohazardous waste. This section pertains to the safe handling, and disposal of such materials. Definition A biological hazard, also known as a biohazard, is an organism or a by-product from an organism that is harmful or potentially harmful to other living things, primarily human beings in that it is potentially infectious. Common types of biological hazards include bacteria, viruses, or toxins that were created by a particular organism or microorganism. The "biohazard symbol" is a familiar sight in hospitals, and any object that carries it should be treated with extreme caution. Biohazard Symbol


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Biohazard Levels: The United States' Center for Disease Control and Prevention http://en.wikipedia.org/wiki/Centers_for_Disease_Control_and_Prevention (CDC) categorizes various diseases in levels of biohazard, Level 1 being minimum risk and Level 4 being extreme risk. Biohazard Level 1: Bacteria and viruses including Bacillus subtilis , canine hepatitis, E.coli, varicella ( chicken pox), as well as some cell cultures and non-infectious bacteria. At this level precautions against the biohazardous materials in question are minimal, most likely involving gloves and some sort of facial protection. Usually, contaminated materials are left in open (but separately indicated) waste receptacles. Decontamination procedures for this level are similar in most respects to modern precautions against everyday viruses (i.e. washing one's hands with anti-bacterial soap, washing all exposed surfaces of the lab with disinfectants, etc.). In a lab environment, all materials used for cell and/or bacteria cultures are decontaminated via autoclave. Biohazard Level 2: Bacteria and viruses that cause only mild disease to humans, or are difficult to contract via aerosol in a lab setting, such as hepatitis A, B, and C, influenza A, Lyme disease, salmonella, mumps, measles, scrapie, dengue fever, and HIV. Routine diagnostic work with clinical specimens can be done safely at Biosafety Level 2, using Biosafety Level 2 practices and procedures. Research work (including co-cultivation, virus replication studies, or manipulations involving concentrated virus) can be done in a BSL-2 (P2) facility, using BSL-3 practices and procedures. Biohazard Level 3: Bacteria and viruses that can cause severe to fatal disease in humans, but for which vaccines or other treatments exist, such as anthrax, West Nile virus, SARS virus, variola virus (smallpox), tuberculosis, typhus, Rift Valley fever, Rocky Mountain Spotted fever , yellow fever and malaria. Among parasites Plasmodium falciparum which causes Malaria, and Trypanosoma cruzi, which causes trypanosomiasis, also come under this level. Biohazard Level 4: Viruses and bacteria that cause severe to fatal disease in humans, and for which vaccines or other treatments are not available, such as Bolivian and Argentine hemorrhagic fevers, Dengue hemorrhagic fever, Marburg virus, Ebola virus, hantaviruses, Lassa fever, Crimean-Congo hemorrhagic fever, and other hemorrhagic diseases. When dealing with biological hazards at this level the use of a Hazmat suit and


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a self-contained oxygen supply is mandatory. The entrance and exit of a Level Four biolab will contain multiple showers, a vacuum room, an ultraviolet light room, autonomous detection system, and other safety precautions designed to destroy all traces of the biohazard. Multiple airlocks are employed and are electronically secured to prevent both doors opening at the same time. All air and water service going to and coming from a Biosafety Level 4 (P4) lab will undergo similar decontamination procedures to eliminate the possibility of an accidental release.

Biosafety Levels:

Biosafety Level 1:

This level is suitable for work involving well-characterized agents not known to consistently cause disease in healthy adult humans, and of minimal potential hazard to laboratory personnel and the environment ( mentioned as Biohazard Level 1). Precautions against the biohazardous materials in question are minimal as mentioned in para above. Laboratory personnel have specific training in the procedures conducted in the laboratory and are supervised by a scientist with general training in microbiology or a related science. Biosafety Level2: This level is similar to Biosafety Level 1 and is suitable for work involving agents of moderate potential hazard to personnel and the environment ( mentioned as Biohazard Level 2) . It requires that: 1. laboratory personnel have specific training in handling pathogenic agents and are

directed by scientists with advanced training; 2. access to the laboratory is limited when work is being conducted 3. extreme precautions are taken with contaminated sharp items 4. certain procedures in which infectious aerosols or splashes may be created are

conducted in biological safety cabinets or other physical containment equipment Biosafety Level 3

This level is applicable to clinical, diagnostic, teaching, research, or production facilities in which work is done with indigenous or exotic agents which may cause serious or potentially lethal disease after inhalation. It includes various bacteria, parasites and viruses that can cause severe to fatal disease in humans but for which treatments exist, such as Leishmania, Mycobacterium tuberculosis, Bacillus anthracis, Chlamydophila

psittaci, as well as viruses mentioned above ( Biohazard Level 3). All procedures involving the manipulation of infectious materials are conducted within biological safety cabinets, specially designed hoods, or other physical containment devices, or by personnel wearing appropriate personal protective clothing and equipment. The laboratory has special engineering and design features. It is recognized, however, that some existing facilities may not have all the facility features recommended for Biosafety Level 3 (i.e., double-door access zone and sealed penetrations). In this circumstance, an acceptable level of safety for the conduct of routine procedures, (e.g., diagnostic procedures involving the propagation of an agent for identification, typing, susceptibility testing, etc.), may be achieved in a biosafety level 2 (P2) facility, providing:


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1. the filtered exhaust air from the laboratory room is discharged to the outdoors, 2. the ventilation to the laboratory is balanced to provide directional airflow into the

room, 3. access to the laboratory is restricted when work is in progress, and 4. the recommended Standard Microbiological Practices, Special Practices, and Safety

Equipment for Biosafety Level 3 are rigorously followed. Biosafety Level 4

This level is required for work with dangerous and exotic agents that pose a high individual risk of aerosol-transmitted laboratory infections, agents which cause severe to fatal disease in humans for which vaccines or other treatments are not available ( mentioned above as Biohazard Level 4). Safety measures are mentioned above. Agents with a close or identical antigenic relationship to Biosafety Level 4 agents are handled at this level until sufficient data is obtained either to confirm continued work at this level, or to work with them at a lower level. Members of the laboratory staff have specific and thorough training in handling extremely hazardous infectious agents and they understand the primary and secondary containment functions of the standard and special practices, the containment equipment, and the laboratory design characteristics. They are supervised by qualified scientists who are trained and experienced in working with these agents. Access to the laboratory is strictly controlled by the laboratory director. The facility is either in a separate building or in a controlled area within a building, which is completely isolated from all other areas of the building. A specific facility operations manual is prepared or adopted. Building protocols for preventing contamination often use negatively pressurized facilities, which, if compromised, would severely inhibit the containment of an outbreak of aerosol pathogens. Within work areas of the facility, all activities are confined to Class III biological safety cabinets, or Class II biological safety cabinets used with one-piece positive pressure personnel suits ventilated by a life support system. Biohazardous Waste

Biohazardous waste, also called infectious waste or biomedical waste, is any waste containing infectious materials or potentially infectious substances such as blood. Of special concern are sharp wastes such as needles, blades, glass pipettes, and other wastes that can cause injury during handling. The biohazardous waste generated may also contain radioactive material and/or hazardous chemicals.

Types of Biohazardous Waste

Biohazardous waste includes the following materials: 1. Human blood and blood products: All human blood, blood products (such as

serum, plasma, and other blood components) in liquid or semi-liquid form. Items contaminated with blood that, if compressed, would release blood in a liquid or semi-


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liquid form, or items caked with dried blood capable of being released during handling.

2. Human Body Fluids: Human body fluids in a liquid or semi-liquid state, including:

semen, vaginal secretions, cerebral spinal fluid, synovial fluid, pleural fluid, pericardial fluid, peritoneal fluid, amniotic fluid, and saliva from dental procedures. Also includes any other human body fluids visibly contaminated with blood.

3. Microbiological Wastes: Laboratory wastes containing or contaminated with

concentrated forms of infectious agents. Such waste includes discarded specimen cultures, stocks of etiologic agents, discarded live and attenuated viruses, blood or body fluids known to contain infectious pathogens, wastes from the production of biologicals and serums, disposable culture dishes, and devices used to transfer, inoculate and mix cultures.

4. Pathological waste: All human tissues, organs, and body parts, including waste biopsy materials, tissues, and anatomical parts from surgery, procedures, or autopsy. Any unfixed human tissue, except skin.

5. Animal waste: All animal carcasses, body parts, and any bedding material from

animals known to be infected with, or that have been inoculated with human pathogenic microorganisms infectious to humans.

6. Sharps waste: Includes needles, blades etc contaminated with blood or above

mentioned hazardous waste . As these items may cause injury special precautions are required for their disposal .They must be treated, packaged, labelled, and transported in separate labelled containers.

Responsibilities of Researcher

Research protocols that generate bio hazardous waste must incorporate the following: 1. Steps ensuring that the waste is correctly treated and disposed off.

2. Packaging of the waste to prevent exposure or injury (needle sticks, cuts) to

anyone handling the waste.

3. Labelling of the waste with the research project’s / researchers name and location within the hospital. Biohazard Waste Minimization

Biohazard waste bags should be used for bio hazardous materials only and not for regular trash. Disposal of non-biohazard waste in a biohazard waste container adds significant costs to waste management.


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The following are examples of items that do not need to be disposed as biohazard waste: 1. Gloves used to handle containers of blood or body fluids;

2. Paper towels or bench paper on which containers of blood or body fluids may

have been placed but did not spill.

3. Any other material used to handle blood indirectly but that did not come into direct contact with the blood.

Disinfecting and Disposing of Bio hazardous Liquids

Bio hazardous liquids and liquids that contain human blood should be disinfected and flushed down the drain. Do not attempt to disinfect solutions that contain a large amount of whole blood to avoid clot formation. To disinfect small amounts: 1. Add a disinfectant such as Wescodyne (iodophor) or Clorox (hypochlorite) until the

solution of disinfectant and waste liquid is one part disinfectant to five parts waste liquid.

2. Make sure there are no bubbles in the solution. 3. Let the solution stand for at least 30 minutes. 4. Pour the solution down the drain with cold water. 5. If using any other disinfectant solution ensure recommended contact time.

Preparing Bio hazardous Waste for Autoclaving or Disposal

Bio hazardous (infectious) wastes that cannot be treated as above include large amounts of protein or clotted blood. Containers of protein, stock solutions, clotted blood, etc., should be steam-sterilized in an infectious waste autoclave dedicated for this purpose.

Labelling

Each bag of bio hazardous waste must be labelled with: 1. The department /location/ room in which the waste was generated, and 2. The date the waste was packaged. Using a permanent marker the information should be written directly on the waste bag.

Packaging

Dry, solid bio hazardous waste must be placed in an autoclave bag. Bags should be closed or covered when not in use or at the end of the day. Do not fill bag more than halfway to allow for a five-inch grip. Tie the bag tightly before transporting.


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Transporting

Bio hazardous waste to be autoclaved must be transported to an autoclave within 14 days of first generating the waste. The use of a cart is recommended for transporting biohazard waste. All bags must be deposited in red, covered holding containers. The waste must be logged in at the autoclave room in a logbook. Plastic Pipette Disposal

Plastic pipettes may be used in many laboratory based research projects. When contaminated, they may be safely disposed of in either an autoclave bag or a sharps container. If not contaminated, intact plastic pipettes should be disposed of in a laboratory glass box for disposal in regular garbage,

Bag Disposal of Plastic Pipettes Contaminated with Biohazardous Material

To dispose of contaminated plastic pipettes in a bag, the pipettes must be intact, placed in clear autoclave biohazard bags and double-bagged. A broken plastic pipette is always considered a sharp, and therefore must be disposed of in a sharps container. Sharps Waste

Sharps include: 1. Needles (whether or not attached to a syringe or covered by a plastic guard); 2. IV tubing with needle attached; 3. Glass Pasteur pipettes; 4. Disposable glass pipettes; 5. Glass slides and cover slips; 6. Scalpels, razor blades, and lancets; and 7. Broken glass and splintered plastic, when contaminated with blood or other potentially

infectious material. Non-contaminated broken lab glass and plastic such as beakers and bottles are NOT considered sharps for disposal purposes.

Categories of Sharps Waste

Sharps waste categories include: 1. Sharps, which are either contaminated or not contaminated with biological material; 2. Radioactive sharps, which are sharps contaminated with radioactive material; and


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3. Chemical sharps (e.g. broken mercury thermometers, or syringes contaminated with chemotherapy drugs). Laboratory glassware is not considered sharps waste for disposal purposes, but may be sharp enough to puncture normal garbage bags and endanger waste handlers. Lab glass includes items such as broken glass beakers or bottles, plastic pipettes and pipette tips. Sharps Waste Minimization

Although sharps containers are often conveniently placed throughout the hospital, it is important to remember these containers are for sharps waste only, and are not to be used for non-sharp biohazard waste or regular trash. Disposal of non-sharp biohazard waste in a sharps container adds significant costs to waste management. The following are examples of items that should not be disposed of as sharps waste: 1. Gloves; 2. Paper towels; 3. Lab glass (includes plastic pipettes and pipette tips); 4. Chemical bottles; 5. Petri dishes or culture plates 6. Plastic vials and conical tubes.

Sharps Waste Disposal Procedures

Sharps are collected in standard sharps containers. The standard (non-radioactive, non-

chemical) sharps waste pickup procedure is as follows: 1. When sharps container is 2/3 to 3/4 full, secure the lid. 2. With a permanent marker, write the project name, number, location and date on the sharp container. 3. Place the sharps container in the hallway for pickup by Housekeeping staff.

Radioactive Sharps Waste Disposal Procedures

Radioactive sharps are collected in standard sharps containers 1. It should be labelled with a radioactive waste label, 2. When possible, isotopes should be segregated in separate radioactive sharps containers. 3. When sharps container is 2/3 to 3/4 full, secure the lid. 4. Arrange for disposal according to existing hospital/ national protocol.

Chemical Sharps Waste Disposal Procedures

Chemical sharps such as broken mercury thermometers or syringes contaminated with chemotherapy agents must not be disposed of in regular red sharps containers.

Special Instructions for Residual Cytotoxic Waste


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Residual cytotoxic waste is any item contaminated with chemotherapy agents, also called antineoplastic or chemotherapeutic agents. Such items most often include contaminated needles, vials, intravenous tubing, bottles and bags, linen, masks, gloves, and lab coats. Wastes containing more than residual amounts (such as non-empty vials or syringes) must be segregated and collected as hazardous chemical waste as described above Residual cytotoxic waste must be separated and disposed of differently from other hazardous chemical wastes and biohazard waste.

Accumulation Solids, including sharps, contaminated with residual cytotoxic wastes should be collected in rigid plastic yellow chemotherapy waste containers or other properly-labelled rigid and leak proof containers. Standard red sharps containers must not be used. Yellow chemotherapy waste bins should be available. Labelling If using a container other than a yellow chemotherapy waste container, it must be clearly labelled Residual Cytotoxic Waste. All containers must be labelled with the project, patient ID date, and location. Collection When the box is full, secure the lid for pickup. Do not place the container in the hallway, and do not autoclave cytotoxic waste.

Disposal options for Cytotoxic Waste

Incineration at high temperatures: Full destruction of all cytotoxic substances may require temperature up to 1200°C. Incineration at lower temperatures may result in the release of hazardous cytotoxic vapours into the atmosphere. Modern double-chamber pyrolytic incinerators are suitable, provided that a temperature of 1200°C with a minimum gas residence time of 2 seconds or 1000°C with a minimum gas residence time of five seconds can be achieved in the second chamber. The incinerator should be fitted with gas cleaning equipment. Incineration is also possible in rotary kilns designed for thermal decomposition of chemical wastes, in foundries, or in cement kilns, which usually have furnaces operating well in excess of 850°C. Incineration is most common by municipal incinerators. Single-chamber incinerators or open-air burning is inappropriate for the disposal of cytotoxic waste. Chemical degradation:

Chemical degradation methods which convert cytotoxic compounds into non-toxic/non-

genotoxic compounds can be used not only for drug residues but also for cleaning of

contaminated urinals, spillages, and protective clothing. The methods are appropriate for

developing countries. Most of these methods are relatively simple and safe; they include

oxidation by potassium permanganate (KMnO4) or sulfuric acid (H2SO4), denitrozation

by hydrobromic acid (HBr), or reduction by nickel and aluminium. The International

Agency for Research on Cancer (IARC) may be contacted for further information.


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7 OTHERS

1.1 INFORMED CONSENT

GUIDELINES FOR DRAFTING AN INFORMED CONSENT FORM

A. Basic elements of informed consent in seeking informed consent the following

information shall be provided to each subject:

(1) A statement that the study involves research, an explanation of the purposes of the

research and the expected duration of the subject's participation, a description of the

procedures to be followed, and identification of any procedures which are experimental.

(2) A description of any reasonably foreseeable risks or discomforts to the subject.

(3) A description of any benefits to the subject or to others which may reasonably be

expected from the research.

(4) A disclosure of appropriate alternative procedures or courses of treatment, if any, that

might be advantageous to the subject.

(5) A statement describing the extent, if any, to which confidentiality of records identifying

the subject will be maintained.

(6) For research involving more than minimal risk, an explanation as to whether any

compensation and an explanation as to whether any medical treatments are available if

injury occurs and, if so, what they consist of, or where further information may be

obtained.

(7) An explanation of whom to contact for answers to pertinent questions about the research

and research subjects' rights, and whom to contact in the event of a research-related

injury to the subject; and

(8) A statement that participation is voluntary, refusal to participate will involve no penalty

or loss of benefits to which the subject is otherwise entitled and the subject may

discontinue participation at any time without penalty or loss of benefits to which the

subject is otherwise entitled.


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B. Additional elements of informed consent. When appropriate, one or more of the

following elements of information shall also be provided to each subject:

(1) A statement that the particular treatment or procedure may involve risks to the subject (or

to the embryo or fetus, if the subject is or may become pregnant) which are currently

unforeseeable.

(2) Anticipated circumstances under which the subject's participation may be terminated by

the investigator without regard to the subject's consent.

(3) Any additional costs to the subject that may result from participation in the research.

(4) The consequences of a subject's decision to withdraw from the research and procedures

for orderly termination of participation by the subject.

(5) A statement that significant new findings developed during the course of the research

which may relate to the subject's willingness to continue participation will be provided to

the subject; and.

(6) The approximate number of subjects involved in the study

Note: All Informed Consent Forms must be in English and Urdu language or any other

language that the subject understands


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7.2 CHECK LIST FOR COMPLETION OF INFORMED CONSENT FORM

A statement that the study involves research

An explanation of the purposes of the research

The expected duration of the subject's participation

A description of the procedures to be followed

Identification of any procedures which are experimental

A description of any reasonably foreseeable risks or discomforts to the subject

A description of any benefits to the subject or to others which may reasonably be expected from the research

A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject

A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained

For research involving more than minimal risk, an explanation as to whether any compensation, and an explanation as to whether any medical treatments are available, if injury occurs and, if so, what they consist of, or where further information may be obtained

Research Qs

Rights Qs

Injury Qs

An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject

A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits, to which the subject is otherwise entitled

Additional elements, as appropriate

A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant), which are currently unforeseeable

Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent

Any additional costs to the subject that may result from participation in the research

The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject

A statement that significant new findings developed during the course of the research, which may relate to the subject's willingness to continue participation, will be provided to the subject

The approximate number of subjects involved in the study


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7.3 RESEARCH INVOLVING PREGNANT WOMEN OR FETUSES

Pregnant women or fetuses may be involved in research if all of the following conditions are met:

(a) Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on non-pregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses.

(b) The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means.

(c) Any risk is the least possible for achieving the objectives of the research.

(d) If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, her consent is obtained in accord with the informed consent provisions of subpart A of this part;

(e) If the research holds out the prospect of direct benefit solely to the fetus then the consent of the pregnant woman and the father is obtained in accord with the informed consent provisions of subpart A of this part, except that the father's consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest.

(f) Each individual providing consent under paragraph (d) or (e) of this section is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate;

(g) For children who are pregnant, assent and permission are obtained in accord with the provisions of subpart D of this part;

(h) No inducements, monetary or otherwise, will be offered to terminate a pregnancy;

(i) Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy; and

(j) Individuals engaged in the research will have no part in determining the viability of a neonate.

7.4 RESEARCH INVOLVING NEONATES


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(a) Neonates of uncertain viability and nonviable neonates may be involved in research if all of the following conditions are met:

(1) Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data for assessing potential risks to neonates.

(2) Each individual providing consent under paragraph (b) (2) or (c) (5) of this section is fully informed regarding the reasonably foreseeable impact of the research on the neonate.

(3) Individuals engaged in the research will have no part in determining the viability of a neonate.

(4) The requirements of paragraph (b) or (c) of this section have been met as applicable.

(b) Neonates of uncertain viability. Until it has been ascertained whether or not a neonate is viable, a neonate may not be involved in research covered by this subpart unless the following additional conditions have been met:

(1) The IRB determines that:

(i) The research holds out the prospect of enhancing the probability of survival of the neonate to the point of viability, and any risk is the least possible for achieving that objective, or

(ii) The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no added risk to the neonate resulting from the research; and

(2) The legally effective informed consent of either parent of the neonate or, if neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent's legally authorized representative is obtained in accord with subpart A of this part, except that the consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest

(c) Nonviable neonates. After delivery nonviable neonate may not be involved in research covered by this subpart unless all of the following additional conditions are met:

(1) Vital functions of the neonate will not be artificially maintained;

(2) The research will not terminate the heartbeat or respiration of the neonate;

(3) There will be no added risk to the neonate resulting from the research;


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(4) The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means; and

(5) The legally effective informed consent of both parents of the neonate is obtained in accord with subpart A of this part, except that the waiver and alteration provisions of §46.116(c) and (d) do not apply. However, if either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the informed consent of one parent of a nonviable neonate will suffice to meet the requirements of this paragraph (c)(5), except that the consent of the father need not be obtained if the pregnancy resulted from rape or incest. The consent of a legally authorized representative of either or both of the parents of a nonviable neonate will not suffice to meet the requirements of this paragraph (c) (5).

(d) Viable neonates. A neonate, after delivery, that has been determined to be viable may be included in research only to the extent permitted by and in accord with the requirements of subparts A and D of this part.

7.5 RESEARCH INVOLVING, AFTER DELIVERY, THE PLACENTA, THE DEAD

FETUS OR FETAL MATERIAL

(a) Research involving, after delivery, the placenta; the dead fetus; macerated fetal material; or cells, tissue, or organs excised from a dead fetus, shall be conducted only in accord with any applicable local laws and regulations regarding such activities.

(b) If information associated with material described in paragraph (a) of this section is recorded for research purposes in a manner that living individuals can be identified, directly or through identifiers linked to those individuals, those individuals are research subjects and all pertinent subparts of this part are applicable.


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7.6 FORM-A

Shifa International Hospital, Shifa College of Medicine& Shifa College of Nursing

Research APPLICATION FORM ____________________________________________________________________________________ Research Department Office: Sector H-8/4 Islamabad Fax: Pakistan Email: [email protected] Located at Department of Medical Staff Affairs ____________________________________________________________________________________

A. Submission Category: (Please check all that apply).

New Protocol: (Study never performed. Include all documents listed in Section B.)

Renewal or Modifications (Please complete Form “B”)

(Study has previously been approved by IRB. Include the IRB Approval letter.

Check all that apply:

Informed Consent Protocol Data Collection Form Other _______________

Application for

Full Review Expedite Review Exempt Review

B. Checklist

Two Copies of Research Proposal Application Form with Checklist

Two Copies of Research Protocol

Two Copies of Data Collection Forms (surveys, questionnaires, telephone scripts, data collection)

Two Copies of Patient Information Sheet and Informed Consent Form English with Urdu Translation Curriculum Vitae And/ Or Other Relevant Documents Evidencing Qualifications of Investigator(S) And Sub-Investigator(S) and all other study team members Approval from the Departmental Head Any additional document that require approval

Copy of this application and study documents filed for personal record

Research Department Ref #

Date Received


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A. COVER PAGE

TITLE OF PROPOSAL

TYPE OF PROJECT

Human Chart Review Diagnostic Therapeutic Laboratory Others

PRINCIPLE INVESTIGATOR OTHER STUDY TEAM MEMBERS

Principal Investigator: (Person noted as Principal Investigator in the IRB approval notice.) PI’s Name (Degree) ___________________________________________________________________________ Department & Division ________________________________________________________ Tel No: _______________________ Fax: __________________________ Email: ________________________ Other Study Team Members

Name & Qualification Title/Position Department Signature

B. ABSTRACT

WHAT IS THE SIGNIFICANCE OF THE STUDY? (Please give a brief background of the study)


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WHAT ARE THE OBJECTIVES OF THE STUDY?

DESCRIPTION OF METHODS USED IN PROTOCOL

SELECTION CRITERIA (Inclusion& Exclusion Criteria)


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DURATION OF THE STUDY

ADVERSE/SERIOUS ADVERSE EFFECTS / POTENTIAL HAZARDS

(Explain how these events would be managed and who will bear the cost?)

POTENTIAL RISK OF THE RESEARCH (To the participating subjects or community as a whole)


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POTENTIAL BENEFIT OF THE RESEARCH (To the participating subjects of community as a whole)

C. SOURCE OF FUNDING

Funds Required (Complete Budget Form C)

Sponsored Please specify the name of the funding source: ___________________________________________

D. SERVICES

Will services at SIH & SCM be utilized which are not considered part of routine medical care?

No Yes

IF yes please check appropriate box

Cath Lab Medical Records Non-Invasive Cardiology

CT Scan Services MRI Nursing/Patient Care

General Radiology Pharmacy Nuclear Medicine

Laboratory Ultrasound

Other special Services or Equipment: (please specify) _______________________________

Payment of Arrangements: If “Yes” is checked in the above section, an explanation of payment arrangements is

required and must be included with this submission packet

E. SETTINGS/FACILITIES TO BE USED FOR THE STUDY (In case of multi-centered studies, kindly list the name of participating centers/countries) (Please check all that apply)


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Inpatient Outpatient

Shifa Department (Please specify) ___________________________________________

F. EXPLAIN WHAT MEASURES WILL BE TAKEN TO SAFEGUARD PATIENT’S/SUBJECT’S

CONFIDENTIALITY.

G. OTHER STUDY RELATED INFORMATION

H. REFERENCES

I. DEPARTMENTAL APPROVAL

I agree to accept responsibility for the scientific and technical conduct of the proposed research and

submission of progress reports if this application is approved. I agree to submit study progress report to the

Research Department and inform the IRB of any new information.

PRINCIPLE INVESTIGATOR

NAME: ________________________________________________ SIGNATURE & STAMP ____________________________________ DATE: _________________________________________________


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DESIGNATION: __________________________________________ DEPARTMENT: __________________________________________ MAILING ADDRESS: ______________________________________ TEL. NO: _______________________________________________ FAX: ___________________________________________________ EMAIL ADD: _____________________________________________

APPROVAL OF DEPARTMENTAL HEAD

I feel that beds and other facilities (if applicable) are adequate. I approve the participation of the concerned

personnel of my department in this study. I hereby approve that there are no potential conflicts within the

department prior to final submission.

NAME: _______________________________________________ SIGNATURE & STAMP: ___________________________________ DATE: ________________________________________________ DESIGNATION: _________________________________________ DEPARTMENT: _________________________________________ MAILING ADDRESS: _____________________________________ TEL NO: ______________________________________________ FAX: _________________________________________________ EMAIL ADD: ___________________________________________

7.7 FORM B

MODIFICATIONS/AMENDMENTS TO RESEARCH PROPOSAL

This form is only applicable for requiring approval on amendments/changes in protocol and other study documents.

(Please attach the original IRB approval letter along with this form)

Research Center Ref #

Date Received Revision No.


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STUDY TITLE:

The following documents have amendments (Please attach the list of amendments/changes along

with this form).

Protocol Data Collection Form

Informed Consent Form Others ____________________

Principle Investigator

Name: ______________________________________________

Designation: _________________________________________

Department: _________________________________________

Signatures & Stamp: ___________________________________

Date: _______________________________________________

7.8 FORM C

BUDGET FORM (ESTIMATES FOR SUPPORT REQUESTED)

Note: The form should be completed if funds are requested from the Research Department, especially for those research proposals dealing with human subjects requiring clinical care.

S. No

BUDGET

CATEGORY

REMARKS

ESTIMATED

COSTS

1. Laboratory (specify)

2. Equipment (specify)


Date Received


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3. Radiology

4. Pharmacy

5. Clinic Visits

6. Nursing

7. Inpatient Days

8. Supplies

9. Consultant Fees

10. Additional Personnel

11. Patient Costs

12. Publication Costs

13. Miscellaneous (specify)

TOTAL

Is there an external sponsor of this study? YES NO

If YES, please specify & also provide details of Financial Disclosure ________________________________

7.9 FORM D

POTENTIAL HAZARDS AND TOXICITY

(Please complete this form if there the study involves toxic or hazardous material)

Proposed Title:

______________________________________________________________________________

______________________________________________________________________________

____________________________________________________________


Date Received


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1. Does the proposed research involve any toxic chemical? Yes No

If yes, name chemicals and describe the nature of hazard involved.

____________________________________________________________________________

____________________________________________________________________________

Also indicate how the safety measures will be taken in the use and disposal of these agents.

____________________________________________________________________________

____________________________________________________________________________

2. Does the proposed research involve any hazardous microorganism? Yes No

If yes, name the organisms and describe the nature of hazards expected.

____________________________________________________________________________

____________________________________________________________________________

Also describe facilities, safety measures and procedures to protect personnel and environment.

____________________________________________________________________________

____________________________________________________________________________

3. Does the proposed research involve the radioactive materials? Yes No

If yes, describe the materials, half-life and methods of disposal and personnel protection.

_____________________________________________________________________________


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_____________________________________________________________________________

4. Does the proposed research involve recombinant DNA? Yes No

If yes, are you familiar with NIH guidelines and do you have the containment

facilities? Yes No

Describe the nature of genes to be cloned, organisms and plasmids to be used.

____________________________________________________________________________

Principal Investigator: _____________________________ Date: ___________________

7.10 REGULATORY COMPLIANCE

CORRESPONDENCES

For all Research Projects/studies, communication, correspondences etc. between

researchers and organizations/institutions/companies shall be made through the Research Office.

CONSULTANTS

We welcome and encourage all faculty/consultants/trainees to come forward with their ideas for research, or proposals for research to the Research Office for review, discussion and formulation of an action plan for successful initiation and timely completion of desired studies.


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We shall provide investigators upon communication, with requirements for research in the form of Research medical officers (after careful assessment of project proposal and need and approval by the Research Office and the Medical Director) who will aid/assist the consultants in their research activities. Your initial communication, i.e. to discuss research projects should be with the head of the department; upon an acquired approval, a research officer will be assigned to the case. The officer will aid in the development of a protocol (proposal) for the research project under supervision of the consultant, and upon completion, this proposal must be approved by the head of the concerned department and IRB/EC. This will be done in the form of a document stating that the research proposal has been reviewed and the project has been given the green signal, signed and dated. While we recognize that all clinical data pertaining to patients at this hospital are the brain work of all our consultants, to protect the patients and the consultants all data review/ collection shall only be made possible after approval of the relevant research project. These patients are under the care of the doctors at Shifa Intl Hospital Ltd and as such their clinical data is hospital property; their privacy is our responsibility as is protecting our consultants. The data belongs to the hospital and reviewing mass amounts of data shall require permission from the IRB/Research Department. Should the collected data be of a sensitive nature, its usage shall be restricted to those that are allowed to view it under the approval of the IRB. All permissions must be documented for official purposes.

POST GRADUATE RESIDENTS

While we encourage all residents to take part in research activities to broaden their horizons, all research activity must require co-sponsoring by a consultant/faculty. We will make ourselves available to help all residents in designing their studies and choosing the best path for conducting research. As required for senior doctors, residents/trainees are also not exempt from their share of paper work and shall be required to submit all documentation for review following approval of their proposed research. While we shall make ourselves available to the residents, we encourage residents to write their own proposals and do their own literature reviews so that they develop and learn how to formulate study designs for research. For the purpose of data collection, and analysis we are available.


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As and when possible, our center will hold workshops for all residents to help them strengthen their competency in research, its conduct and publishing articles. We shall make every effort to involve residents so as to hone their skills in research.

LAB, RADIOLOGICAL, PHARMACY & MEDICAL RECORD

SERVICES

� For research projects requiring services like lab, radiology, MRI/CT scan etc a separate study specific cost code should be created so that study related expenses are not charged from patients pocket and are charged directly to that specific cost centre. � All labs etc for pure academic studies should be done at a discounted rate.

� A Central hospital lab services should be used for all research projects

� Shifa local lab should be the lab of priority for all research projects. Utilization

of external labs should only be encouraged when certain tests cannot be performed locally. � Dedicated Pharmacy services may be assigned for research projects

� Dedicated area in the Medical record room may be established to store and archive study

files/documentation.

8- GUIDELINES FOR RESEARCH

WHAT IS RESEARCH?

“Research” is defined as:

"A systematic investigation, including research development, testing and evaluation, designed to

develop or contribute to generalizable knowledge.”

WHY SHOULD ONE CONDUCT RESEARCH?

Conducting research: � Contributes to the greater good of medicine


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� Expands personal and profession knowledge Clinical research is a tremendous learning process. Participating in, or conducting research as a Resident may spark an interest that otherwise may not have been apparent. Going through the Process may also lead to a greater appreciation for the work and effort involved in the studies Evaluated and incorporated into one’s practice throughout one’s career. TYPES OF RESEARCH:

Clinical research comes in two flavors:

i. Observational Research ii. Experimental Research

i. Observational research study:

An observational study is just as it sounds: passive observation of study participants. Participants can be followed over time, known as a cohort, or be examined at one-point in time, known as cross-sectional. Another type of observational study is the case-controlled study. This is typically a case report comparing those with and without a particular condition. Cohort and case-controlled studies can be retrospective or prospective. A retrospective study looks back in time at a defined sample and collects data about predictor variables after outcomes have occurred.

A prospective study follows events into the future for a select period of time for a sample defined by the researcher with predictor variables measured before outcomes have occurred and outcome variables measured as they occur. Observational studies are passive in that they do not involve manipulation of the variables. A variable can be what is being measured (outcome), or what helps to define the participants (predictor). Observational studies often provide data for larger experimental clinical trials. Cohort studies help provide incidence of a variable, whereas cross-sectional studies provide prevalence of a variable. Cohort studies can lead to more detailed research design, can provide data for hypothesis and insight into risk factors.

ii. Experimental research:

In experimental clinical research, we actively manipulate the independent variables and then


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measure the effects of this manipulation on the dependent variables2. Experimental clinical research studies tend to assess the effectiveness of an intervention. A randomized, blinded trial is the gold standard for establishing the causality and effectiveness of an intervention. Many physicians and scientists will not read or consider a clinical trial unless it is blinded. Blinding describes a process by which information that could skew the results, or introduce bias, is withheld from either just the participants (“single-blinded”), or both the participants and experimenters (“double-blinded”). Including a control group is another way to decrease the bias of the end results. Having half the subjects receive a sham protocol, the other half actual. A randomized study involves the random allocation of different interventions (or treatments) to subjects. Randomization ensures that known and unknown confounding factors are evenly distributed between treatment groups, or the treatment and control groups. NON INTERVENTIOANL STUDY

Non-interventional study: To classify a study as non-interventional, it must meet all of The following criteria: • Are studies involving products with a marketing authorization that are prescribed in the usual manner and used in accordance with the authorization? • When the patient is assigned to a therapeutic strategy within current practice and not according to a protocol; • The diagnostic or monitoring procedures are only those ordinarily applied to the therapeutic strategy; • Epidemiological methods are used to analyze the data.

PHASES OF CLINICAL TRIALS

Clinical trials involving new drugs are commonly classified into four phases. Each phase of the

drug approval process is treated as a separate clinical trial. The drug-development process will

normally proceed through all four phases over many years. If the drug successfully passes

through Phases I, II, and III, it will usually be approved by the national regulatory authority for

use in the general population. Phase IV are 'post-approval' studies.

Before pharmaceutical companies start clinical trials on a drug, they conduct extensive pre-

clinical studies.

Pre-clinical studies


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It involves in vitro (test tube or cell culture) and in vivo (animal) experiments using wide-

ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic

information. Such tests assist pharmaceutical companies to decide whether a drug candidate has

scientific merit for further development as an investigational new drug.

Phase 0

Phase 0 is a recent designation for exploratory, first-in-human trials conducted in accordance

with the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory

Investigational New Drug (IND) Studies. Phase 0 trials are also known as human microdosing

studies and are designed to speed up the development of promising drugs or imaging agents by

establishing very early on whether the drug or agent behaves in human subjects as was expected

from preclinical studies. Distinctive features of Phase 0 trials include the administration of single

subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather

preliminary data on the agent's pharmacodynamics (what the drug does to the body) and

pharmacokinetics (what the body does to the drugs).

A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause

any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug

candidates in order to decide which has the best pharmacokinetic parameters in humans to take

forward into further development. They enable go/no-go decisions to be based on relevant

human models instead of relying on sometimes inconsistent animal data.


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Phase I

Phase I trials are the first stage of testing in human subjects. Normally, a small (20-100) group of

healthy volunteers will be selected. This phase includes trials designed to assess the safety

(pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These

trials are often conducted in an inpatient clinic, where the subject can be observed by full-time

staff. The subject who receives the drug is usually observed until several half-lives of the drug

have passed. Phase I trials also normally include dose-ranging, also called dose escalation,

studies so that the appropriate dose for therapeutic use can be found. The tested range of doses

will usually be a fraction of the dose that causes harm in animal testing. Phase I trials most often

include healthy volunteers. However, there are some circumstances when real patients are used,

such as patients who have terminal cancer or HIV and lack other treatment options. "The reason

for conducting the trial is to discover the point at which a compound is too poisonous to

administer." Volunteers are paid an inconvenience fee for their time spent in the volunteer

centre.

There are different kinds of Phase I trials:

SAD

Single Ascending Dose studies are those in which small groups of subjects are given a single

dose of the drug while they are observed and tested for a period of time. If they do not exhibit

any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe

values, the dose is escalated, and a new group of subjects is then given a higher dose. This is

continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side

effects start showing up (at which point the drug is said to have reached the Maximum tolerated

dose (MTD).

MAD

Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics &

pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives

multiple low doses of the drug, while samples (of blood and other fluids) are collected at various

time points and analyzed to understand how the drug is processed within the body. The dose is

subsequently escalated for further groups, up to a predetermined level.

Food effect

A short trial designed to investigate any differences in absorption of the drug by the body, caused

by eating before the drug is given. These studies are usually run as a crossover study, with

volunteers being given two identical doses of the drug on different occasions; one while fasted,

and one after being fed.

Phase II


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Once the initial safety of the study drug has been confirmed in Phase I trials, Phase II trials are

performed on larger groups (20-300) and are designed to assess how well the drug works, as well

as to continue Phase I safety assessments in a larger group of volunteers and patients. When the

development process for a new drug fails, this usually occurs during Phase II trials when the

drug is discovered not to work as planned, or to have toxic effects.

Phase II studies are sometimes divided into Phase IIA and Phase IIB.

• Phase IIA is specifically designed to assess dosing requirements (how much drug should

be given).

• Phase IIB is specifically designed to study efficacy (how well the drug works at the

prescribed dose(s)

Some trials combine Phase I and Phase II, and test both efficacy and toxicity.

Trial design

Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a

selected group of patients. Other Phase II trials are designed as randomized clinical trials, where

some patients receive the drug/device and others receive placebo/standard treatment.

Randomized Phase II trials have far fewer patients than randomized Phase III trials.

Phase III

Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000

or more depending upon the disease/medical condition studied) and are aimed at being the

definitive assessment of how effective the drug is, in comparison with current 'gold standard'

treatment. Because of their size and comparatively long duration, Phase III trials are the most

expensive, time-consuming and difficult trials to design and run, especially in therapies for

chronic medical conditions.

It is common practice that certain Phase III trials will continue while the regulatory submission is

pending at the appropriate regulatory agency. This allows patients to continue to receive possibly

lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials

at this stage include attempts by the sponsor at "label expansion" (to show the drug works for

additional types of patients/diseases beyond the original use for which the drug was approved for

marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies

in this phase are by some companies categorized as "Phase IIIB studies."

While not required in all cases, it is typically expected that there be at least two successful Phase

III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the

appropriate regulatory agencies such as FDA (USA), or the EMA (European Union), for

example.


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Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined

into a large document containing a comprehensive description of the methods and results of

human and animal studies, manufacturing procedures, formulation details, and shelf life. This

collection of information makes up the "regulatory submission" that is provided for review to the

appropriate regulatory authorities in different countries. They will review the submission, and, it

is hoped, give the sponsor approval to market the drug.

Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper

recommendations and guidelines, but in case of any adverse effects being reported anywhere, the

drugs need to be recalled immediately from the market. While most pharmaceutical companies

refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical

trials in the market.

Phase IV

Phase IV trial is also known as Post-Marketing Surveillance Trial. Phase IV trials involve the

safety surveillance (Pharmacovigilance) and ongoing technical support of a drug after it receives

permission to be sold. Phase IV studies may be required by regulatory authorities or may be

undertaken by the sponsoring company for competitive (finding a new market for the drug) or

other reasons (for example, the drug may not have been tested for interactions with other drugs,

or on certain population groups such as pregnant women, who are unlikely to subject themselves

to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over

a much larger patient population and longer time period than was possible during the Phase I-III

clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer

sold, or restricted to certain uses

DESIGNING A RESEARCH PROJECT

For those with limited to no research experience, designing a research project may seem like the most daunting of all the tasks involved. Seeking guidance from your mentor and people with research experience early in this process is paramount. Where to begin? How do you get to the end? What falls in between? Attacking the research design in a systematic fashion will help clarify the whole process. What is the question? Why is it significant? What will you measure to support your hypothesis? Who will participate? How many participants will you need? How will the data be analyzed? The answers to these questions form an outline for your research project, and need to be included in your proposal. Once the proposal is written, the process that ensues will be much clearer. Parts of a study design include: • Hypothesis • Background


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• Methods

And The Question Is…

First off, what interests you? This project will encompass many hours over the next two to three years, so you don’t want to become sick of it. Rather, try to find something you are passionate about. The objective of the study is encompassed by the hypothesis.. The hypothesis is based on a theory you are trying to prove or disprove. Brainstorm questions that need to be answered to support the study hypothesis. How feasible is it to measure or obtain data about these questions? What is the significance of your hypothesis? How will society benefit from your research? Will it act as a stepping stone for other projects? Will your question be able to be reproduced or replicated? What is the relevance to medical society, pathophysiology and current treatment regimens? Have other studies been done that had hypotheses similar to yours? If so, what were their strengths and weaknesses? Did they leave questions unanswered, or do you want to challenge the outcomes? This information may be included in the introduction or background section of the proposal write-up, but it also plays an important role in helping to form the question you will be investigating. Background

This is where performing a literature review starts to pay off. This section helps to support the theory behind the hypothesis. Include prior studies and relevant outcomes. Include pathopysiology or anatomical correlates. The BACKGROUND sets the stage and will help illicit support for the hypothesis. Methods - What/How To Measure

Now that a question exists, outcomes and how they will be measured need to be selected. If your question is, “What effect does osteopathic manipulation have on the management of knee osteoarthritis?” you need to establish some outcome to measure – daily pain scale, quality of life, amount of medication taken. All are examples of outcome variables. How you measure outcome variables depends on whether you are assessing a dichotomous or a continuous relationship. A dichotomous variable is one for which there are only two possible outcomes. Dichotomous would mean, yes, there was less daily pain on visual analogue scale, or no, there was not less pain on visual analogue scale, OR less amount of medication taken over a seven-day period versus no decrease in medication over a seven-day period. A dichotomous variable does not address the amount of decrease on pain scale or amount of medication taken, just whether there was a change. Dichotomous variables (absolutes such as “Was daily pain decreased?


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Yes/No”) provide less information and require a larger sample sizes. Data will be analyzed by a chi- squared test. Continuous outcome variables are measured via a t-test. They can achieve a greater power with a smaller sample size when compared to dichotomous data. Predictor and outcome variables can be classified into quantitative or categorical variables (1). A quantifiable variable is: 1) continuous, quantified on an infinite scale or 2) ordered discrete, quantified on a finite scale. Categorical variables are classified into categories. If there are only two categories, such as: dead or alive, then this is termed “dichotomous” category. If there are more than two categories this is termed “polychotomous” and is further divided into nominal, such as blood type, and ordinal, such as degree of pain. When designing your study, variable

types help determine how much power your results will have and the efficiency in obtaining

those results. Continuous variables typically give you more “bang for your buck” – more power with a smaller sample size because they offer more information. Methods - subject participation – who, where, how long?

This section will tackle sample size first. Sample size calculation is quite important, because too little and the data will lack power, and too large and your study is inefficient. There does come a point where after a certain sample size, the increase in the power to support the study is no longer significant and more work will be done than gains received.

Do This In The Preliminary Design Phase

Who?

Deciding how you will select or recruit for the study’s sampling population is of great importance. Limiting bias is of course a major factor. Accessing data bases at hospitals, medical offices, public health agencies or relying on other physicians for referrals are all viable options. A captured audience, i.e. nursing home or hospitalized patients offer easy access, though may result in poor follow-up if the study is for an extended period of time and obtaining consent may be more difficult. Of course, a study that is blinded (single or double) has greater strength. Exclusion/Inclusion criteria should be consistent with other published studies. This will allow for greater ease of comparing the studies for outcome efficacy at a later date. Also, keep in mind who you want to generalize the study to. This takes you back to the question phase, i.e. what is the significance of the study, who will be effected by the results, how will the results contribute to our medical understanding or public health policy? The more exclusion criteria involved, the less the study will be generalized. Where?

Where will your project take place? How easy is it to get to? If at a hospital or nursing home, you will need to obtain permission from that particular facility. Obtaining permission in writing is necessary for your IRB application. How long?

You need to figure out how long participants will be committed to the project. The longer a


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project extends, the more likely it is that participants will drop out you need to keep in mind the goal of completing the project. If you are conducting an experimental trial, that translates to 12 months to recruit or obtain participants, conduct study protocol, collect data, have the data analyzed and complete your paper. If you are performing a prospective study measuring outcomes yet to occur, keeping the 12-month time crunch is important as well.

Methods - Data Analysis

This is where all your hard work pays off. Unless you have experience in this arena, finding someone to assist you will be so very helpful. Contact the Biostatistician at the Research center early in your design phase to obtain sample size calculation and to discuss the best way to analyze your prospective data. You also need to have a plan as to how or where you will keep the collected data. It is important to ensure patient confidentiality. Their intake info should be kept in a locked cabinet. You will want to design some sort of computerized data base for electronic storage of the collected information


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DETAILED INSTRUCTIONS FOR PREPARING

RESEARCH PROPOSAL

Please submit ORIGINAL COPY, & email a copy to [email protected]

Cover Page. Please complete all details in the forms provided. Abstract of Proposed Research. Briefly and clearly outline objective, methods and significance of study. (Recommended length – 200 words)

Purpose of Proposed Investigation and Its Significance. A brief description of the immediate and long term goals and purpose of the research, and its significance to human health in general, and to health problems in the Kingdom of Saudi Arabia in particular. (maximum 1 page)

Background Information:

a) Relevant information about the disease (maximum 2 pages)

b) Current status of research on this problem, including literature review (maximum 3 pages)

c) Any previous work done by the investigator (maximum 1 page)

Methods. This is a very important section for a proper evaluation of the scientific merit and feasibility of the proposal. Please include adequate and concise information on the items listed below. (maximum 4 pages)

For clinical studies

a) Patient selection and exclusion criteria b) Methods and procedures of the study, treatment schedule, safety precautions c) Pre-treatment evaluation d) Evaluation during and after study e) Criteria for removal from study f) Attach Flow sheet and data gathering forms

For Laboratory Studies

a) Experimental plan and design b) Analytical and other methods to be used

Statistical Methods a) State number of patients or experiments required b) End point of Study c) Method of Analysis

References to be listed: In addition please select a set of the most relevant references to your research and make it available to the RC members. The principal investigator should submit the reference package to the library. A file title “Research File” is designated for this purpose.


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Budget: If financial support is required, the following should be provided: a) Detailed budget (see attached form) b) Justify request. Explain requirement for personnel and time required. If personnel on site,

approval of supervisor.

Facilities to be used: State whether facilities are available and what additional facilities are required. (maximum one page)

Work Plan: The work plan should clearly state, in graphic term if necessary, the sequence of major events during the progress of the research. This should include a projected time frame and utilization of personnel and support, and the methods to be used for monitoring and evaluating the progress of this project. (maximum one page)

Organization and Management: The plan should clearly state the organization structure and the role and responsibilities of the key personnel and the methods of supervision. (Maximum one

page)

Informed Consent Form: Attach copy of consent form to be translated into Arabic on approval**

Departmental Approval: Approval of all Section head/Chairman of the concerned personnel and facilities involved (see attached form)

Potential Hazards and Toxicity: Fill up attached form.

Curriculum Vitae: (including publications) of Principal Investigators and Co-Investigators should be attached. Complete the “Investigator Personal Data Form” or attach signed and

dated C.V

** The IRB/ Ethics Committee must approve Informed Consent Form.


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9- REFERENCES

1. Ahmed SM, Maurana CA, Engle J, Uddin DE, Glaus KD. A method for assigning

authorship in multi-authored publications. Fam Med. 1997; 29(1): 42-4

2. American Psychological Association. 4th ed, 1994. Publication Manual of the American

Psychological Association. Washington, DC: APA

3. Bhopal R, Rankin J, McColl E, Thomas L, Kaner E, Stacy R, Pearson P et al. The vexed

question of authorship: views of researchers in a British medical faculty. BMJ. 1997; 314:

1009-012

4. Digiusto E. Equity in authorship: A strategy for assigning credit when publishing. Soc

Sci Med. 1994; 38(1): 55-8

5. Erlen JA, Siminoff LA, Sereika SM, Sutton LB. Multiple authorship: Issues and

recommendations. J Professional Nursing. 1997; 13(4): 262-70

6. Huth EJ. Guidelines on authorship of medical papers. Ann Intern Med. 1986; 104: 269-74

7. International Committee of Medical Journal Editors. Guidelines on authorship. BMJ.

1985; 291: 722

8. King CR, McGuire DB, Longman AJ, Carroll-Johnson MR. Peer review, authorship,

ethics, and conflict of interest. J Nursing Scholarship. 1997; 29(2): 163-7

9. Mowatt G, Shirran L, Grimshaw JM, Rennie D, Flanagin A, Yank V, MacLennan,G et al.

Prevalence of Honorary and Ghost Authorship in Cochrane Reviews. JAMA.

2002;287:2769-71

10. Nehring WM, Durham JD. Multiple authorship in nursing. Nurse Educator. 1986; 11(1):

15-8

11. Smith R. Authorship: time for a paradigm shift? BMJ. 1997; 314: 992

12. Yank V, Rennie D. Disclosure of researcher contributions: A study of original research

articles in The Lancet. Ann Intern Med. 1999: 130: 661-70

13. http://www.upenn.edu/grad/authorpolicy_alpha.html

Accessed on December 15, 2005. Contains elaborate information on authorship

guidelines for faculty members and students at the University of Pennsylvania, USA.

14. http://www.mcgill.ca/research-policies/sponsored/policies/ethics/

Accessed on December 15, 2005. Contains research policies and ethics (including

authorship guidelines) outlined by McGill University, Canada.

15. The Belmont Report: The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979

16. The Nuremberg code. Trials of War Criminals before the Nuremberg Military Tribunals

under Control Council Law No. 10, Vol. 2, pp. 181-182. Washington, D.C.: U.S. Government Printing Office, 1949

17. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. (http://www.wma.net/en/30publications/10policies/b3/) accessed on May 1st, 2011.

18. Australian code of practice for the care and use of animals for scientific purposes, National Health and research Council, Australia. 7th edition, 2004