1. Biologicals: A Vision for the Future of Clinical Investigators in Evaluations of New Biological Products Karen Midthun, MD Acting Director Center for Biologics Evaluation And Research February 25, 2010 Add FDA Bar and

2. Biologics Control Act, 1902 The Horse CBER Rode in On Diphtheria antitoxin from a milk horse named Jim 1901: Anti-toxin from Jim was contaminated with tetanus1901: Anti-toxin from Jim was contaminated with tetanus Serum made in St. Louis with no central or uniform controls to ensure potency and purity; no inspectionsSerum made in St. Louis with no central or uniform controls to ensure potency and purity; no inspections Serum bottled & used, resulting in the deaths of 13 childrenSerum bottled & used, resulting in the deaths of 13 children Camden, NJ: 9 children died from tetanus-tainted smallpox vaccineCamden, NJ: 9 children died from tetanus-tainted smallpox vaccine Biologics Control Act: government regulation of biologics; required licensure of products/facilities; authority to inspect and to withhold, suspend, or revoke licensesBiologics Control Act: government regulation of biologics; required licensure of products/facilities; authority to inspect and to withhold, suspend, or revoke licenses One of the first bottles (1895) of diphtheria antitoxin produced at the Hygienic Laboratory

3. Biologics – definition (PHS Act, section 351) Virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component, or derivative, allergenic product, or analogous product …Virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component, or derivative, allergenic product, or analogous product … Applicable to prevention, treatment, or cure of a disease or condition of human beingsApplicable to prevention, treatment, or cure of a disease or condition of human beings

4. Products Regulated by CBER Somatic Cell & Gene Therapies Blood Derivatives Selected Devices Whole Blood Human TissuesXenotransplantation Products Vaccines (preventive and therapeutic) Allergenic Extracts Blood Components

5. How are Biologics Different? Traditional drugs Low molecular wgt. (<1 kDa) Usually organic synthesis Fewer critical process steps Well-characterized Drug substance homogeneity Maximal tolerated dose Linear dose response Usually more specific mechanisms of action Usually metabolized May have p450 interactions Usually not immunogenic Biological products High molecular weight (>50 kDa) Made with/from live cells/organisms  inherent & contamination risk  inherent & contamination risk Many critical process steps Less well-characterized Complex heterogeneous mixtures Optimal biologic dose Non-linear dose response Multiple or even unknown mechanisms of action mechanisms of actionDegraded No P450 interactions Often Immunogenic

6. Clinical Trial Considerations Vaccines for Healthy Children Pivotal studies: typically large RCTs, e.g., several thousand to many thousand children (>70,000 infants in Rotateq rotavirus vaccine trial)Pivotal studies: typically large RCTs, e.g., several thousand to many thousand children (>70,000 infants in Rotateq rotavirus vaccine trial) Control: typically placebo or active control (e.g., a licensed vaccine that may or may not be active against infectious disease of interest)Control: typically placebo or active control (e.g., a licensed vaccine that may or may not be active against infectious disease of interest) Live virus & bacterial vaccines or vectored vaccines assessed for shedding of the organisms (quantity & duration, risk of transmission to unvaccinated)Live virus & bacterial vaccines or vectored vaccines assessed for shedding of the organisms (quantity & duration, risk of transmission to unvaccinated) Adjuvants: vaccines may contain an adjuvant, need to evaluate safety and efficacy of vaccine as a wholeAdjuvants: vaccines may contain an adjuvant, need to evaluate safety and efficacy of vaccine as a whole Vaccines intended for predominantly healthy populations, informs risk/benefit considerationsVaccines intended for predominantly healthy populations, informs risk/benefit considerations

7. Products for Rare Diseases: Use of Flexible Study Designs Historical controls sometimes used, e.g.,Historical controls sometimes used, e.g., ─ Natural history of disease is well characterized & understood Sequential trialsSequential trials ─ Early stopping for strong negative or positive cumulative data Adaptive trialsAdaptive trials ─ Ongoing adjustments to treatment regimen, dosing, participant allocation, and/or sample size Crossover trialsCrossover trials ─ Study participants serve as own controls

8. Historical Safety Incidents Underscore need for control of manufacturing process, product testing, pre and post-market safety surveillance, proactive stance re EIDs 1901: Contaminated diphtheria antitoxin lot  13 fatal tetanus cases; led to Biologics Control Act of 19021901: Contaminated diphtheria antitoxin lot  13 fatal tetanus cases; led to Biologics Control Act of 1902 1955: Deficient viral inactivation (“Cutter incident”) - some lots of inactivated poliovirus vaccine  cases of poliomyelitis in >200 vaccinees and contacts1955: Deficient viral inactivation (“Cutter incident”) - some lots of inactivated poliovirus vaccine  cases of poliomyelitis in >200 vaccinees and contacts 1970's-’85: HIV transmitted through contaminated blood, blood components, and plasma derivatives; donor deferral and testing introduced, significantly reducing risk1970's-’85: HIV transmitted through contaminated blood, blood components, and plasma derivatives; donor deferral and testing introduced, significantly reducing risk 1990s: Variant Creutzfeldt-Jakob Disease (vCJD) recognized; risk-based donor deferral implemented; vCJD transmission by blood/blood products subsequently recognized in UK1990s: Variant Creutzfeldt-Jakob Disease (vCJD) recognized; risk-based donor deferral implemented; vCJD transmission by blood/blood products subsequently recognized in UK 1999: Intussusception after licensure of first rotavirus vaccine; led to vaccine withdrawal; very large safety studies conducted pre-licensure for subsequent rotavirus vaccines1999: Intussusception after licensure of first rotavirus vaccine; led to vaccine withdrawal; very large safety studies conducted pre-licensure for subsequent rotavirus vaccines

9. Complexity of Manufacturing Process: gene therapy example Allogeneic PBMC CD34+ Selection Retroviral vector Growth Factors CD34+ Expressing New Gene Anti-CD34+ MoAB Multiple Cytokines and/or CD34+ transduction Fibronectin coated flasks

10. Investigational Gene Therapy Products Potential risks and benefits Risk of detrimental inflammation:fatal hepatotoxicity in teenager after gene therapy trial for genetic enzyme deficiency using adenovirus vector (1999)Risk of detrimental inflammation: fatal hepatotoxicity in teenager after gene therapy trial for genetic enzyme deficiency using adenovirus vector (1999) Risk of proliferationRisk of proliferation 1 st gene therapy trials for SCID-X1 w/o compatible stem cell donor (Europe)  T cell leukemia arose in 5/20 (construct integrated into a proto-oncogene regulating T cell proliferation - 1 died, 3 cured, 1 still being treated), BUT1 st gene therapy trials for SCID-X1 w/o compatible stem cell donor (Europe)  T cell leukemia arose in 5/20 (construct integrated into a proto-oncogene regulating T cell proliferation - 1 died, 3 cured, 1 still being treated), BUT Potential for cure: good immunity restored in 17/20 (for at least 5-8 years), 12/20 lost need for IV IgG (unusual after stem cell transplant), only 1/20 did not develop any T cellsPotential for cure: good immunity restored in 17/20 (for at least 5-8 years), 12/20 lost need for IV IgG (unusual after stem cell transplant), only 1/20 did not develop any T cells R

11. Cell Scaffold Products: Another Group of Complex Biologicals Cell Scaffold Products: Another Group of Complex Biologicals Autologous or allogeneic cells on collagen or synthetic resorbable matrix for wound repairAutologous or allogeneic cells on collagen or synthetic resorbable matrix for wound repair Cell seeded scaffolds for cardiovascular repairCell seeded scaffolds for cardiovascular repair Encapsulated pancreatic islet cellsEncapsulated pancreatic islet cells Expanded autologous cells on a matrix for collagen repairExpanded autologous cells on a matrix for collagen repair

12. Example: Autologous stem cells (selected using monoclonal antibodies, expanded in culture, matured with cytokines, then given back to patient). Potential benefits of therapy: Potential for much greater potency Applicable to a wide range of very difficult to treat diseases Potential for fewer adverse effects than conventional therapies More targeted Potential risks of therapy: Tumorigenicity Cellular contaminants Adventitious agents Safety of reagents Sterility Product stability Product variability Investigational Cellular Therapy

13. Example: Coagulation factors derived from either human plasma or culture media from genetically engineered cells for replacement therapy to treat patients with congenital deficiencies (e.g. hemophilia) Potential Benefits of Therapy: Effective in controlling bleeding episodes that are life threatening Potential Risks of Therapy: Infections due to adventitious agents Development of neutralizing antibodies due to modifications in the molecule Allergic reactions to impurities Investigational Blood Product

14. Synthetic peptides can be manufactured with very high degrees of product consistency, but variability with autologous or allogeneic cellular products can be enormous (sometimes >100 fold) Consistency of manufacturing: may vary by product

15. SUMMARY Biologicals: diverse, complex products for the treatment and prevention of a broad range of common and rare diseasesBiologicals: diverse, complex products for the treatment and prevention of a broad range of common and rare diseases Complex processes for manufacture, product testing, and for evaluation of safety and efficacyComplex processes for manufacture, product testing, and for evaluation of safety and efficacy Include many products for healthy people – informs risk-benefit considerationsInclude many products for healthy people – informs risk-benefit considerations Include highly innovative products (great potential benefits but risks not fully defined)Include highly innovative products (great potential benefits but risks not fully defined) Clinical trial designs may vary with productClinical trial designs may vary with product