Download As AIDS continues to spread rapidly throughout the world at an ever

Aiding AIDS
Hurdling the Obstacles to the Development of an Effective AIDS Vaccine
Glenn J. Greilsamer
Class of 2002
Harvard Law School
Course and Third-Year Paper
Professor Peter Barton Hutt
April 2002
Table of Contents
Abstract ............................................................................................................................... 3
Introduction ......................................................................................................................... 3
1 The Regulatory Hurdles of AIDS Vaccine Development............................................... 5
2 The Current State of AIDS Vaccine Development ......................................................... 8
2.1 VaxGen: AIDSVAX ............................................................................................... 14
2.2 Aventis Pasteur: ALVAC ....................................................................................... 17
2.3 Merck ...................................................................................................................... 19
3 Scientific Impediments to the Development of a Vaccine............................................ 20
3.1 Correlates of Immunity........................................................................................... 21
3.2 HIV Strain Variation .............................................................................................. 23
3.3 Behavioral Exposure............................................................................................... 24
3.4 Immune System Breakdown ................................................................................... 24
3.5 Animal Models ....................................................................................................... 25
4 Impediments to the Clinical Testing of an AIDS Vaccine ........................................... 26
4.1 Logistical Issues in the Clinical Testing of an AIDS Vaccine ............................... 27
4.2 Ethical Issues in Clinical Trials of an AIDS Vaccine ............................................ 30
4.2.1 The Belmont Report: Three Ethical Principles ................................................ 30
4.2.2 Physical Risks Inherent in AIDS Vaccine Trials ............................................. 37
4.2.3 Social Risks to Participants in AIDS Vaccine Trials ....................................... 39
4.2.4 Minimizing Harm to Participants in Clinical Trials of AIDS Vaccines .......... 43
5 Economic Impediments to the Development of a Vaccine ........................................... 52
5.1 Costs to Development and Financial Return .......................................................... 52
5.2 Manufacturer Liability............................................................................................ 54
5.2.1 Liability Litigation Activity: Past and Present ................................................. 55
5.2.2 Applicable Standards of Liability .................................................................... 57
5.3 Past Attempts to Insulate Manufacturers and Increase Development .................... 65
5.4 Towards an Effective and Workable Solution ........................................................ 70
Conclusion ........................................................................................................................ 74
Greilsamer, Aiding AIDS
Page 3
Abstract
This paper explores the various impediments to the development of a safe and
effective AIDS vaccine, and offers suggestions to help overcome these obstacles.
I begin by discussing the FDA approval process and the current state of AIDS
vaccine development. I then consider the different scientific impediments to the
development of a preventive vaccine. The next section addresses the logistical
and ethical issues in the clinical testing of a vaccine. I discuss the ethical
principles that should guide researchers, demonstrate the social harm that
participation may cause volunteers, and suggest methods to resolve these ethical
dilemmas. Finally, I discuss the economic impediments faced by manufacturers
in the form of high costs, uncertain profit margins, and unpredictable liability.
Using past legislative attempts at restructuring manufacturer incentives as models,
I present recommendations to help encourage manufacturers to produce the safest
and most effective vaccine they can, and make it available as quickly as possible.
Introduction
To date, HIV has infected 40 million people and has killed 25 million more.1 Each day,
15,000 more people become infected.2 As the virus continues to spread rapidly throughout the
world at an ever-increasing rate, and AIDS has become the most widespread pandemic of our
time, we have come to the realization that the only truly effective manner of intervention, the
only possible way even to reduce the spread of the disease to a material degree, is the
development of a preventive vaccine.
Despite the common need for a vaccine throughout the world, however, impediments to
the successful development and marketing of such a product abound. Although research has
progressed significantly in the two decades since our initial discovery of the disease, scientists
still to do this day do not know the proper correlates of protection that must be present in order to
1
2
Jon Cohen, Merck’s Mission and AIDS Vaccine, MIT’S TECH. REV. 56, March 1, 2002.
Ted Griffith, VaxGen Still Hoping for AIDS Vaccine, CBS MARKETWATCH, December 1, 2001.
Greilsamer, Aiding AIDS
Page 4
prevent infection with HIV. In fact, it was only in 1984 that researchers were able to prove with
any certainty that HIV causes AIDS.3
The scientific impediments to the development of a vaccine are substantial, stemming
both from the qualities of the virus itself and from the current state of our technology. In
addition, regulatory and legal constraints significantly slow the process of development. The
need to use human subjects in the testing of vaccines also substantially hampers development.
Finally, the economic barriers involved in research, development, and marketing of an effective
vaccine may preclude any progress, as the sale of vaccines is often one of the least profitable
undertakings that a pharmaceutical company can pursue.
In July 1995, at a meeting of the Presidential Advisory Council on HIV/AIDS (PACHA),
President Clinton challenged scientists to develop an AIDS vaccine by 2005, the 50th anniversary
of Dr. Jonas Salk’s development of the polio vaccine.4 Whether such a goal is attainable—or
even realistic—depends on our inciting scientists, manufacturers, and governments alike to
surmount the current obstacles, and to march forward without the impediments that are presently
hindering the process of development.
In this paper, I will consider these existing impediments to the development and
marketing of an effective AIDS vaccine. I will begin by discussing the current state of affairs in
AIDS vaccine research and development, as well as the Food and Drug Administration’s (FDA)
approval process for vaccines. Next, I will explore the scientific impediments to vaccine
development. I will then examine the course of clinical trials and the ethical and other issues
they present. Subsequently, I will analyze the legal constraints on manufacturers, focusing on
liability and general profitability concerns, and demonstrate how these factors provide economic
3
4
COHEN, supra note 1.
JON COHEN, SHOTS IN THE DARK: THE WAYWARD SEARCH FOR AN AIDS VACCINE 263-64 (2001).
Greilsamer, Aiding AIDS
Page 5
disincentives to manufacturers and hinder development. I will attempt to suggest several
methods to help resolve these issues and to overcome the many obstacles that impede our current
efforts to develop an AIDS vaccine.
1 The Regulatory Hurdles of AIDS Vaccine Development
Section 351 of the Public Health Service Act and the Federal Food, Drug and Cosmetic
Act together grant authority for the regulation of vaccines. The Center for Biologics Evaluation
and Research (CBER) of the FDA is responsible for vaccine regulation in the US.5
Once research begins on a vaccine, scientists attempt to inform themselves on the
biochemistry and physiology of the disease, as well as the ways in which it causes damage.
They focus on the elements necessary to prevent or interrupt the disease process. Before the
FDA will approve clinical testing in humans, preliminary testing is performed in cell cultures
and, subsequently, in animals.6
As with drugs and other biologics, a vaccine sponsor seeking to begin clinical trials must
submit an Investigational New Drug application (IND) to the FDA, which describes the vaccine
and its manufacture, as well as the preclinical tests that have been done so far, especially on
animals, for proof of the vaccine’s safety and its ability to elicit an immune response. Also
included is the sponsor’s plan for human clinical trials.7 Once the FDA deems that there is
enough conclusive evidence in these preclinical evaluations, the vaccine becomes an
investigational vaccine and can proceed to clinical testing in human volunteers.8
5
CBER, Vaccine Product Approval Process (2001), at http://www.fda.gov/cber/vaccine/vacappr.htm.
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, NATIONAL INSTITUTES OF HEALTH, NIH
PUBLICATION NO. 98-4219, UNDERSTANDING VACCINES 21-22 (1998) [hereinafter UNDERSTANDING VACCINES].
7
CBER, supra note 5.
8
UNDERSTANDING VACCINES, supra note 6, at 21-22.
6
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A vaccine must successfully undergo three phases of human clinical trials before the
FDA will license it for public use. A Phase I trial tests for safety and for optimal dosing. Such
trials involve between 20-80 healthy people who are not infected with the virus (here, HIV), and
who have a low risk of contracting it. Using an inactive placebo as a control, the trial tests for
any adverse side effects that may develop as a result. These trials usually last 12 to 18 months.9
Once the vaccine is proven safe, it may proceed to Phase II. This phase of testing
concentrates on safety and on immunogenicity (the ability to provoke an immune response, such
as the creation of antibodies), and enrolls upwards of a hundred volunteers, including both highand low-risk participants, all of whom are HIV-negative. These trials can last up to two years.10
Phase III is the first time that the vaccine is tested for efficacy. Phase III trials often last
from three to four years, and involve thousands of volunteers, all of whom are, again, HIVnegative.11 At this stage, however, researchers seek out individuals who are at high risk of
contracting the virus.12 This use of high-risk populations exclusively is due to the method of
testing for efficacy. In order to test if the vaccine is effective, scientists cannot simply challenge
the vaccine by injecting the participants with the virus, a method which would cause countless
problems—namely, infecting the person with the virus—in the likely case that the vaccine is not
100 percent effective. Rather, scientists challenge the vaccine by involving volunteers who
ordinarily would be at high risk of contracting the disease, under the assumption that some of
them will be exposed to the virus during the duration of the study. As such, Phase III trials are
conducted by using two groups, one of which is injected with the vaccine, the other with a
9
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, NATIONAL INSTITUTES OF HEALTH, HIV VACCINES
EXPLAINED: MAKING HIV VACCINES A REALITY [hereinafter HIV VACCINES EXPLAINED].
10
Id.
11
Id.
12
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Clinical Research on HIV
Vaccines, NIAID Fact Sheet (May 2001), at http://www.niaid.nih.gov/factsheets/clinrsch.htm [hereinafter Clinical
Research].
Greilsamer, Aiding AIDS
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placebo (the control group). After the trial is concluded, scientists compare the rates of infection
between the two groups. If the control group has a higher rate of infection than the group given
the experimental vaccine, and this difference in proportions is statistically significant, then the
vaccine is deemed to be effective at that level of efficacy and significance. Scientists do not
always look for 100 percent efficacy; in fact, a difference in proportions between the two groups
that indicates a 30 to 50 percent effectiveness of an experimental AIDS vaccine will be deemed a
success at this stage of development, as it could still serve to curtail the spread of the disease.
Once enough data is collected on safety and effectiveness, the manufacturer may apply to
the FDA for a license by submitting a Biologics License Application (BLA). The
multidisciplinary FDA reviewer team will then analyze the safety and efficacy information
provided in the application to perform a risk-benefit assessment, from which the team will decide
whether or not to recommend the approval of the vaccine. The approval process will sometimes
also include advice from the FDA’s Vaccines and Related Biological Products Advisory
Committee (VRBPAC), a committee of scientists, physicians, biostatisticians, and a consumer
representative, regarding the vaccine’s safety and efficacy.13
After approval, the FDA continues to oversee the production of the vaccine in order to
ensure continuing safety. The vaccine and its production are monitored, and manufacturers may
be required to submit to the FDA samples of each vaccine lot in order to test for potency, safety,
and purity. In addition, many vaccines go through Phase IV studies after they are already on the
market, in order to recognize and attempt to correct all adverse effects of the vaccine.14 The
13
14
CBER, supra note 5.
Id.
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Vaccine Adverse Event Reporting System (VAERS), a post-marketing surveillance program,
collects information about adverse side effects after the administration of vaccines.15
2 The Current State of AIDS Vaccine Development
While research has progressed markedly over the past two decades, we have yet to see
anything other than a steady increase in the spread of AIDS. Although education and counseling
have achieved some success, they have not even begun to contain the disease, and have in fact
done little more than stem the proliferation of the virus to a still unmanageable level. Such
efforts may curtail the spread of HIV among a small percentage of the population of the US, but
education cannot impede the transmission of HIV from mother to infant, nor can it provide a
person in a poor and remote region of Africa with a condom. A safe and preventive vaccine
seems to be the only route to the eradication of HIV.
The therapeutic medications represent a major rite of passage into the treatment of the
disease, but unfortunately, they, too, will not markedly contribute to the eradication of AIDS.
While they undoubtedly lengthen the life span of those who have been infected with HIV, no
medication has been created that completely cures the infection. In addition, such treatments are
unavailable to the vast majority of the world’s HIV-infected population—over 95 percent of new
infections occur in developing countries—owing to their gross expense combined with the
prevalence of HIV in countries that cannot remotely afford them.16 Moreover, in the US, the
public’s knowledge—and often misunderstanding—of such therapeutic treatments may even
increase the spread of AIDS, as the ignorant sections of the population may rely on the
availability of such medication in order to justify their own risky behavior.
15
CBER, Vaccines (2002), at http://www.fda.gov/cber/vaccines.htm.
DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES, NIAID, NIH, THE JORDAN REPORT: ACCELERATED
DEVELOPMENT OF VACCINES 83 (2000) [hereinafter JORDAN REPORT].
16
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As such, several companies began research into AIDS, the virus that causes the disease
(HIV), and the possible ways to prevent infection. As the gravity of the epidemic has increased,
resources devoted to the development of a vaccine have significantly increased, by both public
and private agencies. The amount of funding at the National Institutes of Health (NIH) for AIDS
vaccine research increased by 93 percent between 1995 and 1999. Much of this funding goes
towards basic, preclinical, and clinical HIV research at the Division of AIDS (DAIDS), which
“emphasizes both fundamental research and traditional empiric-based vaccine evaluation.”17
The National Institute of Allergy and Infectious Diseases (NIAID) has also funded
several initiatives to help “move vaccine concepts from basic research through clinical trials,”
such as the Innovated Grant Program for Approaches in HIV Vaccine Research, the HIV
Research and Design Program, and Integrated Preclinical/Clinical AIDS Vaccine Program.
Other federal agencies such as the Centers for Disease Control and Prevention (CDC), the
Department of Defense, and the FDA, as well as several government-sponsored initiatives
abroad, have similarly contributed significant efforts to AIDS vaccine research and
development.18 In addition, the HIV Vaccine Trials Network (HVTN), an international
collaboration of scientists that is a mixture of an academic community and a commercial vaccine
company, has as its mission to develop a vaccine regimen to reduce the progression of HIV and
its transmission to others.19
The real backbone of AIDS vaccine research, however, has been the research efforts of
the various pharmaceutical companies. Sometimes in conjunction with government agencies
such as the NAIAD, but more often on their own, drug companies have been researching HIV
and attempting to develop a vaccine that could stimulate an antibody response to prevent
17
Id. at 84.
Id. at 84.
19
HIV VACCINE TRIALS NETWORK, THE ROAD TO AN HIV VACCINE 1 (2001).
18
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infection by the virus or teach the immune system to kill already infected cells. Most notable
among the pharmaceutical companies in the search for a vaccine are VaxGen (a spun-off
subsidiary of Genentech, who retains a 25% interest), Aventis Pasteur, and Merck.
Over 50 different preventive vaccine candidates have been studied worldwide since 1987,
29 of which have been tested on humans in NIAID-funded clinical trials.20 “Several preclinical
candidate vaccines have induced strong cellular immune responses and provided impressive
protections against AIDS in non-human primate models; however, candidates that induce
broadly neutralizing antibodies remain elusive.”21
In designing vaccine candidates, scientists focus on certain important targets on HIV and
on infected human cells. One of these targets is glycoprotein 120 (gp120), which is a protein
molecule on the outer coat or envelope of the virus that contains the binding site that attaches to
human cells (120 indicates the molecular weight of the glycoprotein).22 gp120 has been
identified as a target for HIV vaccines because the outer envelope of the virus, where this protein
is located, is the first part of the virus that encounters antibodies.23 In addition, most neutralizing
antibodies in people infected with HIV are aimed against this glycoprotein. Therefore, vaccines
that target such HIV envelope proteins (gp120 and the larger molecule gp160) have been
considered to be the most successful candidates thus far.24 Several different types of
experimental AIDS vaccines exist:
20
Clinical Research, supra note 12.
Margaret I. Johnston & Jorge Flores, Progress in HIV Vaccine Development, CURRENT OPINION IN
PHARMACOLOGY, 2001, at 504, 504.
22
Clinical Research, supra note 12.
23
PATRICIA THOMAS, BIG SHOT 468-69 (2001).
24
Clinical Research, supra note 12.
21
Greilsamer, Aiding AIDS

Page 11
Subunit vaccine. This is the type of vaccine described above, which contains only a
part of the virus. Produced by genetic engineering, it is made from a structural
component of HIV, such as the proteins on the outer surface (gp120 or gp160).25

Live-vector vaccine. This type of vaccine uses a live bacterium or virus, such as
canarypox and vaccinia (used in the smallpox vaccine), modified so it cannot cause
disease, in order to transport HIV or genes that make HIV proteins into the body.26
These vaccines attempt to stimulate an effective immune response, especially by
inducing killer T cell activity.27 T cells (cytotoxic T lymphocytes or CTLs) can
destroy cells infected with a virus, and are currently thought necessary to protect an
individual from HIV infection.28

Prime-boost. This strategy uses a combination of two different types of vaccines in
order to induce different immune responses and to enhance the overall immune
response. For example, it can begin with the administration of a live-vector vaccine
to induce cellular responses, and follow with booster shots of a subunit vaccine to
stimulate antibody production.29

Peptide vaccine. This type of vaccine uses chemically synthesized pieces of HIV
peptides (compounds formed by linking amino acids, which form proteins) to
stimulate HIV-specific immunity.30

Pseudovirion vaccine. Also known as a virus-like particle vaccine, this type of
vaccine is comprised of a non-infectious HIV “look-alike” that has some, but not all,
25
Id.; THOMAS, supra note 23, at 478.
Clinical Research, supra note 12.
27
THOMAS, supra note 23, at 472.
28
Id. at 466.
29
Clinical Research, supra note 12; THOMAS, supra note 23, at 476.
30
Clinical Research, supra note 12.
26
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Page 12
HIV proteins.31 It does not contain its genetic information and cannot replicate, but
may interfere with infection by the real virus.32

DNA vaccine. Also referred to as a nucleic acid vaccine, it involves a direct injection
of genes that code for HIV proteins. It is meant to induce human cells to produce
those proteins and thereby trigger an immune response.33

Whole-killed virus vaccine. This type of vaccines makes use of HIV that has been
made non-infectious by inactivating it with chemicals or irradiation.34

Live-attenuated virus vaccine. Using a weakened form of the virus from which
disease-promoting genes have been deleted, this type of vaccine seeks to induce a
strong immune response without causing the disease. Attenuated viruses are used in
the oral polio vaccine as well as the injected measles, mumps, and rubella vaccines.35
Throughout the two decades of HIV vaccine research, the focus of study has changed
substantially. Attention was diverted from whole-killed virus vaccines and live-attenuated virus
vaccines, which have posed some safety issues when used with HIV. The development of
recombinant DNA technology necessary to produce subunit vaccines introduced a high degree of
safety by removing the possibility that the recipient becomes infected, and therefore initially was
the most common choice of vaccine to develop.36 In addition, it was the logical choice given
that the outer surface of the virus (or envelope), on which the proteins reside, is the primary
target for neutralizing antibodies in persons infected with HIV.37 The antibody response
stimulated by these initial vaccines, however, did not neutralize most strains of the virus, and
31
Id.
THOMAS, supra note 23, at 476.
33
Clinical Research, supra note 12; THOMAS, supra note 23, at 466.
34
Clinical Research, supra note 12.
35
Clinical Research, supra note 12; THOMAS, supra note 23, at 463.
36
HIV VACCINE TRIALS NETWORK, supra note 19, at 1.
37
The NIAID Division of AIDS, HIV Vaccine Development Status Report (May 2000), at
http://www.niaid.nih.gov/daids/vaccine/whsummarystatus.htm.
32
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Page 13
therefore research progressed from its original concentration on the stimulation of an antibody
response through HIV envelope proteins, to a new focus on CTLs and the killing of already
infected cells.38 Live-vector vaccines appear to be among the most promising candidate
vaccines.39 At present, however, “no single vaccine candidate appears to produce all the immune
responses most scientists believe are needed to protect large segments of the world’s population
against HIV.”40 As a result, scientists are beginning to focus more on the use of vaccine
combinations to produce a comprehensive immune response. The leading strategy is to combine
two types of vaccines, one to elicit CTL memory, and the other to induce neutralizing antibody
responses.
In addition, since immune response differs greatly among the various different
strains and clades of HIV, a different HIV vaccine must be produced for each region.41
Vaccine candidates are currently believed to be in the range of 40 to 80 percent effective,
akin to influenza vaccines.42 Although not close to completely effective, however, such vaccines
would still provide a huge benefit, because “as the percentage of new infections decreases, so
does the percentage of people who can spread the virus,” a phenomenon known as herd
immunity.43 The first polio vaccine, for example, was only 60% effective, but reduced the
number of new infections by 96% and virtually eliminated polio in the US.44
Since the first clinical trial of an experimental HIV vaccine was opened in August 1987,
over 60 preventive HIV vaccine trials have been conducted involving 30 vaccines, using more
than 3600 HIV-negative volunteers. There have been Phase I and II trials for at least 13 different
gp120 and gp160 candidates, and the first Phase III trials are currently underway in the US and
38
Clinical Research, supra note 12.
Johnston & Flores, supra note 21, at 505.
40
HIV VACCINE TRIALS NETWORK, supra note 19, at 2.
41
Id. at 4.
42
Id. at 4.
43
VaxGen, Our Vaccine: Determining Efficacy, at http://www.vaxgen.com/vaccine/efficacy.html.
44
VaxGen, AIDSVAX (information sheet from company).
39
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Page 14
Thailand for a VaxGen gp120 vaccine known as AIDSVAX.45 The following HIV vaccine
candidates were in clinical trials as of 2001:
Vaccine
gp120
ALVAC-HIV
ALVAC-HIV
Lipopeptides LP5,
LP6
Vaccinia TBC-3B
DNA-HIV
DNA-HIV, MVAHIV
NYVAC-HIV
DNA-HIV,
Adenovirus-HIV
HIV
Subtype
B/B, B/E
B, E
Producer
VaxGen
Aventis Pasteur
A
B
Aventis Pasteur
ANRS
B
B
A
Therion
Apollon
University of Oxford
B
B
Aventis Pasteur
Merck
Current Status
Phase III trials ongoing in the US and Thailand
In phase II trials in the US, Haiti, Brazil and
Trinidad (subtype B), and Thailand (subtype
E); tested alone or in combination with
gp120
Ready for phase I trial in Uganda
In phase I trials in France
In phase I trials in the US
Phase I trials completed
In phase I trials in the UK and Kenya
Ready for phase I trial in the US
In phase I trials in the US
ALVAC-HIV, recombinant canarypox expressing multiple HIV genes; ANRS, National Agency for AIDS Research,
France; MVA-HIV, modified vaccinia Ankara, an attenuated vaccinia vector, expressing multiple HIV genes;
NYVAC-HIV, an attenuated vaccinia vector expressing multiple HIV genes; TBC-3B, attenuated vaccinia vector
expressing multiple HIV genes.
(Source: Margaret I. Johnston & Jorge Flores, Progress in HIV Vaccine Development, CURRENT OPINION IN
PHARMACOLOGY, 2001, at 504, 504.)
2.1 VaxGen: AIDSVAX
AIDSVAX®, is the trade name for all formulations of HIV/AIDS vaccines produced by
VaxGen. To date, it is the only preventive AIDS vaccine that has advanced to Phase III testing.
AIDSVAX is a subunit vaccine primarily composed of a synthetic version of the gp120
protein. Introducing this protein into the body is meant to cause the immune system to produce
antibodies to gp120, so that if the body is actually exposed to HIV, the immune system is trained
to recognize the virus and produce an appropriate antibody response. In this manner, the virus
would be unable to infect human cells and replicate, as it would be attacked and killed off after a
few hours.46
45
46
The NIAID Division of AIDS, supra note 37.
VaxGen, Our Vaccine: AIDSVAX Description, at http://www.vaxgen.com/vaccine/description.html.
Greilsamer, Aiding AIDS
Page 15
After preclinical testing in which the gp120 vaccine successfully protected chimpanzees
from live HIV challenges, a series of Phase I and Phase II clinical trials showed that AIDSVAX
was safe and produced an antibody response in over 90% of vaccine recipients.47 The vaccine
progressed to the first ever Phase III trial of a preventive HIV/AIDS vaccine on June 28, 1998,
after the FDA found that the evidence from Phases I and II was conclusive enough to grant
permission to launch this large-scale testing.48
The Phase III testing is being conducted in two separate placebo-controlled, double-blind
trials. Each volunteer is vaccinated seven times over a 30-month period, with one “prime”
injection and six boosters.49 The first trial, which is taking place in North America and the
Netherlands, tests the vaccine that is designed to protect against two strains of HIV subtype B
(which predominates in North America, Western Europe, Australia, and parts of South America).
It consists of 5400 volunteers, including 5100 gay men and 300 women, and is expected to
conclude after three years in the winter of 2002.50 This trial is based on the assumptions of an
incidence of a 1.5 percent HIV infection per year and a retention rate of at least 80 percent of the
volunteers through the entire three-year observation period.51 The second trial, being conducted
in Bangkok, is testing a vaccine designed to protect against the two strains predominant in
Southeast Asia. It involves 2500 injection drug users and is expected to conclude in the summer
47
Ralph T. King Jr., FDA Allows Large-Scale Trial of AIDS Vaccine, WALL ST. J., June 3, 1998, at B1; VaxGen,
Our Vaccine: Development of AIDSVAX, at http://www.vaxgen.com/vaccine/development.html; VaxGen, Our
Vaccine: VaxGen Clinical Trials, at http://www.vaxgen.com/vaccine/trials.html [hereinafter VaxGen Clinical
Trials];.
48
King, supra note 47, at B1.
49
VaxGen, Our Vaccine: More Information, at http://www.vaxgen.com/vaccine/10K_p10.html.
50
VaxGen Clinical Trials, supra note 47.
51
VaxGen, supra note 49.
Greilsamer, Aiding AIDS
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of 2003.52 This trial assumes a 4 percent incidence of HIV in the group and a retention rate of
over 75 percent.53
In order to gain regulatory approval in the US from the FDA, VaxGen will need to prove
that the vaccine is at least 30 percent effective, with a statistical significance of 95 percent.
Because of the sample size and other confounding factors in the study, in order to achieve results
that are significant at the 95-percent level, the trials must show an observed reduction of 45 to 65
percent or more in the incidence of HIV in the vaccinated group as compared to the control
group.54
Although the goal of these trials is to determine how well AIDSVAX prevents HIV
infection—by comparing the rate of infection in the placebo group to the rate in the vaccine
group—the data will also be examined to evaluate the vaccine’s effects on any participants who
became infected despite being vaccinated. Specifically, scientists will determine whether the
immune response induced by AIDSVAX can “reduce the amount of HIV to undetectable levels
in vaccinated volunteers who became infected,” and whether it “lowers the amount of virus in
the bloodstream to detectable but manageable levels.” These results could mean that the vaccine
helps HIV-infected people to live longer and reduces their ability to pass on the infection, which
are two so-called “secondary endpoints” of the vaccine.55 Moreover, scientists will perform
different immunological tests on the blood samples in order to more clearly identify the immune
correlates of protection against infection—the immune responses necessary to protect a person
52
VaxGen Clinical Trials, supra note 47.
VaxGen, supra note 49.
54
VaxGen, Our Vaccine: More Information, at http://www.vaxgen.com/vaccine/10K_p12.html.
55
VaxGen, supra note 43.
53
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Page 17
from HIV infection—which are, at present, not fully understood, but which would, if figured out,
allow scientists to more nearly perfect a vaccine.56
An interim analysis of the Phase III trial of AIDSVAX was conducted at the end of 2001
by the Data and Safety Monitoring Board (DSMB), an independent board established to
periodically review trial data for safety and effectiveness, and to recommend whether the study
should be continued, discontinued, or modified due to benefit or harm to volunteers. In its
interim analysis, the DSMB found AIDSVAX safe and recommended that the trial continue on
its scheduled path, as more data is necessary before a final judgment may be made.57
2.2 Aventis Pasteur: ALVAC
Following the strategy universally deemed to be most effective in the development of an
AIDS vaccine, Aventis Pasteur is searching for a vaccine or vaccine combination that will induce
a dual immune response: an antibody response and cellular response. Most research has centered
on the use of a recombinant canarypox virus followed by a booster of HIV proteins. In order to
induce the cellular response, Aventis Pasteur has come up with a technique that makes use of a
canarypox vector called ALVAC. The canarypox vector transports several HIV genes into the
host cells, some of which code for the virus’s proteins. As such proteins are the target of CTLs,
they have been seen to stimulate the production of HIV-specific CTLs in many volunteers—as
many as 78 percent—who received the vaccine.58
After several animal studies had shown the vaccine to have a protective effect against
SIV (simian immunodeficiency virus) in macaques and against HIV in monkeys, this live-vector
vaccine entered the stage of human clinical trials. Approximately twenty Phase I trials have been
56
VaxGen, supra note 54.
The NIAID Division of AIDS, Interim Analysis of Vaxgen’s Phase III AIDSVAX Trial: Questions and Answers
(October 29, 2001), at http://www.niaid.nih.gov/daids/vaccine/studies/vaxgenq&a.htm.
58
Aventis Pasteur, Aventis Pasteur’s Research Program, at http://www.aventispasteur.com/us/media/kit_aids3.html.
57
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completed or are currently underway, and five Phase I/II or II trials are being conducted in the
US and in highly endemic countries like Uganda, Thailand, Trinidad, Haiti, and Brazil.59
Aventis Pasteur hopes to begin a Phase III trial in the near future.60
The HVTN began a Phase II trial of a combined vaccine regimen of ALVAC and
AIDSVAX in 2000 (HVTN 203), in order to test the safety and immunogenicity of ALVAC and
of the combination vaccine approach. The two vaccines together were meant to stimulate both a
CTL response (ALVAC) and an antibody response (AIDSVAX).61 In previous trials, volunteers
who received the vaccine combination had a more extensive immune response than those who
received only one of the vaccines. Here, the volunteers were divided into four groups: Group 1
received ALVAC alone at time 0 and 1 month, and both vaccines at 3 and 6 months; Group 2
received both vaccines at time 0, 1 and 6 months; Group 3 received ALVAC alone at all four
time intervals; and Group 4 received a placebo at all four time intervals.62
The results of HVTN 203 did not prove conclusive enough to justify proceeding with the
planned Phase III trial for efficacy (HVTN 501). In February 2002, NIAID, in consultation with
Aventis Pasteur and VaxGen, decided that the preliminary results of HVTN, while proof that the
vaccines were safe, did not show that ALVAC induced a sufficient CTL immune response to
qualify for Phase III testing.63 They did not believe that the CTL response would meet the
stringent standards of HVTN 501, as there was not a significant difference in immunogenicity
between the ALVAC injections and the placebo injections. However, the HVTN plans to
Aventis Pasteur, Aventis Pasteur’s Candidate Vaccine Trials, at
http://www.aventispasteur.com/us/media/kit_aids5.html.
60
Aventis Pasteur, Introduction, at http://www.aventispasteur.com/us/media/kit_aids1.html.
61
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, NATIONAL INSTITUTES OF HEALTH, A PHASE II
CLINICAL TRIAL TO EVALUATE THE IMMUNOGENICITY AND SAFETY OF A COMBINED REGIMEN USING ALVAC-HIV
(VCP1452) AND AIDSVAX®B/B (HVTN 203) 1 (December 22, 2000).
62
Id. at 4.
63
National Institute of Allergy and Infectious Diseases, National Institutes of Health, First AIDS Vaccine Made at
NIAID’s Vaccine Research Center Enters Clinical Trial (February 25, 2002), at
http://www.niaid.nih.gov/newsroom/releases/phase3hiv.htm
59
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continue testing this and other ALVAC vaccines to determine whether they induce a more
significant immune response when given in different doses, different populations, and in
different vaccine combinations.64 For example, HVTN 039, a Phase I trial to evaluate the safety,
tolerability, and immunogenicity of a higher dose of ALVAC, is being conducted in 10 cities
throughout the US.65 HVTN 026, being conducted in Brazil, Haiti, Peru, and Trinidad, tests for
the immunogenicity of ALVAC alone and in combination with AIDSVAX.66
2.3 Merck
Merck, the company that in 1996 developed one of the best-selling therapeutic HIV drugs
(“protease inhibitor”) on the market, is now a major player in AIDS vaccine research. And,
unlike most other vaccine companies, Merck does not rely heavily on government funding. It is
the one major “deep-pocketed” pharmaceutical company in an environment where “cashstrapped
biotech firms, many of which have no experience making vaccines, have dominated…, often
pushing forward dubious strategies and hyping small advances in desperate attempts to raise
funds from private investors.”67
Last year, Merck released results from its extensive four-year monkey study. Their
strategy has gone in a different direction from that of VaxGen, as researchers there have
completely ignored HIV’s surface proteins and antibodies. The vaccines it tested in these studies
used a gene that codes for a protein from the virus, which was transported into the body by five
different vectors. Although the results of these studies showed that monkeys challenged with the
virus did become infected, the vaccinated monkeys remained healthy, because of the production
64
HVTN, Partners Review Phase II Trial Data (February 25, 2002), at
http://www.hvtn.org/pressroom/press_releases.sht?id=20.
65
Interview with Ian Poynter, possible participant, HVTN 039, in Cambridge, Mass. (April 8, 2002); HVTN, supra
note 64.
66
HVTN, supra note 64.
67
Cohen, supra note 1.
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of killer T cells. Merck is now starting to test a vaccine in humans and plans to begin large-scale
trials in conjunction with the NIH.68
3 Scientific Impediments to the Development of a Vaccine
Any AIDS vaccine that ultimately makes it to the market will be both safe and effective.
Ideally, the vaccine would also be “inexpensive, easy to store and administer, and would elicit
strong, appropriate immune responses that confer long-lasting protection against HIV infection
by exposure to infected blood and by sexual contact. The vaccine would also protect against
exposure to many different strains of HIV.”69 In addition, it would have to prevent the
vaccinated individual from passing on the virus to others.70
Several possible outcomes may result from immunization against HIV:

Sterilizing immunity. No cells contain the integrated virus, so that no virus is
detected in the blood, lymph nodes, or the site of exposure. Also, no antibodies or
CTLs are developed to proteins that are not present in the HIV vaccine.

Transient infection. Here, a low level of virus is detected only within six months of
exposure. Any production of antibodies or CTLs to proteins not present in the
vaccine is only temporary.

Controlled infection. Virus levels fall to and remain at low to undetectable levels
following the acute stage of infection. Antibodies and CTLs to proteins not present in
the vaccine are detected.
68
Id.
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Challenges in Designing HIV
Vaccines, NIAID Fact Sheet (May 2001), at http://www.niaid.nih.gov/factsheets/challvacc.htm [hereinafter
Challenges].
70
Johnston & Flores, supra note 21, at 507.
69
Greilsamer, Aiding AIDS

Page 21
Lack of transmission to others. Here, the levels of virus in the blood and secretions
are insufficient to infect others.71
Despite the incredible progress that has been made in the past two decades, however,
researchers have not been able to develop a vaccine that meets all of these requirements. HIV is
a very distinct virus, significantly different from any virus for which scientists have developed a
vaccine in the past. As such, researchers continue their quest to better understand the virus and
the ways in which it can be prevented, attempting to surmount the scientific obstacles to the
development of a vaccine.
3.1 Correlates of Immunity
First, in order to design an effective vaccine, it is necessary to understand the correlates
of immunity or correlates of protection, that is, which immune responses must be present in
order to protect against the infection. Studies to date have shown that both antibody responses
and CTL responses provide some benefit, and that a combination of the two is more effective
than either alone. Although scientists have definite clues, however, they still do not know for
sure exactly which immune responses are necessary to combat HIV.72 There may even be some
yet undiscovered immunologic agent that need be present in order to fully protect an individual
against HIV. “Believe it or not,” said Ronald Desrosiers, head of Harvard’s primate center and a
pioneering AIDS vaccine researcher, “we have no frickin’ clue what one needs for an effective
immune response.”73
One reason that scientists do not understand the virus as well as they would hope is that
there has been no case of complete recovery from HIV infection. When Edward Jenner was
71
Id. at 507.
Challenges, supra note 69; The NIAID Division of AIDS, supra note 37.
73
Cohen, supra note 1.
72
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developing a smallpox vaccine, for example, he noticed that milkmaids in England would never
develop smallpox if they had been exposed to cowpox and survived the disease, from which he
inferred that it was possible to develop a resistance to the disease.74 Such an example would help
inform researchers as to the necessary elements for protection against HIV. Unlike other
diseases for which there are successful vaccines, however, HIV provides us with no human
model of protection to guide researchers. No one knows whether a “natural protective state
against HIV” exists.75
The closest that researchers have come to finding this model has been identifying certain
long-term survivors, those who, despite having contracted HIV, remain clinically asymptomatic.
It is proof that some people remain “better able than others to resist progression of HIV infection
or developing AIDS.”76 Research on these so-called “non-progressors” makes scientists more
optimistic about the immune system’s efficacy against the virus, since they believe that these
individuals’ not developing AIDS is due to a strong immune response.77 In addition, researchers
are focusing on those people that they know to have been exposed to HIV but who remain
uninfected, including many gay men, intravenous drug users, prostitutes, healthcare workers, and
newborns of HIV-infected mothers. Called “spontaneous immunization,” this phenomenon is
relatively frequent.78 If scientists can prove that these exposed yet uninfected people have active
immune mechanisms that protect them from infection, they may be able to identify the “natural
74
THOMAS A. KERNS, JENNER ON TRIAL: AN ETHICAL EXAMINATION OF VACCINE RESEARCH IN THE AGE OF
SMALLPOX AND THE AGE OF AIDS (1997).
75
Challenges, supra note 69.
76
Id.
77
Aventis Pasteur, supra note 60.
78
Id.
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protective state” and model a vaccine accordingly.79 Despite optimism from these observations,
however, scientists still do not fully understand their occurrence.80
3.2 HIV Strain Variation
HIV is considerably more difficult to deal with than other viruses because it mutates so
rapidly. Once it enters a person’s body, it may undergo significant changes, caused by errors in
the duplication of the genes of the virus, so that several different strains are all present in one
person’s body. Even after one strain is killed, a related resistant variant can develop.81 Because
of the variability of the virus, HIV can escape the antibody response, as antibodies are directed
against the outer surface of HIV.82 Consequently, this genetic mutation and recombination
forces researchers to design vaccines to attack a wide variation of different strains of HIV.83
More than nine genetic subtypes (clades) have been identified. Scientists are attempting
to find the regions of HIV genes that are common to all genetic subtypes, in order to use those
elements in the designing of a vaccine. Without such common regions, it will be necessary for a
vaccine to include several proteins from different strains of the virus in order to create broadbased immunity.84 However, studies show that antibodies’ recognition of the virus does not
completely correlate with such genetic subtypes.85 In addition, because so many different
variants exist, and one vaccine may not protect against other strains of the virus, many
developing countries are not allowing companies to test their vaccines unless they are crafted
79
Challenges, supra note 69.
Aventis Pasteur, supra note 60.
81
Challenges, supra note 69.
82
Aventis Pasteur, A Brief Overview of Immunity and Vaccination, at
http://www.aventispasteur.com/us/media/kit_aids2.html.
83
Challenges, supra note 69.
84
Id.
85
Johnston & Flores, supra note 21, at 507.
80
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specifically to counter the strains of HIV that predominate in their country.86 “The genetic
variation in the AIDS virus, therefore, puts a premium on international cooperation and
coordinated research efforts on a global scale.”87
3.3 Behavioral Exposure
Because most exposure to HIV is through high-risk behaviors, often those who are at
high risk for infection remain at high risk for many years. As such, a vaccine will need to protect
an individual over a long period of time, either by inducing long-lasting immune responses or by
restimulating immune responses through a series of booster shots.88
3.4 Immune System Breakdown
One of the greatest difficulties in developing a vaccine for HIV is that the virus attacks
the very tools that are necessary to combat the virus: the major target of HIV is the immune
system itself. The virus infects the T cells that serve to kill off infected cells, and destroys their
ability to function. Once it enters the body, the virus immediately and rapidly disseminates,
building up in the lymph nodes and other immunologic organs, so that the filtering system which
normally functions to trap pathogens and effect an immune response then works to destroy the
immune system when HIV infects the stream of CTLs that attempt to combat it.89
In addition, since HIV is a so-called retrovirus, it carries its genetic material in the form
of RNA, not DNA, and produces an enzyme called a reverse transcriptase in order to direct a cell
to synthesize DNA from its own RNA (as opposed to the more common synthesis of RNA from
86
The NIAID Division of AIDS, supra note 37.
Philip A. Leider, Domestic AIDS Vaccine Trials: Addressing the Potential for Social Harm to the Subjects of
Human Experiments, 88 CALIF. L. REV. 1185, 1199 (2000).
88
The NIAID Division of AIDS, supra note 37.
89
Challenges, supra note 69.
87
Greilsamer, Aiding AIDS
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DNA).90 As such, once HIV infects a host cell, the virus incorporates its own genetic material
into the cell’s genetic material, so that each time the cell reproduces itself, it creates more cells
that contain the HIV genes. Once these cells are activated, they will produce new viruses. Other
cells also function as “HIV reservoirs, harboring intact viruses that may remain undetected by
the immune system,” in the form of a “provirus.”91 Moreover, since HIV is integrated into the
host cell’s DNA, it may be impossible to completely eradicate the virus from the body, possibly
making long-term control the only real endpoint of a vaccine.92 One reason for optimism is that
effective vaccines have been developed against animal retroviruses in the past.93
3.5 Animal Models
The greatest benefit of animal studies is that tests can be performed on animals that
would be unethical to perform on humans. For example, a vaccine in animals can be directly
challenged by injecting them with a virus, a technique that could not be used in human trials, as
we would risk infecting them. Unfortunately, however, although researchers have learned a
great deal from several animal studies, no perfect animal model exists.94
For example, chimpanzees are the only animals that researchers have successfully been
able to infect with HIV. Despite being infected, however, and developing HIV-like symptoms
upon infection, very few of these animals have ever developed the disease: they do not develop T
cell deficiencies or other symptoms similar to AIDS in humans.95 As such, it is difficult to apply
any results from these tests to humans. In addition, chimpanzees are an endangered species, and
90
THOMAS, supra note 23, at 477.
Challenges, supra note 69.
92
Johnston & Flores, supra note 21, at 507.
93
Aventis Pasteur, supra note 82.
94
Challenges, supra note 69.
95
Leider, supra note 87, at 1201.
91
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they are difficult and costly to maintain.96 Other animal studies have been done on macaques.
The problem with these animals, however, is that scientists must use SIV or SHIV (a genetically
engineered virus with an HIV envelope and an SIV core), which requires producing the SIV or
SHIV analog. Also, due to variation among individual animals, large groups of animals are often
necessary for the study to be successful, and many studies are rendered inconclusive because of
an insufficient number of animals.97
As a result, “[b]ecause of the urgency of the public health need and public attention and
political pressure, human Phase I trials of HIV candidate vaccines began before efficacy was
demonstrated in chimpanzees or any other animal model.”98 A cost-benefit analysis would show
that the benefit of beginning trials in humans, although before definitive efficacy of a vaccine has
been proven in animals, far outweighs the risks present in clinical trials.99
4 Impediments to the Clinical Testing of an AIDS Vaccine
Once an experimental vaccine makes its way through the preclinical phase, it still has
many obstacles to surmount, even if animal and cellular studies have shown it to be both safe and
effective. Besides the obligation of the vaccine’s sponsor to prove it safe, immunogenic, and
effective in humans, and to prove this at a significant enough level to convince the FDA, there
are obstacles inherent in the clinical testing itself that are almost as great as those associated with
obtaining the results sought by those trials. Much of the challenge stems from the simple fact
that clinical trials involve humans. Using humans in a study presents distinct logistical and
ethical issues that need to be addressed, and their resolution must not compromise the desired
96
Challenges, supra note 69.
The NIAID Division of AIDS, supra note 37.
98
CHRISTINE GRADY, THE SEARCH FOR AN AIDS VACCINE: ETHICAL ISSUES IN THE DEVELOPMENT AND TESTING OF
A PREVENTIVE HIV VACCINE 99 (1995).
99
Leider, supra note 87, at 1202.
97
Greilsamer, Aiding AIDS
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benefits of the study itself. Researchers must therefore attempt to strike a balance between ethics
and science in order to create a trial that is safe, feasible, and productive.
4.1 Logistical Issues in the Clinical Testing of an AIDS Vaccine
Because the subjects of clinical testing are humans, collecting data on efficacy of a
vaccine presents a major challenge. Unlike animals, humans cannot be injected with HIV in
order to directly challenge the vaccine in inoculated persons. Because this method would present
an overwhelming risk of infecting the human participants with the virus, researchers must make
greater use of statistics than they do in animal studies. They base their studies on the assumption
that individuals with certain high-risk behaviors are more likely to be exposed to the virus than
individuals in a lower-risk category. Since they believe that in a normal state this group of
people has a relatively high probability of contracting the disease, researchers use this high
percentage as a proxy for direct challenge with the virus. However, whereas with animals
researchers look for a very large difference in proportions of the rates of HIV infection between
the control group and the vaccinated group, since the animals are fully and definitely exposed to
this virus, with humans researchers can anticipate a much smaller difference in proportions, as
not all individuals in both groups have definitely been exposed to the virus.
In addition, the relatively low incidence of HIV infection in industrialized countries—
even in high-risk groups—means that thousands of individuals must participate in the trials in
order to obtain any statistically significant results.100 A large sample size is necessary in order to
prove that a vaccine reduces the risk of contracting HIV—even by only 30 percent—at the 95percent level.
100
Johnston & Flores, supra note 21, at 507.
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Moreover, and due in part to the large number of participants required in each arm of a
trial, there is a large challenge in the recruitment and the retention of individuals in clinical trials
in industrialized countries. At-risk populations are hard to identify and recruit for a trial,
especially women at sexual risk, men at heterosexual risk, and intravenous drug users.101
Furthermore, there is a growing distrust of researchers and the government among these
populations, which makes them harder to recruit.102 And, ensuring that these groups remain in a
trial over its duration of 36 months, including visits both for check-ups and for booster shots, is
incredibly difficult.
There is also a growing misconception of vaccines in general. Many people do not
understand the purpose of a vaccine, and are reluctant to join a test trial, especially when they do
not believe that a test vaccine can in no way infect the vaccinee with the disease.103
Another problem is that there is a limited supply of high-risk individuals on which to
perform clinical tests. Once a person is inoculated with a candidate HIV vaccine, he will likely
be considered “contaminated” by this other “significant variable,” and will no longer be able to
test any subsequent—and possibly more effective—vaccines.104 The current trials could
“‘seriously dent the reservoir’ of people willing to participate in future trials of AIDS vaccines
that might be more promising.”105 And since it is “not easy to gather thousands of uninfected, atrisk people for inclusion in such trials, … scientists don’t want to deplete that pool before the
best vaccines come along.”106
101
Id. at 507.
The NIAID Division of AIDS, supra note 37.
103
Interview with Ian Poynter, supra note 65; Johnston & Flores, supra note 21, at 507.
104
THOMAS A KERNS, ETHICAL ISSUES IN HIV VACCINE TRIALS 100 (1997).
105
King, supra note 47, at B1.
106
Rick Weiss, Large-Scale Test of AIDS Vaccine Set; Approval Viewed as Turning Point, WASH. POST, June 4,
1998, at A1.
102
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Nor due individuals want to decrease their own chances of receiving a more effective
AIDS vaccine in the future. Many people are reluctant to join a test trial because they believe
that scientists will soon develop a more effective vaccine, and that they will be precluded from
reaping its benefits if they have already received a less effective vaccine in a clinical trial. 107
Trials conducted in developing countries have their own set of problems, as well.
Although there is a huge benefit to conducting clinical trials in these countries due to the
incredibly rampant spread of the disease and the resulting high percentage of the population that
is infected with HIV—a 1989 study showed that the prevalence of HIV among drug users at the
Bangkok Metropolitan Administration (BMA) was between 38 and 44 percent—most developing
countries do not have the trained investigators and infrastructure available to conduct a vaccine
trial successfully.108 The countries lack the appropriate training needs, such as science, good
clinical practice, ethics, lab assays, and data management.109 Clinics, labs, equipment, and
supplies are also in short supply, and there are not necessarily enough scientists, researchers, and
clinicians to conduct the trials. In addition, few countries have the regulatory processes to
evaluate proposed experimental vaccine trials.110 National authorities and institutional review
boards are few and far between, and those that do exist are poorly supported by the
governments.111 One notable exception is Thailand, whose history of participation in the
development of other vaccines has allowed it to build the infrastructure and training necessary to
conduct vaccine trials—a “model of industrialized-developing country collaborations.”112 Trials
107
Interview with Ian Poynter, supra note 65.
THOMAS, supra note 23, at 386.
109
Johnston & Flores, supra note 21, at 507.
110
The NIAID Division of AIDS, supra note 37.
111
Johnston & Flores, supra note 21, at 507.
112
The NIAID Division of AIDS, supra note 37.
108
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in Thailand also have the advantage of easier access to high-risk populations, for although heroin
use is illegal in Bangkok, addicts know that the BMA will not turn them over to the police.113
An additional challenge in conducting vaccine trials in developing countries, Thailand
included, is that most candidate HIV vaccines have been based on clade B of the virus, the strain
of HIV most prevalent in the Americas and Western Europe, while the clades most common in
developing countries are not usually the same. As such, separate vaccine candidates much be
developed for testing in developing countries.114 Trials in Thailand, for example, use vaccines
aimed at clades B and E of the virus, which are the most common subtypes in that region.115
4.2 Ethical Issues in Clinical Trials of an AIDS Vaccine
While all medical experiments performed on human subjects present a series of ethical
issues, the testing of vaccines in general—and of AIDS vaccines in particular—present a variety
of additional ethical challenges. Participants in clinical trials are exposed to uncertain risk and
certain adverse social consequences, which render the testing process much more difficult.
4.2.1 The Belmont Report: Three Ethical Principles
Prepared by the National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research in 1979, the Belmont Report outlines three overarching
ethical principles that apply to all medical research involving human beings: autonomy,
beneficence, and justice. First incorporated in 1981 into the Department of Health and Human
113
THOMAS, supra note 23, at 387.
The NIAID Division of AIDS, supra note 37.
115
CDC, Questions and Answers on the Thailand Phase III Vaccine Study and CDC’s Collaboration (February
1999), at http://www.cdc.gov/hiv/pubs/facts/vaccineqa.htm.
114
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Services regulations in the US, these three principles have now become, by international
agreement, the basis for regulation of research on human subjects worldwide.116
Autonomy. This principle, derived from the principle of respect for persons, centers on
the policies of informed consent and of special protection for vulnerable populations.117
Developed in The Nuremberg Code, the principle of informed consent is the foremost
consideration in medical testing on humans and has been placed above all other factors. This
principle is absolute; as the Code says, the “voluntary consent of the human subject is absolutely
essential.”118 The principle of autonomy requires that “those who are capable of deliberation
about their personal choices should be treated with respect for their capacity for selfdetermination,” and that those who are not capable be fully protected. Particularly vulnerable
persons should be made secure from harm or abuse.119
In order to evaluate a participant’s autonomy, the scientist must monitor three elements:
information, comprehension, and voluntariness. Those conducting the study must provide
potential volunteers with full information, such as the subject of the proposed research, what
researchers hope to learn, what is expected of the volunteers, and what the volunteers can expect
to happen to them during the trial, including any foreseeable risks, as well as the rights and
responsibilities that are incumbent upon them.120 This information must be “in language
understandable to the subject,” and the subject must be given “sufficient opportunity to consider”
it. Finally, the volunteer must be able to deliberate freely, without coercion, fraud, duress, or
116
Jeremy Grushcow, The Ethics of Subject Selection for Testing Live-Attenuated HIV Vaccines, 6 U. CHI. L. SCH.
ROUNDTABLE 113, 117-18 (1999); KERNS, supra note 104, at 94.
117
Grushcow, supra note 116, at 118.
118
Id. at 118.
119
KERNS, supra note 104, at 94.
120
Id. at 152.
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undue influence. The ability of each person to make an autonomous decision must be assessed
individually.121
Because of the complexity of the subject matter, it may be more difficult to ensure
complete autonomy in HIV vaccine trials than it is for other medical research. It is not enough
simply to provide the information; researchers must also make a “determined and good faith
effort…to ascertain whether or not the prospective subject has heard and adequately understood”
the information with which he was presented.122 How to assess this, however, leaves researchers
with a wide range of possibilities. So many different thresholds of comprehension exist, ranging
from asking the subject, “Did you understand that?” to giving the subject some sort of test and
requiring a certain percentage of correct answers. Even then, however, it is hard to choose what
type of test to give, as well as what percentage of correct answers—a somewhat imperfect proxy
for comprehension—is acceptable.123 Such an exam may also discourage potential volunteers
and decrease the size of the pool of possible participants, making the “procurement of enough
volunteers an even more daunting task than it is already.”124
In the Phase III trial of AIDSVAX taking place in Thailand, health officials and the CDC
have worked together to design an extensive process in order to ensure comprehension of all
volunteers. All sessions and materials are in the native language and have undergone local
evaluation for reading level and comprehension. Possible participants first attend an education
session on the nature of the study, and there have an opportunity to ask questions. After this
session, volunteers take a comprehension test, followed by a discussion of the correct answers.
They then take the materials home to discuss with their family and peers, after which they return
121
Grushcow, supra note 116, at 118-19.
KERNS, supra note 104, at 156.
123
Id. at 157-58.
124
Id. at 159.
122
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for a second comprehension test. Only those who pass this test may be enrolled, and only after
undergoing the informed consent process. This trial has been reviewed for ethical standards and
subsequently approved by the BMA.125
It is particularly important to allow potential participants enough time to consider fully all
the information. One study suggested that much more time is necessary than most scientists
think to consider the information before a rational and informed decision can be made; the study
found that of the 37 percent of men who were certain of their willingness to participate in a
vaccine trial, only half of them were still willing one year later. The study also found a
correlation between willingness to participate and lower levels of education. “Vaccine trials do
present unique hazards which must be properly explained. Care must be taken to avoid
overestimating the capacity of potential subjects to appreciate the consequences of
participation.”126
Developing countries present a particularly difficult burden in ensuring comprehension.
In many developing nations, the levels of education and of literacy are much lower, and their
beliefs about medicine in general differ greatly from our own, as do their notions of identity and
individuality. However, according to the International Ethical Guidelines for Biomedical
Research Involving Human Subjects, the governing ethical standards must be exactly the same
and applied just as stringently in developing countries as in industrialized nations. “This is good
ethics, but it presents researchers with some almost insurmountable problems.”127
It is the duty of the sponsor of the trial—most often the manufacturer of the vaccine—to
ensure that each participant in the trial has consented voluntarily to a risk about which he is
knowledgeable. Without proof that they obtained the voluntary informed consent of each trial
125
CDC, supra note 115.
Grushcow, supra note 116, at 120.
127
KERNS, supra note 104, at 154.
126
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participant, manufacturers may be subject to liability. In fact, lack of informed consent “is likely
to constitute the major factor leading to manufacturer liability during the course of vaccine
trials.”128 As such, they have an incentive to provide proper information, ensure its
comprehension, and allow volunteers to deliberate free from coercion about their participation in
the trial.
This possibility of liability in a vaccine trial, however, may deter manufacturers from
proceeding with a clinical trial. It is likely that the standard of liability for manufacturers would
be that of negligence, which gives manufacturers a very difficult time in predicting the possible
liability costs that may arise from the clinical trial of a vaccine. The negligence standard leaves
open so many questions as to what degree manufacturers must conform with the precepts of
informed consent, and therefore as to what degree manufacturers may be subject to liability. 129
First, it is difficult to “determine the appropriate type and amount of information that
must be disclosed to subjects in order to meet the knowledge requirement.” This differs across
jurisdictions, and manufacturers must comply with the state laws as well as the federal statutes.
Standards range from the very objective—information that a “reasonable investigator would
disclose”—to the very subjective—information that a “reasonable subject with the characteristics
of the individual involved in the testing would wish to know.”130
Second, manufacturers will likely have a very difficult time complying with the
voluntariness requirement. The high-risk populations that are the usual subjects of HIV vaccine
trials are probably the populations that would be “least likely to have the capacity to withstand
coercion or undue influence.” These minority groups often lack access to public forum to voice
128
Alison Joy Arnold, Comment, Developing, Testing, and Marketing an AIDS Vaccine: Legal Concerns for
Manufacturers, 139 U. PA. L. REV. 1077, 1087 (1991).
129
Id. at 1088.
130
Id. at 1088-89.
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their grievances, adequate medical knowledge to question the experiments and their treatment
therein, adequate legal knowledge to bring lawsuits, and the “physical or financial willpower to
resist the temptation to agree to experimentation in exchange for monetary reimbursement or the
promise of a ‘cure.”131 Therefore, manufacturers must “acknowledge the vulnerability of
potential subjects, and determine how to implement safeguards for their protection while still
keeping access to trials as equitable as possible.”132
Beneficence. Dating as far back as the Hippocratic oath, the principle of beneficence has
been translated into risk-benefit analysis. It requires that “researchers, in addition to refraining
form doing deliberate harm (non-maleficence), must make every reasonable effort to maximize
benefits and goods, and to minimize harms and burdens.”133 According to the International
Ethical Guidelines for Biomedical Research Involving Human Subjects, the risks of research
must be reasonable in relation to the expected benefits, the research design must be sound, and
the researchers must be “competent both to conduct the research and to safeguard the welfare of
the research subjects.”134
This principle of beneficence, therefore, is based on the concept of utilitarianism. It does
not require that there be no possibility of harm at all, but rather that there be a balance struck
between the possibility of harm and the expected benefit; the expected benefit, that is, must
outweigh the expected harm. The Belmont Report, in fact, acknowledges that “avoiding harm
requires learning what is harmful; and, in the process of obtaining this information, persons may
131
Id. at 1089-90.
Id. at 1092.
133
KERNS, supra note 104, at 94.
134
Id. at 94.
132
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be exposed to risk of harm.” The risks must simply be “reasonable in relation to…the
importance of the knowledge that may reasonably be expected to result.”135
Justice. This principle focuses on a “policy of appropriate subject selection to ensure
equitable distribution of the risks and benefits of research.”136 It requires that “every person be
given what is rightly due to them (sic), and that the potential benefits and burdens of medical
research be fairly distributed. Here, too, ‘special provisions must be made for the protection of
the rights and welfare of vulnerable persons.’”137
The precept of justice attempts to ensure a fair process in the selection of research
subjects. According to the Belmont Report, the process should make sure that certain classes are
not “being systematically selected simply because of their easy availability, their compromised
position, or their manipulability, rather than for reasons directly related to the problem being
studied.”138 This principle becomes especially significant when trials are being conducted on
impoverished populations in developing countries. In that situation, many people fear
exploitation of these groups, most of whom do not have ready access to health care.139
The principle of justice also requires that the benefits of the research be shared with those
who participated in the study. There is a great concern that developing countries who host the
trials will not have affordable access to a vaccine that is proven effective.140 The sponsor of the
trial, therefore, has an obligation to share the benefits of the research, and provide any successful
product that results from the research to the community that bore the burden of the research.141
135
Grushcow, supra note 116, at 120.
Id. at 118.
137
KERNS, supra note 104, at 95.
138
Grushcow, supra note 116, at 121.
139
Johnston & Flores, supra note 21, at 507.
140
Id. at 507.
141
Grushcow, supra note 116, at 121-22.
136
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It has been argued that a conflict exists between the principles of autonomy and justice.
Since absolute autonomy requires complete comprehension, claims one author, those who are
most appropriate for an experiment in terms of autonomy will also be the least appropriate in
terms of justice, since those who are fully informed will not engage in risky behaviors and not be
exposed to the virus, and are therefore the least likely to benefit from a successful vaccine. It is
therefore “unjust,” he says, to “impose the burdens of vaccine testing on them.”142 There is a
problem with the underlying assumption in this argument, however, in that this author
presupposes that all highly educated and informed individuals act rationally. Just because
someone understands a concept in theory does not mean that he will, in practice, follow the
logical behavior resulting therefrom. AIDS vaccine testing, in fact, must inherently assume
somewhat irrational behavior even after full comprehension, as completely rational behavior
devoid of all risk would render moot the entire study, since no informed and rational participant
would ever be exposed to the virus. As the CDC says, “some individuals will continue to take
risks…. If behavior change programs were 100% effective, we would not need an HIV
vaccine.”143
4.2.2 Physical Risks Inherent in AIDS Vaccine Trials
Although there is no chance for participants in HIV vaccine trials to be directly infected
with the virus as a result of the inoculation, a variety of associated risks and potential hazards do
exist, which may occur indirectly from an individual’s participation in the trial.
Heightened risk behavior. One major fear among researchers is that participants in the
study might misunderstand the concept of the vaccine trial, and falsely believe that they are fully
142
143
Id. at 122.
CDC, supra note 115.
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protected from contracting HIV. As a result, they might engage in more risky behavior and
consequently increase the spread of the virus.144 This risk becomes especially acute in those
participants who received an inactive placebo and not the experimental vaccine. Researchers,
therefore, must be explicit and assertive when explaining and reinforcing to the participants that
they are not protected from contracting the virus and hence should continue to avoid risky
behaviors.145
Enhanced infectivity. Scientists have in the past observed a so-called “antibody
enhanced infectivity.” This phenomenon shows that in certain instances, some HIV antibodies
can actually help HIV enter host cells and establish an infection, putting volunteers in the
vaccine group—who have likely produced antibodies to HIV in response to the vaccine—at a
greater risk for disease than non-vaccinated persons. In the event that such a reactions occurs,
several possibilities may result: the individual could more easily become infected with the virus;
the virus could more easily progress to AIDS; the virus could be more likely to progress to the
disease at a faster rate; or the person could be more likely to develop a more acute form of the
disease than non-vaccinated persons.146 Although there is still very little data to support this
possibility, the concern—which was made famous by dengue hemorrhagic fever—still has many
outspoken proponents, such as Jean-Paul Lévy, director of the Agence Nationale de Recherches
sur le SIDA, France’s equivalent of the NIH.147
Potential immune tolerance. It is also possible that the experimental vaccine may cause
an immune tolerance in the recipient. The individual would become unresponsive to HIV
invader proteins, and the immune system would not mount any response. This would mean that
144
Weiss, supra note 106, at Al; Leider, supra note 87, at 1199-1200.
KERNS, supra note 104, at 120.
146
Id. at 101-02.
147
COHEN, supra note 4, at 261.
145
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if, in the future, the individual were exposed to HIV, he would be more likely to become
infected, as the immune system would not recognize the virus as an invader and would therefore
not even attempt to combat it. Moreover, if a new effective HIV vaccine were produced, this
person would not be able to respond to it and, consequently, not be able to benefit from it at
all.148 This risk, although small, has functioned as a major disincentive to many potential
volunteers in HIV vaccine trials.149
Unknown and unanticipated risks. Despite prior testing and previous experience, there
always remains the possibility that some unforeseen hazard will result from inoculation with an
experimental vaccine. While Phase III trials are considered safe due to the vaccine’s already
having been tested for safety in two prior trials, Phase I and II trials are still limited in number of
participants and in duration, and therefore the risk remains that some unanticipated effect will
result from the experimental vaccine. We need only think back to the experience with
thalidomide to imagine the possible unanticipated side effects that could manifest themselves
years later.150
4.2.3 Social Risks to Participants in AIDS Vaccine Trials
As a result of an individual’s participation in an HIV vaccine trial, he may be subject to
potential social discrimination. Such discrimination stems mainly from two different sources:
first, participants may be HIV-seropositive (that is, they tested positive on a diagnostic test, such
as an ELISA, for a specific antibody) as a result of injection with the vaccine; and second,
participants may be viewed by others as part of a high-risk group and therefore subject to social
stigma.
148
KERNS, supra note 104, at 101
Interview with Ian Poynter, supra note 65.
150
KERNS, supra note 104, at 126.
149
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Discrimination due to HIV-positive serostatus. Because conventional HIV tests
cannot differentiate between infection and vaccine-induced seropositivity, results of such tests
can lead to possible discrimination. According to a study conducted by the HIV Network for
Prevention Trials (HIVNET), participants in vaccine trials viewed false-positive HIV tests as
their number one concern in terms of social risk. Vaccine-induced seropositivity can have the
same adverse social consequences as does true HIV-positivity. Even in the US, it is common to
“treat people living with HIV/AIDS as social lepers…. AIDS has engendered such prejudice and
apprehension that its diagnosis typically signifies a social death as concrete as the physical one
which follows.”151
Individuals who test positive for HIV may be subject to discrimination in employment,
health insurance, and life insurance.152 They may have problems donating blood and traveling to
and immigrating to other countries.153 In fact, one person with whom I spoke explicitly listed
this as a reason for refusing to participate in the study: since he was planning on moving to South
Africa, he believed that his HIV-positive serostatus would hinder his employment and subject
him to discrimination.154 Although there are tests available to distinguish between true infection
and vaccine-induced seropositivity, such as viral load tests, these tests are not widely available
outside the test sites.155
Researchers, therefore, attempt to “shield participants from harm by limiting disclosure
of their blood-test results.” However, due to various required blood tests, such as for insurance
applicants, military recruits, foreign service officers, prison inmates, and immigrants, it is
unlikely that participants will be able to limit their HIV tests to those given on the research site,
151
Leider, supra note 87, at 1206-07.
The NIAID Division of AIDS, supra note 37.
153
HIV VACCINES EXPLAINED, supra note 9; The NIAID Division of AIDS, supra note 57.
154
Interview with Ian Poynter, supra note 65.
155
Id.
152
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and will therefore probably return a false-positive blood test.156 While all legal and technical
protections may be in place, there are de facto limitations on non-disclosure of seropositivity and
participation in the trial. Even a law mandating a patient’s consent for disclosure of medical
records seems as if it would be doomed to failure, because such a policy would alert the world
that such records do exist; because the participant would likely incur social and personal pressure
as a result; and because often a person’s refusal to release information is seen as damning in
itself and can lead to suspicion and hence discrimination.157
As a result, researchers should pursue the dual policy of trying, as much as possible, to
safeguard the confidentiality of research data, while simultaneously informing the participants of
the probable limits on their ability to completely maintain this confidentiality.
Discrimination due to classification in high-risk group. Knowledge that a person is
participating in an AIDS vaccine trial may in itself foster certain assumptions which may lead to
stereotypes and prejudice. The association between AIDS and homosexuality or drug use, for
example, is great. Both groups are often presumed to be HIV-positive, and those who are HIVpositive are often presumed to be a member of one of these two groups.158 In 1989, Senator
Jesse Helms went as far as to state, “I do not understand why … you went down the road of
including in your definitions people who are HIV-positive, because 85 percent or more of the
HIV positive people in this country are known to be drug users or homosexual or both.”159 Study
participation, therefore, “stands as a virtual proxy for risky behavior such as sodomy, drug use,
156
Leider, supra note 87, at 1205-06.
KERNS, supra note 104, at 111-12.
158
Leider, supra note 87, at 1208.
159
Id. at 1207.
157
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and promiscuity, [and] disclosure of trial participation simply replaces one potential basis of
discrimination with another.”160
As a result, researchers must take care not to add force to these stereotypes in conducting
their studies. They must balance their need for high-risk individuals in clinical trials with the
risk of “reinforcing some of the very associations that stigmatize affected populations…. Each
time a flyer, billboard, newspaper, radio, television, or Internet advertisement publicizes the riskgroups needed for AIDS vaccine trials for recruitment purposes, it also informs those who would
discriminate that participation correlates with high-risk behavior.”161
Discrimination as a disincentive to participation. Discrimination, therefore, acts as a
disincentive to participation in AIDS vaccine trials. It is a threat not only to individuals,
therefore, but also to the vaccine effort as a whole. Many of the volunteers, the majority of
whom are motivated simply by altruism, will see such social harms as a large cost that they may
not be willing to incur for the public good alone. A few publicized incidents of such
discrimination can easily be reported back to the communities to which they belong, thereby
tainting the willingness of such populations to participate and foreclosing the necessary link to
the ideal groups for clinical trials. Such publicity can easily forestall recruitment efforts. 162
Adding such potential for social discrimination to the physical risks of vaccine trials
yields a major deterrent to participation and therefore a major obstacle to successful research.
Without the proper management of social harms early in the trials, and the proper protection of
trial participants, such physical risks and social harms may significantly reduce voluntary
enrollment in clinical trials and hamper the vaccine effort in general.
160
Id. at 1209.
Id. at 1208.
162
Id. at 1208-09.
161
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4.2.4 Minimizing Harm to Participants in Clinical Trials of AIDS Vaccines
In order to allay individuals’ fears about participating in clinical trials of AIDS vaccines
and to protect them against possible social harm, various public and private groups have worked
to minimize the amount of loss volunteers will suffer as a result of their participation. Both to
protect these individuals for their own sake, and to safeguard the pool of participants and
therefore the vaccine effort as a whole, manufacturers and governmental entities have searched
for ways to ensure that participants will be as free as possible from all harm, especially
discrimination.
Efforts of the NIAID and trial sponsors. The NIAID has been working proactively to
reduce the possibility of social discrimination. Since the start of HIV vaccine trials, it has
“viewed addressing issues of trial-related social discrimination as critical to the conduct of HIV
vaccine trials.”163 In working to reduce this discrimination, the NIAID has established strong
ties with many of the communities involved, providing them with sufficient information and
answering their questions in order to address their concerns and work towards their continued
support of and participation in the vaccine effort.164
The NAIAD developed a mechanism to address social discrimination over 13 years
ago—before even the first human clinical trials of any AIDS vaccines had taken place—and this
mechanism is still in place. In a letter sent to trial participants, the NIAID outlined this strategy,
which is five-fold:
(1) informing trial participants beforehand of the risks of revealing their trial
participation; (2) offering participants specialized confirmatory HIV testing; (3)
163
Letter from Patricia Fast, National Institutes of Health, Department of Health and Human Services, to
AVEG/HIVNET trial participants (October 1, 1997).
164
JORDAN REPORT, supra note 16, at 85.
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assisting participants with resolving incidents; (4) tracking incidents of trialrelated social discrimination; and (5) working with insurance companies and HIV
test kit manufacturers to prevent trial-related discrimination.165
The doctors, nurses, and recruiters specifically inform volunteers of the potential
discrimination and make sure that they consider carefully their decision whether or not to
disclose their participation in the trial. Participants are issued an ID card that they can use in the
event of a false-positive test result to explain the possible cause of this result of an HIV antibody
test. Any incidents of social discrimination are handled individually, and the study staff provides
counseling to those individuals who become the subject of discrimination as a result of
participation in the trial. The NIAID will intervene where appropriate, and in most of these
instances of NIAID intervention, the NIAID has proven successful.166
The NIAID continues to reinforce that “working with volunteers is not enough. There is
a responsibility to inform in advance any groups that may be in a position to discriminate against
a vaccine volunteer because of misinterpretation of an HIV antibody test.” In furtherance of this
mission, the NIAID has asked—and continues to ask—insurance companies to cooperate by
assuring “appropriate availability” of health and life insurance to trial participants. In general,
the companies have reacted positively to this request and complied. “Although it is difficult in a
decentralized system to reach all providers of health care, the response to the NIAID request has
been overwhelmingly favorable.”167
Other attempts by the NIAID to raise awareness of the possibility of HIV-seropositivity
due to vaccine trials have included informing the manufacturers of HIV test kits of this possible
165
Letter from Patricia Fast, supra note 163.
Id.
167
Id.
166
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false-positive result. Many of these manufacturers have now changed the language in their kits
as a result of this warning.168
Although the NIAID acknowledges that it is “beyond [their] power to completely prevent
or remedy social discrimination related to the vaccine trials, [they] are committed to making sure
that volunteers understand the risks, and to working with volunteers and others to reduce real and
theoretical risks of social discrimination….” This commitment extends beyond the duration of
the current trials, and as far into the future as necessary in order to minimize social harm to
participants.169
The sponsors of the vaccine trials, as well, engage in extensive counseling with trial
participants in order to minimize any risks that could occur to them as a result of trial
participation. In the Phase III trial of AIDSVAX in Thailand, for instance, the CDC makes sure
that participants do not relax their preventive behaviors, by providing them with individualized
counseling on how to protect themselves from exposure to HIV through behavior change.
Volunteers receive explicit warnings that the vaccine has not yet been proven effective, and that
some participants are actually injected with an inactive placebo. The trial sponsors also attempt
to build peer support for reducing HIV risk by encouraging all volunteers to take part in group
education sessions. And, to further reduce their risk for HIV infection—as well as to help them
stop their drug use—intravenous drug users participating in the trials are enrolled in drug
treatment and maintenance programs at the Thai clinics.170
Although these tactics reduce participants’ exposure to HIV—at least in theory—and
therefore may be seen to partially thwart the goal of the vaccine trial by decreasing the amount
by which the vaccine is challenged with the virus, such counseling is necessary from an ethical
168
Id.
Id.
170
CDC, supra note 115.
169
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standpoint. It helps to balance the physical and social risks of the trial to the participants with its
intended benefits. And it pushes the trial closer to attaining those three overarching ethical
principles that are espoused in all scientific research involving humans: autonomy, beneficence,
and justice. First, it ensures the comprehension of full information for a well-informed and
voluntary decision (autonomy). Next, it reduces the risk to the trial participants and therefore
boosts the relative benefit of the trial (beneficence). And finally, it decreases the opportunity to
take advantage of vulnerable populations (justice).
In order to further comply with the ethical standards of clinical trials, especially that of
justice, if participants in the Thai trial become infected while the trial is in progress, the BMA
has agreed to provide them with medical care. The BMA guidelines provide that HIV-infected
participants will receive preventative treatments for tuberculosis and pneumonia, as well as two
antiretroviral drugs, including AZT, when their T cell counts drop to a certain level or they
develop an HIV-related disease. Volunteers are also entitled to T cell and viral load
monitoring.171
The ADA. In terms of legal protections against trial-related social harms for participants,
researchers began by searching for existing laws that could serve to minimize discrimination.
One of the first places they looked for a source of protection was the Americans with Disabilities
Act of 1990 (ADA). The purpose of the ADA was to “address the major areas of discrimination
faced day-to-day by people with disabilities.”172 It pertains to discrimination in employment,
public services, and public accommodations and services operated by private entities, and applies
to state and local governments, and private employers with fifteen or more employees. 173
171
Id.
Americans with Disabilities Act, 42 U.S.C. § 12101(b)(4) (1994).
173
Leider, supra note 87, at 1210-11.
172
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In searching for an established legal protection for trial participants, therefore,
researchers wondered whether volunteers in AIDS vaccine clinical trials might be included under
the rubric of people with disabilities and therefore protected under the ADA. In order to qualify,
an individual must either: (1) have an “actual disability,” physical or mental, that substantially
limits a major life activity; (2) have a “record of” the impairment; or (3) be “regarded as” having
such an impairment.174 In addition, the individual must be able to perform the essential functions
of the position—with or without reasonable accommodation—and may not pose a direct threat to
the health or safety of others.175
For a participant with an HIV-positive serostatus, the first possibility—having an “actual
disability”—would seem to hold the least merit. The second and third prongs, however, may
well qualify participants as disabled under the Act. Individuals who test false-positive for HIV
certainly do have a “record of” the impairment, which would satisfy the second prong. And, as
for the third prong, a person bringing a suit due to discrimination in employment as a result of a
false-positive test result has a definite claim of having been “regarded as” having this impairment
by his employer.176
The next important question to ask, therefore, is whether HIV infection—albeit the result
of a false-positive test in our case—constitutes an impairment that substantially limits a major
life activity.177
This question was presented to the US Supreme Court in Bragdon v. Abbott.178
In that case, a woman sued her dentist for discrimination in public accommodations after he told
her he would only fill her cavity in a hospital due to her HIV-positive status. The Supreme Court
held that HIV is a physiological impairment even before it manifests symptoms, and that the
174
42 U.S.C. §12102(2).
Leider, supra note 87, at 1211.
176
Id. at 1212.
177
Id. at 1213.
178
Bragdon v. Abbott, 524 U.S. 624 (1998).
175
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plaintiff’s HIV infection limited a major life activity, that of reproduction. As such, the Court
framed HIV infection as an “actual disability,” under the first prong. It did not consider HIV
infection under the second and third prongs, nor did it address whether HIV is a per se disability
under the ADA.179
The Supreme Court, therefore, left much of the analysis of whether HIV is a disability
under the ADA up to individual circumstances. Although it is now considered a per se
impairment, HIV does not necessarily qualify as a disability, for it necessitates finding a
substantial limitation of a major life activity in each case. The Court only discussed
reproduction; but what if, for instance, the plaintiff is a post-menopausal female? There must be
an individualized determination in each case as to whether the life function is major and the
limitation thereof is substantial, leading to a probable line of ad hoc decision-making. This
judicial uncertainty is further complicated by the use in the statute itself of an illustrative but
non-exclusive list of major life activities that qualify for protection. “The resulting
indeterminacy, arising from the fact-specific nature of the substantial limitation inquiry,
effectively undercuts much of the precedential value of Bragdon [and] leaves many key
questions unsettled for subsequent suits.”180
Other disability discrimination law. Although it is still uncertain whether or not the
ADA can protect individuals from discrimination based on their HIV-positive serostatus as a
result of vaccine trial participation, it is much more certain that “disability law does not extend to
discrimination based on AIDS vaccine trial participation.”181 Membership in such a class, that
is, does not per se provide standing to sue under disability law. It would be incredibly difficult to
179
Leider, supra note 87, at 1214-15.
Id. at 1216-18.
181
Id. at 1220.
180
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provide protection to the members of a group which, for the most part, have been specifically
selected from high-risk populations that engage in a variety of high-risk behaviors, such as
prostitution, illegal drug use, and sodomy, since these behaviors are themselves illegal in many
states. “It would be anomalous indeed if federal disability law prevented ‘discrimination’ against
individuals for behavior that would otherwise subject them to criminal sanction.”182
In addition, such laws are usually highly difficult to enact and even more difficult to
enforce. The enactment of such discrimination laws would take on an even greater challenge if
the populations the laws sought to protect were not highly regarded by the community that
sought to enact them. “Laws protecting civil liberties are sometimes difficult to enact even in the
best circumstances of relative civil order, but they can be especially difficult to enact … if the
proposed laws do not really represent the community’s actual standards and beliefs.”183 And,
judging from the major impediments to the enactment of civil rights legislation for the protection
of more highly regarded populations, it seems as if any legislation that proposed to protect
groups that engage in what many see as illegal and immoral behavior would have an even harder
time achieving its goal. “In short, disability law seems poorly suited to cover the myriad adverse
situations vaccines may face as a result of their participation in experimental trials.”184
California has surpassed the rest of the nation in its attempts to foster AIDS vaccine
research. It has passed a set of laws that seek to enhance the vaccine research effort, and
especially to advance the role of clinical trials in this research. In addition to the scheme’s
setting up of an AIDS vaccine victims compensation fund and an AIDS vaccine guaranteed
purchased fund, considered infra with the economic impediments to a vaccine, the scheme offers
some protection against social harms that result from clinical testing. The law provides that: “No
182
Id. at 1220.
KERNS, supra note 104, at 112.
184
Leider, supra note 87, at 1220.
183
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health care service plan, disability insurer, nonprofit hospital service plan, self-insured employee
welfare benefit plan, or life insurer may withhold any settlement or coverage of an individual
solely because of his or her participation in an AIDS/HIV vaccine clinical trial.”185
Although this provision seems to provide a strong basis for protection, however, it is
limited in various respects. First, it uses the language “solely because of.” This language leaves
ample room for an insurer to base his determination of no coverage partly on other factors. For
example, he may state that the individual’s heightened risk of HIV infection was the main reason
for declining coverage, especially if he likens trial participation to intravenous drug use.
Additional limitations to California’s legislation include the substantial exemption of large
employers from state regulation of their insurance plans due to ERISA; the limitation of the
protection of participants to the confines of the state of California; and the limitation of the law
to the insurance sphere, to the exclusion of other areas of possible discrimination.186
Strategies to minimize harm to participants. In order to maintain a viable balance
between the benefits of vaccine research and the risks to trial participants, researchers should
keep in mind the various ethical considerations relevant to working with humans. In ensuring
that volunteers incur the least harm possible as a result of their participation in an AIDS vaccine
trial, we may consider the following suggestions, which, I believe, would keep researchers
focused on the ethical issues inherent in human vaccine trials:

Continue to emphasize the policy of providing complete information, ensuring full
comprehension, and allowing for a voluntary choice free from any coercion, in
accordance with the principle of autonomy. Testing for comprehension and allowing
sufficient time for deliberation are two indispensable elements of this policy.
185
186
CAL. HEALTH & SAFETY CODE § 121280(4)(b).
Leider, supra note 87, at 1223.
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
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Continue the policy of counseling participants against high-risk behavior, and ensure
their knowledge of the experimental vaccines’ effectiveness.

Provide participants with adequate medical care in case of infection with HIV during
the trial. This policy helps to allocate certain benefits to those who incur risk.

Ensure that whatever benefits stem from the research are returned to the populations
that incurred the risk. If a safe, effective, and successful vaccine results, make sure it
is made available to the participants and the communities to which the trial volunteers
belong. This will help to attain the principle of justice.

Minimize social discrimination by maintaining confidentiality as much as possible.
This includes confidentiality of trial participation, as well as of HIV tests results and
medical records.

Continue the NIAID’s five-prong mechanism for minimizing social discrimination as
a result of AIDS vaccine trial participation.

Give participants an express right to compensation for unconsented disclosure of
confidential information, such as participation in the trial, medical records, tests
results, and trial-related communications. Make this right per se, in that, unlike under
the ADA, no adverse action need be taken by the disclosing party, nor does the
claimant need prove his state of mind.187

Create a method for individuals to identify themselves as trial participants solely for
the purpose of HIV tests, so that the proper tests can be done without exposing
participants to harm from disclosure.188
187
188
Id. at 1226.
Id. at 1227.
Greilsamer, Aiding AIDS

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Attempt to formulate some piece of workable legislation whereby it is prohibited to
use an individual’s status as a trial participant as a basis for disparate treatment in
employment, in federal programs, in the limitation or denial of insurance coverage,
and in the granting of a visa or immigration.189

Reinforce to the entire population that vaccine trial participation is not synonymous
with membership in certain groups, and that all participants are not necessarily
chosen due to their being part of a high-risk population.
5 Economic Impediments to the Development of a Vaccine
Not only is there little economic incentive to research and develop a successful AIDS
vaccine, but the economic disincentives to its development are more than substantial. In fact, the
economic issues presented by the development of an AIDS vaccine may prove the most serious
obstacles to its development and the most difficult hurdles to overcome. Development costs are
high, expected returns are small, and potential liability is huge, all of which factors come
together to deter manufacturers from investing in an AIDS vaccine.
5.1 Costs to Development and Financial Return
Like all research and development projects, the search for a successful vaccine is a
gamble. No one can reliably predict how much time or money it will take to go from research to
market, nor can anyone even be assured that the possibility of a vaccine actually exists. What is
fairly certain, however, is that for most pharmaceutical companies, the costs to development will
be incredibly great relative to the expected financial return on their investments.
189
Id. at 1227.
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The vaccine business is “notoriously unprofitable.” Compare the following figures:
worldwide sales for all licensed vaccines in 1999 totaled between $4.3 billion and $6 billion;
sales of Merck’s best-selling drug alone that year (a cholesterol-lowering drug) brought in $4.5
billion. In other words, “one best-selling drug…grossed roughly the same amount of money as
the entire worldwide vaccine market.”190
The expenses entailed by HIV vaccine research are extremely high, and the probable
financial return is small. Costs are already in the many hundreds of millions of dollars.191 The
financial return on even a fairly successful vaccine is often not great. The vaccines are available
to healthy individuals, not as therapeutic treatments. In addition, most vaccines require only one
dose in an individual’s entire lifetime.192 And in theory, once the disease is eradicated, like
smallpox, there will no longer be a market for the vaccine. Moreover, if the primary markets for
the vaccines are in developing nations, as would be the case with an HIV vaccine, ethical
concerns—as well as those of public image—would likely force companies to set the price at a
level that would not be preclusive for poorer nations to afford. Using a monopoly position to set
a prohibitively high price would be seen as “unnecessarily (and unethically) exploitative.”193
As such, “normal market forces are not favorable for enticing private pharmaceutical
companies to commit themselves and their resources to the development of vaccines, and
particularly not to the development of HIV vaccines.”194
190
Cohen, supra note 1.
KERNS, supra note 104, at 44.
192
Kelley E. Cash, Note, The New Restatement (Third) of Torts: Is It the Cure for the AIDS Vaccine Ailment?, 16
REV. LITIG. 413, 419 (1997).
193
KERNS, supra note 104, at 45.
194
Id. at 44.
191
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5.2 Manufacturer Liability
Not only is the profit for dose low, but the expected legal liability per dose is high.
“Despite the elaborate testing and review procedures mandated by the FDA, the lure of profit,
and the dictates of urgent medical necessity, pharmaceutical companies are understandably
concerned about their exposure to liability.” Such concerns undoubtedly retard innovation and
significantly delay the marketing of new vaccines.195
Potential litigation against the manufacturer of an AIDS vaccine could potentially stem
from claims either that the vaccine caused infection—as opposed to a claim that the vaccine
simply did not prevent infection—or that it caused some other adverse effect, such as birth
defects, as seen in the Bendectin controversy, infra.196 Although it is highly certain at this point
that the AIDS vaccines under development cannot cause infection with HIV, other possible
effects of the vaccines, such as those discussed supra, simply cannot be anticipated. Perhaps, for
instance, someone will claim that the vaccine sped the development of AIDS. In addition, AIDS
vaccines present an additional risk to manufacturers, in that AIDS vaccines will likely be
administered to higher-risk populations, who can then claim that “the vaccine actually caused the
virus rather than protected against it.” The unpredictability of such litigation, and the possibility
for financial catastrophe as a result of it, is a “persuasive [force] making vaccine manufacturers
increasingly reluctant to market new products.”197
In addition to the effect on manufacturers of the potential cost of litigation, such risks
have also been appreciated by and imputed to insurers. As a result, many insurers have been
“driven…out of the market” or have absorbed this risk by making premiums to manufacturers
195
John P. Wilson, The Resolution of Legal Impediments to the Manufacture and Administrations of an AIDS
Vaccine, 34 SANTA CLARA L. REV. 495, 504 (1994).
196
Id. at 507.
197
Id. at 507.
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“prohibitively expensive. Companies are forced to self-insure and to devote extra effort toward
improving the safety of product design and the sufficiency of warnings against all conceivable
hazards.”198 This inefficient use of time, money, and other resources—and the resulting decrease
in innovation—has been largely a result of the fear of liability.
5.2.1 Liability Litigation Activity: Past and Present
The increasing refusal of Americans to accept risk, and its consequences, has led to a
substantial shifting of responsibility to medical service providers and manufacturers. Filings of
cases for medical malpractice and product liability have noticeably exploded over the past few
decades, and consequently there now exists not only an increased probability that a plaintiff’s
claim will prevail in a courtroom, but also a “persistent and rapid growth in the average size of
awards.”199
Several past experiences of mass tort litigation highlight the incredible—and often
unanticipated—risk to manufacturers. For example, Merrell Dow had been marketing
Bendectin—a drug for the relief of morning sickness—for a substantial amount of time before
consumers claimed the drug to be the cause of congenital defects. Although the evidence and
epidemiological studies were not conclusive, and therefore Merrell Dow did not lose one case, it
had to give up. The adverse publicity and $18 million annual cost of legal fees and insurance
were not justified by the almost equivalent $20 million in sales.200
As a result of the expansion of liability, the increased probability of recovery, and the
increase in awards, defendants are often forced to settle even weak and unfounded claims. Such
an effect has shown itself in full form in the pharmaceutical industry, and with vaccines in
198
Id. at 507.
Id. at 510.
200
Id. at 506.
199
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particular. Despite proper manufacture of vaccines and proper warnings, juries have not
infrequently imposed high damage awards.201
There is a “widespread belief…[by] people in the business community…that punitive
damages are out of control.” And, although many debate that “the concern about huge numbers
of runaway verdicts is essentially groundless with respect to products cases,” the fact that
manufacturers perceive any chance of a huge punitive damages award will affect their decisions.
Perception, in fact, “may be as important as reality” when it comes to punitive damages. 202 In
the same way that people fear air travel more than car travel, even though there is a significantly
higher risk of being killed in an automobile than in an airplane, risk-averse manufacturers see the
large magnitude of the damages well before they see the low probability.
This is, in fact, exactly what the courts have intended with respect to punitive damages:
they are intended to act as a deterrent, designed to discourage manufacturers from engaging in
similar conduct in the future and to encourage safer products. If it is “to achieve its purpose, it
must ‘sting.’”203
Such a rationale for punitive damages has caused the courts to hold up unbelievably high
punitive damage awards. In Browning-Ferris Industries of Vermont, Inc. v. Kelso Disposal, Inc.,
for example, the US Supreme Court upheld an award of $6 million in punitive damages coupled
with a mere $51,000 in compensatory damages—a ratio of 117:1.204 Justice O’Connor opined:
Awards of punitive damages are skyrocketing. As recently as a decade ago, the
largest award of punitive damages affirmed by an appellate court in a products
liability case was $250,000…. Since then, awards more than 30 times as high
201
Id. at 513.
Id. at 518.
203
Id. at 521.
204
Browning-Ferris Industries of Vermont, Inc. v. Kelso Disposal, Inc., 492 U.S. 257 (1989).
202
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have been sustained on appeal…. The threat of such enormous awards has a
detrimental effect on the research and development of new products. Some
manufacturers of prescriptions drugs, for example, have decided it is better to
avoid uncertain liability than to introduce a new pill or vaccine into the market.205
Notwithstanding the Court’s upholding of such large damage awards, it has also
expressed its concern that punitive damages may “run wild.”206 Many studies reveal that such
large punitive damage awards are, in fact, incredibly rare. “The overwhelming number of U.S.
manufacturers never have a punitive damages award levied against them, and those that do are
guilty of serious misconduct.”207
Perception is key, however, an idea that leads to the prevailing view that “innovative new
products are not being developed or are being withheld from the market because of liability
concerns or inability to obtain adequate insurance.”208 The “increasing number of suits, court
awards, and out-of-court settlements [has forced] manufacturers … to devote an even larger
percentage of the revenue from vaccine sales to costs of insurance and of defending against
potential liability,” making pharmaceutical companies reluctant to develop and market new
products.209
5.2.2 Applicable Standards of Liability
The standard of liability that will apply to a pharmaceutical company in product liability
suits is of utmost importance in determining manufacturer incentives as to research,
205
Id. at 282.
Pacific Mutual Life Insurance Co. v. Haslip, 499 U.S. 1, 18 (1991).
207
Wilson, supra note 195, at 531.
208
ALAN R. NELSON, AMERICAN MEDICAL ASS’N., IMPACT OF PRODUCT LIABILITY ON THE DEVELOPMENT OF NEW
MEDICAL TECHNOLOGIES 1 (1988), in Wilson, supra note 195, at 513.
209
John K. Iglehart, Health Policy Report: Compensating Children with Vaccine-Related Injuries, 1316 NEW
ENGLAND JOURNAL OF MEDICINE 1286, 1286 (1987), in Wilson, supra note 195, at 513-14.
206
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development, and marketing. As the standard chosen in a products liability lawsuit is often
outcome-determinative, manufacturers must consider this closely when deciding whether or not
to develop a product. The applicable standard influences the manufacturer both directly, through
lawsuits themselves, and indirectly, by way of the FDA. FDA decisions “have been affected by,
or taken cognizance of, developments in private liability litigation involving the products that it
regulates.” The policy choices made by public health authorities “respecting the need for
development and production of products are often influenced by private liability concerns….”210
There is a wide spectrum of liability between a defendant-friendly standard of intentional
recklessness and a plaintiff-friendly standard of complete strict liability. In the vaccine arena,
however, the law is yet unsettled as to where on the spectrum the standard will fall. While
“several court decisions have dramatically expanded the liability of manufacturers of vaccines …
for injuries traceable to the use of their products,” other courts have emphasized the public policy
concern of the development of new drugs by restricting the scope of liability for
manufacturers.211
Courts in this area have acted in large part under the guidance of Section 402A of the
Restatement (Second) of Torts. This section, however, is the source of much of the uncertainty
of liability in this area. While the provision itself applies a standard of strict liability, the
accompanying Comment k seems to absolve vaccine manufacturers of this harsh standard. The
resulting conflict among the courts has left open the question of which standard prevails.
Section 402A approach. Section 402A holds that “one who sells any product in a
defective condition unreasonably dangerous to the user or consumer or to his property is subject
to liability for physical harm thereby caused to the ultimate user or consumer … although the
210
211
PETER BARTON HUTT & RICHARD A. MERRILL, FOOD AND DRUG LAW: CASES AND MATERIALS 697 (1991).
Id. at 697.
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seller has exercised all possible care in the preparation and sale of his product.”212 That is,
manufacturers are held strictly liable for defects, notwithstanding the exercise of due care (and,
additionally, even in the absence of privity with the consumer).
This strict liability approach is based on the conception that “public policy demands that
the burden of accidental injuries caused by products intended for consumption be placed upon
those who market them, and be treated as a cost of production against which liability insurance
can be obtained.”213 The approach is justified by the assumption that “manufacturers prepare
more than the public to anticipate hazards in its product,” and is intended to “discourage the
manufacturing of defective products in the first place.”214
In the landmark case of Reyes v. Wyeth Laboratories, Inc., an eight-month-old girl was
fed two drops of the Sabin oral polio vaccine at a health clinic in Texas, and two weeks later was
diagnosed with polio.215 After a jury found that the vaccine was the “producing cause” of the
girl’s polio, the Fifth Circuit on appeal applied a two-step test in a risk-benefit analysis of the
vaccine: first, they had to determine “whether the product is so unsafe that marketing it at all is
‘unreasonably dangerous per se,’” and second, “whether the product has been introduced into the
stream of commerce without sufficient safeguards and is thereby ‘unreasonably dangerous as
marketed.’”216
The court found that “marketing the vaccine [was] justified despite the danger” because
the “potential harmful effects of the product” did not “outweigh the legitimate public interest in
its availability.”217 However, although this part of the balancing test was resolved in favor of the
212
RESTATEMENT (SECOND) OF TORTS § 402A.
Id. § 402A cmt. c.
214
Cash, supra note 192, at 423-24.
215
Reyes v. Wyeth Laboratories, Inc., 498 F.2d 1264 (5 th Cir. 1974), cert. denied, 419 U.S. 1096 (1974).
216
Reyes, 498 F.2d at 1273.
217
Id. at 1274.
213
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defendant, the court went on to say that the manufacturer had failed to supply adequate
safeguards and therefore had not met its duty to warn individual consumers about the risk posed
by the vaccine. Viewed as a “design defect, the manufacturer’s failure to warn caused the
product to be “unreasonably dangerous as marketed” and resulted in the Wyeth’s being held
strictly liable for the harm inflicted. “The legal presumption…thus operates here to provide the
final element necessary to hold Wyeth Laboratories liable for Anita Reyes’ poliomyelitis….”218
Despite the outcome of this case, the court did acknowledge the possible damage to
public policy that such a holding might cause: that “the holding we reached is ‘dangerous’ to the
nation’s preventive medicine programs and contravenes a strong public policy favoring largescale participation in immunization efforts to combat infectious disease….”219 Such a
consideration left ample room for courts in later cases to give priority to Comment k over the
general section 402A strict liability approach.
Comment k approach. Comment k to section 402A recognizes that there are some
products which are “quite incapable of being made safe for their intended and ordinary use,”
especially in the field of drugs. The comment gives as an example the Pasteur treatment of
rabies, and states:
Since the disease itself invariably leads to a dreadful death, both the marketing
and the use of the vaccine are fully justified, notwithstanding the unavoidable
high degree of risk which they involve. Such a product, properly prepared, and
accompanied by proper directions and warning, is not defective, nor is it
unreasonably dangerous.220
218
Id. at 1282.
Id. at 12.93.
220
RESTATEMENT (SECOND) OF TORTS § 402A cmt. k.
219
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As long as they are properly prepared and marketed, with an adequate warning, therefore, such
“unavoidably unsafe products” do not force their sellers “to be held to strict liability for the
unfortunate consequences attending their use, merely because [they have] undertaken to supply
the public with an apparently useful and desirable product, attended with a known but apparently
reasonable risk.”221
En route to a more expansive interpretation of Comment k, courts began to develop tests
to determine whether a product was “unavoidably unsafe” and therefore qualified for exemption
from strict liability under Comment k. At first, courts declined to apply a blanket exception from
strict liability for all vaccines for being “unavoidably unsafe,” preferring to decide on a case-bycase basis. The court in Toner v. Lederle Laboratories applied a three-prong test originally
outlined in Kearl v. Lederle Laboratories, including whether the interest in making the drug
available to the public outweighed the interest in holding manufacturers accountable through
strict liability; whether the risk of the drug was substantial and unavoidable, in that no feasible
alternative existed with a lesser risk; and whether the drug provided a benefit that was so
“exceptionally important” as to make its availability highly desirable.222
Use of the Kearl test was overruled, however, in Brown v. Superior Court.223 There, the
California Supreme Court rejected “the portion of Kearl which holds that comment k should not
be applied to a prescription drug unless the trial court first determines that the drug is
‘unavoidably dangerous.’”224 Rather, it held,
the comment was intended to and should apply to all prescription drugs….
Almost all jurisdictions that have adopted the rule stated in the comment view its
221
Id. § 402A cmt. k.
Kearl v. Lederle Laboratories, 218 Cal. Rptr. 453, 172 Cal. App. 3d 812 (Cal. Ct. App. 1985); Toner v. Lederle
Laboratories, 112 Idaho 328, 732 P.2d 297 (1987).
223
Brown v. Superior Court, 751 P.2d 470 (Cal. 1988).
224
Brown, 751 P.2d at 482.
222
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provisions as granting immunity from strict liability to all such drugs. In addition,
as we make clear from our discussion of Kearl, the benefit of the negligence
standard stated in the comment would be greatly diminished if all drugs were
required to run the gauntlet of a risk/benefit analysis in order to qualify for
application of the standard.225
Therefore, as long as the drug was properly prepared and provided adequate warnings of known
or “reasonably scientifically knowable” risks, the manufacturer cannot be held strictly liable for
injuries.226
As Comment k and its application demonstrate, “[p]ublic policy favors the development
and marketing of beneficial new drugs, even though some risks, perhaps serious ones, might
accompany their introduction, because drugs can save lives and reduce pain and suffering.”227
The Court in Brown outlined the costs of applying a standard of strict liability, as well as the
public policy benefits of restricting the scope of liability for drug manufacturers:
If drug manufacturers were subject to strict liability, they might be reluctant to
undertake research programs to develop some pharmaceuticals that would prove
beneficial or to distribute others that are available to be marketed, because of the
fear of large adverse monetary judgments. Further, the additional expense of
insuring against such liability—assuming insurance would be available—and of
research programs to reveal possible dangers not detectable by available scientific
225
Id. at 482, note 11 (emphasis added).
Id. at 482-83.
227
Sally-Anne Danner, The Vaccine Ailment: A Cure to Encourage Litigation-Shy Pharmaceutical Companies to
Manufacture an AIDS Vaccine, 14 HAMLINE J. PUB. L. & POL’Y 67, 72 (1993).
226
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methods could place the cost of medication beyond the reach of those who need it
most.228
These considerations provide the justification for those courts which attempt to apply a more
expansive reading of Comment k. They appreciate the public’s interest in the innovation of
vaccines and prescription drugs.
Which standard applies? Despite the public policy concerns that would force courts to
give priority to Comment k, the question of which standard of liability the courts will apply is yet
unresolved. In general, courts have taken either the more expansive reading of Comment k—the
approach of blanket immunity from strict liability—or the more restrictive approach, applying a
case-by-case risk-benefit analysis of whether a product is “avoidably unsafe.”229
In addition, although Comment k exempts “unavoidably unsafe” products from strict
liability, it does not provide the standard under which those products should be judged. It is
unclear if they are exempted from all liability or simply subject to a lower standard, such as
negligence.230
The uncertainty across jurisdictions, combined with the unpredictability in each one, has
instilled a fear in pharmaceutical companies, forcing them to err on the more conservative side
and restrict development and marketing of drugs. As such, “[t]hese divergent applications of
comment k prevent the provision from achieving its underlying policy goal: encouraging the
production of helpful, life saving drugs.”231
With regard to AIDS vaccines, therefore, manufacturers will not be able to “predict their
potential liability for a nationally distributed vaccine which would subject them to tort liability in
228
Brown, 751 P.2d at 479.
Cash, supra note 192, at 425-26.
230
Id. at 425.
231
Id. at 428.
229
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all fifty states.”232 We could, however, attempt to foresee how an AIDS vaccine would stand up
in court, by testing it against the more restrictive approach. This approach would likely require
the drug to satisfy the three conditions that most courts have described in order to be
characterized as “unavoidably unsafe.”
If the vaccine is effective in providing protection from HIV and reducing the incidence of
AIDS, it will likely satisfy the first requirement, a risk-benefit analysis. Any vaccine that has
survived three phases of clinical testing and has gone far enough to make it to the market should
easily meet this condition. Secondly, after years of FDA oversight and manufacturer testing of a
vaccine, it is likely that the vaccine that the company chooses to market will “embody the safest
design known at the time of [its] distribution.” The manufacturer will have little reason to design
the vaccine in a manner that is less than the safest possible. Finally, it is unlikely that a vaccine
will exist that is equal in effectiveness yet superior in safety to the vaccine on the market. At
least two vaccines need be marketed before such concerns can be more than speculative.233
Despite the potential of an AIDS vaccine to hold up in court, however, the uncertainty
and risk of enormous liability—even if only in a few states—prevents manufacturers from
properly insuring themselves against potential liability.234 The “size of awards and the
uncertainty and predictability regarding the courts’ application of [Comment k] have
dramatically increased the cost of liability insurance for manufacturers and have driven most
vaccine manufacturers out of the market.” Even the deep-pocketed pharmaceutical giant BristolMyers has stated that “concerns about liability forced them to abandon anything that was not
100% effective.”235 As one AIDS researcher observed, “[I]f a vaccine protects 99 people and
232
Id. at 428.
Arnold, supra note 128, at 1106-08.
234
Cash, supra note 192, at 428.
235
Danner, supra note 227, at 72-73.
233
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one person develops complications and they trace that back to the vaccine, that one case will
send the company down the drain.”236
5.3 Past Attempts to Insulate Manufacturers and Increase Development
Acknowledging the incredible economic impediments to the development of an effective
and successful AIDS vaccine, several attempts have been made by public entities to spur
research and development of possible vaccine candidates. Government entities have teamed up
with private companies in order to combine research efforts and funds. In addition, state and
federal governments have experimented with statutes that would limit the scope of liability for
manufacturers, building on past experiences with certain legal projects in the pharmaceutical
industry.
In June 2000 the NAIAD announced four new public-private partnerships “to accelerate
development of promising HIV/AIDS vaccines for use around the world.” Dubbed HIV Vaccine
Design and Development Teams (HVDDT), these four partnerships were allocated $70 million
for use over five years. The money goes into incentive-based contracts that are aimed at vaccine
candidates in the middle of the development process, but not yet in clinical testing.237 In March
of this year, GenVec signed a contract with the NIAID with a potential value of $10.2 million,
under which the company will attempt to develop a preventive AIDS vaccine with the use of its
adenovector technology.238
Anthony S. Fauci, director of NIAID, explained the program: “The HVDDT program is a
unique addition to this model that encourages the private sector to increase their AIDS vaccine
236
Jon Cohen, Is Liability Slowing AIDS Vaccines?, SCIENCE, April 10, 1992, at 168, in Danner, supra note 227, at
74.
237
National Institute of Allergy and Infectious Diseases, National Institutes of Health, NIAID Public-Private
Partnerships Seek to Develop HIV/AIDS Vaccine (June 27, 2000), at
http://www.niaid.nih.gov/newsroom/releases/hvddt.htm [hereinafter NIAID Public-Private Partnerships].
238
AIDS Vaccine: GenVec, Inc., Signs $10 Million Contract with NIAID, VACCINE WKLY., March 13, 2002, at 8.
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efforts while allowing NIAID to work closely with its partners throughout the development
process.” Another NIAID official added: “The…program encourages pharmaceutical companies
to invest more in AIDS vaccine research by partially offsetting their financial risk. In essence,
HVDDT contracts ‘prime the pump’ to get the vaccine-production engine running….”239
In addition, academic and government researchers in 1996 instituted the International
AIDS Vaccine Initiative, setting up product development teams composed of both scientists and
biotech firms from all over the world, in a quest for an affordable vaccine. The NIH developed
its own Vaccine Research Center to manufacture experimental vaccines, as did European
researchers in a consortium known as EuroVac.240
Viewing these steps as an increased pressure to develop and market a successful vaccine,
pharmaceutical companies feel up to the task. In fact, Merck CEO Ray Gilmartin has rebuffed
the assertion that the market has influenced his company’s efforts: “There’s a commitment to say
that if the science is there and it’s possible to do, we’re going to do it…. The commercial
success takes care of itself.”241
Despite these optimistic assertions, many have felt that legislative protection is necessary
if manufacturers are ever going to seriously consider putting an AIDS vaccine on the market.
The General Counsel of Johnson and Johnson, for instance, has said that even if his company
were to develop a vaccine, he “would not recommend that it be marketed until Congress passed
protective legislation.”242 A federal statute, many believe, is the necessary precursor to the
239
NIAID Public-Private Partnerships, supra note 237.
Cohen, supra note 1.
241
Id.
242
Wilson, supra note 195, at 547-48.
240
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successful marketing of any AIDS vaccine. And, “[t]he urgent need to develop an AIDS vaccine
appears to be a situation where such legislation is warranted.”243
Congress has had experience in the past with such protective legislation. After a
breakout of swine flu in 1976, and in fear of an epidemic, Congress appropriated $135 million in
order to vaccinate every US citizen against the disease. However, after the Reyes decision and in
the face of huge potential liability under strict liability, insurance companies refused to insure
manufacturers, pharmaceutical companies refused to bear the risk themselves, and consequently
a stalemate developed.244
In order to bridge this gap, therefore, Congress approved the National Swine Flu
Immunization Program of 1976.245 Under this legislation, “the exclusive remedy for all injury
claims arising out of the swine flu immunization program were to be brought against the United
States government.”246 The government thus “assumed the burden of strict liability [as well as]
the burden of litigating unmeritorious claims.”247 Only if a program participant was negligent or
violated its contractual obligations did a cause of action arise in the government.248
After it was claimed that the swine flu vaccine had been causing paralysis (Guillian-Barre
syndrome), the government halted the program, a mere four months after it was initiated. Fortyfive million people had been inoculated. Within 10 years, 4169 claims had been filed against the
government.249 Settlements and adverse judgments cost the government over $100 million, with
no reimbursement from a manufacturer having been obtained.250
243
Id. at 548.
Thomas Baynes, Liability for Vaccine Related Injuries: Public Health Considerations and Some Reflections on
the Swine Fly Experience, 21 ST. LOUIS U. L.J. 44 (1977), in HUTT, supra note 210, at 716-18.
245
National Swine Flu Immunization Program, 90 Stat. 1113 (1976), 42 U.S.C. §§ 247b(j)-(l).
246
Baynes, supra note 244.
247
Danner, supra note 227, at 75.
248
Baynes, supra note 244.
249
Wilson, supra note 195, at 506.
250
Id. at 552.
244
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In the National Childhood Vaccine Injury Act of 1986 (NCVI), the federal government
made another attempt to promote the development and marketing of vaccines through the
insulating of manufacturers from potential liability.251 This act created a no-fault compensation
system, funded by an excise tax levied on sales by vaccine manufacturers, by which any
vaccinee suffering from specific symptoms for a certain period of time after an inoculation could
recover without having to prove causation. The government, however, retains a right to prove
alternative causation in order to absolve itself of liability. Punitive damages are prohibited, and
there is a $250,000 cap on pain and suffering or death benefits. In addition, the claimant has a
right to reject his recovery under the act—and thereby forfeit his compensation—and instead sue
under state tort law, although the act discourages this by “legislatively overruling the Reyes
decision” and by exculpating manufacturers from liability for unavoidable side effects provided
the vaccine was prepared properly and adequate warning was given.252
The program seems to have succeeded in decreasing the number of lawsuits filed against
manufacturers. “The purpose of the statute—to provide reimbursement to injured claimants
while avoiding the hazards and delay of litigation—appears to have been met.”253 The act,
therefore, does “respond at least in part to the need for a Federal insurance program that will
guarantee adequate compensation to persons who are injured, provide manufacturers reasonable
certainty respecting their liability exposure, and thereby promote vaccination while encouraging
development of new vaccines.”254
Whether this type of program will have the same effect with an AIDS vaccine is a
question yet unanswered. Views on the success of such a statute differ greatly. One “practical
251
National Childhood Vaccine Injury Act, 42 U.S.C. § 300aa-1 et seq.
HUTT, supra note 210, at 719.
253
Wilson, supra note 195, at 556.
254
HUTT, supra note 210, at 719.
252
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obstacle” to extending the NCVI to cover AIDS vaccines is that “in order to simplify the process
of determining eligibility for compensation, the act presumes that certain injuries have been
caused by the vaccine. It will … be virtually impossible to identify the times of onset in order to
establish a credible schedule of compensable injuries before any AIDS vaccine is tested or
distributed.”255
California, on the other hand, was much more optimistic. In pursuance of an AIDS
vaccine and a statute that would provide manufacturers with the economic incentives necessary
for its development, California in 1986 established the AIDS Vaccine Victims Compensation
Fund, geared towards providing assistance to manufacturers in both the clinical testing and the
marketing phases of vaccine development, in order to encourage the development of an effective
AIDS vaccine and combat the economic deterrents seen by manufacturers, such as uncertain
costs, profitability, and liability risk.256 The legislature also sought to ensure that any innocent
victim injured by an AIDS vaccine was fairly compensated.257
Under this program, a surcharge levied on the sale of each unit of a vaccine is put into the
fund. Any person whose injury was caused by the administration of a vaccine will receive
compensation for all direct medical costs, loss of earnings, and damages for pain and suffering
up to $550,000, limited by the amount of money in the fund.258 Like the NCVI, the California
legislation provides compensation for claimants, thereby limiting manufacturer litigation costs.
But unlike the NCVI, claimants are allowed to make a concurrent claim against manufacturers,
without forfeiting the recovery received from the fund.259 This may be a significant limitation on
255
Arnold, supra note 128, at 1112.
CAL. HEALTH & SAFETY CODE § 199.45 et seq.
257
Wilson, supra note 195, at 556-57.
258
Id. at 557.
259
Danner, supra note 227, at 77.
256
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the ability of the California legislation to put manufacturers’ minds—and pockets—at ease, and
therefore on the increased economic incentives to develop a vaccine.
The California legislation provides an additional economic incentive to manufacturers in
the form of a purchase guarantee: the state has promised to buy at least 500,000 units of any
FDA-approved vaccine at a price of up to $20 per unit. The “insured market for potential
vaccine products” guarantees a minimum market, and allows manufacturers to “spread their
fixed costs over a greater number of units, thus lowering the average cost per unit” and helping
to allay manufacturers’ concerns about profitability. 260
5.4 Towards an Effective and Workable Solution
Although none of these past legislative efforts in itself creates the ideal incentives for
manufacturers or completely clears a path towards the development and marketing of a
successful AIDS vaccine, they provide good models on which lawmakers can build in order to
produce a workable piece of legislation, one that would furnish manufacturers with the proper
inducement towards this goal. If a statute is in fact attempted, it must be federal legislation, in
order to give pharmaceutical companies one consistent standard to meet across all jurisdictions.
Since uncertainty is a key problem for manufacturers, providing them with some concrete
method of forecasting their costs would make them more likely to enter the vaccine game.
Reliance on the common law tort system for relief seems, at this point, to be no longer an
option. The tort system does have its benefits, such as encouraging manufacturers to exercise
care to produce safe and effective products, having manufacturers internalize their own costs in
the most efficient manner possible and incorporate them into their production and marketing
decisions, and providing victims with “fair” or “just” compensation. But although there are
260
Arnold, supra note 128, at 1120.
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definite benefits to this type of regime, the drawbacks of leaving resolution to the courts—such
as the potential huge liability cost and the possibility that manufacturers will be ordered to
compensate victims for harms they did not cause—are immeasurable, and far outweigh the
benefits. Holding manufacturers solely responsible for recouping their costs, marketing their
vaccines, and defending against potential liability—all of which are so uncertain as to keep
manufacturers in a total guessing game as to their profit margin, if any—has proven to be an
impracticable method for spurring innovation. “Reliance on the common law to compensate
those injured by correctly prepared vaccines is not sufficient to balance a healthy vaccine market
with just compensation to the unfortunate individuals who suffer adverse reactions. [Rather,]
government intervention is required to provide a reliable, stable means of compensation.”261
One unified piece of federal legislation, therefore, seems indispensable for our nation to
come even close to meeting President Clinton’s projected time-frame for the development of an
AIDS vaccine. The legislation must bring us closer to meeting the dual goal of the swift
availability of a safe and effective vaccine and the fair compensation of victims. It must spur
innovation by limiting liability and stabilizing costs, while simultaneously deterring
manufacturer misconduct.
Towards these goals, then, I would recommend the following general strategies for such a
piece of legislation:
1. Provide economic incentives to manufacturers. Subsidize their business, limit
their liability, and allow them to make a reliable prediction of their costs and
potential profitability. Providing certainty to manufacturers is the key here.
261
H. William Smith III, Vaccinating AIDS Vaccine Manufacturers Against Product Liability, 42 CASE W. RES. L.
REV. 207, 239 (1992).
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2. Deter manufacturer misconduct. Incentivize manufacturers to develop the
safest vaccine possible and provide adequate warnings. This entails balancing
this strategy with the former.
3. Provide adequate compensation. Ensure that injured victims can recover an
amount that is fair compensation. This strategy is limited by the first strategy, as
well as by the proper social allocation of government funds, in that there must be
a cap on recovery.
4. Pool risks. The legislation should have several qualities of insurance, the primary
goal of which is “to spread the risks of an activity over a population so that no one
individual has to bear the full cost of an injury.”262 Since the science and
economics of an AIDS vaccine are yet unknown, we should not impose the full
cost on any one entity. Although manufacturers are often viewed as the most
efficient bearers of risk, allocating the full risk to manufacturers will not achieve
the overarching goal of the development and marketing of an AIDS vaccine.
5. Allow for flexibility. Since potential injuries and costs are uncertain, the
legislation must leave room for the accommodation of unforeseen developments.
In order to accomplish these goals, we may take some of the positive elements out of past
activities and legislation, and combine them, after altering them to meet the specific needs of an
AIDS vaccine. Specifically, therefore, we might consider the following elements to put in a
legislation proposal, in furtherance of the above general strategies:

Continue to create and fund public-private partnerships between the government,
small biotech companies, and large pharmaceutical companies, both domestic and
262
Id. at 239.
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worldwide, merging their knowledge and money to create a successful AIDS vaccine.
Encourage global cooperation in the vaccine effort.

Create a compensation fund akin to the California AIDS Vaccine Victims
Compensation Fund, from which potential claimants will be able to be compensated.

Funding for this program should be mixed. Sources of funding may include an excise
tax on each unit of vaccine sold or administered (as in the California fund and the
NCVI) and general tax revenues. Like an insurance premium, the tax would match
the benefits directly to those who pay (vaccinees would recover from a fund to which
they contributed through the excise tax), while the use of government funds would,
through the use of society’s funds, in return provide society with a benefit—the
reduction in the spread of HIV and the resulting savings in public health care costs.
Therefore, these two sources of funding both speak to societal benefit as a whole and
target the populations who bear the majority of the cost.

The government should guarantee to purchase a minimum number of units of any
vaccine that receives FDA approval, as in California.

Recovery for potential claimants should be almost exclusively from the compensation
fund. This is essential in order to limit manufacturer liability and thereby allow them
to project their costs with certain liability exposure, thus stabilizing the market.

Unlike in the NCVI, which allows the forfeit of fund compensation, and the
California fund, which allows concurrent recovery, both of which make
manufacturers’ liability uncertain, this program should provide for recovery solely
from the fund, except for gross negligence on the part of a manufacturer. That is,
lawsuits would be permitted, but the standard of liability would be incredibly high,
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permitting recovery from manufacturers only in cases in which they cannot prove
they exercised due care. This will discourage lawsuits, while ensuring safety by
encouraging manufacturers to perform a risk-benefit analysis in the exercise of due
care. Manufacturers, however, should have the benefit of certain safe harbors, such
as compliance with FDA regulations and adequate warnings, and be liable solely for
those consequences that they reasonably could have anticipated. Furthermore,
punitive damages should be very limited or subject to a cap.

Claimants should be able to recover a specified amount from the fund in accordance
with a compensation schedule, as in the NCVI. However, recovery should be capped.
This provides a quick and certain method of recovery for claimants in return for
relinquishing the right to sue manufacturers for a possibly larger yet unpredictable
sum.

Regarding recovery, it is essential to leave room for flexibility in order to deal with
unforeseen effects. This important element was absent from the NCVI, but the
novelty of an AIDS vaccine requires it.

Legislators should engage in periodic review of the legislation and make any
necessary adaptations, to maintain flexibility.
Conclusion
In our two decades of experience with HIV and AIDS, we have learned nothing if not
that the only way to significantly control the pandemic is through a preventive AIDS vaccine.
Though education has slowed the spread of the virus in industrialized countries, and therapeutic
treatments have slowed the onslaught of the disease, these two responses to AIDS have not even
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put a dent in the proliferation of the disease. A preventive vaccine is therefore the solution
towards which the world must strive.
Although AIDS is a novel and elusive disease to scientists, researchers have made
significant inroads over the past several years in understanding the virus and in figuring out the
most plausible methods of developing a vaccine. Manufacturers have already progressed to
Phase III testing of AIDS vaccines, a sign of great promise in the quest for a safe and effective
vaccine. Through the coordinated work of researchers and manufacturers, public and private,
domestic and international, we may still believe that a cure for AIDS is achievable by the end of
the decade.
In order do get there, however, we need to ensure the protection of the parties involved in
each stage. This entails our performing a series of balancing tests, so that we can protect these
parties and still achieve our goals. In the clinical testing stage, we have an ethical obligation to
protect trial participants from physical and social harms, and this protection must be balanced
against the need for meaningful test results. In terms of development and marketing, we must
protect manufacturers from economic hardship by assuring them a stable market and predictable
liability, while simultaneously encouraging them to develop the safest and most effective drug
possible. We must spur them towards the development and marketing of a successful vaccine
while not sacrificing the right of any injured vacinees to just compensation.
Fortunately, these tasks are not mutually exclusive. Indeed, it is not only possible, but
also essential, to keep all these factors in mind in our quest for the development of a vaccine.
The intermixing and balancing of all these elements will lead us on the quickest path to a
successful vaccine.