# Presentation: 213723

## ZOSTAVAXTMZoster Vaccine Live (Oka/Merck)

- Vaccines and Related Biological ProductsAdvisory Committee MeetingDecember 15, 2005

- Merck Research Laboratories

## Medical Need for ZOSTAVAXTM

- Herpes zoster (HZ) is common in individuals ≥50 years of age
- No medical treatment can prevent HZ
- Acute and chronic HZ pain are debilitating
- Available therapies for HZ pain have limitations

## ZOSTAVAXTM Program Hypothesis

- Vaccination with a live, attenuated Oka/Merck varicella-zoster virus (VZV) vaccine will address an important unmet medical need by:
- Reducing the incidence of HZ
- Reducing the frequency and/or severity of the complications of HZ, including postherpetic neuralgia (PHN)
- PHN defined as clinically significant pain present ≥90 days after HZ rash onset

## ZOSTAVAXTM Product Profile

- Live, attenuated varicella-zoster virus vaccine
- Same Oka/Merck strain as in VARIVAX®
- Distinct indications
- Different target population
- No preservative
- Lyophilized product
- Single subcutaneous dose
- Same excipients as VARIVAX®
- Contains a minimum of 19,400 PFU† per dose
- ~14 times the minimum potency of VARIVAX®

- † Plaque-forming units.

## ZOSTAVAXTM Proposed Indications

- ZOSTAVAXTM is indicated for:
- Prevention of herpes zoster (shingles)
- Prevention of postherpetic neuralgia (PHN)
- Reduction of acute and chronic zoster-associated pain
- ZOSTAVAXTM is indicated for immunization of individuals50 years of age or older

## ZOSTAVAXTM Clinical Program

- 8 ZOSTAVAXTM clinical trials
- Shingles Prevention Study
- Pivotal, multicenter, randomized, placebo-controlled study enrolling 38,546 subjects
- The studies have demonstrated that ZOSTAVAXTM:
- Is efficacious
- Prevention of HZ and PHN
- Reduction of pain burden of illness (BOI) related to HZ
- Reduction of the duration and severity of pain
- Reduction of overall risk of activities of daily living (ADL) interference due to HZ
- Is immunogenic
- Has an excellent safety profile

## Collaborators Associated with   the Shingles Prevention Study

## ZOSTAVAXTM Consultants

## ZOSTAVAXTM Agenda

**Introduction**
- David Gutsch, M.D.Director, Regulatory Affairs
**Epidemiology and the****Clinical Development Program**
- Jeffrey Silber, M.D.Senior Director, Clinical Research
**Concluding Remarks**
- David Gutsch, M.D.Director, Regulatory Affairs

## Discussion Topics

- Epidemiology of HZ and PHN
- Clinical Development Program
- Shingles Prevention Study
- Study design
- Key results
- Immunogenicity
- Safety
- Summary of Clinical Results

## HZ Is a Consequence of VZV Reactivation

- Copyright ©2005 by Merck & Co., Inc., All rights reserved.

## HZ Epidemiology

- An estimated 1 million cases of HZ per year in the US
- 50,000 to 60,000 hospitalizations
- 12,000 to 19,000 with primary diagnosis of HZ
- 70 to 80% of those hospitalized with HZ are immunocompetent
- Lifetime risk of developing HZ ~30%
- Among people who reach the age of 85 years, up to ~50% will have developed one or more episodes of HZ
- Risk factors for HZ: age, immunosuppression

## Epidemiology of HZ/PHN

- Occurrence by Age

- Hope-Simpson, RE. Postherpetic Neuralgia. *J. Royal College of General Practictioners *1975; 25:571-5.

## Herpes Zoster Incidence*

- United States – 2005

- * Hope-Simpson, RE. Postherpetic Neuralgia. *J. Royal College of General Practictioners *1975; 25:571-5.
- † Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat.
- ‡ The number of HZ cases was calculated by applying the Hope-Simpson HZ incidence rates to the 2005 US population.

## HZ Eruption

- Courtesy of Dr. Kenneth Schmader, Duke University and Durham VA Medical Centers.

##  Ophthalmic Zoster 

- Courtesy of MN Oxman UCSD/San Diego VAMC.

## Neurologic
Acute neuritic pain (>90%)
Postherpetic neuralgia (PHN) 
Limb weakness
Sensory loss
Autonomic dysfunction
Meningitis
Myelitis 
Encephalitis

- Acute neuritic pain (>90%)
- Postherpetic neuralgia (PHN)
- Limb weakness
- Sensory loss
- Autonomic dysfunction
- Meningitis
- Myelitis
- Encephalitis

- Ocular
- Visual impairment
- Cutaneous
- Scarring
- Bacterial superinfection
- Disseminated disease
- Mortality rate up to 40%

- Complications of HZ

## Comparison of Pain Severity

- Reprinted from Katz J, Melzack R.  Measurements of pain.** ***Surg Clin N Amer* 1999;79:231-52,
- with permission from Elsevier.

**Chronic Pain Conditions**

**Acute Pain Conditions**

## Postherpetic Neuralgia (PHN)

- Pain in area of the rash that is present after HZ resolution
- Constant or intermittent
- Dull and achy or sharp and lancinating
- Allodynia (exaggerated pain provoked by light touch) often the most troublesome symptom
- 10 to 20% of HZ patients develop PHN
- Risk increases dramatically with age
- Impact can be physical, psychological, social, functional
- Can persist for months to years
- Estimated 500,000+ prevalent PHN cases in the US

## Percentage of HZ Patients with Persistent Pain

- Percentage of HZ Patients with Persistent Pain

## Medical Need:Limitations of Current Therapies

- For HZ
- Antivirals (acyclovir, famciclovir, valacylovir)
- Reduce severity of acute HZ
- May shorten duration of PHN
- Limited effect on PHN incidence
- Corticosteroids
- No effect on incidence or severity of PHN
- For PHN
- Available therapies have limited benefit
- Side effects can be dose-limiting

## Rationale for ZOSTAVAXTM Development

- Risk for HZ and PHN
- 87,000,000 people in the US are ≥50 years of age
- Limitations of current therapies
- No existing intervention can prevent HZ and PHN

## Discussion Topics

- Epidemiology of HZ and PHN
- Clinical Development Program
- Shingles Prevention Study
- Study design
- Key results
- Immunogenicity
- Safety
- Summary of Clinical Results

## Proof of ConceptUsing Inactivated Oka/Merck VZV Vaccine

- Redman, et al., *J Infect Dis* (1997) – Bone marrow transplant recipients
- Reduced incidence of PHN
- Reduced severity of HZ
- Hata, et al., *NEJM* (2002) – Stem cell transplant recipients
- Reduced incidence of HZ

## Clinical Development Plan

- Dose selection
- Establish vaccine potency that is immunogenic and well tolerated
- ZOSTAVAXTM N=583, Placebo N=91
- Efficacy
- Determine vaccine impact on incidence of HZ and complications
- ZOSTAVAXTM N=19,270, Placebo N=19,276
- Two-dose/booster
- Safety and immunogenicity of a second dose
- ZOSTAVAXTM N=300, Placebo N=105
- Safety
- Determine safety profile:
- VZV-inexperienced - ZOSTAVAXTM N=159, Placebo N=3
- High potency - ZOSTAVAXTM N=695, Placebo N=0
- TOTAL: ZOSTAVAXTM N=21,007   Placebo N=19,475

- Study Objectives

## Rationale for ZOSTAVAXTM Potency Range

- Potencies evaluated in clinical studies ranged from 2,000 PFU to 207,000 PFU
- Early studies suggested that a single dose of ~17,000 PFU or higher boosts VZV-specific cell-mediated immunity (CMI)
- These data formed the basis for selection of target minimum potency of ~19,000 PFU in the efficacy study

## Study Population for ZOSTAVAXTM 

- ZOSTAVAXTM has been studied in adults 30 to 99 years of age, with a broad variety of underlying medical conditions
- Enrollment by gender
- Male	12,051	(57.8%) 	Female	8812	(42.2%)
- Ethnicity of study population
- White	19,914	(95.5%)	Native American	37	(0.2%)
- Black	412	(2.0%)	Other	73	(0.4%)
- Hispanic	298	(1.4%)	Unknown	3	(0.0%)
- With the exception of age-related trends, no differences in efficacy, immunogenicity, or safety by race and gender

## Discussion Topics

- Epidemiology of HZ and PHN
- Clinical Development Program
- Shingles Prevention Study
- Study design
- Key results
- Immunogenicity
- Safety
- Summary of Clinical Results

## Shingles Prevention Study (SPS) 

- Double-blind, placebo-controlled, multicenter trial, 22 sites
- Study timeline: Nov-1998 to Apr-2004
- Dept. of Veteran Affairs Cooperative Studies Program (VA CSP) collaboration with the National Institutes of Health (NIH) and Merck & Co., Inc.
- 38,546 subjects ≥60 years of age
- Age-stratified (60 to 69 years, ≥70 years)
- 90% had one or more underlying medical conditions
- Randomized 1:1 to receive ZOSTAVAXTM or placebo
- Most doses administered near proposed expiry potency
- Monthly telephone follow-up to identify HZ cases, monitor adverse experiences, and ensure subject retention
- All subjects actively contacted at the end of the study

## SPS Study Population

- Gender:MaleFemale
- Age (in years):MeanRange
- Race:BlackHispanicWhiteOther

- Placebo

- 11,357 (58.9%)   7919 (41.1%)
-          69.4      59 to 94
-      420 (2.2%)     248 (1.3%)18,381 (95.4%)     223 (1.2%)

- ZOSTAVAX**TM**

- 11,403 (59.2%)   7867 (40.8%)
-          69.4      60 to 99
-      395 (2.0%)     265 (1.4%)18,393 (95.4%)     214 (1.1%)

## Most Frequently Reported Prior Medical Conditions in SPS

- >20%
- Arthritis
- Hypertension
- >10 to 20%
- Prostate disorder
- Allergic reaction
- Gastrointestinal disorder
- Hypothyroidism
- Hypercholesterolemia

- >5 to 10%
- Coronary artery disease
- Diabetes mellitus
- Hyperlipidemia
- Osteoporosis
- Depression
- Glaucoma

## Most Frequently ReportedPrior Medical Conditions in SPS (Cont’d)

- 1 to 5%
- Carcinoma
- Edema
- Headache
- Hernia
- Pain
- Back pain
- Colitis
- Constipation
- Esophagitis
- Anemia
- Gout
- Bone disorder
- Joint disorder
- Anxiety

- Cerebrovascular accident
- Insomnia
- Neuropathy
- Sleep disorder
- Asthma
- Emphysema
- Lung disorder
- Rhinitis
- Sinusitis
- Acne
- Skin carcinoma
- Psoriasis
- Skin disorder
- Cataract

- Deafness
- Ear disorder
- Eye disorder
- Prostate carcinoma
- Impotence
- Menopause
- Urinary    incontinence

## SPS Substudy Design

- Adverse Event Monitoring Substudy (N=6616)
- Conducted at all 22 study sites
- Detailed safety assessment
- Cell-mediated Immunity Substudy (N=1395)
- Conducted at 2 study sites
- Specimens obtained at baseline and postvaccination    (6 weeks; 1, 2, and 3 years)
- Persistence of Efficacy Substudy (N~7500)
- Conducted at 12 study sites
- Ongoing follow-up from efficacy study
- Projected to continue through ~10 years postvaccination

## SPS Subject Randomization

## SPS Subject Disposition

## Summary of Day 42 Safety Follow-up(Whole Population in SPS)

- ZOSTAVAXTM (N=19,270)92.8% with contact by Day 60

- Placebo (N=19,276)93.0% with contact by Day 60

## Follow-up of Suspected HZ Cases

- Subjects with signs or symptoms suggestive of HZ were asked to report to study site within 24 hours, to initiate 6 months of follow-up
- Study sites conducted the following activities:
- Performed clinical evaluation
- Made provisional diagnosis
- Sampled lesions for PCR (+/- viral culture)
- Obtained digital photographs of HZ eruption
- Collected blood samples for immunological testing
- Administered HZ pain and health-related quality-of-life questionnaires
- Provided treatment for HZ
- Famciclovir and pain management

## Efficacy Endpoints Supporting Label Indications

- Incidence of HZ
- Incidence of PHN
- HZ pain burden of illness (BOI)

- Pain was evaluated on a 0-to-10 scaleusing a validated questionnaire
- Efficacy analyses were based on amodified intention-to-treat (MITT) population

## Rationale for Selection of Endpoints in SPS

- At initiation of study, existing scientific data suggested vaccination may prevent PHN and ameliorate HZ-associated pain
- Co-primary endpoints of HZ BOI and PHN were deemed most clinically relevant
- Tertiary endpoint on incidence of HZ was subsequently elevated to a key secondary endpoint
- Risk of PHN increases after age 60
- Study enrolled subjects ≥60 years of age in order to provide adequate power for PHN endpoint

## SPS Efficacy Endpoint Definitions

- Herpes zoster
- Suspected HZ: 6 months of protocol-specified follow-up
- All suspected HZ cases were clinically adjudicated according to detailed Standard Operating Procedure
- Confirmed HZ: Determined by PCR, viral culture, and clinical adjudication
- Postherpetic neuralgia
- Pain score ≥3 beyond 90 days after HZ rash onset

## HZ pain burden of illness (BOI)
Population measure
Sensitive to the incidence, duration and severity of HZ pain over 6 months

Primary analysis was performed on entire efficacy (MITT) population
Severity-by-duration (AUC) calculated for each HZ case
Subjects without HZ were assumed to have no HZ-associated pain (i.e., AUC=0)

- Population measure
- Sensitive to the incidence, duration and severity of HZ pain over 6 months
- Primary analysis was performed on entire efficacy (MITT) population
- Severity-by-duration (AUC) calculated for each HZ case
- Subjects without HZ were assumed to have no HZ-associated pain (i.e., AUC=0)

- SPS Efficacy Endpoint Definitions

## Hypothetical Example of HZ BOI:Reduction in HZ Incidence but Not Severity

## Hypothetical Example of HZ BOI:Reduction in HZ Severity but Not Incidence

## Hypothetical Example of HZ:  Reduction in Both Incidence and Severity of HZ

## SPS Efficacy Population

- Suspected Cases of HZ
- 1,308

- Placebo
- 827

- ZOSTAVAXTM
- 481

- 156	  Not HZ
-     3  Not seen until after crusted

- 161  	Not HZ
-     4	  Not seen until after crusted

## SPS Efficacy Population

- Suspected Cases of HZ
- 1,308

## ZOSTAVAXTM Efficacy

## ZOSTAVAXTM Efficacy: HZ Incidence

- Estimate of the Cumulative Incidence of HZ Over Time by Vaccination Group (MITT Population)

## Rate of HZ Complication

- * Incidence rate = per 1000 person years (total population).
- † Excluding pain.

- (MITT Population)

## ZOSTAVAXTM Efficacy: PHN Incidence

- Estimate of the Cumulative Incidence of PHN Over Time by Vaccination Group (MITT Population)

## ZOSTAVAXTM Efficacy on HZ Pain BOI and its Components

- VEBOI:  61.1% (95% CI [51.1%, 69.1%])
- Incidence
- Severity-by-Duration

## Summary of Severity-by-Duration Scores of HZ Pain Among Evaluable HZ Cases

- 22% reduction in pain among vaccinated subjects

## HZ Pain Severity-by-Duration (AUC) Scores Among HZ Cases with Severe, Long-Lasting HZ Pain (MITT Population) 

- HZ Pain Severity-by-Duration (AUC) Scores Among HZ Cases with Severe, Long-Lasting HZ Pain (MITT Population)

## ZOSTAVAXTM Reduces the Severity-by-Duration of PHN

- 57% reduction in pain among vaccinated subjects

## ZOSTAVAXTM Efficacy by Age Stratum

## ZOSTAVAXTM Effect on Interference with Activities of Daily Living (ADL)

- Evaluated using a validated questionnaire (0-to-10 scale)
- Average score based on 7 ADL questions
- Overall reduction in ADL interference score
- 66.2% (95% CI: 55.4%, 74.4%)
- Reduction in incidence of moderate-to-severe ADL interference (ADL score ≥2 for ≥7 days)
- Overall, 55.3% (95% CI: 44.2%, 64.2%)
- Removing contribution of VEHZ (prespecified endpoint), reduction was 8.2% (95% CI: -9.4%, 22.9%)

## Duration of ZOSTAVAXTM Efficacy

- After initial drop during the first year, point estimates for VEHZ and VEPHN were stable through 48 months of follow-up
- Subject follow-up is continuing (persistence substudy) at 12 of 22 study sites

## ZOSTAVAXTM Efficacy Summary

- ZOSTAVAXTM significantly reduces
- Incidence of HZ
- Incidence of PHN
- BOI related to HZ pain
- Duration of pain due to HZ
- Risk of ADL interference due to HZ
- ZOSTAVAXTM efficacy against HZ and PHN persists through 4 years of follow-up

## Discussion Topics

- Epidemiology of HZ and PHN
- Clinical Development Program
- Shingles Prevention Study
- Study design
- Key results
- Immunogenicity
- Safety
- Summary of Clinical Results

## ZOSTAVAXTM Immunogenicity Endpoints

- Declining VZV-specific immunity is thought to be a precursor for development of HZ
- Immune responses were measured in the CMI      substudy (N=1395) by:
- VZV-specific interferon-gamma enzyme-linked immunospot (IFN-γ ELISPOT) assay
- Glycoprotein enzyme-linked immunosorbent assay (gpELISA)
- Endpoints assessed at 6 weeks postvaccination
- Ratio of geometric mean titer (GMT) or geometric mean count (GMC) between vaccine and placebo groups
- Geometric mean fold rise from baseline

## SPS: Immunogenicity Results

- † Spot-forming cells per 106  peripheral blood mononuclear cells.

## Correlation of Immune Response with Efficacy at Week 6 Postvaccination

- Regression model of correlation with efficacy:
- gpELISA
- IFN-γ ELISPOT
- Best correlation with clinical efficacy: gpELISA

## SPS: Immune Responses by Age

- Immunogenicity by age cohort at 6 weeks postvaccination supports observed efficacy trend for HZ in SPS

## Protocol 010: Immune Responses by Age

- Immunogenicity at 4 weeks postvaccination comparable among subjects 50 to 59 years of age and older subjects

## Immunogenicity Summary

- In the face of pre-existing immunity, ZOSTAVAXTM elicits an increase in VZV-specific immunity compared with placebo at6 weeks postvaccination, as measured by gpELISA and IFN-γ ELISPOT
- VZV antibody response measured by gpELISA correlates well with protection against HZ

## Discussion Topics

- Epidemiology of HZ and PHN
- Clinical Development Program
- Shingles Prevention Study
- Study design
- Key results
- Immunogenicity
- Safety
- Summary of Clinical Results

## Builds on extensive VARIVAX® safety database
56 million doses distributed since licensure in 1995
Clinical evaluation in over 20,000 subjects vaccinated with ZOSTAVAXTM
Over 19,000 placebo controls 
Allowed for observation of uncommon adverse experiences

ZOSTAVAXTM is well tolerated in adults ≥50 years of age

- 56 million doses distributed since licensure in 1995
- Clinical evaluation in over 20,000 subjects vaccinated with ZOSTAVAXTM
- Over 19,000 placebo controls
- Allowed for observation of uncommon adverse experiences
- ZOSTAVAXTM is well tolerated in adults ≥50 years of age

- ZOSTAVAXTM Safety Experience

## SPS: Postvaccination Safety Evaluation

- Days 0 to 42 postvaccination
- Adverse experiences were collected on all subjects
- Subjects were contacted shortly after Day 42 postvaccination to ascertain full reporting of serious adverse experiences
- From Day 42 postvaccination through end of study
- Vaccine-related serious adverse experiences
- Deaths

## SPS: Adverse Event Monitoring Substudy

- Safety Substudy was conducted at all 22 study sites
- 3345 received ZOSTAVAXTM
- 3271 received placebo
- Postvaccination safety evaluation also included:
- Vaccination Report Card, completed through Day 42 postvaccination
- Hospitalizations, reported until end of study

## SPS: Serious Adverse Experiences

## SPS: Serious Adverse Experiences

- † Includes 1 reported on Day 53 postvaccination.

## SPS: Adverse Event Monitoring Substudy

- * Statistically significant.

## Protocol 009:ZOSTAVAXTM at a Higher Potency

- Controlled, double-blind, multicenter trial
- Randomized (2:1) to receive 1 injection of ZOSTAVAXTM at a higher (207,000 PFU) or a lower potency (58,000 PFU)
- 698 subjects ≥50 years of age
- Age-stratified (50 to 59 years [n=185], ≥60 years [n=513])
- Safety follow-up for 42 days postvaccination
- Vaccine well tolerated at both potencies administered

## Safety of ZOSTAVAXTM at a Higher Potency in Subjects ≥50 Years of Age (Protocol 009)

- Adverse Experiencesby Age Group

- Injection-site:  50 to 59 years  ≥60 years
- Systemic:  50 to 59 years  ≥60 years
- Elevated temperature≥101.0°F (≥38.3°C):  50 to 59 years  ≥60 years

- Higher Potency(N=461)
- %

- 82.955.7
- 40.736.3
- 0.41.1

- Lower Potency(N=234)
- %

- 69.456.4
- 45.237.2
- 0.90.4

## Safety Among VZV-Seronegative Subjects

- No VZV-seronegative adults detected in SPS
- VZV-seronegative adults sought in 2 protocols
- Protocol 003 screened 1148 varicella history-negative people ≥30 years of age in tropical countries; n=21 enrolled
- In Protocol 049 (adolescent/adult VARIVAX® study) 142 subjects were ≥30 years of age; n=17 were VZV-seronegative
- Conclusions regarding VZV-seronegative individuals
- VZV-seronegativity is rare after 30 years of age
- No safety issues identified

## ZOSTAVAXTM-Associated Rash

- Across the ZOSTAVAXTM database, 0.3% of subjects reported a VZV-like rash through Day 42 postvaccination
- Oka/Merck VZV strain was identified by PCR analysis of lesion specimens from only 2 subjects
- Oka/Merck VZV strain was not identified in any SPS subject suspected of having HZ

## Summary of ZOSTAVAXTM Safety Results

- ZOSTAVAXTM is well tolerated in adults ≥50 years of age
- Transient injection-site reactions in about half of the vaccine recipients
- No clinically important differences between ZOSTAVAXTM and placebo with respect to
- Serious adverse experiences
- Systemic clinical adverse experiences
- Following a dose of ZOSTAVAXTM, vaccine-associated rashes are uncommon

## Discussion Topics

- Epidemiology of HZ and PHN
- Clinical Development Program
- Shingles Prevention Study
- Study design
- Key results
- Immunogenicity
- Safety
- Summary of Clinical Results

## Rationale for Beginning Routine Zoster Vaccination at 50 Years of Age

- Prevent work productivity loss
- ~70% of individuals 50 to 59 years of age are employed, with an estimated 600,000 to 700,000 work days lost annually due to HZ
- Severity and healthcare use in acute HZ comparable in those 50 to 59 and 60 to 69 years of age

## Rationale for Beginning Routine Zoster Vaccination at 50 Years of Age

- Efficacy
- VEHZ 64% in subjects 60 to 69 years of age
- VEHZ in the 60-to-69 age group should predict VEHZ in persons 50 to 59 years of age
- Immunogenicity
- Immune responses were comparable across age cohorts in the Shingles Prevention Study
- Similar age-related findings were observed in other ZOSTAVAXTM clinical studies
- Safety
- In Protocol 009, higher frequency of local reactions (mild/moderate, transient) in subjects 50 to 59 years of age than in subjects ≥60 years of age but generally well tolerated
- Similar results seen in Protocol 049 among seropositive and seronegative subjects ≥13 years of age

## Summary of ZOSTAVAXTM 

- Extensive ZOSTAVAXTM clinical database
- Over 40,000 subjects enrolled; over 20,000 vaccinated
- Prevents HZ (VE=51%)
- Prevents PHN (VE=67%)
- Reduces HZ pain BOI (VE=61%)
- Efficacy persists for 4 years postvaccination
- Elicits a VZV-specific CMI response
- Has an excellent safety profile

## ZOSTAVAXTM Agenda

**Introduction**
- David Gutsch, M.D.Director, Regulatory Affairs
**Epidemiology and the****Clinical Development Program**
- Jeffrey Silber, M.D.Senior Director, Clinical Research
**Concluding Remarks**
- David Gutsch, M.D.Director, Regulatory Affairs

## Ongoing/Planned ZOSTAVAXTM Activities

- Durability of efficacy in SPS subjects
- Vaccination of SPS and Protocol 007 placebo recipients
- Bridging study: Transition from frozen to refrigerated formulation
- Inactivated influenza vaccine concomitant use
- Pharmacovigilance Plan
- Postmarketing surveillance for adverse events
- VZV Identification Program
- Clinical specimens submitted for PCR analysis
- Pregnancy Registry

## Benefits/Risks

- HZ and PHN are often debilitating diseases, for whichthere is an unmet medical need for better management
- ZOSTAVAXTM would be the first intervention to prevent HZ and its complications, including PHN
- Beyond the benefits from prevention, ZOSTAVAXTM reduces the severe pain associated with HZ and PHN
- ZOSTAVAXTM has an excellent safety profile

- ZOSTAVAXTM will address important medical and public health needs

## ZOSTAVAXTM Proposed Indications

- ZOSTAVAXTM is indicated for:
- Prevention of herpes zoster (shingles)
- Prevention of postherpetic neuralgia (PHN)
- Reduction of acute and chronic zoster-associated pain
- ZOSTAVAXTM is indicated for immunization of individuals50 years of age or older