CBER Regulates Complex (MCM) Products

Transcription

1 Tissues Cell & Gene Therapies CBER Regulates Complex (MCM) Products Mesenchymal Stem Cells Skin, tissues Pathogen-specific Immunoglobulins Blood, Blood Components and Derivatives Anthrax, Botulinum, Smallpox, Flu Vaccines: Preventive & Therapeutic Xenotransplantation Products Post-Marketing Surveillance Related Devices Allergenic Products

2 CBER Mission: Role of Regulatory Science Novel Product Licensed Product Public Health Regulatory Challenge Improved Data Benefit/Risk Regulatory Policy/Decision Regulatory Science Discovery New Tools

3 Scope of CBER s MCM-Related Regulatory Science Program Agents/Diseases Anthrax Botulism Tularemia Smallpox Viral hemorrhagic fevers Pandemic Influenza Emerging Infectious Disease Chemical/Rad/Nuc Cell therapies Approaches to address Manufacturing Potency, other lot release assays Animal models Biomarkers/correlates of protection Clinical trial design Post-marketing safety

4 FDA s MCMi: Pillar 2 Animal Model Biomarker Program Clinical Biomarker and Immunology Program Ensuring MCM Product Quality Risk Communication Strategies in Public Health Emergencies Radiation Injury Protection and Response Program Development of Diagnostic Platforms for CBRN/Flu Health Informatics/Scientific Computing

5 Animal Model Biomarker Needs Identify in vitro or in vivo correlates of bioactivity, safety, toxicity Methods development Develop and evaluate animal models Anticipated Public Health Outcomes Earlier identification of toxicity Improved means to assess potential for efficacy Improved guidance to sponsors on how to implement the Animal Rule

6 Animal Model Biomarker Stages of Anthrax Infection in vivo using IVIS Stage I Stage II Stage II/III Stage III Courtesy of Tod Merkel, CBER

7 Claudin-5 (relative to control) Identifying New Biomarkers of Vascular Pathology Induced by Anthrax Lethal Toxin 1.2 No Toxin Lethal Toxin Time (h) Claudin-5 expression disrupted in vivo Human endothelial culture models Anthrax Animal Models Courtesy of Felice D Agnillo, CBER

8 Clinical Biomarker and Immunology Needs: How to bridge from animal studies to the immune response to vaccines in humans Insufficient knowledge of human disease Clinical Trial Design Anticipated Public Health Outcomes: New scientific tools and biomarkers facilitate development of safe and effective MCM biologics Improved guidance to sponsors on how to develop MCM biologics

9 Developing New Methods to evaluate human responses to INFLUENZA Vaccine and Adjuvants Using Phage-Display-Library H5N1 vaccine + adjuvant Broader antibody profile Khurana & Golding, CBER

10 Relative NA activity (%) Developing New Methods for Clinical Vaccine Evaluation New-generation vaccines may contain other influenza components that contribute to protection in addition to HA NFS anti-h1n1 anti-h3n Serum dilution Miniaturized neuraminidase inhibition assay sensitive and specific method to quantify antibody response to viral NA Courtesy of Sandbulte & Eichelberger, CBER

11 Ensuring MCM Product Quality Needs: Measurable product characteristics that correlate with safety and efficacy Improved methods to assess new cell substrates New methods that incorporate new technology and are faster, use less animals, have improved sensitivity/specificity Anticipated Public Health Outcomes: New scientific tools and methods to facilitate development of safe and effective MCM biologics Improved guidance to sponsors on how to evaluate MCM biologics products

12 Improve Reagents for Potency Assay, Anthrax Vaccines: Cytotoxic activity of LF preparations The N-terminal amino acid of LF significantly affects its activity in cell-based assays Recombinant forms of LF should be designed with this characteristic in mind Care should be taken to ensure that proteolytic nicking of the N-terminal residue does not occur during purification Courtesy of Drusilla Burns, CBER

13 Faster Methods to Generate Reference Reagents for Influenza Vaccines Current techniques require availability and preparation of virus, and HA purification before immunization to generate strain-specific antibody - not always successful (e.g., H5N1, pandemic H1N1) Using recombinant techniques, potency antibody can be generated in absence of virus growth and HA purification A/Vietnam Vaccine A/ Vietnam Traditional HA (μg/ml) A/Vietnam Alternative Lot / /-11 Lot / /30 Courtesy of Schmeisser, Vodeiko, Lugovtsev & Weir, CBER

14 Improve Detection of Adventitious Agents Challenge: Detect and identify even unknown infectious agents in complex samples (e.g., cell substrates, raw materials) that contain interfering cellular nucleic acids. Enrichment/Purification Techniques coupled with Massively Parallel Sequencing Microarray Chips Multi-plex PCR

15 Radiation Injury Protection and Response Program Needs: Improved tools to assess critical product attributes of cell therapy-based products used to treat radiation injury Animal models to evaluate product safety and potential for efficacy Anticipated Public Health Outcomes: New scientific tools and methods to facilitate development of safe and effective MCM biologics Improved guidance to sponsors on how to evaluate MCM biologics products

16 Identification and correlation of product characteristics with in vivo and in vitro assays predictive of safety and efficacy In vivo model of critical hind limb ischemia Multipotent Stem Cell Characterization Markers/ Attributes In vitro quantitative proliferation and differentiation adipogenesis In vitro immunosuppression MSC T Alterman, Bauer, Hursh, McCright, Moos, Puri, Wei labs

17 Needs Health Informatics and Scientific Computing Improved means to detect rare adverse events Improved methods and access to healthcare data sources to monitor safety of marketed MCM biologics Improved use of high performance computing Tools/Models for Risk Assessment Anticipated Public Health Outcomes More rapid detection of safety signals associated with risk Improved decision-making for benefit:risk

18 Automating AE Report Classification Initial Review Reduced from 6,034 to 535 MOs review Text Miner Pos Neg Totals Pos Neg Totals Sensitivity: 77.2% Specificity: 94.0% PPV: 34.2% Misclassification error: 6.7% Courtesy of Taxiarchis Botsis, et al., CBER

19 H1N1 Pandemic Influenza Vaccine Safety Monitoring

20 Risk Assessment Providing quantitative, probabilistic risk assessments to support regulatory decision-making Developing new tools for risk:benefit assessment Currently conducting vaccine safety assessments

21 With Thanks to Many in CBER Counter-Terrorism, Sr Advisor, Cynthia Kelley Office of Biostatistics and Epidemiology Steven Anderson Richard Forshee Office of Blood Research and Review Felice D Agnillo Robert Fisher Michael Kennedy Dorothy Scott Office of Cellular Tissues and Gene Therapies Steven Bauer Malcolm Moos Office of Vaccines Research and Review Drusilla Burns Hana Golding Tod Merkel Jerry Weir