Biologicals: A Vision for the Future of Clinical Investigators in Evaluations of New Biological Products

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. Diphtheria antitoxin from a milk horse named Jim 1901: 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 inspections Serum bottled & used, resulting in the deaths of 13 children Camden, 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 licenses Biologics Control Act, 1902The Horse CBER Rode in On 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 … • Applicable to prevention, treatment, or cure of a disease or condition of human beings

4. Vaccines (preventive and therapeutic) Blood Derivatives Whole Blood AllergenicExtracts Blood Components Selected Devices Human Tissues Xenotransplantation Products Products Regulated by CBER   Somatic Cell & Gene Therapies

5. 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 Many critical process steps Less well-characterized Complex heterogeneous mixtures Optimal biologic dose Non-linear dose response Multiple or even unknown mechanisms of action Degraded No P450 interactions Often Immunogenic How are Biologics Different?

6. Clinical Trial ConsiderationsVaccines for Healthy Children • 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) • 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 whole • Vaccines 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., • Natural history of disease is well characterized & understood • Sequential trials • Early stopping for strong negative or positive cumulative data • Adaptive trials • Ongoing adjustments to treatment regimen, dosing, participant allocation, and/or sample size • Crossover trials • Study participants serve as own controls

8. Historical Safety IncidentsUnderscore 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 1902 • 1955: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 risk • 1990s:Variant Creutzfeldt-Jakob Disease (vCJD) recognized; risk-based donor deferral implemented; vCJD transmission by blood/blood products subsequentlyrecognized in UK • 1999:Intussusception after licensure of first rotavirus vaccine; led to vaccine withdrawal; very large safety studies conducted pre-licensure for subsequent rotavirus vaccines

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

10. Investigational Gene Therapy ProductsPotential 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 proliferation • 1st 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 cells R

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

12. Investigational Cellular Therapy Example: Autologous stem cells (selected using monoclonal antibodies, expanded in culture, matured with cytokines, then given back to patient). • Potential risks oftherapy: • Tumorigenicity • Cellular contaminants • Adventitious agents • Safety of reagents • Sterility • Product stability • Product variability • 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

13. Investigational Blood Product  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 Risks of Therapy: • Infections due to adventitious agents • Development of neutralizing antibodies due to modifications in the molecule • Allergic reactions to impurities • Potential Benefits of Therapy: • Effective in controlling bleeding episodes that are life threatening

14. Consistency of manufacturing: may vary by product  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)

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