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
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-
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).
- Provide a broad overview of current efforts underway at FDA and other agencies within HHS and the Department of Defense (DoD) to support the research, development, evaluation, and production of MCMs.
- Review novel scientific methodologies used by academia and industry to facilitate development of next generation vaccines, biologics, drugs, and devices.
- Identify major gaps in currently available tools to predict and evaluate product safety, efficacy, and quality.
- Identify opportunities for collaboration and coordination with FDA and among relevant federal and industry programs to support the MCM initiative’s regulatory science program, and to develop more clearly defined pathways for product approval.
- Identify regulatory science tools and methodologies to address emerging technologies, targets, and novel products as well as innovative approaches for predicting safety and efficacy (e.g., biomarkers, in silico modeling).
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.
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.
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.
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);
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
CHALLENGES TO MCM DEVELOPMENT
- Increasing costs of product development
- Low success rates
- Uncertainties throughout the process
- Uncertain market for MCM products
- Highly variable time frames for product development, production, and mobilization in response to an emergency
- Limited application, thus far, of systems biology, new technologies, and high-level computational science approaches to product development (approaches that are routinely applied at the basic science level)
FRAMEWORK FOR THE FDA REGULATORY SCIENCE INITIATIVE
- Leadership and coordination across the agency, and development of an agency-wide strategic science and innovation plan
- Support for applied regulatory science research, both within FDA and through collaborations
- Scientific and professional development
- Recruitment and retention of highly qualified personnel in key areas
QUESTIONS TO BE ADDRESSED
- What tools and capacity are needed to develop and evaluate the products of today?
- What will be needed to evaluate products and technologies on the horizon?
- How can uncertainty around platform technologies be reduced, so the risk of failure in an emergency is reduced?
- How can collaboration be improved? How can FDA better take advantage of resources across the government and the private sector?
- How should FDA prioritize its scientific work if presented with additional resources? In the absence of new resources, what areas are most critical?
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.
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.
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
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.
- 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.
- 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.
Regulatory Framework for Review and Approval of MCMs
Although the focus of the workshop was regulatory science, there was also significant discussion of the closely related topic of the regulatory framework for review and approval of MCMs (which is being addressed in Pillar 3 of the FDA MCM initiative). Major regulatory framework themes are summarized in this sidebar.
There is significant intersection and overlap across the three pillars of the FDA MCM initiative. This workshop stems from Pillar 2 and was therefore limited in scope to discussions of advancing FDA regulatory science for MCM. However, science must also be interpreted, and regulatory and policy decisions must be made. Throughout the workshop, participants also offered comments regarding the review process as it relates to MCMs, and the underlying legal, regulatory, and policy framework. The topics most often mentioned by participants were the need for an alternate paradigm for approval of MCMs for disaster situations, and modifications to requirements under the Animal Rule. There were also concerns about the liability of MCM developers.
Approval with Conditions
There was much discussion about the need to adapt the existing regulatory framework to support MCM development prior to an emergency declaration. Eric Rose, CEO and chair of the Board of Directors of SIGA Technologies, Inc., noted that the existing emergency use authorization (EUA)a mechanism works well as an FDA response process, but it is not a preparedness mechanism. A number of participants advocated for a“provisional approval” mechanism for novel MCM. Products would meet the existing criteria for use under an EUA but could be provisionally or conditionally licensed prior to an actual emergency declaration. There would be advance determination of what would trigger issuance of an EUA and what monitoring would be required once the product was in use.
Rose defined such products as those that (1) may be effective in meeting an otherwise unmet clinical or public health need posed by the potential emergency, (2) have strong evidence of safety relative to the risks and consequences of the unmet need, and(3) have a reasonable basis for dosimetry. Such a product would not be used until there was a disaster, at which point FDA would conduct one final review of the current situation and authorize its use. Subsequent full approval of provisionally approved MCMs could occur when substantial evidence of effectiveness, robust evidence of safety relative to risks and consequences, and a robust basis of dosimetry were available. Many participants emphasized that the threshold for what constitutes practical efficacy data should be set with the understanding that these products fill an unmet need in a very-high-consequence scenario.
A participant cautioned that, regardless of the terminology used, if a provisionally or conditionally approved or licensed intervention is still considered to be an investigational product, there are statutory barriers to the DoD administering investigational products to troops, and insurance companies tend not to cover products that do not have full FDA approval. It was suggested that instead, FDA already has the authority to approve products with conditions for their safe use. Under this authority, some argued that FDA could impose conditions such as, for example, that the MCM is only ever used under an EUA, only from the SNS, or only for specified needs. Ed Nuzum, chief of the Biodefense Vaccines and Other Biological Products Development Section at NIAID, suggested that having a defined provisional approval step—a clear and potentially attainable goal short of full approval—could help to incentivize small companies and their investors to develop MCM.
Goodman of FDA noted that FDA is actively discussing these issues and potential mechanisms.
Note: Some participants referred to such a mechanism of provisional approval prior to an emergency as a “pre-EUA.” However, Michael Kurilla, director of the Office of BioDefense Research Affairs and associate director of Biodefense Product Development at NIAID, explained that the term pre-EUA is used by FDA to refer to a submission from a sponsor regarding potential future emergency use of a product, for the purposes of allowing FDA to begin to formulate draft EUA documentation, so that these drafts could be finalized more quickly should an emergency be declared. He noted that there has been variability as to when in the development of a product it could be considered eligible for data to be submitted for pre-EUA status, and what the pre-EUA package should look like is vague and ill defined. (The EUA itself is not a product approval pathway. Rather, it authorizes the use of an unapproved medical product, or an unapproved use of an approved medical product, during a declared emergency. This is based on FDA’s assessment that the data conclude that the known and potential benefits are likely to exceed the known and potential risks.)
The Animal Rule
In addition to discussions of the regulatory science aspects of the Animal Ruleb (see Chapter 3), participants expressed concerns about the implementation of the rule by FDA. It was noted that there are different interpretations of the rule across FDA divisions—and sometimes between reviewers within the same division—of how to apply to the Animal Rule. As a result, the rule is often inconsistently applied to sponsors. Elizabeth Leffel, director of nonclinical sciences at PharmAthene, said that a strategic plan for utilizing the Animal Rule is needed, starting with finalizing the current draft guidance.
Rose noted in his remarks that the Animal Rule is the primary obstacle to demonstrating substantial effectiveness of a product. He pointed out that many threat agents are not testable in clinical scenarios (one could not conduct a randomized trial of an Ebola treatment, for example), yet the Animal Rule has never been the basis for approval of a new chemical entity. Rose raised concerns that decision making at FDA on the definition of acceptable animal efficacy data for specific products is riddled with delay. He also suggested that FDA approval of new indications for previously approved drugs (e.g., ciprofloxicin approval for anthrax postexposure prophylaxis) sets a precedent for imputing substantial evidence of effectiveness from animal models.
The Public Readiness and Emergency Preparedness (PREP) Act provides liability coverage for manufacturers whose MCM product is used under an EUA. There is also liability protection for a company that advances a product under contract with BARDA. It was noted, however, that liability concerns persist. For example, if an MCM were approved and subsequently provided to the public in a different manner (e.g., not under an EUA, not from the SNS), liability protection likely would not be available. A participant suggested a legislative change be made to include nonvaccine MCMs under the National Vaccine Injury Compensation Program.
a Under Section 564 of the Federal Food, Drug, and Cosmetic Act, as amended by Project BioShield Act of 2004, the FDA commissioner may authorize the use of an unapproved medical product, or an unapproved use of an approved 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 accessed June 9 2011
b The Animal Rule (21 CFR 314.600 for drugs; 21 CFR 601.90 for biological products) establishes a regulatory process for FDA approval of certain new drugs and biologics used to reduce or prevent the toxicity of CBRN substances based on animal data, when adequate and well-controlled efficacy studies in humans cannot be ethically conducted and field trials are not feasible. See Guidance for Industry, Animal Models—Essential Elements to Address Efficacy Under the Animal Rule (Draft Guidance) http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM078923.pdf (accessed June 9, 2011).