U.S. Medical Countermeasure Development Since 2001: A Long Way Yet to Go

Abstract

The U.S. government has taken significant steps toward developing and acquiring vaccines, drugs, and other medical countermeasures (MCMs) to protect and treat the population after a biological attack. In contrast to 2001, there is now a procedure for the Department of Health and Human Services (HHS) to develop, license, and stockpile MCMs for civilian use. Another major accomplishment is smallpox preparedness: There is now an adequate supply of vaccine for every person in the U.S., and there is an alternative vaccine meant for immunocompromised people and those with close contact with them. In spite of these and other accomplishments, the U.S. government MCM effort has been criticized by federal advisory committees, National Academy of Sciences reports, a congressional commission, and outside analysts who state that the efforts lack central leadership and accountability and that the pace of progress has been slow. A clear operational strategy for using MCMs, which would guide their development and acquisition, is also lacking. In this article, we review key areas of progress made since 2001 to develop and acquire MCMs, and we summarize what we judge to be the most critical and often mentioned areas where improvements are needed.

Medical countermeasures (MCMs)—drugs, vaccines, diagnostic tests, and other medical devices—are an important part of preparedness against a biological attack. According to a 2011 Department of Health and Human Services (HHS) review of the MCM development process, “Our nation must have the nimble, flexible capacity to produce MCMs rapidly in the face of any attack or threat, known or unknown, including a novel, previously unrecognized naturally occurring emerging infectious disease.”¹ Having a robust MCM enterprise to provide biodefense countermeasures has been a stated goal for both the Obama and George W. Bush administrations.

While drug and vaccine development for biosecurity threats predates 2001, it was the anthrax letter attacks that spurred the U.S. government to prepare in earnest. In this review, we describe the biggest successes since that time: countermeasures for smallpox, and the development of a process so that MCMs could be developed and stockpiled for civilian use. While these successes and other procurements are notable accomplishments, the U.S. government has been criticized for its progress in preparations for other disease emergencies, especially anthrax. Federal advisory committees, National Academy of Sciences reports, a congressional commission, and outside analysts have pointed to a lack of leadership, a lack of accountability, and slow progress in MCM efforts in both the Department of Defense (DoD) and the Department of Health and Human Services. We have highlighted several recurring critiques of the U.S. government MCM efforts, which, in our judgment, are the most important to be addressed in order to make progress in MCM development and acquisition.

Major Success: Smallpox Preparedness

One of the immediate worries after the 2001 anthrax letter attacks was that the next attack could be with smallpox, and the U.S. and the rest of the world's population would be vulnerable. Smallpox was declared eradicated from nature in 1980, but routine vaccination stopped in the U.S. in 1972. By 2001, most people 30 years old or younger would not have had any immunity to an infection that kills 30% of its victims. Those people who had gotten the vaccine in the past but who hadn't been revaccinated since the 1970s would also be incompletely protected.

In addition to a naïve population in which the virus could easily spread, smallpox was a concern because of insufficient vaccine supplies to stop the chain of transmission. It was thought that there were about 14 million doses of smallpox vaccine (Dryvax) left in the U.S., but the supplies were decades old and had been made with an antique manufacturing process that would no longer meet FDA standards: The vaccinia virus had been harvested from the skin of infected calves.² Supplies of vaccinia immunoglobulin (VIG), administered for some types of rare vaccine adverse reactions, had dwindled, and stocks were discolored pink from a component leaching from the storage container caps.³ Even before the anthrax attacks, it was increasingly understood that the U.S. was not prepared for a smallpox attack.⁴

Today, the U.S. is much better prepared for smallpox. In 2002, the decision was made to acquire enough smallpox vaccine for the entire U.S. population, and that goal was achieved. There are currently more than 300 million doses of stockpiled FDA-approved vaccine, called ACAM2000, which was made using modern cell culture methods.⁵ Another 20 million doses of a different smallpox vaccine are to be stockpiled (modified vaccinia Ankara or MVA, manufactured by Bavarian Nordic under the trade name Imvamune).⁶ This vaccine could be given to the more than 10 million Americans who are unable to receive the ACAM2000 vaccine, either because they are immunocompromised, have close contact with immunocompromised people, or are otherwise at high risk for adverse reactions.^7,8 VIG supplies in the stockpile have been replenished.⁹ ST-246 (manufactured by Siga), a drug that could treat those who are already infected, has been ordered, though the contract is currently in dispute.¹⁰

Smallpox was considered to be one of the greatest vulnerabilities in 2001, and now some critics are questioning whether it isn't time to stop preparing for smallpox at the expense of preparing for other biological threats.¹¹

Civilian Acquisition of MCMs

Another major success for U.S. government MCM development has been the setting up of a process to develop and acquire MCMs. Since 2001, a system has been put in place in HHS, piece by piece, which should be able to support development of a medical countermeasure from the research stage through clinical trials, FDA licensure, and stockpiling for an emergency.

Unfortunately, it was not possible for the government to wait for MCMs for biological weapon threats to become commercially available for purchase. Biodefense countermeasures are a small, relatively unprofitable market with an uncertain regulatory path to FDA licensure, making it a financially unattractive investment for large, experienced pharmaceutical companies. It takes a great deal of resources to make a drug or vaccine—some 10 to 20 years and in the range of $1 billion to make an MCM.^12,13 Because MCMs specific to biological weapon threats—including smallpox, anthrax, and ebola virus—do not have commercial markets, governments will be the only purchasers. Making MCMs for biological weapon threats is thus a government responsibility, and government funding is usually required at every stage of MCM development.

Thanks to the Project BioShield Act of 2004 (PL 108-276), which authorized $5.6 billion over 10 years for advanced development and purchase of priority MCMs, the U.S. government is now able to purchase new vaccines and drugs for bioweapon threats. Once purchased, the MCMs can be placed in the Strategic National Stockpile (SNS), which is managed by the Centers for Disease Control and Prevention (CDC). In addition to purchasing products that are either ready or nearly ready for use, HHS may fund products during the development process through the Biomedical Advanced Research and Development Authority, or BARDA, which was created by the 2006 Pandemic and All Hazards Preparedness Act. Smallpox vaccine was acquired prior to BioShield or BARDA, but through this process, a number of vaccines, therapies, and diagnostics have ended up in the stockpile.¹⁴

There is also now a process that should help MCMs achieve FDA licensure: the Animal Efficacy Rule, which allows countermeasures to be tested for efficacy in animal models.¹⁵ Many bioweapon threats cause natural disease, but they are extremely rare, and without the Rule it would be difficult to satisfy the requirement of demonstrating efficacy in humans. In practice this is a qualified success, as the Animal Efficacy Rule has not yet been used for a novel product but only for products that have extensive human data for other indications.^16,17 However, the fact that there exists a process for acquiring MCMs for the civilian population is substantial progress.

Other Notable Successes

Preparation for botulism has been another MCM success. Botulism toxin has been developed into a biological weapon in past offensive biological weapon programs, it is extremely lethal, and the toxin is not considered to be difficult to manufacture.¹⁸ In 2001 there were few options for treatment, but the stockpile now contains 200,000 doses of botulism antitoxin, derived from horses, which could be useful in treating patients suffering from the major subtypes of botulism.^19,20 The U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID) shares credit for this success, as researchers there developed 2 investigational antitoxins; these were further developed by Cangene, which ultimately supplied the antitoxin to the stockpile.²¹

Perhaps the major countermeasure success for DoD since 2001 is their role in maintaining the FDA-licensed anthrax vaccine, AVA. In the late 1990s, Bioport, the company that manufactured AVA (Bioport had purchased the vaccine production assets from the Michigan Department of Public Health, and the company was renamed Emergent in 2004), had several problematic inspections by the FDA, and their license was nearly revoked.²² A group of anthrax specialists from USAMRIID helped solve the technical issues surrounding licensure,²³ particularly the refining of a potency test for the vaccine. DoD lent major assistance, with FDA guidance, for manufacturing improvements, and, ultimately, the vaccine was reapproved for human use in 2002.²⁴ While the vaccine has been recommended for updating, the dedicated efforts at DoD prevented a situation in which there would be no preventive measure for the military to use against anthrax, a biological weapon that has been developed by past government biological weapons programs²⁵ and which was used in the letter attacks in 2001.

What HHS and DoD Successes Have in Common

One key factor present in all of these successes—maintaining FDA licensure of AVA and acquiring ACAM2000 smallpox vaccine, VIG, and others—has been direct engagement and oversight by senior government leadership. The involvement of senior leadership allowed other parts of the MCM processes to function as intended: Goals were established early on, aggressive timelines were set and adhered to, bureaucratic obstacles were pushed aside and dealt with as needed, and there was cooperation among the involved agencies. Dedicated assistance by the FDA was also important to flag and fix problems right away, and there was a notable absence of political interference from lobbyists and from Congress. When problems came to light, there was direct communication between program managers (who had considerable experience with the best practices of private industry) and experienced contractors to get them solved. It is hard to overstate the impact that the involvement and commitment of senior leadership had in achieving each success, which allowed many hard-working people beneath them to ultimately be successful in their individual missions.

Critiques of the MCM Efforts

“If achieving national MCM goals is likened to climbing a mountain, then most of the mountain remains to be climbed.” —National Biodefense Science Board, 2010 ²⁶

In spite of the successes described above, there have been major critiques of how the government has engaged in MCM development (see Table 1 for summaries of selected reports). On the civilian side, the National Biodefense Science Board (NBSB), a federal advisory committee to the HHS Secretary, published a report titled “Optimizing Industrial Involvement in Medical Countermeasure Development” in February 2010.²⁷ The report described barriers to industry involvement in medical countermeasures, including inconsistent federal funding, lack of clarity on requirements, and lack of coordination among federal agencies. The NBSB followed with an additional report, “Where Are the Countermeasures? Protecting America's Health from CBRN Threats,” which described the entire federal MCM program as uncoordinated and disjointed, and criticized the approach for not tapping the talents residing in DoD and DHS.²⁶ HHS Secretary Kathleen Sebelius said in a review of the MCM process, “The pipeline we rely on to provide those critical countermeasures—diagnostics, vaccines, antivirals, antibiotics—is full of leaks, choke points and dead ends.”²⁸

Table 1.

Selected Reports and Articles Chronicling Need for Improvement in Medical Countermeasures

Year	Report Authors	Summary of Findings
2000	Independent experts tasked by the Deputy Secretary of Defense	Top Report: Report to the Deputy Secretary of Defense by the Independent Panel of Experts Summary: Found that the DoD vaccine acquisition approach was “insufficient and will fail.” Recommended that DoD consolidate its vaccine programs for bioweapons and natural disease protection; develop a distinct acquisition process to resemble best industry practice for vaccines; and hire qualified staff at all levels. Recommended forming a government-owned contractor-operated vaccine production facility.
2002	Institute of Medicine	Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military Summary: Recommended that DoD merge vaccine efforts for BW threats and for natural diseases and restructure their acquisition process to be tailored to the vaccine development process. Urged greater coordination with the civilian sector.
2004	Institute of Medicine and National Research Council of the National Academies	Giving Full Measure to Countermeasures: Addressing Problems in the DoD Program to Develop Medical Countermeasures Against Biological Warfare Agents Summary: Producing MCMs has not been given sufficient priority. Management of the effort was disjointed, and DoD leadership lacked “an adequate grasp of the commitment, time, scientific expertise, organizational structure and financial resources required for success in developing vaccines and other pharmaceutical products.” Documented 10 years of failure to produce vaccines, starting from the 1990-91 Gulf War. Recommended a complete reorganization of the program, with regular external review, staffed and led by people with industry experience, consolidated into a separate DoD agency.
2010	Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism	Prevention of WMD Proliferation and Terrorism Report Card, An Assessment of the U.S. Government's Progress in Protecting the United States from Weapons of Mass Destruction Proliferation and Terrorism Summary: The nation received an “F” grade for failing to enhance the nation's capabilities for rapid response to prevent biological attacks from inflicting mass casualties, particularly “the lack of priority given to the development of medical countermeasures.” The Chair, Senator Bob Graham, and Vice-Chair, Senator Jim Talent, believed there was inadequate expertise and investment in countermeasures, “a symptom of a failure of the U.S. government to grasp the threat of biological weapons.”
2010	National Biodefense Science Board	Optimizing Industrial Involvement in Medical Countermeasure Development Summary: Identified barriers between government and industry that hamper progress, including inconsistent funding; slow, unwieldy contracting; lack of clarity about MCM requirements; and lack of coordination between federal partners. They also found that government had an inadequate understanding of how industry makes drugs and vaccines. Recommended that MCM leadership be centralized and deficiencies addressed.
2010	National Biodefense Science Board	Where Are the Countermeasures? Protecting America's Health from CBRN Threats Summary: Thought the MCM development effort required more prioritization, synchronization between government agencies, and leadership. Found that the various gov't agencies are not coordinating, and that there is no unifying strategy for developing and using CBRN MCMs. Recommended that there be increased accountability in the MCM process and a clarified regulatory process, and recommended coordination versus reorganization.
2010	Department of Health and Human Services	The Public Health Emergency Medical Countermeasures Enterprise Review: Transforming the Enterprise to Meet Long-Range National Needs Summary: Stated that the nation should prepare for known and novel threats, man-made or naturally occurring. Strategy addressed shortfalls in MCM development, which should include increased focus on regulatory science; plans to build a flexible manufacturing capability; adding early development teams to assist in translating basic research to eventual products; establishing an “MCM development leader”; setting up an Enterprise Senior Council, replacing the Enterprise Governance Board as a decision forum for MCM policy and implementation. Recommended that ASPR/BARDA increase contracting speed.
2011	Bipartisan WMD Terrorism Research Center	Bio-Response Report Card Summary: The nation received a “D” grade; there still existed a lack of clearly defined requirements for MCMs, common set of prioritized R&D goals, coordination with budget requests, and sufficient and sustained funding. Noted that external advice given to HHS in March 2010 by the National Biodefense Science Board was not taken.
2011	Government Accountability Office	Improvements Needed for Acquiring Medical Countermeasures to Threats from Terrorism and Other Sources Summary: Credited HHS for beginning to address recommendations from its internal 2010 review, but faulted them for not developing “an adequate strategy to monitor implementation” and stated that their process will not allow for measuring progress across medical countermeasure initiatives. They also pointed out that the 2007 HHS plan for countermeasure priorities has not been updated biennially as promised.

The medical countermeasures development process for DoD has also been the focus of critical high-level reports in 2001, 2002, and 2004. The Biologic Warfare Defense Vaccine Research Development Programs report, or the “Top Report” as it is known after its chairman Franklin Top, reported in 2001 that the DoD approach to vaccines was “insufficient and will fail.”²⁹ The National Academy of Sciences, in a 2002 report, Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military, criticized the acquisition process for vaccines as “putting military readiness at risk.”^30(p6) In 2004, another NAS committee saw “dismal prospects for successful results (and no prospects for faster results) … to produce medical biodefense countermeasures.”^31(p4) The problems were laid out in great detail, and possible solutions were described, but the recommendations have not been enacted.

The DoD medical countermeasure effort has also recently come under criticism for the Transformational Medical Technologies Initiative (TMTI). Originally, TMTI was conceived as a way to defend against unpredictable or unknown threats. Instead of developing medical countermeasures that would protect against one individual pathogen, such as a vaccine against tularemia or a drug that treats ebola virus, this program would look for common pathways that pathogens use to infect humans and target those pathways to produce broad-spectrum drugs or adaptable platforms. In the end, however, the program was not considered a success.³² After 5 years of searching for broad-spectrum therapies, 3 candidate drugs for ebola virus were in clinical trials, all from the same company (AVI BioPharma), which has not yet brought a product to licensure.³³ No antibiotics are yet in clinical trials. While the program is to award a major contract next year for influenza, that disease already has a great deal of research support outside of DoD. The $1.5 billion program has been reorganized “amid charges it is failing in its mission.”³²

Recommendations for Change

There are a number of commonalities among assessments of U.S. government medical countermeasure development regarding what needs to be improved and specific suggestions for improvement. What follows are some of the most prevalent areas of concern and, in our judgment, the problems most in need of attention to improve the MCM program and U.S. preparedness.

New Anthrax Vaccine Needed

If there were an anthrax attack, demand would be high for a safe, quick-acting, easy-to-deliver vaccine. Common sense suggests that many people, even those who do not live in the same place as the attack, would want to be vaccinated to prevent being affected by a possible second event. However, an anthrax vaccine with these qualities is not available. Though the Institute of Medicine (IOM) determined a new vaccine was “urgently needed” in 2002, the only available anthrax vaccine is AVA, manufactured by Emergent BioSolutions. The vaccine takes weeks to build immunity, and it requires 5 shots and yearly boosters to be effective.³⁴ Though more than 2 dozen peer-reviewed studies have demonstrated AVA to be safe, the vaccine is controversial—some service members have resigned or risked court martial rather than receive it—and the manufacturing process is not easily scalable in case of increased demand.²¹ The vaccine also has a limited shelf life, so the stockpile needs periodic replenishment.³⁵

There was an attempt to develop a second-generation vaccine with an abbreviated dosing schedule. In 2002, at the request of HHS, the National Institute of Allergy and Infectious Diseases (NIAID) initiated a development program with 2 contractors for a second-generation anthrax vaccine based on the research on rPA done at USAMRIID. In November 2004, the first HHS BioShield contract was awarded to VaxGen, Inc., for 75 million doses of a second-generation anthrax vaccine at a price of $877.5 million. However, on December 19, 2006, HHS canceled the contract for default, citing that stability problems in the vaccine formulation prevented it from being tested in clinical trials within the contract period. There were reports in the press, as well as a report from the Center for American Progress (a think tank), that political lobbying contributed significantly to the demise of the contract.^36,37 Soon after the VaxGen failure, Emergent bought the intellectual property rights from VaxGen for the updated anthrax vaccine.³⁸ Emergent received a $186.6 million contract for work on an rPA vaccine, which is in Phase 2,³⁹ and has also supplied more of the original AVA vaccine to the stockpile.⁴⁰

The SNS has a supply of oral antibiotics that could be used for treating anthrax disease for 60 million individuals with a 60-day course of treatment, and there is enough vaccine available to respond to a “three-city attack.”³⁷ However, even if the anthrax is susceptible to antibiotics, a vaccine would still be needed, likely in quantities that far exceed supply. Under current planning, people who are exposed to anthrax spores will be prescribed antibiotics for 60 days, which can produce significant and painful side effects, long-term negative changes to their intestinal microbial flora, and, occasionally, serious adverse events.⁴¹ There is also the matter of nonadherence: About 2,000 postal workers in Washington, DC, were prescribed 60 days of postexposure prophylaxis with antibiotics after the anthrax attacks in 2001, but only 40% were able to take the medication.⁴² In the Morgan postal facility in New York City, the adherence rate was 21%.⁴³

An effective vaccine could protect people who are unable to take the full course, or it could make the full course unnecessary. The CDC has stated that it will recommend that 3 doses of AVA anthrax vaccine be taken by people exposed to anthrax spores, 2 weeks between doses, to counter the effects of nonadherence.⁴⁴ But however much it is needed, a more immediately effective, easy-to-deliver vaccine for anthrax that provides long-lasting immunity is still not on the horizon.

Coordination Between Government Agencies

Developing medical countermeasures is an expensive, time-intensive process. Efforts must be coordinated so that progress is made within a reasonable amount of time. Unfortunately, several reports, cited below, have found that there is a lack of coordination within the HHS agencies that have responsibility for MCM development; there is a lack of coordination within the DoD agencies; and there is a lack of coordination between HHS and DoD. The consequences of this lack of coordination are that the entire MCM development process is slowed; specific MCMs are worked on and then dropped; and private industry, which makes the countermeasures, is left without a consistent partner in government.

There are several government agencies that have responsibilities for MCM development, and the structure is intended to yield cooperation among them. At the top is the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE), which was put into place in 2006. PHEMCE is led by the Assistant Secretary for Preparedness and Response (ASPR), and it includes 3 HHS agencies: CDC; the National Institutes of Health (NIH); and the Biomedical Advanced Research and Development Authority (BARDA). It also includes other non-HHS agencies that have responsibilities for MCM development: the Department of Homeland Security (DHS), DoD, the Department of Veterans Affairs (VA), and the Department of Agriculture (USDA).

While not every product has conformed to this model, the beginning stages of research into medical countermeasures in HHS are the responsibility of the NIH, specifically NIAID. BARDA is responsible for advanced research and development of MCMs.

NIAID has received the bulk of biodefense monies for MCM development since 2001, at levels sometimes 15 times that given to other agencies for advanced development, in addition to capital projects such as high-containment laboratories and funding for pandemic influenza.²⁶ Since 2003, it has received about $1.6 billion each year, but according to a New York Times investigation, NIAID has not put those dollars toward the small number of specific disease priorities set by DHS in concert with HHS and the White House. Instead, the article maintains, about 70% of the funds have been directed to research for natural diseases, including AIDS, SARS, and malaria.³⁷ The mismatch of DHS and NIAID visions for biodefense is also seen in a NIAID document:

NIAID biodefense funding supports research on … more than 50 organisms.…This list includes “traditional” biodefense pathogens such as those that cause anthrax and smallpox; newly emerging infectious agents such as the SARS coronavirus; and pathogens that cause long-standing serious global health problems, such as multidrug-resistant tuberculosis; influenza; and enteric diseases due to Escherichia coli, Vibrio cholerae, Salmonella and Listeria. These diseases have public health significance because of their dual potential, i.e., they can occur naturally or result from the deliberate release of an infectious agent.^45(p5)

BARDA, which is supposed to shepherd prioritized MCMs for inclusion into the stockpile has, according to an HHS report, “insufficient numbers of reasonably mature advanced products in the pipeline to be procured.”^1(p9) Though the money they have is not proportionate to their requirements, using biopharma industry benchmarks,^12,46 a lack of coordination has slowed their effectiveness as well, according to the New York Times.³⁷ As one example, contracting officers were removed from BARDA and placed in the office of the ASPR, adding another layer to interact with companies and ultimately diminishing BARDA's effectiveness.³⁷ The National Biodefense Science Board wrote, “America expects orchestration within HHS's scientific endeavors, not cacophony,”^26(p79) but that has not yet been achieved.

Coordination Within DoD

Until 2003, the Department of Defense was responsible for most MCM development in the U.S. government, but their “customer” is the warfighter, not the entire U.S. population. Their emphasis has been on vaccines versus therapeutics for biological weapon threats. Requirements for countermeasures are set by the Joint Requirements Office (JRO). The Chemical and Biological Defense Program (CBDP), which is responsible for turning those requirements into products, has several components: Research and discovery are performed by the Defense Threat Reduction Agency Joint Science and Technology Office (DTRA-JSTO), or sometimes by the Defense Advanced Research Projects Agency (DARPA). They are also a responsibility of the Transformational Medical Technologies Initiative, or TMTI, which had responsibilities from research and discovery through manufacturing before it was folded into other components. Advanced development of DTRA-JSTO products is undertaken by the Joint Program Executive Office—Chemical/Biological Defense (JPEO-CBD).

There have been multiple reorganizations in the past 15 years for biological weapon defense, and the disruptions any reorganization causes have been flagged as one reason for slow progress in developing MCMs.³¹ But another significant limitation has been a lack of coordination between advanced development of countermeasures and countermeasure discovery. A consequence of this lack of coordination is that flawed products have failed later than they should, using resources that could have been put toward other more promising MCMs. There are not many vaccines in advanced development, and the timelines are long: rBV A/B for botulism, which is projected for fielding in 2017; rF1V for plague, projected for fielding in 2016; and Trivalent Filovirus Vaccine, which is not projected to be fielded until 2024.^47-49 Other priorities that were identified in 1996, when a prime systems contract was awarded to DynPort Vaccine Production company, are no longer even being pursued for a variety of technical and budgetary reasons; these include a second-generation anthrax vaccine and vaccines for tularemia, Q fever, ricin, SEB, and EEE/WEE/VEE.³¹

Coordination Between DoD and HHS

In one sign of progress, there is now an agreement between HHS and DoD for an Integrated Portfolio of MCMs, established in 2010, and there is now a set of common definitions for HHS and DoD for technology readiness levels (TRLs) to facilitate communication about specific countermeasures.²⁶ But there is still evidence that more coordination could benefit MCM development.

One concrete example of lack of coordination is the investment in high-containment laboratories. Since 2001, there has been a marked expansion of BSL-4 laboratories.^50,51 Through NIH, new construction has taken place at the NIAID Integrated Research Facility in Fort Detrick, Maryland; the National Biocontainment Laboratory (NBL) at Boston University; the NBL at the University of Texas Medical Branch in Galveston, Texas; the Rocky Mountain Laboratory (RML) Integrated Research Facility in Montana; and new facilities at the CDC Special Pathogens Branch, Emerging Infectious Diseases Laboratory. Through DHS, new laboratories include the DHS National Biodefense Analysis and Countermeasure Center in Fort Detrick, Maryland, and the DHS National Bio- and Agro-Defense Facility (NBAF) in Kansas, which has recently been put on hold due to budget constraints.⁵² Through DoD, new construction includes the USAMRIID Recapitalization in Fort Detrick (which will replace the existing USAMRIID laboratory) and the Medical Countermeasures Test and Evaluation (MCMT&E) facility, also at Fort Detrick, which is still in the planning stage. There has also been a significant increase of BSL-3 laboratory space.^50,51

Constructing these facilities is expensive: The MCMT&E facility is projected to cost $584 million,⁵³ and one estimate of the cost to operate these facilities puts it at about 300% that of a noncontainment facility.⁵⁴ Given the costs that will continue on each year, and the amount of personnel training required to work productively in these laboratories, enhanced coordination might have saved DoD and HHS money, resources, and time.

Coordination Between Government and Private Industry

The NBSB review found that there are substantial barriers to interactions with industry, including “slow, unwieldy, expensive, and opaque” contracting with the U.S. government.^27(p17) Simply put, the standard federal contracting process under the Federal Acquisition Regulations is not well suited to the development of medical countermeasures. It is impossible to emulate the best scientific practices in the pharmaceutical industry, as the government contracting process is slow, cumbersome, inflexible, and difficult to manage and ultimately inhibits effective communication between program managers and contractors. The process places a very large, sometime onerous administrative burden on contractors, which in part explains the reluctance of large pharmaceutical companies to become engaged. It is a process that usually builds in unnecessary delays in the product development process and also allows and encourages micromanagement by government officials. The process continues to be used because it minimizes short-term administrative risks, even as it increases the risks of ultimately failing to produce a countermeasure. And a much more flexible and suitable method of contracting is available: Other Transaction Authority (OTA) enables a more effective and flexible partnership between the government and the product developer. However, OTA has only been used for medical countermeasure research by DARPA, rarely by other parts of DoD, and not at all by HHS, even though legislative barriers to the use of OTA for MCMs have been removed.

Regulatory Process Needs Improvement

Despite years of research and funding, there have essentially been no novel vaccines or drugs approved by the FDA as MCMs. One stumbling block is the limited scientific and clinical data for many of the diseases important for biodefense. The lack of data and appropriate clinical endpoints adds complexity and uncertainty for both MCM developers and for those who need to evaluate the products for safety and efficacy. Additionally, there is no government-wide concept for how specific MCMs would be used in an emergency, which adds to lack of clarity among the MCM developers.

In July 2002, the FDA put forth the Animal Efficacy Rule, which was created to allow testing of medical countermeasures that could not ethically be tested on humans.¹⁵ Countermeasures for such diseases as ebola, Marburg, anthrax, and plague would still need to be tested in humans for safety, but only animals would be challenged with the actual pathogen to see if the countermeasures treat infection or prevent disease. Despite years of effort, however, there have been only 2 approvals under the Rule, and both of those MCMs were already used extensively in humans but for other indications.¹⁶ In essence, there have been no new approvals. This is a conundrum for MCM preparedness, as HHS intends to seek FDA approval for all MCMs in the SNS procured with BioShield funds, and it is the stated policy of DoD that they will aspire to use only FDA-licensed countermeasures on warfighters. The DoD can use an Investigational New Drug (IND), but to use experimental products they would first need to seek advised consent from every person who receives them, which poses logistical challenges in an emergency. For DoD to use an IND without advised consent, a presidential waiver is required.^55,56

An example of the mismatch between the traditional regulatory pathway and what is needed for biodefense countermeasures can be found in the Human Genome Sciences (HGS) product for anthrax infection. The product, raxibacumab, is an antibody to Bacillus anthracis, the causative bacteria of anthrax disease. Presumably, it would be used together with an antibiotic after an anthrax exposure, which would help counter the effects of nonadherence to the antibiotic for the full course of 60 days. If the infection was antibiotic-resistant, raxibacumab would be used by itself. There is no government-wide utilization policy for how such a product would be used in the aftermath of an anthrax attack, however, and so the drug was evaluated in the same way as any other traditional therapy. In October 2009, the FDA decided not to license raxibacumab because it was not shown to be more effective than the existing anthrax treatment. BioShield contracts purchased 65,000 doses for the SNS, however, and, according to their press releases, HGS plans to do additional testing and will resubmit their application to the FDA in 2012 or 2013.^16,57,58 Efficient and effective development of a countermeasure requires that all parties involved—including end users, project officers, contracting officers, industrial developers, and regulatory officials—agree on the concept of operational use of the product and the regulatory strategy needed for approval. Achieving this consensus across the government requires effective leadership.

The NBSB review of FDA's approach to MCMs found that “advancement of regulatory science and support for a robust scientific capacity at FDA are needed.”^1(p8) Regarding the Animal Efficacy Rule, it has been suggested that different species should be able to be used to demonstrate different aspects of the safety and efficacy of a product, and that one animal species should not have to (indeed, can't) model all aspects of the human condition.¹⁶ The FDA has since launched an MCM initiative to enhance the review process for high-priority MCMs; to advance regulatory science in order to better evaluate the MCMs; and to modernize the legal and regulatory framework to support the emergency public health preparedness mission.⁵⁹ FDA has also signed a memorandum of understanding (MOU) with DARPA to develop new tools to evaluate safety and efficacy data when limited human data are available, and they are revising the guidance for implementing the Animal Efficacy Rule.² These and other recent FDA efforts to contribute to MCM development and licensure are positive developments, but as MCM development timelines are long and complex, and coordination with other government agencies is required, improvements to the overall process may take time.

Greater Commitment to Developing MCMs

Developing medical countermeasures is expensive and takes years, and every candidate product has a high risk of failure before licensure. So for the U.S. to demonstrate a lack of commitment to the process, as critics have charged, adds delay, hampers progress, and makes preparedness difficult. In 2010, the Congressional Commission on the Prevention of Weapons of Mass Destruction Proliferation and Terrorism (WMD Commission) gave the nation an “F” grade for the “lack of U.S. capability to rapidly recognize, respond, and recover from a biological attack” and found that “especially troubling is the lack of priority given to the development of medical countermeasures—the vaccines and medicines that would be required to mitigate the consequences of an attack.”^2(p6) The NBSB wrote that “[t]he need for defense against the human consequences of exposure to CBRN agents has persisted for decades, with too little progress toward a comprehensive cache of MCMs,” “the resources provided have not been commensurate with the threat or with the tasks that must be accomplished,” and that what has been done to date are “fragmented half-measures.”^26(p17)

“Fragmented half-measures” was how a National Academies committee described the DoD effort to produce MCMs in 2004:

[T]his task has not been given sufficient priority by DoD to produce the intended results. Furthermore, the disjointed and ineffective management and inadequate funding of current efforts are clear indications that DoD leaders lack an adequate grasp of the commitment, time, scientific expertise, organizational structure, and financial resources required for success in developing vaccines and other pharmaceutical products.^31(p4)

Exemplifying a lack of commitment to MCMs, the BioShield Special Reserve Fund, intended to purchase MCMs for the stockpile, has been raided for funds. In FY2009, $412 million was taken for pandemic influenza MCMs.⁶⁰ In FY2010, $600 million was diverted: $305 million to fund advanced research and development in BARDA, and another $304 million to NIAID.⁶¹ The consequences of this not only harm current progress but further damage the willingness of private industry to risk having the U.S. government as a partner in MCM development.²⁷

Leadership and Accountability Required

There are many people working very hard in the government MCM development effort, but for modest success. The NBSB characterized it as “a good effort conducted by talented people, but lacking in centralized leadership and with poor synchronization of the agencies.”^26(p5) The NBSB recommended that the government “centralize its leadership for MCM development, procurement, and approval” so that all of the components are working toward the same goals.^27(p7) Centralized leadership has also been recommended by others.^31,62,63 The NBSB also recommended that metrics be adhered to that track accountability, so that the status of funding of MCM projects can be easily checked and investigated, such as the average times to achieve milestones or the average time to award contracts.²⁷

A clear operational strategy for using MCMs would help to track progress in developing and acquiring MCMs. Currently, such a concept of operations (conops) is lacking, which has led to policies that do not appear to be practical. For example, the latest BARDA strategy for 2011-2016 emphasized multipurpose MCMs, particularly antibacterial and antiviral drugs. While concentrating on broad-spectrum therapies over development of vaccines may appear to be an efficient use of diminishing resources, it differs from what common sense dictates would likely happen in the event of a biological weapons attack: One city may be attacked, but the rest of the country's population would want to be vaccinated so that they and their families would be protected from additional attacks. BARDA's strategic goals also appear to be overly optimistic: According to their plan, many of the products in the development pipeline will become mature enough for acquisition and regulatory review over the next 5 years, which exceeds expectations for large pharmaceutical companies.^14,64

The WMD Commission recommended that 1 high-level person be put in charge of the entire MCM process so that there would be continuity and more focus on meeting the goal to produce a final product.⁶⁵ The Obama administration has been criticized because, in contrast to the George W. Bush administration, there is no national security council position for biodefense countermeasures, and it has been maintained that this has resulted in biodefense becoming a subjugated responsibility.

The DoD may have fewer agencies involved in the MCM process, but the same problem exists: Early research (DTRA-JSTO) has been separate from advanced development (JPEO), and, as a result, products that had undesirable safety profiles or were known to be less effective were transitioned to advanced development, where they eventually fail. This situation is being corrected with a management overhaul and the addition of experts with management experience,^33,66 but the organizational separation of basic and advanced research persists.

We Can Do Better

The need for MCMs is well understood and is the stated goal of the White House as well as HHS, DHS, DoD, and other agencies, but successes thus far have been modest. This situation is detrimental to national security. Great things have been accomplished when there was a unanimity of focus and a willingness to coordinate and collaborate,⁶³ but those attributes cannot exist only in a time of crisis or the nation will never be prepared for a serious emergency. Further, it is a disservice to the many hard-working people involved in the MCM effort that they are not rewarded with final products of success.

In describing the generation of new vaccines after WWII compared to today, Kendall Hoyt recently wrote, “While pathogen security threats have survived the test of time, our ability to respond to them has not.”^63(p160) Since 2001, the slow progress of MCM development and procurement has received attention from NAS reviews, congressional commissions, newspaper articles, and advisory boards, which have given consistent advice to the MCM development effort. In those reports are many suggestions for specific ways to address the problems we have summarized, including adjusting contracting mechanisms and types, coordinating more closely the activities of various agencies, and increasing the participation of expert advisors from industry, and there have been strong recommendations for increased accountability and leadership.

We believe there are many different strategies that are likely to improve government MCM development, even in times of budget shortfalls. The main considerations, however, should be that industrial best practices should be followed, expert outside advice should be more influential, and a strong commitment to success should be a matter of national security.

Footnotes

Acknowledgments

The authors thank the Alfred P. Sloan Foundation for its support. Dr. Russell is a director at PaxVax and iBio and Scientific Advisor to Pharmathene.

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