# Presentation: 726422

## ACAM2000(Smallpox Vaccine)

**Steven Rosenthal, M.D., M.P.H.**
**Team Leader Vaccine Clinical Trials Branch**
**CBER/OVRR/DVRPA**
**VRBPAC**
**May 17, 2007**

## Smallpox (variola major)Category A Bioterrorism Agent

**Large proportion of world population susceptible**
**Can be manufactured in large quantities**
**Stored indefinitely**
**High transmission rate**
**High case fatality rate**
**Social disruption**
**Public health preparedness requires special action **

## Smallpox vaccine

**Dryvax limited supply **
**Percutaneous administration**
***Take***** pustular lesion 7-10 days post vaccination**
***Take***** rate correlate of vaccine efficacy**
**Dryvax has >90% *****take***** rate**

## Vaccination ComplicationsEradication Era

**Generalized vaccinia**
**Eczema vaccinatum **
**Progressive vaccinia **
**Postvaccinial encephalitis**
**Fetal vaccinia**
**Inadvertent inoculation**
**Death**

## Vaccination Complications2002-Present

**Myocarditis most frequent SAE in the CDC/DoD**
**	****1 case per 2,000 primary vaccinations in civilian program**
**	****1 case per 6,000 primary vaccinations in DoD**** ****program**
**ACAM2000 Phase 3 trials designed to monitor closely for myocarditis**
**The trials were stopped prior to full enrollment**

## Dryvax® Package Insert Updated 8/2005

**Black Box Warning**
**Clinical data from ACAM2000 program added to package insert**

## ACAM2000 Phase 3 Clinical Trials

**Compare the immunogenicity of ACAM2000 and Dryvax vaccines:  **
**the proportion who develop successful vaccination (*****Take*****)**
**the geometric mean vaccinia neutralizing antibody titer on Day 30**
**Compare the safety of ACAM2000 and Dryvax vaccines in healthy adults**

**Notes:**
...

## Design Overview

**Randomized, double-blind, controlled, multi-center (72 sites)**
**Randomized 3:1 to receive either ACAM2000 or Dryvax®**
**H-400-009**
**Adults 18-30 years of age naïve to smallpox vaccine**
**H-400-012**
**Adults 31-84 years of age previously vaccinated with smallpox vaccine**

## Co-Primary Efficacy Endpoints

**The proportion of subjects with successful vaccination, based on a major cutaneous reaction (*****take*****)**
**Geometric mean neutralizing antibody titer (GMT) on Day 30**

## Subject Disposition 

| Population | ACAM2000 | Dryvax | Total | Planned Total |
| --- | --- | --- | --- | --- |
| H-400-009 (naïve) |  |  |  |  |
| ITT | 780 | 257 | 1037 | 2720 |
| EE | 776 | 257 | 1033 |  |
| AnE | 565 | 190 | 755 |  |
| H-400-012 (non-naïve) |  |  |  |  |
| ITT | 1242 | 405 | 1674 | 2720 |
| EE | 1189 | 388 | 1577 |  |
| AnE | 734 | 376 | 1110 |  |

**ITT = Intent to Treat (Safety), EE = Efficacy Evaluable (*****Take Rates*****), AnE = Antibody Evaluable (GMT)**

- • **Both trials stopped prematurely due to cases of myopericarditis after vaccination in trial H-0400-009**
**•**** ****Four sites (255 subjects excluded in final efficacy analyses for GCP deficiencies on inspection**

## Efficacy Assessments

**Vaccination site examination Days 0, 7, 10, 21, and 30**
**Digital photograph Day 7**
**Major Cutaneous Reaction**
**pustular, vesicular, or ulcerative lesion of measurable size on Day 7 and/or 10**
**Primary investigator in H-400-009, IRC review of digital site photos in H-400-012**

## Vaccination Success Rates (Take Rates)

| Trial / Take | ACAM2000
N (%) |  | Dryvax
N (%) |
| --- | --- | --- | --- |
| H-400-009 (naïve) | 776 |  | 257 |
| Yes | 747 (96) |  | 255 (99) |
| No | 29 (4) |  | 2 (<1) |
| Lower bound 97.5% CI on rate difference (ACAM2000-Dryvax) | - 4.67% (>- 5.00% needed) |  |  |
| H-400-012 (non-naïve) | 1189 | 388 |  |
| Yes | 998 (84) | 381 (98) |  |
| No | 191 (16) | 7 (2) |  |
| Lower bound 97.5% CI on rate difference (ACAM2000-Dryvax) | - 17% (>- 10% needed) |  |  |

## Geometric Mean Titers

| Trial | ACAM2000 | Dryvax |
| --- | --- | --- |
| H-400-009 (naïve) | 166 | 255 |
| Lower bound 97.5% CI on difference in mean (ACAM2000-Dryvax)

 | - 0.307 (>- 0.301 needed) |  |
| H-400-012 (non-naïve) | 286 | 445 |
| Lower bound 97.5% CI on difference in mean (ACAM2000-Dryvax)
 | - 0.275 (> - 0.301 needed) |  |

## Co-Primary Endpoints Summary

| Trial | Endpoint | Meet Test for Non-Inferiority |
| --- | --- | --- |
| H-400-009 | Take | Yes |
|  | GMT | No |
| H-400-012 | Take | No |
|  | GMT | Yes |

## Safety Monitoring

**Physical exams: Days 0, 7, 10, and/or 21**
**ECG: Screening, Days 10, 21**
**Clinical Laboratory: Troponin I Screening Day 10**
**Structured Interview: Days 7, 10, 21, 30**
**Myocarditis**
**Cases identified by clinical symptoms and laboratory evaluations (ECG, troponin I)**
**Chest pain, shortness of breath, palpitations**
**Evaluated by cardiologist**
**F/U 12 months, longer for cardiac abnormalities**

## Safety Results

| Adverse Event Classification | ACAM2000
N=873
% | Dryvax
N=289
%
 | ACAM2000
N=1371
% | Dryvax
N=448
%
 |
| --- | --- | --- | --- | --- |
| All | 99 | >99 | 97 | 99 |
| Moderate/Severe | 49 | 55 | 34 | 42 |
| Severe | 10 | 12 | 5 | 8 |

- H-400-009

- H-400-012

## Common Adverse Events

|  | ACAM2000
N=873
(%)
 | Dryvax
N=289
(%) | ACAM2000
N=1371
(%) | Dryvax
N=448
(%) |
| --- | --- | --- | --- | --- |
| Vax Site Pain | 67 | 72 | 37 | 47 |
| Lymph Node Pain | 57 | 69 | 22 | 30 |
| Headache | 50 | 52 | 32 | 37 |
| Fatigue | 48 | 56 | 34 | 41 |
| Myalgia | 46 | 51 | 27 | 33 |

- H-400-009

- H-400-012

## Severe Adverse Events

|  | ACAM2000
N=873
n (%)
 | Dryvax
N=289
n (%) | ACAM2000
N=1371
n (%)
 | Dryvax
N=448
n (%) |
| --- | --- | --- | --- | --- |
| Local Site Reactions | 32 (4) | 25 (9) | 26 (2) | 10 (2) |
| Feels Hot | 5 (1) | 2 (1) | 4 (0) | 3 (0) |
| Lymph node pain | 12 (1) | 5 (2)
 | 0 | 1 (0) |
| Malaise | 7 (1) | 2 (1)
 | 4 (0) | 0 |
| Nausea | 5 (1) | 5 (2)
 | 7 (1) | 1 (0) |
| Headache | 10 (1) | 4 (1)
 | 10 (1) | 6 (1) |

- H-400-009

- H-400-012

## Myopericarditis

**10 cases suspect/probable overall**
**1 case per 145 vaccinations**
**7 cases received ACAM2000**
**rate 5.73 per 1000 vaccinations**
**3 cases received Dryvax**
**rate 10.38 per 1000 vaccinations**
**Rate difference not statistically significant**

## Myopericarditis

**9 male, mean age 21 years (range 18-24)**
**7 Caucasian **
**Mean time to onset 11 days (range 9-20)**
**2 Subjects hospitalized for acute cardiac symptoms**
**1 Female with 27-32% LVEF at 2.5 years**

## Current Concerns

**Transmission**
**Eczema vaccinatum**
**Vulvar vaccinia**
**Death**
**VAERS under reporting**
**ACAM2000 clinical data limited**

## Risk Minimization Action Plan (RiskMAP) Goals

**Minimize risk of autoinoculation and transmission**
**Inform vaccinee of risk of myocarditis and other potential AEs**
**Ensure vaccine is administered correctly for effectiveness and safety**
**Balance risk minimization requirements in context of emergency use**

## RiskMAP Components

**Vaccine distribution**
**Vaccinee and provider education**
**Expedited AE reporting**
**Post-licensure pharmacovigilance**
**Program assessment**

## Acambis, Inc. Distribution Plan

**Sponsor has no intention to distribute ACAM2000 in the U.S. outside of sales to the U.S. Government for the Strategic National Stockpile**
**Ensures that vaccine will given under conditions that would minimize risk of adverse events**

## Education and Outreach

**Health Provider ****(warnings and precautions, vaccination technique, counseling)**
**Package Insert with Black Box Warning**
**Provider education programs**
**Patient ****(prevent autoinoculation, transmission, communicate risks)**
**Medication Guide (21 CFR 208)**

## Expedited Reporting of Adverse Events

**Require reporting of serious adverse events after ACAM2000 to FDA within 15 days, e.g.:**
**Myocarditis**
**Contact transmission**
**Death**
**Autoinoculation**
**CNS events**
**Fetal vaccinia**
**Progressive vaccinia**
**Eczema vaccinatum**

## Post-Licensure Pharmacovigilance Goals

**Study larger population than possible in pre-licensure studies looking for known and unknown adverse effects**
**Determine long-term outcome of myopericarditis**
**Determine risk factors for developing myopericarditis**
**Genetic**
**Immunologic/biomarker**
**Demographic**

## Post-Licensure Pharmacovigilance

**Phase 4 cohort study in 10,000 military vaccinees**
**f/u 8-12 days with structured interview, Troponin I**
**ECG if clinical indication or elevated Troponin**
**Enhanced surveillance in 1-200,000 vaccinees**
**1-2 years duration**
**Myocarditis registry**
**Anticipates up to 150 cases**

## Pharmacovigilance Concerns

**Inadequate case ascertainment**
**Increase sensitivity**
**Increase sample size**
**Availability of resources**
**Logistic issues for long term follow-up**
**How to track across civilian/military health systems**
**Vaccine adverse event surveillance**
**completeness**
**timeliness**

## RiskMAP Assessment

**Vaccine Adverse Event Reporting System (VAERS) for health outcomes**
**Achieve goals?**
**Information used to guide improvements**
**Complete and timely reporting**
**Process audits?**
**Lessons learned in the DoD experience would benefit civilian use in an emergency**

## Conclusions

**Data from Phase 3 clinical trials provide reasonable expectation that ACAM2000 would be effective, and relatively safe, for persons at high risk of exposure to smallpox**
**ACAM2000 safety data is limited**
**ACAM2000 risk profile is clinically important and unusual for a preventive vaccine**
**RiskMAP would be valuable in overall risk management**

## Acknowledgements

**Edward Wolfgang**
**Ann McMahon**
**Mike Merchlinsky**
**Mridul Chowdhury**
**Robert Ball**
**Norman Baylor**
**Florence Houn**
**Marion Gruber**
**Miles Braun**
**Douglas Pratt**
**Loris McVittie**

## Questions

- 1. **Are the efficacy data sufficient to support the use of ACAM2000 in situations where it is determined that there is high risk of exposure to smallpox virus?****	**

## Questions

**2. Are the safety data sufficient to support the use of ACAM2000 in situations where it is determined that there is high risk of exposure to smallpox virus?**

## Discussion

**3. Please discuss benefits vs. risks of ACAM2000 for use in high risk situations.**

## Questions

**4. Does the committee agree that a Risk Minimization Action Plan (RiskMAP) for ACAM2000 composed of the following is needed?**
**a) vaccinee education, **
**b) health care provider education, **
**c) expedited reporting of certain serious adverse events, **
**d) Phase 4 studies to better define the safety profile, long-term outcomes and risk factors for myocarditis, **
**e) and evaluation of the RiskMAP**

## Discussion

**5. Discuss methods to increase sensitivity of case ascertainment of myocarditis and long-term follow-up, and methods to evaluate the effectiveness of the RiskMAP.**