email Dr Kerns
As if the questions we have been
asking so far have not been problematic enough, still more questions
come to mind, especially in the minds of those who hold the Antithesis
position. Among these questions are the following:
Is it truly realistic, especially in developing nations, to expect
that researchers and sponsors will actually comply with these
ethical guidelines? Won't researchers be tempted to cut ethical
corners? Might it even be possible that Ethics Review Committees
will not actually require strict adherence to CIOMS Guidelines,
but instead will require researchers only to "make a reasonable
effort" to comply with the guidelines? If this were to happen,
the results could be disastrous for the research sponsors and
for the future of the vaccine trials. Such ethical laxity could
run the serious risk of actually, in the long run, completely
derailing a research protocol, and setting back for years the
possible development of a successful vaccine.
In fact, if such ethical laxity were to come to pass, could it
not happen that twenty years from now we would all be looking
back - as today we look back on the Willowbrook hepatitis study,
and on the Tuskegee syphilis study, and on the experiments observing
the effects of close-range nuclear radiation on human beings -
that we would all be looking back with condemnation at scandalous
human experiments that were perpetrated upon masses of innocent
and vulnerable peoples in developing nations? Could it be that
we will be watching 20/20 exposés of large pharmaceutical
companies, and large Western government agencies, exploiting naive
and desperate (and inexpensive) peoples in lesser developed countries?
Could it happen that historians will be appalled that one of the
reasons pharmaceutical companies wanted to do research in underdeveloped
communities was because it was less expensive to do the research
there, where subjects were pliable and ready at hand, and where
labor was cheap? Could it be that we will discover that their
bottom line was profit, and not the benefit of the human species?
Or instead might it be that we will discover in retrospect that
these were times of courage and heroism, times in which many individuals
and even some governments were committed to discovering a vaccine
that would help the world contain a plague which threatened to
do immense damage to human society?
Whichever scenario turns out to be closer to reality will depend
largely on the work of those who sponsor, design, and implement
these phase III vaccine protocols. It will also depend on the
work of ethicists who examine the principles that apply in such
trials, and on the work of Ethics Review Committees which will
be examining in minute detail each protocol brought before them.
The four main questions these ERCs will be asking are:
1) Is this proposed protocol scientifically
sound? Has it undergone a thorough scientific review and has it
been determined that there is solid scientific justification for
going ahead with this study? Are all the investigators involved
competent to be overseeing, directing or participating in the
study? Is the design of the protocol sufficient to meet, in Robert
Levine's terms, "the nearly universal standards of the relevant
scientific discipline". This scientific review process is
normally done well before the ethical review, so the ERC will
have some solid data to review on this score.
ERCs will ask, for example, some of the following questions: Have
researchers satisfied themselves that HIV truly is the significant
etiologic agent against which we must vaccinate? (See chapter
5a. above on the question of etiologicity.) Do laboratory and
animal studies provide strong evidence that this vaccine will
protect against more than one strain of the virus, and that it
will last for more than a few months? Are researchers convinced
that the vaccine will probably not cause more harm than good?
Are they confident that HIV will not simply mutate its way around
this vaccine? Have researchers faced the issues of the emerging
"Darwinian medicine?" Have they dealt with the issues
surrounding the evolution of virulence?
Also, have researchers determined whether the criterion of vaccine
success is prevention of infection (an almost impossibly high
and strict criterion of success), prevention of disease (the most
historically common criterion of success in vaccines for other
infectious diseases), postponement of disease, or attenuation
of disease (more modest, and perhaps more realistic, criteria
of success)?
Furthermore, is the actual design of the protocol scientifically
sound? Have researchers adequately isolated the significant variables?
Is the protocol sufficiently double-blinded and randomized? Is
there a control group of adequate size and randomness? Have sponsors
clarified how long the study will last, and are their reasons
for choosing that time period sound?
An ethics committee's interest in these questions will not be
cursory or perfunctory. The reason for an ERC's interest in questions
of scientific methodology is that for a sponsor to initiate a
human subjects study without a sound scientific foundation is
ipso facto a serious breach of ethical principles, most
importantly because it may expose subjects to inconvenience and
risk for no sound purpose. A poorly designed study could end up
being all risk and no benefit to anyone at all. As Robert Levine
so clearly states,
[T]he requirement for good research
design is an ethical requirement. Moreover, it is a requirement
of such importance that it must be satisfied first. If it cannot
be satisfied, there is no need to consider such other requirements
as informed consent or equitable selection of subjects.
In addition, a poorly designed trial, i.e., one that failed to
adequately answer the scientific question, "is a waste of
precious time and resources, both human and economic".
2) The second kind of question ERCs will ask
is whether there is an acceptable and proportionate potential-harm
to potential-benefit ratio for each individual research subject.
This is one of the most important questions ERCs ask and it is
taken very seriously. Yet, in HIV vaccine trials, one is hard
pressed to find anything that could be counted as a direct benefit
to individual volunteers. What might they gain from participating
in this research that could possibly balance the amount of risk
they are undertaking? Will they be paid for their trouble? Will
they be given free medical care? Yes, of course, but they will
not be paid very much, or given very much medical care, because
that would violate the proscription against undue inducement.
The only thing that might really be called a benefit for the individual
volunteers is the provision that "the population in which
the vaccine is tested is entitled to first priority in receiving
the vaccine after its safety and efficacy have been established".
If such a vaccine is proven safe and effective, it must be provided
to these populations (and particularly to those vaccine research
subjects who received the placebo vaccine) at minimal or no cost.
It is considered essential that a vaccine or vaccines developed or evaluated through international scientific collaboration be made available to developing countries under the most advantageous possible conditions.
This is a benefit, of course, but
it is more a benefit to population groups than it is to individual
subjects. In addition, this benefit, if it ever did come to pass,
would not be available for a good many years. Some subjects participating
in these trials would probably not still be alive to enjoy this
benefit.
It might be a bit of a stretch, therefore, (the Antithesis position
will argue) to claim that there is any proportionate balance of
risks and benefits for volunteers participating in these vaccine
trials.
Yet this is one of the essential requirements in an ethically
sound human subjects research protocol.
3) A third question ERCs will ask is whether
investigators will realistically be able to protect their subjects
against significant harm, whether that harm be physical, psychological
or social.
The World Medical Association, meeting for the 41st World Medical
Assembly in Hong Kong, in 1989, amended and reaffirmed the Declaration
of Helsinki of 1964. This declaration is a set of recommendations
for "guiding physicians in biomedical research involving
human subjects". Its principles provided the foundation for
the CIOMS document we have been examining in this book. The recommendations
are very clear about the obligation of researchers to protect
the wellbeing of subjects who participate in their research:
In...medical research carried out on a human being, it is the duty of the physician to remain the protector of the life and health of that person on whom biomedical research is being carried out.
These recommendations emphasize
that this is particularly applicable in those research protocols
(such as HIV vaccine trials) which have no therapeutic purposes,
that is, which are not intended to cure anything. These same recommendations
also emphasize that the individual rights of volunteers must always
take higher precedence than any social or scientific benefit that
might be foreseen. "In research on man," says this document,
"the interest of science and society should never take precedence
over considerations related to the wellbeing of the [individual
research] subject".
Ethics committees will therefore be asking how well researchers
and their sponsors will be able to protect their subjects against
the kinds of hazards - physical, social, psychological, and economic
- described above in chapter 11.
Those who hold the Antithesis position may have serious doubts.
4) Will investigators be able to obtain every single subject's properly informed and freely given consent? We have seen ways in which this may prove to be quite difficult.
In reflecting on some of these impossibly
difficult ethical issues facing HIV vaccine trials in developing
nations, some intelligent yet frustrated readers may find themselves
almost desperately hoping for some larger and simpler solution
to this whole tangle of ethical and research problems. "Maybe
we will never even have to do vaccine trials after all. Maybe
some other solution to the AIDS problem will come to us from the
genetics researchers, or from the recombinant DNA laboratories,
or from NASA's studies of how life forms procreate in gravity-free
conditions. Or from anywhere. Somewhere. Please!"
While such a fantasized solution would be something devoutly to
be wished, there is nothing on the visible horizon to inspire
any realistic soul's feeling of hopefulness in this direction.
Creative solutions of all sorts should be imagined and sought,
of course, but we would not be wise to hold our breath waiting
for them.
"Or maybe," thinks our hypothetically frustrated reader,
"maybe we should just not do vaccine trials in developing
nations at all. Maybe we should just do the research on populations
here in (insert 'the UK,' or 'France,' or 'the US') instead."
There is a certain altruistic and self-sacrificing spirit in such
a reaction, as well as a commendable desire to avoid even the
appearance of exploiting vulnerable peoples. But there are two
serious problems with this "solution."
The first problem is that, even if we could avoid testing vaccines
in developing nations, we would still have to test them in vulnerable
and disadvantaged populations somewhere. Why? Because these are
the groups that are disproportionately at high risk for infection
with HIV, and therefore they are the groups that need a vaccine
the most. If we want to develop a vaccine that will work for anybody,
we want one that will work for the vulnerable and oppressed peoples
of the earth, that is, for those people most at risk and most
in need of a vaccine. If a vaccine will ever work for them, then
at some point it must be tested on them.
The second problem with that imagined solution is that there are
a wide variety of strains of HIV, and there are significantly
different strains in different parts of the world. There are also
different modes of transmission, different endemic diseases and
other underlying health problems, potentially significant genetic
differences, and different microbiological ecologies in different
regions of the world. If we did not test vaccines in any developing
nations, we would probably not end up with a vaccine that would
be effective against the strains of HIV, and its modes of transmission,
predominant in those countries. As the CIOMS Guidelines
make clear
[M]odes of transmission of the infection, and the natural history of the disease, may differ substantially among communities. Moreover, strains of HIV are different in various regions of the world, and the current scientific understanding is that different strains may respond differently to vaccines or drugs. If research were conducted only in developed countries and communities, developing countries could be deprived of many of the benefits of such research.
In other words, not testing candidate vaccines in the populations most at risk would also be a serious ethical blunder.