# Presentation: 740394

## 

Vaccines and Related Biological ProductsAdvisory Committee Meeting
December 15, 2005

Patricia Rohan, M.D.
FDA / CBER / OVRR

**Vaccines and Related Biological Products****Advisory Committee Meeting**
**December 15, 2005**
**Patricia Rohan, M.D.**
**FDA / CBER / OVRR**

## ZOSTAVAXTM Overview

- Proposed indication
- Introduction / background
- ZOSTAVAXTM clinical development
- Protocol 004 review
- Protocol 009 review
- Summary
- Questions / Discussion

## ZOSTAVAXTM Proposed Indication

- Prevention of herpes zoster (shingles)
- Prevention of postherpetic neuralgia (PHN)
- Reduction of acute and chronic zoster-associated pain as measured by the  burden of illness (BOI) score developed by the sponsor
- In individuals 50 years of age or older

## Varicella Zoster Virus

- Persists in sensory nerve ganglia
- Reactivation associated with aging, immunosuppression
- Pruritic, vesicular rash - localized or diffuse
- Hospitalization ~3/1,000
- Death ~1/60,000

## Herpes Zoster (HZ) Complications

- Neurologic
- Postherpetic neuralgia
- Ocular
- Encephalitis
- Cranial and peripheral nerve palsies
- Visceral
- Pneumonia (adults)
- Hepatitis
- Bacterial infection
- Superinfection of skin and underlying structures
- Bacterial pneumonia
- Septicemia, toxic shock syndrome

## Postherpetic Neuralgia (PHN) 

- PHN usually resolves within a few weeks, but in some cases severe, debilitating pain and paresthesia may persist for a year or more
- Pain control may be inadequate in more severe or protracted cases

## VZV Epidemiology - 1

- VARIVAX® licensed 1995
- By 2003: 85% vaccination rate nationwide in population for whom recommended
- Varicella decreased in same period ~ 85% (CDC Varicella Active Surveillance Project)
- Future adult populations in U.S. may rely on vaccination for protection from primary VZV infection

## VZV Epidemiology - 2

- Exposure to varicella disease in the community suggested as preventing reactivation of VZV and subsequent HZ and its manifestations.
- From 1999 to 2003, age-standardized rates of overall herpes zoster occurrence increased from 2.77/1,000 to 5.25/1,000 (90%).
- Upward trends in both crude & adjusted rates were highly significant (p < 0.001), specifically in the 25–44 year and 65+ year age groups
- Massachusetts Behavioral Risk Factor Surveillance System
- Yih 2005

## Slide 9

## Slide 10

## ZOSTAVAXTM Clinical Development

| 1995 | VARIVAXTM licensed |
| --- | --- |
| 02-95 | AUC (Brief Pain Inventory) compared to subjective responses in HZ patients published (Lydick) |
| 09-96 | ZOSTAVAXTM IND submitted |
| 09-01 | Last vaccination (Protocol 004)	 |
| 11-03 | Last HZ case accrued (Protocol 004) |
| 12-03 | PHN definition changed from ≥ 30 to ≥ 90 days (Protocol 004) |
| 04-04 | Protocol 004 Ended |
| 06-04 | Incidence HZ, duration HZ pain & SADLI elevated from tertiary to secondary endpoints; success criteria submitted (Protocol 004) |
| 06-04 | Protocol 009 Ended |
| 08-04 | Validation of HZ BOI published (Coplan) |
| 04-05 | ZOSTAVAXTM BLA submitted |

## Comparison to Varivax® 

|  | VARIVAX® | ZOSTAVAXTM |
| --- | --- | --- |
| Disease | Primary Varicella | Herpes Zoster |
| Dose | 1,350 – 17,000 pfu | 19,400 – 207,000 pfu |
| # Doses | 12 mos.-12 yrs: 1  optional 2nd dose
≥ 13 years:  2 | 1 |

## ZOSTAVAXTM Clinical Trials

| Protocol | 001 | 002 | 003 | 004 | 005 | 007 | 009 |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Phase | 1 | 2b | 2b | 3 | 2b | 2a | 3 |
| # Subjects | 276 | 398 | 21 | 38,546 | 196 | 210 | 698 |
| Age (yrs.) | ≥60 | ≥60 | ≥30 | ≥60 | ≥60 | ≥ 60 | ≥ 50 |
| Safety | X | X | X | X | X | X | X |
| Immuno | X | X | X | X | X | X |  |
| Efficacy |  |  |  | X |  |  |  |
| Total Safety Database = 21,000 ZOSTAVAXTM recipients  |  |  |  |  |  |  |  |

## 
ZOSTAVAXTM
Protocol 004

**ZOSTAVAXTM**
**Protocol 004**

## Objectives Protocol 004

- Primary
- Reduce incidence/severity HZ and  complications in those ≥ 60 yrs. as measured by the Burden of Illness Score (BOI)
- Reduce incidence of PHN

## Objectives Protocol 004

- Secondary
- Reduce incidence of HZ
- Reduce duration of HZ pain
- Reduce Activities of Daily Living Interference (ADLI) in subjects w/ HZ

## HZ BOI ScoreProtocol 004	

- Zoster Brief Pain Inventory (ZBPI), Coplan 2004
- 121 subjects enrolled w/in 14 days of HZ rash onset
- ZBPI severity-duration associated w/ severity-duration ADLI & worsening QoL
- Score ≥ 3, 90 days or more after HZ rash had high agreement with pain worse than mild using Present Pain Intensity Scale (PPI), modified from the McGill Pain Questionnaire (kappa = 0.72)

## Study Design Protocol 004

- Prospective, randomized, double-blinded, placebo-controlled, multi-center study
- Adults **≥ 60 yrs**
- Randomized 1:1 to vaccine : placebo
- Stratified by age
- 60-69 yrs. (N =20,747); ≥ 70 yrs. (N =17,799)
- 12 clinical lots
- 9 accelerated-aged to mimic end-expiry potency

## Pertinent Exclusion CriteriaProtocol 004

- More than intermittent use of topical or inhaled corticosteroid
- Life-expectancy < 5 years
- Bed-ridden or homebound
- Cognitive impairment, severe hearing loss (no specific criteria)

## ZOSTAVAXTM lots  administeredProtocol 004

|  | Grp 1* | Grp 2** | Grp 3** | Grp 4** |
| --- | --- | --- | --- | --- |
| N | 835 | 978 | 8720 | 8737 |
| PFU/
Dose (103) | 50-62 | 34-42 | 26-33 | 21-26 |
| Dates | 11/98 11/99 | 04/99 
11/99 | 07/99 12/00 | 07/00 09/01 |
| Avg. F/U
(days) | 1400 | 1400 | 1200 | 900 |
| *Group 1 comprised of 3 unaged clinical lots
**Each group comprised of 3 of the 9 accelerated aged clinical lots |  |  |  |  |

## Slide 21

|  | 
Protocol 004

 |  |  |  |
| --- | --- | --- | --- | --- |
|  | Randomized 1:1
N = 38,546 |  |  | 
 |
|  |  |  |  |  |
| ZOSTAVAXTM
N = 19,270 |  |  | Placebo
N = 19,276 |  |

## Overview of Study Procedures Protocol 004

| 
Postvaccination |  | AE 
Monitoring
Substudy | Routine Monitoring Cohort | CMI
Substudy |
| --- | --- | --- | --- | --- |
| VRC | D 0-42 | X |  |  |
| ATRS Safety | D 42 | X | X | X |
| ATRS
HZ | Monthly thru study end | X
Hospitalization | X | X |
| Immuno | D 1, W 6, 
M 12, 24, 36 |  |  | X |
| Following HZ rash                       All Subjects |  |  |  |  |
| Immuno | D 1, W 3 & 6 | X |  |  |
| IZIQ, ZBPI | D 0-182 | X |  |  |
| ATRS:  Automated Telephone Response System |  |  |  |  |

## Population for Analysis Protocol 004

- ITT – all randomized
- Evaluable HZ by PCR, culture, CEC; safety
- MITT (modified ITT)
**Primary efficacy analyses**
- Followed ≥ 30 days postvaccination
- Did not develop evaluable HZ w/in 30 days
- Evaluable HZ per hierachical testing
- 	(PCR, culture, CEC determination)
- MITT2
- MITT, but _evaluable HZ per Clinical Evaluation Committee (CEC)_

## ResultsProtocol 004

## DemographicsProtocol 004

|  | ZOSTAVAXTM | Placebo |
| --- | --- | --- |
| Male | 59.2% | 58.9% |
| Female | 40.8% | 41.1% |
| Black | 2.0% | 2.2% |
| Hispanic | 1.4% | 1.3% |
| White | 95.4% | 95.4% |
| Other | 1.1% | 1.2% |
| Mean Age | 69.4 yrs. | 69.4 yrs. |
| Age Range | 60-99 | 59-94 |

## DispositionProtocol 004

|  | ZOSTAVAXTM | Placebo |
| --- | --- | --- |
| Enrolled | 19,270 | 19,276 |
| Completed | 18,359 (95.3%) | 18,357
(95.2%) |
| Died | 793
(4.1%) | 792
(4.1%) |
| Withdrawn | 57
(0.3%) | 75
(0.4%) |
| Lost to follow- up | 53
(0.3%) | 40
(0.2%) |

## Hierarchical HZ DeterminationProtocol 004

- PCR + or –
- 93.4% (894/957) of evaluable HZ cases
- Wild type VZV, Oka/Merck attenuated VZV, HSV
- No Oka/Merck VZV isolated from lesions
- If +VZV _and_ +HSV, determined by CEC (1 case)
- Viral Culture +
- 1.0% (10/957) of evaluable HZ cases
- VZV, HSV
- CEC Adjudication
- 5.5% (53/957) of evaluable HZ cases
- Determination if not diagnosed by PCR or culture
- All HZ cases reviewed by Clinical Evaluation Committee

## “Co-Primary” Endpoint – 1Protocol 004

**Decrease in HZ Burden-of-Illness (BOI)**
**61.1% (51.1, 69.1)**
- Mean sum of areas under curve
- ≤ 6 months in HZ cases
- X
- Proportion of subjects with HZ
- in treatment arm
- Success Criteria: point estimate > 47%; LL 95% CI > 25%

## “Co-Primary” Endpoints – 2Protocol 004

**Decrease in Incidence of PHN**
**	****	****66.5% (47.5, 79.2)**
- Pain ≥ 3 (0-10 point scale, 10 = worst pain)
- Occurring/persisting 90 days after HZ onset
- 30 day cutoff changed after last HZ case accrued
- Success Criteria:  point estimate > 62%; LL 95% CI > 25%

## Secondary Endpoint - 1Protocol 004

**Decrease in Incidence HZ**
**	****51.3% (44.2. 57.6)**
- Elevated to secondary endpoint after last HZ case accrued but prior to formal unblinding
- Success Criteria:  LL 95% CI > 25%

## Secondary Endpoint – 2Protocol 004

**Duration of clinically significant pain**
**	****20 days (vaccine) vs. 22 days (placebo)**
- Clinically significant = pain score ≥ 3, 0-10 pt. scale
- P-value < 0.001 (MITT)
- P-value = 0.041 (Evaluable HZ cases only)
- Elevated to secondary endpoint after last HZ case accrued but prior to formal unblinding
- Success Criteria:  p-value < 0.001

## Secondary Endpoint – 3Protocol 004

**Substantial Interference with **
**Activities of Daily Living (SADLI)**
- “Because Substantial ADLI can only occur
- among HZ cases, the benefit of vaccination in
- reducing the incidence of Substantial ADLI
- was confounded by the benefit of vaccination
- in reducing HZ incidence.”
- (Clinical Study Report, page 108)

## Secondary Endpoint – 4Protocol 004

**Substantial Interference with **
**Activities of Daily Living (SADLI)**
- Combined ADLI score ≥2 for ≥7 days
- 36.2% (ZOSTAVAX) vs. 39.4% (Placebo)
- 8.2% (-9.4, 22.9) in ZOSTAVAX group beyond the reduction in HZ incidence
- P-value = 0.341
- Does not include vaccine effect on HZ incidence, unlike other major endpoints
- Elevated to secondary endpoint after last HZ case accrued but prior to formal unblinding
- Success Criteria:  p-value  0.05; LL 95% CI > 0

## Effect of Covariates on Pain Severity-by-Duration Scores Among Evaluable HZ cases Protocol 004

| Parameter | Estimate | Std. Error | P-Value1 |
| --- | --- | --- | --- |
| Vaccine v. Placebo | -35.065 | 13.909 | 0.012 |
| Female v. male | -19.691 | 13.967 | 0.159 |
| Age (yrs.) | 4.665 | 1.092 | <0.001 |
| Antiviral drug use2 | 30.915 | 20.822 | 0.138 |
| Analgesic drug use2 | 161.626 | 16.744 | <0.001 |
| 1: Based on analysis of covariance (ANCOVA) model; severity-by-duration score of HZ pain = response variable, and listed parameters as explanatory variables.
2: Yes or No, in 6-months following onset HZ rash
p-values (interactions): treatment-by-gender = 0.143; 
treatment-by-age = 0.031; treatment-by-antiviral use = 0.381; treatment-by-analgesic use = 0.293
MITT population |  |  |  |

## Immune Status at HZ OnsetProtocol 004

|  |  | ZOSTAVAXTM
N = 19,270 |  | Placebo
N = 19,276 |  |
| --- | --- | --- | --- | --- | --- |
| # Subjects immunosuppressed at onset of HZ (n)/Total HZ cases (m) |  | 17/320 | 5.3% | 16/659 | 2.4% |
|  |  | n | % | n | % |
|  | Corticosteroids | 5 | 29.4 | 6 | 37.5 |
|  | Chemotherapy | 4 | 23.5 | 6 | 37.5 |
|  | Transplantation | 1 | 5.9 | 1 | 6.3 |
|  | Malignancy | 9 | 52.9 | 9 | 56.3 |
|  | Other* | 7 | 41.2 | 3 | 18.8 |
| *Includes use of methotrexate, radiation therapy, neoplasm, emphysems, polymyalgia rheumatica, pulmonary fibrosis. |  |  |  |  |  |

## HZ BOI Efficacy by YearProtocol 004

| Yr | ZOSTAVAXTM
 |  |  |  | Placebo
 |  |  |  | Efficacy 
(95% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | n | m | F/U | Incid. | n | m | F/U | Incid. |  |
| 1 | 76 | 19254 | 19132 | 0.427 | 201 | 19274 | 19081 | 2.075 | 0.79 (0.68, 0.87) |
| 2 | 103 | 18994 | 18827 | 0.801 | 194 | 18915 | 18679 | 1.661 | 0.52 (0.27, 0.68) |
| 3 | 98 | 18626 | 14505 | 0.809 | 171 | 18422 | 14327 | 1.482 | 0.45 (0.19, 0.63) |
| 4 | 35 | 9943 | 5412 | 0.367 | 70 | 9806 | 5325 | 1.007 | 0.64 (0.25, 0.82) |
| 5 | 3 | 1906 | 327 | 0.094 | 6 | 1856 | 324 | 0.375 | 0.75 (0.19, 0.92) |
| F/U: in person-yrs.        Incidence: per 1000 person-yrs
n = # with event in time period    m = # followed in time period |  |  |  |  |  |  |  |  |  |

## PHN Efficacy by YearProtocol 004

| Yr | ZOSTAVAXTM
 |  |  |  | Placebo
 |  |  |  | Efficacy 
(95% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | n | m | F/U | Incid. | n | m | F/U | Incid. |  |
| 1 | 5 | 19254 | 19132 | 0.261 | 33 | 19274 | 19081 | 1.729 | 0.85 (0.61, 0.95) |
| 2 | 8 | 18994 | 18827 | 0.425 | 22 | 18915 | 18679 | 1.178 | 0.64 (0.16, 0.86) |
| 3 | 10 | 18626 | 14505 | 0.689 | 17 | 18422 | 14327 | 1.187 | 0.42 (-0.34, 0.76) |
| 4 | 3 | 9943 | 5412 | 0.554 | 7 | 9806 | 5325 | 1.315 | 0.58 (-0.85, 0.93) |
| 5 | 1 | 1906 | 327 | 3.061 | 1 | 1856 | 324 | 3.083 | 0.007 (-76.93, 0.99) |
| F/U: in person-yrs.        Incidence: per 1000 person-yrs
n = # with event in time period    m = # followed in time period |  |  |  |  |  |  |  |  |  |

## HZ Efficacy by YearProtocol 004

| Yr | ZOSTAVAXTM
 |  |  |  | Placebo
 |  |  |  | Efficacy 
(95% CI) |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  | n | m | F/U | Incid. | n | m | F/U | Incid. |  |
| 1 | 76 | 19254 | 19132 | 3.972 | 201 | 19274 | 19081 | 10.534 | 0.62 (0.51, 0.71) |
| 2 | 103 | 18994 | 18827 | 5.471 | 194 | 18915 | 18679 | 10.386 | 0.47 (0.33, 0.59) |
| 3 | 98 | 18626 | 14505 | 6/756 | 171 | 18422 | 14327 | 11.936 | 0.43 (0.27, 0.56) |
| 4 | 35 | 9943 | 5412 | 6.467 | 70 | 9806 | 5325 | 13.145 | 0.51 (0.25, 0.68) |
| 5 | 3 | 1906 | 327 | 9.183 | 6 | 1856 | 324 | 18.500 | 0.50 (-1.32, 0.92) |
| F/U: in person-yrs.        Incidence: per 1000 person-yrs
n = # with event in time period    m = # followed in time period |  |  |  |  |  |  |  |  |  |

## Mean Worst HZ Pain (ITT)Protocol 004

| 
 | 
ZOSTAVAXTM
(95% CI) | 
Placebo
(95% CI) |
| --- | --- | --- |
| D 1 (rash onset) | 3.6 (2.5, 4.8) | 5.0 (4.3, 5.7) |
| D 2 | 4.1 (3.3, 4.8) | 4.3 (3.8, 4.7) |
| D 3 | 4.3 (3.7, 4.8) | 4.2 (3.8, 4.7) |
| D 4-5 | 4.6 (4.2, 5.0) | 4.3 (4.1, 4.6) |
| D 9-11 | 3.6 (3.2, 4.0) | 3.6 (3.4, 3.8) |
| Wk 4 | 1.9 (1.5, 2.2) | 2.0 (1.8, 2.2) |
| Wk 6 | 1.2 (0.9, 1.4) | 1.3 (1.1, 1.5) |
| Wk 8 | 0.8 (0.6, 1.0) | 1.1 (0.9, 1.3) |
| Wk 12 | 0.5 (0.4, 0.7) | 0.8 (0.6, 0.9) |
| Wk 16 | 0.4 (0.2, 0.5) | 0.6 (0.4, 0.7) |
| Wk 26 | 0.2 (0.1, 0.2) | 0.4 (0.3, 0.5) |

## Effect of Age on EfficacyProtocol 004

|  |  | Efficacy (95% CI) |
| --- | --- | --- |
| BOI | 60-69 yrs. | 0.655 (0.515, 0.755) |
|  | ≥ 70 yrs.  | 0.554 (0.399, 0.669) |
|  |  |  |
| Incidence PHN | 60-69 yrs. | 0.656 (0.204, 0.867) |
|  | ≥ 70 yrs.  | 0.668 (0.433, 0.813) |
|  |  |  |
| Incidence HZ | 60-69 yrs. | 0.639 (0.555, 0.709) |
|  | ≥ 70 yrs.  | 0.376 (0.250, 0.481) |

## Vaccine Efficacy on HZ Incidence by AgeFDA exploratory analysis - Protocol 004

| Age (Yrs.) | Incidence rate / 1000 person yrs.
(# HZ cases / # subjects in age group) |  | Vaccine Efficacy (HZ) |
| --- | --- | --- | --- |
|  | ZOSTAVAXTM | Placebo |  |
| 59-64 | 3.441 (54/5216) | 9.945 (153/5198) | 0.654 (0.528, 0.746) |
| 65-69 | 4.351 (68/5154) | 11.626 (181/5158) | 0.626 (0.506, 0.717) |
| 70-74 | 6.435 (89/4545) | 11.438 (158/4560) | 0.437 (0.271, 0.566) |
| 75-79 | 7.182 (67/3076) | 11.312 (103/2999) | 0.360 (0.129, 0.530) |
| 80-84 | 9.773 (31/1063) | 12.230 (39/1097) | 0.201 (-0.281, 0.501) |
| 85-89 | 10.040 (5/181) | 11.570 (7/210) | 0.132 (-1.734, 0.725) |
| 90+ | 19.608 (1/19) | 14.286 (1/25) | -0.373 (-20.945, 0.91.4) |

## Vaccine Efficacy Above and Beyond VEHZFDA Exploratory Analyses - Protocol 004

- Median HZ BOI among HZ cases
- 82.50 (ZOSTAVAX)
- 87.75 (Placebo)
- P-value (Wilcoxon) = 0.25
- Percent of HZ cases with PHN
- 8.57% (ZOSTAVAX)
- 12.5% (Placebo)
- P-value (Fisher) = 0.08
- Duration of clinically significant pain (days)
- 19 (ZOSTAVAX)
- 22 (Placebo)
- P-value (Wilcoxon) = 0.09

## Comparison of distributions of BOI between Placebo and ZOSTAVAX group among HZ casesFDA Exploratory Analysis- Protocol 004

## FDA Exploratory Analysis – Protocol 004

## Comparison of BOI between Placebo and Zostavax group among HZ casesFDA Exploratory Analysis – Protocol 004

- Test                     p-value                p-value(age-adjusted)
- Log-Rank            0.0863                  0.0330
- Wilcoxon             0.2460                  0.0985
- Tarone                0.1848                  0.0679
- Peto                    0.2530                  0.1083
- Modified Peto     0.2535                  0.1088
- Fleming(ρ=1)        0.2460                  0.1064
- Kolmogorov -Smirnov       0.7907

## FDA Exploratory Analysis – Protocol 004

## Comparison of distributions of BOI between Placebo and ZOSTAVAX group among PHN casesFDA Exploratory Analysis – Protocol 004

## Comparison of BOI among PHN casesFDA Exploratory Analysis – Protocol 004

## Comparison of BOI between Placebo and Zostavax group among PHN casesFDA Exploratory Analysis – Protocol 004

- Test                   p-value                p-value(age-adjusted)
- Log-Rank            0.1138                  0.1019
- Wilcoxon             0.1486                  0.1593
- Tarone                0.1262                  0.1153
- Peto                    0.1482                  0.1449
- Modified Peto     0.1493                  0.1468
- Fleming(ρ=1)        0.1486                  0.1415
- Kolmogorov -Smirnov       0.4579

## Immunogenicity

## Immunogenicity AssaysProtocol 004

- gpELISA
- Responder Cell Frequency (RCF)
- IFN-γ ELISPOT

## gpELISA Fold Rise  6 wks postvaccinationProtocol 004

| Clinical Lot* | GMF (95% CI) |
| --- | --- |
| 1562W-E471 | 1.7 (1.5, 2.0) |
| 1563W-E472 | 1.8 (1.5, 2.1) |
| 1564W-E473 | 1.9 (1.6, 2.3) |
| 1588W-G479 | 1.7 (1.5, 1.9) |
| 1589W-G480 | 1.6 (1.4, 1.8) |
| 15990W-G481 | 1.6 (1.4, 1.8) |
| * Accelerated aged lots |  |

## gpELISA by HZ StatusProtocol 004

|  |  | ZOSTAVAX | Placebo |
| --- | --- | --- | --- |
| GMT (6wk)
gpELISA units/mL | HZ | 272 (162, 457)
N = 9 | 182 (134, 247)
N = 23 |
|  | No HZ
 | 478 (445, 515)
N = 658 | 296 (273, 321)
N = 661 |
| GMFR 
D 0 – Wk 6 | HZ
 | 1.1 (0.9, 1.4)
N = 9 | 0.9 (0.8, 1.1)
N = 23 |
|  | No HZ
 | 1.7 (1.6, 1.8)
N = 646 | 1.0 (1.0, 1.0)
N = 650 |

## HZ Risk by 6 Wk gpELISA TiterFDA Exploratory Analysis - Protocol 004 

| gpELISA | ZOSTAVAXTM |  | Placebo |  |  |
| --- | --- | --- | --- | --- | --- |
| gpELISA u/mL | n/N | % | n/N | % |  |
| ≤100  | 0/24 | 0% | 5/92 | 5.43% | N = # subjects in group w/given titer |
| 100 - ≤ 200 | 3/86 | 3.49% | 6/147 | 4.08% |  |
| 200 - ≤ 300 | 3/108 | 2.78% | 5/118 | 4.24% |  |
| 300 - ≤ 400 | 1/121 | 0.83% | 6/111 | 5.41% | 
n = # subjects in group developing HZ |
| 400 - ≤ 500 | 1/18 | 5.56%  | 0/14 | 0% |  |
| 500 - ≤ 600 | 0/31 | 0% | 0/32 | 0% |  |
| 600 - ≤ 700 | 0/34 | 0% | 1/16 | 6.25% |  |
| 700 - ≤ 800 | 0/35 | 0% | 0/20 | 0% |  |
| 800 - ≤ 900 | 0/29 | 0% | 0/17 | 0% |  |
| 900 - ≤ 1000 | 0/23 | 0% | 0/12 | 0% |  |
| > 1000 | 1/146 | 0.68% | 0/94 | 0% |  |

## Herpes ZosterProtocol 004

- No clear difference in rates of various reported complications among HZ cases in the treatment groups
- HZ associated w/immunosuppression
- Number of immunosuppressed subjects w/HZ in each treatment group was equal
- 2 placebo subjects & 1 ZOSTAVAX subject developed multiple evaluable cases of HZ (only data from 1st case used in analyses)

## gpELISA: ZOSTAVAX vs. Naturally Occurring HZProtocol 004

|  | Following receipt of 
ZOSTAVAXTM | Naturally Occurring HZ following: |  |
| --- | --- | --- | --- |
|  |  | ZOSTAVAXTM | Placebo |
| After  | Vaccination | Rash Onset | Rash Onset |
| GMT
6wk | 475 
(442, 511) | 2042 
(1805, 2309) | 2260
(2070, 2467) |
| GMFR 
D 0 – 6 wk | 1.7
(1.6, 1.8) | 3.2
(2.6, 3.9) | 3.1
(2.7, 3.5) |

## Safety

## Slide 58

|  | Protocol 004 |  |  |  |
| --- | --- | --- | --- | --- |
|  | Randomized 1:1
N = 38,546 |  |  | 
 |
|  |  |  |  |  |
| ZOSTAVAXTM
N = 19,270 |  |  | Placebo
N = 19,276 |  |
| ↓ |  |  | ↓ |  |
| AE Monitoring Substudy
N = 3,345 |  |  | AE Monitoring Substudy
N = 3,271 |  |
| OR |  |  | OR |  |
| Routine Monitoring Cohort
N = 15,925 |  |  | Routine Monitoring Cohort
N = 16,006 |  |
| CMI Substudy
N = 691 |  |  | CMI Substudy
N = 704 |  |

## Safety Monitoring – 1Protocol 004

**AE Substudy (N = 6,616)**
- Vaccine Report Cards
- Solicited local AEs Days 0-4
- Temperature Days 0-21
- Rashes, other complaints, illness Days 0-42
- Automated Telephone Response System (ATRS)
- Day 42 Safety specific follow-up
- Rash, unusual reactions, hospitalizations, disability, life-threatening events, new diagnosis of cancer, overdose of any medication
- Monthly for suspected HZ, hospitalization
- Medical record review on or around Day 42 (AEs, HZ)

## Safety Monitoring – 2Protocol 004

**Routine Monitoring Cohort (N = 31,930)**
- ATRS Day 42 Safety Follow-up
- Rash, unusual reactions, hospitalizations, disability, life-threatening events, new diagnosis of cancer, overdose of any medication
- Available Medical record review  ~ Day 42
- AEs
- HZ
- Otherwise safety monitoring – passive
- 	(Monthly ATRS monitored for suspected HZ)

## ATRS 42 Day Safety Follow-Up By Subject  - Protocol 004

| 				 |  | N |  | % |  |
| --- | --- | --- | --- | --- | --- |
| Total Population - Protocol 004  |  | 38,546 |  | 100% |  |
| Subjects in Day 42 ATRS Dataset    |  | 25,613 |  |   66% |  |
|  | Calls made by subjects per protocol |  | 21,117 |  | 55% |
|  | Calls made by staff for subjects |  | 4,496 |  | 11% |

## ATRS 42 Day Safety Follow-Up - 2

- 601 of 6616 subjects (9%) from AE Monitoring Cohort Included in ATRS Day 42 Dataset
- 1,240 additional reports (≥ 6) for  subjects after initial entry of their data over ~ 3 year period

## ATRS 42 Day Safety Follow-UpReports by Source and Time - Protocol 004 (includes subjects with multiple  entries)

| Days Postvaccination | Subject Contact | Staff Called for Subject |
| --- | --- | --- |
| -5 – 28 | 13 | 2 |
| 29-42 | 10 | 69 |
| 43 | 15 | 101 |
| 44 | 17,248 | 510 |
| 45 | 1,702 | 207 |
| 46 | 987 | 137 |
| 47 | 477 | 137 |
| 48 | 434 | 87 |
| 49 | 193 | 131 |
| 50 | 213 | 112 |
| 51-1095 | 2 | 4639 |

## AE Rates From AE Monitoring Substudy from VRC Days 0-42 - Protocol 004

|  | ZOSTAVAX | Placebo |
| --- | --- | --- |
| Number of subjects with VRCs | 3345 | 3271 |
| Solicited AEs |  |  |
| Temperature ≥ 38.3°C | 0.8% | 0.9% |
| Temperature “abnormal” but < 38.3°C | 7.2% | 6.0% |
| Erythema* | 36% | 7% |
| Pain/Tenderness* | 35% | 9% |
| Swelling* | 26% | 4.5% |
| Unsolicited AEs |  |  |
| Pruritis | 7% | 1% |
| Warmth | 1.7% | 0.3% |
| *Specifically queried on VRC; all had p-value for risk difference < 0.001
Abnormal temperature = qualitatively abnormal |  |  |

## Systemic AEs (> 1%)AE Monitoring SubstudyDays 0 – 42 Protocol 004

|  | ZOSTAVAXTM | Placebo |
| --- | --- | --- |
| Subjects w/ follow-up | 3326 | 3249 |
| Cardiovascular | 1.2% | 1.2% |
| Digestive | 3.7% | 3.8% |
| General body | 10.5% | 9.8% |
|      Headache | 2.7% | 2.6% |
| Musculoskeletal | 1.4% | 1.2% |
| Nervous System | 1.7% | 1.8% |
| Respiratory | 7.2% | 6.2% |
|      Respiratory disorder | 2.0% | 1.7% |
|      Respiratory infection  | 1.1% | 0.8% |
| Skin | 7.6% | 7.3% |

## Serious Adverse Event Rates Days 0-42 - Protocol 004

|  |  | ZOSTAVAXTM | Placebo |
| --- | --- | --- | --- |
| Routine Monitoring Cohort
N = 31,930 | SAE | 1.24%
N = 191 | 1.38%
N = 213 |
| AE Monitoring Substudy
N = 6,616 | SAE | 1.92%
N = 64 | 1.26%
N = 41 |
| AE Monitoring Substudy
60-69 yrs.  N = 3,459 | SAE | 1.27%
N = 22 | 1.05%
N = 18 |
| AE Monitoring Substudy
≥ 70 yrs. N = 3,157 | SAE | 2.63%
N = 42 | 1.49%
N = 23  |
| Overall Study N = 38,546 | Death* | N = 14 | N = 16 |
|  |  |  |  |

## Deaths* Resulting in SAEs Days 0-42

| Protocol 004 | Number of Events |  |
| --- | --- | --- |
|  | ZOSTAVAXTM
N = 19,270 | Placebo
N = 19,276 |
| All SAEs resulting in death | 14 | 16 |
| Myocardial infarction | 7 | 5 |
| Cardiovascular Dz. | 2 | 0 |
| Heart arrest | 0 | 2 |
| Heart failure | 1 | 0 |
| Sudden death | 0 | 1 |
| Cerebrovascular accident | 2 | 1 |
| Carcinoma | 2 | 4 |
| Aspiration pneumonia | 0 | 1 |
| Gangrene, intestinal | 0 | 1 |
| Liver failure | 0 | 1 |
| *26 of 30 deaths reported from Routine Monitoring Cohort |  |  |

## Hospitalization: Day 0 - Study EndAE Monitoring Substudy Protocol 004 

|  | ZOSTAVAXTM
N = 3345 |  | Placebo
N = 3271 |  |
| --- | --- | --- | --- | --- |
|  | n/m
 | Rate/
1000 pt.- yrs.
(95% CI) | n/m | Rate/
1000 pt.- yrs.
(95% CI) |
| All | 1137/3342 | 107.48 
(101.3, 113.9) | 1115/3266 | 107.30 
(101.1, 113.8) |
| HZ-related |    5/3342 | 0.38 
(0.12, 0.89) | 6/3266 | 0.47 
(0.17, 1.030) |
| N = # subjects in AE Monitoring Substudy in each treatment group
n = # subjects in category with hospitalization
m = # subjects randomized
No vaccine-related hospitalizations were reported |  |  |  |  |

## Deaths Overall:  Day 0 – Study End Protocol 004

|  | ZOSTAVAXTM
N = 19,270 |  | Placebo
N = 19,276 |  |
| --- | --- | --- | --- | --- |
| Age (yrs.) | n/m (%) | Death rate / 1000-person yrs. 
(95% CI) | n/m (%) | Death rate / 1000-person yrs. (95% CI) |
| 60-69 | 218/10378 | 6.2 
(5.4, 7.08) | 246/10369 | 7.00 
(6.15, 7.93) |
| ≥ 70  | 575/8892 | 19.08 
(17.55, 20.70) | 549/8907 | 18.12 
(16.64, 19.70) |
| All
 | 793/19270 | 12.14
(11.31, 13.02) | 795/19276 | 12.15
(11.32, 13.02) |
| n - # subjects in group who died during study
m - # subjects originally randomized to age group |  |  |  |  |

## Safety Follow-upDay 43 – Study End – 1Protocol 004

- No information on proportion of subjects with ATRS contact at each month, overall, by group and by site. (AE Monitoring Cohort queried for hospitalizations.)
- “Due to the passive and inconsistent nature of safety data collection in the Routine Monitoring Cohort...from Day 43 through study end, caution should be exercised when interpreting these particular data.” (Clinical Study Report, p. 309)

## AE Monitoring SubstudyAEs > 1%, Day 43 – Study End

|  | ZOSTAVAXTM | Placebo |
| --- | --- | --- |
| Subjects w/ follow-up | 3342 | 3271 |
| Cardiovascular | 11.0% | 11.5% |
| Digestive | 6.4% | 5.5% |
| General Body | 9.5% | 10.5% |
| Genitourinary | 5.0% | 5.6% |
| Metabolic/nutritional | 1.0% | 1.3% |
| Musculoskeletal | 6.6% | 7.0% |
| Nervous system | 4.5% | 4.7% |
| Respiratory | 4.3% | 4.7% |
| Skin | 3.1% | 3.1% |

## 

Protocol 009

**Protocol 009**

## Objective - Protocol 009

- Comparison of safety and tolerability profile of a higher potency zoster vaccine with that of a lower potency dose
- Among adults ≥ 50 years of age, the higher potency ZOSTAVAXTM would be generally well tolerated as compared with the lower potency ZOSTAVAXTM

## Design - Protocol 009

- Double-blind, comparator study
- Randomized 2:1 (high : low potency)
- Subjects ≥ 50 yrs. old
- 	Stratified:	50-59 yrs. (N = 185)
- 				≥ 60 yrs. (N = 513)
- Dose comparison
- 	58,000 pfu (N = 234) and 207,000 pfu (N = 461)
- 42 Day safety follow-up
- Vaccine Report Cards
- Local and systemic AEs
- Varicella, varicella-like rash
- HZ, HZ-like rash

## Primary Endpoints – Protocol 009

- Difference between higher and lower potency vaccine groups in risk of _vaccine-related*_ serious clinical adverse experiences occurring Day 1 - 42 postvaccination (2-sided, 0.05 level)
- Upper bound of the 95% CI for incidence rate of moderate or severe injection site pain, tenderness, soreness or swelling occurring Day 1 - 5 postvaccination in the higher potency vaccine group be less than 21.5%
- 	(historical rate reported with PNEUMOVAXTM23).
- *Vaccine-related as determined by study investigator

## Secondary Endpoints – Protocol 009

- Varicella or varicella-like rash with > 100 lesions Days 1 – 42 postvaccination
- HZ or HZ-like rash Days 1 – 42 postvaccination
- Fever ≥ 38.3°C (oral) Days 1 – 21 postvaccination

## Results 1 - Protocol 009

**Primary Endpoints**
- Vaccine-related* SAEs – No occurrence
- Rate of composite local AEs in high potency group:  17.2% (13.9, 21.0)
- Prespecified criteria:  Upper limit of 95% CI < 21.5%
-  	based upon PNEUMOVAXTM23 historical data
- *Vaccine-related as determined by study investigator

## Results 2 - Protocol 009

**Secondary Endpoints**
- Varicella or varicella-like rash (>100 lesions) – no occurrence in either treatment group
- Zoster or zosteriform rash
- 	3 (0.7) high potency vs. 3 (1.3%) low potency
- 	p-value:  0.399
- Elevated temperature, ≥38.3 °C
- 	4 (0.9%) high potency vs. 2 (0.9%) low potency

## Safety - 1 SAEs Days 0-42 - Protocol 009

| ZOSTAVAXTM High Potency |  |  |  |
| --- | --- | --- | --- |
| Gender | Age | Day of Onset* | SAE |
| Female | 66 | 13 | Coronary artery dz. |
| Male | 61 | 25 | Angina pectoris |
| Female | 54 | 29 | Depression |
| Female | 56 | 41 | Enteritis |
| ZOSTAVAXTM Low Potency |  |  |  |
| Gender | Age | Day of Onset | SAE |
| Male | 58 | 3 | Lung cancer |
| *Number of days postvaccination |  |  |  |

## Safety - 2 Days 0-42 - Protocol 009

- Deaths:  None
- Injection-site reactions composite endpoint:
- 	17.2% (13.9, 21.0) in high potency group
- 	9.0% (5.6, 13.1) in low potency group
- Higher rates of injection site reactions in younger subjects more marked in those receiving high potency  vaccine:  83% in 50-59 yr. olds vs. 55% in ≥ 60 yr. olds.

## 

Summary of ZOSTAVAXTM Issues

- Summary of ZOSTAVAXTM Issues

## ZOSTAVAXTM Summary - Protocol 004 

- Reduction in HZ incidence:  51% (44, 58) in relatively healthy adults ≥ 60 years old postvaccination; 64% (56, 71) in those 60-69 yrs., but only 38% (25, 48) in those ≥ 70 years.
- Reduction in PHN incidence: 67% (48, 79) at 90 days following HZ rash onset.
- Reduction in HZ BOI score:  61% (51, 69) over 6 months following HZ rash onset.
- Effect on PHN incidence and BOI appears relatively small after accounting for the effect of the vaccine on the incidence of HZ.

## ZOSTAVAXTM Summary - Protocol 004

- In persons with HZ, no clear correlations seen between reduction of BOI scores and measures of clinical benefit, e.g., mortality, serious morbidity, hospitalizations, use of pain medications or interference with ADLs.
- Completeness of safety, ATRS and study termination follow-up is unclear.
- Age appears to be the strongest factor determining vaccine effect and in an exploratory analysis, efficacy appears minimal in subjects ~ 75 years and older (the age group with potentially the largest burden of illness).

## ZOSTAVAXTM Summary - Protocol 004

- Relative increase in rate of SAEs seen (D 0-42) in the AE Monitoring Substudy, most notably in subjects aged ≥ 70 years old; however, no specific pattern of SAEs was seen.
- Exclusion crtieria (not expected to live ≥ 5 more years, not ambulatory, chronic corticosteroid use, cognitive impairment) make it difficult to draw conclusions as to generalizability of the Protocol 004 efficacy and safety analyses to a typical population aged 60 years and older.

## ZOSTAVAXTM Summary - Protocol 009

- Includes younger subjects (50-59 years old) but no comparison of older age strata to previous similar age groups in previous ZOSTAVAXTM studies
- Vaccine dose 4 times higher than any previously  studied, but has no comparison or bridging to previous ZOSTAVAXTM studies
- Clinical relevance of study endpoints unclear:
- Comparison of composite endpoint (local injection-site events) to historical rate in PNEUMOVAXTM23
- Comparison of _investigator-determined, vaccine-related_ SAEs by dose

## 

Questions for the Committee

**Questions for the Committee**

## Questions for the Committee

- 1.  Are the available data adequate to support the efficacy of ZOSTAVAXTM when administered to individuals ≥ 50 years of age in:
- 	a.  Preventing herpes zoster?
- 	b.  Preventing post-herpetic neuralgia?  Preventing post-herpetic neuralgia beyond the effect on the prevention of herpes zoster?
- 	c.  Decreasing the burden of illness (BOI)?  Decreasing the burden of illness (BOI) beyond the effect on the prevention of herpes zoster?
- If not, what additional information should be provided?

## Questions for the Committee

- 2.  Are the available data adequate to support the safety of ZOSTAVAXTM when administered to individuals ≥ 50 years of age?
- 	If not, what additional information should be provided?

## Questions for the Committee

- 3.	Please identify any other issues that should be addressed, including post-licensure studies.  In particular please address:
- 	a.  Use of the vaccine in persons with co-morbid 	   	  conditions, e.g., those who might typically reside in 	  assisted living residences and nursing homes.
- 	b.  Use of the vaccine among persons taking chronic 	  immunosuppressive therapies, including 	 	  corticosteroids.
- 	c.  Use of the vaccine in certain subsets of the 	   	 sponsor’s proposed age indication, e.g., those ≥ 70 	 years, those ≥ 80 years.
- 	d.  Duration of immunity.
- 	c.  The sponsor’s proposed pharmcovigilance plan.

## Acknowledgments

- Sang Ahnn, PhD
- Douglas Pratt, MD, MPH
- Theresa Finn, PhD
- Karen Goldenthal, MD
- CAPT Katherine Matrakas

## Acronyms

- AE:    	Adverse event
- ATRS: 	Automated telephone response system
- BOI:  	Burden of illness
- CEC:    	Clinical evaluation committee
- CMI:  	Cell-mediated immunity
- HSV:	Herpes simplex virus
- HZ:	Herpes zoster
- ITT:    	Intent to treat
- IZIQ:	Initial Zoster Impact Questionnaire
- MITT: 	Modified intent to treat
- PFU:  	Plaque-forming units
- PHN: 	Post herpetic neuralgia
- PPI:	Present pain intensity scale
- QoL:	Quality of life
- SADLI: 	Substantial interference with activities of daily living
- VZV:	Varicella zoster virus
- ZBPI: 	Zoster brief pain inventory

## 

Additional Slides

**Additional Slides**

## Cummulative Incidence of HZProtocol 004

| 
Through year | HZ Incidence / 1000 person-yrs.  |  | 
Efficacy (95% CI) |
| --- | --- | --- | --- |
|  | ZOSTAVAXTM | Placebo |  |
| 1 | 3.970 | 10.527 | 62.3% (51.0, 71.0) |
| 2 | 4.712 | 10.454 | 54.9% (46.3, 62.2) |
| 3 | 5.278 | 10.862 | 51.4% (43.9, 57.9) |

## Determination of HZ Protocol 004

|  | ZOSTAVAX |  | Placebo |  |
| --- | --- | --- | --- | --- |
|  | Evaluable
N (%) | Non-Evaluable
N (%) | Evaluable
N (%) | Non-Evaluable
N (%) |
| Total | 316 (67.7) | 151 (32.3) | 644 (80.6) | 155 (19.4) |
| PCR VZV+ | 295 (63.2) | --- | 602 (75.3) | --- |
| PCR VZV -- | --- | 88 (18.8) | --- | 91 (11.4) |
| PCR HSV+ | --- | 23 (4.9) | --- | 21 (2.6) |
| PCR VZV+ / HSV+ | -- | -- | -- | 1 (0.1) |
| Viral Culture VZV+ | 2 (0.4) | -- | 8 (1.0) | -- |
| Viral Culture HSV+  | -- | 1 (0.20) | -- | -- |
| HZ by CEC early | 19 (4.1) | -- | 34 (4.3) | -- |
| HZ by CEC late | -- | 3 (0.6) | -- | 4 (0.5) |
| Non-HZ by CEC | -- | 36 (7.7) | -- | 36 (4.5) |
| Early:  seen during rash stage (crusted vesicles or earlier)
Late:  seen beyond crusting stage |  |  |  |  |

## Lot ConsistencyProtocol 004

- 6 clinical lots, accelerated aged
- Paired clinical lots derived from same parental lot
- Data pooled from each pair of aged lots
- Clinical EPs
- HZ BOI
- Incidence of PHN
- Incidence of HZ
- No apparent differences reported by sponsor
- Relatively wide CI for incidence of PHN due to few cases per clinical lot.