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
BloodComponents
Allergenic Extracts
Xenotransplantation
BloodDevices
FDA Critical Path Initiative Facilitate product development through better tools
and latest technologies for safety, efficacy and product manufacturing www.fda.gov/oc/initiatives/criticalpath/whitepaper
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 HealthAccomplishments 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 ProgramsCBER 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 IICBER 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 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:H1292-301
Assay development and validation Single-tube fluorescent product-enhanced reverse transcriptase
assay with Ampliwax (STF-PERT) for retrovirus quantitation. J Virol Methods 2003 108:139-42
Adeno Vector-associated Lung Diseasein Setting of Pre-existing Liver Disease
30 μmA
Adenovirus inside lung macrophages in rat with liver disease
adenovirusmacrophage
Lung cellnucleus
Public Health Promise of Blood “Substitutes”
Donor derived blood products carry risks, e.g., infection & allergic responses, currently managed by product testing and donor evaluationMost blood products have short shelf lives and must be refrigerated/frozenDonors often in limited supply (especially in critical situations such as war or bioterrorism)Effective blood “substitutes” could enhance supply and reduce risks associated with donors
2,3 DPG
Red Cell Perfluorocarbonemulsion
Surfactant(lecithin)
Hemoglobintetramer
Cross-linked Tetramer
Polymer Encapsulation
Conjugated Tetramer
Liposome
PFC
PFC
PFC
Various forms of Red Cell Substitutes
• 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 2003 31:83-6
Early detection of endogenous retroviruses in chemically induced mouse cells. Virus Res 2001 79:39-45
Porcine Endogenous Retrovirus Infects but Does Not Replicate in Nonhuman Primate Primary Cells and Cell Lines. J Virol 2002 76:11312-11320
Critical Path Research: Recent Examples in
Product Characterization Product Characterization 26%
Development of assays, standards and use of novel technology in regulatory settingPRODUCT IDENTITY:Genetic and phenotypic
analysis of reassortants of high growth and low growth strains of influenza B virus. Vaccine 2003 21:3867-3874
Detection and Genotyping of Human Group A Rotaviruses by Oligonucleotide Microarray Hybridization. J Clin Microbiol 2002 40:2398-2407
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 2002 70:4414-4423
Application of NMR, molecular simulation, and hydrodynamics to conformational analysis of trisaccharides. Biopolymers 2003 69:448-60
Gene Expression in Human Embryonic Stem Cell Lines: Unique Molecular Signature. Blood 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 2003 112:67-78
Endotoxin content of standardized allergen vaccines. J Allergy Clin Immunol 2003 111:777-83
Characterization and comparison of commercially available German and American cockroach allergen extracts. Clin Exp Allergy 2002 32:721-7
Product CharacterizationPotency
Development of a novel vaccinia-neutralization assay based on reporter-gene expression. J Infect Dis 2003 188:440-8
Enabled both smallpox vaccine production and VIG testing by multiple manufacturers
Methods DevelopmentUse of Coefficient of Variation in Assessing Variability of Quantitative Assays. Clin Diagn Lab Immunol 2002 9:1235-1239
Lot consistency as an equivalence problem. Control Clin Trials 2003 24: 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 2002 105:253
Comparative Immune Response to PE and PE_PGRS Antigens of Mycobacterium tuberculosis. Infect Immun 2001 69:5606-11
Innate and adaptive immune responses to an intracellular bacterium, Francisella tularensis live vaccine strain. Microbes Infect 2003 5:135-42
Efficacy Surrogate measures of efficacy, cont’d
Correlates of immunity for pneumococcal conjugate vaccines. Vaccine 2003 21:2199-205
Immunoglobulin G3 from Polyclonal Human Immunodeficiency Virus (HIV) Immune Globulin Is More Potent than Other Subclasses in Neutralizing HIV Type 1. J Virol 2001 75:6558-65
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 2000 12:91-101
DNA vaccine expressing conserved influenza virus proteins protective against H5N1 challenge infection in mice Emerg Infect Dis 2002 8: 796-801
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 2003 22:3823-42
“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
