Advancing Regulatory Science for Medical Countermeasure Development Workshop Summary (2011) / Chapter Skim
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2 MCM Enterprise and Stakeholder Perspectives
2 MCM Enterprise and Stakeholder Perspectives
Pages 15-28
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From page 15... ...
, and Center for Devices and Radiological Health (CDRH) provided a broad overview of current efforts underway at the agency to support research, development, and evaluation of MCMs, and discussed current challenges and how regula tory science can assist in advancing MCM development and evaluation.
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From page 16... ...
In closing, McCune said, CDER has a robust regulatory science pro gram with significant expertise to support the research agenda of the MCM initiative, and CDER researchers and reviewers are eager to collaborate on efforts to advance the regulatory science needs of the initiative. NDA/BLA Postmarketing Review Surveillance Pre-IND IND • Adverse • Identification • Phase I studies event of potential • Phase II studies reporting compounds • Phase III studies • Data mining • Animal • Manufacturing toxicology studies FIGURE 2-1 FDA regulatory review cycle.
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From page 17... ...
One example of current CBER research on animal model biomarkers involves luciferase-expressing Bacillus anthracis, which allows for more precise staging of the bacterial infection in mice, and improved design for studies of such things as postexposure prophylaxis and combination therapies. This approach is generalizable, Wilson said, and could be applied to other pathogens and to the development of improved animal models.
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18 ADVANCING REGULATORY SCIENCE FOR MCM DEVELOPMENT TABLE 2-1 Examples of Potential Areas for Pillar 2 Research in CDER Phase of Development Potential CDER Research Areas Identification of Repurposing drugs Potential Molecules for Molecular modeling Study Screen approved drugs for other pathogens Effects of combinations of antimicrobials Animal Toxicology Animal models: Studies and For pregnancy Animal Models for Modeling of disease states in general MCM To study toxin effects on organ systems Qualified through the drug development tools qualification process For combination added benefit studies For placebo studies For postexposure prophylaxis To evaluate potential safety signals For studies of natural history and pathophysiology of disease Conversion of data from animal model studies to standard format Animal model database Human Safety Studies Evaluation of the effects of genetic variations for MCMs or Studies of dosage forms for special populations Clinical Safety and Extrapolation models from animal to human, Efficacy Studies for including dose scaling for special populations Influenza Pediatric safety studies, including ethical issues Understanding human disease through the world literature Development of clinical endpoints for seriously ill influenza patients Development of threat-based data standards Development of standardized case report forms for data collection Modeling drug interaction studies Modeling of PK/PD to labeled drugs for special populations Manufacturing and Therapeutic protein PK/PD comparability studies Product Quality Shelf-life extension studies Develop stable product formulations Rapid detection of problems with marketed products
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19 MCM ENTERPRISE AND STAKEHOLDER PERSPECTIVES TABLE 2-1 Continued Phase of Development Potential CDER Research Areas Incident-Related Studies Develop hospital networks for rapid information transfer Communication studies on emergency notification Data mining for adverse events associated with therapy Develop protocols for use during events Real-world use studies on home preparation instructions Real-time epidemiology cluster monitoring NOTE: PK/PD, pharmacokinetic/pharmacodynamic. TABLE 2-2 Examples of Potential Areas for Pillar 2 Research in CBER Pillar 2 Program Research Needs Animal Model Biomarker Identify in vitro or in vivo correlates of bioactivity, Program safety, toxicity Methods development Develop and evaluate animal models Clinical Biomarker and How to bridge from animal studies to the human Immunology Program immune response to vaccines Insufficient knowledge of human disease Clinical trial design Ensuring MCM Product Measurable product characteristics that correlate with Quality safety and efficacy Improved methods to assess new cell substrates New methods that incorporate new technology and are faster, use fewer animals, and have improved sensitivity/specificity Radiation Injury Protection Improved tools to assess critical product attributes of and Response Program cell therapy-based products used to treat radiation injury Animal models to evaluate product safety and potential for efficacy Health Informatics/ Improved means to detect rare adverse events Scientific Computing Improved methods and access to health care data sources to monitor safety of marketed MCM biologics Improved use of high-performance computing Tools/models for risk assessment
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From page 20... ...
Malin highlighted the regulatory science priorities in CDRH, noting that they are similar to those of the other centers: • evelop infrastructure to support development of diagnostics and d other MCMs; • haracterize the medical device supply chain; c • nable real-time or near-real-time surveillance of supply, utiliza e tion, and availability of medical devices to avoid shortages; • ddress special needs populations, point of care, and personalized a use of MCMs; • nhance ability to capture, monitor, and analyze large datasets; e • reate statistical tools to develop innovative clinical trials, perform c comparative effectiveness research, and perform active surveil lance of adverse event reports; • enomic sequencing devices and assays for the detection of patho g gens and antimicrobial drug resistance; • ultiplex/microarray diagnostic devices capable of simultaneous m detection/identification of multiple organisms; • evelop new tools to evaluate nanotechnology-based devices, d including use as diagnostic markers; • ncrease scientific capacity and expertise to prepare for and facili i tate new technologies; • evelop guidance for development of multiuse products and plat d forms to expand MCM product pipelines during emergencies; • nfrastructure, comparator sequencing database, data processing, i and resources to enhance reviews of MCMs, facilitate innovative statistical techniques and clinical trials, and develop regulatory pathways for MCMs; • greement with Centers for Medicare and Medicaid Services (CMS) a on data necessary for Clinical Laboratory Improvement Amend ments (CLIA)
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From page 21... ...
Wilson pointed out that CBER has "research reviewers" who are actively engaged in both the regulatory science agenda and review activi ties. Research reviewers can help identify gaps in the science, as well as methods, tools, and reference materials that could help move a technology or a whole product area forward.
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The FDA panelists suggested that metrics should be associated with smaller, incremental steps, such as solving a problem that allows for a potency assay in vitro instead of in hundreds of animals, thereby increasing speed and decreasing the cost of that potency assay. ENTERPRISE PARTNER AND STAKEHOLDER PERSPECTIVES Immediately following the panel presentations from FDA representatives, stakeholders representing the other key components of the MCM enterprise provided remarks in which they identified key issues in MCM development and utilization that can be addressed through regulatory science and offered suggestions of regulatory science needs or priorities to advance MCM development.
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National Institute of Allergy and Infectious Diseases (NIAID) Michael Kurilla, of NIAID, explained that NIAID is taking a compre hensive approach to MCM development, with certain general criteria for vaccines, therapeutics, and diagnostics.
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From page 24... ...
However, the traditional regulatory paradigm is regulation in the context of a product, and there is little interaction with the agency in the absence of a specific product. Product developers approach FDA when they are ready to take a product into pivotal efficacy and safety studies, and it is at that late point that some of the development tools, such as the animal models used thus far, begin to be critically reviewed and questioned (e.g., is the species relevant, is the challenge strain appropriate)
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, a key national stakeholder in the MCM enterprise, is currently facing a variety of challenges in the area of diag nostics development, said May Chu, director of the Laboratory Science Policy and Practice Program at CDC. Chu described CDC's most significant current challenge as obtaining FDA clearance of LRN-developed assays (including 11 polymerase chain reaction [PCR]
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It will be important to educate the public regarding advances in regulatory science, Lyons pointed out, particularly the use of animal models for approval of products. It has been difficult, for example, to convince people to be vaccinated, or to have their children vaccinated, with prod ucts that have been FDA approved based on clinical trials in humans.
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From page 27... ...
Rose concluded by noting that while robust evidence of meaningful outcomes from controlled clinical trials remains the scientific gold standard for efficacy, the challenges facing MCM development are not neces sarily new, and FDA has helped foster other industry segments in the absence of feasible trials, including, for example, orphan drugs, complex medical devices (e.g., artificial hearts) , and diagnostics.
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From page 28... ...
Key Messages: Enterprise Stakeholder Perspectives • The regulatory paradigm for MCM development needs to be supported by new regulatory science and evaluative tools that are product-independent. There is a need for a format to permit engagement between product developers and FDA outside the context of a specific product approval.
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