The Public Health Emergency Medical Countermeasures Enterprise Innovative Strategies to Enhance Products from Discovery Through Approval: Workshop Summary (2010) / Chapter Skim
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Workshop Summary
Workshop Summary
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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)
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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.
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. 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.
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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.
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. Two of these briefings, #1 and #3, were developed into white papers that serve as Appendixes D and E of this workshop summary.
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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)
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government's medical countermeasures enterprise has made several important advances in improving the environment for countermeasure 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.
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. 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.
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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)
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• 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)
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. 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 countermeasures enterprise.
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The organization's primary focus will be education, ensuring that those in leadership positions in the federal government understand the imminent threat that biological weapons present. Larson urged workshop participants working with and within government on the countermeasures enterprise to request the Department of Homeland Security Office of Science and Technology's population threat assessment briefing.
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Over the past 2 years, Marinissen said, ASPR has been pursuing a strategy to work with international partners to build a sustainable global infrastructure for medical countermeasures. For developed countries, one effort under way uses the Global Health Security Initiative (GHSI)
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Reliance on an unwieldy and ineffective contracting process is a primary challenge across the board for all participants in the countermeasures enterprise. The Federal Acquisition Regulation (FAR)
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The Animal Rule says FDA may grant approval when "the results of those animal studies establish that the drug is reasonably likely to produce clinical benefit in humans." However, the guidance is significantly more restrictive than the Animal Rule itself and is being appropriately administered relative to the regulation of vaccines for biodefense, Mary Pendergast and Russell said. As will be discussed later in the report, the lack of central leadership impacts the ability to bring together the numerous agencies involved in the countermeasures enterprise.
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This also leads to continued uncertainty among the private sector about long-term, stable funding for countermeasures research and development. FDA Funding and Scientific Infrastructure To highlight the challenges facing FDA today, Gail Cassell, workshop chair and vice president, Scientific Affairs, at Eli Lilly and Company reviewed the findings of the report FDA Science and Mission at Risk (FDA, 2007)
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They are critical to the agency's role in development of medical countermeasures for biodefense. Although the world of drug discovery and development has undergone revolutionary change -- shifting from cellular to molecular and gene-based approaches -- FDA evaluation methods have remained largely unchanged over the past half century.
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Other participants concurred, noting that there is no surge capacity at the FDA, or that in fact it is already operating at surge capacity. Challenges Facing the Innovative Biopharmaceutical Industry A focus of the workshop was to identify how to improve innovation in ways that respond to national priorities, including how to better engage the nation's commercial drug, biologic, and device manufacturers in the countermeasures enterprise.
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So while the PHEMCE does provide some highly desirable predictability with regard to identification of the targets for discovery and development, companies have no information regarding the planning scenario for which they are trying to build a product. Although it is understandable that industry is not included in the PHEMCE, this leaves the countermeasures enterprise itself with a critical lack of business and capital markets expertise.
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Lack of market incentive aside, Thomas Monath of Kleiner Perkins Caufield & Byers pointed out, participation in the countermeasures enterprise has a huge opportunity cost -- taking away a company's ability to focus on its commercial opportunity market. Woollett, of Engel & Novitt, added that the industry is actively making products that are saving lives, and asked whether those lives are any less important than a putative potential threat.
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From a human resources perspective, advanced development manufacturing is really an apprentice model. University training to grow a pool of talent is limited, if it even exists, said Phillip Gomez of PRTM.
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A new antibiotic may be deemed so important that it is not used, reserved only for situations when all else fails, which presents a problem for companies who plan to recover some of their development costs though sales. Pricing of the new antibiotic is also a challenge, especially when the new drug has only been shown to 9 In filing an Abbreviated New Drug Application, the generic manufacturer does not have to conduct clinical trials; rather, it must demonstrate that the generic product is bioequivalent to the innovator drug.
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A unique scientific issue for countermeasures research is not having the disease to study in many cases, and the development of clinical disease/clinical injury models for trial simulation would be very useful to help speed the process. Innovation also needs to be brought to clinical trial design (e.g., adaptive clinical trial design)
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There is also liability in terms of what must be disclosed for informed consent in case of an emergency. End Users: Challenges for Public Health and Providers Although public health officials at the state and local levels are not directly involved in the research and development of countermeasures, they are responsible for ensuring the safety of the public by implementing whatever comes out of the countermeasures enterprise.
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EXAMPLES OF SUCCESSFUL COUNTERMEASURES DEVELOPMENT AND DEPLOYMENT Features of Successful Government Countermeasures Efforts Russell, identified earlier, presented several examples of products that were successfully developed by the government over the past 30 years, including the U.S. Army's development of products for adenovirus, meningococcus, hepatitis A, nerve gas, and malaria, and recent HHS efforts on smallpox.
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. BOX 5 Characteristics of Successful Government Product Development Programs • Direction and management by scientists experienced in the product development process, and empowered program managers in the government • Close working relationship with a major manufacturer/partner, with open, effective, and direct communication • Good leadership from both government and industry • In-house capability for process development, pilot manufacturing, and clinical trials • Full support of senior leadership and recognition of the need • Good working relationships with the FDA • Minimal interference by the contracting officers in the process and the communication between the government developer and the industrial developer • Little or no interference by Congress or lobbyists Transformational Medical Technologies Initiative A new DoD initiative is the Transformational Medical Technologies Initiative (TMTI)
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The TMTI strategy is to move hemorrhagic fever viruses therapeutics through IND into the regulatory critical path, move intracellular bacterial pathogen therapeutics through IND submission into the regulatory critical path, advance animal models suitable for pivotal animal studies supporting licensure, develop pathogen gene lists and attributes for assessing pathways and target identification in order to recommend medical countermeasures, and finally to integrate all of these activities to identify candidate medical countermeasures against unknown pathogens. To date, hemorrhagic fever viruses candidates are moving onto clinical trials, intracellular bacterial pathogen candidates are moving into clinical trials,
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Problem solving and flexible approaches need to be integrated into countermeasure development and emergency planning. For example, because of a study that was funded by NIAID through the Collaborative Antiviral Study Group, there were data that had not yet been published on the appropriate dosing of Tamiflu® for children with influenza.
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By managing the portfolio in this manner, the company has a clear regulatory pathway to approval and a definitive, definable market size that engenders interest on the part of private capital. The company can leverage that position if the opportunity arises to maintain a position in biodefense.
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David Gilbert of Providence Health & Services commented that efforts to develop new antibacterials for multidrug-resistant, gram-negative rods for the civilian population would benefit the countermeasures enterprise as well. Countermeasures as Orphan Drugs An orphan disease in the United States is one affecting fewer than 200,000 people.
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Many of these groups are partnering successfully with industry, approaching biotechnology companies directly and offering funding for research in their area of interest. Margaret Anderson of FasterCures described two new rare diseaserelated activities that, if implemented effectively, may also serve as an opportunity for improved medical countermeasure development -- the Cures Acceleration Network (CAN)
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Companies can no longer afford to have the source of ideas, the source of capacity or capability, and the source of funding all under one roof, he said. The Phenotypic Drug Discovery program is one example of the fully integrated pharmaceutical network approach.
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. Melese cited several models of open innovation, which may serve as valuable models for the countermeasures enterprise (Box 6)
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Public–Private Partnerships Public–private partnerships were of special interest to many participants representing all sectors of the countermeasures enterprise -- small biotechs, large pharmaceutical companies, academia, and government. While industry involvement in medical countermeasure product research and development is important, it cannot be relied upon to solve all the problems.
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government, and others have funded to advance the development of vaccines, drugs, and diagnostics for poor populations around the world include the Malaria Vaccine Initiative, the Human Hookworm Vaccine Initiative, and the Global Alliance for TB Drugs. As a result of those investments, Rajeev Venkayya of the Bill & Melinda Gates Foundation said, 86 different products are in the pipeline at various stages of development (the majority in preclinical development and Phase I clinical trials)
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government support organization. The purpose would be to help specifically advance single-use targets where large pharmaceutical companies or small biotechs could not be relied upon to take on such targets due to minimal profit margins.
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Strategic Investor Model Although every year $30–$65 billion in new investments from venture capital and industry support innovation and biotechnology, almost none of that money goes toward countermeasure development, commented Monath, of Kleiner Perkins Caufield & Byers (PhRMA, 2010)
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government agen cies and open to working with additional agencies • Engages a range of companies from start-ups to established compa nies, as well as universities, research laboratories, entrepreneurs, and venture capitalists • Development agreements are aimed at building capabilities for the In Q-Tel client base • Takes equity in the companies in which it invests • Concentrates on three broad commercial technology areas: Physical and Biological Technologies, Security, Software and Infrastructure ENGAGING INDUSTRY Incentives: Push vs. Pull Incentives used to engage the participation of commercial parties are generally thought of as either "push" or "pull" incentives, with push funding inputs, and pull funding or rewarding outputs.
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. A report by BIO Ventures for Global Health supports the use of market-based incentives, in particular, advanced market commitments (BVGH, 2006)
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o May provide a timing incentive. • Patent extensions, data protection • Liability protection Regarding market exclusivity as an incentive, it was noted that medical countermeasures have very small, variable, or even nonexistent markets, and such exclusivity will not give rise to a strong private-sector reaction.
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As a small business enterprise, her company would be able to obtain a Priority Review Voucher, but most likely could not use it for the company for another product. Because no company has redeemed one yet, it is unclear what value it would hold for a large pharmaceutical company if the small company would try to sell it.
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When industry looks at medical countermeasures in terms of the larger company portfolio, it sees low margin and low volume. Consequently, the U.S.
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, participants discussed a host of other potential paradigms, strategies, and tactics for consideration. Outsourcing Program Management Several participants suggested variations of a paradigm where the government would outsource the facilitation responsibilities associated with the coordination of countermeasures development activities to a single entity.
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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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The countermeasures enterprise should have a focus on multiuse products and multiuse platform technologies that span the entire public health product-development portfolio (i.e., existing and emerging public health problems and deliberately released public health problems) , NIAID's Fauci said.
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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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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.
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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.
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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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• 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.
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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.
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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.
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There is no one specific right incentive, or one specific model that is best suited to advanced development of countermeasures against chemical, biological, radiological, and nuclear agents. No single player is ideally positioned to meet the needs of the medical countermeasures enterprise.
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These approaches are not mutually exclusive, and the ideal countermeasures 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.
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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.
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