Advancing Regulatory Science for Medical Countermeasure Development: Workshop Summary (2011)

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Introduction¹

During public health emergencies such as influenza pandemics or chemical, biological, radiological/nuclear (CBRN) attacks, safe and effective vaccines, drugs, diagnostics, and other medical countermeasures (MCMs) are essential to protecting national security and the well-being of the public. The U.S. Food and Drug Administration (FDA) plays a central and crucial role in domestic preparedness through its regulation of drugs, biologics, medical devices, and radiation-emitting products. However, recent reports have highlighted the need for improved regulatory science to help address the novel regulatory issues the agency faces in its review and approval of many MCMs (e.g., ethical or practicality barriers to conducting standard clinical trials, balancing benefit and risk for products that would be used only under dire circumstances) (FDA, 2007; NBSB, 2010). A report from the National Biodefense Science Board concluded that

FDA has not been able to fulfill its implicit national security mission, in large part because of a lack of resources…. It is imperative for America’s health and progress for FDA to be provided adequate resources to bring

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¹ This workshop was organized by an independent planning committee whose role was limited to 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 they should not be construed as reflecting any group consensus.

its regulatory science into the 21st century. Doing so will greatly enhance FDA’s ability to support MCM development and licensing. (NBSB, 2010, pp. 43–44)

In August 2010, the U.S. Department of Health and Human Services (HHS) released its review of the Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) and made numerous recommendations to transform the MCM enterprise to increase its speed, agility, capacity, and success rate, including the promotion of regulatory innovation and investment in regulatory science at FDA (ASPR, 2010).² In this regard, FDA has established an MCM initiative that includes (1) enhancing the regulatory review process for the highest-priority MCMs and related technologies; (2) advancing regulatory science to support MCM development and evaluation; and (3) modernizing the legal and regulatory framework to support public health preparedness and response.

At the request of FDA, the Institute of Medicine’s (IOM’s) Forum on Drug Discovery, Development, and Translation and the IOM’s Forum on Medical and Public Health Preparedness for Catastrophic Events jointly convened a workshop on March 29–30, 2011. The workshop, titled Advancing Regulatory Science for Medical Countermeasure Development, was designed to (1) examine ways to advance regulatory science for MCM development and regulatory evaluation; (2) identify scientific opportunities to improve, simplify, or speed MCM development; and (3) identify tools and methods to improve the predictability and success rate of candidate MCMs (see Box 1-1).

Workshop speakers and attendees consisted of experts from federal government agencies, the private sector, and academia, who were invited to discuss the applicability of cutting-edge science to MCM discovery and development with the goal of informing the FDA MCM initiative and the regulatory science-based product review process. Speakers were asked to introduce their comments by providing a brief overview of scientific advances or emerging technologies holding promise to facilitate development of MCMs, and then to focus on what regulatory science advances are needed to address gaps in currently available tools to predict and evaluate product safety, efficacy, and quality. They were also asked to identify how innovative regulatory science methodologies can address emerging tech-

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² As part of the PHEMCE review, and at the request of the Secretary of HHS and the HHS Assistant Secretary for Preparedness and Response, the IOM’s Forums on Drug Discovery, Development, and Translation and Medical and Public Health Preparedness for Catastrophic Events collaborated to host a workshop in February 2010, which addressed challenges facing the PHEMCE. Workshop participants discussed federal policies and procedures affecting the research, development, and approval of medical countermeasures and explored opportunities to improve the process and protect Americans’ safety and health (IOM, 2010).

nologies, targets, and novel products. Each speaker was asked to identify the top 2–3 regulatory science needs or priorities, and to comment on partnerships or collaborations that could serve as models for, or facilitate achieving, this regulatory science agenda.

Invited discussants were asked to provide brief remarks during the context of a panel discussion to offer a case study or example illuminating success stories or lessons learned with respect to the subject of the panel discussion in which they were invited to participate.

This workshop summary identifies key issues and raises awareness of opportunities and challenges in advancing regulatory science underpinning regulatory decision making about MCM products. After first providing context and background, the summary presents enterprise stakeholder perspectives (federal and private sector) on the key regulatory science needs and priorities to advance MCM development (Chapter 2);highlights novel science as well as regulatory science tools to address that novel science (Chapter 3); and discusses challenges in applying regulatory science to MCM development specific to at-risk populations such as children and pregnant women(Chapter 4). Chapters 5 and 6 summarize crosscutting themes and provide concluding remarks.

The summary provides an overview of the highlights from the substantial discussions that took place at the workshop. A key goal of the workshop was to identify regulatory science tools and methods that are available or under development, as well as major gaps in currently avail-

able regulatory science tools. This summary report includes key and crosscutting themes and compiles a number of suggestions offered by workshop attendees. Throughout the workshop a number of participants noted that further work, including meetings and formation of working groups, will be important to drill down more deeply in each scientific area to fill out a more robust regulatory science agenda and priorities with respect to each area of science.

DEFINING REGULATORY SCIENCE

FDA defines regulatory science as “the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality and performance of FDA-regulated products” (FDA, 2010). Jesse Goodman, chief scientist and deputy commissioner for science and public health at FDA, emphasized that regulatory science is a critical bridge between basic science discoveries and early work in industry and the approval of new products that can help patients. With regard to MCMs, enhanced regulatory science is needed to reduce uncertainty and provide clear regulatory pathways for MCM development. Exercising the principles of regulatory science requires underlying capacity and expertise at FDA, Goodman added.

George Korch, acting principal deputy assistant secretary for preparedness and response, HHS, expanded on the definition of regulatory science given by Goodman, suggesting that in context of the PHEMCE review, it means specifically that:

• Regulatory pathways for difficult issues in development of medical products against CBRN and emerging infectious disease threats are better defined.
• Industry, the Biomedical Advanced Research and Development Authority (BARDA), the National Institutes of Health (NIH), and the regulatory community work in partnership to identify and prioritize the most urgent needs.
• The commercial sector helps FDA where it can, in gaining access to new technologies that ultimately need regulatory oversight for product approvals.
• All centers at FDA benefit from research investment, and all centers work collaboratively to maximize the impact of these funds in accelerating the pace of product approvals for PHEMCE-related countermeasures.

• The PHEMCE partners³ actively support FDA’s efforts to continue to benefit from investments made in regulatory science.

CHARGE TO THE WORKSHOP PARTICIPANTS

In his keynote address and charge to the workshop participants, Goodman reviewed some of the challenges of MCM development, described the framework for the FDA Regulatory Science Initiative, and listed key questions FDA is seeking expert input on (summarized in Box 1-2).

Goodman also emphasized the importance of engaging the agency early in the MCM development process, so FDA regulatory science can be brought to bear in a highly interactive manner with the product sponsor. He remarked that there is a need for broad collaboration, as no single agency or entity has all the necessary tools or expertise to meet the challenge of bringing MCMs to market. He noted that a component of the FDA MCM initiative is aimed at facilitating engagement between sponsors and FDA early in development, working together to identify where the gaps are, and coming to general agreement on what models, outcomes, and data are needed to allow for emergency use of a product, and he remarked that this model of engagement is different than how commercial drug development is normally done.

IMPLEMENTING THE 2010 PHEMCE REVIEW

As noted above, in the summer of 2010, HHS released its review of the MCM enterprise(ASPR, 2010). Korch quoted HHS Secretary Kathleen Sebelius’ vision for the MCM enterprise as follows:

Our nation must have the nimble, flexible capacity to produce MCMs rapidly in the face of any attack or threat, known or unknown, including a novel, previously unrecognized naturally occurring emerging infectious disease. (ASPR, 2010, p. 6)

In conducting the review of the MCM enterprise, Korch said, several major areas of risk for MCM product developers were identified:

• technical risk for product development (e.g., access to core manufacturing and accessory services, limited or no ability for translation and incubation of promising ideas from technology base to early product development);

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³ The PHEMCE partners comprise certain operating divisions within HHS (CDC, FDA, NIH, BARDA) and other partners in the Departments of Defense, Homeland Security, Agriculture, and Veterans Affairs.

• regulatory risk (e.g., uncertain or high-risk pathway for product licensure, need for greater resources at FDA to mitigate risk profile); • business risk (e.g., financial pressures for capital for start-up or maturing businesses, lack of integrated business expertise in new organizations); and
• governmental risks (e.g., deficient coordination across multiple agency and departmental programs; lack of ability to project and prioritize long-range needs through an integrated multiyear program and budget process).

Based on the identified barriers and challenges, the review highlighted a variety of opportunities for improvement, the first of which

is enhancing regulatory innovation, science, and capacity at FDA. Recommendations for optimizing the enterprise were made as well. Korch highlighted five key initiatives recommended in the report: major investments in upgrading science at FDA; establishing Centers of Excellence in Advanced Development and Manufacturing; expanding the pipeline at the National Institute of Allergies and Infectious Diseases (NIAID); addressing the immediate needs for influenza vaccines (e.g., sterility, potency, optimization);and establishing a strategic investment fund to increase government investment in entrepreneurial commercial ventures. He noted that this IOM workshop is directly related to the first initiative on upgrading regulatory science at FDA.

In summary, Korch said, the U.S. government has made a tremendous investment over the last 10 years, and there are many successes and capabilities that did not exist a decade ago, but gaps remain. The PHEMCE review addressed gaps in the ability of the government to increase the product pipeline and lower the risks for commercial partners, and focused on the development of a capabilities-based (rather than threat-based) strategy for medical defense. “You get the system that you reward,” Korch said, so moving forward, the MCM enterprise needs to reward flexibility, fresh thinking, and a vision of how to prepare against low-probability, high-consequence events.

OVERVIEW OF THE FDA MCM INITIATIVE

The mission of the FDA MCM initiative is to promote the development and availability of MCMs by establishing clear regulatory pathways based on the best available science, explained Luciana Borio, acting director of the Office of Counterterrorism and Emerging Threats at FDA. To achieve this, FDA is aggressively taking action in three major areas, referred to as the “pillars” of the initiative:

• Pillar 1: Enhance the MCM review process;
• Pillar 2: Advance regulatory science for MCM development and evaluation; and
• Pillar 3: Optimize the legal, regulatory, and policy framework to support preparedness and response.

In addition to increasing review capacity and expertise in the medical products centers, Pillar 1 will establish public health and security action teams to support FDA reviewers. Teams may, for example, provide targeted briefings for reviewers on threats and risks associated with high-priority MCMs. Although established under Pillar 1, the teams are charged with considering the whole range of regulatory, scientific, and

policy issues facing MCM development and approval. The first action team launched, for example, is helping to develop novel regulatory approaches to address the complex regulatory challenges associated with multiplex in vitro diagnostic tests for infectious diseases (which may detect hundreds of agents in a single assay).

When the scientific foundations that underpin regulatory assessments are immature, as they often are in the case of MCMs, Borio said, product development suffers. The Pillar 2 regulatory science program seeks to develop solutions to complex scientific regulatory problems, identify situations in which the application of new science could simplify or speed product development and review, and establish FDA capacity to meet high-priority public health needs, especially during emergencies. Pillar 2 regulatory science was the topic of this workshop.

Borio emphasized that to achieve these goals, FDA will need to access all available expertise and leverage both FDA and non-FDA resources. As such, the MCM initiative involves internal collaborative research, as well as partnerships with other U.S. government agencies, academia, and industry.⁴ FDA has stood up internal regulatory science research projects to support product development, approval, and use by making available to product review teams the most up-to-date science-based methods available for regulatory assessment of MCMs. Projects are being funded through internal FDA funds under an interactive peer-review process involving enterprise partners, including NIAID, BARDA, and the Department of Defense (DoD), which helps ensure alignment with MCM enterprise priorities. The discussions at this IOM workshop will help to refine FDA internal programs and identify opportunities for collaborations and partnerships, she said.

SUMMARY OF KEY WORKSHOP THEMES

The workshop was structured in three broad modules. First, stakeholders in the MCM enterprise (public and private) presented their views on the current state of MCM regulatory science and the needs and opportunities for development of MCM regulatory science. Second, a series of panel discussions, anchored by presentations, was held that reviewed novel scientific methodologies in MCM development and identified high-priority MCM regulatory science needs and opportunities. Third, in a summary discussion session, themes, priorities, and future directions were identified by the workshop participants. Over the course of the

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⁴ Borio also noted that use of funding for the MCM initiative is currently restricted to pandemic influenza activities. FDA is working with congressional leaders to remedy this to allow FDA to use existing appropriations to broadly implement the strategies of the MCM initiative.

workshop, numerous individual suggestions were made for priorities and future directions for advancing regulatory science for MCM development, and in this process a number of crosscutting themes arose that resounded across panel topics. These themes and“big ideas” were synthesized into a high-level summary discussion facilitated by workshop co-chair John Rex, Vice President of Clinical Infection of AstraZeneca. Due to their crosscutting nature, resonating themes and “big ideas” are listed below as a means of orienting the subsequent workshop summary, which summarizes the discussions underlying and supporting these themes.

The themes and “big ideas” listed below are not inclusive of the many individual suggestions that were made throughout the workshop and are summarized elsewhere in this workshop summary. They are compiled 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.

Themes

• Incentives drive the process of development, and “you get what you reward.” Reward of flexibility and innovative thinking will advance the MCM enterprise.
• Education and training are essential, and there is a need to promote an interdisciplinary regulatory science workforce.
• Defining metrics of success is not straightforward. Workshop participants offered a number of potential success indicators, such as development of assays and biomarkers, definition of regulatory or approval pathways, product approvals, and addition of products to the Strategic National Stockpile (SNS).
• The benefit-risk calculus may be different for MCMs to be used in low-probability/high-consequence events than for traditional products.
• Precompetitive collaborations exist and should be promoted and strengthened; data sharing within FDA should be enhanced.
• There is a need for better understanding of animal models and how to apply them.
• Early engagement between product developers and FDA is imperative to support effective application of regulatory science to the product development process.
• Cross-enterprise collaboration, including FDA, other HHS divisions, DoD, industry, and academia, is essential. There is a need for real-time, ongoing, unimpeded collaboration among product developers, government managers, and regulatory review and FDA research scientists.

• MCM product development should be viewed as an opportunity to advance the development of regulatory science more broadly, and these advances could have implications for and influence on the traditional biopharma product development model.

Big Ideas

• Promote “big science” to make assays for all human proteins. To accomplish this there is a need to overcome challenges in statistical design.
• Animal models: Build databases of existing animal models (genome to phenome) including information of what is known about animal and human responses for key diseases.
  • Develop partnerships and collaborations for data sharing to enhance knowledge on animal models.
  • Work toward approval of an MCM product based on safety and efficacy data from an animal model but with information on clinical dosing.
• “App” technology for public education and communication, surveillance, response, and adverse event monitoring holds promise.
• With respect to diagnostics, there is a need for development of a universal transport matrix to “move the sample” during an event, and development of a local test that allows remote data analysis (“move the data”).
• The promise of new statistics such as Bayesian-augmented control design was discussed.
• Participants noted that there is a need for universal data standards for common data elements in naming and defining variables.
• To enhance vaccine development, it was suggested to create platforms for antigens and adjuvants, with accompanying licensure pathways. Workshop participants also suggested that collaborative working groups be convened to share data and experiences with respect to such things as safety biomarkers and platforms.

Additional individual suggestions made by workshop participants are listed at the end of the subsections in Chapter 3 of this workshop summary.

Urgency of the Need

From the outset of and throughout the workshop many participants emphasized the urgency of the need for action to enhance regulatory science and facilitate the development of safe and effective MCMs. In

his keynote address, Goodman remarked that MCMs are a unique product in that they are needed for very specific threats and they must be available on a much shorter timeline than that which is seen in more traditional pharmaceutical development efforts. Goodman added that FDA had requested the workshop be held on a very short timeline due to the need to provide information to the FDA MCM initiative as early as possible. Gerald Parker, deputy assistant secretary to the secretary of defense for chemical and biological defense at the DoD, emphasized that “perhaps complacency may be our biggest threat.” He noted that it may be more useful to acknowledge that the issues are “high probability, high consequence” ones, and that there is a need to appreciate the sense of urgency associated with this threat to create the important social drivers needed to effect change.

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