Public Health and the Law New FDA Drug Approval Policies and HIV Vaccine Development WENDY K. MARINER, JD, LLM, MPH Introduction A new era in drug research seems to have dawned, largely as the result of the pressing need to treat acquired immunodeficiency syndrome (AIDS).' The Food and Drug Administration (FDA) is changing the way it approves new drugs for persons with AIDS, both to speed up the process and to increase access to experimental drugs.23 The need for new drugs to effectively treat AIDS is undeniable. So is the need for vaccines to prevent HIV infection. Yet virtually none of the changes in FDA policy, or the publicity attending them, refers to HIV vaccines. One reason for the absence of vaccines from this policy debate may be the immediate need to treat persons already suffering from AIDS. Another may be the somewhat discouraging results from studies of vaccine preparations .4-9 But the years of vaccine research may pay off after all. Reports in the summer of 1989 indicate that monkeys may be protected against simian immunodeficiency virus (SIV) by a whole killed preparation of the virus.'0"11 This suggests that an animal model for HIV infection and immunity may be possible. Preliminary reports indicate that experimental vaccine preparations may produce some antibody response, although their ability to achieve protective immunity has not been demonstrated.21'3 In addition, several researchers have reported promising results with passive immunization in a 14','5 Such few chimpanzees already infected with HIV." preparations are more like drugs, in that they are intended to retard disease progression in persons already infected with HIV, than true vaccines, which are intended to prevent active infection in healthy persons. Nevertheless, they may offer new knowledge to pursue vaccine development. These new developments have renewed hopes for a marketable vaccine. But because a marketable vaccine remains many years away, it is somewhat surprising that there have not been more calls for speeding up the review of candidate HIV vaccines. To examine the possibilities for expediting HIV vaccine review, I conducted a study of FDA law and policy including interviews with FDA officials in the Center for Biologics Evaluation and Research and the Office of the General Counsel. That study suggests that the new FDA drug review policies do not fit vaccines. Instead, the nature of vaccines, and HIV vaccines in particular, argues for adherence to a more rigorous form of review. Address reprint requests to Wendy K. Mariner, JD, LLM, MPH, Associate Professor of Health Law, Boston University, Schools of Public Health and Medicine, 80 East Concord Street, Boston, MA 02118. George J. Annas, JD, MPH, Edward R. Utley Professor of Health Law at Boston University is editor of the Public Health & the Law section.
C( 1990 American Journal of Public Health 0090-0036/90$1.50 336
New Drug Review Policies Current FDA policy on HIV vaccines is essentially
consistent with long-standing policy for the review of all candidate vaccines and biologics. However, the FDA rewrote its regulations governing the requirements for seeking approval for licensure'6 and conducting clinical trials'7 in 1985 and 1987, respectively. Since that time, the agency has taken additional steps to accelerate the drug review process18 and to expand the distribution of investigational drugs. These efforts have changed the climate for reviewing candidate HIV vaccines at the FDA. The agency recognizes the need for expediting the testing and review of new HIV vaccine preparations. However, while its new regulations technically apply to vaccines and other biologics, as well as pharmaceuticals and antibiotics, they have not been used for vaccines and, indeed, do not appear to be suitable for vaccines. The first step in expediting new drug distribution was the issuance of the Treatment IND (investigational new drug) regulations on May 22, 1987.'9 These permit investigational new drugs to be used to "treat" patients before the clinical trials are completed where no alternative therapy exists. However, only investigational drugs "intended to treat a serious or immediately life-threatening disease" qualify for such use.'9 The term "serious disease" is not defined, and "immediately-life threatening disease" is defined -quite broadly.'0 But HIV vaccines are not likely to qualify as intended to treat either condition. In its explanation of the regulations, the FDA mentioned advanced cases of AIDS as the first example of an immediately life-threatening disease, but did not include AIDS in its list of examples of serious diseases.'9,2' It explained that some diseases, like multiple sclerosis, are not serious at earlier stages, and that the Treatment IND regulations would not apply to drugs intended to treat those earlier stages of disease. On this reasoning, candidate vaccines that are intended to prevent HIV infection in the first place would not qualify. Some FDA officials currently take the position that the Treatment IND regulations are not intended to apply to vaccines at all. Some biologics, such as the one being studied by Salk,'1 may be intended to treat HIV infection by preventing progression to AIDS. But if these are intended for patients with asymptomatic infection or minimal symptoms, they would not qualify because the target disease is not serious enough. The second step in expediting new drug distribution was the FDA's adoption in late 1988 of its accelerated review procedures.22 The Treatment IND regulations did not disturb the traditional three-phase clinical trial format; they allowed the "therapeutic" use of investigational drugs undergoing clinical trials. In contrast, the accelerated procedures regulations permit FDA review and approval of new drugs before all three phases of the clinical trials are completed.22 These AJPH March 1990, Vol. 80, No. 3
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regulations apply to new therapies intended to treat persons with "life-threatening and severely-debilitating illnesses."22 Like the Treatment IND rules, the accelerated review regulations technically apply to vaccines and other biological products, but their general thrust makes it unlikely that an HIV vaccine could qualify. Life-threatening illnesses are defined as "[d]iseases or conditions where the likelihood of death is high unless the course of the disease is interrupted; and [d]iseases or conditions with potentially fatal outcomes, where the end point of clinical trials analysis is survival." 22 This is a more expansive definition than that for an "immediately life-threatening disease" to which Treatment IND rules apply. While AIDS would qualify under the first clause of that definition, mere HIV infection might not. Both could be expected to qualify under the definition of "severely debilitating," which means "diseases or conditions that cause major irreversible morbidity."22 But again, vaccines are intended to prevent infection, not to treat these conditions. Therefore, they also fall outside the scope of products eligible for accelerated review. The regulations formalize a procedure for sponsors to meet with FDA reviewers to agree on the design of preclinical and clinical studies. These are intended to develop a study design for phase 2 trials that would produce results sufficient to gain marketing approval for the drug without undergoing phase 3 trials. While such meetings and agreements have always been possible,23 in practice they have occurred infrequently. Of even greater importance is the indication that the FDA will apply the general standards of safety and effectiveness more leniently to such drugs. The regulations provide that the agency will use a "medical risk-benefit judgment" in applying the statutory standards.22 They state the FDA's belief that "physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses."22 This language, however, reinforces the general impression that the accelerated procedures are intended to apply to drugs, but not to vaccines for preventing HIV infection. These regulations do raise the question of whether an accelerated process should be used for the review of candidate HIV vaccines. The FDA maintains that the new regulations merely formalize options available under existing agency authority. If this were true, the regulations' exclusion of vaccines would pose no barrier to using the same procedures to expedite HIV vaccine approval and distribution. However, the regulations have made a change. Whatever the FDA's general authority to review investigational drugs, the agency had insisted on the three-phase clinical trial format for almost 25 years. The accelerated procedures rules were modeled after the zidovudine (AZT) approval process. But that success would be difficult to repeat. Zidovudine had already undergone extensive preclinical testing at the National Cancer Institute and elsewhere as a possible anticancer agent before it was considered as a possible anti-viral drug.24 That experience enabled researchers to introduce the drug in the middle of the research process, so to speak. Months, if not years, of review and testing were eliminated. Moreover, introducing the accelerated procedures, the FDA called them "a new and innovative approach", as well as one that built on "past practices." 22 The zidovudine story apart, the possibility of dispensing with phase 2 or 3 was a clear break with tradition. AJPH March 1990, Vol. 80, No. 3
That this break was within the FDA's authority all along is a harder position to argue. The Food, Drug, and Cosmetic Act (FDCA) grants the FDA the power to approve new drugs that are safe and effective, but it prohibits approval unless the drug sponsor affirmatively demonstrates that the drug is in fact safe and effective.25 In the absence of information that the drug is safe or substantial evidence of effectiveness, the statute forbids approval. This is a heavy burden of proof to satisfy. Moreover, the United States Supreme Court has held, in a unanimous decision, that the Act makes no exception for even terminally ill patients.26 On the other hand, as I have argued elsewhere, the FDA retains considerable leeway in determining what constitutes sufficient evidence of safety and effectiveness.27 The statute does not define safety. Substantial evidence of effectiveness is to consist of "adequate and well controlled investigations... by experts" that fairly permit such experts to conclude that the drug will have its intended effect.28 The FDA, not Congress, developed the 3-phase structure for clinical trials, as well as rules for in vitro and animal tests, to produce adequate measures of safety and effectiveness. This structure may simply have formalized the procedures that evolved for tests after the Kefauver amendments of 1962. In principle, any other format that resulted in equally valid measures could satisfy the statutory requirements.27 Thus, eliminating phase 2 or 3 would not necessarily violate the statute, provided that the data yielded credible results. In some cases, phase 3 studies served to clean up sloppy phase 2 trials, answering remaining doubts. Perhaps if phase 2 studies were done perfectly in the first place there would be no need for phase 3. Nevertheless, for better or worse, omitting phase 3 does represent a real change in the drug review process. Interestingly, the change so far has been more cosmetic than real.29 Few drug sponsors have sought accelerated review. One reason may be the expense required to mount a trial that can produce evidence of effectiveness sufficient to warrant approval for marketing. Drug companies may prefer to conduct a limited phase 2 trial to get a reading on the probability that a drug works before committing itself to a major phase 3 study. In addition, a small phase 2 trial may be needed to determine the minimum sample size and other study design parameters for a trial of effectiveness. Similarly, few sponsors have sought to have investigational drugs distributed to patients under a Treatment IND.30 Aside from these formal procedures for expediting drug trials, the FDA has attempted to get investigational drugs to a larger population by encouraging innovative testing and distribution techniques. One of these is known as the paralleltrack approach to clinical trials.31 Practicing physicians could prescribe experimental drugs as therapy for their AIDS patients who are not in clinical trials.31 The approach differs from the compassionate use of experimental drugs33 both because of the larger numbers of patients who could receive the drug, and because physicians would report to the FDA or drug sponsor on how their patient fared. The information would be spottier than clinical trials data and of limited utility, especially where it covered persons quite different from those in the trials. The parallel-track proposal has engendered considerable controversy. Its only advantage would be to offer investigational drugs to AIDS patients who are not willing or eligible to enter clinical trials. But this advantage, if it is one, is not applicable to vaccines either. Even if one believes that investigational drugs are therapy-a hotly disputed concept3,29,34-vaccines cannot be considered 337
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treatment for patients who already have AIDS. Thus, the parallel-track approach also seems unsuitable for vaccines. A much more dramatic departure from past practice was the FDA's decision to permit persons with life-threatening illnesses, including AIDS, to import from abroad drugs not licensed in the United States.35 This was accomplished by expanding an administrative exception to existing FDA policy banning imports. The importation of unapproved drugs, even for personal use, had been considered a violation of the FDCA's prohibitions against holding drugs for sale in interstate commerce.27,36 In one sense, allowing AIDS patients to obtain such drugs is consistent with the FDA's efforts to increase access to AIDS drugs. But it also differs in an important way. The new regulations do not authorize patient access to drugs that are not being studied in United States clinical trials. The new import policy does. But the current policy's limitation to persons with life-threatening illnesses makes it as unsuitable for vaccines as the new formal regulations. Reviewing Vaccines The FDA is trying to assume a new, more creative role in drug distribution. Shedding its images as consumer protection agency par excellence or rigid bureaucracy, it has publicly adopted a new philosophy to expedite drug marketing. Given the urgency of the AIDS epidemic, new attention to prompt drug review is welcome. This new philosophy, however, is not without problems. First, it focuses not on developing new drugs, but on distributing them. The new procedures seek to accelerate the internal review process at the FDA and to expand the use of investigational drugs among patients while that review is taking place. This can have only an indirect effect on new drug development. To the extent that drug companies believe their products might be brought to market sooner, and paid for during the investigational phases,37 they may be encouraged to develop new drugs for AIDS. But, in spite of its increased efforts in research, the FDA is not in any position to initiate sponsorship of a new drug. So it is unclear whether these new approaches will actually result in more and better new drugs, rather than the same drugs sooner. Second, this new philosophy does not work well for vaccines. Most new procedures for expanded uses of investigational drugs have been justified by the need of persons with HIV infection or AIDS for help. This reasoning hardly applies to vaccines. It is possible that expedited review could encourage vaccine developers to pursue FDA approval, but realistically the new expedited procedures do not apply to vaccines. Moreover, testing the safety and effectiveness of experimental vaccines in healthy human beings requires scrupulous attention to differences in the health status of those who receive the vaccine and those who do not. If healthy persons took the vaccine outside supervised trials, epidemiological evidence of the incidence of infection or adverse reactions-which may be necessary to speed up the trials-will be compromised. The results of trials could be
meaningless. Ironically, the drug importation policy could result in AIDS patients obtaining experimental vaccine products from overseas far more readily than investigational drugs in clinical trials in the United States. Persons with AIDS might wish to try an experimental vaccine being tested or sold in a foreign country in the hope that it might help them as much as any unproven new drug. If so, they may try to characterize 338
the vaccine as a prophylactic drug (like aerosolized pentamidine to prevent an initial episode of pneumocystis carinii pneumonia, for example) in order to qualify it for the importation policy. Once in the country, it would be difficult to limit distribution. Healthy persons at risk of HIV infection might wish to take even an experimental vaccine prophylactically. Some antibodies have been shown to enhance an existing infection.38-41 The possibility, however remote, of immune enhancement or of suppression of the immune system makes any unstudied vaccine dangerous. Moreover, the use of unapproved vaccines could disqualify a person from participating in regular clinical trials. If undisclosed, the use could compromise the results of such trials. Changes in FDA policies applicable to AIDS drugs are not likely to prove useful in encouraging the development or expediting the marketing of a safe and effective HIV vaccine. Indeed, the new drug import policy may be detrimental if used for vaccines. Under pressure from the Federal Office of Management and Budget, the FDA sought to reduce the time it took to approve new drugs. By the time it had rewritten the IND and NDA (new drug application) regulations in 1987, the agency seemed satisfied that it had streamlined its internal review process as much as possible.16,17 The only place left to cut was in the trials themselves. Reducing the length of trials meant making a choice. The time for trials could be reduced, but at the expense of collecting inadequate data to assess safety and, especially, effectiveness. The same information could be collected in less time only by making the studies much more efficient. The agency chose the latter approach in its accelerated procedures rule. This allowed continued emphasis on studying the effectiveness of drugs, while appeasing the Administration's eagerness for speedy review. But it will work only ifthe agency persuades sponsors to plan truly efficient studies well in advance and carry them out rigorously. It is likely to be easier to forge an efficient working relationship between the agency and industry to review vaccines than to review drugs. This is because, for the most part, vaccines differ from one another more than drugs do. In order to compare the multiplicity of drugs reviewed within a category (such as anti-inflammatories), drug review staff are likely to insist on testing new products in much the same way as earlier products were tested. With few exceptions, there has been only one vaccine substance for a given disease. Thus, biologic review officials are more accustomed to creating new study designs for each new candidate. The result is somewhat greater flexibility in reviewing vaccines than in reviewing drugs. Vaccine reviewers may also be more receptive to condensing study length and developing new data collection designs than drug reviewers. Thus, it seems possible to create an accelerated review procedure for candidate HIV vaccines, in spite of the practical inapplicability of the new rules. Any new procedures, however, should be specifically tailored to vaccines. The approach available for drugs should not be transplanted wholesale to vaccine trials.
Differences between Vaccines and Drugs There are important differences between drugs and vaccines. New drugs are intended to treat existing disease in people with the disease. Even experimental drugs might possibly result in some personal benefit to research subjects who have the disease at issue. Drug trials are not intended to treat disease, of course; they only determine whether the AJPH March 1990, Vol. 80, No. 3
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experimental drug does treat the disease. But if the drug does work, the research subject may be helped. Moreover, subjects in clinical trials may be willing to accept some significant risks of adverse drug reactions if the drug is intended to treat the disease, especially where the disease is probably fatal and no alternative treatment exists. Tests of zidovudine and dideoxyinosine are obvious examples. In contrast, the intended purpose of a new vaccine is to prevent disease from occurring in healthy persons in the future. And investigational vaccines are tested in healthy human beings. Thus, vaccine trials cannot offer any immediate benefit to research subjects.5 If such subjects face any risk of disease, it is a future risk, not one that could serve to balance the immediate risks of adverse reactions to the experimental vaccine. Moreover, prospective adult research subjects ordinarily can protect themselves from HIV infection by avoiding behavior that could expose them to the virus. So, even if it worked, an experimental vaccine could not necessarily provide any greater protection against disease than the subjects could provide themselves. The only reasonably foreseeable benefit of the trials inures not to the individual subjects, but to society as whole in the knowledge to be gained. Under the Helsinki principles, and other generally accepted ethical principles governing the protection of human subjects of research, "The interests of science and society should never take precedence over considerations related to the well-being of the subject."42 In the absence of any real personal benefit to the subject, ethical principles preclude research involving more than minimal risk to human beings.5.42-4 Mere participation in vaccine trials has been thought to involve social risks to the subject.5.45 While concerns about discrimination arising from such participation may have abated somewhat, there is no doubt that research subjects risk being identified as infected with HIV and losing opportunities for jobs, housing, insurance, and foreign travel. Even if such risks are minimal, the addition of any risk of personal injury raises the level of aggregate risk above the minimal level. For these reasons the level of risk that may be expected from a candidate vaccine must be exceedingly small before the vaccine can be justifiably introduced into healthy human beings. There may be no ethical basis for clinical trials of any candidate vaccine that could cause any foreseeable adverse reaction. Since not all adverse reactions can be predicted by laboratory and animal studies, it is essential to conduct sufficient preclinical tests to ensure that the vaccine does not have any property that may be capable of triggering any adverse reaction beyond such transient and self-limiting conditions as soreness or nausea. To evaluate effectiveness, subjects must be followed for long time periods to see whether they become infected or develop disease as a result of inadvertent exposure.45.46 In the absence of any "cure" for AIDS, "challenging" human subjects with an injection of HIV itself would not be acceptable. But "natural" exposure to the virus may not occur for several years, especially if research subjects take appropriate precautions to avoid infection. Even if infection occurs, it may not be detected by existing antibody tests for weeks, or perhaps years.40'47 Thus, the probability of an experimental vaccine's effectiveness will not become known for at least several years after administration, and possibly a decade. In contrast, drug effectiveness can often be determined within a few weeks or months by measuring biological or physiological parameters, such as levels of p24 antigen or CD4 lymphocytes. AJPH March 1990, Vol. 80, No. 3
These differences between drugs and vaccines point to the relatively greater imperative to ensure safety in experimental vaccines before they are tested in human beings. There can be no guarantee against the possibility of any adverse reaction. But it is especially important to conduct sufficient research, particularly in vitro and in animals, to satisfy an experienced researcher that no foreseeable toxicity or side effect will occur. This ethical imperative gains added force from the prevalence of HIV vaccine trial research subjects who elect to participate for purely altruistic reasons. They deserve the maximum protection possible. The FDA does not appear to embrace this special emphasis on assuring the safety of experimental vaccines for clinical trials. Safety appears to be considered only in comparison with the benefit of effectiveness. This may be inevitable with respect to drugs. Given that no drug is entirely free from side effects, safety is always a relative matter. Bone marrow depletion may seem an acceptable side effect for a drug that inhibits the development of AIDS, but not for a common cold remedy. Thus, the agency has traditionally viewed safety not as a defined (or even definable) standard, but as relative to the benefits of individual drugs. There does not appear to be any general definition of safety. Safety is described by example and in comparison to benefits. The benefit of a vaccine lies in its effectiveness in preventing infection and disease. In the absence of any indication of effectiveness, a vaccine can be expected only to expose research subjects to risk without any commensurate benefit, even to society as a whole. Thus, before testing any candidate vaccine in human beings, it is essential to have adequate evidence of the probability of its effectiveness. This has proved especially difficult for HIV vaccines. In spite of rapidly growing knowledge of the pathogenesis of the virus and its genetic structure, it remains unclear exactly how HIV acts either to kill human cells or to enter cells and begin the process of replication and spread to other cells.4048.49 Preventing or stopping viral activity may require blocking the virus's ability to destroy healthy cells, preventing its initial entry into a cell, and halting its replication within infected cells.5.39.4546.49 With the increased knowledge of HIV's mechanisms of attachment to cells, it ultimately should be possible to identify the protein on the viral envelope where intervention may be effective. However, HIV's genetic diversity and ability to mutate during infection greatly complicate the search.50-55 Although research is more promising than ever, it has not yet solved the problem. In the meantime, it remains nearly impossible to determine whether vaccine preparations that appear to block targeted activity actually produce the immunity necessary to prevent disease in human beings. The mere presence of neutralizing antibodies is not a reliable indicator of immunity, as it has been with earlier vaccines, like those to prevent poliomyelitis and measles.46.56.57 Laboratory studies therefore may not be able to provide any meaningful indication of the probability of effectiveness until more is known about the immune response. This leaves tests of the vaccine in animals as the only source of information about effectiveness. While chimpanzees represent the best animal model to date, they have not developed the same type of pathogenic responses as humans.56.58.59 Monkeys may prove to be a useful animal model, especially in light of recent reports oftheir developing protective immune responses to a simian form of immunodeficiency virus, SIV.10,59 Whether that virus and their responses are sufficiently similar to provide adequate models for HIV in human beings remains to be demonstrated. 339
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Until a reliable animal model is found, there is really no way to test the effectiveness of candidate vaccines without using chimpanzees or human subjects. Investigational vaccines to prevent measles, mumps, and rubella, human adenovirus, were tested in human beings for lack of an adequate animal model.4' But those do not provide a comfortable precedent. Those attenuated live virus vaccines were tested in human beings because the diseases were not life threatening in this country. Attenuated live or killed whole virus is not considered a safe option for HIV vaccines in part because of the possibility that vaccine-induced infection (as from inadequately inactivated virus) could produce AIDS.58 Moreover, the earlier diseases could be prevented by inducing neutralizing antibody; while HIV infection apparently will
not.4' Evaluating effectiveness first in animal models is especially important because of the large number of candidate vaccines being studied in various laboratories. More than two dozen vaccine preparations are under research. Obviously, not all of these will prove safe or effective. Not all of them should be tested in human beings. Part of the process for determining whether a vaccine should be approved for phase 1 trials should include an analysis of its demonstrated effectiveness in inducing both humoral and cellular immune responses in animal models, plus a comparison with similar effectiveness data from other candidate vaccines. Only those very few with the highest probability of effectiveness should be approved for clinical trials.
Conclusions The need for new drugs to treat AIDS has helped to inaugurate a reevaluation of the process for reviewing and approving investigational drugs. Even scientists skeptical of speeding up the system and distributing experimental drugs are beginning to accept the idea that the drug review process might benefit from some creative thinking. The same may be true for the vaccine review process. However, the FDA's new drug review policies cannot practically apply to investigational vaccines to prevent HIV infection. The differences between vaccines and drugs argue against adopting the new drug review policies for vaccines. In particular, the FDA should not permit vaccine sponsors to charge research subjects for vaccines, as sponsors of drug trials are sometimes permitted to do.28 Neither should the FDA permit the importation of vaccines not yet approved and licensed in this country. Rather, vaccines warrant separate treatment to ensure that those who receive them are protected. Thus, the FDA should continue to review candidate HIV vaccines in its vaccine unit separately from drugs. The difficulty of defining safety for the diverse types of vaccine preparations argues for retaining the flexibility that has characterized the FDA's vaccine review process. Specific new standards defining the precise study design for clinical trials of investigational vaccines could undermine the objective of expediting review. On the other hand, there is merit in having an established testing process set forth in general terms. This is especially important for HIV vaccine trials because of the number and variety of potential candidate vaccine sponsors. Many small biotechnology companies may have little experience with clinical trials, especially of the size and complexity required for testing candidate HIV vaccines. With a standard testing format, everyone knows the general rules, and all potential investigators can plan valid studies rapidly as soon as a candidate vaccine is shown to 340
have a high probability of safety and effectiveness in laboratory and animal studies. To limit the number of research subjects, the FDA should develop strict selection criteria for approving candidate vaccines for phase 1 trials. The criteria being developed by the HIV vaccine panel for the National Institute of Allergy and Infectious Diseases (NIAID) offers a useful model. Their criteria, which apply only to candidate vaccines that NIAID is asked to test, can be refined to apply to all candidates submitted to the FDA, regardless of who is to conduct the trials. Threshold criteria for approving clinical trials of any candidate HIV vaccine in human subjects should include demonstrated evidence of safety and effectiveness in both laboratory and animal studies, at least until it is proved that animal models are unnecessary to establish a high probability of effectiveness. If several candidate vaccines meet these threshold criteria, only those two or three that rank highest in probable safety and effectiveness ought to be permitted to proceed to clinical trials. Other criteria should include the probability that the population to be tested will be able to benefit from the vaccine should it prove to be effective. In order to speed up the time required for clinical trials, it should be possible in some cases to incorporate phase 2 tests of immunogenicity into phase 1 trials. Tests of actual effectiveness in human beings can then be left to a phase 3 trial. In view of the length of time required to evaluate effectiveness in human beings, it seems unnecessary to begin to estimate effectiveness in phase 2 trials if immunogenicity can be established in phase 1. Restructuring the trial phases requires careful planning and extensive discussions with FDA reviewers to ensure valid results and minimal risk to human subjects. This, in turn, is likely to require additional resources at the FDA. The agency cannot be expected to devote perhaps two to three times as much time as is ordinarily spent now evaluating candidate vaccines and working with sponsors to develop appropriate studies with existing resources. This type of review process is basically a more intense form of existing procedures, although it imposes a stricter standard of safety and effectiveness for candidate HIV vaccines than traditionally needed or used for other vaccines. This is because of the nature of the virus and the remaining gaps in our knowledge of the necessary immune response. But it should be made explicit because of the changes being made in the drug review process. In spite of difficulties in development and review, an HIV vaccine will be expedited by treating it like a vaccine and not like a new drug for AIDS. ACKNOWLEDGMENTS Research for this paper was supported by Grant No. 000657 from the American Foundation for AIDS Research.
REFERENCES 1. Levine C: Has AIDS changed the ethics of human subjects research? Law Med Health Care 1988; 16:167-173. 2. Hilts PJ: How the AIDS crisis made the drug regulators speed up. New York Times Sept. 24, 1989; 4:5. 3. Palca AJ: AIDS drug trials enter new age. Science 1989; 246:19-21. 4. Ada G: Prospects for a vaccine against HIV. Nature 1989; 339:331-332. 5. Mariner WK: Why clinical trials of AIDS vaccines are premature. Am J Public Health 1989; 79:86-91. 6. Newmark P: Receding hopes of AIDS vaccines. Nature 1988; 333:699. 7. Prince AM, Horowitz B, Baker L, et al: Failure of a human immunodeficiency virus (HIV) immune globulin to protect chimpanzees against experimental challenge with HIV. Proc Natl Acad Sci USA 1988; 85:69446948.
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PUBLIC HEALTH AND THE LAW 8. Hu S-L, Fultz PN, McClure HM, et al: Effect of immunization with a vaccinia-HIV env recombinant on HIV infection of chimpanzees. Nature 1987; 328:721-723. 9. Berman BW, Groopman JE, Gregory T, et al: Human immunodeficiency virus type I challenge of chimpanzees immunized with recombinant envelope glycoprotein gpl2O. Proc Natl Acad Sci USA 1988; 85:52005204. 10. Desrosiers RC, Wyand MS, Kodama T, et al: Vaccine protection against simian immunodeficiency virus infection. Proc Natl Acad Sci USA 1989; 86:6353-6357. 11. Foreman J: New hope as AIDS talks start: vaccine tests on animals fuel scientists' optimism. Boston Globe Aug 21, 1989; 3. 12. Zagury D, Bernard J, Cheynier R, et al: A group specific anamnestic immune reaction against HIV-1 induced by a candidate vaccine against AIDS. Nature 1988; 332:728-731. 13. Cherfas J: Hope for AIDS vaccines. Science 1989; 246:23-24. 14. Knox RA: Vaccine seen promising in early stages of AIDS. Boston Globe Oct 17, 1989; 1. 15. Salk J: The whole virus approach to immunization. In: Fauci AS (moderator): Development and evaluation of a vaccine for human immunodeficiency virus. Ann Intern Med 1989; 110:378-381. 16. Rules governing the review and approval of new drug applications (NDA) were rewritten between 1982 and 1985 (NDA rewrite), and issued on February 22, 1985. Fed Reg 50:7452; codified at 21 C.F.R. 314 (1987). 17. Rules governing the use of investigational new drugs (IND) were revised between 1983 and 1987 (IND rewrite), and issued on March 19, 1987 (effective June 17, 1987), Fed Reg 52:8798; codified at 21 C.F.R. 312 (1987). 18. For example, FDA regulations were revised to permit expanded use of foreign data in support of INDS, 21 C.F.R. 312.120 (b), and as sole evidence for approving NDAs, 21 C.F.R. 314.106. 19. DHHS, FDA: Investigational new drug, antibiotic, and biological drug product regulations; Treatment, use, and sale. Fed Reg 52:19466-19477 (May 22, 1987), codified at 21 C.F.R. 312.34 (1988). (The issuance of these rules two months after publication of the IND rewrite indicates some disagreement within the agency about their value or how they should apply.) 20. 21 C.F.R. 312.34 (b) (3) (iii). 21. Young FE, Norris JA, Levitt JA, Nightingale SL: The FDA's new procedures for the use of investigational drugs in treatment. JAMA 1988; 259:2267-2270. 22. DHHS, FDA: Investigational new drug, antibiotic, and biological drug product regulations; Procedures for drugs intended to treat life-threatening and severely debilitating illnesses. Fed Reg 53:41516-41524 (Oct 21, 1988) (issued as interim rule, but with immediate effect). 23. 21 C.F.R. 312.47 (1987). (Earlier rules encouraged "End of phase 2" meetings to determine the safety of proceeding to phase 3 and to plan phase 3 studies.) 24. Mitsuya H, Weinhold K, Yarchoan R, et al: Credit government scientists with developing anti-AIDS drug. (letter) New York Times, Sept 28, 1989; A26. 25. 21 U.S.C. 355(b) (I)N(5). 26. United States v. Rutherford, 442 U.S. 549 (1979). (In issuing the treatment IND regulations, the agency made a careful, if not entirely convincing, argument that the new rules were consistent with Rutherford. It made no argument at all for the accelerated review rule.) 27. Mariner WK: Equitable access to biomedical advances: Getting beyond the rights impasse. Conn L Rev 1989; 21 (3):571-603. 28. 21 U.S.C. 355(d). 29. Annas GJ: Faith (Healing), Hope and Charity at the FDA: The politics of AIDS drug trials. Vill L Rev 1989; 34:771-797. 30. Bristol-Myers recently obtained treatment IND status for dideoxyinosine (ddl), and will distribute it widely alongside its phase 2 trial of the investigational drug. FDA okays wider availability of ddl in trials, IND status. AIDS Policy Law 1989; 4(18):6. 31. Kolata G: AIDS studies head seeks wide access to drugs in tests. New
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York Times, June 26, 1989; Al. 32. Staver S: 'Parallel track' seen as a way to boost access to AIDS drugs. Am Med News July 14, 1989; 3-5. 33. Emergency use of an investigational new drug is authorized under 21 C.F.R. 312.36. 34. Goyan JE: Drug regulation: quo vadis? JAMA Nov 1988; 260:3052-3053. 35. Boffey PM: FDA will allow patients to import AIDS medicines. New York Times July 25, 1988; A15. 36. Gadler v. United States, 425 F. Supp. 244 (D. Minn. 1977). 37. 21. C.F.R. 312.7(d). 38. Robinson WE, Montefiori DC, Mitchell WM: Antibody-dependent enhancement of human immunodeficiency virus type 1 infection. Lancet 1988; 1:790-795. 39. Robinson WE Jr, Montefiori DC, Gillespie DH, Mitchell WM: Complement-mediated, antibody-dependent enhancement of HIV infection in vitro is characterized by increased protein and RNA synthesis and infectious virus release. J AIDS 1989; 2:33-42. 40. Levy JA: Human immunodeficiency viruses and the pathogenesis of AIDS. JAMA 1989; 261:2997-3006. 41. Hilleman MR: An overview of technical and ethical considerations for the testing of experimental AIDS vaccines in human beings (presented at the World Health Organization Consultation on Criteria for International Testing of Candidate HIV Vaccines, Geneva Feb 27-Mar 2, 1989). 42. World Medical Assembly: Declaration of Helsinki, Basic Principles III:4. 43. Levine RJ: Ethics and the Regulation of Clinical Research 2d Ed. Baltimore: Urban & Schwartzenberg, 1986. 44. 21 C.F.R. 312. 45. Koff WC, Hoth DF: Development and testing of AIDS vaccines. Science 1988; 241:426-432. 46. Fauci AS, Fischinger PJ: The development of an AIDS vaccine: progress and promise. Public Health Rep 1988; 103:230-236. 47. Imagawa DT, Lee MH, Wolinsky SM, et al: Human immunodeficiency virus type 1 infection in homosexual men who remain seronegative for prolonged periods. N Engl J Med 1989; 320:1458-1462. 48. Cullen BR, Greene WC: Regulatory pathways governing HIV replication. Cell 1989; 58:423-426. 49. Gallo RC, Bolognesi DP, Nerurkar LS: The immune response to infection with the virus. In: Fauci AS (moderator): Development and evaluation of a vaccine for human immunodeficiency virus. Ann Intern Med 1989; 110:374-377. 50. Starcich BR, Hann BH, Shaw GM, et al: Identification and characterization of conserved and variable regions in the envelope gene of HTLV III/LAV, and retrovirus of AIDS. Cell 1986; 45:637-648. 51. Levy JA, Evans LA, Pan L-Z, et al: The biologic heterogeneity of HIV and host immune response during HIV infection. In: Ginsberg H, Lerner R, Chanock R (eds): Vaccines 1987. Cold Spring Harbor, NY, 1987; 168-173. 52. Coffin JM: Genetic variation in AIDS viruses. Cell 1986; 46:1-4. 53. Fenyo EM, Morfeldt-Manson L, Chiodi F, et al: Distinct replicative and cytopathic characteristics of human immunodeficiency virus isolates. J Virol 1988; 62:4414-4419. 54. Meyerhans A, Cheynier R, Albert J, et al: Temporal fluctuations in HIV quasispecies in vivo are not reflected by sequential HIV isolations. Cell 1989; 58:901-910. 55. Tersmette M, Gruters RA, deWold F, et al: Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates. J Virol 1989; 63:2118-2125. 56. Robert-Guroff M, Brown M, Gallo RC: HTLV-III-neutralizing antibodies in patients with AIDS and AIDS related complex. Nature 1985; 316:72-74. 57. Fauci AS: Development and evaluation of a vaccine for human immunodeficiency virus (HIV) infection. Ann Intern Med 1989; 110:373-374. 58. Mariner WK, Gallo RC: Getting to market: the scientific and legal climate for developing an AIDS vaccine. Law Med Health Care 1987; 15:17-26. 59. Desrosiers RC, Letvin NL: Animal models for acquired immunodeficiency syndrome. Rev Infect Dis 1987; 9:438-446.
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New Drug Review Policies Current FDA policy on HIV vaccines is essentially
consistent with long-standing policy for the review of all candidate vaccines and biologics. However, the FDA rewrote its regulations governing the requirements for seeking approval for licensure'6 and conducting clinical trials'7 in 1985 and 1987, respectively. Since that time, the agency has taken additional steps to accelerate the drug review process18 and to expand the distribution of investigational drugs. These efforts have changed the climate for reviewing candidate HIV vaccines at the FDA. The agency recognizes the need for expediting the testing and review of new HIV vaccine preparations. However, while its new regulations technically apply to vaccines and other biologics, as well as pharmaceuticals and antibiotics, they have not been used for vaccines and, indeed, do not appear to be suitable for vaccines. The first step in expediting new drug distribution was the issuance of the Treatment IND (investigational new drug) regulations on May 22, 1987.'9 These permit investigational new drugs to be used to "treat" patients before the clinical trials are completed where no alternative therapy exists. However, only investigational drugs "intended to treat a serious or immediately life-threatening disease" qualify for such use.'9 The term "serious disease" is not defined, and "immediately-life threatening disease" is defined -quite broadly.'0 But HIV vaccines are not likely to qualify as intended to treat either condition. In its explanation of the regulations, the FDA mentioned advanced cases of AIDS as the first example of an immediately life-threatening disease, but did not include AIDS in its list of examples of serious diseases.'9,2' It explained that some diseases, like multiple sclerosis, are not serious at earlier stages, and that the Treatment IND regulations would not apply to drugs intended to treat those earlier stages of disease. On this reasoning, candidate vaccines that are intended to prevent HIV infection in the first place would not qualify. Some FDA officials currently take the position that the Treatment IND regulations are not intended to apply to vaccines at all. Some biologics, such as the one being studied by Salk,'1 may be intended to treat HIV infection by preventing progression to AIDS. But if these are intended for patients with asymptomatic infection or minimal symptoms, they would not qualify because the target disease is not serious enough. The second step in expediting new drug distribution was the FDA's adoption in late 1988 of its accelerated review procedures.22 The Treatment IND regulations did not disturb the traditional three-phase clinical trial format; they allowed the "therapeutic" use of investigational drugs undergoing clinical trials. In contrast, the accelerated procedures regulations permit FDA review and approval of new drugs before all three phases of the clinical trials are completed.22 These AJPH March 1990, Vol. 80, No. 3
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regulations apply to new therapies intended to treat persons with "life-threatening and severely-debilitating illnesses."22 Like the Treatment IND rules, the accelerated review regulations technically apply to vaccines and other biological products, but their general thrust makes it unlikely that an HIV vaccine could qualify. Life-threatening illnesses are defined as "[d]iseases or conditions where the likelihood of death is high unless the course of the disease is interrupted; and [d]iseases or conditions with potentially fatal outcomes, where the end point of clinical trials analysis is survival." 22 This is a more expansive definition than that for an "immediately life-threatening disease" to which Treatment IND rules apply. While AIDS would qualify under the first clause of that definition, mere HIV infection might not. Both could be expected to qualify under the definition of "severely debilitating," which means "diseases or conditions that cause major irreversible morbidity."22 But again, vaccines are intended to prevent infection, not to treat these conditions. Therefore, they also fall outside the scope of products eligible for accelerated review. The regulations formalize a procedure for sponsors to meet with FDA reviewers to agree on the design of preclinical and clinical studies. These are intended to develop a study design for phase 2 trials that would produce results sufficient to gain marketing approval for the drug without undergoing phase 3 trials. While such meetings and agreements have always been possible,23 in practice they have occurred infrequently. Of even greater importance is the indication that the FDA will apply the general standards of safety and effectiveness more leniently to such drugs. The regulations provide that the agency will use a "medical risk-benefit judgment" in applying the statutory standards.22 They state the FDA's belief that "physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely-debilitating illnesses, than they would accept from products that treat less serious illnesses."22 This language, however, reinforces the general impression that the accelerated procedures are intended to apply to drugs, but not to vaccines for preventing HIV infection. These regulations do raise the question of whether an accelerated process should be used for the review of candidate HIV vaccines. The FDA maintains that the new regulations merely formalize options available under existing agency authority. If this were true, the regulations' exclusion of vaccines would pose no barrier to using the same procedures to expedite HIV vaccine approval and distribution. However, the regulations have made a change. Whatever the FDA's general authority to review investigational drugs, the agency had insisted on the three-phase clinical trial format for almost 25 years. The accelerated procedures rules were modeled after the zidovudine (AZT) approval process. But that success would be difficult to repeat. Zidovudine had already undergone extensive preclinical testing at the National Cancer Institute and elsewhere as a possible anticancer agent before it was considered as a possible anti-viral drug.24 That experience enabled researchers to introduce the drug in the middle of the research process, so to speak. Months, if not years, of review and testing were eliminated. Moreover, introducing the accelerated procedures, the FDA called them "a new and innovative approach", as well as one that built on "past practices." 22 The zidovudine story apart, the possibility of dispensing with phase 2 or 3 was a clear break with tradition. AJPH March 1990, Vol. 80, No. 3
That this break was within the FDA's authority all along is a harder position to argue. The Food, Drug, and Cosmetic Act (FDCA) grants the FDA the power to approve new drugs that are safe and effective, but it prohibits approval unless the drug sponsor affirmatively demonstrates that the drug is in fact safe and effective.25 In the absence of information that the drug is safe or substantial evidence of effectiveness, the statute forbids approval. This is a heavy burden of proof to satisfy. Moreover, the United States Supreme Court has held, in a unanimous decision, that the Act makes no exception for even terminally ill patients.26 On the other hand, as I have argued elsewhere, the FDA retains considerable leeway in determining what constitutes sufficient evidence of safety and effectiveness.27 The statute does not define safety. Substantial evidence of effectiveness is to consist of "adequate and well controlled investigations... by experts" that fairly permit such experts to conclude that the drug will have its intended effect.28 The FDA, not Congress, developed the 3-phase structure for clinical trials, as well as rules for in vitro and animal tests, to produce adequate measures of safety and effectiveness. This structure may simply have formalized the procedures that evolved for tests after the Kefauver amendments of 1962. In principle, any other format that resulted in equally valid measures could satisfy the statutory requirements.27 Thus, eliminating phase 2 or 3 would not necessarily violate the statute, provided that the data yielded credible results. In some cases, phase 3 studies served to clean up sloppy phase 2 trials, answering remaining doubts. Perhaps if phase 2 studies were done perfectly in the first place there would be no need for phase 3. Nevertheless, for better or worse, omitting phase 3 does represent a real change in the drug review process. Interestingly, the change so far has been more cosmetic than real.29 Few drug sponsors have sought accelerated review. One reason may be the expense required to mount a trial that can produce evidence of effectiveness sufficient to warrant approval for marketing. Drug companies may prefer to conduct a limited phase 2 trial to get a reading on the probability that a drug works before committing itself to a major phase 3 study. In addition, a small phase 2 trial may be needed to determine the minimum sample size and other study design parameters for a trial of effectiveness. Similarly, few sponsors have sought to have investigational drugs distributed to patients under a Treatment IND.30 Aside from these formal procedures for expediting drug trials, the FDA has attempted to get investigational drugs to a larger population by encouraging innovative testing and distribution techniques. One of these is known as the paralleltrack approach to clinical trials.31 Practicing physicians could prescribe experimental drugs as therapy for their AIDS patients who are not in clinical trials.31 The approach differs from the compassionate use of experimental drugs33 both because of the larger numbers of patients who could receive the drug, and because physicians would report to the FDA or drug sponsor on how their patient fared. The information would be spottier than clinical trials data and of limited utility, especially where it covered persons quite different from those in the trials. The parallel-track proposal has engendered considerable controversy. Its only advantage would be to offer investigational drugs to AIDS patients who are not willing or eligible to enter clinical trials. But this advantage, if it is one, is not applicable to vaccines either. Even if one believes that investigational drugs are therapy-a hotly disputed concept3,29,34-vaccines cannot be considered 337
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treatment for patients who already have AIDS. Thus, the parallel-track approach also seems unsuitable for vaccines. A much more dramatic departure from past practice was the FDA's decision to permit persons with life-threatening illnesses, including AIDS, to import from abroad drugs not licensed in the United States.35 This was accomplished by expanding an administrative exception to existing FDA policy banning imports. The importation of unapproved drugs, even for personal use, had been considered a violation of the FDCA's prohibitions against holding drugs for sale in interstate commerce.27,36 In one sense, allowing AIDS patients to obtain such drugs is consistent with the FDA's efforts to increase access to AIDS drugs. But it also differs in an important way. The new regulations do not authorize patient access to drugs that are not being studied in United States clinical trials. The new import policy does. But the current policy's limitation to persons with life-threatening illnesses makes it as unsuitable for vaccines as the new formal regulations. Reviewing Vaccines The FDA is trying to assume a new, more creative role in drug distribution. Shedding its images as consumer protection agency par excellence or rigid bureaucracy, it has publicly adopted a new philosophy to expedite drug marketing. Given the urgency of the AIDS epidemic, new attention to prompt drug review is welcome. This new philosophy, however, is not without problems. First, it focuses not on developing new drugs, but on distributing them. The new procedures seek to accelerate the internal review process at the FDA and to expand the use of investigational drugs among patients while that review is taking place. This can have only an indirect effect on new drug development. To the extent that drug companies believe their products might be brought to market sooner, and paid for during the investigational phases,37 they may be encouraged to develop new drugs for AIDS. But, in spite of its increased efforts in research, the FDA is not in any position to initiate sponsorship of a new drug. So it is unclear whether these new approaches will actually result in more and better new drugs, rather than the same drugs sooner. Second, this new philosophy does not work well for vaccines. Most new procedures for expanded uses of investigational drugs have been justified by the need of persons with HIV infection or AIDS for help. This reasoning hardly applies to vaccines. It is possible that expedited review could encourage vaccine developers to pursue FDA approval, but realistically the new expedited procedures do not apply to vaccines. Moreover, testing the safety and effectiveness of experimental vaccines in healthy human beings requires scrupulous attention to differences in the health status of those who receive the vaccine and those who do not. If healthy persons took the vaccine outside supervised trials, epidemiological evidence of the incidence of infection or adverse reactions-which may be necessary to speed up the trials-will be compromised. The results of trials could be
meaningless. Ironically, the drug importation policy could result in AIDS patients obtaining experimental vaccine products from overseas far more readily than investigational drugs in clinical trials in the United States. Persons with AIDS might wish to try an experimental vaccine being tested or sold in a foreign country in the hope that it might help them as much as any unproven new drug. If so, they may try to characterize 338
the vaccine as a prophylactic drug (like aerosolized pentamidine to prevent an initial episode of pneumocystis carinii pneumonia, for example) in order to qualify it for the importation policy. Once in the country, it would be difficult to limit distribution. Healthy persons at risk of HIV infection might wish to take even an experimental vaccine prophylactically. Some antibodies have been shown to enhance an existing infection.38-41 The possibility, however remote, of immune enhancement or of suppression of the immune system makes any unstudied vaccine dangerous. Moreover, the use of unapproved vaccines could disqualify a person from participating in regular clinical trials. If undisclosed, the use could compromise the results of such trials. Changes in FDA policies applicable to AIDS drugs are not likely to prove useful in encouraging the development or expediting the marketing of a safe and effective HIV vaccine. Indeed, the new drug import policy may be detrimental if used for vaccines. Under pressure from the Federal Office of Management and Budget, the FDA sought to reduce the time it took to approve new drugs. By the time it had rewritten the IND and NDA (new drug application) regulations in 1987, the agency seemed satisfied that it had streamlined its internal review process as much as possible.16,17 The only place left to cut was in the trials themselves. Reducing the length of trials meant making a choice. The time for trials could be reduced, but at the expense of collecting inadequate data to assess safety and, especially, effectiveness. The same information could be collected in less time only by making the studies much more efficient. The agency chose the latter approach in its accelerated procedures rule. This allowed continued emphasis on studying the effectiveness of drugs, while appeasing the Administration's eagerness for speedy review. But it will work only ifthe agency persuades sponsors to plan truly efficient studies well in advance and carry them out rigorously. It is likely to be easier to forge an efficient working relationship between the agency and industry to review vaccines than to review drugs. This is because, for the most part, vaccines differ from one another more than drugs do. In order to compare the multiplicity of drugs reviewed within a category (such as anti-inflammatories), drug review staff are likely to insist on testing new products in much the same way as earlier products were tested. With few exceptions, there has been only one vaccine substance for a given disease. Thus, biologic review officials are more accustomed to creating new study designs for each new candidate. The result is somewhat greater flexibility in reviewing vaccines than in reviewing drugs. Vaccine reviewers may also be more receptive to condensing study length and developing new data collection designs than drug reviewers. Thus, it seems possible to create an accelerated review procedure for candidate HIV vaccines, in spite of the practical inapplicability of the new rules. Any new procedures, however, should be specifically tailored to vaccines. The approach available for drugs should not be transplanted wholesale to vaccine trials.
Differences between Vaccines and Drugs There are important differences between drugs and vaccines. New drugs are intended to treat existing disease in people with the disease. Even experimental drugs might possibly result in some personal benefit to research subjects who have the disease at issue. Drug trials are not intended to treat disease, of course; they only determine whether the AJPH March 1990, Vol. 80, No. 3
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experimental drug does treat the disease. But if the drug does work, the research subject may be helped. Moreover, subjects in clinical trials may be willing to accept some significant risks of adverse drug reactions if the drug is intended to treat the disease, especially where the disease is probably fatal and no alternative treatment exists. Tests of zidovudine and dideoxyinosine are obvious examples. In contrast, the intended purpose of a new vaccine is to prevent disease from occurring in healthy persons in the future. And investigational vaccines are tested in healthy human beings. Thus, vaccine trials cannot offer any immediate benefit to research subjects.5 If such subjects face any risk of disease, it is a future risk, not one that could serve to balance the immediate risks of adverse reactions to the experimental vaccine. Moreover, prospective adult research subjects ordinarily can protect themselves from HIV infection by avoiding behavior that could expose them to the virus. So, even if it worked, an experimental vaccine could not necessarily provide any greater protection against disease than the subjects could provide themselves. The only reasonably foreseeable benefit of the trials inures not to the individual subjects, but to society as whole in the knowledge to be gained. Under the Helsinki principles, and other generally accepted ethical principles governing the protection of human subjects of research, "The interests of science and society should never take precedence over considerations related to the well-being of the subject."42 In the absence of any real personal benefit to the subject, ethical principles preclude research involving more than minimal risk to human beings.5.42-4 Mere participation in vaccine trials has been thought to involve social risks to the subject.5.45 While concerns about discrimination arising from such participation may have abated somewhat, there is no doubt that research subjects risk being identified as infected with HIV and losing opportunities for jobs, housing, insurance, and foreign travel. Even if such risks are minimal, the addition of any risk of personal injury raises the level of aggregate risk above the minimal level. For these reasons the level of risk that may be expected from a candidate vaccine must be exceedingly small before the vaccine can be justifiably introduced into healthy human beings. There may be no ethical basis for clinical trials of any candidate vaccine that could cause any foreseeable adverse reaction. Since not all adverse reactions can be predicted by laboratory and animal studies, it is essential to conduct sufficient preclinical tests to ensure that the vaccine does not have any property that may be capable of triggering any adverse reaction beyond such transient and self-limiting conditions as soreness or nausea. To evaluate effectiveness, subjects must be followed for long time periods to see whether they become infected or develop disease as a result of inadvertent exposure.45.46 In the absence of any "cure" for AIDS, "challenging" human subjects with an injection of HIV itself would not be acceptable. But "natural" exposure to the virus may not occur for several years, especially if research subjects take appropriate precautions to avoid infection. Even if infection occurs, it may not be detected by existing antibody tests for weeks, or perhaps years.40'47 Thus, the probability of an experimental vaccine's effectiveness will not become known for at least several years after administration, and possibly a decade. In contrast, drug effectiveness can often be determined within a few weeks or months by measuring biological or physiological parameters, such as levels of p24 antigen or CD4 lymphocytes. AJPH March 1990, Vol. 80, No. 3
These differences between drugs and vaccines point to the relatively greater imperative to ensure safety in experimental vaccines before they are tested in human beings. There can be no guarantee against the possibility of any adverse reaction. But it is especially important to conduct sufficient research, particularly in vitro and in animals, to satisfy an experienced researcher that no foreseeable toxicity or side effect will occur. This ethical imperative gains added force from the prevalence of HIV vaccine trial research subjects who elect to participate for purely altruistic reasons. They deserve the maximum protection possible. The FDA does not appear to embrace this special emphasis on assuring the safety of experimental vaccines for clinical trials. Safety appears to be considered only in comparison with the benefit of effectiveness. This may be inevitable with respect to drugs. Given that no drug is entirely free from side effects, safety is always a relative matter. Bone marrow depletion may seem an acceptable side effect for a drug that inhibits the development of AIDS, but not for a common cold remedy. Thus, the agency has traditionally viewed safety not as a defined (or even definable) standard, but as relative to the benefits of individual drugs. There does not appear to be any general definition of safety. Safety is described by example and in comparison to benefits. The benefit of a vaccine lies in its effectiveness in preventing infection and disease. In the absence of any indication of effectiveness, a vaccine can be expected only to expose research subjects to risk without any commensurate benefit, even to society as a whole. Thus, before testing any candidate vaccine in human beings, it is essential to have adequate evidence of the probability of its effectiveness. This has proved especially difficult for HIV vaccines. In spite of rapidly growing knowledge of the pathogenesis of the virus and its genetic structure, it remains unclear exactly how HIV acts either to kill human cells or to enter cells and begin the process of replication and spread to other cells.4048.49 Preventing or stopping viral activity may require blocking the virus's ability to destroy healthy cells, preventing its initial entry into a cell, and halting its replication within infected cells.5.39.4546.49 With the increased knowledge of HIV's mechanisms of attachment to cells, it ultimately should be possible to identify the protein on the viral envelope where intervention may be effective. However, HIV's genetic diversity and ability to mutate during infection greatly complicate the search.50-55 Although research is more promising than ever, it has not yet solved the problem. In the meantime, it remains nearly impossible to determine whether vaccine preparations that appear to block targeted activity actually produce the immunity necessary to prevent disease in human beings. The mere presence of neutralizing antibodies is not a reliable indicator of immunity, as it has been with earlier vaccines, like those to prevent poliomyelitis and measles.46.56.57 Laboratory studies therefore may not be able to provide any meaningful indication of the probability of effectiveness until more is known about the immune response. This leaves tests of the vaccine in animals as the only source of information about effectiveness. While chimpanzees represent the best animal model to date, they have not developed the same type of pathogenic responses as humans.56.58.59 Monkeys may prove to be a useful animal model, especially in light of recent reports oftheir developing protective immune responses to a simian form of immunodeficiency virus, SIV.10,59 Whether that virus and their responses are sufficiently similar to provide adequate models for HIV in human beings remains to be demonstrated. 339
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Until a reliable animal model is found, there is really no way to test the effectiveness of candidate vaccines without using chimpanzees or human subjects. Investigational vaccines to prevent measles, mumps, and rubella, human adenovirus, were tested in human beings for lack of an adequate animal model.4' But those do not provide a comfortable precedent. Those attenuated live virus vaccines were tested in human beings because the diseases were not life threatening in this country. Attenuated live or killed whole virus is not considered a safe option for HIV vaccines in part because of the possibility that vaccine-induced infection (as from inadequately inactivated virus) could produce AIDS.58 Moreover, the earlier diseases could be prevented by inducing neutralizing antibody; while HIV infection apparently will
not.4' Evaluating effectiveness first in animal models is especially important because of the large number of candidate vaccines being studied in various laboratories. More than two dozen vaccine preparations are under research. Obviously, not all of these will prove safe or effective. Not all of them should be tested in human beings. Part of the process for determining whether a vaccine should be approved for phase 1 trials should include an analysis of its demonstrated effectiveness in inducing both humoral and cellular immune responses in animal models, plus a comparison with similar effectiveness data from other candidate vaccines. Only those very few with the highest probability of effectiveness should be approved for clinical trials.
Conclusions The need for new drugs to treat AIDS has helped to inaugurate a reevaluation of the process for reviewing and approving investigational drugs. Even scientists skeptical of speeding up the system and distributing experimental drugs are beginning to accept the idea that the drug review process might benefit from some creative thinking. The same may be true for the vaccine review process. However, the FDA's new drug review policies cannot practically apply to investigational vaccines to prevent HIV infection. The differences between vaccines and drugs argue against adopting the new drug review policies for vaccines. In particular, the FDA should not permit vaccine sponsors to charge research subjects for vaccines, as sponsors of drug trials are sometimes permitted to do.28 Neither should the FDA permit the importation of vaccines not yet approved and licensed in this country. Rather, vaccines warrant separate treatment to ensure that those who receive them are protected. Thus, the FDA should continue to review candidate HIV vaccines in its vaccine unit separately from drugs. The difficulty of defining safety for the diverse types of vaccine preparations argues for retaining the flexibility that has characterized the FDA's vaccine review process. Specific new standards defining the precise study design for clinical trials of investigational vaccines could undermine the objective of expediting review. On the other hand, there is merit in having an established testing process set forth in general terms. This is especially important for HIV vaccine trials because of the number and variety of potential candidate vaccine sponsors. Many small biotechnology companies may have little experience with clinical trials, especially of the size and complexity required for testing candidate HIV vaccines. With a standard testing format, everyone knows the general rules, and all potential investigators can plan valid studies rapidly as soon as a candidate vaccine is shown to 340
have a high probability of safety and effectiveness in laboratory and animal studies. To limit the number of research subjects, the FDA should develop strict selection criteria for approving candidate vaccines for phase 1 trials. The criteria being developed by the HIV vaccine panel for the National Institute of Allergy and Infectious Diseases (NIAID) offers a useful model. Their criteria, which apply only to candidate vaccines that NIAID is asked to test, can be refined to apply to all candidates submitted to the FDA, regardless of who is to conduct the trials. Threshold criteria for approving clinical trials of any candidate HIV vaccine in human subjects should include demonstrated evidence of safety and effectiveness in both laboratory and animal studies, at least until it is proved that animal models are unnecessary to establish a high probability of effectiveness. If several candidate vaccines meet these threshold criteria, only those two or three that rank highest in probable safety and effectiveness ought to be permitted to proceed to clinical trials. Other criteria should include the probability that the population to be tested will be able to benefit from the vaccine should it prove to be effective. In order to speed up the time required for clinical trials, it should be possible in some cases to incorporate phase 2 tests of immunogenicity into phase 1 trials. Tests of actual effectiveness in human beings can then be left to a phase 3 trial. In view of the length of time required to evaluate effectiveness in human beings, it seems unnecessary to begin to estimate effectiveness in phase 2 trials if immunogenicity can be established in phase 1. Restructuring the trial phases requires careful planning and extensive discussions with FDA reviewers to ensure valid results and minimal risk to human subjects. This, in turn, is likely to require additional resources at the FDA. The agency cannot be expected to devote perhaps two to three times as much time as is ordinarily spent now evaluating candidate vaccines and working with sponsors to develop appropriate studies with existing resources. This type of review process is basically a more intense form of existing procedures, although it imposes a stricter standard of safety and effectiveness for candidate HIV vaccines than traditionally needed or used for other vaccines. This is because of the nature of the virus and the remaining gaps in our knowledge of the necessary immune response. But it should be made explicit because of the changes being made in the drug review process. In spite of difficulties in development and review, an HIV vaccine will be expedited by treating it like a vaccine and not like a new drug for AIDS. ACKNOWLEDGMENTS Research for this paper was supported by Grant No. 000657 from the American Foundation for AIDS Research.
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