Developing a single vaccine can take a sponsor 10 years and cost at least $800 million – with no guarantee that the vaccine will finally secure Food and Drug Administration (FDA) approval for marketing and distribution. In this costly and time-consuming process, the vaccine sponsor must first submit an Investigational New Drug (IND) application – to FDA’s Center for Biologics Evaluation & Research (CBER) – that describes the vaccine’s results in animal testing, manufacturing details, quality control information, and plans for human testing (clinical trials).
If and when the IND is accepted, the vaccine must pass three phases of clinical trials. In Phase I, safety and immunogenicity studies are performed on a small number of human subjects. If Phase I results are acceptable, Phase 2 studies, using hundreds of human subjects, are carried out to determine appropriate and safe vaccine dosages. If results of the Phase 2 study are found acceptable, Phase 3 studies begin, using thousands of human subjects to provide acceptable documentation of the vaccine’s effectiveness and safety.
The sponsor then submits a Biologics License Application (BLA) for review by an FDA team of medical experts; meanwhile, the sponsor’s proposed manufacturing facility is closely inspected as it manufactures the vaccine. Today, it is not surprising – with over 80 percent of the vaccines submitted failing to attain FDA approval, despite huge sponsor investments – that the financial incentives are limited. In addition, unfortunately, there are no processes in place to fund private developers of vaccines.
CBER, OCET & FDA-Expedited Processes
A more expeditious program has been developed, though, whereby FDA staff are able to participate, in several of the agency’s centers, in the development of vaccines against bioterror agents. In this expedited program – designed to enable the federal government to quickly produce and/or stockpile vaccines on a large scale to protect Americans from the risk of a bioterror attack – FDA’s CBER oversees the safety, effectiveness, quality, and availability of the vaccines being produced. The CBER staff participate both in facilitating the development of a quality product and in the manufacturing process. In addition, FDA’s Office of Counterterrorism and Emerging Threats (OCET) coordinates FDA’s counterterrorism policy initiatives and develops the agency’s vaccination strategies. OCET also facilitates communications with private-sector collaborators and coordinates vaccine Emergency Use Authorization (EUA) activities.
A separate FDA center – the Office of Crisis Management (OCM) – coordinates emergency response activities involving FDA-regulated vaccines and works closely with the other FDA centers as well as with the U.S. Department of Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response to develop policies for emergency response.
In the expedited process, FDA staff and outside experts quickly move vaccine candidates for agents on the DHS (Department of Homeland Security) “threat list” through all of the steps necessary for FDA approval – i.e., the regulatory and manufacturing processes, pre-clinical as well as clinical testing, and the licensing and approval processes. However, it is important to note that agents used by bioterrorists may be genetically engineered to evade vaccine-induced immunity, a problem that adds time to the process and delays the production of critical vaccines.
Preparedness efforts are also delayed by the large number of potential biothreat agents now available. Among the pathogens identified by DHS as potential biological warfare agents are those that cause smallpox, anthrax, plague, botulism, tularemia, and hemorrhagic fevers. And in the end, even the expedited, counterterrorism, FDA vaccine-approval process cannot keep pace with the needs of the Department of Homeland Security during times when biowarfare is threatening.
The BARDA Alternative & Several New Advances
Understanding this dangerous gap in the nation’s biodefense capabilities, Congress created a new agency four years ago within the previously mentioned HHS Office of the Assistant Secretary for Preparedness and Response. The goal of that agency – the Biomedical Advanced Research and Development Authority, or BARDA – is to provide a better integrated and more systematic approach to the development and purchase of vaccines and other tools for public health medical emergencies.
BARDA also manages Project BioShield, which means that, in the field of vaccines, BARDA provides a comprehensive integrated portfolio approach to advanced research and development, stockpile acquisition, innovation, and manufacturing of the vaccines needed to cope with public health medical emergencies – including but not necessarily limited to biological threats, pandemic influenza, and other emerging infectious diseases.
In August 2010, HHS Secretary Kathleen Sebelius approved the release of a Public Health Emergency Medical Countermeasure Enterprise Review article that revealed the need for new technologies and approaches to overcome seriously limiting factors encountered in vaccine development against natural and manmade biothreats. Despite the urgency of developing and stockpiling such vaccines, BARDA has been receiving only $200 million per year rather than the $3 billion the agency believes is required annually to give teeth to BARDA’s mission. At this time, $476 million is budgeted for 2011, but appropriation of those funds is far from certain as Washington’s interests turn to other needs in a flagging economy.
New Contracts Awarded, But Budget Shortfalls Anticipated
Last month (on 21 September), BARDA awarded a relatively large number of contracts geared in part toward accelerating the technology needed, and used, to: (a) evaluate candidate vaccines and therapeutics; (b) improve vaccine delivery technology; and (c) improve bioprocess development and manufacturing. The total cost of those contracts is projected to reach $55 million for the initial contract phase and up to $100 million over three years.
One contract, awarded to VaxDesign, funds the development of an accelerated vaccine evaluation alternative to animal testing. Another contract, awarded to PATH (an international medical research organization), funds the development of different methodologies that increase vaccine shelf life. In addition: (1) The Infectious Disease Research Institute (IDRI) was awarded a contract to develop vaccine formulations that have enhanced immunogenicity against the virus at hand and against its next generation of viral mutations. (2) Pfenex was awarded a contract to optimize the bioprocesses used for producing anthrax vaccine. (3) Novartis Vaccines and Diagnostics was awarded a contract to investigate the optimized development and distribution of influenza seed virus for those times when a rapid response may be required for newly identified strains. (4) Rapid Micro Biosystems was awarded a contract to develop accelerated vaccine sterility-testing methodology.
On a separate front, the U.S. Army’s Medical Research Institute of Infectious Diseases has developed several vaccines against biothreat agents. (In the field of vaccines, the Department of Defense (DOD) focuses on protecting the nation’s armed forces; HHS focuses primarily on biothreats to the civilian population. Each department uses its own vaccine development and production processes – but there are, of course, several areas of commonality.)
In light of current and projected budget shortfalls, and to more effectively address these common areas, BARDA, working in a close partnership with other HHS and DOD stakeholders, plays a leading role in an Integrated National Biodefense Medical Countermeasure Portfolio to leverage resources and programs related to vaccines and other medical countermeasures involving a large number of federal agencies.
Diana Hopkins is the creator of the consulting firm “Solutions for Standards” (www.solutionsforstandards.com). She is a 12-year veteran of AOAC INTERNATIONAL and former senior director of AOAC Standards Development. Most of her work since the 2001 terrorist attacks has focused on standards development in the fields of homeland security and emergency management. In addition to being an advocate of ethics and quality in standards development, Hopkins is also a certified first responder and a recognized expert in technical administration, governance, and process development and improvement.