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New Prevention

  Module 6:
 Overview of research ethics: origins, guidelines,
   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
   Use of ARVs for prevention vs treatment
What is “Ethics”?

      is a way of understanding and
 Ethics
 examining what is “right” and what is

 Bioethicsis a way of understanding and
 examining what is “right” and what is
 “wrong” in biomedical research and

What is your understanding of these
words ?
  Respect
  Harm
  Fairness
Principles of Research Ethics

    Respect for Persons

    Beneficence/Non-Maleficence

    Justice/Non-Exploitation
Respect for Persons

  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

 Protection of the study participants is the
  most important responsibility of the

 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.

 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.

   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.

What are the potential     What are the potential
RISKS of becoming          BENEFITS of becoming
involved in a prevention   involved in a prevention
trial?                     trial?
    For participants?         For participants?
    For communities?          For communities?
Participant Risks vs. Benefits

           RISKS                     BENEFITS

 Biologic/Physical           Improved access to
 Social/Emotional
                               health care
                              Better prevention
   From the product: side         Risk reduction counseling
    effects                        STD treatment
   From HIV/STI testing           Condoms
   Partner issues            Other
   Stigma                         Cash
                                   Sense of social
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”
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
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
   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
                                                        Condom only
Risk                                       `                          Condoms +
                                                                      placebo gel

                                                                      Condoms +
                                                                      (if it works)
             Before trial   During Trial
Important Ethics Concepts
 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
Therapeutic Misconception
“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.”
Voluntary Informed Consent

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;

    Has made the choice to participate (or not
    participate) without coercion.
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);
   Voluntary participation and withdrawal.
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
Legal and moral agenda can sometimes conflict

    Indemnify the research institution
  Facilitate collaborative decision making

Length of forms
Degree of technical information imparted
Written versus oral consent
Emphasis on right to withdraw
Informed Consent is a Process

 Informed consent is a process of collaborative
  communication and decision making, not the signing of a
 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
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?
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
     Case Study – Informed Consent
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.
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
 What might you recommend as an appropriate
  way to respect both of these values in this

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
   The health and well-being of the participant can
    never be sacrificed for “research’s sake” or the
    “greater global good”
Who are the Players in HIV NPT
 Academic researchers and universities
 Community members and organizations,
  community advisory boards
 Private sector – pharmaceutical and biotech
 Government funders and regulators

 Health care providers
 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
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
   advocate for investment in NPT research and development
Private Sector
   invest in research and development, manufacturing and
   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
   translational research: generate data, clinical materials
          Public Funding is Essential
                              Global Annual Microbicides R&D
                             Investment 2009 in USD$ millions
                           Source: HIV Vaccines and Microbicides
Why aren’t large             Resource Tracking Working Group


   Perceived low
   Liability concerns
   Lack of in-house
   Uncertain regulatory
Government Funders and
   provide funding for NPT research programs,
    academic researchers, conferences
   coordinate domestic and global efforts
   ensure that adequate clinical research facilities
   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
Health Care Providers

   Monitoring, prevention and control of
    HIV/AIDS and STIs
   Help with NPT delivery, education and
   With ARV-based NPTs, may need to be
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
…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
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
“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.
   “Host Community”

refers to the individuals
living in the area of the
trial, their leaders, and
organizations that serve
or represent them
directly. This can also
include traditional
healers, local radio, and
other community
structures (including
  “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.
      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
or media.
    Issues of Power
•   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
    Why do we need
    Community Involvement?
   Ethical principle of beneficence
   Maximize benefits and minimizes risks for
    participants and for host communities.
   Minimize exposure to controversy and risk of
   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
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
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
• Why is so
  much blood

• What do you
  do with the
  left over

• Are the
“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
“We will not let Cambodians be
   used as guinea pigs…”
       Cambodian prime minister
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
Cameroon falls next
Lessons Learned:
Community Consultation
                   Must extend beyond local trial
                    community to include NGOs and
                    other opinion leaders and
                   Requires adequate lead time and a
                    specialized skill set;
                   Must begin early when input can
                    still effect change
                   Demands separate line item in the
                   Formative research cannot
                    substitute for a consultative
       Authentic Community Involvement

Evolution of Norms for Community Involvement in Research

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

                                       ~ Global Campaign for Microbicides
Researcher Obligations
 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
“Can” implies “Ought”
 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
   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
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
   The duty not to exploit the vulnerable or
    less powerful
                (Nuffield Council on Bioethics, 2002)
What Makes Research Ethical?
 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)
           Seven Steps for Ethical Research
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
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
Standard of Care
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
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
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
 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
 Universal Standard Position

“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
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
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
 “Highest achievable” standard should be the goal (Benatar &
  Singer, BMJ, 2000)
Standard of prevention and care in
biomedical prevention trials
(Undue)        Inducement
 Informed consent can be undermined by
   incentives that lead to “undue pressure”,
   “coercion” or “undue inducement” to
 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)
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
“…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
   Red herring: this requirement could make it difficult
    (impossible?) to analyze results of HIV prevention
   Undue burden on researchers?
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,
   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+?
STEP Trial
   Found enhanced susceptibility to HIV among
    those in the experimental arm = trial related
   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
Balancing methodological and ethical gold standards

  Should future trials exclude uncircumcised
  Should trials offer/require/encourage
   circumcision among male participants?
Thai PrEP trial
Ethics Case Study
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
   No clean needles or needle exchange being provided to
Discussion Questions
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
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
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
Use of ARVs for
Prevention versus
The convergence of treatment and
   Can Antiretroviral treatment provide the best
    prevention intervention?
“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.”
Should ARVs be
prioritized for prevention
or for treatment?

PrEP Case Study
   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

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