Ethical predicaments emerge from
every quarter when we try to test HIV vaccines in human subjects.
Moreover, the ethical complexities multiply like the Hydra's head,
and become even more challenging when the populations in which
we want to test these vaccines are among the more disadvantaged,
poor and oppressed peoples of the earth.
The purpose of this book is to lay out the details of these ethical
questions so they can become part of the public discourse. These
trials, already in the planning and initial implementation stages,
raise ethical difficulties at least as complex as (perhaps more
complex than) any ethical problems we have yet had to deal with
in human subjects research.
Policymakers can expect to be faced with some extremely difficult
choices in the years just ahead.
...
In a hotly debated decision in June of 1994, the United States
National Institutes of Health chose to reject the application
for large scale HIV vaccine efficacy trials with the gp120 candidate
vaccines developed by Genentech and Biocene. Their reasons, though
never fully articulated, may have included some of the following:
Perhaps they believed there was too little chance that the vaccines
would prove successful. Or perhaps they believed that expensive
efficacy trials were not the best way to allocate scarce AIDS
resources. Or perhaps there was simply too much political pressure
from AIDS activists. Or perhaps it was some one of a host of other
possible reasons,varying according to your place among the meeting's
constituencies.
Then, in October of 1994, four months later, a consultative meeting of AIDS experts from around the globe convened at the World Health Organization's Global Programme on AIDS in Geneva to address the same question: approval or disapproval of large scale efficacy trials for the very same candidate vaccine. This group heard testimony, deliberated, discussed and chose finally to recommend approval of large scale efficacy trials with that same candidate vaccine, developed by the same pharmaceutical company (Genentech), to be carried out in one (or more) of three developing nations:
The World Health Organization announced Friday that it had approved the first large-scale trials of possible HIV vaccines. The unnamed vaccines will be tested in Brazil, Uganda, and [Thailand]. The announcement came after a two-day meeting in Geneva, in which experts agreed that some genetically-engineered vaccines had proven in preliminary trials to be safe and to help create HIV immunity.
This juxtaposition of these two opposite judgments by two reflective and responsible world organizations should alert us to the fact that the questions they are dealing with are extremely controversial. The questions are controversial because the science involved is complex, difficult, and rich with ambiguities; because the politics involved is so multifaceted; and because the ethical issues involved are so complicated, difficult and open to varied interpretations. Though this book will look briefly at some of the science and politics involved, it will focus primarily on the ethical issues raised by the prospect of undertaking these trials.
The clearest way to lay out the complexity of these ethical quandaries is to formulate them in terms of the two primary opposing positions, one of which will be termed the Thesis position, and the other of which will be termed the Antithesis position. The central effort of this book, then, will be to articulate the thinking of each of these two positions as clearly as possible, in hopes that a fuller, more informed discussion of each will eventually yield (if Hegel can be trusted) a viable Synthesis position.
The Thesis statement will be articulated thus:
In the face of so much growing personal tragedy associated with HIV infection, and in the face of such a rapidly expanding global pandemic, waiting any longer to initiate phase I and II trials for HIV vaccines is simply wrong. These trials must be initiated immediately, so that we can quickly move on to large scale efficacy trials as soon as it is scientifically, politically, and ethically feasible.
The opposing Antithesis statement will be phrased thus:
We must, under no circumstances, begin phase I, II, or III HIV vaccine trials until we can insure that the individual rights and well-being of all those who volunteer for the trials will be protected to the fullest extent possible, as required by The Nuremberg Code and WHO/CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects. Anything short of full compliance with these guidelines would be wrong, would be a violation of internationally accepted ethical codes, and would endanger any potential successful outcome of these trials; it may even have disastrous consequences that would impact future research protocols (as the legacy of the Tuskegee study haunts the efforts of medical researchers still today).
Each of these positions represents
a strong moral stance, and each position, as we will see, defends
its stance with clearly articulated reasons.
The position taken by the US NIH as a result of its June 1994
meeting is more reflective of the sentiments expressed by the
Antithesis position. The position taken by the WHO/GPA consultative
group in October of 1994 is clearly more reflective of the sentiments
expressed by the Thesis position.
The focus of this book will be to
deal most fully with the ethical issues entailed by the Antithesis
position. The reasons for holding the Thesis position, however,
are very strong and deserve to be stated clearly. They are, in
fact, so strong as to almost demand assent. They will include
the following arguments.
We must initiate large scale efficacy trials for HIV preventive
vaccines as soon as politically and ethically feasible, says the
Thesis position, because:
1. The epidemic is daily growing worse; indeed it is accelerating.
It is no exaggeration to say that the global HIV/AIDS pandemic
is out of control.
2. Because of the high incidence of new HIV infections, the viral
pool is increasing daily. This daily increase in the viral pool
leads to two serious consequences:
a. As the pool of viral particles grows, the opportunities for
new infections also increase. The larger the viral pool, the higher
the incidence of new infections; that is, the faster it grows,
the faster it grows.
b. As the viral pool increases, the chances for new and more pathogenic
variants of HIV to develop also increases. In theory, at least,
there is nothing to prevent the emergence of new variants that
are more readily transmissible (Joshua Lederberg has raised the
possibility even of airborne variants of HIV), or variants that
cause faster progression to disease, or cause worse disease (if
that is possible), or the emergence of variants that are even
more readily resistant to the few treatments we have available.
3. The immense burden of personal tragedy is also increasing daily.
Every day that we do not have a vaccine, every day that we delay
testing of candidate vaccines, is another quantum increase of
approximately 10,000 (in 1995) new individual infections and new
personal tragedies.
4. The economic impact, particularly in developing communities,
is already serious and is growing daily more severe. These costs
are already devastating in some communities, as we will see, and
are expected to become even more dramatic.
When measured in years of potential life lost (YPLL), the impact
of the pandemic is particularly severe because the age group that
is most susceptible to infection is so young. It is also the age
group, of course, that does much of the productive work in a society,
and that does most of the child care in families as well.
5. The mutual interactions between HIV disease and tuberculosis
have contributed to an increasingly severe recrudescence of TB
(which is the one opportunistic infection that can be readily
transmitted to non-HIV-infected persons), and to increasingly
numerous strains of multi-drug-resistant TB (MDRTB). These developing
TB epidemics around the world also take their own tolls on persons,
on families, and on regional economies.
6. Nor can we ignore the possibility of HIV's developing interactions
with other microbes in a manner that could potentiate either or
both of them. Although there is as yet no evidence for this in
present strains of HIV, the longer we wait before gaining control
of the AIDS pandemic, the greater potential there is for unanticipated
interactions to develop between HIV and other microbes.
7. Finally, must we not acknowledge that when the well-being of
the larger community is at risk, it may be best that certain forms
of individual freedom be temporarily modified. The concepts of
legal military conscription, of laws of taxation, of regional
zoning ordinances, and so on, are all based on the principle that
sometimes individual freedoms must be temporarily modified for
the well-being of the larger community. In the case of the HIV/AIDS
pandemic, some societies (and even the larger human community)
seem to be at significant risk. If it is even partially true that
"AIDS is the single greatest threat to well-being facing
the world's population today," then, in order to develop
a successful preventive measure such as a vaccine, some codes
and guidelines that have usually governed medical research in
the developed world may need to temporarily take a back seat to
the needs of the larger community, until we find some ways to
get this pandemic under adequate control.
All these reasons provide strong
support for the claim that, for the common good of society (and
of the human species), efficacy trials for HIV candidate vaccines
should be undertaken as soon as possible. Some researchers argue
that this is especially true given the fact that we do already
have available candidate vaccines that have proven to be both
safe and immunogenic (as we will see later). Some viral subunit
candidate vaccines have even been proven partially efficacious
in some animal models.
Given these considerations, say some researchers, it would seem
grossly unethical to continue postponing these trials, especially
in developing nations which are themselves anxious to have the
trials take place among their own populations.
In other words, say Thesis proponents, we must consider the ethics
of waiting. To wait, after all, is an act, an act that has consequences,
and in this case it has severe consequences. If we choose to not
support the Thesis position, and to instead recommend delay of
the trials, then we should be aware that that choice will be attended
by costs, and they are costs that deserve our serious attention.
These reasons lead us to the conclusion that we must not delay
initiation of HIV vaccine trials any longer; rather, we must boldly
go forward with them. The longer we wait, the greater the tragic
cost will be.
If the Thesis position primarily
urges boldness and moving ahead toward finding a safe and effective
vaccine, out of a deep concern for the protection of those not
yet infected, the Antithesis position primarily urges caution,
reflection, wariness of haste; it urges a profound concern for
the well-being of those tens of thousands of volunteers who will
probably be participating in the trials.
The Antithesis position holds that we must, under no circumstances,
begin phase I, II, or III HIV vaccine trials until we can insure
that the individual rights and well-being of all volunteers will
be protected to the fullest extent possible, as required by The
Nuremberg Code and WHO/CIOMS Ethical Guidelines.
In order to get a brief glimpse of some of the ethical issues
raised by those who hold the Antithesis position, consider this
one question (among numerous others that could equally well be
posed):
Why would any sensible, even moderately self-interested person
ever consent to participate in experiments which entail the potential
for so much risk to their personal health and their social well-being,
and which have so little potential for any personal benefit? Might
the reasons be that perhaps they simply have not been made fully
aware of the degree of risk involved? Perhaps they were not fully
informed by researchers? Or if they did participate in an "informing
session," perhaps the information they were given did not
register with them; perhaps they did not fully understand what
they were told? Or perhaps they were, in some subtle way, deluded
into thinking there would be some potential benefit to them in
the form of possible protection against HIV infection? Perhaps
they were offered some inducement, by research sponsors, to participate?
Perhaps they were in some way persuaded, or pressured, or possibly
even coerced into participation by someone at the institution
where the research is being conducted. Perhaps they were pressured
or coerced by government or community leaders, or perhaps even
by someone else close to them, such as a spouse or boss. When
there is so much to potentially lose, and almost no likelihood
of any personal benefit, why would anyone choose to volunteer
for such trials?
These questions, and numerous others like them, are raised by
those who hold the Antithesis position. They insist that it would
probably be illegal, that it would certainly be immoral, and that
it would likely have disastrous consequences for future research
protocols if trials were to be initiated without fully adequate
compliance with all requisite ethical guidelines.
In the largest sections of this book I will be primarily exploring and defending the point of view expressed by the Antithesis position, though it will be the task of this book to lay out the reasoning, the concepts, and the information that lie behind both of these positions. It is hoped that when the full force of the Thesis and Antithesis positions are more clearly understood, then the chances for a viable Synthesis position to emerge will become more promising.
Ethicists and researchers at the World Health Organization in Geneva and at the National Institutes of Health in the US have already been discussing these issues, of course, but as of the summer of 1995 many of the issues are still undecided and remain quite controversial. Educated citizens of the world community will want to be aware of the enormity of the decisions being faced. I intend this book to foster public discussion about these issues.
Most of the ethical quandaries discussed
in this book will be understood only by the reader's having some
prior familiarity with:
a) the present state of the HIV/AIDS pandemic, and its predicted
future course;
b) some characteristics of the human immunodeficiency virus (HIV);
c) the basic nature of the human immune system; and
d) the various kinds of vaccines and how they work.
Accordingly, this book can be seen
as having three main parts: the first several chapters (1-7) outline
some of these essential concepts and some of the basic (and more
recent) information necessary for appreciating the ethical issues.
Any adequate understanding of the two positions, particularly
of the Thesis position, requires familiarity with the concepts
and information in these chapters.
The central chapters in the book (8-23) then lay out some of the
ethical difficulties faced by those who would wish to test HIV
vaccines for use in human populations. This portion of the book
is more representative of the Antithesis position, and details
some of the operative ethical principles that ethicists use in
assessing biomedical research. Some of the potential risks to
research subjects are outlined, as well as some of the potential
motivations which subjects might have for participating in these
trials. This portion of the book also describes some of the problems
involved in obtaining ethically appropriate informed consent from
prospective subjects, problems with improper inducement of volunteers
to participate in the trials, and issues relating to the problems
of compensating volunteers for injuries suffered as a result of
their participation in the studies.
A brief sampling of some of the questions raised in this section
would include the following:
How will researchers be able to execute an ethically adequate
informed consent procedure when the amount of information necessary
for subjects to understand is so great and the nature of it so
complicated? How will researchers be able to provide information
about the nature of vaccines and immune responses to persons (particularly
in developing nations) who may hold conceptions of disease and
disease-causality that are quite different from the conceptions
of disease held by the researchers? How can research sponsors
properly assess whether prospective subjects have understood enough
information so that they are able to give adequately informed
consent? How can research counselors effectively counsel subjects
to not engage in risky behaviors when they themselves realize,
at some level, that the research protocol itself requires that
subjects do engage in those risk behaviors? What are some of the
potential harms that might reasonably be expected to accrue to
subjects who participate in these trials, and what are some benefits
they might theoretically expect which could counterbalance the
risks they could be taking? What is to be done about protecting
volunteers' confidentiality, and how can these volunteers be protected
against unfair discrimination based on their new serostatus which
will (often) result from their participation in the studies? And
underlying all these specific questions are deeper meta-questions,
such as: Should the main operative ethical principles in this
international vaccine research be different in different countries,
varying according to the particular mores and cultural standards
in each country, or should there be a set of common, agreed-upon
international ethical standards for the protection of research
subjects, applicable to all research protocols regardless of the
country in which the research is conducted?
These questions and numerous others related to them, usually raised
by persons sympathetic to the Antithesis position, will not be
easy to deal with, nor will the answers to them be simple.
The final chapters of the book (24-27) offer one or two metaphors
and some concluding suggestions for guiding our thinking about
these difficult and yet unresolved complex questions. Another
of my books (Jenner on Trial: An Ethical Examination of Edward
Jenner's Smallpox Vaccination Experiment, and the Implications
for HIV Vaccine Research, yet unpublished) also offers suggestions
for how best to approach these difficult ethical questions concerning
vaccine research.
People sometimes ask me which of
the two key positions represented in this book, the Thesis position
or the Antithesis position, I am personally more inclined toward
holding. The simple answer to this question is that I see the
validity in both positions, and that I am hoping a viable synthesis
position will emerge very soon.
The more complicated answer, however, would go something like
this: I am a friend of the Thesis position. It seems to me that
all the principles of human compassion require that we do everything
in our power to find some truly effective ways to prevent any
new infections with a microbe that causes such devastating personal
disease and social havoc. Vaccines have traditionally been by
far the most effective public health intervention ever devised
- probably excepting only the provision of clean water - for preventing
infectious disease. If there is any hope at all for developing
an effective vaccine against this terrible disease, we should
put enormous resources into doing so.
However, HIV vaccine trials will also pose ethical difficulties
on a scale never before faced by biomedical researchers, and those
ethical difficulties must be thoughtfully and thoroughly addressed
as well.
In the Roman Catholic tradition, when the name of a (deceased)
holy person is brought before the canonization tribunal to determine
whether that person should be officially counted among the blessed,
the process which the tribunal goes through for determining sainthood
is both lengthy and thorough. The Church goes to such great lengths
because she considers the matter of canonization to be of the
highest importance. As all the evidence is being gathered to support
the naming of this candidate to sainthood, one church official
in the tribunal is assigned the contrary task of arguing that
the candidate under consideration for sainthood should not be
canonized. This official's job, while all the others on the tribunal
are weighing evidence that favors canonization, is to find as
much evidence and as many reasons as possible that count against
this candidate's canonization.
The church's thinking is that the efforts of such an official
- traditionally designated the "devil's advocate" -
help insure that, if the candidate for sainthood is eventually
canonized, the canonization process will have been performed as
thoroughly and as critically as is humanly possible.
I see my own position as in some ways analogous to that of the
devil's advocate: Just as he favors a valid canonization, so I
too favor the rapid development of a safe and effective vaccine
to protect against what is probably the most devastating personal
and communal disease of our era (so far). I see myself as a friend
of the Thesis efforts, but as a friend who is temporarily voicing
the arguments for the opposition; as a friend who wants to help
insure that one position prevails, and is trying to help it prevail
by opposing it.
I take this position for two reasons: First, because it seems
clear to me that the arguments supporting the Thesis position
are so strong, so cogent and so convincing to intelligent, informed
persons of good will, that we need to insure that the arguments
of the opposing position are heard as well. Secondly, those who
presently hold the Thesis position will ultimately be required
(primarily by Ethics Review Committees) to answer the arguments
urged by those who hold the Antithesis position. Therefore it
will be best if they can hear these arguments presented in as
clear and persuasive a manner as possible.
The issues involved in the planning
of international HIV vaccine efficacy trials are difficult and
serious. "It is anticipated that such trials will be large
and complex undertakings, and probable that several trials will
be necessary." Thousands, hundreds of thousands, and perhaps
eventually millions, of human lives will be directly affected
by the decisions we make in the next few years.
Readers are urged, therefore, to give these matters the full good
judgment they deserve.
* To see the citations associated with material in this chapter, see a published printed copy of the book, or contact the author directly.
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