Cost/success projections for US biodefense countermeasure development

To the Editor:

To protect civilians against biological weapons and bioterrorism, the US Department of Health and Human Services (HHS) has developed a list of essential medical countermeasure requirements. We performed a survey of candidate biodefense countermeasures in development and estimated their future clinical development costs, based on historical drug and vaccine development data. The cost of supporting existing candidates through clinical development is estimated to be $4.1 billion over the next seven years, with costs of $817 million in fiscal year 2009, alone. Given the high failure rate of biopharmaceutical development, the probability of developing approved products from the existing pipeline is between 12% and 85% per HHS requirement. To increase the probability to 90%, two to nine additional candidates will be needed per requirement, at a total seven-year clinical development cost of $14.0 billion. To date, the primary government program tasked with supporting clinical development of medical countermeasures has received only $201 million.

In 2006, the Pandemic and All-hazards Preparedness Act (PAHPA, PL 109-417) was signed into law and created the Biomedical Advanced Research and Development Authority (BARDA) within the HHS. One of BARDA's core missions, as defined by PAHPA, is to promote the clinical development of medical countermeasures (MCMs)—including drugs and vaccines—effective against chemical, biological, radiological and nuclear (CBRN) threats to the United States¹. BARDA was intended to bridge the 'valley of death' between National Institute of Allergy and Infectious Diseases (NIAID) funding for basic research and early preclinical development, and procurement of successfully developed products via the BioShield program that was established by law in 2004 (P.L. 108-276) (Supplementary Fig. 1 online).

In the April 2007 Public Health Emergency Medical Countermeasure Enterprise (PHEMCE) Implementation Plan¹, HHS defined a series of requirements for MCMs deemed essential to protect civilians against CBRN threats. Currently, several of these MCMs are under development and are in, or have the potential to soon enter, clinical development, making them eligible for funding from BARDA. Since its creation, BARDA has received a total of $201 million from the US Congress, in fiscal years (FY) 2007 and 2008 (refs. 2,3). However, to date, there has been no estimate of the actual costs of developing these MCMs, or of the probability of successful licensure given current and potential future funding levels.

We surveyed the pipeline of MCM candidates in or entering clinical development that are responsive to the eight HHS biodefense MCM requirements described in the HHS PHEMCE Implementation Plan¹ (Supplementary Box 1 online and Table 1). Candidates were identified from pharmaceutical and biotech companies' press releases and quarterly and/or annual reports, news reports, US government agency reports and databases (http://www3.niaid.nih.gov/topics/BiodefenseRelated/Biodefense/research/funding/default.htm; http://clinicaltrials.gov/), a 2006 biodefense market survey⁴ and through discussions with HHS staff and members of the Alliance for Biosecurity (http://www.allianceforbiosecurity.org)—a collaboration between the Center for Biosecurity of the University of Pittsburgh Medical Center and 13 biopharmaceutical companies. Our analysis included only biodefense drug and vaccine requirements and thus excluded countermeasures against radiological, nuclear or chemical weapons, as well as diagnostics and biodosimetry assays.

Table 1 Probability of existing candidates satisfying HHS requirements

Mean development out-of-pocket costs, durations and development phase transition probabilities were based on historical data (Supplementary Methods online). Candidate MCMs in clinical development in FY2009 were projected by assuming that candidate MCMs now in preclinical development will be in phase 1 trials with probability equal to the average preclinical-phase 1 transition probability; those now in phase 1 trials will enter phase 2 trials with probability equal to the average phase 1–phase 2 transition probability; and those now in phase 2 trials will, assuming they are now mid-phase, remain in their current phase for all of FY2009 (Supplementary Table 2 online).

Total costs of clinical development for existing candidate MCMs were calculated by multiplying the number of candidate MCMs projected to be in each clinical phase, by the respective costs per remaining phases and those phases' respective transition probabilities. FY2009 costs of clinical development for existing candidate MCMs were calculated by multiplying the number of candidate MCMs projected to be in each clinical phase, by the respective annual cost per FY2009 phase. The probability of at least one approved product per requirement was calculated as:

where Ni is the number of candidates at stage i. These probabilities are based on historical, aggregate data and are not judgments of the merits of particular products. BARDA documentation does not set targets for the probability of US Food and Drug Administration (Rockville, MD) approval. We estimated costs for approval probabilities of 70%, 80% and 90%.

Our January 2008 survey identified 32 candidates that could fulfill HHS biodefense MCM requirements, including 12 small-molecule drugs, 15 vaccines and 5 biological therapeutics (Supplementary Table 1 online). Of these candidates, 21 are, as of this writing, in preclinical development, 10 are in phase 1 trials, and one is in phase 2 trials. Given expected costs, timelines and success rates (Supplementary Table 2), the direct (out-of-pocket) costs for clinical development of all existing candidates up to failure or approval would total $4,097 million over the next seven years—the mean duration of clinical development. Costs for FY2009, alone, would total $817 million (Supplementary Table 3 online).

On the basis of historical pharmaceutical failure rates, the probability of at least one approved product per HHS requirement within the existing pipeline is 12% for the broad-spectrum antibiotics, 23% for a Junin virus antiviral, 41% for a filovirus antiviral, 53% for a smallpox antiviral, 63% for a filovirus vaccine, 72% for an anthrax antitoxin and 85% for an anthrax vaccine (Table 1).

To yield at least a 90% probability of one approved product for each of the eight HHS biodefense requirements identified in this study, the pipeline of candidate MCMs will need to be expanded by two to nine additional candidates per requirement (Table 2). Supporting the clinical development of these additional candidates up to failure or approval would cost ∼$9.9 billion over seven years. Adding those costs to the clinical development costs of existing candidates, the clinical development costs for a pipeline large enough to have a 90% probability of yielding at least one approved MCM per HHS requirement would thus be $14.0 billion over seven years, and $3.39 billion in FY2009.

Table 2 Additional candidates needed to increase probability of satisfying HHS requirements

Our estimates for BARDA's funding needs are significantly higher than the $102 million appropriated by the Congress for FY2008 and the $250 million requested in the President's FY2009 budget. In fact, one year of $102 million in funding to BARDA is sufficient to support only two candidate MCMs for one year; and based on historical success rates, each of those candidates would have at most a 30% probability of eventually gaining FDA approval.

Our analysis illustrates that, based on historical data of biopharmaceutical development, funding allocations for clinical development of biodefense MCMs have direct impacts on the probability of successfully satisfying PHEMCE requirements. The US government, including the White House, HHS and Congress, must decide what probability of failure it is willing to tolerate, and make the associated commitment to MCM development. On August 1, 2008, the White House submitted a request to Congress to amend the President's FY2009 budget request for BARDA's MCM advanced development mission from $250 million to $723 million. As of this writing, Congress has not finalized the BARDA FY2009 appropriation. If funding does not significantly increase, HHS cannot respond to all of the biological agents currently designated by the Department of Homeland Security as “material threats” (and subsequently listed as requirements in the PHEMCE Implementation Plan).

In addition to increasing funding, we suggest that indirect economic incentives for biodefense MCM development, such as priority review vouchers, should be created to further promote MCM development^5,6. In 2007, legislation was passed to provide priority review vouchers to firms that develop pharmaceuticals targeting diseases that predominantly affect developing countries⁷. This incentive could also be expanded to include biodefense countermeasures, at no cost to taxpayers⁵.

Absent appropriate funding, BARDA could consider focusing its limited funds on the one or two biological agents believed to present the greatest risk. Alternatively, BARDA could shift some of its funding from agent-specific countermeasures to more “flexible defenses” that address multiple pathogens, such as broad-spectrum countermeasures and platform technologies (e.g., vaccine adjuvants and delivery systems and MCM rapid development and production technologies). Although flexible defenses may take longer to develop and have higher technical risk, they might prove more cost effective in the long run⁸.

Note: Supplementary information is available on the Nature Biotechnology website.