Center for Biologics Evaluation and Research Current Activities Future Directions Washington, DC January 25, 2010 Karen Midthun, MD Acting Director, CBER
CBER Our Mission To ensure the safety, purity, potency, and effectiveness of biological products, including vaccines, blood and blood products, and cells, tissues, and gene therapies for the prevention, diagnosis, and treatment of human diseases, conditions, or injury; and help to defend the public against the threats of emerging infectious diseases and bioterrorism.
CBER Our Vision Using sound science and regulation to: Protect and improve public and individual health in the US and globally Facilitate development, approval, and access to safe and effective products and promising new technologies Strengthen CBER as a pre-eminent eminent regulatory organization for biologics
CBER Regulates Complex Products Cell & Gene Therapies Blood, Blood Components and Derivatives Tissues Xenotransplantation Products Vaccines: Preventive & Therapeutic Related Devices Allergenic Products
CBER Regulatory Issues Complex products Source materials may be living cells, organisms, or tissues Inherent risks from infectious agents Complex manufacturing processes, facilities, & products Difficult products to characterize Stemagen via Bloomberg News Multiple mechanisms of action that are not always predictable
CBER Priorities Enhance the nation s s preparedness for health emergencies Protect and promote public health globally Keep products and patients safe Improve the quality and safety of biological products Bring innovative products to patients Strengthen our human resources and performance
Using Science and Regulation to Using Science and Regulation to Advance Product Development Internal Discussion Review of Data Submitted to FDA Mission-directed Research External Input & Discussion
Using Science and Regulation to Advance Product Development Cell Therapy Challenges Poor understanding of how cells interact with their microenvironment Inadequate markers predictive of cell state and cell fate Poor survival of cells post transplantation Limited supplies of starting & source material Complex assay development and testing issues
Stem Cells Developing Tools, Methods, and Regulatory Recommendations CBER performs critical path research to identify characteristics of stem cells in order to facilitate development of safe and effective products Guiding sponsors on what to measure Developing assay tools and methods Learning how to predict product safety and effectiveness
Final: NEW CBER GUIDANCES Clarifying Pathways for Developing Innovative Cell & Gene Therapy Products Minimally Manipulated, Unrelated Allogeneic Placental/ Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications IND Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications Draft: Clinical Considerations for Therapeutic Cancer Vaccines Considerations for Allogeneic Pancreatic Islet Cell Products Somatic Cell Therapy for Cardiac Disease Current Good Tissue Practice and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products
Using Science and Regulation to Advance Product Development The Influenza Program & Other Vaccines Photo: Wikimedia Commons
The Influenza Program Develops new high-growth growth influenza virus reference strains for vaccines Evaluates manufacturers influenza seed viruses before vaccine production Prepares influenza virus reagents to determine potency of influenza vaccines Expanded post-market ongoing safety assessment Photo: Wikimedia Commons
The Influenza Program CBER Develops Reference Strains for Vaccine Production Development of Reference Virus WHO & CDC Classical WHO, CDC & CBER Reverse Genetics WHO & CDC CDC/WHO confirms ref. strains Provided to manufacturers WHO, CDC & CBER
Influenza Vaccine and FDA s s Sentinel Initiative Initial Vision: Development of a nationwide electronic safety monitoring system Under FDAAA, section 905, FDA is required to link to disparate sources of safety data in order to access 25 million patient records by 2010 and100 million by 2012 Example of a CBER/CMS collaboration: Rapid analysis of Guillain-Barr Barré Syndrome after flu vaccine in 2006.* Vaccinations 14,000,000 12,000,000 10,000,000 8,000,000 6,000,000 4,000,000 2,000,000 0 GBS Cases Per Million 3.5 3 2.5 2 1.5 1 0.5 0 8/25/2006 9/1/2006 9/8/2006 9/15/2006 9/22/2006 9/29/2006 10/6/2006 10/13/2006 10/20/2006 10/27/2006 11/3/2006 11/10/2006 11/17/2006 11/24/2006 12/1/2006 12/8/2006 12/15/2006 12/22/2006 12/29/2006 * GBS rate not elevated compared to background rate
Influenza Vaccine Current and Future Challenges Improving reagent preparation & calibration for potency Expediting calibration process Developing back-up procedures to ensure reagent availability Developing new methods for potency determination Increasing sensitivity Methods that are not antibody dependent Developing new technologies to determine potency of new- generation vaccines Cell culture-derived derived vaccines Adjuvanted vaccines DNA vaccines Recombinant-protein protein-based vaccines including virus- like particles
Alternatives for Reagent Production Current process Growth of influenza virus and HA purification Immunize sheep with purified HA to make potency antibody Process sometimes problematic (e.g., pandemic H1N1) Alternative approach Recombinant techniques can be used to express HA and generate potency antibody Does not depend on growing the influenza virus and purifying HA from it Potential for more rapid reagent availability Testing at CBER has shown comparable results for HA content of influenza vaccines using potency antibody obtained through traditional and recombinant techniques (Future CBER publication in Vaccine)
Improving the Current Reagent Calibration Process Recently reported mass spectrometry (MS) technique (CDC) uses isotope dilution approach to quantify HA in complex mixtures (Williams et al, CDC) Multi-Center collaboration (FDA/CDC) to evaluate use of MS to determine absolute quantity of HA in primary influenza standard If correlated with current methods, time necessary for calibration could be reduced from weeks to days
Other Vaccine Initiatives Evaluating New Technologies and Methods for Vaccine Characterization
Developing Models Improving Evaluation of Novel Vaccine Cell Substrates Sensitive & Quantitative Animal Models to Assess DNA Oncogenicity Issue: no standardized assay to assess cancer risk posed by introduction n of oncogene via contaminating cellular DNA CBER research findings: 6-month assay (newborn CD3 epsilon mice) detected tumors with 800 pg plasmid carrying two known oncogenes; ; 100 ug MDCK DNA did not cause tumors. Implications: The assay in CD3 epsilon mice might be sensitive enough to assess the oncogenicity of cell-substrate DNA. Mice with tumors (%) MDCK DNA MDCK DNA + ras/myc Groups of Mice Inoculated
Universal Virus Detection Project Challenge: Detect and identify even unknown viral contaminants in complex samples (e.g., cell substrates, raw materials) that contain interfering cellular nucleic acids Develop robust approaches to enrich for viral contaminants (e.g., asymmetrical field flow fractionation & other separation techniques) Universal signal amplification Adapt high throughput sequencing to identify amplified sequences Develop approaches to analyze & manage large amounts of sequencing data Current work is advancing the state of the art*. Similar approaches are being used by sponsors to qualify new cell substrates. *(J Clin Virol 2009; 44(4):337-9, J Virol Methods 2008; 152:18-24)
Evaluating NMR Spectroscopy for Vaccine Characterization Atomic Resolution Non-Destructive Quantitative Distinguish between standard, diluted & adulterated vaccines Molecular Analysis: Polysaccharides, proteins, DNA, RNA, adjuvants, excipients Product Quality: Consistency, adulteration, lot release, structural integrity, validation of assay steps
Using Science and Regulation to Advance Product Development Blood and Blood Products
Blood & Blood Products Novel Products Licensed with New Regulatory Pathways ATryn: : recombinant human antithrombin produced in milk of transgenic goats To prevent perioperative/peripartum thromboembolism in hereditary antithrombin deficiency
Evaluating Novel Technologies for Blood Screening: Nanotechnology Identification of Influenza A viruses: H1N1, H3N2, H5N1 and swine 2009 A (H1N1) Seasonal H1N1 Array Seasonal H3N2 Array Swine Flu 2009 H1N1 Array virus RNA PCR-free RNA detection using gold nanoparticles and silver stain enhancement H1N1 H3N2 H5N1 swh1n1 HA and NA genes are highly specific for each strain There are some cross interaction for M gene captures between swine flu and other three strains Current array can specifically identify swine flu 2009 A (H1N1)
Blood Safety Guidances Address Agents of Emerging Infectious Disease Draft Guidance for Industry: Recommendations for the Assessment of Blood Donor Suitability, Blood Product Safety, and Preservation of the Blood Supply in Response to Pandemic (H1N1) 2009 Virus (11/13/2009) Guidance for Industry: Use of Nucleic Acid Tests to Reduce the Risk of Transmission of West Nile Virus from Donors of Whole Blood and Blood B Components Intended for Transfusion (11/6/2009) Guidance for Industry: Recommendations for Management of Donors at Increased Risk for Human Immunodeficiency Virus Type 1 (HIV-1) Group O Infection (8/2009) Guidance for Industry: Nucleic Acid Testing (NAT) to Reduce the Possible Risk of Parvovirus B19 Transmission by Plasma-Derived Products (7/28/2009) Draft Guidance for Industry: Use of Serological Test to Reduce the Risk of Transmission of Trypanosoma cruzi Infection in Whole Blood and Blood Components for Transfusion and Human Cells, Tissues, and Cellular r and Tissue-Based Products (3/2009)
Blood Safety Workshop Addressing Agents of Emerging Infectious Disease Public Workshops: Emerging Arboviruses: : Evaluating the Threat to Transfusion and Transplantation Safety (Dec. 14-15, 15, 2009) Transfusion-Transmitted Transmitted Babesiosis in the United States (Sept. 12, 2008)
Using Science and Regulation to Advance Product Development Maintaining Product Safety FEMA/Mark Wolfe
CBER Safety Teams 3 Office-based teams Tissue Safety Team (Cellular, Tissue, & Gene Therapies) Blood Safety Team (Blood Research & Review) Vaccine Safety Team (Vaccines Research & Review) With multi-disciplinary collaborations within CBER Office of Biostatistics & Epidemiology Office of Compliance & Biologics Quality Office of Communication, Outreach & Development Office of the Center Director
CBER Post-Marketing Safety Collaborations Vaccine Adverse Event Reporting System (with CDC) Centers for Medicaid & Medicare Services (CMS): 45 million enrollees Department of Defense Vaccine Safety Database (managed by CDC) Department of Veterans Affairs Indian Health Service Post-Licensure Rapid Immunization Safety Monitoring (linking state immunization registries with health care database medical records) International collaborations (e.g., WHO and many regulatory and public health agencies worldwide)
CBER Is a Partner in Biologics Development & Production 1. Characterizing the Product 2. Guidance Workshops Advisory Committees Informal Communications Identifying & selecting critical quality attributes 4. Relating quality attributes to safety & efficacy 3. Relating process control to quality
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