Transcript Ethics in international Research

Ethics in international
Research
Justice across national
boundaries
Clinical Trials Group (ACTG) 076:
Vertical Perinatal HIV Transmission
Antiretroviral drug zidovudine administered
orally in the prenatal period, intravenously
during labor, and administered orally to the
newborn reduced HIV infection in the
newborn by two-thirds
Study terminated at first interim analysis
Within two months the Public Health
Service announced that HIV positive
women should receive this treatment.
Post-ACTG 076: USA
zidovudine was
estimated to have
reduced neonatal HIV
death by 50% in the
US and Europe.
Post ACTG-076: Africa
In Africa, accounting
for 70% of the global
HIV burden, therapy
played no role
because of cost
Therapeutic regimens
as effective but less
expensive than
zidovudine needed for
developing countries
Research design to search for a
less expensive regimen?
June, 1994, WHO convened expert panel to
advise research agenda for perinatal HIV
transmission
“Placebo-controlled trials offer the best
option for a rapid and scientifically valid
assessment of alternative antiretroviral
drug regiments to prevent [perinatal]
transmission of HIV.” (WHO 1994)
18 trials to explore alternative
interventions
* In trials conducted in the US, subjects in
all study groups had full access to
zidovudine or other antiretroviral drugs.
In 15 of the 16 trials in developing
countries, some or all of the patients were
not provided with antiretroviral drugs.
9/15 studies conducted in other countries
were funded by the US government
through the CDC or NIH.
Declaration of Helsinki
First written in 1962;
rewritten in 1975;
modified three times
since its rewrite.
All versions placed
the benefit and wellbeing of the subject
as the pre-eminent
concern
Debate over Declaration Revisions
establishment of general rather than local
ethical review committees
a more liberal view towards the use of
placebos; and
allowing for local determination of access
to health care
Polarization
“Some argued that the
proposed revision established
a model for human biomedical
research ethics that
encouraged utility and
efficiency at the expense of
patient autonomy and wellbeing. Those who defended
the amendments said they
were more in line with
contemporary ethical thinking
….”
Deutsch Edinburgh 2000
633-641
Declaration of Helsinki (2000)
Significant rewrite
Emphasizing again that the rights of the
individual should take precedence over the
interests of science and society
Emphasizes the protection of vulnerable
populations.
Local versus international rule unclear
Modification of Helsinki (2001)
Para 29: “The benefits, risks, burdens and
effectiveness of a new method should be
tested against those of the best current
…methods. This does not exclude the use
of placebo, or no treatment in studies
where no proven…method exists”
Amendment: “a placebo-controlled trial
may be ethically acceptable, even if a
proven therapy is available”(2001 revision)
Issues behind the Declaration
Local versus global standards of care
Informed Consent
Equipose
Placebo controlled studies versus no
placebo (“Science versus Ethics”)
Shared Burden of Risk/Equity
Standard of care: local versus
global
“A global view of justice,
which endorses
international equity,
cannot be squared with
international research
guidelines that allow
‘local conditions’ to define
the scope of duty to the
control group”
de Zulueta P Bioethics 2001
289-311
Standard of care: local versus global
(con)
Should the standard be the standard of the
host country, the standard of the
sponsoring country or some global
standard?
– Is it appropriate to assume that a standard set
by industrialized countries can be/should be
applied to developing countries?
– Should standards of care differ based on the
sponsoring country ?
Standard of care: local versus global
(con)
Many instances of possibly “unethical
exploitation” occur in a two-tiered system
* Local scientists and physicians argue that
only because of the two-tiered system did
their country have any access to these
studies.
An argument has been made that even if
the funding is external, if the researchers
are local, local standards can be used.
Standard of care: local versus global (con)
Are local investigators, who have much to gain both
financially and by reputation, by receiving funding
from the US, in the position to take an appropriate
ethical stance?
“,,,[A] local standard may benefit participants and nonparticipants alike in impoverished countries, but it comes at
the cost of using a double standard for what is considered
ethical human experimentation.”Rothman BMJ 2000 442-444
“...[t]he heated debate reflects a tension, if not an
outright war, between two conflicting meta-ethical
systems, or incommensurable paradigms, that underpin
scientific research involving human subjects…” de
Zulueta P Bioethics 2001 289-311
Informed Consent:
What constitutes “informed consent”---especially
among those who are vulnerable because of
age, mental or physical disability, level of
education, or degree of poverty?
Is it appropriate to ask a potential subject in a
developing country who lives under an entirely
different legal system to complete an informed
consent that is consistent with the legal
expectations of the sponsoring country
Can we explain concepts of risk and protection
to persons with little education?
Informed Consent, con.
Study in the Gambia of 137 acceptors and
52 refusors of Hemophilus influenza type
B conjugate:
* 90% knew purpose of vaccine was to prevent
disease
* 93% of acceptors did so to receive the vaccine
* “placebo control” was understood by only 10%
Leach et al Soc Sci Med 1999: 139-48
Informed Consent, con.
What does a vaccine that may have fifty percent
efficacy mean to an illiterate woman?
How do we establish that we have explained
something clearly?
Are some populations so vulnerable, so
dependent that the concept of “informed,
voluntary consent” may be unachievable?
Are genuinely consensual relations possible
between the research community and
participants who otherwise have little or no
access to healthcare or other basic rights and
liberties?....
Equipoise
The state in which we have no reason to
believe that one experimental condition or
intervention is superior to another
“The necessity for investigators to be in
this state of equipoise applies to placebocontrolled trials, as well. Only when there
is no known effective treatment is it ethical
to compare a potential new treatment with
a placebo”. Angell NEJM 1997 847-849
Placebo Control versus no
control (“Science versus ethics”)
Equipoise: the gateway to and the foundation
for a placebo-controlled trial.
The randomized, placebo-controlled trial is
upheld as the paradigm of the excellence in
science
If there is not equipoise, there is not a basis for
genuine scientific query
Is the overarching need for a placebo-controlled
trial “placing science ahead of ethics”?
Placebo Control versus no control
(“Science versus ethics”) (con.)
Placebo group provides the benchmark
Placebo-controlled trials withhold existing
therapy in order to further observe the
natural course of infection and disease
Placebo=a fixed and reliable reference
point ?
At times already approved medications
can be ineffective
Reasonable risk
Central component of justice: individual or
group should neither shoulder a
disproportionate percentage of risk nor
receive more than “fair share” of benefits
~90% of medical research conducted on
diseases that cause only 10% of the global
burden of disease
Reasonable Risk, con.
Is this a fair sharing of the burden of risk? Of the
possible benefit? If he were to receive a
higher sum, would this make the study
more ethical—or less ethical? Would
offering him a lower stipend for
participation make it more ethical? Is
there a different way that he could be
compensated? Would the “ethics” change
if the disease prevalence remained the
same in his country, but relative to other
diseases, it was more prominent?
Reasonable Risk, con.
Would it change if his education level
were higher? Are we concerned that he
cannot understand the concept of a
vaccine that is 65% efficacious? Would it
change if he were not a peasant farmer
but were a US soldier stationed abroad
would the situation be more ethical? If
the sponsoring agency were not the US
but his own country, would this change the
ethics of the situation?
“Fair Benefits": An ethical solution
or a utilitarian compromise?
Benefits to Participants During the Research
Improvements to health and health care
Collateral health services unnecessary for research stud
Benefits to Population During the Research
Collateral health services unnecessary for research
Public health measures
Employment and economic activity
Benefits to Population After the Research
Reasonable availability of effective Research and
medical care capacity development
Public health measures
Long-term research
Sharing of financial rewards from research results
Supplemental components to “Fair Benefits
* Collaborative Partnership
Community involvement at all stages
Free, uncoerced decision-making by population
bearing the burdens of the research
* Transparency
Central, publicly accessible repository of benefit
agreements
Process of community consultations
Ethical aspects of Research in Developing Countries Science 2002 21