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Research ethics
Hoang Bao Long, MD MPH
College of Health Sciences, VinUniversity
Learning objectives
Key objectives
• Explain three principles of ethics in human research in Belmont reports
• Map the three ethical principles to the processes in preparing and
conducting human research
Additional objectives
• Describe the sections of an informed consent form
• List the important events in the history of ethics in human research
2
Scenario
3
Scenario
• An open-label randomized trial
compares the efficacy of drug A (a
new drug) vs. drug B (current first
line) in patients with a severe
condition X
• A patient is approached by their
treatment doctor, who presents
briefly the trial. Read what they
explains to the patient (right panel)
“There’s a program being
implemented here. Your condition
is severe and requires treatment.
You should join the program
because it provides you with free
drugs. The program is very good
for you. If you agree to join,
please sign this document.”
4
What is your opinion about
the doctor’s explanation?
5
Scenario
• This explanation clearly has some
problems
• In the class today, we’ll learn about
ethical principles and their practical
applications in conducting research
“There’s a program being
implemented here. Your condition
is severe and requires treatment.
You should join the program
because it provides you with free
drugs. The program is very good
for you. If you agree to join,
please sign this document.”
6
Before that, let’s talk about
the dilemma of trials!
7
Clinical practice vs. Clinical trial
Clinical practice Clinical trial
Activities Treating people with health problems Answering a research question about a
(new) treatment
8
Clinical practice vs. Clinical trial
Clinical practice Clinical trial
Activities Treating people with health problems Answering a research question about a
(new) treatment
Outcomes Patients recover from the health
problems
Producing complete and accurate data
to be able to answer the question
9
Clinical practice vs. Clinical trial
Clinical practice Clinical trial
Activities Treating people with health problems Answering a research question about a
(new) treatment
Outcomes Patients recover from the health
problems
Producing complete and accurate data
to be able to answer the question
Risks and
benefits for
patients
Doctors always try to maximize benefits
and minimize risks; every treatment must
be approved after clear benefits and
absence / low levels of risks have been
justified
In many cases, we have no knowledge
of the benefits and risks of a treatment.
Data are needed to estimate these
benefits / risks
10
Dilemma of clinical trials
• At the same time, we want to
• Have good data to answer research questions
• Give the research patients more benefits and less harm
• But because of the nature of clinical trials
• We are not sure the benefits from the treatment is adequate
• There are potential risks: health, economy, exploitation
• Therefore, clinical trial researchers face a dilemma: “I want to find out the
answer but I don’t know if my research will cause harm to participants”
• Research ethics is needed!!!
11
The ethical problem is not
confined to trials!
12
Research participants
can be harmed even in
observational studies
13
1
History of ethics in human research
14
Major events in the history of research ethics
• 1946: Nuremberg trial on the Nazi experiments
• 1964: Declaration of Helsinki
• 1978: Belmont reports on the Tuskegee experiments
• 1996: Good Clinical Practice (GCP) guideline
15
1946: Nazi experiments
• Inhumane experiments, leaving
severe consequences
• Nuremberg trials were held in 1946
• Then in 1947, Nuremberg codes:
• Potential subjects must voluntarily
agree to participate in the study after
being fully informed about the study
• Experiments must aim to provide
benefits based on scientific judgment
and employ protective measures for
participants
Roelcke V. Nazi medicine and research on human beings. Lancet. 2004;364
Suppl 1:s6-s7. doi:10.1016/S0140-6736(04)17619-8
16
1964: Declaration of Helsinki
• Adopted by the World Medical Association (WMA)
• First version (1964): 11 statements
• Newest: 8th version (2013)
• Combined the principles in Nuremberg codes and modified some details
• Changed “human experimentation” to “clinical research”
• Read it here: https://www.wma.net/policies-post/wma-declaration-of-
helsinki-ethical-principles-for-medical-research-involving-human-subjects/
17
1978: Tuskegee experiment
• Started as a study in 6 months, but
turned out to last for 40 years
(1932–1972)
• Study subjects: poor Black manual
workers in Alabama
• Study objectives: natural
progression of syphilis
Image: https://catalog.archives.gov/id/956104#.XJ5hbXPD1lE.link
18
1978: Tuskegee experiment
• What did they tell the study
participants?
• They were treated for “bad blood”
• They received free exam, free meals,
and burial insurance
• But they were not treated with
penicillin (available since 1943)
• Consequences
• Deaths from syphilis
• New infections Image: https://www.cdc.gov/tuskegee/timeline.htm
19
1978: Tuskegee experiment
• Ethical issues:
• No clear protocol, not ethically
considered
• Study participants not treated with
pencillin
• Selection of vulnerable population
without protection measures
• Subjected participated in the study
while not adequately informed
20
Image: https://www.cdc.gov/tuskegee/timeline.htm
1978: Tuskegee experiment
• Terminated in 1972
• Established the Tuskegee Health
Benefit Program (THBP) to provide
medical cares for study subjects
and their families
• 1978: Belmont report
21
Image: https://www.cdc.gov/tuskegee/timeline.htm
1996: Good Clinical Practice
• 1996: Proposed by the
International Council for
Harmonisation of Technical
Requirements for Pharmaceuticals
for Human Use (ICH)
• Latest version: E6 R2
• R3 has been endorsed and prepared
for publication
22
1996: Good Clinical Practice
• GCP is mainly for clinical trials
• But is applicable to observational
studies
• Major themes:
• Trials must be conducted based on
ethical principles, scientific evidence,
and clear protocols
• Benefits must outweigh risks
• Ensures rights, benefits, safety, and
health of study participants
• Data completely and accurately
recorded
23
24
Do you think we’re good?
329 Study (GSK)
• 1994–2001:
• Evaluated the efficacy of paroxetine
• Subjects: adolescents
• Conclusions: good tolerance and
efficacious in adolescent major
depression
• Paroxetine approved for major
depression patients <18
25
329 Study (GSK)
• 2012: US government requested 3
billion fine for concealing study
reports and illegal promotion of
products
• 2015: Reanalysis revealed an
increased risk of suicide in
adolescents
26
https://www.justice.gov/opa/pr/glaxosmithkline-plead-guilty-and-pay-3-billion-
resolve-fraud-allegations-and-failure-report
https://www.bmj.com/content/351/bmj.h4320
27
Faking data / analysis is
also unethical
Donald Morisky
• Author of the Morisky Medication
Adherence Scale-8 (MMAS-8)
• The scale has been commercialized
• Very expensive (flat $6,000 for first
1,000 subjects)
• Morisky sued anyone who obtained
the scale and used for free
• Original paper retracted in 2023
due to problems with data analysis
• Many big trials have used this scale to
measure important outcomes
28
https://onlinelibrary.wiley.com/doi/10.1111/jch.14718
2
Three principles of ethics in human research
29
gần giống 5 nguyên lý y đức
Belmont report (1978)
30
RESPECT
Informed consent
BENEFICIENCE
Balance risks and benefits
(Study protocol)
JUSTICE
Selection and recruitment of
participants
tôn trọng - hướng thiện - công bằng
31
Respect
32
Autonomy
“I decide whether I want to
participate in the study”
33
Reflection of the Tuskegee experiment
• Study subjects lost their autonomy:
• Not fully informed of the study procedures
• Not known about the effectiveness of penicillin for syphilis
• Lost the opportunity to consider whether to remain in the study
• How does this violation to autonomy manifest?
• Coercion
• Undue influence
ép buộc
dụ dỗ phi lý
Coercion
• Coercion: making potential
subjects worried or scared, so
that they have to participate in the
study although they don’t agree
• As a clinician, it’s very easy to
coerce patients “unconsciously”
due to the nature of patient-doctor
relationship
34
You’ll get this painful
injection if you don’t
participate!
Modified from:
https://tallskinnykiwi.typepad.com/tallskinnykiwi/HPV.JPG
Undue influence
• Undue influence: Clouding the
judgment with very good benefits
and profits, making potential
subjects unable to evaluate the
risks of the study
• Often occurs in pharmaceutical-
sponsored trials
35
Just an injection of a
new vaccine. 3
injections, $1000 for
youuuuu!!!
Modified from: http://www.bookwormroom.com/2015/12/08/the-
enemies-of-liberty-view-government-coercion-as-a-good-thing/
36
Vulnerable
Susceptible to coercion or undue influence
(45 CFR 46.111), unable to protect oneself’s
option(CIOMS 2002, guideline 13)
Vulnerable populations
• Lost or at risk of losing autonomy
• Examples:
• Severe patients
• Old people, pregnant women, children
• Poor, low education, disabled,
minorities, homeless, refugees
• Prisoners, soldiers
37
Unemployed people lining up for free food. They are a vulnerable population.
https://brewminate.com/unimagined-lows-the-depths-of-the-great-depression/
38
Sexual abuse in US military
• Very common (78%–90%) had a history of being sexually abused (Bastian
et al. 1996; Murdoch and Nichol 1995)
• Abusers: soldiers in the same or higher ranks
• Most did not report because they were afraid that it would affect their
career
• 30% female soldiers were raped but 75% of them did not report (Sadler et al. 2003)
• 1 in 100 male soldiers were sexually abused, but army only recorded 78 cases in 12
years (in a total of 1 million soldiers)
Henrietta Lacks (1920-1951)
• Cervical cancer, treated at Johns Hopkins Hospital
• Specimens obtained without informing the patient
• Cells cultured and became the famous immortal HeLa
cell line
• After Lacks died, her family continued to receive
request for blood sampling without clear explanation
• They were very poor and not financially supported
• Only received compensation in 2013 after the story was revealed
• Scientists and pharmaceutical companies have already earned a
lot of money using the HeLa cell line
39
dòng TB bất tử
40
Summary – Respect
• Protect autonomy
• Protect vulnerable populations
• Not only applicable to clinical trials
• Risk of losing autonomy
• Exploited for profits
• Health and safety affected
41
Beneficience
42
“primum non nocere”
First, do no harm!
43
Beneficience
• Maximizes benefits, minimizes risks
• If an intervention is associated with clear risks: it cannot be studied
• However, benefits and risks in clinical trials are unknown!
• Safety: investigational products can be harmful or cause adverse effects
• Effectiveness: investigational products may not be effective
• So how do we protect trial patients?
• By monitoring: timely detection of adverse events and continuously evaluating the
possibility to continue / halt the trial
Ellen Roche (1977–2001)
• Lab technician at Johns Hopkins University
• Volunteered to join the hexamethonium trial
• An antihypertensive banned since 1972 due to no
effectiveness
• Trial objective: evaluated airway constriction in health
subjects
• Roche was the third volunteer:
• Developed irreversible airway constriction
• Died after 1 month
44
https://www.hopkinsmedicine.org/news/articl
es/no-room-for-error
Ellen Roche (1977–2001)
• This event caused a pause to all studies at JHU
for investigation
• They found the report of the first volunteer:
• Mild dyspnea, improved after a few days
• But the researchers did not pause the trial and did not
report to the internal assessment committee
• They thought it was an adverse drug reaction and would
be self-limiting
• Roche would not have died had they reviewed the first
case more carefully (?)
45
Steinbrook R. Protecting research subjects--the
crisis at Johns Hopkins [published correction
appears in N Engl J Med 2002 May
23;346(21):1678]. N Engl J Med. 2002;346(9):716-
720. doi:10.1056/NEJM200202283460924
46
Justice
47
Justice
• Benefits and risks should be equally shared
• Some examples of injustice:
• Study conducted in vulnerable populations → they suffer from an unequal burden of
risk
• Prioritizes care for some patients
• Consider these questions:
• Who can receive benefits and risks from this study?
• How to share the benefits and risks equally?
• Protect vulnerable people
• Comply with selection criteria and study procedures
3
Application of ethical principles in the practice of human research
48
Belmont report (1978)
49
RESPECT
Informed consent
BENEFICIENCE
Balance risks and benefits
(Study protocol)
JUSTICE
Selection and recruitment of
participants
Belmont report (1978)
50
RESPECT
Informed consent
BENEFICIENCE
Balance risks and benefits
(Study protocol)
JUSTICE
Selection and recruitment of
participants
51
Consent
“I voluntarily agree to
participate in the study”
52
Consent
• Two types of consent:
• Verbal: provides verbal agreement after receiving information, not documented
• Written: agreement documented in a document of which content has been ethically
approved
• Informed consent: Study participants provide written consent after being
fully informed
• Therefore, informed consent is always written consent
• What to do when you obtain informed consent:
• Ensure that participants have fully understood the study
• Ensure that participants have voluntarily agreed
đc thông qua bởi hội đồng đạo đức
53
When is informed consent needed?
• Clinical trials
• Observational studies
• Human genetic (even only using biospecimens)
• Collecting new samples
• Collecting sensitive data
• Requiring follow-up
• Qualitative studies
• Requireing recording (photo, video, audio)
• When the IRB requests
Bệnh phẩm có gen người (các loại dịch sinh học như
lấy máu mà không cho mục đích lâm sàng
Thông tin đc coi là nhạy cảm khi: các bệnh truyền nhiễm như HIV, HPV, xu hướng
tình dục, quan hệ tình dục...
NC định tính
Informed consent procedures
• Introduce “this is a study”
• Purposes, procedures, risks and
benefits, compensation, contact
• Ask and answer
• Informed consent form (ICF)
• Sign and date
• Two copies, one for participants and
one for investigators
54
55
True or False?
56
“Informed consent is the consent
provided at the beginning of the study”
57
“After providing informed consent,
participants must comply with the
study protocol”
58
“ICF protects the investigators
because participants have to be
responsible for their participation”
59
All are incorrect!
• Informed consent is a process that lasts for the entire study
• Participants can
• refuse to participate,
• withdraw from the study at any time, and
• request to be removed from the study even after they finish the study
• Informed consent only protected study participants
• Investigators must do everything to protect the study participants (e.g., when they
develop adverse events)
Belmont report (1978)
60
RESPECT
Informed consent
BENEFICIENCE
Balance risks and benefits
(Study protocol)
JUSTICE
Selection and recruitment of
participants
61
Protocol
“A document specifying all study activities,
with which investigators have to comply”
62
How beneficience manifests in the protocol?
• Have you weighed the risks and benefits?
• Clear risks: study cannot be conducted
• Unclear risks and benefits: how are you going to control the possible risks?
• In the protocol:
• Provides information about the reported safety and effectiveness of the investigational
product
• Provides plan for monitoring and managing adverse events
• Protocol must be ethically approved by IRB
• Study must be frequently reported to relevant stakeholders
63
What is an ethical committee?
• Independent ethical committee (IEC) or Institutional Review Board (IRB)
• An ethical body that considers the ethical adequacy of studies in human subjects
• Can approve, request for modification, or reject a study
• Who are they?
• Must be at least 5 members
• Diverse in nature: sex, occupations, having both experts and non-experts, must have
a lawyer
• Includes representatives of vulnerable populations, if applicable
64
IRB review
• Three modes of review:
• Full-board: all members meet and evaluate the protocol, then vote
• Expedited: often only two members review the protocol and decide
• Usually applicable to risk-free or minimal-risk studies, or amendments of approved studies
• May request full-board review if expedited review deemed inadequate
• Waived: not reviewed at all, rarely done
• Procedures:
• Investigators submit protocol and other documents to the IRB
• IRB decides the appropriate mode of review
• Investigators may present the protocol and answer questions during full-board review,
and modify the protocol according to the comments of IRB members
• Study is approved (or rejected)
65
Examples of beneficience
• Beneficience is in fact associated with actual practice more than
theoretical plans in the protocol
• Example 1: Study on pregnant pre-adolescents
• Conducted home interview on an HIV-infected subject
• Accidentally revealed the HIV status to people → participant suffered from stigma
• Example 2: Study on S. suis patients
• Conducted home follow-up for a pig slaughterer
• Accidentally revealed the infection history to people
• People knew the patient sold sick pigs → stopped buying their meat → economically
affected
Belmont report (1978)
66
RESPECT
Informed consent
BENEFICIENCE
Balance risks and benefits
(Study protocol)
JUSTICE
Selection and recruitment of
participants
67
Screening
“Selection of eligible participants using the
selection criteria defined in the protocol”
68
Screening and recruitment
• Must be done in accordance with the approved protocol
• You must not:
• Provide benefits for only a group of patients
• Recruit ineligible patients
• Recruit patients because they are easier to be recruited (e.g., poor patients, patients
in a coma, end-stage patients)
69
Back to our scenario
Scenario
• Back to our scenario, what’s the
problem here? “There’s a program being
implemented here. Your condition
is severe and requires treatment.
You should join the program
because it provides you with free
drugs. The program is very good
for you. If you agree to join,
please sign this document.”
70
Scenario
• Back to our scenario, what’s the
problem here?
• Not mentioned this is a study
“There’s a program being
implemented here. Your condition
is severe and requires treatment.
You should join the program
because it provides you with free
drugs. The program is very good
for you. If you agree to join,
please sign this document.”
71
Scenario
• Back to our scenario, what’s the
problem here?
• Not mentioned this is a study
• A form of coercion
“There’s a program being
implemented here. Your
condition is severe and
requires treatment. You should
join the program because it
provides you with free drugs. The
program is very good for you. If
you agree to join, please sign this
document.”
72
Scenario
• Back to our scenario, what’s the
problem here?
• Not mentioned this is a study
• A form of coercion
• A form of undue influence
“There’s a program being
implemented here. Your condition
is severe and requires treatment.
You should join the program
because it provides you with
free drugs. The program is very
good for you. If you agree to join,
please sign this document.”
73
Scenario
• Back to our scenario, what’s the
problem here?
• Not mentioned this is a study
• A form of coercion
• A form of undue influence
• Only provided information about
benefits
“There’s a program being
implemented here. Your condition
is severe and requires treatment.
You should join the program
because it provides you with free
drugs. The program is very
good for you. If you agree to
join, please sign this document.”
74
Scenario
• Back to our scenario, what’s the
problem here?
• Not mentioned this is a study
• A form of coercion
• A form of undue influence
• Only provided information about
benefits
• Did not give time for questions and
consideration
“There’s a program being
implemented here. Your condition
is severe and requires treatment.
You should join the program
because it provides you with free
drugs. The program is very good
for you. If you agree to join,
please sign this document.”
75
76
Violation to Respect
77
Summary
• Why is research ethics important?
• Unclear risks and benefits for patients
• While data integrity is required
• Principles of research ethics
• Respect: autonomy → informed consent
• Benefience: maximize benefits, minimize risks → protocol
• Justice: equal sharing of risks and benefits → screening and recruitment
4
Practice
78
79
Research idea
• Background
• Amphotericin B and Itraconazole are often used for Talaromyces infection in HIV
patients
• First-line: amphoB x 2 weeks + itra x 6 months
• AmphoB: expensive, many ADRs, IV use → requires hospitalization
• Itra: cheap, fewer and milder ADRs, oral use → can be treated at home
• Research question: In HIV patients with Talaromyces marneffei infection,
does itraconazole have a non-inferior 6-month risk of death compared to
amphotericin B?
80
Study design
• Open-label RCT
• Main outcome: death at 6 months
• Procedures:
• Screening, obtaining informed consent, randomization
• Ampho B / High-dose itra x 2 weeks → maintenance dose itra until 6 months
• Follow-up at 2 weeks and 1, 2, 3, 4, 5, and 6 months
• Blood culture for fungal count at 1, 3, 5, 7, 10, and 14 days
• Blood test (CBC, biochemistry) at follow-up visits
81
Discussion
What are the potential
ethical issues of this study?
82
Ethical issues
• Think in terms of three principles
• Respect
• HIV patients are vulnerable
• How do we obtain informed consent?
• Coercion: Who should obtain informed consent? How information should be delivered?
How to make sure patients and family members understand?
• Undue influence: How much do we compensate / reimburse for patients?
• Are we recruiting comatose patients? Will we seek their informed consent after they
regain their consciousness?
• How are we protecting their HIV status? Where do we interview them? How do we
avoid disclosing their status at follow-up visits?
• If they are lost to follow up, how will we treat them with respect?
83
Ethical issues
• Beneficience
• Is clinical equipoise judged?
Clinical equipoise
• Both intervention and control arms cannot
demonstrate a superior effect
• Meaning that “because we don’t have evidence of which
one is better, we can do a clinical trial to determine that”
• Otherwise, you must administer the superior treatment
• Important principle before any decision on
designing a new trial, but easily neglected
• Fergusson (2005): more RCTs conducted after 1993
despite clear evidence of benefits of aprotinin
Image: Fergusson D, Glass KC, Hutton B, Shapiro S. Randomized controlled trials of aprotinin in cardiac surgery:
could clinical equipoise have stopped the bleeding?. Clin Trials. 2005;2(3):218-232.
doi:10.1191/1740774505cn085oa
84
85
Ethical issues
• Beneficience
• Is clinical equipoise judged?
• Is the sample size properly calculated?
• Planning for monitoring and managing adverse events?
• Protecting confidential and private information (e.g., HIV status)?
• Justice
• Are selection criteria clear and reasonable?
• Any vulnerable population that we need to specifically care about?
• Are the burdens of risks and benefits shared equally between two arms?
• Are the investigators adequately equipped to ensure ethical integrity?
86
Ethical issues
• Examples of issues in informed consent
• Unclear explanation: This drug is good, just join!
• HIV patients often self-stigmatize and are dependent on healthcare workers → they
may have questions but are afraid to ask
• Talaromyces patients are often extremely tired → don’t want to think much, just agree
with whatever doctors offer
• Disclosure of HIV status
87
Ethical issues
• Solutions:
• Choose a space that creates a sense of privacy, confidentiality, and safety
• Explains carefully about the study, but don’t make it too long
• Encourage patients to ask
• Invite family members to join (so that patients don’t feel scared, and they may support
the patients to answer questions when patients are too tired)
88
Summary
89
Summary
• Ethics in human research is a process throughout a study
• Begins with ethical consideration during protocol development: what are the risks for
study participants and how to mitigate?
• Developing ethical documents (patient information sheet, informed consent form,
consenting procedures, etc.)
• IRB submission
• Ensuring ethical compliance across all study procedures (screening, obtaining
informed consent, data collection, etc.)
• It’s best to assume that you need ethical consultation
The end
Thank you for contributing to the class!

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CCSC6142 Week 3 Research ethics - Long Hoang.pdf

  • 1. Research ethics Hoang Bao Long, MD MPH College of Health Sciences, VinUniversity
  • 2. Learning objectives Key objectives • Explain three principles of ethics in human research in Belmont reports • Map the three ethical principles to the processes in preparing and conducting human research Additional objectives • Describe the sections of an informed consent form • List the important events in the history of ethics in human research 2
  • 4. Scenario • An open-label randomized trial compares the efficacy of drug A (a new drug) vs. drug B (current first line) in patients with a severe condition X • A patient is approached by their treatment doctor, who presents briefly the trial. Read what they explains to the patient (right panel) “There’s a program being implemented here. Your condition is severe and requires treatment. You should join the program because it provides you with free drugs. The program is very good for you. If you agree to join, please sign this document.” 4
  • 5. What is your opinion about the doctor’s explanation? 5
  • 6. Scenario • This explanation clearly has some problems • In the class today, we’ll learn about ethical principles and their practical applications in conducting research “There’s a program being implemented here. Your condition is severe and requires treatment. You should join the program because it provides you with free drugs. The program is very good for you. If you agree to join, please sign this document.” 6
  • 7. Before that, let’s talk about the dilemma of trials! 7
  • 8. Clinical practice vs. Clinical trial Clinical practice Clinical trial Activities Treating people with health problems Answering a research question about a (new) treatment 8
  • 9. Clinical practice vs. Clinical trial Clinical practice Clinical trial Activities Treating people with health problems Answering a research question about a (new) treatment Outcomes Patients recover from the health problems Producing complete and accurate data to be able to answer the question 9
  • 10. Clinical practice vs. Clinical trial Clinical practice Clinical trial Activities Treating people with health problems Answering a research question about a (new) treatment Outcomes Patients recover from the health problems Producing complete and accurate data to be able to answer the question Risks and benefits for patients Doctors always try to maximize benefits and minimize risks; every treatment must be approved after clear benefits and absence / low levels of risks have been justified In many cases, we have no knowledge of the benefits and risks of a treatment. Data are needed to estimate these benefits / risks 10
  • 11. Dilemma of clinical trials • At the same time, we want to • Have good data to answer research questions • Give the research patients more benefits and less harm • But because of the nature of clinical trials • We are not sure the benefits from the treatment is adequate • There are potential risks: health, economy, exploitation • Therefore, clinical trial researchers face a dilemma: “I want to find out the answer but I don’t know if my research will cause harm to participants” • Research ethics is needed!!! 11
  • 12. The ethical problem is not confined to trials! 12
  • 13. Research participants can be harmed even in observational studies 13
  • 14. 1 History of ethics in human research 14
  • 15. Major events in the history of research ethics • 1946: Nuremberg trial on the Nazi experiments • 1964: Declaration of Helsinki • 1978: Belmont reports on the Tuskegee experiments • 1996: Good Clinical Practice (GCP) guideline 15
  • 16. 1946: Nazi experiments • Inhumane experiments, leaving severe consequences • Nuremberg trials were held in 1946 • Then in 1947, Nuremberg codes: • Potential subjects must voluntarily agree to participate in the study after being fully informed about the study • Experiments must aim to provide benefits based on scientific judgment and employ protective measures for participants Roelcke V. Nazi medicine and research on human beings. Lancet. 2004;364 Suppl 1:s6-s7. doi:10.1016/S0140-6736(04)17619-8 16
  • 17. 1964: Declaration of Helsinki • Adopted by the World Medical Association (WMA) • First version (1964): 11 statements • Newest: 8th version (2013) • Combined the principles in Nuremberg codes and modified some details • Changed “human experimentation” to “clinical research” • Read it here: https://www.wma.net/policies-post/wma-declaration-of- helsinki-ethical-principles-for-medical-research-involving-human-subjects/ 17
  • 18. 1978: Tuskegee experiment • Started as a study in 6 months, but turned out to last for 40 years (1932–1972) • Study subjects: poor Black manual workers in Alabama • Study objectives: natural progression of syphilis Image: https://catalog.archives.gov/id/956104#.XJ5hbXPD1lE.link 18
  • 19. 1978: Tuskegee experiment • What did they tell the study participants? • They were treated for “bad blood” • They received free exam, free meals, and burial insurance • But they were not treated with penicillin (available since 1943) • Consequences • Deaths from syphilis • New infections Image: https://www.cdc.gov/tuskegee/timeline.htm 19
  • 20. 1978: Tuskegee experiment • Ethical issues: • No clear protocol, not ethically considered • Study participants not treated with pencillin • Selection of vulnerable population without protection measures • Subjected participated in the study while not adequately informed 20 Image: https://www.cdc.gov/tuskegee/timeline.htm
  • 21. 1978: Tuskegee experiment • Terminated in 1972 • Established the Tuskegee Health Benefit Program (THBP) to provide medical cares for study subjects and their families • 1978: Belmont report 21 Image: https://www.cdc.gov/tuskegee/timeline.htm
  • 22. 1996: Good Clinical Practice • 1996: Proposed by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) • Latest version: E6 R2 • R3 has been endorsed and prepared for publication 22
  • 23. 1996: Good Clinical Practice • GCP is mainly for clinical trials • But is applicable to observational studies • Major themes: • Trials must be conducted based on ethical principles, scientific evidence, and clear protocols • Benefits must outweigh risks • Ensures rights, benefits, safety, and health of study participants • Data completely and accurately recorded 23
  • 24. 24 Do you think we’re good?
  • 25. 329 Study (GSK) • 1994–2001: • Evaluated the efficacy of paroxetine • Subjects: adolescents • Conclusions: good tolerance and efficacious in adolescent major depression • Paroxetine approved for major depression patients <18 25
  • 26. 329 Study (GSK) • 2012: US government requested 3 billion fine for concealing study reports and illegal promotion of products • 2015: Reanalysis revealed an increased risk of suicide in adolescents 26 https://www.justice.gov/opa/pr/glaxosmithkline-plead-guilty-and-pay-3-billion- resolve-fraud-allegations-and-failure-report https://www.bmj.com/content/351/bmj.h4320
  • 27. 27 Faking data / analysis is also unethical
  • 28. Donald Morisky • Author of the Morisky Medication Adherence Scale-8 (MMAS-8) • The scale has been commercialized • Very expensive (flat $6,000 for first 1,000 subjects) • Morisky sued anyone who obtained the scale and used for free • Original paper retracted in 2023 due to problems with data analysis • Many big trials have used this scale to measure important outcomes 28 https://onlinelibrary.wiley.com/doi/10.1111/jch.14718
  • 29. 2 Three principles of ethics in human research 29 gần giống 5 nguyên lý y đức
  • 30. Belmont report (1978) 30 RESPECT Informed consent BENEFICIENCE Balance risks and benefits (Study protocol) JUSTICE Selection and recruitment of participants tôn trọng - hướng thiện - công bằng
  • 32. 32 Autonomy “I decide whether I want to participate in the study”
  • 33. 33 Reflection of the Tuskegee experiment • Study subjects lost their autonomy: • Not fully informed of the study procedures • Not known about the effectiveness of penicillin for syphilis • Lost the opportunity to consider whether to remain in the study • How does this violation to autonomy manifest? • Coercion • Undue influence ép buộc dụ dỗ phi lý
  • 34. Coercion • Coercion: making potential subjects worried or scared, so that they have to participate in the study although they don’t agree • As a clinician, it’s very easy to coerce patients “unconsciously” due to the nature of patient-doctor relationship 34 You’ll get this painful injection if you don’t participate! Modified from: https://tallskinnykiwi.typepad.com/tallskinnykiwi/HPV.JPG
  • 35. Undue influence • Undue influence: Clouding the judgment with very good benefits and profits, making potential subjects unable to evaluate the risks of the study • Often occurs in pharmaceutical- sponsored trials 35 Just an injection of a new vaccine. 3 injections, $1000 for youuuuu!!! Modified from: http://www.bookwormroom.com/2015/12/08/the- enemies-of-liberty-view-government-coercion-as-a-good-thing/
  • 36. 36 Vulnerable Susceptible to coercion or undue influence (45 CFR 46.111), unable to protect oneself’s option(CIOMS 2002, guideline 13)
  • 37. Vulnerable populations • Lost or at risk of losing autonomy • Examples: • Severe patients • Old people, pregnant women, children • Poor, low education, disabled, minorities, homeless, refugees • Prisoners, soldiers 37 Unemployed people lining up for free food. They are a vulnerable population. https://brewminate.com/unimagined-lows-the-depths-of-the-great-depression/
  • 38. 38 Sexual abuse in US military • Very common (78%–90%) had a history of being sexually abused (Bastian et al. 1996; Murdoch and Nichol 1995) • Abusers: soldiers in the same or higher ranks • Most did not report because they were afraid that it would affect their career • 30% female soldiers were raped but 75% of them did not report (Sadler et al. 2003) • 1 in 100 male soldiers were sexually abused, but army only recorded 78 cases in 12 years (in a total of 1 million soldiers)
  • 39. Henrietta Lacks (1920-1951) • Cervical cancer, treated at Johns Hopkins Hospital • Specimens obtained without informing the patient • Cells cultured and became the famous immortal HeLa cell line • After Lacks died, her family continued to receive request for blood sampling without clear explanation • They were very poor and not financially supported • Only received compensation in 2013 after the story was revealed • Scientists and pharmaceutical companies have already earned a lot of money using the HeLa cell line 39 dòng TB bất tử
  • 40. 40 Summary – Respect • Protect autonomy • Protect vulnerable populations • Not only applicable to clinical trials • Risk of losing autonomy • Exploited for profits • Health and safety affected
  • 43. 43 Beneficience • Maximizes benefits, minimizes risks • If an intervention is associated with clear risks: it cannot be studied • However, benefits and risks in clinical trials are unknown! • Safety: investigational products can be harmful or cause adverse effects • Effectiveness: investigational products may not be effective • So how do we protect trial patients? • By monitoring: timely detection of adverse events and continuously evaluating the possibility to continue / halt the trial
  • 44. Ellen Roche (1977–2001) • Lab technician at Johns Hopkins University • Volunteered to join the hexamethonium trial • An antihypertensive banned since 1972 due to no effectiveness • Trial objective: evaluated airway constriction in health subjects • Roche was the third volunteer: • Developed irreversible airway constriction • Died after 1 month 44 https://www.hopkinsmedicine.org/news/articl es/no-room-for-error
  • 45. Ellen Roche (1977–2001) • This event caused a pause to all studies at JHU for investigation • They found the report of the first volunteer: • Mild dyspnea, improved after a few days • But the researchers did not pause the trial and did not report to the internal assessment committee • They thought it was an adverse drug reaction and would be self-limiting • Roche would not have died had they reviewed the first case more carefully (?) 45 Steinbrook R. Protecting research subjects--the crisis at Johns Hopkins [published correction appears in N Engl J Med 2002 May 23;346(21):1678]. N Engl J Med. 2002;346(9):716- 720. doi:10.1056/NEJM200202283460924
  • 47. 47 Justice • Benefits and risks should be equally shared • Some examples of injustice: • Study conducted in vulnerable populations → they suffer from an unequal burden of risk • Prioritizes care for some patients • Consider these questions: • Who can receive benefits and risks from this study? • How to share the benefits and risks equally? • Protect vulnerable people • Comply with selection criteria and study procedures
  • 48. 3 Application of ethical principles in the practice of human research 48
  • 49. Belmont report (1978) 49 RESPECT Informed consent BENEFICIENCE Balance risks and benefits (Study protocol) JUSTICE Selection and recruitment of participants
  • 50. Belmont report (1978) 50 RESPECT Informed consent BENEFICIENCE Balance risks and benefits (Study protocol) JUSTICE Selection and recruitment of participants
  • 51. 51 Consent “I voluntarily agree to participate in the study”
  • 52. 52 Consent • Two types of consent: • Verbal: provides verbal agreement after receiving information, not documented • Written: agreement documented in a document of which content has been ethically approved • Informed consent: Study participants provide written consent after being fully informed • Therefore, informed consent is always written consent • What to do when you obtain informed consent: • Ensure that participants have fully understood the study • Ensure that participants have voluntarily agreed đc thông qua bởi hội đồng đạo đức
  • 53. 53 When is informed consent needed? • Clinical trials • Observational studies • Human genetic (even only using biospecimens) • Collecting new samples • Collecting sensitive data • Requiring follow-up • Qualitative studies • Requireing recording (photo, video, audio) • When the IRB requests Bệnh phẩm có gen người (các loại dịch sinh học như lấy máu mà không cho mục đích lâm sàng Thông tin đc coi là nhạy cảm khi: các bệnh truyền nhiễm như HIV, HPV, xu hướng tình dục, quan hệ tình dục... NC định tính
  • 54. Informed consent procedures • Introduce “this is a study” • Purposes, procedures, risks and benefits, compensation, contact • Ask and answer • Informed consent form (ICF) • Sign and date • Two copies, one for participants and one for investigators 54
  • 56. 56 “Informed consent is the consent provided at the beginning of the study”
  • 57. 57 “After providing informed consent, participants must comply with the study protocol”
  • 58. 58 “ICF protects the investigators because participants have to be responsible for their participation”
  • 59. 59 All are incorrect! • Informed consent is a process that lasts for the entire study • Participants can • refuse to participate, • withdraw from the study at any time, and • request to be removed from the study even after they finish the study • Informed consent only protected study participants • Investigators must do everything to protect the study participants (e.g., when they develop adverse events)
  • 60. Belmont report (1978) 60 RESPECT Informed consent BENEFICIENCE Balance risks and benefits (Study protocol) JUSTICE Selection and recruitment of participants
  • 61. 61 Protocol “A document specifying all study activities, with which investigators have to comply”
  • 62. 62 How beneficience manifests in the protocol? • Have you weighed the risks and benefits? • Clear risks: study cannot be conducted • Unclear risks and benefits: how are you going to control the possible risks? • In the protocol: • Provides information about the reported safety and effectiveness of the investigational product • Provides plan for monitoring and managing adverse events • Protocol must be ethically approved by IRB • Study must be frequently reported to relevant stakeholders
  • 63. 63 What is an ethical committee? • Independent ethical committee (IEC) or Institutional Review Board (IRB) • An ethical body that considers the ethical adequacy of studies in human subjects • Can approve, request for modification, or reject a study • Who are they? • Must be at least 5 members • Diverse in nature: sex, occupations, having both experts and non-experts, must have a lawyer • Includes representatives of vulnerable populations, if applicable
  • 64. 64 IRB review • Three modes of review: • Full-board: all members meet and evaluate the protocol, then vote • Expedited: often only two members review the protocol and decide • Usually applicable to risk-free or minimal-risk studies, or amendments of approved studies • May request full-board review if expedited review deemed inadequate • Waived: not reviewed at all, rarely done • Procedures: • Investigators submit protocol and other documents to the IRB • IRB decides the appropriate mode of review • Investigators may present the protocol and answer questions during full-board review, and modify the protocol according to the comments of IRB members • Study is approved (or rejected)
  • 65. 65 Examples of beneficience • Beneficience is in fact associated with actual practice more than theoretical plans in the protocol • Example 1: Study on pregnant pre-adolescents • Conducted home interview on an HIV-infected subject • Accidentally revealed the HIV status to people → participant suffered from stigma • Example 2: Study on S. suis patients • Conducted home follow-up for a pig slaughterer • Accidentally revealed the infection history to people • People knew the patient sold sick pigs → stopped buying their meat → economically affected
  • 66. Belmont report (1978) 66 RESPECT Informed consent BENEFICIENCE Balance risks and benefits (Study protocol) JUSTICE Selection and recruitment of participants
  • 67. 67 Screening “Selection of eligible participants using the selection criteria defined in the protocol”
  • 68. 68 Screening and recruitment • Must be done in accordance with the approved protocol • You must not: • Provide benefits for only a group of patients • Recruit ineligible patients • Recruit patients because they are easier to be recruited (e.g., poor patients, patients in a coma, end-stage patients)
  • 69. 69 Back to our scenario
  • 70. Scenario • Back to our scenario, what’s the problem here? “There’s a program being implemented here. Your condition is severe and requires treatment. You should join the program because it provides you with free drugs. The program is very good for you. If you agree to join, please sign this document.” 70
  • 71. Scenario • Back to our scenario, what’s the problem here? • Not mentioned this is a study “There’s a program being implemented here. Your condition is severe and requires treatment. You should join the program because it provides you with free drugs. The program is very good for you. If you agree to join, please sign this document.” 71
  • 72. Scenario • Back to our scenario, what’s the problem here? • Not mentioned this is a study • A form of coercion “There’s a program being implemented here. Your condition is severe and requires treatment. You should join the program because it provides you with free drugs. The program is very good for you. If you agree to join, please sign this document.” 72
  • 73. Scenario • Back to our scenario, what’s the problem here? • Not mentioned this is a study • A form of coercion • A form of undue influence “There’s a program being implemented here. Your condition is severe and requires treatment. You should join the program because it provides you with free drugs. The program is very good for you. If you agree to join, please sign this document.” 73
  • 74. Scenario • Back to our scenario, what’s the problem here? • Not mentioned this is a study • A form of coercion • A form of undue influence • Only provided information about benefits “There’s a program being implemented here. Your condition is severe and requires treatment. You should join the program because it provides you with free drugs. The program is very good for you. If you agree to join, please sign this document.” 74
  • 75. Scenario • Back to our scenario, what’s the problem here? • Not mentioned this is a study • A form of coercion • A form of undue influence • Only provided information about benefits • Did not give time for questions and consideration “There’s a program being implemented here. Your condition is severe and requires treatment. You should join the program because it provides you with free drugs. The program is very good for you. If you agree to join, please sign this document.” 75
  • 77. 77 Summary • Why is research ethics important? • Unclear risks and benefits for patients • While data integrity is required • Principles of research ethics • Respect: autonomy → informed consent • Benefience: maximize benefits, minimize risks → protocol • Justice: equal sharing of risks and benefits → screening and recruitment
  • 79. 79 Research idea • Background • Amphotericin B and Itraconazole are often used for Talaromyces infection in HIV patients • First-line: amphoB x 2 weeks + itra x 6 months • AmphoB: expensive, many ADRs, IV use → requires hospitalization • Itra: cheap, fewer and milder ADRs, oral use → can be treated at home • Research question: In HIV patients with Talaromyces marneffei infection, does itraconazole have a non-inferior 6-month risk of death compared to amphotericin B?
  • 80. 80 Study design • Open-label RCT • Main outcome: death at 6 months • Procedures: • Screening, obtaining informed consent, randomization • Ampho B / High-dose itra x 2 weeks → maintenance dose itra until 6 months • Follow-up at 2 weeks and 1, 2, 3, 4, 5, and 6 months • Blood culture for fungal count at 1, 3, 5, 7, 10, and 14 days • Blood test (CBC, biochemistry) at follow-up visits
  • 81. 81 Discussion What are the potential ethical issues of this study?
  • 82. 82 Ethical issues • Think in terms of three principles • Respect • HIV patients are vulnerable • How do we obtain informed consent? • Coercion: Who should obtain informed consent? How information should be delivered? How to make sure patients and family members understand? • Undue influence: How much do we compensate / reimburse for patients? • Are we recruiting comatose patients? Will we seek their informed consent after they regain their consciousness? • How are we protecting their HIV status? Where do we interview them? How do we avoid disclosing their status at follow-up visits? • If they are lost to follow up, how will we treat them with respect?
  • 83. 83 Ethical issues • Beneficience • Is clinical equipoise judged?
  • 84. Clinical equipoise • Both intervention and control arms cannot demonstrate a superior effect • Meaning that “because we don’t have evidence of which one is better, we can do a clinical trial to determine that” • Otherwise, you must administer the superior treatment • Important principle before any decision on designing a new trial, but easily neglected • Fergusson (2005): more RCTs conducted after 1993 despite clear evidence of benefits of aprotinin Image: Fergusson D, Glass KC, Hutton B, Shapiro S. Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding?. Clin Trials. 2005;2(3):218-232. doi:10.1191/1740774505cn085oa 84
  • 85. 85 Ethical issues • Beneficience • Is clinical equipoise judged? • Is the sample size properly calculated? • Planning for monitoring and managing adverse events? • Protecting confidential and private information (e.g., HIV status)? • Justice • Are selection criteria clear and reasonable? • Any vulnerable population that we need to specifically care about? • Are the burdens of risks and benefits shared equally between two arms? • Are the investigators adequately equipped to ensure ethical integrity?
  • 86. 86 Ethical issues • Examples of issues in informed consent • Unclear explanation: This drug is good, just join! • HIV patients often self-stigmatize and are dependent on healthcare workers → they may have questions but are afraid to ask • Talaromyces patients are often extremely tired → don’t want to think much, just agree with whatever doctors offer • Disclosure of HIV status
  • 87. 87 Ethical issues • Solutions: • Choose a space that creates a sense of privacy, confidentiality, and safety • Explains carefully about the study, but don’t make it too long • Encourage patients to ask • Invite family members to join (so that patients don’t feel scared, and they may support the patients to answer questions when patients are too tired)
  • 89. 89 Summary • Ethics in human research is a process throughout a study • Begins with ethical consideration during protocol development: what are the risks for study participants and how to mitigate? • Developing ethical documents (patient information sheet, informed consent form, consenting procedures, etc.) • IRB submission • Ensuring ethical compliance across all study procedures (screening, obtaining informed consent, data collection, etc.) • It’s best to assume that you need ethical consultation
  • 90. The end Thank you for contributing to the class!