Transcript Topical Microbicides: New Hope for STI/HIV Prevention

Ethical Challenges in Clinical Testing of
Microbicides
On-Going Discussion
and Debate
Lori Heise
Microbicides 2004
GCM Role in Ethics
• GCM goals viz a viz ethics:
– Help give voice to community and civil society
perspectives on trial design and ethics issues
– Help forge consensus around ethical debates that
could delay progress
– Negotiate difficult line between urgency of the HIV
epidemic and maintaining rigorous ethical
standards
– Build capacity in the activist/community sector for
ethical deliberation and debate
Microbicide Ethics Consultations
Earliest ethics consultation initiated
by advocates in 1997 – 55
participants from 23 countries
Pre-dated launch of phase II or III
studies of novel microbicides in
developing countries
Ethics working group of HPTN
Global Campaign ethics
consultations held in March and
October of 2004
Special Challenges in Microbicide
Trials
•
•
•
•
•
•
Complex clinical trial design
New, unfamiliar type of product
Healthy individuals -- yet at “high risk”
Results affected by user behavior
Sensitive issues – sex, power, gender
Stigma associated with HIV and sexual
activity
• Transnational collaborations
Experience of a Phase 3 participant
Family Planning
Condom
plus placebo
INFORMED
CONSENT to
be SCREENED
Recruitment:
Participant
receives
information
about the
trial.
INFORMED
CONSENT to
be ENROLL
Screening Visit 1:
Education about
the trial, HIV and
pregnancy test,
STD tests and
treatment, baseline
data collected
Screening Visit 2:
Results of tests,
counseling,
reinforce
education about
trial
Raqndomization:
Participant
assigned by
chance to a
group.
Condom
only ????
Condom plus
experimental gel
Ethical Issues in Microbicide Trials
• Equitable distribution of burdens and benefits -Avoiding exploitation
• Avoiding “wishful thinking” – also known as the
“therapeutic misconception”
• Standard of care for trial participants
– What package of prevention and care should be provided
to trial participants?
– What obligation do we have to those who seroconvert
during a trial?
Avoiding Exploitation
• “Are trial participants guinea pigs?”
– Based in historic experience of exploitation of
vulnerable populations for research
– Why are you doing the trial here?
– Need to “unpack” the issues and implications
around this statement.
Unpacking Concerns
• Who is conducting the research?
• Who benefits from the research?
• Why do the research among this population/
community?
• What will the research contribute?
• Are trial participants “expendable?”
• Who makes decisions about this research?
Why are most of the phase III trials
taking place in Africa and Asia?
• Microbicide trials require large numbers of women
at risk of vaginally transmitted HIV
–
–
–
–
High incidence
Relatively stable (non-transient population)
Little or no injection drug use
Anal sex relatively uncommon
• Most populations of women in the US or Europe
with high HIV incidence also use IV drugs
Sample Size Calculations
Effectiveness
20%
30%
40%
50%
60%
70%
80%
90%
Annual HIV Sero-Incidence
1%
2%
3%
4%
110266
46315
24539
14736
9560
6529
4621
3353
54638
22965
12176
7320
4753
3249
2304
1673
36094
15181
8056
4847
3612
2158
1532
1115
26824
11289
5995
3609
2351
1612
1144
835
5%
21259
8955
4760
2868
1868
1282
913
666
Notes: Significance level = .05, power = 90%, test statistics and log rank test, two-tailed, equal size
groups. Assumes 15 percent loss to follow-up. Figures prepared by Charlotte Ellertson and Kelly
Blanchard using nQuery (version 1.0) survival analysis option.
clinical trial sites
Antwerp, Belgium
London, UK
Washington, USA
Los Angeles, USA
Houston, USA
Birmingham, USA
Miami, USA
Dominican Republic
New York, USA
Cincinnati, USA
Providence, USA
Philadelphia, USA
Baltimore, USA
Norfolk, USA
Ghana
Côte d’Ivoire
Nigeria
Yaoundé, Cameroon
Brazil
Zambia
Botswana
India
Chiang Rai,
Thailand
Uganda
Tanzania
Malawi
Zimbabwe
South Africa
Alliance for Microbicide Development
Will participating in trials increase
women’s risk of HIV?
• Generally, no...
• Women will become infected during the trial but not
because of the trial
• Women in both arms should have lower HIV prevalence
than women in the general community
Condoms only
Condom only
Risk
`
Condoms +
placebo gel
Condoms +
microbicide
Before trial
During Trial
(if it works)
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” in microbicide trials
“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
• It has been used variously to refer to:
– the general care and treatment that investigators agree
to provide all participants in clinical research
• And more specifically to:
– 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 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
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?
Investigator’s Dilemma
The more effective your prevention package is, the more
difficult it becomes to determine whether the product works
Standard of Care (continued)
• What other health 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+?
Issues raised
• Is it ever ethical to provide different health packages
in different settings?
• Should we be more concerned about North/South
inequities or exacerbating local inequities?
• Is it possible to conduct ethical research in a
fundamentally unjust world?
• Whose voices should be part of the decision making
process?
HIV Treatment in the context of
prevention trials
• Discourse has changed dramatically since 1997 – ART not
even topic of discussion at the first microbicide ethics
consultation
• Long and complex discussion has taken place in the vaccine
community – led by UNAIDS
• In earlier UNAIDS regional consultations delegates were
unable to reach consensus over whether vaccine trials should
guarantee access to ART
• Drop in drug prices has re-kindled debate and brought ART
within grasp of the developing world
Divergent Regional Conclusions
UNAIDS Vaccine consultations 1998-2001
• Brazil: At the level of the sponsor country and should include
ART at least for the duration of the trial and longer, if so
negotiated
• Thailand: At a level decided upon by the host country,
including monitoring, prevention and treatment of
opportunistic infections and palliative care, but not necessarily
including ART, but what ever provided should be made
reasonably available for the lifetime of the participants
• Uganda: At the level consistent with that available in the host
country; there is no imperative to provide a level of care
consistent with that in the sponsoring country or with the
highest available in the world.
Competing considerations
•
Belief that sponsors have an ethical obligation to provide care and
treatment according to their resources
•
A desire to achieve equity in care and treatment received by
participants in sponsor and host countries
•
Belief that participants deserve the best available care in light of the
risks they have assumed for the larger good
VS.
•
Concern by some that promising ART to trial participants might
create “undue inducement” to participate if drugs are otherwise
unavailable locally
•
Concern that providing ART only to trial participants might
exacerbate local inequities and create problems within families and
communities
Competing Considerations (continued)
• The notion that sovereign nations and communities have the
right to determine for themselves the balance of risks and
benefits they are willing to accept
• Concern that governments might abdicate on their responsibility
to provide care and treatment if sponsors fill this role
• The belief that host communities themselves should have a say
in helping decide the package of care and services that
maximize the benefit of the trial to participants and the
community
• Desire to ensure that poorer countries could continue to attract
research to their countries in order to address the critical need
of their populations for an HIV vaccine
Discussion in Microbicide World
•
Enormous commitment to improving local standard of care, including
HIV care
•
Less clarity that ART should be guaranteed in all cases – concern to
also emphasize other aspects of care
•
Trial sponsors are actively debating their policies, and exploring
mechanisms for providing care
•
Interest in getting more input from the host communities on their
opinions
•
Concern about local inequities created, including what to do with
hundreds of HIV positive women screened out of trials
•
Recognition that what vaccine community does may create precedent
for other prevention trials
Emerging consensus among vaccine trial
sponsors
•
Participants who seroconvert during a trial should be provided
treatment, including ART
•
Still disagreement about whether this is an ethical minimum/
obligation, or a morally praiseworthy act
•
Continued debate about whose obligation it is to provide this
treatment – the trial sponsors, host country governments, sponsoring
nations?
•
Clear commitment to try to leverage outside resources to maximize
likelihood that ART will be made available in trial communities
•
Focus to date has been on treatment of those who seroconvert, not
those screened out, partners of family members.
The debate continues…
• Is access to ART the best way to maximize justice
and social good in microbicide trials?
• Is it fair for participants to get ART, but those who
are screened out get nothing?
• Would it be better to provide less high tech care to
more people?
• Is the sustainability of an interventional morally
relevant?
• Who should decide?
Moving the debate from Geneva to
Capetown
• Ethics is a process of moral reflection, not a set of rules
• How decisions are arrived at is ethically relevant
• Whose voice is represented in the debate is therefore
important
• Advocates and communities must prepare themselves to
become active participants in these debates
GCM Course in Ethical Reasoning