Transcript The tipping point: When do placebos become unethical

The tipping point: When do
placebos become unethical?
Bridget Haire
Overview
• PrEP= pre-exposure prophylaxis= HIV negative
people taking antiretroviral drugs to reduce
HIV risk
• Outline the evidentiary context for preexposure
• Critique a current French PrEP trial
• Consider precedents in HIV prevention
research
• Assess the ramifications of this approach
Study
Population
iPrEX
Men who have sex 44%
with men
FTC/TDF
Serodiscordant
67% TDF
couples
75% FTC/TDF
Heterosexual
62% FTC/TDF
people
Partners PrEP
TDF-2
Result
FEM PrEP
Women
Futility FTC/TDF
VOICE
Women
Futility TDF
Futility TDF gel
Futility FTC/TDF
Bangkok PrEP
People who inject
drugs
49% TDF
PrEP (FTC/TDF) approved by US FDA for
prevention of HIV
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From: US Food & Drug
Administration
When: 16 July 2012
For: Gilead Sciences oral
TDF/FTC in the US
What: Regulatory approval
in
• the US for daily oral TDF/
• FTC (Truvada) for PrEP in
• HIV-negative adults
Efficacy and adherence
• Bangkok: 71% in DOT participants
• iPrEX: 92% in high adherers (measured blood
levels)
• FEM-PrEP: less than ¼ of participants had
detectable drug levels
• VOICE: less than half of participants on active
drug had detectable blood levels
Ipergay
• Tests intermittent PrEP
against placebo in gay
men/MSM
• France and Canada
• Began in Feb 2012
• No marketing
authorisation for PrEP
in the European Union
Rationale
• Optimal design for ‘rigorous assessment’
• Reduce risk of behavioural disinhibition*
• FTC/TDF has not been evaluated in ‘real life’
conditions in USA
• No detrimental in terms of prevention and
health promotion
• Participants would be no worse off
Rationale for best practice for research
participants
• Prevents vulnerable* participants being used
to test drugs for those more privileged
• People enrolled in HIV prevention trials are
generally at the highest risk of HIV infection
• Best practice standards of care recognise the
contribution that research participants make
to the research endeavour
Guidelines
• UNAIDS 2007, updated 2012
• Declaration of Helsinki 2008
• Council for International Organizations of
Medical Sciences (CIOMS) 2002
• HPTN 2009
UNAIDS, Guideline 13
• … appropriate counselling and access to all
state of the art HIV risk reduction methods are
provided to participants throughout the
duration of the biomedical HIV prevention
trial. New HIV risk-reduction methods should
be added, based on consultation among all
research stakeholders including the
community, as they are scientifically validated
or as they are approved by relevant
authorities…
HPTN Guideline 9
• In partnership with key stakeholders, HPTN
should establish a package of effective,
comprehensive and locally sustainable
prevention services to be offered to
participants in each HPTN study.
Response to Ipergay design
• ANRS consulted regarding continuation of study, and
concluded the study should continue as designed in
October 2012
• Decision based largely upon the scientific
committee’s advice that the FDA approval of PrEP
was not based on new information
• ‘Associative committee’ (community advisory board)
majority requested access to daily PrEP for
participants
• Minority disagreed
Community responses
• Split between ACT-UP Paris and Warning
• Warning called for Ipergay’s closure or change
to the design on ethical grounds
• Other community groups ruled themselves
not competent to judge scientifically or
ethically
• AIDES demanded ‘temporary marketing
approval’ of PrEP in France
Response to community critique
• ‘…whatever the randomization arm, the
enrolment of participants is not detrimental in
terms of prevention or health promotion’ ANRS
Press release
• Research organisation is setting up a working
group with non-profit organisations to discuss
optimisation of HIV prevention research
History repeating
• Mirrors aspects of the mother-to-child
prevention debate of 1997
• Like the mother-to-child controversy, the
argument for including a placebo in Ipergay is
both methodological (getting robust data) and
dependent on lack of access to the best
proven prevention option in the population
How Ipergay is different form the motherto-child debate
• Daily PrEP is clearly affordable and feasible in
a trial context in France, though it is not yet
available through the health system
Burning scientific question
• Would intermittent PrEP dosing work better or
worse that continuous daily dosing?
• Positivist view: Too many confounders in a
comparative study to isolate efficacy
• Rebuttal: the question is about situated
effectiveness of the different strategies
• Effectiveness rather than efficacy
Why choose a placebo-controlled
design? Summary
• Faster, cheaper, easier-to-interpret answer to
the question of whether intermittent PrEP is
effective
• Asserts the primacy of local regulations as key
in what constitutes standard of care
• Reinforces the lowest denominator regarding
what constitutes fair treatment of research
subjects: leaving them no worse off