critical path: overview of selected ongoing cber efforts and future opportunities jesse l. goodman,...

Download Critical Path: Overview of Selected Ongoing CBER Efforts and Future Opportunities Jesse L. Goodman, M.D., M.P.H Director Center for Biologics Evaluation

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  • Critical Path: Overview of Selected Ongoing CBER Efforts and Future Opportunities Jesse L. Goodman, M.D., M.P.H Director Center for Biologics Evaluation and Research
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  • Whole Blood Gene, Cell, Tissue Therapy Vaccines Tissues Blood Derivatives Blood Components Allergenic Extracts Xenotransplantation Blood Devices
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  • FDA Critical Path Initiative Facilitate product development through better tools and latest technologies for safety, efficacy and product manufacturing Focus intramural and extramural science as resources permit Includes identifying areas, especially new technologies, where needed standards, methods, assays, guidance can be helpful e.g. gene therapy, tissue engineering, stem cells, new vaccine technologies, blood substitutes, pathogen inactivation & detection Assure internal expertise, appropriate partnerships with industry, academic/scientific community and consumers Identify roadblocks, scientific and regulatory, and develop appropriate solutions e.g. VIG potency assay, rapid bacterial testing methods Guidance, standards, outreach, creative approaches to product development, safety/efficacy assessment and review, consistent production
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  • FDA Critical Path Initiative Assures internal expertise, appropriate partnerships with industry, academic/scientific community and consumers Benefits multiple sponsors; communication Maintains staff cutting edge expertise needed for dealing with evolving biotechnologies Scientific expertise and confidence foster objectivity Reduces risks of reflexive over- or under-protectiveness Make regulation more scientific, less defensive
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  • Recent Public Health Accomplishments With Critical Path Components WNV Blood Donor Screening initiated in 8 months Unprecedented collaboration with provision of samples, standards, methods, guidance New HIV, Hep C tests Intensive interactions with sponsors, expertise sharing TRANSNET Supply Monitoring Pilot Successful response to SARS, other EID events: including outreach on product development, needed laboratory studies and standards, vaccine strains Risk Assessment/Guidances re: TSE, CT & blood safety in house and collaborative expertise and modeling to address intervention strategies
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  • Selected Regulatory Activities With Critical Path Contributions New Technologies Successful management of SCID/Gene Therapy adverse events BRMACs re: Development of islet cell transplantation, cellular therapies for cardiac disease Outreach/international activities in gene therapy/xenotransplantation Cell Substrate Guidance Standards and outreach: e.g. adenovirus, plasma derivatives (Factor VIII), thrombin
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  • CBER Research Programs Increasing orientation toward Critical Path issues ~ 50% time/effort in regulatory review, inspection, lot release, regulatory policy development ~ 50% time/effort in critical path/product related research > 120 Biologics Licensing Applications & > 340 Investigational New Drug Applications directly supported by/related to Research Programs Evaluated at Site Visits by Advisory Committees Plan to extend evaluation to broad programmatic areas and include identifying unmet needs and opportunities
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  • CBER Research Programs II ~200 publications in FY03 Collaborations with >120 outside institutions, including collaborative research and formal leveraging arrangements (~35%) Other Government Agencies (CDC, NIH, NCI, DOD) Academia, some focused CRADAs with industry
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  • Critical Path Research: Recent Examples; Product Safety Product Safety: 42% of Research Programs Mechanisms of toxicity Unexpected pulmonary uptake of adenovirus vectors in animals with chronic liver disease. Gene Ther 2004 11:431-8Gene Ther 2004 11:431-8 Comparison of effects of two hemoglobin-based O(2) carriers on intestinal integrity and microvascular leakage. Am J Physiol Heart Circ Physiol 2002 283:H1292-301Am J Physiol Heart Circ Physiol 2002 283:H1292-301 Assay development and validation Single-tube fluorescent product-enhanced reverse transcriptase assay with Ampliwax (STF-PERT) for retrovirus quantitation. J Virol Methods 2003 108:139-42J Virol Methods 2003 108:139-42
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  • Adeno Vector-associated Lung Disease in Setting of Pre-existing Liver Disease 30 m A Adenovirus inside lung macrophages in rat with liver disease adenovirus macrophage Lung cell nucleus
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  • Public Health Promise of Blood Substitutes u Donor derived blood products carry risks, e.g., infection & allergic responses, currently managed by product testing and donor evaluation u Most blood products have short shelf lives and must be refrigerated/frozen u Donors often in limited supply (especially in critical situations such as war or bioterrorism) u Effective blood substitutes could enhance supply and reduce risks associated with donors
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  • Early blood substitutes associated with toxicities such as hypertension, inflammation, tissue damage Evaluate strategies to prevent hemoglobin toxicity, providing knowledge and pathway for manufacturing of second generation products Identified the link between the oxidative chemistry of a given hemoglobin and its toxicity Developed Endothelial Cell-based Model System to promote understanding of blood substitute toxicity and allow more accurate product testing during development CBER Collaborative Safety Research on Blood Oxygen Carriers
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  • Cell Substrates for Biologics Manufacturing: Safety Studies Adventitious Agents Stability of the prion protein-encoding (PRNP) gene in HeLa cells. Biologicals 2003 31:83-6iologicals 2003 31:83-6 Early detection of endogenous retroviruses in chemically induced mouse cells. Virus Res 2001 79:39-45Virus Res 2001 79:39-45 Porcine Endogenous Retrovirus Infects but Does Not Replicate in Nonhuman Primate Primary Cells and Cell Lines. J Virol 2002 76:11312-11320J Virol 2002 76:11312-11320
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  • Critical Path Research: Recent Examples in Product Characterization Product Characterization 26% Development of assays, standards and use of novel technology in regulatory setting PRODUCT IDENTITY:Genetic and phenotypic analysis of reassortants of high growth and low growth strains of influenza B virus. Vaccine 2003 21:3867-3874Vaccine 2003 21:3867-3874 Detection and Genotyping of Human Group A Rotaviruses by Oligonucleotide Microarray Hybridization. J Clin Microbiol 2002 40:2398- 2407J Clin Microbiol 2002 40:2398- 2407
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  • Product Characterization Product Identity, contd Molecular Cloning and Characterization of Genes for Shigella sonnei Form I O Polysaccharide: Proposed Biosynthetic Pathway and Stable Expression in a Live Salmonella Vaccine Vector. Infect Immun 2002 70:4414-4423Infect Immun 2002 70:4414-4423 Application of NMR, molecular simulation, and hydrodynamics to conformational analysis of trisaccharides. Biopolymers 2003 69:448-60Biopolymers 2003 69:448-60 Gene Expression in Human Embryonic Stem Cell Lines: Unique Molecular Signature. Blood 2003 Dec 30Blood 2003 Dec 30
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  • Characterization of Stem Cells to Assure Safety & Effectiveness Normal stem cells can form a variety of tissues and cell types, including blood, brain, bone, muscle etc. Safety concerns exist that include: Risk of unregulated growth after inoculation (cancer) Contamination with infectious agents Characterization of the stem cells is important in regulating their use as a medical therapy Inoculated in or expanded from one form, change to another state Need novel technological methods for accurate characterization
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  • Quality Assessment of Stem Cells by Gene Expression Profile Microarray CBER scientists have developed a method to identify and characterize 86 common stemness genes in 6 stem cell lines CD24 GTCM-1
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  • Product Characterization Purity Detection and discrimination of orthopoxviruses using microarrays of immobilized oligonucleotides. J Virol Methods 2003 112:67-78J Virol Methods 2003 112:67-78 Endotoxin content of standardized allergen vaccines. J Allergy Clin Immunol 2003 111:777-83J Allergy Clin Immunol 2003 111:777-83 Characterization and comparison of commercially available German and American cockroach allergen extracts. Clin Exp Allergy 2002 32:721-7Clin Exp Allergy 2002 32:721-7
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  • Product Characterization Potency Development of a novel vaccinia-neutralization assay based on reporter-gene expression. J Infect Dis 2003 188:440-8J Infect Dis 2003 188:440-8 Enabled both smallpox vaccine production and VIG testing by multiple manufacturers Methods Development Use of Coefficient of Variation in Assessing Variability of Quantitative Assays. Clin Diagn Lab Immunol 2002 9:1235-1239Clin Diagn Lab Immunol 2002 9:1235-1239 Lot consistency as an equivalence problem. Control Clin Trials 2003 24: 88 Suppl.
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  • Critical Path Research:Efficacy Product Efficacy 20% Surrogate measures of efficacy Sensitivity and reproducibility of HCV quantitation in chimpanzee sera using TaqMan real-time PCR assay. J Virol Methods 2002 105:253J Virol Methods 2002 105:253 Comparative Immune Response to PE and PE_PGRS Antigens of Mycobacterium tuberculosis. Infect Immun 2001 69:5606-11Infect


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