# Presentation: 852173

## 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 p****ersons:**
- 	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

- 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., MenactraTM 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