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

Whole Blood Gene, Cell, Tissue Therapy Vaccines Tissues Blood Derivatives Blood Components Allergenic Extracts Xenotransplantation Blood Devices

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

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”

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

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

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

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

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 :431-8Gene Ther :431-8 Comparison of effects of two hemoglobin-based O(2) carriers on intestinal integrity and microvascular leakage. Am J Physiol Heart Circ Physiol :H Am J Physiol Heart Circ Physiol :H Assay development and validation Single-tube fluorescent product-enhanced reverse transcriptase assay with Ampliwax (STF-PERT) for retrovirus quantitation. J Virol Methods :139-42J Virol Methods :139-42

Adeno Vector-associated Lung Disease in Setting of Pre-existing Liver Disease 30 μm A Adenovirus inside lung macrophages in rat with liver disease adenovirus macrophage Lung cell nucleus

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

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

Cell Substrates for Biologics Manufacturing: Safety Studies Adventitious Agents Stability of the prion protein-encoding (PRNP) gene in HeLa cells. Biologicals :83-6iologicals :83-6 Early detection of endogenous retroviruses in chemically induced mouse cells. Virus Res :39-45Virus Res :39-45 Porcine Endogenous Retrovirus Infects but Does Not Replicate in Nonhuman Primate Primary Cells and Cell Lines. J Virol : J Virol :

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 : Vaccine : Detection and Genotyping of Human Group A Rotaviruses by Oligonucleotide Microarray Hybridization. J Clin Microbiol : J Clin Microbiol :

Product Characterization  Product Identity, cont’d 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 : Infect Immun : Application of NMR, molecular simulation, and hydrodynamics to conformational analysis of trisaccharides. Biopolymers :448-60Biopolymers : Gene Expression in Human Embryonic Stem Cell Lines: Unique Molecular Signature. Blood 2003 Dec 30Blood 2003 Dec 30

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

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

Product Characterization  Purity Detection and discrimination of orthopoxviruses using microarrays of immobilized oligonucleotides. J Virol Methods :67-78J Virol Methods :67-78 Endotoxin content of standardized allergen vaccines. J Allergy Clin Immunol :777-83J Allergy Clin Immunol : Characterization and comparison of commercially available German and American cockroach allergen extracts. Clin Exp Allergy :721-7Clin Exp Allergy :721-7

Product Characterization  Potency Development of a novel vaccinia-neutralization assay based on reporter-gene expression. J Infect Dis :440-8J Infect Dis :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 : Clin Diagn Lab Immunol : Lot consistency as an equivalence problem. Control Clin Trials : 88 Suppl.

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 :253J Virol Methods :253 Comparative Immune Response to PE and PE_PGRS Antigens of Mycobacterium tuberculosis. Infect Immun : Infect Immun : Innate and adaptive immune responses to an intracellular bacterium, Francisella tularensis live vaccine strain. Microbes Infect : Microbes Infect :135-42

Efficacy  Surrogate measures of efficacy, cont’d Correlates of immunity for pneumococcal conjugate vaccines. Vaccine : accine : Immunoglobulin G3 from Polyclonal Human Immunodeficiency Virus (HIV) Immune Globulin Is More Potent than Other Subclasses in Neutralizing HIV Type 1. J Virol : J Virol :  Animal models Vaccination with DNA encoding internal proteins of influenza virus does not require CD8(+) cytotoxic T lymphocytes: either CD4(+) or CD8(+) T cells can promote survival and recovery after challenge. Int Immunol :91-101Int Immunol : DNA vaccine expressing conserved influenza virus proteins protective against H5N1 challenge infection in mice Emerg Infect Dis : Emerg Infect Dis :

Efficacy  Statistical and Epidemiological Analysis Biomarkers and surrogate endpoints in renal transplantation: present status and considerations for clinical trial design. Am J Transplant 2004 Apr;4(4):451-7 Proper metrics for clinical trials: transformations and other procedures to remove non-normality effects. Stat Med :  “Other” 7% Anticipated products, e.g., SARS

Examples of Major Critical Path Investment Opportunities New vaccine delivery systems, rapid use vectors Develop/make available well characterized cell banks (and related methods to assay for safety/adventitious agents) useful for vaccine and other biologics production – and update guidance for use Characterization of cell therapies & links to standardized outcomes (e.g. HPSCs) Methods & validation of pathogen inactivation for blood, plasma, tissues and other products Multipathogen and rapid detection methodologies for biologics including blood and tissue products Improving longevity/storage of blood and tissues

New Delivery Methods for Vaccines and Gene Therapies  DNA vaccines & vectors: distribution, integration  Safety testing: Tumorigenicity  New vaccine platforms: Plug and play-ability to generalize and predict immunogenicity and safety  Transgenic plant vaccines  Adjuvants & immune stimulants CpG, lipid nanotech particles, mucosal/transdermal patch delivery, maternal vaccination  Tumor vaccines  Parasite vaccines

Characterize Cellular Products and Link to Outcomes  Develop well characterized standard and innovative biomarkers predictive of product toxicity and efficacy (e.g. genomic and proteomic profiles)  In vitro expanded, selected and genetically modified cell lines Identify meaningful changes in cell specifications or environmental “stress” on cells  Link molecular and immunologic data to standardized and measurable clinical outcomes across similar studies and products Types and gene expression patterns of stem cells that will predictably and reproducibly perform well as medical therapy

Develop and Facilitate Availability of Cell Substrates for Biologics Products  Vaccines, gene therapies, and recombinant proteins increasingly cell derived  Cell based vaccines may offer enhanced flexibility and capacity for urgent production (e.g. influenza)  Increased number diversity of screened, well characterized cell banks needed to be “on the shelf” for biologics manufacture Capable of needed performance (e.g. diverse virus types) Tested for relevant transmissible infectious agents Tested by well characterized and predictive tumorigenicity assays Can reduce/eliminate use of animal products in biologics manufacture

Detection & Inactivation of Emerging Pathogens in Blood, cell/tissue & Vaccine Products  Multipathogen testing Need to engage new, rapidly adaptable platforms Nanotechnology and “flow through” assays Bacterial contamination  TSE rapid screening  Blood and plasma products – methods to inactivate In process determination of clearance of viruses& prions New approaches to TSE’s Nanofiltration to reduce viral contamination Chemical treatments  Mechanisms for testing and decontamination of human tissues that preserve integrity

Better, Longer Lasting Blood, Cellular and Tissue Products  Improved cryopreservation and thawing methods: development and validation (e.g. for RBC stockpiles, other cellular products)  Improved hemopoeitic stem cell production, quality, and preservation  Enhanced platelet preservation and quality  Blood “substitutes” for field/urgent use

Improved Methods of Clinical Data Quality and Analysis  Combined clinical trial data analysis Development of standardized outcomes measures among product classes Data mining New statistical approaches, e.g., pediatric dosing  Large, simple trials to obtain key data and reduce costs, pre- and post-marketing  Develop consensus on handling of “missing data”

Thanks!  We believe that FDA can help to identify opportunities and develop better tools to improve the safety, efficacy and predictability of product development along the “critical path” to patients  We look forward to continuing engagement with colleagues and stakeholders in academia, industry, and the public both to further identify and target areas for scientific investment  Together we can enhance successful product development that promotes public health CBER: INNOVATIVE TECHNOLOGY ADVANCING PUBLIC HEALTH