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Presentation at a Research Methodology Course for Paediatrics Residency Program held via Zoom at Prince Sultan Military Medical City on 23 February 2021. By Professor Omar Hasan Kasule Sr. MB ChB (MUK). MPH (Harvard), DrPH (Harvard) Chairman of the Ethics Committee King Fahad Medical City.
BACKGROUND INFORMATION
ABOUT THE RESEARCH:
► Therapeutic Research
► Clinical Trials On Humans: Phase
1,2,3,4
► Non Therapeutic Experiments
► Community-Based Experimentation
PRIORITIZING
HUMAN RESEARCH:
► The general order of priorities is:
1. necessities, dharuraat,
2. needs, hajiyaat,
3. complimentaries, mukamillaat,
4. embellishments, tahsinaat.
5. excesses, israfaat
6. wastage, tabdhiraat.
► Medical research is a necessity for
two reasons: (a) better therapies: more effective, cheaper, easier (b) better
physicians.
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
PURPOSES OF
HUMAN EXPERIMENTATION, con’t.:
► The principle of intention, qasd
► The principle of certainty, yaqeen
► The principle of injury, dharar
► The principle of hardship, mashaqqat
► The principle of custom or precedent,
aadat/urf
► Others:
§
The doctrine of continuity, istishaab
§
The doctrine of personal preference, istihsaan
§
The doctrine of public interest, istislaah
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.
HELSINKI DECLARATION 1962, 1996:
► Generally accepted scientific
principles
► Risk-benefit assessment
► Subject integrity and welfare
► Full disclosure
GOOD CLINICAL PRACTICE GUIDELINES:
► Follow the 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
MAJOR ETHICAL ISSUES IN RESEARCH - 1:
► Informed
consent / autonomy
§
Frequently violated
§
Autonomous right to protect life, hifdh al nafs
§
Self interest in consent
§
Competence to consent
► The
benefit-risk ratio
§
The principle of injury, qa'idat al dharar
§
Research policy aims at minimizing risk to research
subjects
§
Report and management of adverse events
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).
ADVERSE EVENTS AND PROTOCOL DEVIATIONS / VIOLATIONS
DATIX REPORTING:
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
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.
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.
DISCUSSION CASES ON THE PROCESSES OF INFORMED CONSENT -
1:
► A randomized study was carried out
among pregnant women to study the impact of iron supplementation on pre
delivery hemoglobin levels. Informed consent was obtained after full disclosure
of all facts. A questionnaire at the end of the study surprised researchers
because the women 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:
► Patients in a randomized cancer drug
trial had to read a 5 page Arabic translation of the disclosure statement and
then sign the consent; 2/10 signed without reading but listened to a 2-minute
explanation by the principal researcher. 18/20 decided to take it home for
study and brought it back fully signed and dated.
DISCUSSION CASES ON THE PROCESSES OF INFORMED CONSENT
- 4:
► A terminal cancer patient 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 his interests
and will not contribute to his welfare. The principal investigator was called
to convince the patient. He told him 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 patient reluctantly
signed the informed consent form.
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 teenager’s every
day. 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 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?
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.
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.
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.
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.
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 hypertensives 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.