Licensure of New Pneumococcal Vaccines For Adult Indications Vaccines and Related Biologic Products Advisory Committee Meeting November 17, 2005 Douglas Pratt, MD, MPH DVRPA/OVRR/CBER

Overview of CBER Presentation Regulatory background of PNEUMOVAX 23 Clinical endpoint efficacy/effectiveness study scenarios Immunologic endpoints and regulatory pathways Opsonophagocytic antibody (OPA) Other considerations NP colonization; accelerated approval Summary

PNEUMOVAX 23 (Merck) Purified polysaccharides of 23 of the most common pneumococcal serotypes (23V PS) 1977: 14-valent vaccine licensed (50 µg/serotype) 1983: 23-valent vaccine licensed (25 µg/serotype) Licensed Indication: Routine use in adults age ≥ 50 yrs ACIP Recommendations: Routine use in adults ≥ 65 yrs

PNEUMOVAX 23: Indication and Usage PNEUMOVAX 23 is indicated for vaccination against pneumococcal disease caused by those pneumococcal types included in the vaccine. Vaccination is recommended for selected individuals including: Immunocompetent persons: Routine vaccination for persons 50 years of age and older Persons aged ≥ 2 years with certain cardiac, pulmonary, or liver diseases, asplenia, persons living in special environments Immunocompromised persons: Persons aged ≥ 2 years with HIV, leukemia, lymphoma, Hodgkins disease, generalized malignancy, chronic renal failure, nephrotic syndrome, receiving immunosuppressive therapy, organ or bone marrow transplant.

PNEUMOVAX 23: Efficacy Basis for Licensure South African gold miner study of 12-valent vaccine Mean age ~22 yrs; began enrollment in 1974

PNEUMOVAX 23: Reformulation 14-valent (50 µg) to 23-valent (25 µg) Clinical immunogenicity and safety study Adults age 21-64 years 2-fold Rise (RIA) 22-valent 50 µg N= 23 100% 22-valent 25 µg N= 29 87-100% Type 33 added at 25 µg Safety: minor adverse reactions in 5-25%; severe reactions unusual; favorable risk/benefit

Effectiveness of 23V PS in the Elderly and High-Risk Groups Multiple observational studies and meta-analyses Studies of have yielded variable results ACIP recommendations for routine use in adults ≥ 65 years of age based on: Case-control studies Prevention of invasive disease, 56% to 81% Effectiveness for non-bacteremic disease has not been demonstrated.

Effectiveness of 23V PS in the Elderly and High-Risk Groups Jackson LA et al. NEJM 2003; 348: 1747 Retrospective cohort study, N >47,000 Persons ≥ 65 yrs Effectiveness of 23V PS: Pneumococcal bacteremia: 44% (95%CI: 7%, 67%) All cause pneumonia: No effect French N et al. Lancet 2000; 355: 2106 HIV-infected Ugandan adults, N= 1392 Randomized, placebo-controlled No efficacy for any pneumococcal outcome

New Pneumococcal Vaccines: Efficacy Endpoint Considerations Clinically Meaningful Evidence of Benefit to the Individual Feasibility

Clinical Trial Considerations: Age of Study Population ≥ 65 years (high-risk) May be difficult to study in randomized placebo-controlled trials Ethical concerns about delaying a recommended vaccine Many elderly already vaccinated with 23V PS 50-64 years (moderately high-risk) Placebo-controlled trials may be feasible May not predict effectiveness in higher risk groups

Efficacy and Effectiveness Trials Scenarios: Age 50-64 years Invasive pneumococcal disease All cause community acquired pneumonia (CAP) Presumptive pneumococcal pneumonia

Scenario 1: Efficacy Trial for Invasive Pneumococcal Disease Invasive Pneumococcal Disease Endpoint Sterile body fluid isolate of vaccine type pneumococcus Age range 50-64 years Placebo control, 1:1 randomization Rate of invasive disease: 25-50/100,000 per year 2.5 years of follow-up for case ascertainment Assume 60-85% of invasive pneumococcal disease covered by serotypes in new vaccine 90% power

Scenario 1: Efficacy Trial for Invasive Pneumococcal Disease Assumptions and Sample Size Estimates (50-64 yr)

Effectiveness Trials Vaccine “effectiveness” trials evaluate less specific disease case definitions (e.g., all cause pneumonia) Effectiveness estimates may be low (<50%) Effectiveness studies are generally supported by separate culture-confirmed studies

FluMist Example: Effectiveness Trial Supporting Licensed Indication Prevention of Influenza-like Illness in Adults (18-49 yr) Reduction of: Any febrile Illness 10.9% (-5%, 24%) Severe Febrile Illness 19.5% (3%, 33%) Febrile URI 23.7% (7%, 38%) Provided the primary basis of effectiveness of FluMist in adults Prevention of culture-proven influenza in children had been demonstrated

Scenario 2: Effectiveness Trial for All Cause Community Acquired Pneumonia Pneumonia Endpoint Hospital Discharge Diagnosis Age range 50-64 years Placebo control, 1:1 randomization Rate of CAP: 300-600/100,000 per year 2.5 years of follow-up for case ascertainment Assume 60-85% of pneumococci covered by vaccine 90% power

Scenario 2: Efficacy Trial for All Cause Community Acquired Pneumonia (CAP) Assumptions and Sample Size Estimates (50-64 yr)

Presumptive Pneumococcal Pneumonia: Increase Specificity of Diagnosis Fever, productive cough Chest X-ray Sputum gram stain/culture (+/-quantitative) Quantitative urine antigen C-reactive protein/procalcitonin Nucleic acid amplification (e.g., PCR) Serology

Scenario 3: Presumptive Pneumococcal Pneumonia Endpoint CXR; sputum culture, Gm stain; urine antigen Age range 50-64 years Placebo control; 1:1 randomization Rate of Pneumococcal CAP: 100-200/100,000/year 2.5 years of follow-up for case ascertainment Assume 60-85% of pneumococci covered by vaccine 90% power

Scenario 3: Efficacy Trial for Presumptive Pneumococcal Pneumonia Assumptions and Sample Size Estimates (50-64 yr)

Clinical Efficacy Trial Designs among Persons ≥ 65 year old Delay 23V PS, use placebo control i.e., New Vax vs. placebo Might be acceptable in well-monitored study Evaluate efficacy over background of 23V PS i.e., New Vax + 23V PS vs. 23V PS For non-bacteremic disease endpoint in this population, 23V PS may be similar to placebo control

Clinical Efficacy Trial Designs among Persons ≥ 65 year old Compare to licensed 23V PS vaccine i.e., New Vax vs. 23V PS Non-inferiority or superiority design Endpoint: All pneumococcal disease Three arm study: i.e., New Vax vs. placebo vs. 23V PS Power for comparison to placebo

Immunologic Evaluation: Comparison to 23V PS in Adults Inferred efficacy based on non-inferiority comparison to a licensed vaccine Regulatory pathway has precedent e.g., Menactra™ compared to Menomune® Approach consistent with advice of 2001 VRBPAC regarding licensure pathways for new pneumococcal conjugate vaccines for infants For infants, comparative assessment of antibody concentration as measured by standardized ELISA

Effectiveness Based on Immunologic Critieria: Considerations Immunologic criteria based on infant studies are not valid criteria for adults Antibody levels that correlate with protection in older adults and elderly have not been identified Vaccine evaluation in adults more dependent on induction of serum opsonic antibody titers

Opsonophagocytic Antibody (OPA) A measure of functional antibody (vs. binding antibody) Central role in protection against pneumococcus In vivo protection mediated by antibody binding to bacterial surface, and complement-mediated uptake into phagocytic cells In vitro assay (OPA) provides evidence of in vivo protection

Opsonophagocytic Antibody -- Unknowns Phagocytic cells of the elderly, and other high-risk populations, may not function like the cultured phagocytic cells (HL60) used in the OPA assay Quantitative relationship of OPA with efficacy in prospective clinical trials in adults has not yet been established Quantitative relationship may differ by disease, i.e., invasive disease vs. pneumonia

Immunologic Evaluation: Comparison to 23V PS in Adults Non-inferiority comparison of new conjugate vaccine to 23V PS using OPA: For common serotypes, comparison could be straightforward For serotypes only in 23V PS, new vaccine would fail non-inferiority comparison How to account for missing serotypes?

Immunologic Evaluation: Superior Immune Response Demonstration of “superior” immune response compared to licensed vaccine (23V PS) for serotypes in common: Criteria not defined Not demonstrated that higher antibody levels (OPA) result in greater effectiveness Lack of precedent for regulatory decisions Novel approach needs scientific consensus and VRBPAC agreement

Use of New Vaccine in Combination with 23V PS Vaccine: Regulatory Issues Labeling: Indication and Usage (21CFR 201.57) Possible implications for labeling of Pneumovax 23 Uncertain regulatory status of new vaccine if Pneumovax 23 is not available

Pneumococcal Vaccines Targeting Non-Capsular Antigens Immunologic comparability to infer effectiveness may not be possible Ability to induce functional antibody (OPA) uncertain Clinical endpoint efficacy trial in an adult population appears necessary Efficacy endpoint studies more feasible if serotype coverage is broad

Nasopharyngeal (NP) Colonization/Carriage Indirect effects of PCV7 thought due to prevention of NP colonization Prevention of NP colonization “Clinical” evidence of vaccine effect Not direct clinical benefit for the individual Would need acceptance as a surrogate of protection Studies likely feasible

Accelerated Approval -- 21 CFR 601 Subpart E Approval based on surrogate endpoint Reasonably likely to predict clinical benefit Applies if: Severe, life-threatening condition Meaningful benefit over existing treatments Confirmatory clinical endpoint study must be completed post-licensure Example: Fluarix (GSK)

Summary New pneumococcal vaccines for use in adults and elderly are being developed by multiple manufacturers Evidence of effectiveness to support licensure might be based on: Clinical endpoint efficacy studies Immunologic criteria (e.g., OPA) Advice of VRBPAC sought regarding most appropriate endpoints, trial designs, and study populations to support licensure of new pneumococcal vaccines for adult indications

Acknowledgements Marion Gruber Jingyee Kou Antonia Geber Karen Goldenthal Dale Horne Rose Tiernan Lucia Lee Margaret Bash Carl Frasch Milan Blake

PNEUMOVAX 23: Efficacy Basis for Licensure South African gold miner study of 6-valent vaccine Mean age ~21 yrs; enrollment began in 1973