# Presentation: 547863

## Design of Trials for Licensure of New Adult Pneumococcal Vaccine  Indications--An FDA Reviewer’s Perspective

- R. Douglas Pratt, MD, MPH
- DVRPA/OVRR/CBER

## CFR: Evidence of Effectiveness

- 21CFR Sec. 314.125 (5) ...substantial evidence consisting of _adequate and well-controlled investigations_... that the drug product will have the effect it purports ... to have under the conditions of use prescribed, recommended, or suggested in its proposed labeling.

## CFR: Evidence of Effectiveness

- 21 CFR Sec. 314.126:  Adequate and well-controlled studies
- Comparison to control for valid quantitative assessment
- Unbiased assignment to treatment group (randomization)
- Measures to minimize bias of investigators (blinding)
- Assessment of response is well-defined and reliable (endpoints)

## New Pneumococcal Vaccines:  Efficacy Endpoint Considerations

- Precedents
- Feasibility
- Scientific Consensus
- Clinically Meaningful
- Cost-Effectiveness is NOT a criterion of effectiveness for licensure purposes
- Advice of Vaccines and Related Biological Products Advisory Committee (VRBPAC)

## Effectiveness of Pneumococcal Vaccines Based on Immunologic Bridging: Considerations

- Antibody level that correlates with protection has not been identified
- Protective antibody levels may differ by disease
-  e.g., invasive disease vs pneumonia vs AOM
- Conclusions about protective antibody levels based on infant studies may not be valid for disease in adults
- Quantitative effect of a pneumococcal vaccine on disease for public health decisions is not provided by evaluation of immune parameters

## Prevnar, Serotype 19F: Correlation between Efficacy and Immunogenicity

| Disease Endpoint | Efficacy Estimate*

(95% CI) | GMC**
(mcg/mL)

(95% CI) |
| --- | --- | --- |
| Invasive Disease
(NCKP) | 100%
(60%, 100%) | 1.39
(1.16, 1.68) |
| Otitis Media
(Finnish) | 25% 
(-14%, 51%) | 3.30 
(2.57, 4.18) |

- * Per protocol analysis                        **GMCs (ELISA), Post dose 3

## Efficacy Trials

- Vaccine efficacy trials evaluate prevention of disease caused by specific etiologic agent
- More specific case definitions (e.g., culture-confirmed, serotype-specific) will usually result in greater estimates of the treatment effect (>80%)
- For most vaccines, 95% lower bound of efficacy estimate should be substantially above 0 (e.g., 50-60%)

## Effectiveness Trials

- Vaccine “effectiveness” trials evaluate less specific disease definitions (e.g., pneumonia, regardless of etiology)
- Effectiveness estimates may be low (<50%)
- Studies using effectiveness endpoints do not usually provide the sole basis for vaccine licensure

## Effectiveness Trials Supporting Licensed Indications 

-   **Prevnar:  Otitis media**
- All otitis media, regardless of etiology, in NCKP trial was reduced **7%** (95%CI: 4.1%, 9.7%) compared to control
- Culture-proven pneumococcal AOM due to vaccine serotypes in Finnish study was reduced **57%** (95%CI: 44%, 67%) compared to control
- Prevnar had been licensed previously for prevention of invasive pneumococcal disease based on culture-proven disease

## Effectiveness Trials Supporting Licensed Indications

-  **FluMist: Prevention of Flu-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%)
- Effectiveness data provided the primary basis of effectiveness of FluMist in adults
- Prevention of culture-proven influenza in children had been demonstrated

## Clinical Trial Considerations:  Age of Study Population

- High-risk populations, for whom 23V PS vaccine is currently recommended (e.g., > 64 years), should not receive placebo in randomized trials
- Placebo-controlled trials in moderately high-risk population may be feasible (e.g., 50-64 years)
- If public health recommendation (ACIP) is made for adults >50 years, placebo-controlled trials may be more difficult to conduct in this population
- Fewer adults not already vaccinated
- Ethical considerations

## Scenario: Efficacy Trial

- Invasive Pneumococcal Disease Endpoint
- Sterile body fluid isolate of any pneumococcus
- Age range 50-64 years
- Placebo control, 1:1 randomization
- Rate of invasive disease:  25-50/100,000 per year
- 3 years of follow-up
- Assume 90% of pneumococci covered by vaccine
- Assume 80% reduction (0.9 x 0.9) for all pneumococci
- Sample size:  ~ 13,000-27,000/group

## Scenario: Efficacy Trial for   Invasive  Pneumococcal Disease

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

| Assumed Vaccine Efficacy | Background Event Rate per 100,000/yr | Years of Follow-up | Power
% | 95% CI | Sample Size per Group |
| --- | --- | --- | --- | --- | --- |
| 0.8 | 25 | 3 | 80 | 0.29, 0.96 | 20,000 |
|  |  | 3 | 90 | 0.40, 0.95 | 27,000 |
| 0.8 | 50 | 3 | 80 | 0.29, 0.96 | 10,000 |
|  |  | 3 | 90 | 0.40, 0.95 | 13,000 |
|  |  | 3 | 98 | 0.51, 0.93 | 20,000 |

## Scenario: Effectiveness Trial for Community Acquired Pneumonia

- Pneumonia Endpoint
- CXR confirmed
- Age range 50-64 years
- Placebo control, 1:1 randomization
- Assume:
- Rate of pneumococcal pneumonia is: 100-200/100,000
- Rate of community acquire pneumonia is:  350-700/100,000
- Assume 50%-80% reduction in pneumococcal pneumonia (15%-24% reduction in CAP)
- Sample size:  ~12,000-80,000 per group

## Scenario: Effectiveness Trial for   Community Acquired Pneumonia

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

| Assumed Vaccine Efficacy | Background Event Rate
 per 100,000/yr | Years of Follow-up | Power
% | 95% CI | Sample Size per Group |
| --- | --- | --- | --- | --- | --- |
| 0.8 x 0.3=
0.24 | 350 | 3 | 80
90 | 0.08, 0.38
0.10, 0.35 | 23,000
33,000 |
|  | 700 | 3 | 80
90 | 0.08, 0.38
0.10, 0.38 | 12,000
16,600 |
| 0.5 x 0.3=
0.15 | 350 | 3 | 80
90 | 0.05, 0.24
0.06, 0.23 | 66,000
83,000 |
|  | 700 | 3 | 80
90 | 0.05, 0.24
0.06, 0.23 | 33,000
41,600 |

## Presumptive Pneumococcal Pneumonia: Increase Specificity of Diagnosis

- Fever, productive cough
- Chest X-ray
- Sputum gram stain
- Sputum culture (+/-quantitative)
- Serology
- Urine antigen

## Scenario: 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
- Assume background rate of pneumococcal pneumonia is:  125-250/100,000/year
- Assume 50%-80% reduction in presumptive pneumococcal pneumonia

## Scenario: Vaccine Trial for   Presumptive Pneumococcal Pneumonia

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

| Assumed Vaccine Efficacy | Background Event Rate
 per 100,000/yr | Years of Follow-up | Power
% | 95% CI | Sample Size per Group |
| --- | --- | --- | --- | --- | --- |
| 0.8  | 125 | 3 | 80
90 | 0.29, 0.96
0.51, 0.93 | 4,000
5,300 |
|  | 250 | 3 | 80
90 | 0.29, 0.96
0.51, 0.93 | 2,000
2,700 |
| 0.5 | 125 | 3 | 80
90 | 0.04, 0.75
0.12, 0.72 | 8,000
11,000 |
|  | 250 | 3 | 80
90 | 0.04, 0.75
0.12, 0.72 | 4,000
5,500 |

## Scenario: Extend Recommended Age Range for 23-V PS Vaccine to 50 years

- From Pneumovax Label:
- 	“Vaccination with PNEUMOVAX 23 is recommended for selected individuals as follows:
- 	Immunocompetent persons:
- routine vaccination for persons 50 years of age or older”
- No regulatory action needed to support extended recommendation

## Scenario: Pneumococcal Conjugate Vaccine for Adults

- Non-inferiority comparison to licensed (23-V PS) vaccine for common serotypes based on immunologic criteria (ELISA or OPA) may be possible
- Overall determination of non-inferiority difficult to assess due to contribution of serotypes in 23V-PS, but not in conjugate
- Vaccine effectiveness for pneumococcal disease might be estimated from epidemiology of disease by serotypes

## Scenario: Pneumococcal Conjugate Vaccine for Adults

-  Efficacy (invasive disease) or effectiveness (pneumonia) clinical endpoint trials in adults may provide clearest path to licensure
- Placebo-controlled for 18-64 year olds
- Comparison to licensed 23-valent PS vaccine for  65 year olds

## Scenario: Conjugate Vaccine plus 23-Valent Polysaccharide Vaccine

- Demonstration of non-inferior immune response of combination compared to licensed vaccine (23-V PS) is not meaningful
- Superior immune response relative to licensed vaccine (23-V PS) is of uncertain significance
- No precedent
- Not clear if more antibody (ELISA or OPA) results in greater effectiveness
- Need scientific consensus & VRBPAC advice
- Efficacy or effectiveness trials may be needed to support indication for combined use

## Scenario:  Protein-Based Pneumococcal Vaccine

- Comparison to licensed vaccines based on immunologic criteria (e.g., OPA) may not be possible
- Efficacy (invasive disease) or effectiveness (pneumonia) clinical endpoint trials in adults may provide most direct path to licensure
- Placebo-controlled for 18-64 year olds
- Comparison to licensed 23-valent PS vaccine in elderly

## Safety Database Considerations

- Safety database should include “several thousand” well-monitored study subjects
- Comparisons to non-reactogenic placebo (saline) or licensed vaccine
-  Much of safety data can be obtained in efficacy/effectiveness trials
- Safety follow-up for at least 6 months after the last vaccine dose to assess late-onset adverse events

## Acknowledgement

- Jingyee Kou, Ph.D
- 	Biostatistics/CBER