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Presentation at KSHC Research Day held at King Fahad Medical City, Riyadh on 28th October 2019. By: Professor Omar Hasan Kasule Sr. MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Chairman, Institutional Review Board (IRB) - KFMC
BACKGROUND
INFORMATION ABOUT THE RESEARCH:
} Therapeutic Research
} Non Therapeutic Experiments
} Community-Based Experimentation
} Clinical Trials On Humans: Phase 1,2,3,4
PRIORITIZING HUMAN
RESEARCH:
} The general order
of priorities is:
§ necessities, dharuraat,
§ needs, hajiyaat,
§ complimentaries, mukamillaat,
§ embellishments, tahsinaat.
§ excesses, israfaat
§ wastage, tabdhiraat.
} Medical research
is a necessity for two reasons:
§ better therapies
§ 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
PRINCIPLES OF
HUMAN EXPERIMENTATION:
} 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 NUREMBER CODE 1946:
} Voluntary Informed Consent
} No Random or Unnecessary Experiments
} Animal Experiments
} 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 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:
} 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
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
} Funding of research
} Dissemination of knowledge and publication bias
} Research malpractice
} Conflict of interest
DISCUSSION CASES
ON CONFLICT OF INTERESTS:
} 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.
} 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 s 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:
} 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 aborts for research purposes. No questions were
asked about the causes of the abortion.
} 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.
} 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.
} 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 - 2:
} 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.
} 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 of 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:
} 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’
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.
} 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.
} 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.
} 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 - 2:
} 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.
} 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:
} 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?
} 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.
} 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.
} 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 - 2:
} 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.
} 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:
} 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.
} 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:
} 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.
} 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.
} Residents
submitted a proposal promptly rejected by IRB for lack of proper consent
procedures and the 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.