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Presentation at the Health Research Methodology Course organized by
the Pediatrics Research Committee Princess Nourah University held on 08 January
2024 by Professor Omar Hasan Kasule Sr. MB ChB (MUK), MPH (Harvard),
DrPH (Harvard) Chairman of the Research Ethics Committee KAAUH
Objectives:
►
Main
objective:
1. To learn about the key concepts of ethical conduct of
research
►
Sub-objectives:
1. To understand informed consent in pediatrics assent or
dissent and subject respect
2. Managing conflict of interest: Industry
funding/Confidentiality, ruth and accuracy in reporting results
3. Plagiarism
4. Steps in submitting to PNU REB
Contents:
► Define research priorities and purposes (5%)
► Explain research ethics codes: Nuremberg, Helsinki,
GCP (5%)
► Define the 2 major ethical issues: consent &
adverse events (5%)
► Define other ethical issues related to patient safety:
confidentiality, conflict of interest, truth telling and disclosure, research
validity, and plagiarism (5%)
► Discuss informed consent: elements and issues (10%)
► Discuss adverse events: reporting and avoidance (10%)
► Analyze and discuss practical case scenarios involving
ethical issues (60%)
Prioritizing Human Research:
► The general order of priorities is:
1. necessities, dharuraat,
2. needs, hajiyaat,
3. complimentary, mukamillaat,
4. embellishments, tahsinaat,
5. excesses, israfaat,
6. wastage, tabdhiraat.
► Medical research is a necessity (dharuraat) for
two reasons:
1. Better therapies: more effective, alternative,
cheaper, easier
2. Better physicians intellectually alive, up-to-date
knowledge, inquisitive learners.
Purposes of Human Experimentation:
► Purpose 1: preserving
morality, hifdh al ddiin
► Purpose 2: protection of
life, hifdh al nafs
► Purpose 3: protection of
progeny, hifdh al nasl
► Purpose 4: protection of the
mind, hifdh al aql
► Purpose 5: protection of
wealth, hifdh al maal
RESEARCH ETHICS CODES
Nuremberg Trials of Nazi Doctors:
The Nuremberg Code at the end of the trials:
The Nuremberg Code 1946:
► Voluntary Informed Consent
► No Random Or Unnecessary Experiments
► Animal Experiments first
► Knowledge Of Disease Natural History
► Avoiding Unnecessary Physical And Mental Suffering
► The Researchers Must Be Scientifically Qualified
► Subjects Can Withdraw At Any Time
► The Investigation Is Stopped If The Patient Is In
Danger.
Declaration of Helsinki Document 1964:
Helsinki Declaration 1962, 1996:
► Generally Accepted Scientific Principles
► Risk-Benefit Assessment
► Subject Integrity And Welfare
► Full Disclosure
Good Clinical Practice Guidelines:
► Follow ethical principles of the Helsinki declaration
► Benefits justify risks
► Rights of patient > rights and interests of society
► Prior clinical and non-clinical information
► Follow protocol
► Qualified physicians
► Free informed consent
► Confidentiality
► Good manufacturing practice
► Quality control
Sections of the GCP Manual:
► The Institutional Review Board
► The investigator
► The sponsor
► Clinical trial protocol
► Investigator brochure
Good Manufacturing Practice Guidelines:
Saudi Ethics of Research on Living Creatures:
Major Ethical Issues in Research:
►
Informed
consent / autonomy:
1. Frequently violated
2. Autonomous right to protect life, hifdh al nafs
3. Self interest in consent
4. Competence to consent
►
The
benefit-risk ratio:
1. The principle of injury, qa'idat al dharar
2. Research policy aims at minimizing risk to research
subjects
3. Report and management of adverse events
INFORMED CONSENT:
Informed Consent Checklist (Required Elements):
► Participating, supporting, or organizing institutions
and those who may benefit from the project’s results listed?
► A statement that the study involves research.
► An explanation of the purposes of the research.
► The expected duration of the participant’s
participation.
► A description of the procedures to be followed.
► Identification of any procedures which are
experimental (vs. standard care).
► A description of any reasonably foreseeable risks or
discomforts to the participant.
► A description of any benefits to the participant or to
others which may reasonably be expected from the research.
Informed Consent Checklist (Required Elements) con’t. - 1:
► A disclosure of appropriate alternative procedures or
courses of treatment, if any, that might be advantageous to the participant.
► A statement describing the extent, if any, to which
confidentiality of records identifying the participant will be maintained.
► If the research is subject to SFDA regulation, a
statement that notes the possibility that SFDA may inspect the records.
► For research involving more than minimal risk, an
explanation as to whether any compensation is available if injury occurs.
► An explanation as to whether any medical treatments
are available if injury occurs.
Informed Consent Checklist (Required Elements) con’t. - 2:
► If so, what they consist of, or where further
information may be obtained.
► An explanation of whom to contact for answers to
pertinent questions about the research and research participants’ rights.
► Who to contact in the event of a research-related
injury to the participant.
► A statement that participation is voluntary.
► A statement that refusal to participate will involve
no penalty or loss of benefits to which the participant is otherwise entitled.
Informed Consent Checklist (Required Elements) con’t. - 3:
► A statement that the particular treatment or procedure
may involve risks to the participant which are currently unforeseeable.
► The subject’s responsibilities.
► Any additional costs to the participant that may
result from participation in the research.
► The anticipated prorated payment, if any, to the
subject for participating in the trial.
► A statement that significant new findings developed
during the course of the research which may relate to the participant’s
willingness to continue participation will be provided to the participant.
Informed Consent Checklist (Required Elements) con’t. - 4:
► Anticipated circumstances under which the
participant’s participation may be terminated by the investigator without
regard to the participant’s consent.
► The approximate number of participants involved in the
study (at this site and all sites).
Issues about consent:
► Competence and capacity in research
► Oral vs written/signed consent
► Payments in research
► Withdrawal of consent
► Research without consent
SAFETY OF RESEARCH SUBJECTS AND ADVERSE EVENTS
REPORTING:
Three Main Categories of Research According to Risk:
► Exempt - no physical
human risk. Approved immediately by the chairman and one or more members.
Examples: interviews, questionnaires, information from records.
► Expedited - minimal human
risk comparable to risk of routine outpatient procedures. Can be approved by
the chairman with/without one or more members.
► Full review - major risk due
to intervention on the human body either using drugs or devices. Approval
follows discussion in a full meeting of the committee. The researchers may be
invited to explain. Experts may also be consulted.
Discussion Cases on Risk-Benefit Considerations - 1:
► A resident refused to assist his consultant in a
clinical trial on the grounds that from his personal experience the side
effects of and reaction to the experimental drug were worse than the migraine
headache. The consultant had a different view of the risk-benefit equation. The
IRB had approved the study based on similar studies overseas with no reports of
severe adverse reactions.
Discussion Cases on Risk-Benefit Considerations - 2:
► A systematic review of the literature showed that the
proposed study had already been carried out in several countries and that the
research question had been answered. The researchers still went ahead to submit
the study to the IRB which approved it on the basis that the study had not been
carried out locally.
Adverse events and protocol deviations / violations
Datix reporting:
RESEARCH ETHICS BOARD / INSTITUTIONAL REVIEW BOARD
(IRB):
The
Institutional Review Board (IRB):
► Functions of IRB: assesses protocols that have ethical
implications or has confidentiality issues, protect research subjects, protect
researcher, protect the institution, monitor conduct of the research.
► Membership of IRB: professional and lay members.
► Procedures of IRB.
► Criteria of assessing research: Informed consent,
clear objectives, sound research design, risks vs benefits, researcher
qualifications, research facilities, data security.
► Follow-up of research: reports, onsite inspections,
adverse event reports, protocol adherence.
Regulation of Research by Policies and Regulations:
► Balance between research and care delivery
► Equity and justice in research
► Ethics of funding of research
► Dissemination of knowledge and publication bias
► Research malpractice
► Conflict of interest
Steps of Submission to IRB:
► Research application form: exempt, expedited, full
review
► CV and research ethics certificate
► Research proposal/protocol with necessary attachments
eg questionnaire, case report form, informed consent form
► Amendment form
► Progress report
► Manuscript approval
► Journal submission
CASE SCENARIOS ON INFORMED CONSENT:
Consent for Children in Emergencies - 1:
► A 16-year old boy was brought into the emergency room
by the police with a severe crash injury of both lower limbs with severe life
threatening bleeding. Emergency room physicians could not control the bleeding.
Surgeons called for consultation decided on amputation. The patient overhear
the discussions and protested loudly but later became semi-conscious. Three
consultants signed the consent but before going to theater arrived and agreed
to sign to save life. She called to tell the father who refused and said he was
coming to the hospital to confront the surgeons. Time was running out with BP
falling very low despite transfusions.
Consent for Children in Emergencies - 2:
► Both parents obtained court permission to marry of
their 16-year daughter.
► She became pregnant and went into labor at the age of
17 years. Due to cephalo-pelvic disproportion labor was obstructed. She refused
cesarean section and was supported by her mother who argued that given more
time she would deliver naturally.
► After 4 hours the obstetricians diagnosed uterine
rupture accompanied by profuse bleeding with impending shock.
► The daughter was willing to accept surgery that would
be accompanied by hysterectomy to control the bleeding. The mother was in favor
but the father was vehemently opposed to an operation that would end her
obstetric career.
Discussion Cases on the Processes of Informed Consent
- 1:
► A randomized study was carried out among non-anemic
sickle call children aged 5-10 to study the impact of daily folic acid
supplementation on hemoglobin levels.
► Informed consent was obtained from both parents after
full disclosure of all facts but the children were not informed.
► A questionnaire at the end of the study surprised
researchers because the parents could not remember that any research was
carried out; they knew it was all routine medical care.
Discussion Cases on the Processes of Informed Consent
- 2:
► Parents signed informed consent after full disclosure.
Asked after two months they remembered that the research was about finding an
effective drug but could not remember the randomization of children to two
groups and were not aware that the children received different treatments.
Discussion Cases on the Processes of Informed Consent
- 3:
► Parents were informed that their child had terminal
cancer and was put on DNA.
► The parents refused participation in a randomized
trial of a new chemotherapeutic agent claiming that he had a right to refuse
and that the research was not in the interests of his child.
► The principal investigator who was a senior and famous
professor was called to convince the parents. He told them that participation
was a duty on each citizen and that it was immoral to shirk that duty. He said
‘if everybody refused to participate how can be develop new drugs?’. The
parents reluctantly signed the informed consent form.
CONFLICT OF INTEREST:
Discussion Cases on Conflict of Interests - 1:
► The local branch of the pharmaceutical companies was
very careful not to violate ethical guidelines while sponsoring physicians to
conferences overseas. They never required them to say or write anything in
favor of the company or any of its products. One day one researcher was
surprised when his young daughter complained that the family had gone on
company-sponsored summer trips to attend scientific conferences in Europe every
year for 3 consecutive years but they had not gone this year. The researcher thought
very hard; he remembered his last publication that had generated controversy
about a new drug manufactured by the pharmaceutical company. They had made no
public comment on the paper.
Discussion Cases on Conflict of Interests - 2:
► The pharmaceutical company wanted to conduct a 4th
phase study of its new unpopular headache medication and offered SAR500 to
physicians in private practice and SAR20 to physicians in public hospitals for
every patient recruited into the study. All the physician had to do was to
prescribe the drug and complete a short 5-item questionnaire. A company
representative would pick up the data sheets at the end of every day’s work.
PAYMENT TO RESEARCH SUBJECTS:
Discussion Cases on Payment to Research Subjects - 1:
► A researcher on cloning advertised in the newspapers
with wide distribution in a poor inner city neighborhood for a clinic admitting
patients with threatened abortion. If the abortion became inevitable all
procedures would be completed for free with USD3000 being given to help in the
recuperation phase. The woman would have to sign a statement releasing the
abortus for research purposes. No questions were asked about the causes of the
abortion.
Discussion Cases on Payment to Research Subjects - 2:
► A researcher interested in the effect of daily aspirin
on fine motor activity advertised for volunteers in the local newspaper with a
payment of USD50 per 10-minute visit to the study center for completing a
questionnaire and undergoing some tests. Volunteers could make as many visits
as they liked but no more than 5 in a week. The researchers were overwhelmed by
the response. They were also surprised that none of the volunteers had admitted
having gastric ulcers or reported any previous gastric problems with aspirin.
Discussion Cases on Payment to Research Subjects - 3:
► Researchers advertised for male obese youths aged
18-25 years to join a randomized study that compared dietary control to
surgical control of obesity. The surgery used was innovative including
laparotomy and surgical dissection of lipid tissue from the abdominal cavity.
Subjects undergoing surgery were each paid USD2000 before operation and USD8000
after 6 months of follow up.
RESEARCH WITHOUT CONSENT:
Discussion Cases on Research Without Consent - 1:
► Researchers wanted to study the effect of restricting
teenager’s pocket money on their cigarette addiction. Parents were randomized
to various amounts of pocket money for teenagers everyday. Observers acting as
spies hanged out with the teenagers and reported on their smoking behaviors.
IRB was asked to approve the study without disclosure of its objectives and
procedures to the teenagers because that would invalidate the results.
Discussion Cases on Research Without Consent - 2:
► The IRB refused to approve a randomized study of the
impact of explanation of the mechanisms of drug action on the response to an
analgesic because the principal investigator wanted to research without
informed consent. He argued that informed consent would involve too much
disclosure that the study would be invalidated.
Discussion Cases on Research Without Consent - 3:
► We want to research the impact of an emergency room
intervention but all patients are brought in unconscious and we cannot get
informed consent. Neither are relatives available. How can we improve our care
without research?
ISSUES OF JUSTICE IN RESEARCH:
Discussion Cases on Justice - 1:
► A heated argument arose between the principal
investigator who concluded from interim results on 15 patients that the
experimental drug made a difference (25% tumor regression in 4/7 treated vs 1/8
controls) and the statistician who wanted to recruit more patients to reach
statistical significance. The PI’s conscience was disturbed that those in the
control arm were missing out on a useful drug.
Discussion Cases on Justice - 2:
► Patients excluded from a randomized clinical trial on
valid exclusion criteria complained to the Ministry of Health because they were
denied access to a new experimental therapy available only to those in the
randomized trial. They argued that since the drug was brought using public
funds they had a right to it They had heard that the drug was known from phase
1 and phase 2 studies to be effective.
Discussion Cases on Justice - 3:
► Patients in the control arm of a randomized trial were
angry that they had not benefited from the drug that proved to be effective.
They planned to take the principal investigator to court. They argued that
animal, phase 1 and phase 2 studies had already showed the benefit of the drug.
They thought that the principal investigator misled them when he recruited them
in the phase 3 study because there was nothing new to fund out.
Discussion Cases on Justice - 4:
► The consultant warmed his resident to make sure no
women in the child bearing age are systematically excluded from a randomized
study of a new drug whose teratogenic properties were unknown.
RESEARCH IN DEVELOPING COUNTRIES:
Discussion Cases on Clinical Trials in Developing Countries - 1:
► A developing country IRB refused to allow a clinical
trial of a new antibiotic by an
international pharmaceutical company. It cited the injustice of the 10/90 gap
(10% of world research dollars are allocated to research on 90% of the world
problems) and the high cost of drugs due to the unfair patent policies and
practices. The IRB argued that the local people will not afford the new
antibiotic; why should they be used merely as guinea pigs?
Discussion Cases on Clinical Trials in Developing Countries - 2:
► An angry exchange between a Minister of Health from a
developing country and the president of an international pharmaceutical
manufacturer. The Minister accused pharmaceutical companies of exploitative and
risky research in developing countries because research regulation is weak and
standards of care are lower. The president of the pharmaceutical company
accused the developing countries of benefiting from drugs developed by exposing
first world citizens to risks of clinical trials. He said citizens of developing
countries must contribute to the research by taking some of the risk.
Discussion Cases on Clinical Trials in Developing Countries - 3:
► AZT given in the last trimester, during delivery, and
post-natally was shown to prevent neonatal HIV transmission in a developed
country. This treatment was too expensive for Africa. A new study was carried
out in a modified way. Women were randomized to AZT and placebo in the last
week of pregnancy and rates of neonatal transmission were observed in the two
groups.
PUBLICATION BIAS:
Discussion Cases on Publication Bias - 1:
► A researcher studying two treatments compared outcome
on discharge from the hospital. The outcome results of 10 out of 90 patients
were lost due to a computer error and there was no paper back up because all
the research was computerized. The patients could also not be traced. The
researcher decided on a worst case scenario and assigned all the 10 to the
worst outcome and analyzed the results. Fearing confusing the reviewers and
readers, he did not mention the assignment of outcome.
Discussion Cases on Publication Bias - 2:
► A systematic literature review carried out before
writing the proposal on use of an existing drug for a new indication led to
contradictory conclusions. Research overseas of >5 years ago indicated low
adverse effects while research <5 years ago indicated high adverse
reactions. Local experience with the drug showed it to be very safe. The
researchers who already had a grant from the pharmaceutical company went ahead
with the research but decided to exclude the negative information from their
literature review in order not to confuse the IRB members who would review the
proposal.
Discussion Cases on Publication Bias - 3:
► The editorial board of the faculty journal had an
unwritten understanding shared by all members that negative clinical trials
would not be published because they would have no new information for the
readers. The message trickled through and researchers stopped submitting such
trials for publication. As a result the journal became famous for the being the
source of breakthrough research on new therapies.
Discussion Cases on Publication Bias - 4:
► The head of department a senior professor of surgery
asked his residents to undertake research comparing two surgical techniques. He
gave them detailed guidelines on literature survey, study design, and study
execution. He never took part in the actual research or the writing of the
paper but gave advice on a daily basis whenever they asked him. When the
manuscript was ready for publication he asked that his name be put as the first
author. The residents wanted him to be the last author.
PLAGIARISM:
Discussion Cases on Plagiarism - 1:
► Two professors cooperated on a study and shared the
work, one wrote the introduction and methods while one wrote the results and
the discussion. The study was published in a reputable journal. The first
professor wanted to publish a follow up study on his own and reproduced with
paraphrasing some paragraphs from the introduction of the first paper. Since
this was his own work he saw no reason to cite the paper. The second professor
was angry and complained to the journal editor.
Discussion Cases on Plagiarism - 2:
► A famous research professor submitted a clinical trial
in which he was comparing the efficacy and safety of an established therapy
against the same therapy using a different vehicle. He refused to submit
details about the vehicle arguing that it was a patentable secret formula that
he feared could be stolen by members of IRB and disclosed to others causing him
financial loss. The IRB refused to approve proposal and the professor appealed
to the National Ethics Commission threatening that if not satisfied he will go
to court.
OTHER DISCUSSION CASES:
Other Discussion Cases - 1:
► Internists were frustrated at the high rate of CVA
among male hypertensive patients on regular treatment. On questioning they
discovered that most patients were not compliant because medications impaired
their sexual function. The physicians decided to carry out a series of studies
to compare various hypertensive and select the one with the least impairment of
sexual function. They were not sure how to design the study and submit it to
IRB.
Other Discussion Cases - 2:
► A post approval IRB review revealed that a randomized
study of secondary indications for Viagra had recruited 98% of its ‘volunteers’
from men with diabetes mellitus aged 60-65 years. The advertisement had not
mentioned any age or gender restrictions.
Other Discussion Cases - 3:
► Residents submitted a proposal promptly rejected by
IRB for lack of proper consent procedures and inexperience of the
investigators. They resubmitted it with a senior consultant as principal
investigator, changed the wording of the title, and changed nothing else. The
proposal was accepted.