1. New Prevention
Technologies
Workshop
Module 6:
Ethics
WWW.ICAD-CISD.COM

2. HUMAN RIGHTS AND
ETHICAL CHALLENGES IN
NPT RESEARCH

3.  Overview of research ethics: origins, guidelines,
principles
 Overview of role of various players in
biomedical prevention research
 Community engagement: models, challenges,
vulnerability and targeted populations
 Dynamics of North-South research
 Case study: Cambodia, Cameroon, Thai trials
 Standard of prevention and care for trial
participants
 Use of ARVs for prevention vs treatment
OUTLINE

4. What is “Ethics”?
Ethics is a way of understanding and
examining what is “right” and what is
“wrong”
Bioethics is a way of understanding and
examining what is “right” and what is
“wrong” in biomedical research and
practice.

5. What is your understanding of these
words ?
 Respect
 Harm
 Fairness
Activity

6. Principles of Research Ethics
 Respect for Persons
 Beneficence/Non-Maleficence
 Justice/Non-Exploitation

7. Respect for Persons
Autonomy
 Says that each individual:
 Is unique and free;
 Has the right and capacity to decide;
 Has value and dignity; and
 Has the right to informed consent.
Protection for vulnerable persons
 Special protections must be in place for those whose
decision–making capacity is impaired or diminished,
whether due to physical or social factors

8. Beneficence/Non-Maleficence
Protection of the study participants is the
most important responsibility of the
researcher
Researchers must:
 Protect the physical, mental and social well-
being of each research participant;
 Minimizes physical and social risks;
 Maximize the possible benefits; and
 Retain the community perspective.

9. Beneficence/Non-Maleficence
ON BALANCE:
The research should generate more
good than harm; and
Risks of research should be reasonable
in light of the expected benefits to the
individual and to society.

10. Justice/Non-Exploitation
 The principle that calls for fairness in the conduct of
research is the principle of justice/non-exploitation
 Research must:
 Ensure a fair distribution of risks and benefits
 Research should not be done in a community
that is not likely to benefit from the result
 Conduct equitable recruitment of research
participants; and
 Provide special protection for vulnerable groups.

11. What are the potential
RISKS of becoming
involved in a prevention
trial?
For participants?
For communities?
RISKS and BENEFITS
What are the potential
BENEFITS of becoming
involved in a prevention
trial?
For participants?
For communities?
DISCUSSION QUESTIONS

12. Participant Risks vs. Benefits
Biologic/Physical
Social/Emotional
 From the product: side
effects
 From HIV/STI testing
 Partner issues
 Stigma
 Improved access to
health care
 Better prevention
 Risk reduction counseling
 STD treatment
 Condoms
 Other
 Cash
 Sense of social
contribution
RISKS BENEFITS

13. Participants Have Said the Benefits of
Participating in Microbicide Trials Include:
 Access to medical services and regular health checks is
considered the biggest benefit
 Counseling about women’s bodies, sexuality,
reproductive tract infections, STIs, and HIV
 Good relationships with study staff
 Feeling empowered; improved communication with male
partners and children
 Access to study gel; improved sex due to gel
 Contributing to a women’s health cause: “One is helped
but is also helping others”

14. Participants Have Said the Risks and Burdens
of Microbicide Trials Include:
 HIV testing considered biggest burden
 Discomfort during pelvic exam
 Long waiting times at clinic
 Feeling of loss at end of study
 Worries about side effects

15. Community Burdens and Benefits
 Risks and Burdens
Possible stigma
Diversion of local health personnel
 Benefits
Improved health infrastructure
Training
Community education on HIV/research
Preferential access to product if it proves
effective

16. Will participating in trials increase
people’s risk of HIV?
 Generally, no...
 People will become infected during the trial but not because of
the trial
 People in both arms should have lower HIV prevalence than
people in the general community
Condoms only
`
Before trial During Trial
Condoms +
placebo gel
Condoms +
microbicide
(if it works)
Risk
Condom only

17. Important Ethics Concepts

18.  Equipoise is a state of genuine uncertainty or
doubt about whether one intervention or
treatment is superior to another
 Equipoise is a necessary condition for clinical
research to be morally acceptable
 If the scientific community “knows” that one
treatment is better than another, it would be
considered unethical to withhold it
 Questions remain, however, about how to
decide when “scientific or clinical consensus”
exists about the relative merits of different
treatments
Equipoise

19. “Therapeutic misconception” refers to the
tendency of some research participants to
wrongly assume that whatever drug or
intervention they are offered must work or be
beneficial (or why would it be offered?)
It occurs when the goals of research and
those of therapy or “health care” become
confused in the participants mind.
The therapeutic misconception is a major
threat to “informed consent.”
Therapeutic Misconception

20. Voluntary informed consent is the agreement
given by a well-informed person who:
Has received the necessary information
expressed in spoken words and in writing;
Has adequately understood the information;
and
Has made the choice to participate (or not
participate) without coercion.
Voluntary Informed Consent

21. Essential Elements for Informed Consent
 Research description (what is being studied, what is the
procedure, who is sponsoring the study?);
 Risks of participating;
 Benefits of participating;
 Alternatives to participation, such as other studies or
services in the area;
 Assurance that information will be kept confidential;
 Compensation for time, travel or possible harm;
 Contacts (whom to contact with questions/concerns);
and
 Voluntary participation and withdrawal.

22. Informed Consent, Cont’d
 Adequate understanding includes the difference
between research and health care
 related concept: “therapeutic misconception”
 After thinking seriously about the information, the
person can arrive at a decision without being forced,
threatened or offered something so valuable that
free choice is impossible
 related concepts: “coercion” and “undue
inducement”

23. Legal and moral agenda can sometimes conflict
Indemnify the research institution
VERSUS
Facilitate collaborative decision making
Length of forms
Degree of technical information imparted
Written versus oral consent
Emphasis on right to withdraw

24. Informed Consent is a Process
 Informed consent is a process of collaborative
communication and decision making, not the signing of a
form
 Informed consent requires that prospective participants:
 Be appropriately informed about the nature of the research
 Adequately understand this information and its implications
 Voluntarily decide to participate, without coercion
 Explicitly consent to participate, orally or in writing

25. Discussion questions:
What are good ways to convey this kind
of information to people to ensure that
if they agree to participate in a study,
they are giving informed consent?
How do you know if people have
understood the information and are
making a free choice to participate?
Activity

26. Balancing respect for culture and respect for persons
 concept of “individual autonomy” may be
in conflict with entrenched cultural norms
or expectations
 example: may be expected that a woman’s
husband has the right and authority to
make decisions regarding her health care
 While recognizing local value and ethical
pluralisms, ethics is also concerned with
universal principles of conduct

27. A microbicide study is taking place in an African country.
Focus groups in the community have shown that many
women are interested in a microbicide because they are not
able to negotiate condom use with their partners. Many
women are coming to the study clinic to enroll in the trial.
A community advisory group is formed with community
leaders and representatives. A male member of the group
says that he does not approve of the study because the
women are not required to get the consent of their partners
to enroll.
A local women’s group expresses concern that a woman
who enrolls in the trial without telling their partner risks
being harmed if her partner finds out she is participating.
Case Study – Informed Consent

28. In some settings it is generally expected that a
woman’s husband has the right and authority
to make decisions regarding her health care
In this instance, how should one balance respect
for persons with respect for culture?
Should sexual partners be involved? Are there
creative strategies for encouraging partner
engagement?
What might you recommend as an appropriate
way to respect both of these values in this
instance?
ACTIVITY

29. OVERVIEW OF ROLE
OF VARIOUS PLAYERS

30. Who?
Ethical
Research

31. Who Decides?
 Decisions have to be made about what the
acceptable balance is between risks and benefits
 CABs and ethics committees can help judge
acceptability of risk:benefit ratio overall
 The informed consent process helps an individual
make his/her own judgment about the risks and
benefits
 The health and well-being of the participant can
never be sacrificed for “research’s sake” or the
“greater global good”

32. Who are the Players in HIV NPT
Research?
 Academic researchers and universities
 Community members and organizations,
community advisory boards
 Private sector – pharmaceutical and biotech
companies
 Government funders and regulators
 Health care providers

33. Academic Researchers
Basic Researchers
 lead the scientific discovery and development of NPT
candidate concepts and products
Clinical Researchers
 lead the clinical testing of candidate NPT products, testing
efficacy as well as issues of acceptance and accessibility
 establish and maintain the highest standards of ethical
conduct of clinical trials
Social Researchers
 conduct research on acceptability, preparedness, access and
delivery issues
 work alongside clinical research to understand usability and
acceptance of NPTs

34. Community Roles
 develop community acceptance and preparedness for NPTs
 anticipate and mitigate stigma associated with trial
 raise awareness about the role community based
organizations can play before, during and after trials
 facilitate clinical trial recruitment
 incorporate NPTs into prevention education and training
programs for specific vulnerable populations
 develop strategies for promoting and distributing NPTs once
available
 advocate for investment in NPT research and development

35. Private Sector
 invest in research and development, manufacturing and
production
 technical innovation
 establish clinical infrastructure (e.g., epidemiological
laboratories, trials infrastructure) during the pre-clinical
development of the NPT that will be needed in clinical
research
 translational research: generate data, clinical materials

36. Why aren’t large
pharmaceutical
companies
investing?
 Perceived low
profitability
 Liability concerns
 Lack of in-house
expertise
 Uncertain regulatory
environment
Public Funding is Essential
Global Annual Microbicides R&D
Investment 2009 in USD$ millions
Source: HIV Vaccines and Microbicides
Resource Tracking Working Group

37. Government Funders and
Regulators
 provide funding for NPT research programs,
academic researchers, conferences
 coordinate domestic and global efforts
 ensure that adequate clinical research facilities
exist
 ensure availability of properly trained staff
 help build public awareness and support for
research and development
 achieve speedy and appropriate access once a
NPT becomes available

38. Health Care Providers
 Monitoring, prevention and control of
HIV/AIDS and STIs
 Help with NPT delivery, education and
access
 With ARV-based NPTs, may need to be
prescribers

39. COMMUNITY
ENGAGEMENT

40. WHAT DO WE MEAN
BY COMMUNITY?

41. Competing & Changing
Definitions of Community
 “…separate and overlapping groups of people who are
infected and affected by HIV in various ways”
Good Participatory Practice, UNAIDS/AVAC
 “ …trial participants, their families and partners, other
local stakeholders, and service providers/community
groups within the geographic parameters of the clinical
trial location.
MDS Civil Society Working Group Report
 “…the group of people who will participate in or are
likely to be affected by or have an influence on the
conduct of the research.”
HIV Prevention Trials Network, Community Program FAQs

42. …Or No Definition At All
In addition to many competing
definitions, often times people talk about
“community” without defining what they
mean or who they are specifically
referring to

43. Locating Community
 When we talk about community, it is
important to frame the discussion in
terms of:
 Who is included in the particular “community”
we are discussing?
 And distinguish which “level” we are referring
to

45. “Trial Participants &
Study Staff”
refers to the
individuals directly
participating in the
trial, in some
instances their
partner(s), and study
staff working at the
trial site.

46. “Host Community”
refers to the individuals
living in the area of the
trial, their leaders, and
community-based
organizations that serve
or represent them
directly. This can also
include traditional
healers, local radio, and
other community
structures (including
CABs)

47. “National Stakeholders”
describes anyone who has a
role to play in the political,
scientific, and social
enterprise of microbicide
development in the larger,
national community.
It includes political decision-
makers, MoH, regulatory
bodies, ethical review
committees, national NGOs,
donors, national media, etc.

48. “International
Civil Society”
refers to non-profit,
organized, citizen-led
movements or groups
interested in the goals,
process, and outcomes
of microbicide research,
and/or in the rights of
communities or research
participants.
Civil society includes
international or regional
NGOs (GCM/UNAIDS),
international
or media.

49. • Power imbalances exist across multiple
lines: Principal investigators versus field
staff, Northern researchers versus
Southern; community versus research
enterprise; within communities and CABs
• One goal of community involvement and
NPT advocacy is to work towards reduced
power disparities
• Pretending that power imbalances do not
exist, however, breeds the worst form of
tokenism
Issues of Power

50.  Ethical principle of beneficence
 Maximize benefits and minimizes risks for
participants and for host communities.
 Minimize exposure to controversy and risk of
disruption
 Increase the transparency and accountability of
the research to the community
 Improve quality of trials, participant retention,
adherence and accurate self-reporting: ensuring
trial procedures are acceptable to participants
and other decision-makers
 Strengthen local capacity and infrastructure
Why do we need
Community Involvement?

51. Community Involvement Strategies
 Community advisory structures (CABs, CAGs, CACs,
participant representatives)
 Community preparedness
 Community mappings
 Radio & local media
 Dramas and community events
 Network community working groups
 Cross-network community involvement

52. Community Advisory Groups
 Also Community Advisory Boards (CABs)
 CAGs are now required by many research
sponsors and trial networks
 A CAG is a group of volunteers from the general
public and from the diverse communities
affected by a condition like HIV/AIDS
 A CAG is organized to assist and advise
researchers within a given network or site

54. • Why is so
much blood
taken?
• What do you
do with the
left over
blood?
• Are the
needles
safe/clean?

55. “No one wins when a trial is stopped for non-scientific
reasons. But the only way to prevent this is to invest
the time and resources needed to build the kind of
mutual trust on which collaborative partnerships can
be based.”
-
Anna Forbes & Sanushka Mudaliar
Preventing Prevention Trial Failures: A Case Study and Lessons for Future
Trials from the 2004 Tenofovir Trial in Cambodia

56. “We will not let Cambodians be
used as guinea pigs…”
Cambodian prime minister

57. Case Study: Cambodia Tenofovir Study
 2003: Preparations begin for the conduct of a tenofovir
PrEP study among sex workers in Phnom Penh
 Many miscommunications and misunderstandings
between community groups and researchers
 Protests at the International AIDS Conference, Bangkok
 Press release by activist groups denounce trial
 Media storm & negative reaction from Cambodia PM
 2004: Trial halted by Cambodia government

58. Cameroon falls next

59. Lessons Learned:
Community Consultation
 Must extend beyond local trial
community to include NGOs and
other opinion leaders and
stakeholders
 Requires adequate lead time and a
specialized skill set;
 Must begin early when input can
still effect change
 Demands separate line item in the
budget
 Formative research cannot
substitute for a consultative
process

60. ~ Global Campaign for Microbicides
Authentic Community
Involvement
Partnership and
Mobilization
Research
implementation exists
alongside specific
process goals that
strengthen the role
and capacity of
community to
articulate and address
its own development
needs including future
research priorities.
Historical
No involvement
of community
except as pool
from which to
draw research
participants
Advisory
Community
representatives
provide input
into specific
areas of the
study as
requested by the
research team
Collaborative
Community
representatives
and research
team cooperate
in developing
and
implementing
the research
Evolution of Norms for Community Involvement in Research

61. DYNAMICS OF
NORTH-SOUTH RESEARCH

62.  Ethically, researchers must provide
participants with medical care and
compensation for study-related injuries
 Legally, researchers may not have to
provide treatment and compensation
 For example, US law only requires that
study participants be told what types of
compensation or treatment will be
available
Researcher Obligations

63.  A person’s duty to benefit another is
related to his or her capacity to do so,
whether financial or practical.
 If a benefit cannot be provided for reasons of
practical constraint, the duty to do so is
weakened.
 Conversely, if a country’s wealth allows it to
confer a benefit on the inhabitants of
another country, the wealthier country has a
stronger duty to provide that benefit
“Can” implies “Ought”

64. An alternative articulation of
Core Ethical Principles
 The duty to alleviate suffering
 The duty to show respect for persons
 The duty to be sensitive to cultural
difference
 The duty not to exploit the vulnerable or
less powerful
(Nuffield Council on Bioethics, 2002)

65. PUTTING IT ALL
TOGETHER:
WHAT MAKES
RESEARCH ETHICAL?

66.  Social or scientific value
 Scientific validity
 Fair subject selection
 Favorable risk-benefit ratio
 Independent review
 Informed consent
 Respect for potential and enrolled subjects
 Collaborative partnership
(Emanual et al., JAMA, 283, 2000)
What Makes Research Ethical?

67. 1. Priorities: Did the study address a priority issue? Whose?
2. Planning: Was the study well designed to optimize the chances of
generating useful knowledge and protecting subjects?
3. Permission: Was the project reviewed and cleared by the
relevant institutions? Did the investigators obtain informed
consent?
4. Performance: Was the study conducted in a way that respected
the rights of the subjects and minimized the risks to them?
5. Processing: Were the results correctly analyzed and interpreted?
6. Publication: Were the results published and disseminated?
7. Programming: Have the findings been translated to policy and
action?
Seven Steps for Ethical Research

68. STANDARD OF
PREVENTION AND
CARE FOR TRIAL
PARTICIPANTS

69. The term “Standard of care” refers to the
nature of the prevention and/or care that will
be provided to participants in research
 the general care and treatment that
investigators agree to provide all
participants in clinical research
 the quality of care that should be provided
to people in the control arm of a RCT – i.e.
those that are not receiving the
experimental intervention
Standard of Care

70. The Standard of Care Debate
 The appropriate “Standard of Care” in international trials has
been subject to intense discussion and debate
 Debate heated up around controversial HIV trials to prevent
mother to child transmission in the developing world
 Commentators questioned the ethics of trials that used a
“placebo” when an existing regimen 076 had been shown to
reduce peri-natal transmission of HIV in the United States
 Defenders argued that the 076 protocol was not “relevant” to
the health care needs or priorities of the developing world,
because it could not viably be implemented

71. 076/Placebo Controversy
 Is it ever acceptable to have different standards
of health care in different parts of the world?
 Should the control arm receive a “universal”
standard of care (i.e. the best available
anywhere) or is some other standard morally
acceptable?
 Pits principle of non exploitation of those who
are vulnerable against the desire to generate
findings that are relevant to and sustainable in
the settings where they are needed

72. “I believe that our ethical standards should not depend
on where the research is performed. Furthermore I
believe the nature of investigator’s responsibility for
the welfare of their subjects should not be influenced
by the political or economic conditions of the region. In
practical terms any other position could lead to the
exploitation of people in developing countries, in order
to conduct research that could not be performed in the
sponsoring country.”
Marcia Angell, Editor, NEJM
Universal Standard Position

73. Ratcheting Up Standard
“As it is unlikely that an overall universal standard of
care can be rapidly achieved in research projects in
developing countries, the goal should be to
implement reasonable standards that are
significantly higher than available in the host country
and closer to standards in the sponsoring country.
These ideas should be applied in a way that
progressively ratchets SOC upwards, both for
subsequent research projects and for local health
care infrastructure through genuine partnerships and
capacity building, leaving participants and their
communities better off after the trial than before.”
Shapiro and Benatar, 2003

74. What does ethics guidance say?
Individuals in the control arm must receive:
 “An established effective intervention” (CIOMS)
 “The best current prophylactic, diagnostic and therapeutic
method” (Declaration of Helsinki, 2002)
 Ideal: “best proven therapy;” Minimum: “highest level of care
attainable in light of … the circumstances listed" (UNAIDS
vaccine guidance)
 Ideal: “best proven;” Minimum: “the best intervention available
for the disease as part of the national health system” (Nuffield
Council)
 “Highest achievable” standard should be the goal (Benatar &
Singer, BMJ, 2000)

76. Standard of prevention and care in
biomedical prevention trials

77.  Informed consent can be undermined by
incentives that lead to “undue pressure”,
“coercion” or “undue inducement” to
participate
 An inducement may persuade an individual to
change his or her mind about entering a
research project, but this in itself is not
enough to make it inappropriate
 An “inducement” becomes inappropriate
when it causes a person to assume risks that
they would ordinarily view as unacceptable
(Nuffield Council on Bioethics)
(Undue) Inducement

78. How Do You Decide If It’s “Undue”?
Harmfulness: the nature of the potential risks to
the participant’s health
Proportionality: whether the inducement is in
proportion to the risks and costs of research
Vulnerability: whether prospective participants are
especially vulnerable to influence
Reciprocal Justice: someone who benefits from the
investment and sacrifice of others owes them
proportional recompense

79. “…access to all state of the art HIV
risk reduction methods”
 Traditionally means sexual counseling and condoms
 New HIV risk reduction methods should be added as
they are scientifically validated
 Would that include a partially effective vaccine or
microbicide when available? PrEP? Male
circumcision?
 Red herring: this requirement could make it difficult
(impossible?) to analyze results of HIV prevention
trials
 Undue burden on researchers?

80. SOC Debate as Applied to Microbicides
 What package of prevention services should participants in
the control arm of a trial be provided?
 High standard HIV counseling, condoms, STD screening,
treatment?
 What other care should be provided during the trial?
 Pap tests? Family Planning? Malaria Rx?
 What HIV care should individuals who seroconvert during
the trial be provided?
 TB prophylaxis, nutrition counseling, support groups,
MTCT, ARVs?
 What care, if any is due women who are screened out of the
trial because they are already HIV+?

81. STEP Trial
 Found enhanced susceptibility to HIV among
those in the experimental arm = trial related
harm
 Calls for enhanced obligation to patients for care
and treatment follow-up – monitoring of viral
loads and ARV
 BUT no time limit was discussed – generally
accepted as 5 years

82. Balancing methodological and ethical gold standards
 Should future trials exclude uncircumcised
men?
 Should trials offer/require/encourage
circumcision among male participants?

83. Thai PrEP trial
Ethics Case Study

84. Thai PrEP Trial
 CDC trial in Thailand: examining the safety and efficacy of
tenofovir as PrEP
 Conducted in collaboration with the Bangkok Metropolitan
Administration and the Thailand Ministry of Public Health
 is enrolling 2,400 HIV-negative intravenous drug users (IDUs)
– male and female – at 17 drug treatment clinics in Bangkok
 Participants are recruited at the drug treatment clinics, at
community outreach sites, and through a peer referral
program.
 No clean needles or needle exchange being provided to
participants

85. 1. Which ethical principles are potentially being
violated in the Thai PrEP trial?
2. Should the researchers be expected
to provide needle exchange when such
programs are not available in Thailand?
3. How could the trial have been designed to
be more ethical?
4. What impact do you think these ethical
concerns have on the validity of the trial
results?
Discussion Questions

86. Standard of Care and Prevention
How do we choose?
 Unilateral decision – FDA regulations?
 By following existing country standards?
 Consensus following debate – Helsinki
 In consultation with research participants
 By considering the reasons or motivations for
the research—crucial introspection
 Using research to improve health care
 -- Solomon Benatar, University of Capetown

87. Standard of Care
How do we achieve new ideals?
 Heightened sensitivity to exploitation
 Aim for reasonable practical limits
 Ratchet the standard upwards
 Build capacity through real partnerships
 Follow the ‘spirit’ of Declarations
 Avoid ‘cook-book’ attitudes to ethics
 Consider: context / safety / logistics / harm
benefit / sustainability

88. Use of ARVs for
Prevention versus
Treatment

89. The convergence of treatment and
prevention
 Can Antiretroviral treatment provide the best
prevention intervention?

90. “In view of the potential effect of HAART on HIV
transmission, what would be the implications of an
alternative prevention-centred strategy for the use of
HAART? This approach would be based on the notion that
new HIV infections are overwhelmingly contributed to by
index HIV-infected individuals who are not on HAART. A
prevention-centred approach would therefore argue that
treating 100% of HIV-infected individuals at once could
greatly reduce HIV transmission. While this would be costly in
the short term, it could prove highly cost effective. The
short-term cost of treatment of all HIV-infected individuals
would be more than offset by the number of new infections
that it would prevent.”

91. DEBATE
Should ARVs be
prioritized for prevention
or for treatment?
PrEP Case Study

92. Debate
 Group 1: Form three arguments for focusing ARV
distribution globally on treating people already
infected with HIV
 Group 2: Form three arguments for focusing ARV
distribution globally as a prevention method with
those who are not yet infected
 Plenary debrief: which argument is more
convincing and why?
 Consensus statement