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Vaccines and Bioterrorism Clinical Trial Challenges & the Animal Efficacy Rule The clinical testing process presents significant obstacles to the production of bioterror vaccines.1-3 The Food and Drug Administration (FDA) requires rigorous safety and efficacy standards which all vaccine candidates must meet in order to be licensed. Furthermore, researchers involved in vaccine development must abide by certain ethical guidelines, while Institutional Review Boards (IRBs) monitor the safety of human subjects and ensure that subjects are not placed at undue risk. The development of bioterror vaccines is complicated by the scarcity of such pathogens in nature. Typically, a small number of research subjects naturally become infected with a target pathogen throughout the course of a new vaccine's development: these infections are necessary to assess the clinical efficacy of the vaccine being studied. It is unlikely, however, that subjects in bioterror vaccine clinical trials will naturally encounter those target pathogens, however. While researchers can measure whether a new vaccine generates a robust immune response in research subjects, such data are less valuable than evidence showing whether those vaccinated actually are protected from infection. Obviously, legal and ethical regulations prohibit the deliberate exposure of research subjects to dangerous pathogens, resulting in a significant challenge for assessing the efficacy of bioterror vaccines in development. Recognizing the difficulties inherent in the development of bioterror vaccines, in 2002 the FDA instituted a regulatory exception permitting the licensure of certain vaccines and drugs without data from human efficacy studies. The FDA amended its drug and biological product regulations so that certain pharmacological entities, those for which typical human clinical testing is not possible or those intended to relieve or prevent severe or life-threatening conditions, could be licensed based on "substantial evidence" of efficacy in two animal species. The "Animal Efficacy Rule" contained the caveat that products would be withdrawn from the market if post-licensure evidence indicated intolerable risk or lack of efficacy.4 While the Animal Efficacy Rule succeeded in addressing conflicts between the FDA and the Department of Defense (DoD), the use of animal surrogates is an imperfect method of determining clinical efficacy in humans.5 The specific immune responses that lead to protection in humans often cannot be determined through animal trials. While the safety of a vaccine can generally be ascertained, efficacy cannot be assessed with confidence until vaccinated humans are exposed to the target pathogen. While attempting to infer human response to a vaccine, researchers may employ models that mimic patterns of human disease and statistical analyses that determine immune correlates between species.6 Though it may sometimes be possible to approximate a human reaction through animal trials, some diseases--such as smallpox and dengue fever--only affect human beings, complicating vaccine development even further. An alternate approach is needed for evaluating safety and efficacy when animal trials are impossible. Though the FDA may resist pressure to relax testing requirements, bioethicist Jonathan Moreno suggests that, in the event of a severe public health crisis, it might be ethical to expose fully informed volunteers to pathogens in order to test a pharmaceutical or vaccine candidate.7 The Role of the Pharmaceutical Industry in Defense A group within the Department of Health and Human Services (HHS), the Biomedical Advanced Research and Development Authority (BARDA), manages the preparation and procurement of drugs, vaccines, and therapies for potential public health crises.8 In 2004 BARDA implemented Project BioShield, an initiative dedicated to advancing the development, production and purchase of "medical countermeasures" for chemical and biological threats.9 Though Congress allocated over $5 billion to the project, the world's major pharmaceutical companies have nonetheless largely eschewed government contracts for bioterror vaccine research and development. Such ventures promise little profit potential and present a major financial risk.10 Vaccines for bioterror threats occupy a limited market niche and their production involves substantial challenges such as establishing technical feasibility, constructing manufacturing facilities, assuring containment, and successfully conducting clinical testing. Furthermore, Project BioShield does not offer legal immunity to industry, and corporations are wary of potential litigation, particularly regarding vaccines.11-12 Major pharmaceutical companies are also often reluctant to agree to federal contracts for the exclusive development and purchase of drugs or vaccines.13 Government contracts typically yield low profit margins, as there is little or no market competition. There is also concern that security restrictions might severely limit information access and impede subsequent research and development. In the past, production costs have also been vastly underestimated, leading to financing difficulties. In addition, while the prospect of bioterrorism is deeply troubling, it is very likely that any particular threat will never materialize and that vaccines will go unused. While this is desirable from a security perspective, it provides no rationale for long-term corporate investment. Because of this, government contracts are generally awarded to smaller biotechnology companies eager for research subsidies and the possibility of large payments upon product delivery.14 These companies tend to be less established than larger corporations, with less product diversity and little record of developing and producing successful vaccines. To the dismay of the pharmaceutical industry, the Institute of Medicine and some government officials have demanded the nationalization of vaccine production, formally proposing the National Vaccine Authority Act in 2002.15 The act quickly stalled in Congress, however, and the centralization of vaccine production is highly unlikely in the near future. Critics of centralized production have instead advocated for additional collaboration and communication between the public and private sectors. Last published in 1994, the United States' National Vaccine Plan (NVP) is currently undergoing review. The revised plan is expected to address new challenges that have emerged in recent years, including complications regarding vaccine development and funding.16 The National Vaccine Program Office (NVPO) has encouraged the collaboration of the government, health care providers, vaccine manufacturers, and consumers throughout the drafting process. A draft released in 2008 identifies advancing the research of bioterror vaccines as a priority, and specifically cites bioterror vaccines among its target candidates for development. The final plan is expected to be released in late 2010. -- By Katelin Hoskins, University of Pennsylvania (hoskinsk@nursing.upenn.edu); Updated July 2010.
1 Pollack A. (2001). A nation challenged: The vaccines; Rush for new drugs raises questions about testing. New York Times. |
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