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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
What is Ethics?
Ethics
is a way of understanding and examining what is right and what is wrong is a way of understanding and examining what is right and what is wrong in biomedical research and practice.
Bioethics
Activity
What is your understanding of these words ? Respect Harm Fairness
Beneficence/Non-Maleficence
Justice/Non-Exploitation
Beneficence/Non-Maleficence
Protection
being of each research participant; Minimizes physical and social risks; Maximize the possible benefits; and Retain the community perspective.
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.
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.
BENEFITS
Improved access to
Risk reduction counseling STD treatment Condoms Cash Sense of social contribution
Other
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
Benefits
Improved health infrastructure Training Community education on HIV/research Preferential access to product if it proves
effective
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
Before trial
During Trial
(if it works)
Therapeutic Misconception
Equipoise
Equipoise
Equipoise is a state of genuine uncertainty or
decide when scientific or clinical consensus exists about the relative merits of different treatments
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.
and
Has made the choice to participate (or not
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.
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
Length of forms Degree of technical information imparted Written versus oral consent Emphasis on right to withdraw
Activity
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?
husband has the right and authority to make decisions regarding her health care
While recognizing local value and ethical
ACTIVITY
In some settings it is generally expected that a womans 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?
Who?
Ethics Committees and Review Boards
Ethical Research
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 researchs sake or the greater global good
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
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
Global Annual Microbicides R&D Investment 2009 in USD$ millions Source: HIV Vaccines and Microbicides Resource Tracking Working Group
Perceived low profitability Liability concerns Lack of in-house expertise Uncertain regulatory environment
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
COMMUNITY ENGAGEMENT
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:
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 community-based organizations that serve or represent them directly. This can also include traditional healers, local radio, and other community structures (including CABs)
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 decisionmakers, MoH, regulatory bodies, ethical review committees, national NGOs, donors, national media, etc.
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.
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 tokenism
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 advisory structures (CABs, CAGs, CACs, participant representatives) Community preparedness Community mappings
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 taken? What do you do with the left over blood? Are the needles safe/clean?
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
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
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
Collaborative Community representatives and research team cooperate in developing and implementing the research
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.
Researcher Obligations
Ethically, researchers must provide
confer a benefit on the inhabitants of another country, the wealthier country has a stronger duty to provide that benefit
The duty to alleviate suffering The duty to show respect for persons The duty to be sensitive to cultural difference
Collaborative partnership
(Emanual et al., JAMA, 283, 2000)
3.
4. 5. 6. 7.
generating useful knowledge and protecting subjects? Permission: Was the project reviewed and cleared by the relevant institutions? Did the investigators obtain informed consent? Performance: Was the study conducted in a way that respected the rights of the subjects and minimized the risks to them? Processing: Were the results correctly analyzed and interpreted? Publication: Were the results published and disseminated? Programming: Have the findings been translated to policy and action?
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
to people in the control arm of a RCT i.e. those that are not receiving the experimental intervention
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
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
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.
(Undue)
Inducement
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)
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?
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+?
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
men?
Should trials offer/require/encourage
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
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 results?
Standard of Care
How do we achieve new ideals?
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.
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