From: Fauci, Anthony (NIH/NIAID) [E]
Sent: Thursday, February 11, 2010 8:15 PM
To: 'Avery, Heidi E.'
Cc: Hatchett, Richard (NIH/NIAID) [E]
Subject: FW: Draft Strategy
Heidi:
I spoke to Richard a little while ago and he asked me to focus mainly on the Introduction and the Multi-Use Principle, which I have done. I will leave it to others to examine their components in order to get this back to you quickly since I know that you have to prepare something tonight for the POTUS. The document looks quite good. I have made a few changes that are tracked and have explained why I have done this. Please let me know if you have any questions or if you need to speak with me later. I am available. You were an amazing model of flexibility today. I hope that my comments on the phone call helped. Best regards,
Tony
From: Avery, Heidi E. [mailto: @who.eop.gov]
Sent: Thursday, February 11, 2010 6:58 PM
To: @hhs.gov; @niaid.nih.gov; @fda.hhs.gov; @osd.mil; @cdc.gov;
@hhs.gov; @niaid.nih.gov; @fda.hhs.gov; @hhs.gov;
@osd.mil; Emanuel, Ezekiel J.; Holdren, John P.; Petrou, Laura (OS)
Cc: Hatchett, Richard J.; Lawler, James V.
Subject: Draft Strategy
Attached is the revised draft strategy. Hunting typos, but thought it would be useful to see sooner than later.
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Heidi E. Avery
Deputy Assistant to the President
for Homeland Security
The White House
From: Avery, Heidi E.
Sent: Thursday, February 11, 2010 4:26 PM
To: @hhs.gov'; @niaid.nih.gov'; @fda.hhs.gov'; @osd.mil'; @cdc.gov';
' @hhs.gov'; @niaid.nih.gov'; @fda.hhs.gov'; ' @hhs.gov';
' @osd.mil'; Emanuel, Ezekiel J.; Holdren, John P.; 'Petrou, Laura (HHS/OS)'
Cc: Hatchett, Richard J.; Lawler, James V.; Severn, Deborah; ' @hhs.gov'; @fda.hhs.gov';
' @cdc.gov'; Bafford, Elizabeth A.; McLaughlin, Patricia M.; ' @niaid.nih.gov'
Subject: Conference Call Today at 6pm
Greetings – Believe it would be useful for us to talk briefly today at 6pm. Our meeting with the President remains scheduled for 2pm tomorrow in the WHSR. During the call we will clarify the meeting intent, discuss any concerns, and generally seek to set all of us up for success.
Meanwhile, we will have a new version of the draft strategy to you soon. Appreciate all of the very good comments. And,
to be clear, we expect the draft strategy will be further adjusted based on consultations. The ongoing MCM review, PCAST
study, and talks with industry will be critical to further shape the way forward. We remain early in the process. Thanks, Heidi
BRIDGE NUMBER:
CONFEREE PASSCODE:
--------------
Heidi E. Avery
Deputy Assistant to the President
for Homeland Security
The White House
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forces by investing in multi-use products is straightforward. Diagnostic platforms and multiplex technologies can address biodefense needs while simultaneously seeking access to durable and well-defined commercial markets. Many pathways and strategies for finding dual utility exist for therapeutics and these need not be enumerated here.
While it is true that some required products (e.g., vaccines, antitoxins) have inherently circumscribed uses, it does not follow that market forces cannot be leveraged to support their development. One way to leverage market forces is to reduce the risk and costs of development and manufacturing to such an extent that the existing, circumscribed market becomes a sufficient incentive in itself to drive development. A more sustainable strategy, however, is to support the development of limited-use products by investing in enabling, “multi-use” platforms and technologies that reduce the complexity, time, and cost of developing the desired product. These platforms and technologies can then be turned to other commercial applications that will provide the return on investment that private sector partners seek while also providing our chief defense against newly emerging threats. The U.S. Government has already made substantial investments in such platforms and technologies through the Transformational Medical Technologies Initiative Program supported by the Department of Defense (DoD) and numerous investments at the National Institutes of Health (NIH).
To lower cost and risk in pursuing novel multi-use products and platforms, the U.S. Department of
Health and Human Services (HHS) and DoD can assist the pharmaceutical industry by providing scientific expertise, critical reagents, repositories of essential specimens and products, animal facilities, pilot lot manufacturing facilities, and clinical trial networks. The goal in so doing is not only to partner with industry and decrease their investment risk while facilitating the development of specific products needed for public health and national security, but also to foster and promote the development of multi-use products, platforms and technologies in which industry would otherwise not invest because of the prohibitive costs. Once developed, these technologies could be used by industry for the development of products that would attract a considerable commercial market outside of the realm of biodefense and pandemics. In turn, once up and running, these platforms and technologies could be adapted to the development of countermeasures against unpredictable threats to public health, either deliberate or naturally occurring.
The challenge is to accept that in general our guiding principle should be we shouldto directconstrain our investments to products and approaches that embrace the concept of multi-use. Over time, the cascading benefits of accepting this fundamental principleconstraint promise to be enormous. Focusing on multi-use products, platforms, and technologies that provide our private sector partners with access to legitimate commercial markets will accelerate and simplify medical countermeasure development, decrease our partners’ dependency on direct government subsidies, assure ongoing manufacturing capability, and decrease aggregate cost and risk to the U.S. Government.
Perhaps the greatest benefit of adopting the multi-use principle is that it represents the only true path to long-term sustainability for the iPHEMCE. Under our current one-bug, one-drug, onevaccine paradigm, the aggregate costs over time of discovery, development, procurement, stockpile maintenance, and securing ongoing access to surge manufacturing capability for each of the many countermeasures we require are prohibitive. And these costs are just for the threats we know about and can predict. By adopting the multi-use principle, and by sharing the costs of discovery and development with the private sector, which will have a vested interest in maintaining the multi-use
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of individual firms to make investments in newer approaches. One such example is the continued use of chicken eggs for the growth of influenza virus for use in vaccines.
In recent years, however, as biomedical research and drug development have become more expensive, biomedical research has become more of an information science, technical barriers to information sharing have declined, cultural shifts favoring large-scale collaborations have occurred, and biotechnology and pharmaceutical firms have explored new ways to partner with each other and with government to solve common problems and make the leap to new technology and practices. Such collaborations and partnerships are based on shared goals that are critical for progress but that cannot be monetized (i.e., exploited as stand-alone profit-making opportunities) and cannot feasibly be achieved by a single organization. In such circumstances, “precompetitive” collaborations and partnerships have been established to reduce cost and risk to individual partners while pursuing advances that benefit all participants.
Such collaborations and partnerships have a considerable track record. They have been used to develop new standards and tools, to generate or aggregate data, and to create new knowledge or develop products by accessing resources and capabilities across organizations. Consortia have been established to foster process innovation, to enable discovery, and to serve as innovation incubators. Pooling resources to invest in sector-wide process and technology improvements leverages the investments of and minimizes risk for individual partners while enabling downstream processes that create market value and unlock creative capital and dormant intellectual property.
A convergence of factors has also led to the emergence of more robust and innovative publicprivate partnerships in various domains of biomedicine. These factors include the flattening of NIH budgets in recent years, the declining productivity of freestanding research and development programs within the biotechnology and pharmaceutical industries, the escalating complexity of biomedical science, the challenges posed by regulatory processes, and the emergence of viable collaborative models. Precompetitive collaborations that have enhanced public-private partnerships include (among others) the Biomarkers Consortium, which is managed by the Foundation for NIH and includes NIH, FDA, CMS, PhRMA, BIO, non-profit organizations, and multiple biotechnology and pharmaceutical firms as partners, and the partnerships and consortia supported through FDA’s Critical Path Initiative that engage NIH, patient organizations, academia, and multiple biotechnology and pharmaceutical firms to facilitate advances in regulatory science, including innovation in product development, safety assessment and clinical trials. These diverse efforts provide models of collaboration likely to be very helpful in advancing relevant biodefense and public health focused projects. Through existing U.S. Government networks and alliances here and abroad, such partnerships could be extended internationally, to include allied nations as well as overseas clinical trial sites and other valuable components of the product development pathway.
As a part of the initiative to transform our countermeasure enterprise, the U.S. Government will work with industry partners to leverage existing or to create new public-private partnerships to propel much-needed advancements in pharmaceutical product discovery, development, and manufacturing. Input from industry partners will focus the capabilities and operating concepts of these partnerships so that they meet the needs of all participants. These partnerships will foster advances in enabling science and technology that facilitate the development of countermeasures against public health threats, and they will be guided by the multi-use principle in concentrating resources on those that will have broader application for other products.
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III.Regulatory Innovation and Advancement of Regulatory Science
A very significant barrier to participation of capable large pharmaceutical firms in the development of countermeasures against public health threats is the complex, time-consuming, and uncertain path to approval. Novel countermeasures for public health threats face all of the challenges associated with traditional drug development plus the uncertainties associated with diseases that are difficult to study and the complexities of the FDA “animal rule” pathway to product approval. These uncertainties, and the challenges of developing suitable animal models (or alternative paths to approval), have created conditions of intolerable risk for pharmaceutical companies where biodefense and other public health products are concerned.
These challenges can be addressed in two ways, by advancing the regulatory science that governs the approval process and by ensuring that FDA has the resources and staff to be more responsive and accessible to industry partners at every stage of the development process. Modernizing and streamlining our regulatory process to create pathways to approval that are more predictable, transparent, and rapid than currently exist is an indispensable condition of participation for large pharmaceutical firms.
The best way to map out such pathways is collaboratively, in particular by advancing the emerging field of regulatory science. Working with industry partners to improve the efficiency of product development and evaluation, while simultaneously enhancing regulators’ confidence in the safety and effectiveness of regulated products, will facilitate the path to approval, thereby reducing cost, risk, and uncertainty for our partners and accelerating the delivery of the medical countermeasures that we need. This type of close interaction, beginning very early in product development and continuing through and after approval, is of tremendous value to industry and a proven ingredient in those public health product development efforts that have been successful to date. In addition to smoothing the path to approval, such an approach identifies scientific gaps and potential product problems early, allowing them to be addressed more efficiently and effectively, or, if needed, supporting a need to change course.
To generate much-needed advancements in regulatory science, the FDA will establish and manage a
regulatory science center. This program will evolve, evaluate, and validate new tools and practices that can facilitate biomedical product development, evaluation and manufacturing. The center will also examine and make recommendations for changes of regulatory policies where there is an opportunity to improve simplicity, transparency, speed, and effectiveness of regulatory oversight.
The FDA program will directly engage with the partnerships described in the section above to create opportunities to explore solutions that assist FDA and industry in improving speed and effectiveness in regulatory testing and evaluation. Pharmaceutical firms will be offered the opportunity to collaborate with each other and directly with FDA staff to address regulatory problems of common concern, advance regulatory science, and promote regulatory evolution. FDA will benefit by building core expertise in new regulatory technologies, predictive models, and approaches to statistical analysis. FDA and industry will both benefit from the earlier introduction of novel ideas and practices for regulatory scrutiny and troubleshooting. Finally, and most importantly, the public will benefit from the introduction of new technology into the medical product development process that lowers the time and cost of development, while simultaneously improving the quality of safety and efficacy assessment.
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The Center will initially focus on projects that have demonstrable value for all parties. Such projects could focus on:
• Comparatively advanced manufacturing platforms with which FDA already has some familiarity (e.g., monoclonal antibodies, therapeutics based on RNA interference (RNAi), various protein expression systems for vaccines and therapeutics, novel adjuvants, widely available automated high throughput diagnostic platforms for nucleic acids, proteins and antibodies);
• Good Laboratory Practice (GLP) animal-efficacy model development for new vaccines, antibiotics and antiviral medications;
• Validation of improved potency and rapid sterility assays; and
• New approaches to statistical analysis of clinical trials.
Over time, the Center could expand its focus to address other regulatory challenges, including:
• Development and validation of biomarkers for use as alternative clinical endpoints and to enhance prediction of safety;
• Cell culture and in silico modeling of efficacy;
• Non-animal toxicological and safety evaluation;
• Defining pathways for novel vaccine manufacturing platforms (e.g., virus-like particles and DNA vaccines targeted to novel antigens); and
• Defining pathways for point-of-care diagnostics with ability to subtype influenza or detect antimicrobial resistance.
IV. Product Development and Manufacturing Services
Advanced development and manufacturing account for a large proportion of the total cost of medical countermeasure development. These costs represent a substantial barrier to the participation of large pharmaceutical firms, which prefer a more favorable return on investment, and
to the progress of smaller biotechnology firms, which typically lack the necessary capital and
expertise required to succeed.
Compounding these problems, the Federal contracting mechanisms most often used to support advanced development and manufacturing can impose long lead times and significant transaction costs. Contracts may further impose a form of reverse moral hazard, in that the difficulty and publicity associated with their cancellation often lead program staff and government agencies to become more failure-averse. Federal contracting must be streamlined and accelerated, and future contracts to support the development of medical countermeasures against public health threats must be structured in a way that facilitates early down-selection of projects that are not making appropriate progress. Given the high attrition rates associated with drug development, government agencies must configure themselves to be highly tolerant of failure and to have mechanisms that allow projects, if they are to fail, to “fail fast and fail cheap.”
Going forward, and as needs dictate, the U.S. Government will also employ other mechanisms, including service and cooperative agreements, other transaction authorities, and challenge grants to facilitate public-private partnerships and expedite countermeasure development and manufacturing. Such mechanisms will augment the more traditional contracting processes currently used to support advanced development and manufacturing activities, enabling the Enterprise to be more flexible,
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adaptive, and responsive in engaging with industry to promote medical countermeasure development.
The opportunity costs and risk assumed by private sector partners can be lowered substantially through the direct provision of advanced product development and manufacturing services. To provide such services, the U.S. Government must work with industry to establish prioritized access
to advanced development and manufacturing capabilities for these countermeasure products. The
capabilities specified and prioritized by the U.S. Government would build on an existing domestic infrastructure composed of an integrated network of industrial facilities able to provide assistance in product development or in manufacturing clinical investigational lots or commercial scale lots of countermeasure products.
Components of this advanced product development and manufacturing services capability could be assembled in multiple, non-exclusive ways by establishing contract partnerships with academia, contract research and manufacturing organizations, and industry, or by establishing Manufacturing and Development Centers of Excellence or a non-profit, Federally Funded Research & Development Center or Centers. In whatever form the capability is established, it would provide a full range of pre-clinical and advanced product development services2 (including animal-efficacy model development and validation) as well as dedicated scale-up, validation, and production capabilities using flexible manufacturing technologies. Technical expertise in scale up and manufacturing process development as well as commercial scale manufacturing will be provided by Biodefense Advanced Research and Development Authority (BARDA) to industry partners in need of these skills. The infrastructure required to provide this end-to-end range of services would be operated by industry under U.S. Government oversight. Important downstream benefits of establishing this capability are that it will make life cycle management and replenishment of needed countermeasures more cost effective and provide expanded domestic emergency manufacturing capacity.
One of the core product development services the U.S. Government will provide is identifying and addressing regulatory challenges prospectively and providing assistance with regulatory filings. Regulatory officers from NIH, BARDA, and DoD with deep knowledge of the “animal rule” and FDA concerns will provide expert support to private-sector partners and facilitate and participate in formal and informal interactions with FDA.
By providing subject matter and animal model expertise, developing and validating screening and GLP animal models, anticipating and addressing regulatory challenges prospectively, and establishing an advanced development and manufacturing capability, the U.S. Government will drastically reduce the opportunity costs and other barriers that limit investment by the pharmaceutical and biotechnology industries in public health countermeasure projects. This intensive and direct support by the U.S. Government will reduce the absolute investment of company resources in particular projects and fundamentally alter the calculus of return on investment. A much more favorable return on investment will, in turn, enable pharmaceutical and
2 For example, Good Laboratory Practice (GLP) toxicology and safety pharmacology studies, formulation methodology,
current Good Manufacturing Practice (cGMP) manufacturing support, stability studies, non-pivotal screening and efficacy evaluations, GLP pivotal efficacy studies in validated animal models, and support for Phase I clinical safety and pharmacokinetic studies.
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biotechnology firms to pursue the development of products that meet our national security and overall public health needs.
While the capital outlay necessary to establish this advanced development and manufacturing capability will be substantial, the benefits in terms of increased research and development productivity will more than justify the cost. Implementation of the multi-use principle will substantially reduce the costs associated with individual projects since multi-use value will enhance access to private capital markets, justify independent development, and reduce the need for advanced development and manufacturing support.3
V. End-to-end Multidisciplinary Project Management
U.S. Government support for the development of countermeasures against deliberately released and naturally occurring health threats is parceled out across numerous departments and agencies, and the release of requests for proposals and other targeted solicitations across this bureaucratic space is not well synchronized. While there have been efforts to coordinate U.S. Government countermeasure investments in an “Integrated National Portfolio” approach, a unified approach to budgeting and governance has not been achieved. For many private-sector partners, unfortunately, the IPHEMCE remains a confusing welter of acronyms, agencies, and funding mechanisms. This complex funding and policy environment is exceptionally difficult to navigate, particularly for the smaller firms and academic start-ups that are the main engines for innovation. Coupling the challenges of negotiating this terrain with the challenges of product development and the quirks of the “animal rule” pathway to product licensure has created an environment that is inhospitable to the translation of promising basic-science discoveries into clinically useful products.
The U.S. Government will implement a new program of end-to-end multidisciplinary project management to mitigate the complexity of our current institutional arrangements, identify relevant funding opportunities, facilitate handoffs between different departments and agencies, and inform private-sector partners at every stage of product development about relevant policy and the path to product approval. Multidisciplinary project management teams will include program managers,
subject matter experts from DoD, NIH, BARDA, and the Centers for Disease Control and
Prevention (CDC), a liaison from FDA, and, as needed, regulatory officers from NIH and BARDA.
The role of these teams will be to serve as “Sherpas” to our academic and private sector partners. Sherpas, of course, are members of a people of Tibetan descent who in modern times have achieved renown as expert guides on Himalayan mountaineering expeditions. During such expeditions, each climber is assigned a Sherpa to carry his or her gear, cook food, and set up camp. The Sherpa’s role is to make the climb as easy as possible for the person being guided. All the climber has to focus on is climbing. Experienced Sherpas also recognize when a climber is not going to make it and can take appropriate action. The multidisciplinary project management teams would play an analogous role for academic and private sector partners, providing strategic recommendations where appropriate, and helping them negotiate the bureaucratic, scientific, policy, and funding terrain. It will be the responsibility of the project management teams to ensure the coordinated transition of
3 In the optimal case of an already licensed product with dual utility and a substantial human safety database, the costs
of development will be limited to the costs of demonstrating efficacy in validated animal models and filing a supplemental New Drug Application (NDA).
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projects between departments and agencies and from stage to stage of product development and testing.
Conclusion
The development of drugs, diagnostics, and vaccines against naturally occurring pandemics and emerging infectious diseases, as well as against deliberately propagated bioterror and other threats, is a national security imperative. But the substantial U.S. Government investments made since 2002 have not succeeded in producing the desired flow of new and next-generation countermeasures. We now recognize that it is only by attacking the direct barriers to the development of countermeasures against public health threats that we will increase our prospects of success. To say this is not to belie the value of incentives external to the drug development process. It is merely to point out that external incentives by themselves are insufficient.
Going forward, the U.S. Government will change the way it defines its mission and role in supporting the development and acquisition of medical countermeasures against public health threats. We will pursue a strategy with five critical pillars for biodefense product development:
I. The Multi-Use Principle – for individual products but also platforms and technologies II. Precompetitive Collaboration III. Regulatory Innovation and Advancement in Regulatory Science IV. Product Development and Manufacturing Services V. End-to-end Multidisciplinary Project Management
By implementing these pillars rigorously and without delay, the U.S. Government can transform the nature of the public-private partnerships it supports in this area. Ultimately, these changes will create a new template for government partnership in the arena of private-sector drug development in all the many areas where progress has been impeded by apparent market failures, will increase the productivity of our investments in the life sciences, and will enhance U.S. competitiveness.
This approach is expected to provide the following clear advantages for biotechnology companies, large pharmaceutical firms, and the U.S. Government:
Advantages for biotechnology companies
• Increases speed and lowers risks in the development of countermeasures;
• Offloads downstream development activities where expertise is lacking and more difficult to obtain;
• Allows for greater focus on discovery translation and technology innovation; and
• Creates a more durable business model.
Advantages for large pharmaceutical firms
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• Increases speed and lowers risks in the development of countermeasures against public health threats;
• Enhances innovation by providing access to newer technologies sooner;
• Provides an incubator and test bed for new platforms and technologies for future use in the development of commercially desirable products; and
• Enables more productive engagement with the FDA
Advantages for the U.S. Government
• Increases speed and lowers costs and risks in the development of medical countermeasures;
• Ensures sustained domestic U.S. production capability;
• Enhances USG surge capacity available for emerging and reemerging diseases;
• Provides for a critical mass of technical expertise that is available for a more rapid response when needed;
• Enables more overall drug development effort due to lower investment cost;
• Raises the potential to partner with NGOs and others to address global health problems; and
• Establishes a model for drugs, diagnostics, and vaccines for any and all diseases, including in cases where commercial viability is doubtful.
The strategy outlined is a significant departure from the U.S. Government’s previous approach. It is not without some risk. But to eschew the uncertain risk associated with establishing a new business model and continue with the certain risk of unacceptable return that our current model continues to demonstrate would be untenable. Even if we were better able to produce effective countermeasures with our current model, over time our one-bug, one-drug, one-vaccine approach will inevitably lead
to a lack of sustainability for the Enterprise as a whole, as the costs of discovery, development,
procurement, stockpile maintenance, and securing ongoing access to surge manufacturing capability are aggregated for each of the many countermeasures we require.
A critical factor for successful implementation of our new strategy is a holistic approach to knocking down barriers impeding progress. There currently exists pockets of effort attempting to address these barriers and adopt some of the pillars of the strategy outlined here, but an ad hoc and incomplete approach will not create the conditions for a breakthrough in establishing a successful, sustainable approach. Incremental improvements will not achieve our goals. Only by leaping forward, employing the outlined strategy pillars comprehensively and broadly, will we achieve the output for which many in the IPHEMCE have worked tirelessly.
Now is the time to establish an approach yielding dramatically improved return on investment. Our return will not be measured in dollars but in the protection of the safety and security of the American people. In pursuing this fundamental charge of the Federal government, it is abundantly clear that failure is not an option.
3 quoted messages inside this reply
Anthony Fauci· FW: Draft StrategyThursday, February 11, 2010 8:15 PM
Heidi E. [mailto: ] Avery· Draft StrategyThursday, February 11, 2010 6:58 PM
Heidi AveryThursday, February 11, 2010 4:26 PM