  |
||||||||||
        |
Vaccines against Potential Agents of Bioterrorism Clinical Trial Challenges & the Animal Rule Clinical testing is a tremendous obstacle in the production of new vaccines designed to protect against intentionally released, harmful pathogens. 1, 2, 3 For all vaccines, the FDA has rigorous safety and efficacy standards that new products must meet before they are granted licensure; all investigators are also required to follow ethical guidelines in the conduct of medical research. The safety of human subjects is monitored by an Institutional Review Board (IRB) to ensure that subjects are not placed at undue risk. In order to assess the effectiveness of the vaccine candidate, typical clinical research depends on some subjects being naturally infected with the target pathogen during the research period. This is overwhelmingly improbable for agents of bioterror, and for basic rules of research ethics prevent the deliberate exposure of research subjects with the pathogens for which protection is sought. Realizing the difficulties presented by this obstacle toward successful testing, in 1999, the FDA proposed a regulatory exception that would allow the agency to license vaccines and drugs against bioweapons without data from human efficacy studies. This proposal was formalized in the Public Health Security and Bioterrorism Preparedness and Response Act of 2002. The FDA amended its drug and biological product regulations so that approval for new products 1) intended to relieve or prevent severe or life-threatening conditions and 2) unable to be tested in classic trials could be based on "substantial evidence" from studies in two animal species. Products must be pulled from the market if post-licensure evidence indicates efficacy failure. The amendment is known as the "Animal Rule." While the Animal Rule reduced conflicts between the FDA and DoD, the use of animal surrogates to determine clinical efficacy is viewed by some as an imperfect solution to this problem.4 Despite evidence garnered from animal trials, researchers are often unsure of the specific immune responses that lead to protection in humans. While evidence of safety can be observed, clinical efficacy cannot be ascertained with confidence until those vaccinated are exposed to the pathogen in question. Models that accurately mimic human disease must be utilized in evaluating the validity of animal efficacy studies, as well as correlative statistical analyses.5 Further complicating bioterror vaccine research is the fact that some diseases, such as smallpox and dengue, only affect human beings. In the absence of animal efficacy data, a new approach must be developed for testing product safety and efficacy in human beings. Though the FDA may resist pressure to relax testing requirements, bioethicist Jonathan D. Moreno suggests that in a severe emergency, it might be ethical to expose fully informed volunteers to pathogens in order to test a pharmaceutical or vaccine candidate.6 The Role of the Pharmaceutical Industry in Defense Despite over $5 billion allocated to Project BioShield, the biowarfare defense program first passed in 2003, the world's major pharmaceutical companies have largely eschewed government contracts for bioterror vaccine research and development, seeing little profit potential but the possibility of major financial risk.7 Given their obligation to shareholders, these companies generally believe that vaccines for bioterror threats fill a limited market niche and present substantial challenges in establishing technical feasibility, constructing manufacturing facilities, assuring biocontainment, and successful clinical testing. In addition, the specter of litigation looms large since Project BioShield does not offer legal immunity to industry.8-9 Major pharmaceutical companies have been wary of an association with the military for a number of reasons.10 Government contracts typically yield lower profit margins, given that governments are the dominant (if not sole) purchasers. Another industry concern is that tightened security restrictions could obstruct the flow of knowledge leading to new research innovations. Meanwhile, bioterrorism threats are many, but there is the significant likelihood that they may not materialize, meaning that any vaccines developed would not be used. While this possibility is much hoped for from the perspective of national security, it further dampens the business rationale for heavy investment in bioterror vaccines by the major players in the pharmaceutical industry. Government contracts instead have gone to smaller biotechnology companies eager for research subsidies and the possibility of large government payments upon product delivery.11 Yet these companies are almost exclusively less well established, less diversified in their product pipeline, and lacking a track record of successfully developing and producing vaccines. Costs for the middle stages of project development have been underestimated, leading to large financing gaps. In contrast to DoD contracts, HHS does not have the legal authority to allocate public funds to shore up companies facing precarious financial conditions. To the dismay of the pharmaceutical industry, the Institute of Medicine and government leaders have called for a national entity, tentatively titled the National Vaccine Authority, to address vaccine shortages, inadequate production capacities, and the failure of market forces to encourage vaccine investments.12 The National Vaccine Authority would oversee the research, development, and distribution of vaccines deemed too risky or too unprofitable by industry to meet both civilian and military needs. A central component of this proposal is a government-owned, contractor-operated vaccine manufacturing plant. Industry executives have argued that the investment of tax dollars into a massive federal project such as this would lead to failure. One biotech CEO suggested that government should not invest in production facilities, but rather in the basic science of infectious diseases, enticing academics into industry partnerships.13 No decision has been reached, and at present, such a centralized authority appears unlikely in the near future. -- By Katelin Hoskins, University of Pennsylvania (hoskinsk@nursing.upenn.edu)
1Pollack A. (2001). A nation challenged: The vaccines; Rush for new drugs raises questions about testing. New York Times. Available at http://query.nytimes.com/gst/fullpage.html?res=9C01EFD61439F936A35752C1A9679C8B63&sec=&spon=. |
|||||||||
Site Notice |
Contact Us |
University of Pennsylvania |
Penn Center for Bioethics
© 2005—2009, University of Pennsylvania Center for Bioethics. 3401 Market Street, Suite 320, Philadelphia, PA 19104 215-898-7136  VaccineEthics.org is supported by a grant from The Greenwall Foundation. |
||||||||||
