Policy and Implementation
Effective preparedness for countering bioterrorism will not only require focused and sustained efforts to build the nation’s public and agricultural health infrastructures (including the training of health care professionals in detection, surveillance, prevention, and response); it will also require substantial changes in the way government-supported research is executed. Several overarching strategies are needed to provide the necessary funding for research and development (R&D), mechanisms for response, integration of efforts, and translation of findings into application. The recommendations listed below, which support and facilitate the R&D priorities outlined in previous sections of this report, are offered in that spirit.
DEVELOP SCIENTIFIC AND TECHNOLOGICAL HUMAN RESOURCES
The public and private sectors should explore new funding mechanisms that select for the best ideas and the most productive scientists, that offer great flexibility, and that provide the freedom to pursue bioterrorism-related research in a protected environment (i.e., not subject to 1- or 2-year budget fluctuations or constraints). The traditional system of reviewing and funding grants and contracts can be lengthy and averse to highly focused, highly managed research initiatives. Although basic and discovery science will continue to be a critical underpinning of all research in countering bioterrorism, a more focused, outcomes-based approach is also warranted. Balance between basic and applied research approaches will be crucial.
One model worth considering is a central organization that directs R&D
projects whose risks and payoffs are very high—that is, whose successes may provide dramatic advances—and that pursues these projects with both flexibility and speed. There is a real need for NIH, particularly NIAID, to adopt an approach like this for funding the kinds of high-payoff, high-risk projects that might create innovative scientific tools for addressing bioterror threats.
Recommendation 15: Create special research organizations to build expertise in countermeasures to bioterrorism. Federal agencies must build human resources in threat-agent characteristics, pathogenic mechanisms, and responses to bioterrorism-induced disease. Protected environments that foster innovation must be developed to support a cadre of leaders, scientists, engineers, policy experts, and strategic thinkers. These designated research organizations should address both classified and unclassified issues, and special mechanisms for rapid funding should be created to support external research efforts as the needs and opportunities emerge. New mechanisms for funding high-risk, long-term, high-payoff projects should be created in NIH.
Ideally, the new organizations recommended above would be small but have strong interactions with universities and government agencies. They would work in basic and applied science—specifically, to understand pathogenic (virulence) factors at the molecular level and how they affect mammalian systems. And they would also work in product development—specifically, in diagnostics, antiviral and antibacterial drugs, and all stages of vaccine manufacture, from development to pilot production. Clearly, drugs and diagnostics should have dual use, and the range of pathogens studied will inevitably have dual-use spinoffs. As a companion to this initiative, a mechanism for rapid funding should be established for bioterrorism-related research conducted extramurally; this mechanism would select for creative ideas quickly, with a minimum of bureaucracy.
NEED FOR STANDARDS AND STANDARDIZATION
The goals for research on surveillance and clinical diagnostics include rapid diagnostic assays for common pathogens and biological warfare agents. These assays could be used in primary-care settings (point of care) as well as referral laboratories. But standards are needed by which they may be rigorously evaluated and validated, and centralized repositories of standardized reagents and samples are needed as well. Because the development and evaluation of diagnostics require interdisciplinary applied research, however, it is currently difficult to find targeted funding sources and mechanisms.
Recommendation 16: Establish laboratory standards. Set up an oversight standards laboratory to evaluate diagnostic and detection tools; to ensure
the availability of standard reagents for academia, industry, and government; and to develop appropriate standards on a continuing basis.
The National Institute of Standards and Technology (NIST) is one agency where these sorts of efforts might appropriately be undertaken.
It is to be expected that many new products will be introduced for detecting and responding to bioterrorist threats, but no mechanism currently exists for evaluating them and comparing their effectiveness. An oversight standards laboratory would have the capacity to evaluate biosensors and diagnostic systems for infectious diseases, develop taxonomies of syndromes and data classifications, improve the quality of the expanding DNA and protein databases, validate methods, develop reagents, create internal standards for diagnostic comparisons for the scientific community, and evaluate methods and standards for personal protective equipment and decontamination.
FACILITATE DEVELOPMENT OF THERAPEUTICS AND VACCINES: ENGAGEMENT OF INDUSTRY
Government has a vital role to play in basic research on countering biological warfare agents through its own institutions, many of which have enormous expertise that has long been brought to bear in the fight against infectious diseases. It would be inefficient, however—and ultimately ineffective—for government to go it alone, without actively engaging private industry in the race to deploy needed biomedical countermeasures. Indeed, the greatest efficiency in this urgent effort is likely to come from working the broadest possible network of synergy among all institutions of established expertise—public sector entities, academic laboratories, private research institutes, biotechnology start-up ventures, and pharmaceutical companies. The fight is big enough and difficult enough to demand that the entire spectrum of available talent and resources be productively engaged. To build this network, a new partnership model for industry and government is needed that goes beyond the current models of government contracting.
Existing mechanisms for government interactions with the private sector cover a wide range: from simply acting as a customer in the marketplace, through NIH grants, to the comprehensive R&D contracting done by DOD. There seems to be no one best way among these mechanisms, nor any clearly better way beyond them. They all have valid applications, and, in practice, different cases will probably require different solutions. However, there is one principle that must serve as the foundation for any partnership aimed at developing countermeasures for bioterrorism. It is the principle of risk sharing.
Drug and vaccine development is an incredibly high-risk business. Frontend costs start big and grow bigger as development proceeds. The total is often something like $800 million by the time a successful drug is launched—10 years
or more from the day it was discovered. The odds against success are long—one compound in 5,000 makes it all the way from the test tube to the pharmacy shelf. And even among newly launched products, only one in three earns back its development costs. Public policy makers must consider whether drugs and vaccines could be developed more cheaply, given the compounds that are languishing in the developmental pipeline because bioterrorism is a small and uncertain market.
At the front end, government could help defray some of the costs associated with discovery and early-stage development. Grants and other forms of direct investment might help, especially with smaller organizations. But given the current needs related to antibiotic resistance in naturally occurring pathogens and to the decline of innovation in antibiotic-drug discovery, risk sharing may need to be considered more broadly.
Government could further reduce the risk to industry by providing some form of legal relief from the product-liability issues associated with new countermeasures. Risk sharing could also help to lower the costs of purchasing and storing biodefense drugs—whether existing or to be developed.
The government’s current practice is to determine what quantity of a given material it may need, issue a contract to purchase that quantity, and then stockpile it until needed. This process works well for some products, but it is a very expensive way to purchase pharmaceuticals. A more cost-effective approach would be to contract with drug manufacturers for assured access to the necessary quantities. The manufacturers would have to be able to prove beyond doubt that they could deliver the requisite quantities within the needed time frame. It is essential that production capability occurs at more than one facility and that these facilities be based within the United States. The government would reimburse the cost, build and maintain the inventory, and add a modest profit. In the event of an attack, the government would take control of the inventory at no additional cost. Meanwhile, responsibility for addressing such additional risks as unforeseen spoilage would rest with the manufacturers.
Recommendation 17: Facilitate vaccine and therapeutics production. Through public-private partnerships, create research, development, and manufacturing capacities to produce diagnostics, therapeutics, vaccines, and devices to counter terrorism and an oversight laboratory to evaluate, prepare, and standardize methodologies.
Traditional market mechanisms for the development of new diagnostics and vaccines are failing with regard to pubic health generally and response to bioterrorism in particular, where the principal market is likely to be federal and state governments. National orphan vaccine centers, perhaps created as government-owned, contractor-operated (GOCO) facilities, are needed to help bring vaccines for otherwise rare diseases to the stages of mass manufacture. Such centers could help coordinate extramural R&D activities in the public and private sectors as
well as perform critical research. In particular, national orphan vaccine centers could coordinate the clinical trials and studies with animals on which licensing would be based, and could serve as conduits for production at industrial facilities (including development of surge vaccine-manufacturing capacity and the training of personnel to produce vaccines that meet FDA standards). Such collaboration would require the establishment of new relationships between the public and private sectors.
For development of broad-spectrum antibiotics and antivirals, federal funding should encourage the large pharmaceutical and biotechnology companies to enter the field with the expectation that at least some drugs developed for bioterrorist threats will have dual use—that is, they may be applicable to common infectious diseases as well. Such encouragement for undertaking R&D on new drugs against bioterrorism agents could take the form of streamlined grant mechanisms, financial incentives, and regulatory changes.
Maintaining public confidence in vaccines, and in medical products in general, is critical to assuring overall confidence in the nation’s public health programs. But bioterrorism is a moving target, not a single disease of predictable epidemiology, and all potential product uses may not be anticipated. This complicates many decisions about product use.
Current biodefense-related activities at the FDA include meeting with sponsors and sister agencies to encourage interest in developing safe and effective new products, performing research that ultimately facilitates the development of these products, and intensively interacting with product sponsors to expedite availability.
Other steps that the FDA has employed in an attempt to safely speed up the licensure process include the following:
Emergency use under investigational new drug (IND) status allows rapid access to products that have not yet completed requirements for licensure. While IND status makes available potentially lifesaving items, a disadvantage of emergency use under this rule is that the product is not licensed, which not only reflects the true scientific limitations of the data but also raises important issues about public perception.
Fast-track processes can speed up the review procedure so that the FDA can evaluate information as it becomes available and as soon as the sponsor submits it.
Accelerated approval uses surrogate end points to demonstrate benefit. For bioterrorism agents, this might include protective-antibody levels for vaccines. The use of CD4 cells for assessment of antiviral treatment for HIV was one of the first surrogates to be approved under this rule.
The “Animal Rule”5is extremely important with respect to bioterror agents. It states that where human efficacy trials are not feasible or are unethical, the use of animal-efficacy data may be accepted as they relate to the desired benefit in humans—usually a significant outcome such as mortality or major morbidity. Clinical studies are still required for establishing pharmacokinetics and for assessing safety. The Animal Rule has postmarketing and labeling restrictions, however, and it does not apply if the product could be approved on the basis of any other standard under the FDA’s regulation.
Much more research is needed to establish acceptable criteria for reduction in morbidity and mortality. Human diseases caused by many of the CDC Category A agents are so poorly understood at present that meaningfully defining such criteria for the Animal Rule will be difficult. For some agents—for example, smallpox—appropriate animal models are lacking, and many existing animal models are poorly characterized with respect to lesion character and disease progression.
Animal models (with the exception of those for anthrax) remain poorly characterized with respect to aerosol challenge and disease characteristics in animals receiving sublethal challenge doses. Criteria need to be established with respect to end points that will be acceptable to the FDA for reduction in morbidity and mortality and similarity to human disease—i.e., route of inoculation, challenge doses and strains of organisms to be used, strain and species of animals, and duration of observation periods for reduction in morbidity according the FDA’s Animal Rule regardless of route of challenge.
Recommendation 18: Allow regulatory exceptions for development of therapeutics and vaccines against bioterrorism threats. The FDA should convene a broadly based conference to consider options and plausible mechanisms for expedited approvals under specific emergency conditions. In addition, for new drugs and vaccines that cannot be tested in humans, mechanisms for indemnification in the case of adverse effects will need to be developed. The possibility of encouraging collaboration between pharmaceutical companies in this area by waiving antitrust restrictions—in specific cases justified by the national interest—must also be considered. Thus, in addition to the FDA, the Departments of Commerce, Treasury, and Justice should also be involved in these discussions.
The Animal Rule is Code of Federal Regulation (CFR) Title 21, Parts 314 and 601: “New Drug and Biological Drug Products; Evidence Needed to Demonstrate Effectiveness of New Drugs when Human Efficacy Studies Are Not Ethical or Feasible.” The final version of this rule was published in the Federal Register on May 31, 2002, and will take effect June 30, 2002. The final rule can be viewed at <http://www.fda.gov/OHRMS/DOCKETS/98fr/98n-0237-nfr0001-vol1.pdf>
Clearly, in an emergency, someone or some agency has to be authorized to decide, for example, that INDs may not be required, that the informed consent process can be modified, that companies might have to be indemnified, or that companies might have to exchange information or work together, which would require a waiver of antitrust law. The factors that go into such decisions should be discussed by government and industry, and possible approaches recommended to federal agencies.