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VACCINES, UNCERTAINTIES, AND ETHICAL CHALLENGES |
The author is with the Baylor College of Medicine, Houston, Tex.
Correspondence: Requests for reprints should be sent to Rosemary B. Quigley, One Baylor Plaza, IREL 401, Houston, TX 77030 (e-mail: rquigley{at}bcm.tmc.edu).
ABSTRACT
Without an accurate assessment of the prospect of bioterrorist attack, it is especially challenging to evaluate the protocols for testing smallpox vaccines in the pediatric population. Usual regulatory mechanisms cannot shepherd research protocols with benefits that can only be characterized as "uncertain" in the face of more than minimal risk.
When a protocol is placed in a government forum for analysis, the public has a unique opportunity to debate the balancing of research risks and benefits on behalf of children who are unable to assent to research themselves, as well as to express views about vaccination policy broadly. This model for review of pediatric research that may be without benefit will be especially important as challenging studies of various vaccines against a range of infectious properties, such as anthrax and severe acute respiratory syndrome (SARS), emerge.
THE PROSPECT OF bioterrorist attack has spurred a range of public policy debates about the need for vaccinating various segments of the US population against smallpox.1 Whatever strategy is pursued—ring vaccination of those in direct contact with diagnosed smallpox patients in the event of an attack, preparatory vaccination of first responders, or voluntary population vaccination—urgency attaches to our understanding of how renewed administration of the vaccine will impact public health. In particular, is the risk involved with the administration of the smallpox vaccine outweighed by the benefit to be derived from inoculation against smallpox? A major factor in the cessation of population vaccination programs in the early 1970s was that the risk of smallpox exposure did not outweigh the side effects of the vaccine.2 The critical issue in this respect is how real the risk of smallpox attack is in the first place. Based on intelligence that is publicly available, the potential for a smallpox incident is perhaps slightly greater than hypothetical, especially given recent revelations about unanticipated possessors of the smallpox virus.3
A fast-tracked protocol to evaluate the safety and effectiveness of the standard and diluted doses of the Dryvax smallpox vaccine in children aged 2 to 5 years, which was recently reviewed at the Department of Health and Human Services and the Food and Drug Administration, provided a valuable case study of this balance.4 Given benefit that can only be characterized as "uncertain" in the face of more than minimal risk, it becomes impossible to pursue clinical research on the vaccine in children under usual regulatory mechanisms, via institution-based review. The protocol must be considered by a federal panel offering ethical analysis of the planned protocol with opportunity for public input. The ultimate decision about proceeding with this research was the domain of the secretary of the Department of Health and Human Services and the commissioner of the Food and Drug Administration. This mechanism removes the smallpox vaccine protocol from the institutional mores governing the protection of research subjects and places it in a unique forum of public policymaking.
VACCINE RISKS AND REGULATORY REVIEW
Risks
The proposed protocol involves use of the Dryvax vaccine, the same agent that was administered in population vaccination programs before 1972. Although there is a new, sterile smallpox vaccine in development, in the short-term the stockpile of Dryvax will be our only primary preventive intervention in the event of a smallpox attack. Then Dryvax will likely be administered, possibly in diluted form to maximize the number of doses while not sacrificing the successful "take" rate of the vaccine. Administration of the vaccine within 3 days of exposure is known to reduce the ultimate appearance of a smallpox case, with each case bearing an estimated 30% mortality rate.5
Data from the earlier smallpox vaccination of the general population suggest that Dryvax was relatively safe, with low rates of serious complications. Nevertheless, the cohort of potentially serious adverse events is daunting, including progressive vaccinia (3.2 cases/million vaccinated), generalized vaccinia (233.4/million), encephalitis (9.5/million), and eczema vaccinatum (44.2/million).6 The risk of death from vaccination, generally resulting from 1 of the aforementioned complications, is extremely low, less than 1 death in 1 million recipients older than 1 year and 5 deaths in 1 million in recipients younger than 1 year.7 The smallpox vaccine also poses some risk of third-party inoculation, as vaccinia can shed from the vaccination site and infect others. The possible rate of cross-infection with vaccinia is unknown, but the 1968 state surveys pegged the rate at 44.6 cases per million in a society already being systematically vaccinated. This impact may well be intensified if vaccination is resumed given the large number of naïve (previously uninoculated) individuals in the current population.
The susceptibility to having an adverse reaction after either primary or secondary exposure has presumably increased since mass vaccination was stopped because the rate of risk factors in the population has increased markedly.8 Previous atopic dermatitis rates of 3% to 6% have increased to 6% to 22%. Also, there are more immunocompromised individuals because of the numbers of people who have HIV infection or are receiving immunosuppressive drugs for transplantation or cancer treatment, putting increasing numbers at serious risk.
The risks of the vaccine in individuals not previously inoculated have been described in recently conducted adult trials of the Dryvax vaccine at various dilutions.9 Across dilutions, a significant percentage of individuals in these trials experienced adverse events that were not serious but were quite debilitating for short periods of time. Almost 9% experienced fever. Headaches were common and in some cases severe. Participants reported moderate to severe muscle aches (20.6%) and chills (6.5%); 14.3% developed rashes at a site other than the vaccination site. More than one third were sufficiently ill to miss school, work, or recreational activities or to have trouble sleeping. This study raises concern about the potentially high rate of adverse events in the pediatric population.
The Bush administration had been pursuing the first phase of a national program to voluntarily vaccinate some 500 000 first responders who would be protected and able to provide care in the event of a smallpox attack, primarily civilian medical professionals.10 Many health care workers declined vaccination, in some cases because of concern about cross-inoculating other, susceptible individuals with whom they have daily professional contact, for instance immunocompromised pediatric patients or cancer patients.11 The voluntary program was recently halted, but not before important new risks associated with the vaccine were revealed, particularly heart inflammation in those with underlying cardiac disease.12 Between January 24 and May 16, 2003, 37 608 civilian emergency health workers were inoculated; 108 serious adverse events were reported, including a handful of deaths, with 46 of these established as associated with the smallpox vaccine, and 539 other, nonserious adverse events were also reported.13
Review
Because the regulatory framework governing research in children involves vigorous requirements protecting children from unreasonable risks when there is no prospect of benefit, it is sometimes a particular challenge to conduct research in this population. Clinical research in children can be conducted under 1 of 4 guidelines in the federal rules for protection of human subjects in research: 45 Code of Federal Regulations (CFR) 
46.404, 46.405, 46.406, and 46.407. Under 46.404, research may be approved if it offers no more than minimal risk. Approval under 46.405 applies when research involves greater than minimal risk but presents the prospect of direct benefit to the participant, thus justifying the risk. Under 46.406, research involving a minor increase over minimal risk and offering no prospect of direct benefit, but likely to yield generalizable knowledge about the participant’s disorder or condition, is permissible. The vast majority of pediatric research is approvable by institutional review boards under 1 of these 3 regulatory categories. If a protocol does not clearly meet these criteria balancing risk and benefit, a protocol involving pediatric participants may still be approved pursuant to 46.407 if it "presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children." If it is at all approvable, the smallpox vaccine trial in a pediatric population must qualify under 1 of the previously mentioned subsections of the federal regulations.
BALANCING RISKS WITH UNCERTAIN BENEFIT
The institutional review boards reviewing the federally sponsored trial of smallpox vaccine in children differed on what interpretation of the protocol qualified it for approval under the federal rules. Institutional review boards at Kaiser Permanente and Cincinnati Children’s Hospital concluded that the protocol offered the prospect of direct benefit to the pediatric participants.14 The institutional review boards at Harbor-UCLA Medical Center did not find the research readily approvable, questioning the prospect of direct benefit and referred the protocol to the Department of Health and Human Services’ Office of Human Research Protections so that an expert panel could be constituted and public input solicited.
Regarding risk, the protocol certainly involved the potential for complications more serious "than those ordinarily encountered [by children] in daily life."15 This conclusion must be reached not for the low risk of dire outcomes resulting in disability or death, as the risks of these fates might be comparable to, say, those of walking to school along a commuter road. Rather, the potentially high risk of short-term symptoms of variable severity, with some requiring medical treatment, may make the protocol appreciably riskier than what a child would normally encounter. Although pediatric patients can generally be screened effectively for most factors indicating heightened risk after the age of 2 years, the possible range and severity of potential complications from the smallpox vaccine makes its administration more than minimally risky. The protocol also has the unique character of posing a risk to third parties. Even within this wellcontrolled trial, potential transmission of vaccinia, along with the increased susceptibility of the population, sets this protocol apart and contributes to an assessment of more than minimal risk. Still, these risks were once acceptably assumed in promotion of health, are well understood, and may be minimized by thorough screening.
As to benefit, prospects for reaping the smallpox vaccine’s protective effect may have been overstated, a threat to credibility that a trial involving risk to children cannot absorb. At best, the protocol is of unknown benefit to these child participants. In the absence of more precise predictive information from the government, the risk of a smallpox attack in this country seems unlikely, though possible. The slim chance that the children in this protocol will be in close proximity to the occurrence of a smallpox case makes the prospect of direct benefit through preemptive vaccination even more remote. Given this uncertainty, the protocol cannot now be construed as having benefits that outweigh some likely harms, making it unapprovable under the usual institution-based regulatory guidelines. However, the protocol is ripe for review by the 46.407 panel to assess the research’s broad-based value and the ethical conduct of the particular trial.
ETHICAL ANALYSIS OF RESEARCH IN CHILDREN
In considering the ethics of pediatric research, the federal Advisory Committee on Human Radiation Experiments observed, "If human research never proceeded in the face of uncertainty, there would be no such experiments. How little uncertainty is acceptable in research involving children is a question that remains unresolved."16 The committee was generally engaged with questions of uncertainty in assessment of radiation research risks; the smallpox vaccine trial raises the flip side issue of uncertain research benefits. Some ethicists considering the question of enrolling children in research have suggested that benefit to society cannot morally outweigh exposing children to more than minimal risk without prospect of direct therapeutic benefit, as children should not be used as a means to an end even with parental permission.17,18 Furthermore, a state court has recently ruled, "We do not feel that it serves proper public policy concerns to permit children to be placed in situations of potential harm, during nontherapeutic procedures, even if parents, or other surrogates, consent."19(p850) Such positions become more entrenched in trials in which there is no potential for pediatric asset and parents must act as the child’s consenting authority, despite having quite distinct interests from those of their child. In particular, parents may be excessively concerned about their child’s security in the event of a bioterrorist attack, thus making it difficult for them to weigh true prospects of benefit. Misconceptions in calibration of risks and benefits are unfortunately common among trial participants in modern clinical research. Finally, in the case of smallpox vaccine it is tempting to suggest that it is unreasonable to object to a risk we imposed on children routinely only 30 years ago. However, there are many risks that we would not acceptably bear now that we did then, such as allowing our children to ride in cars without car seats and seatbelts. As risks and technology change, so must our assessments of what is acceptable.
This leads back to the unusual exception in the federal rules under 46.407, making possible research that offers quite small and unpredictable prospect of direct benefit but also imposes considerable risk of at least mild to moderate physical harms. This guideline allows the panel to recommend approval of the research because it "presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children."20 The smallpox vaccine protocol is the very sort of research this subsection of the rules seems designed to allow. If a bioterrorist attack occurred today, the information derived from a protocol particular to the safety and effectiveness of inoculating children with diluted vaccine might be essential, whether for incidental ring vaccination or the inception of a mass vaccination program. The protocol would also answer questions about administration methods (e.g., the number of needle pricks for the vaccine to be effective) and efficacy of site dressing in preventing shedding and third-party inoculation with vaccinia. The knowledge would also be reassuring because it is generally unreliable to extrapolate from adult studies where issues of immunogenicity are concerned. Given the urgent popular interest,21 the smallpox vaccine is an active concern in care of children, and it is essential to have answers about the impact of the currently available vaccine in today’s population as a means of preparatory public health. This reasoning recently motivated the American Academy of Pediatrics to endorse this vaccine research at this time.22 Hesitation in describing trial enrollment as beneficial makes it seem that the 40 children to be enrolled are being placed in service to others. However, the participants are contributing to a standard of care and public health preparedness in the face of modern risks that serves the entire pediatric population, including the trial participants themselves, in the event of a smallpox attack. Otherwise, as commentators noted, "Are we really willing to potentially allow greater than 70 million children to be part of an emergency experiment because we did not do the necessary studies to prove that these smallpox vaccines are safe and effective in children?"23(p1432)
OTHER ETHICAL ISSUES WITH THE PROTOCOL
Approval under the last subsection of the federal rules requires an assessment by the panel that the research will be "conducted in accordance with sound ethical principles."24 The federal rules do not provide guidance about what these principles entail, but presumably they refer to mechanisms ensuring informed consent and fairness. At least 2 aspects of the proposed pediatric smallpox vaccine trial raised questions about whether the protocol fulfilled this ethical requirement.
As the protocol reads at present, the parents of the potential research participant are to be extensively screened for the child’s and the family’s ability to participate in the trial. However, the parents were asked to sign the informed consent allowing their child to be admitted to the trial before the investigators’ review of the child’s medical record and the results of blood tests for conditions including HIV status and processing of the child through the inclusion and exclusion criteria. Although an initial consent may be obtained for permission to have their child screened and the child’s medical record reviewed, the informed consent for administration of the vaccine should be obtained only after these preliminary steps are complete. Potential research participants often gain understanding of the trial as they are checked against the clinical eligibility criteria, as well as by the experience of any initial tests such as blood draws. This process can enhance the all-important appreciation of the risks and burdens of the trial. If the parents have already signed the consent form for enrollment and receipt of the vaccine, it becomes much more difficult to extricate their child, despite assurances that consent may be withdrawn at any time. Although the introduction of a 2-step consent process would impose an additional task on investigators, the informed consent process would be vitally enhanced in a trial in which publicity might contribute to misapprehension about the incidence of risks and the prospect of benefit.
The protocol also made no provision for the coverage of treatment for adverse events related to receipt of the vaccine. The informed consent document stated: "If your child is injured because of this research, emergency medical care will be available. The care will not necessarily be free of charge" (original emphasis). Although such provisions for coverage are still rare and are not required under the federal regulations, both the Institute of Medicine25 and the National Bioethics Advisory Commission26 have recently advocated the development of a system to compensate participants for medical and rehabilitative costs resulting from research-related injuries. In the context of smallpox vaccine research on otherwise healthy and nonassenting children, coverage assurances should be required because of the potential harm to the trial participants without them. There is at least the possibility that parents will be reluctant to seek medical care for moderate to severe symptoms related to vaccine administration if they face the prospect of bearing the costs associated with emergency room treatment or hospital admission. It is certainly unlikely that any private insurer would cover such research-related costs. Expense should simply not be a factor when any delay in treating an adverse event resulting from vaccination poses the risk of irreparable harm to the child. A mechanism for covering these costs, at least in the critical period, must be established, and third-party reactions to vaccinia exposure should also be covered. And given the real but remote chance of long-term injury, from an encephalitis event, for instance, the possibility of a fund for support of such individuals should at least be explored with the country’s existing mechanism for vaccine injury compensation as a model.27 Without assurances, this protocol and similar trials teeter in an ethically precarious position regarding fiduciary duties to healthy pediatric volunteers.
CONCLUSION
Given the relative rarity of 46.407 panel reviews, it seems that protocols involving more than minimal risk without a sufficient counterbalancing prospect of benefit are also unusual. More likely, institutional review boards have taken advantage of the ill-described terms imbedded in the federal rules, including variable interpretation of "risk" and "benefit."28,29 Still, it is likely that forthcoming research—for example, trials evaluating vaccines against other infectious biological agents such as anthrax, severe acute respiratory syndrome (SARS), or the Marburg virus—will raise the need for these panel analyses. The area of genetics, especially trials assessing tests for presymptomatic risks or pharmacological targeting, may also raise issues of considerable risks in the face of uncertain benefits. An example is the expert panel constituted in August 2002 to review a protocol identifying precursors to diabetes in Japanese American youngsters.30
The process of public input may be influenced by panelists drawn from professional groups inclined to clinical interventions and curious about the answers to scientific conundrums. The public should maintain awareness of such reviews to take advantage of the comment period and offer a voice of skepticism when necessary. In this case, the salient question may be, is this pediatric trial one you will want to have done if a smallpox event occurs? And given such an event, is it unethical not to have done more current research with the standard or diluted vaccine in this population? The public has a unique stake in and perspective on the answer to these questions, making the trial especially appropriate for more open dialogue on research objectives. The health of children and adults alike is implicated by these vaccination policies, as exposure to a vaccinated individual is currently rare and may represent special risks for unvaccinated third parties with dermatologic or immunocompromised conditions.
Although the panel recommenders were unanimous in supporting approval of the pediatric smallpox vaccination protocol, the secretary and commissioner determined that the trial need not be conducted "in the absence of plans to use diluted Dryvax in children," presumably because the stockpile has been reinforced.31 However, this determination left open the possibility that such study may be required as other synthetic smallpox vaccines come down the pike. Indeed, recent experience with the monkeypox outbreak in the Midwest, where smallpox vaccine was administered prophylactically to those who had come in contact with infected animals,32 indicates that there may be numerous public health circumstances necessitating our optimal understanding of smallpox administration and dosage.
In closing, it should be emphasized that any results indicating the relative safety of a vaccine dose in a pediatric research population should not necessarily be readily applied to consideration of broader population vaccination schemes. In this smallpox vaccine protocol, the chance of a serious adverse event’s occurring was thankfully limited because of what would no doubt have been vigorous screening of potential trial participants and their contacts for pertinent risk factors. It would be virtually impossible to replicate this intensive and controlled circumstance in a nonresearch setting, especially in an emergency. Nevertheless, we can derive security from certain research information about the appropriate response in the event that a smallpox incident necessitates vaccination of pediatric patients. A scientifically verified vaccination protocol will promote clear heads in a crisis and minimize the potential of any cascading tragedy affecting children.
Footnotes
Accepted for publication July 18, 2003.
References
1. Advisory Committee on Immunization Practices, Centers for Disease Control and Prevention. Draft supplemental recommendation of the ACIP: use of smallpox (vaccinia) vaccine. June 2002. Available at: http://www.cdc.gov/nip/smallpox/supp_recs.htm. Accessed January 2003.
2. Neff JM. The case for abolishing routine childhood smallpox vaccination in the United States. Am J Epidemiol.1971;93:245–247.
3. Gellman B. 4 nations thought to possess smallpox. Washington Post. November 5, 2002;A1.
4. Office for Human Rights Protections. US Department of Health and Human Services Web site. A multicenter, randomized dose response study of the safety, clinical and immune responses of Dryvax administered to children 2 to 5 years of age. Available at: http://ohrp.osophs.dhhs.gov/dpanel/tdryvax.pdf. Accessed November 11, 2002.
5. Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: medical and public health management. JAMA.1999;281:2127–2137.
6. Lane JM, Ruben FL, Neff JM, Millar JD. Complication of smallpox vaccination, 1968: results of ten statewide surveys. J Infect Dis. 1970;122:303–309.[Web of Science][Medline]
7. Lane J, Millar J. Risks of smallpox vaccine complications in the United States. Am J Epidemiol.1971;93:238.
8. Neff JM, Lane MJ, Fulginiti VA, Henderson DA. Contact vaccinia—transmission of vaccinia from smallpox vaccination. JAMA.2002;288:1901–1905.
9. Frey SE, Couch RB, Tacket CO, et al. Clinical responses to undiluted and diluted smallpox vaccine. N Engl J Med.2002;346:1265–1274.
10. Centers for Disease Control and Prevention. Recommendations for using smallpox vaccine in a pre-event vaccination Program. MMWR Morb Mortal Wkly Rep. 2003;52(RR-07):1–16. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5207a1.htm. Accessed July 6, 2003.[Medline]
11. McNeil DG. Many balking at vaccination of smallpox. New York Times. February 7, 2003;A1.
12. McNeil DG. 2 programs to vaccinate for smallpox are "paused." New York Times. June 19, 2003;A13.
13. Centers for Disease Control and Prevention. Smallpox adverse event reports. Available at: http://www.cdc.gov/od/oc/media/spadverse.htm. Accessed July 6, 2003.
14. Office for Human Rights Protections. US Department of Health and Human Services Web site. Available at: http://ohrp.osophs.dhhs.gov/dpanel/dpindex.htm. Accessed November 11, 2002.
16. Advisory Committee on Human Radiation Experiment—Final Report. Washington, DC: US Government Printing Office, 1995. Part II, Chapter 7.
17. Ramsey P. The Patient as Person. New Haven, Conn: Yale University Press; 1970.
18. Ross LF. Children as research subjects: a proposal to revise the current federal regulations using a moral framework. Stanford Law Policy Rev.1997;8:159–171.
19. Grimes v Kennedy Krieger Institute, Inc., 782 A2d 807,850 (Md 2001).
21. Chase M. Demand grows for vaccinations against smallpox. Wall Street J. November 6, 2001;A28.
22. Committee on Infectious Diseases, American Academy of Pediatrics. Policy statement: smallpox vaccine. Pediatrics.2002;110:841–845.
23. Abramson JS, McMillan, JA, Baltimore RS. The US smallpox vaccination plan. Pediatrics.2003;11:1431–1432.
25. Institute of Medicine. Responsible Research: A Systems Approach to Protecting Research Participants. Washington, DC: National Academy Press; 2002.
26. Ethical and Policy Issues in Research Involving Human Participants. Rockville, Md: National Bioethics Advisory Commission; 2001.
27. Mariner WK. The national vaccine injury compensation program. Health Affairs.1992;11:255–265.[Medline]
28. Report and Recommendations: Research Involving Children. Washington, DC: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research; 1977.
29. Brock DW. Ethical issues in exposing children to risks in research. In: Grodin MA, Glantz LH, eds. Children as Research Subjects, Science, Ethics & Law. New York: Oxford University Press; 1994:81–101.
30. Steinbrook R. Testing medications in children. N Engl J Med.2002;347:1462–1470.
31. Determination letter of Irene Stith-Coleman, DHHS, and David A Lepay, FDA, to Stewart Laidlaw, Harbor-UCLA Medical Center. Available at: http://ohrp.osophs.dhhs.gov/dpanel/determ.pdf. Accessed July 8, 2003.
32. Altman LK. Smallpox vaccinations are urged and prairie dogs are banned to halt monkeypox, New York Times. June 12, 2003;A24.
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