Licensure of New Pneumococcal Vaccines For Adult Indications

Vaccines and Related Biologic Products Advisory Committee Meeting

November 17, 2005

Douglas Pratt, MD, MPHDVRPA/OVRR/CBER

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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

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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

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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.

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PNEUMOVAX 23: Efficacy Basis for Licensure

South African gold miner study of 12-valent vaccine Mean age ~22 yrs; began enrollment in 1974

Pneumococcal Disease* Occurring More than 14 Days Following Vaccination

Vaccine Type Total No.

Vaccinated No.

Cases Cases/ 1000

Protective Efficacy

Pneumococcus 718 1 1.4

Meningococcus A&C 775 9 11.6

Placebo 718 16 22.6

91.7%

*Verified by blood, sputum or nasopharyngeal culture, or by mouse inoculation test.

Adapted from Table 13, Ref 19 of PNEUMOVAX License Application

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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

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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.

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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

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New Pneumococcal Vaccines: Efficacy Endpoint Considerations

Clinically Meaningful

Evidence of Benefit to the Individual

Feasibility

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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

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Efficacy and Effectiveness Trials

Scenarios: Age 50-64 years

1. Invasive pneumococcal disease

2. All cause community acquired pneumonia (CAP)

3. Presumptive pneumococcal pneumonia

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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

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Scenario 1: Efficacy Trial for Invasive Pneumococcal Disease

Assumptions and Sample Size Estimates (50-64 yr)

Event Rate /105 /yr

Serotype coverage

Assumed Efficacy

Lower 95% CI

Sample Size Per Group

70% 38% 82,000 80% 46% 59,000

60%

90% 50% 44,000 70% 38% 58,000 80% 46% 42,000

25

85%

90% 50% 31,000 70% 38% 41,000 80% 46% 30,000

60%

90% 50% 22,000 70% 38% 29,000 80% 46% 21,000

50

85%

90% 50% 16,000

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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

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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

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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

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Scenario 2: Efficacy Trial for All Cause Community Acquired Pneumonia (CAP)

Assumptions and Sample Size Estimates (50-64 yr)All CAP Event Rate

/105/yr

CAP Rate due

to All S. pneumo

/105/yr

Serotype coverage

Assumed Efficacy Vaccine Serotype

CAP

Efficacy All

Cause CAP

Lower 95% CI

Sample Size per Group

70% 13% 5% 166,000 80% 14% 6% 126,000

60%

90% 22% 9% 54,000 70% 18% 7% 81,000 80% 20% 8% 61,000

300

100

85% 90% 23% 10% 48,000 70% 13% 5% 83,000 80% 14% 6% 63,000

60%

90% 22% 9% 27,000 70% 18% 7% 40,000 80% 20% 8% 30,000

600

200

85% 90% 23% 10% 24,000

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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

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Scenario 3: Presumptive Pneumococcal Pneumonia Endpoint

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

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Scenario 3: Efficacy Trial for Presumptive Pneumococcal Pneumonia

Assumptions and Sample Size Estimates (50-64 yr)Event Rate

/105/yr

Serotype coverage

Assumed Efficacy for CAP due to

Vaccine Serotype

Lower 95% CI

Sample Size Per Group

60% 28% 29,000 70% 38% 20,000

60%

80% 46% 15,000 60% 28% 21,000 70% 38% 14,000

100

85% 80% 46% 10,000 60% 28% 15,000 70% 38% 10,000

60%

80% 46% 7,000 60% 28% 10,000 70% 38% 7,000

200

85% 80% 46% 5,000

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Clinical Efficacy Trial Designs among Persons ≥ 65 year old

1. Delay 23V PS, use placebo control

i.e., New Vax vs. placebo

Might be acceptable in well-monitored study

2. 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

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Clinical Efficacy Trial Designs among Persons ≥ 65 year old

3. Compare to licensed 23V PS vaccine

i.e., New Vax vs. 23V PS Non-inferiority or superiority design Endpoint: All pneumococcal disease

4. Three arm study:

i.e., New Vax vs. placebo vs. 23V PS Power for comparison to placebo

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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

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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

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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

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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

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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?

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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

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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

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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

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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

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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)

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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

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Acknowledgements

Marion Gruber

Jingyee Kou

Antonia Geber

Karen Goldenthal

Dale Horne

Rose Tiernan

Lucia Lee

Margaret Bash

Carl Frasch

Milan Blake

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PNEUMOVAX 23: Efficacy Basis for Licensure

South African gold miner study of 6-valent vaccine Mean age ~21 yrs; enrollment began in 1973

Pneumococcal Disease* Occurring More than 14 Days Following Vaccination

Vaccine Type Total No.

Vaccinated No.

Cases Cases/ 1000

Protective Efficacy

Pneumococcus 983 9 9.2

Meningococcus A&C 1051 40 38.1

Placebo 985 38 38.6

76%

*Verified by blood, sputum or nasopharyngeal culture, or by mouse inoculation test.

Adapted from Table 13, Ref 18 of PNEUMOVAX License Application