210523P - ISSUES IN RESEARCH ETHICS

Presentation at a workshop on Week I: Bioethics Module - CRC Program held at King Fahad Medical City via Zoom on 23 May 2021 at 13:00-14:00 pm by Professor Omar Hasan Kasule MB ChB (MUK), MPH (Harvard), DrPH (Harvard) Professor of Epidemiology and Bioethics, King Fahad Medical City

 

 

THE NUREMBER CODE 1946:

1. Voluntary Informed Consent

2. No Random Or Unnecessary Experiments
3. Animal Experiments first
4. Knowledge Of Disease Natural History
5. Avoiding Unnecessary Physical And Mental Suffering
6. The Researchers Must Be Scientifically Qualified
7. Subjects Can Withdraw At Any Time

8. The Investigation Is Stopped If The Patient Is In Danger.

 

HELSINKI DECLARATION 1962, 1996:

1. Generally Accepted Scientific Principles

2. Risk-Benefit Assessment.

3. Subject Integrity And Welfare

4. 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 - 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.

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

 

INFORMED CONSENT CHECKLIST (Required Elements) con’t. - 1:

► 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. 

► 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. - 2:

► 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. 

► 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.