LEDA at Harvard Law
School LEDA at Harvard Law
School
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
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.
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 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 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.
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]
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 high- and 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, HIV-negative.[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 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 Vaccine Adverse Event Reporting System (VAERS), a post-marketing surveillance program, collects information about adverse side effects after the administration of vaccines.[15]
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.
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 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:
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 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 Thailand for a VaxGen gp120 vaccine known as AIDSVAX.[45] The following HIV vaccine candidates were in clinical trials as of 2001:
|
Vaccine
|
HIV Subtype
|
Producer
|
Current Status
|
|
gp120
|
B/B, B/E
|
VaxGen
|
Phase III trials ongoing in the US and
Thailand
|
|
ALVAC-HIV
|
B, E
|
Aventis Pasteur
|
In phase II trials in the US, Haiti, Brazil and
Trinidad (subtype B), and Thailand (subtype E); tested alone or in
combination with gp120
|
|
ALVAC-HIV
|
A
|
Aventis Pasteur
|
Ready for phase I trial in Uganda
|
|
Lipopeptides LP5, LP6
|
B
|
ANRS
|
In phase I trials in France
|
|
Vaccinia TBC-3B
|
B
|
Therion
|
In phase I trials in the US
|
|
DNA-HIV
|
B
|
Apollon
|
Phase I trials completed
|
|
DNA-HIV, MVA-HIV
|
A
|
University of Oxford
|
In phase I trials in the UK and Kenya
|
|
NYVAC-HIV
|
B
|
Aventis Pasteur
|
Ready for phase I trial in the US
|
|
DNA-HIV, Adenovirus-HIV
|
B
|
Merck
|
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, at504, 504 .)
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]
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 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 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]
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 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 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]
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 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]
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:
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.
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 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 protective state” and model a vaccine accordingly.[79] Despite optimism from these observations, however, scientists still do not fully understand their occurrence.[80]
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 broad-based 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 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]
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]
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 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]
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 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]
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 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.
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 95-percent level.
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, at-risk people for inclusion in such trials, ... scientists don’t want to deplete that pool before the best vaccines come along.”[106]
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 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]
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.
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 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 self-determination,” 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 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 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 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 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 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]
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]
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 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 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]
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.
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, 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 HIV-positive 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, 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 risk-groups 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.
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) assisting participants with resolving incidents; (4) tracking incidents of trial-related 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 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 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]
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 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 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 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:
Not only is there little economic incentive to research and develop a successful AIDS vaccine, but the economic dis incentives 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.
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.
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]
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 “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.
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 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 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]
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, 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 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 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 large-scale 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]
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-by-case 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 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 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 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 Bristol-Myers 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 one person develops complications and they trace that back to the vaccine, that one case will send the company down the drain.”[236]
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 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 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. Forty-five 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]
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 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 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]
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 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:
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:
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 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.
[1] Jon Cohen, Merck’s Mission and AIDS Vaccine , MIT’S TECH. REV. 56, March 1, 2002.
[2] Ted Griffith, VaxGen Still Hoping for AIDS Vaccine , CBS MARKETWATCH , December 1, 2001.
[3] COHEN , supra note 1.
[4] JON COHEN, SHOTS IN THE DARK: THE WAYWARD SEARCH FOR AN AIDS VACCINE 263-64 (2001).
[5] CBER, Vaccine Product Approval Process (2001), at http://www.fda.gov/cber/vaccine/vacappr.htm .
[6] 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.
[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 ].
[13] CBER, supra note 5.
[14] Id .
[15] CBER, Vaccines (2002), at http://www.fda.gov/cber/vaccines.htm .
[16] DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES, NIAID, NIH , THE JORDAN REPORT: ACCELERATED DEVELOPMENT OF VACCINES 83 (2000) [hereinafter JORDAN REPORT ].
[17] Id . at 84.
[18] Id . at 84.
[19] HIV VACCINE TRIALS NETWORK, THE ROAD TO AN HIV VACCINE 1 (2001).
[20] Clinical Research , supra note 12.
[21] Margaret I. Johnston & Jorge Flores, Progress in HIV Vaccine Development , CURRENT OPINION IN PHARMACOLOGY, 2001, at504, 504.
[22] Clinical Research , supra note 12.
[23] PATRICIA THOMAS, BIG SHOT 468-69 (2001).
[24] Clinical Research , supra note 12.
[25] Id .; THOMAS , supra note 23, at 478.
[26] 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.
[31] Id.
[32] 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 .
[38] Clinical Research , supra note 12.
[39] 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).
[45] The NIAID Division of AIDS, supra note 37.
[46] VaxGen, Our Vaccine: AIDSVAX Description , at http://www.vaxgen.com/vaccine/description.html .
[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.
[52] VaxGen Clinical Trials , supra note 47.
[53] VaxGen, supra note 49.
[54] VaxGen, Our Vaccine: More Information , at http://www.vaxgen.com/vaccine/10K_p12.html .
[55] VaxGen, supra note 43.
[56] VaxGen, supra note 54.
[57] 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 .
[59] 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
[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.
[68] Id .
[69] 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.
[71] Id . at 507.
[72] Challenges , supra note 69; The NIAID Division of AIDS, supra note 37.
[73] Cohen, supra note 1.
[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 .
[79] Challenges , supra note 69.
[80] 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.
[86] The NIAID Division of AIDS, supra note 37.
[87] 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.
[90] THOMAS , supra note 23, at 477.
[91] 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.
[96] Challenges , supra note 69.
[97] 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.
[100] Johnston & Flores, supra note 21, at 507.
[101] Id . at 507.
[102] 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.
[107] Interview with Ian Poynter, supra note 65.
[108] 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.
[113] THOMAS , supra note 23, at 387.
[114] 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 .
[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.
[121] Grushcow, supra note 116, at 118-19.
[122] KERNS , supra note 104, at 156.
[123] Id . at 157-58.
[124] Id . at 159.
[125] CDC, supra note 115.
[126] Grushcow, supra note 116, at 120.
[127] KERNS , supra note 104, at 154.
[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.
[131] Id . at 1089-90.
[132] Id . at 1092.
[133] KERNS , supra note 104, at 94.
[134] Id . at 94.
[135] Grushcow, supra note 116, at 120.
[136] 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.
[142] Id . at 122.
[143] CDC, supra note 115.
[144] Weiss, supra note 106, at Al; Leider, supra note 87, at 1199-1200.
[145] KERNS , supra note 104, at 120.
[146] Id . at 101-02.
[147] COHEN , supra note 4, at 261.
[148] KERNS , supra note 104, at 101
[149] Interview with Ian Poynter, supra note 65.
[150] KERNS , supra note 104, at 126.
[151] Leider, supra note 87, at 1206-07.
[152] 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 .
[156] Leider, supra note 87, at 1205-06.
[157] KERNS , supra note 104, at 111-12.
[158] Leider, supra note 87, at 1208.
[159] Id . at 1207.
[160] Id . at 1209.
[161] Id . at 1208.
[162] Id . at 1208-09.
[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.
[165] Letter from Patricia Fast, supra note 163.
[166] Id .
[167] Id .
[168] Id .
[169] Id .
[170] CDC, supra note 115.
[171] Id .
[172] Americans with Disabilities Act, 42 U.S.C. § 12101(b)(4) (1994).
[173] Leider, supra note 87, at 1210-11.
[174] 42 U.S.C. §12102(2).
[175] Leider, supra note 87, at 1211.
[176] Id . at 1212.
[177] Id . at 1213.
[178] Bragdon v. Abbott, 524 U.S. 624 (1998).
[179] Leider, supra note 87, at 1214-15.
[180] Id . at 1216-18.
[181] Id . at 1220.
[182] Id . at 1220.
[183] KERNS , supra note 104, at 112.
[184] Leider, supra note 87, at 1220.
[185] CAL. HEALTH & SAFETY CODE § 121280(4)(b).
[186] Leider, supra note 87, at 1223.
[187] Id . at 1226.
[188] Id . at 1227.
[189] Id . at 1227.
[190] Cohen, supra note 1.
[191] 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.
[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.
[198] Id . at 507.
[199] Id . at 510.
[200] Id . at 506.
[201] Id . at 513.
[202] Id . at 518.
[203] Id . at 521.
[204] Browning-Ferris Industries of Vermont, Inc. v. Kelso Disposal, Inc., 492 U.S. 257 (1989).
[205] Id . at 282.
[206] 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.
[210] PETER BARTON HUTT & RICHARD A. MERRILL, FOOD AND DRUG LAW: CASES AND MATERIALS 697 (1991).
[211] Id . at 697.
[212] RESTATEMENT (SECOND) OF TORTS § 402A.
[213] Id. § 402A cmt. c.
[214] Cash, supra note 192, at 423-24.
[215] Reyes v. Wyeth Laboratories, Inc., 498 F.2d 1264 (5th Cir. 1974), cert. denied , 419 U.S. 1096 (1974).
[216] Reyes , 498 F.2d at 1273.
[217] Id . at 1274.
[218] Id . at 1282.
[219] Id . at 12.93.
[220] RESTATEMENT (SECOND) OF TORTS § 402A cmt. k.
[221] Id . § 402A cmt. k.
[222] 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.
[225] Id . at 482, note 11 (emphasis added).
[226] 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).
[228] Brown , 751 P.2d at 479.
[229] Cash, supra note 192, at 425-26.
[230] Id . at 425.
[231] Id . at 428.
[232] Id . at 428.
[233] Arnold, supra note 128, at 1106-08.
[234] Cash, supra note 192, at 428.
[235] Danner, supra note 227, at 72-73.
[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, at8 .
[239] NIAID Public-Private Partnerships , supra note 237.
[240] Cohen, supra note 1.
[241] Id .
[242] Wilson, supra note 195, at 547-48.
[243] Id . at 548.
[244] 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.
[251] National Childhood Vaccine Injury Act, 42 U.S.C. § 300aa-1 et seq .
[252] HUTT, supra note 210, at 719.
[253] Wilson, supra note 195, at 556.
[254] HUTT, supra note 210, at 719.
[255] Arnold, supra note 128, at 1112.
[256] 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.
[260] Arnold, supra note 128, at 1120.
[261] H. William Smith III, Vaccinating AIDS Vaccine Manufacturers Against Product Liability , 42 CASE W. RES. L. REV. 207, 239 (1992).
[262] Id . at 239.