1. 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

2. 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

3. PNEUMOVAX (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

4. 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.

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

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

7. 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.

8. 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

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

10. 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

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

12. Scenario 1: Efficacy Trial for Invasive Pneumococcal Disease
Invasive Pneumococcal Disease Endpoint
Sterile body fluid isolate of vaccine type pneumococcus
Age range years
Placebo control, 1:1 randomization
Rate of invasive disease: /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

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

14. 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

15. 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 % (7%, 38%)
Provided the primary basis of effectiveness of FluMist in adults
Prevention of culture-proven influenza in children had been demonstrated

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

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

18. 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

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

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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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?

28. 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

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

30. 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

31. 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

32. 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)

33. 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

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

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