INTRODUCTION1

“We are launching a new initiative that will give us the capacity to respond faster and more effectively to bioterrorism or an infectious disease—a plan that will counter threats at home and strengthen public health abroad.”

—President Barack Obama, 2010 State of the Union Address


Safe and effective medical countermeasures, including vaccines, drugs, and diagnostics, are critical for responding to large-scale public health emergencies. Such situations, be they natural (e.g., pandemic influenza) or man-made (e.g., terrorism), have the potential to rapidly overwhelm public health and medical systems. America’s national security depends on having appropriately licensed chemical, biological, radiological, and nuclear medical countermeasures in its arsenal of defenses.

The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE or countermeasures enterprise)2 encompasses diverse

1

The workshop was organized by an independent planning committee whose role was limited to the identification of topics and speakers. This workshop summary was prepared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or verified by the Forums or the National Academies, and should not be construed as reflecting any group consensus. Furthermore, although the current affiliations of speakers and panelists are noted in the report, many qualified their comments as being based on personal experience over the course of a career, and not being presented formally on behalf of their organization (unless specifically noted).

2

The PHEMCE, led by the Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response, includes the Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health. Interagency partners include the Department of Homeland Security, the Department of Defense, the Department of Veterans Affairs, and the Department of Agriculture. The



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INTRODUCTION 1 “We are launching a new initiative that will give us the capacity to respond faster and more effectively to bioterrorism or an infectious disease—a plan that will counter threats at home and strengthen public health abroad.” —President Barack Obama, 2010 State of the Union Address Safe and effective medical countermeasures, including vaccines, drugs, and diagnostics, are critical for responding to large-scale public health emergencies. Such situations, be they natural (e.g., pandemic influenza) or man-made (e.g., terrorism), have the potential to rapidly overwhelm public health and medical systems. America’s national security depends on having appropriately licensed chemical, biological, radiological, and nuclear medical countermeasures in its arsenal of defenses. The Public Health Emergency Medical Countermeasures Enterprise (PHEMCE or countermeasures enterprise) 2 encompasses diverse 1 The workshop was organized by an independent planning committee whose role was limited to the identification of topics and speakers. This workshop summary was pre- pared by the rapporteurs as a factual summary of the presentations and discussions that took place at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants, and are not necessarily endorsed or veri- fied by the Forums or the National Academies, and should not be construed as reflecting any group consensus. Furthermore, although the current affiliations of speakers and pan- elists are noted in the report, many qualified their comments as being based on personal experience over the course of a career, and not being presented formally on behalf of their organization (unless specifically noted). 2 The PHEMCE, led by the Health and Human Services (HHS) Office of the Assistant Secretary for Preparedness and Response, includes the Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health. Interagency partners include the Department of Homeland Security, the Department of Defense, the Department of Veterans Affairs, and the Department of Agriculture. The 1

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2 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE partners from across federal, state, and local governments, industry, and academia. Despite its successes, certain structural, strategic, and technical elements of the countermeasures enterprise continue to impede research, development, and production of medical countermeasures. The National Institutes of Health (NIH) and the Department of Defense (DoD) support much of the basic research in the relevant health and disease areas. However, this research is not always aligned with the top priorities identified based on threat assessments, which limits the number of discoveries that are applicable for further development as medical countermeasures. Once potential candidates for advanced development are identified, they are often not yet at a stage of development where they can be handed off to the Biomedical Advance Research and Development Authority (BARDA) 3 in the U.S. Department of Health and Human Services (HHS). Furthermore, because the commercial market is limited for most medical countermeasures, it can be difficult to engage private-sector pharmaceutical and biotechnology companies to participate in the development and manufacturing of these products. To begin to address the efficiency and effectiveness issues of the PHEMCE, on December 1, 2009, HHS Secretary Kathleen Sebelius charged the “Office of the Assistant Secretary for Preparedness and Response [ASPR] to lead a review of its entire public health countermeasures enterprise, to be completed in the first quarter of next year.” Subsequently, in response to a request from the Assistant Secretary, the Institute of Medicine’s (IOM’s) Forum on Medical and Public Health Preparedness for Catastrophic Events and Forum on Drug Discovery, Development, and Translation jointly convened a workshop on February 22–24, 2010, titled The Public Health Emergency Medical Countermeasures Enterprise: Innovative Strategies to Enhance Products from Discovery Through Approval. The workshop was designed to examine federal policies and activities that affect medical countermeasure discovery, development, and approval, and to explore potential opportunities to enhance the countermeasures enterprise by PHEMCE mission is to optimize national preparedness for public health emergencies, specifically by the creation, stockpiling, and use of medical countermeasures. 3 BARDA’s mission is to provide countermeasures for chemical, biological, radiological, and nuclear threats, pandemic influenza, and emerging infectious diseases through prod- uct requirement setting, product development, stockpile acquisition/building, manufactur- ing infrastructure building, and product innovation. BARDA resides within ASPR, man- ages the PHEMCE, and has the procurement authority for Project BioShield acquisitions using the Special Reserve Fund (http://www.hhs.gov/aspr/barda/index.html).

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WORKSHOP SUMMARY 3 evaluating existing models or systems having similar goals of developing medical products with low commercial viability (Box 1). 4 BOX 1 Workshop Objectives • Identify and discuss strategies to optimize the federal public health emergency medical countermeasures enterprise, and explore resources and/or other supporting components needed for accomp- lishing goals of countermeasure discovery, development, approval, and production. • Examine strategies to further enhance the translation of early phase investments in basic science into potential public health interventions. • Identify and discuss models for enhancing current partnerships and establishing new ones among federal programs, innovators, and the commercial marketplace to enhance our nation’s capabilities to meet public health emergency preparedness goals. • Consider market forces acting on the advanced development biodefense community (pharma/biotech) that incentivize/ disincen- tivize efforts to develop and license products in support of the national response. • Examine ways the regulatory oversight process for public health emergency medical countermeasures might evolve and identify ways to enable more efficient approval and use. • Review the innovative approaches being used to advance drug development for orphan diseases (i.e., rare, neglected, or tropical diseases) or any other area that does not have a ready and sustainable commercial market (e.g., oncology therapeutics) and identify the shared challenges and opportunities for strategies that might be adopted by the countermeasures enterprise. About This Summary This document highlights and summarizes the work presented at the workshop with the hope that this information will help federal officials to conduct a thorough review of the pipeline through approval spectrum of our national programs and to assist in the ultimate goal of improving the efficiency and effectiveness of the countermeasures enterprise. When- ever possible, unique ideas or concepts presented at the meetings are at- tributed in this report to the individual who first advanced those con- cepts. In situations where many attendees made similar points, the 4 Audio files, slides, and the meeting transcript are available for download via the Prepar- edness Forum’s website, http://www.iom.edu/preparednessforum.

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4 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE recurring themes are identified. The final section of the summary lists a number of suggestions for improving the medical countermeasures en- terprise, including a number of suggestions focused on countermeasure regulation and licensure. They are compiled here as part of the factual summary of the workshop, and should not be construed as reflecting con- sensus or endorsement by the workshop, the Forums, or the National Academies. Investigating details about the feasibility and implementation of these ideas were beyond the scope of the workshop and this summary. Charge to Workshop Participants In her opening comments and charge to the workshop participants, the HHS Assistant Secretary for Preparedness and Response, Nicole Lurie, said that time and time again, it has been apparent that the United States does not necessarily have the countermeasures needed to respond to a public health emergency, regardless of whether it is natural or initiated by humans. Although signs of progress have been apparent in recent years, much more work is needed to protect the nation against the range of potential threats. Using the recent H1N1 influenza pandemic as an example, she also noted that even when countermeasures are available, low levels of public acceptance of the countermeasure can inhibit an effective response, and significant public education efforts may be required. A primary goal of the end-to-end review of the public health countermeasures enterprise is to understand, in enough detail to be actionable, the challenges related to the current approach to develop countermeasures and the opportunities to improve them. Many of the challenges are already well known. Lurie urged workshop participants to be frank and forthcoming in offering creative solutions, calling for a very granular and specific focus on understanding the needs and developing strategies for systemic change. ASPR is seeking to understand how the incentive structures, policies, and procedures are, or are not, aligned with the needs of the pharmaceutical and biotechnology industries, the United States government, and the American people. The discussions at the workshop also helped inform the deliberations that were under way by the National Biodefense Science Board (NBSB), 5 which was charged by 5 The National Biodefense Science Board was created under the authority of the Pan- demic and All-Hazards Preparedness Act (Public Law 109-417) “to provide expert advice to the Secretary on scientific, technical and other matters of special interest to HHS re- garding current and future chemical, biological, nuclear and radiological agents, whether naturally occurring, accidental or deliberate. The Board may also provide advice and

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WORKSHOP SUMMARY 5 HHS to conduct a parallel examination of the related strategic management, leadership and accountability structure of the PHEMCE (NBSB, 2010a). BACKGROUND To aid their review, ASPR commissioned a set of briefings from PRTM Management Consultants that was presented at the workshop (Box 2). Two of these briefings, #1 and #3, were developed into white papers that serve as Appendixes D and E of this workshop summary. BOX 2 Highlights of Commissioned White Papers Case Studies of the HHS Medical Countermeasure Programs: Briefing #1 Select case studies of Department of Health and Human Services (HHS) medical countermeasure programs were examined (anthrax, smallpox, hematopoietic acute radiation syndrome, viral hemorrhagic fevers, broad-spectrum antibiotics for bacterial threats) to evaluate: What were the successful elements of each program? What were the setbacks, real or perceived failures, of each program? What improvements could be made to improve future programs? Although there is not one event/characteristic that portends failure or guarantees success, there are shared risks identified in each case study, and some common factors that appear to increase the likelihood of success. Three factors that impact successful drug development are a failure in efficacy, a failure in safety (accounting for about two-thirds of failures), and failure in commercial considerations (e.g., cost to bring the product to market, perceived profitability of the product). Common factors of successful programs are strong leadership from the top, realistic expectations, experienced people, mature organizations, and adequate resources. guidance to the Secretary on other matters related to public health emergency prepared- ness and response” (http://www.hhs.gov/aspr/omsph/nbsb/).

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6 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE Optimizing the Medical Countermeasure Product Pipeline from the Science Base Through Advanced Development: Briefing #2 This briefing addresses how the product pipeline can be increased to improve the chances of producing approved products for the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE), identifying challenges and looking to other programs for solutions. Although no single model or specific solution ensures success, observations from comparative research and development models sug- gest that better management structures, strategic decision making, better definition of requirements, target product profiles, and defined metrics of success may increase the PHEMCE pipeline of candidate products. Successful models have incorporated partnerships to optimize limited funding, market assurance, and pursuing products with multiuse potential. Synthesis of Business Models and Economic and Market Incentives for Vaccines and Therapeutics: Briefing #3 Increasing the level and mix of pharmaceutical and biotechnology company engagement can bring critical knowledge and experience to the PHEMCE. Based on interviews and the literature, three major deterrents to industry engagement in medical countermeasures development were identified: requirements (insufficient granularity/clarity about what the government wants, what companies are being asked to make, how it will be sold); return on investment (unpredictable, unsustainable market); and uncertainty in the regulatory pathway. This briefing explored multiple push and pull incentives for attracting industry participation that have been proposed or implemented in other contexts, but have not yet been applied to medical countermeasures development. No one push or pull incentive is sufficient to attract ex- perienced companies to participate in medical countermeasures de- velopment. Similarly, there is no “silver bullet” combination of incentives. The right response depends on context. A report by the NBSB titled Optimizing Industrial Involvement with Medical Countermeasure Development was also presented as background for the discussions. John Grabenstein of Merck Vaccines, who is a member of the NBSB, said numerous chemical, biological, radiological, and nuclear countermeasures are still needed beyond those licensed medical countermeasures currently available in the Strategic National Stockpile (NBSB, 2010b). The Project BioShield Act provided for a procurement fund to foster the development of medical products that did not yet exist. Although subsequent legislation attempted to target resources for the advanced development of countermeasures, this funding has never been adequate. Although it is important to ensure the procurement resources remain available, Grabenstein explained, far

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WORKSHOP SUMMARY 7 greater resources are currently required to ensure necessary countermeasures research and development. In describing the findings from the NBSB report, Grabenstein said the U.S. government’s medical countermeasures enterprise has made several important advances in improving the environment for counter- measure development, including the creation of BARDA, the option for an Emergency Use Authorization (EUA), 6 and the Animal Rule, 7 as well as the new HHS and DoD commitment toward an “Integrated Portfolio,” and the PHEMCE holding stakeholder meetings and workshops. How- ever, barriers hindering industry involvement in the development of countermeasures remain, including inadequate and inconsistent funding, opportunity costs (e.g., distractions from other company priorities), eco- nomics (e.g., financial margins and low volumes), uncertain regulatory pathways, finite human capital (a limited number of people having the necessary, specialized skill sets), the complexity of working with multi- ple federal agencies, inadequate federal government understanding of the commercial biopharmaceutical enterprise, and the use of an acquisition system that was originally created to procure complex mechanical equipment such as aircraft, vehicles, and ships (NBSB, 2010b). To begin to address these issues, the NBSB report offers a list of eight specific recommendation for the government, which are further detailed in the full report (Box 3). 6 Under Section 564 of the Federal Food, Drug, and Cosmetic Act, as amended by Project BioShield Act of 2004, the Commissioner of the Food and Drug Administration may authorize the use of an unapproved medical product, or an unapproved use of an ap- proved medical product, during a declared emergency involving a heightened risk of attack on the public or U.S. military forces, or a significant potential to affect national security (http://www.fda.gov/RegulatoryInformation/Guidances/ucm125127.htm). 7 The Animal Rule allows for the approval of drugs (21 C.F.R. 314.600) or biological products (21 C.F.R. 601.90) based on evidence of effectiveness from studies in animals under certain conditions when human efficacy studies are not ethical or feasible.

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8 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE BOX 3 Specific Recommendation of the National Biodefense Science Board to the U.S. Government 1. To harness the national industrial base, the U.S. Congress and the Executive Branch must provide adequate, consistent funding (for both advanced development and procurement). 2. The U.S. government must accelerate the pace of medical counter- measure development and acquisition and optimize distribution methods. 3. The U.S. government must centralize its leadership for medical counter- measure development, procurement, and approval. 4. The U.S. government must demonstrate long-term commitment to its industry collaborators. 5. The U.S. government must create, sustain, and enhance innovative partnerships with private industry. 6. The U.S. government should expand medical countermeasure markets to include international partners, state, local, and tribal governments, laboratorians, and first responders in each of these sectors. 7. The U.S. government must do a better job of preparing for emergencies that can be anticipated. 8. Various departments, agencies, and entities of the U.S. government must act in concert to ensure success. SOURCE: NBSB (2010b). The Public Health Perspective on Medical Countermeasure Development, Acquisition, and Use A key challenge for the countermeasures enterprise is how to achieve the greatest health impact in the face of diminishing resources. Thomas Frieden, director, Centers for Disease Control and Prevention (CDC), said an effective response starts with several basic principles, as follows: • Define what is needed. Identify and characterize the threats; identify the at-risk groups and the specific needs of different at-risk subgroups (e.g., pediatric use); determine if new countermeasures are needed; and interface with the intelligence community. Defining what is needed involves a combination of pathogenesis, patho- physiology, the likelihood of use, and the likelihood of dispersal. • Decide what to make, and make it. Assess countermeasure availability; secure EUA as needed; develop stockpiling, distribution, and dispensing logistics; plan for countermeasure use and response; and secure licensure. This will require significant and consistent

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WORKSHOP SUMMARY 9 investments, and a consistent way to work with industry pro- ductively, collaboratively, and perhaps most important, predictably. • Ensure that the countermeasures that are developed reach the people who need them most, using everyday systems that can be scaled up. This may require investing in the establishment or enhancement of more everyday systems (e.g., laboratory, epidem- iological, vaccination, or healthcare systems). In this regard, Frieden cited the public health response to the recent H1N1 influenza pandemic. Over 100 million doses of vaccine were distributed with next-day delivery to more than 70,000 sites for vaccination. Despite several recalls, the distribution system for H1N1 vaccination worked extremely well because it used the infrastructure of the Vaccines for Children Program. In contrast, there were significant challenges with the distribution of antiviral medications because the public health system does not have an everyday route for dissemination. • Monitor the countermeasures and communicate with the public. Assess effectiveness, determine if supplies are sufficient to meet demand, determine how to increase demand to improve protection of the public, identify and interpret adverse effects, and look for changes in susceptibility of the pathogen to the countermeasure. Public acceptance of countermeasures depends on monitoring safety signals, analyzing risk, and communicating results frequently. Going forward, Frieden said, better countermeasure delivery will require better intelligence about the presence, modification, and weaponization of different agents; storage and deployment logistics, evidence-based clinical recommendations and algorithms for use; and laboratory capacity that can adapt to the unexpected. The FDA Perspective on the Countermeasures Enterprise: Moving Forward In his keynote address to the workshop, Jesse Goodman, chief scientist and deputy commissioner for science and public health (acting) of the Food and Drug Administration (FDA) emphasized that the time is right for action on medical countermeasures and pandemic preparedness. The public health and national security needs are clear; there are multiple insights from the accomplishments and limitations of Project BioShield and from the experiences with 2009 H1N1 influenza; the public, policy makers, and the administration are interested; and there is bipartisan engagement and collaboration across agencies.

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10 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE In that regard, Goodman highlighted the FDA’s February 24, 2010, announcement with the NIH of a new partnership to advance translation of innovations from basic science to products, including a focus on regulatory science. The agencies will establish a joint leadership council, and jointly issue a Request For Applications with the intent of awarding $6.75 million for research on novel technologies and approaches applicable to the development and regulatory review of medical products. Going forward, Goodman said, FDA is focusing on the following four key principles: • End-to-end partnering, including highly interactive and collaborative engagement and outcomes-oriented management. This means defining how products will be used up front, determining the pathways necessary to evaluate and regulate the product, and identifying scientific gaps. Making regulatory requirements clear is needed to reduce uncertainty. Oversight and review of progress at high levels is also necessary. • Increased attention to regulatory science, to expand agency capacity and knowledge and thereby enhance the quality and integrity of FDA decision making. Develop, assess, and provide tools, methods, models, standards, guidance, and pathways to evaluate product safety, efficacy, and quality (e.g., biomarkers; surrogate endpoints; adaptive and other flexible clinical trial designs; rapid scale-up of production; and rapid methods to assess purity, potency, quality, and contamination). Key elements include leadership and coordination within the agency, training and development of FDA staff, and targeted research within the agency. • More agile platform and multiuse technologies (e.g., vaccine, diagnostic, or monoclonal platforms) that can be rapidly adaptable to address new pathogens. (Goodman noted that platforms will not perform for all pathogens and diseases, and concrete experience with real products is needed to provide enhanced predictability of results and reduce regulatory requirements.) • Policies that meet public health needs. For example, although the EUA is a public health success, it can be cumbersome; the Animal Rule needs to reexamined in light of experience and scientific needs and realities; and consideration of accelerated approval approaches needs to be expanded. Are there other approaches or statuses short of full approval that should be considered?

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WORKSHOP SUMMARY 11 Government Procurement of Science Michael Kurilla, director of the Office of Biodefense Research Affairs at the National Institute of Allergy and Infectious Diseases (NIAID), explained that from the NIH perspective, there are three basic mechanisms for procuring science, with increasing focus and control. The first mechanism is geared toward increasing basic science knowledge and generating novel concepts, and the primary mechanism is grants. When the intent is vetting concepts (i.e., reduction to practice to demonstrate feasibility), the mechanism usually involved is a cooperative agreement, including small business grants and technology- transfer arrangements. When the goal is to take a product forward, from target identification to lead to candidate to human testing, the NIH relies on contracts with defined deliverables. In addition to funding, NIH provides a number of services. Specialized services are available as needed and include, for example, sequencing, reagents, screening, animal model development, and containment. Gap-filling services are focused efforts to advance products, and involve traditional preclinical and clinical drug and vaccine development activities. To facilitate the discussions, Kurilla offered a quick review of programmatic terminology (Table 1). TABLE 1 National Institutes of Health Programmatic Terminology Term Activities Management and Review Project Single effort focused on a specific Success in meeting milestones and candidate countermeasure against a time lines specific agent Portfolio Focused effort typically organized Adequacy of individual projects to around a single threat agent with cover the range of desired candidates, multiple countermeasures technical approaches, and developmental maturity Program Overall effort focused on multiple Progress across total threat space with countermeasures against multiple emphasis on desired approaches threats PARTNERS IN A SINGLE MISSION, DIVERSE CONCERNS AND CHALLENGES Over the course of the workshop, participants highlighted some of the challenges, gaps, and barriers facing those involved in the counter- measures enterprise. While by no means a comprehensive review, these are some of the more pressing concerns that informed the subsequent

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46 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE One caution noted by Gomez of PRTM is that while it is fairly easy to know when a product has failed, it can be very difficult to tell when a platform has failed because there is always an improvement, always a new disease target. Revised PHEMCE Implementation Plan As discussed above, a challenge for industry is that the PHEMCE implementation plan itself provides limited guidance in that it is essentially a list of pathogens and agents of interest to the government. Rose proposed a use-based medical countermeasure acquisition matrix (Figure 2). The concept of operations is similar across all of the organisms listed. There is a need for pre-event prophylaxis, particularly for the military and first responders. Treatments are needed for people who develop symptomatic illness when an outbreak occurs. For those who are exposed but not yet ill, postexposure prophylaxis is needed to keep them from developing illness. Rose noted that the matrix is for healthy adults and a similar matrix for children or the elderly would show significantly more yellow and red. Threat Pre-Event Treatment Post-exp. General Prophylaxis Prophylaxis Prophylaxis Antibiotics +/− Anthrax Vaccine Antibiotics, Vaccine MoAb Vaccine Smallpox Vaccine None Vaccine Vaccine Plague None Antibiotics Antibiotics None Tularemia None Antibiotics Antibiotics None Viral Hem. None None None None Fevers FIGURE 2 Use-based medical countermeasure acquisition matrix (Healthy Adults 18– 64). Green: product is available; yellow: product is not yet approved; red: no products for development. SOURCE: Eric Rose. 2010. Presentation at IOM Workshop; The Public Health Emergency Medical Countermeasures Enterprise: Innovative strategies to enhance products from discovery through approval.

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WORKSHOP SUMMARY 47 EXISTING REGULATORY TOOLS AND APPROACHES THAT CAN BE APPLIED TO ADVANCE COUNTERMEASURES DEVELOPMENT Boris Lushniak, assistant commissioner for Counterterrorism Policy at FDA, said the agency’s mission is very clear: safety, efficacy, and quality. Lushniak and Jeanne Novak, of CBR International Corp., both drew attention to policies and programs already in place that could be used to facilitate medical countermeasure development. However, throughout the workshop, it was repeatedly noted that there is a need for a clear regulatory pathway necessary to evaluate and regulate the biodefense products as well as a number of additional gaps and associated opportunities. Opportunities for Accelerating Approval of Medical Countermeasures: Evolving the Regulatory Framework Numerous individual suggestions were made about addressing the regulatory aspect of the medical countermeasures enterprise. They are compiled here as part of the factual summary of the workshop, and should not be construed as reflecting consensus or endorsement by the workshop, the Forums, or The National Academies. They are as follows: • Fund, support, and enable regulatory science. Develop, assess, and provide tools, methods, models, standards, guidance, and pathways to evaluate product safety, efficacy, and quality (e.g., biomarkers; surrogate endpoints; adaptive and other flexible clinical trial designs; rapid scale-up of production; rapid methods to assess purity, potency, quality, contamination). • Declare medical countermeasure to be a priority at the FDA, which would entail providing security clearances to senior FDA employees and briefing all medical officers across the entire agency about the real risks and the immediate need for products. • Create a designation indicating that a program is relevant to national security and establish priority review for medical countermeasure applications. For products so designated, FDA can then provide additional assistance, perhaps some form of priority review or acceleration of time lines consistent with the product being part of a national security countermeasures development program.

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48 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE • Consider creating an alternative approval mechanism for medical countermeasures with criteria more stringent than EUA and less stringent than normal licensure for commercial products. • Formalize the EUA process. The existing EUA mechanism works well as an emergency response process, but it is not a preparedness mechanism. A formal EUA approval process would use existing criteria for the EUA, with the exception of the actual declaration of an emergency, and would differ from the current process, in which submission of pre-EUA data is encouraged, but no response is required, and typically no response is generated. • Balance data needs according to risk/benefit. Because medical countermeasures will be used in situations of grave risk, the amount of data needed for approval may be less than that for a more mainstream product. Early HIV interventions were cited as a parallel situation. • Facilitate communication with product sponsors. In-person meetings and site visits between the FDA and with companies developing medical countermeasures could be done with increased frequency and flexibility, without having to formally request the existing FDA A, B, and C meeting categories. 12 • Send FDA agency staff into the field to assist companies as needed. This was done, for example, when Genentech was developing the first recombinant human growth hormone, a product for which there was urgent need. An FDA senior chemist spent 3 months at Genentech, working with its staff to prepare manufacturing for approval. • Abandon the Draft Guidance on the Animal Rule, which is significantly more restrictive than the Animal Rule itself. The Rule says FDA may grant approval when “the results of those animal 12 Through the 1997 FDA Modernization Act, the FDA established three main categories of meetings—A, B, or C—that describe the various types of formal industry meetings that occur (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmission Requirents/ElectronicSubmissions/DataStandardsManualmonographs/ucm071774.htm).

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WORKSHOP SUMMARY 49 studies establish that the drug is reasonably likely to produce clinical benefit in humans.” • Emphasize emergency preparedness throughout the FDA. Instill cultural change though an agency-wide focus on emergency preparedness/national security in the regulatory environment, and encourage use of many of the tools that already exist in the current regulatory laws and regulations, in a more efficient, focused way. • Provide regulatory and licensure guidance to funding agencies on development programs. FDA personnel can assist funding agency (HHS and DoD) reviews of medical countermeasures development programs. This would facilitate progress by providing a “unified” development method. Specialized Review and Development Teams could be formed at the FDA (center and division levels). Funding agencies would have access to the Specialized Review and Development Teams in order to seek expert FDA opinion about progress of a particular development program. • Reflect FDA data needs in NIH trial design and conduct. NIH funds many large clinical trials, which are then incorporated into an application for product approval. Many times the data are not adequate to support FDA decision making in terms of safety, efficacy, and labeling claims. If FDA is at the table with NIH when these trials are being planned, and when they are being executed, they can make sure the supporting data are available when needed for regulatory decisions. The Way Forward: Themes from the Workshop Additional suggestions regarding a wide variety of areas relevant to medical countermeasures development were presented by individuals during the workshop and are compiled here. Investigating details about the feasibility and implementation of these ideas were beyond the scope of the workshop. The additional suggestions are the following: • Institute a single, unified management structure for the federal countermeasures enterprise. The hallmark of a successful developmental program is strong leadership that can have a singular focus on developing products—a system that could direct basic and applied research and have the power to force alignment of all the

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50 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE components. BARDA currently does not have this authority. However, consideration should be made for the complementary, but separate, missions of HHS and the DoD. • Facilitate improved end-to-end partnering between federal agencies (NIH, ASPR/BARDA, DoD, FDA), industry, and academia throughout research and development of medical countermeasures. • Declassify threat analysis data to allow transparency for potential product requirements, and thus to improve the understanding among the public, legislators, and industry about the scope of the threat. • Provide additional venues for classified briefings for all segments of the countermeasures enterprise, including private-sector stakeholders. Two examples are the Joint Civilian Orientation Conference sponsored by DoD and the FBI’s National Security Higher Education Advisory Board, where leaders in business and academia get security clearance, are briefed on issues, and contribute to discussions on national security matters. Something comparable could be established for the leadership from pharmaceutical and biotechnology companies. • Develop target product profiles. Define the product, including both the indication (i.e., disease/condition to be treated) and what an appropriate product would be to use in a public health emergency. Prospectively establish the metrics that define success for a product, then build an experimental plan that assesses whether a product has critical attributes. • Utilize grants and contracts to incentivize research and development in multi-use agents. BARDA, and other government grants and contracts, as well as milestone payments serve as important incentives for the development of multi-use agents, in particular for agents like antibiotics, which do not always have a very high profit margin. • Empower program managers. Provide increased authority to program managers to develop a vision of what a successful project or program encompasses, and then to go out and secure the resources

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WORKSHOP SUMMARY 51 necessary to put that vision together. Small companies would benefit from project managers and/or FDA being able to reach out proactively at the beginning of a contract to discuss how the company could avoid potential hurdles and common mistakes related to complex areas such as the Animal Rule, GLP toxicology studies, etc. • Use the Federal Acquisition Regulation to create commercial markets for biodefense products. FAR § 12.102(f)(1) states that contracting officers “may treat any acquisition of supplies or services that, as determined by the head of the agency, are to be used to facilitate defense against or recovery from nuclear, biological, chemical, or radiological attack, as an acquisition of commercial items.” This establishes the authority to designate a countermeasure as a commercial item (not a cost-plus item) that can be compared to other drugs and vaccines already in the commercial markets. • Simplify the intellectual property system and improve alignment between FDA approval and when a patent is granted. Ascribe value to the data themselves. The data are what determine whether the product is of any value to the public. Consider a full 20-year patent term for government-chosen medical countermeasures and a data protection period of 20 years, both running from the day of FDA approval. • Establish incentives and public private partnerships to encourage greater investment by the private sector. Particular focus should also be made on how to incentive the development of countermeasures for children and other special populations. • Ensure integrity of Project Bioshield funds and increase funding for countermeasures research and development. It is important to guarantee that procurement resources remain available, but far greater resources are currently required to ensure necessary countermeasures research and development. Removing funds from Project Bioshield’s Reserve Fund for research and development could have serious repercussions on the government’s ability to guarantee a suitable marketplace for future countermeasure procurement. It also would contribute to uncertainty among the private sector about long-term, stable funding for countermeasures research and development.

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52 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE • Commit to multiyear federal funding of CBRN/pandemic countermeasures to ensure companies are able to maintain a continuous development program. • Consider a tax benefit for equipment purchased for use in the development or manufacturing of medical counter-measures. The Department of the Treasury could approve an accelerated depreciation schedule for equipment that is required for biodefense products exclusively (i.e., that has to be separate from the rest of the equipment in a research and development or manufacturing facility). • Make the federal government the defendant in all the tort claims resulting from countermeasures. The government is the defendant in the Vaccine Injury Compensation Act, but not in the existing PREP Act. Legislatively eliminate the cause of action and replace it with this administrative compensation system. • Make suspension of state liability in a federally declared emer- gency a condition for receipt of biodefense money for the states. The federal government cannot force states to pass legislation, but it can withhold preparedness funding if the state fails to comply with the conditions of the grant. • Institutionalize capacities. Planning is important, but adaptability and rapid responses are critical elements for success. Integrate prob- lem solving and flexible approaches into countermeasure develop- ment and emergency planning. Institutionalize capacities throughout the countermeasures enterprise rather than reserve them for a crisis. The Illinois Department of Public Health, for example, sent 42 senior staff members to be trained in the National Incident Management System, providing them with useful background on an organizational approach to managing problems. These skills were of great value during the 2009 H1N1 pandemic. • Sponsor a contracting office training course, covering best practices to address countermeasure development, licensure, manufacturing, and procurement with biodefense, and updating officers on available options.

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WORKSHOP SUMMARY 53 • Establish more agile platforms and multiuse technologies (e.g., vaccine, diagnostic, or monoclonal platforms) that can be rapidly adaptable to address new pathogens. • Engage end users, specifically public health professionals and healthcare providers, in requirement setting. Incorporating end- user perspectives in the requirement setting for product development will help ensure that the final product that is stockpiled or distributed will be able to be administered effectively and efficiently to the tar- get population. In this regard, the needs of special populations, in- cluding children, are part of planning, research, and development. • Improve public engagement. Robust and continued public engagement helps to ensure the legitimacy of the counter-measures enterprise, communicates the risk, communicates those plans currently in place, and helps produce the best possible result. Engage faith-based institutions. Use the educational system; develop a message that becomes part of a school curriculum. Work to dispel myths and misperceptions. • Create technical centers of excellence to help ensure the necessary expertise, including dedicated capabilities and core resources and manufacturing facilities. • Invest in career development strategies to ensure the necessary scientific and regulatory expertise. Define a curriculum at universities that could support the countermeasures enterprise. The government could sponsor educational opportunities to improve human capital capacity. For example, a fellowship for graduate degree candidates established by FDA and BARDA could enrich the countermeasures enterprise and bring new people in the system. CONCLUSION Deliberate acts of bioterrorism and emerging natural infections will continue to be a major public health concern. There is no one specific right incentive, or one specific model that is best suited to advanced development of countermeasures against chemical, biological, radio- logical, and nuclear agents. No single player is ideally positioned to meet the needs of the medical countermeasures enterprise.

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54 EMERGENCY MEDICAL COUNTERMEASURES ENTERPRISE There are at least two different ideological approaches to the development of medical countermeasures, as follows: • Consider it to be a critical national security issue, with an urgent need to develop countermeasures for an imminent threat. • Focus on addressing important unmet medical needs that are present today, and while these needs are somewhat different, some benefit can be derived for the national security mission in the end. These approaches are not mutually exclusive, and the ideal counter- measures enterprise would have a multiuse focus on existing, emerging, and deliberately released threats. However even if cross-indications are feasible, a national threat may, or likely will, occur without notice. Therefore, without emphasis upfront on the national security implica- tions at the federal level on development pathways, medical countermea- sures are less likely to be available when needed. The use of these two approaches in combination could provide the basis of a robust develop- ment strategy and would allow federal systems to be in place to deal with imminent threats, in distinction from standard drug development processes. Assistant Secretary Lurie reminded attendees that engaging industry in the countermeasures enterprise is essential. A dramatic transformation is needed in the way the federal government interacts with industry. Government and industry must come together as trusted partners, and this relationship must be sustained—not only in a time of a crisis. There is no one push or pull incentive that is sufficient to attract experienced companies to the enterprise. Similarly, there is no “silver bullet” combination of incentives that suits all situations. Seeking private-sector participation in developing these products is not about saving the public money. It is about bringing innovation, human capital, entrepreneurship, and private-sector expertise to bear on important public health issues. Market incentives cost money. The U.S. government should be willing to pay for countermeasures, to the extent that there are national security and public health needs. Throughout the workshop it was frequently asserted that partners in the countermeasures development enterprise should be able to expect the following:

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WORKSHOP SUMMARY 55 • A clear articulation of the threats • A very clear articulation of the target product profile (indication, formulation, manufacturing needs, predicted demand) • Clear time lines (what activities are on an urgency timeline vs. a long-term timeline) • Predictability of finance (e.g., if a company delivers according to specifications, there will be a purchaser on the other end, and that purchaser will be the U.S. government) • Predictability from the regulatory environment Regardless of the approach taken, all participants in the medical countermeasures enterprise should remember the end goal: ensuring the health of the people. The medical countermeasures research and devel- opment enterprise should continue to develop and implement models that, while respecting industry and governmental needs and goals, foster collaborative relationships among government and industry to ensure maximum use of their respective strengths and capabilities for the protec- tion of the nation’s health.

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