# Presentation: 062452

## Evaluating the Safety of a Rotavirus VaccineThe REST of the Story

- Joseph F. HeyseMerck Research Laboratories

- Vaccine Safety EvaluationPost Marketing Surveillance ConferenceNational Institutes for HealthBethesda, MarylandApril 10-11, 2007

## Overview

- Safety profiles evolve throughout the research and development program into post-marketing.
- Statistical aspects of design and analysis play an important role in defining the safety profile of vaccine candidates.
- Concepts of safety differ from the traditional efficacy model.
- Acceptable safety threshold depends on factors like the incidence and severity of the disease and the effectiveness of the intervention.
- Criteria for acceptable safety are difficult to establish.

## Concluding Remarks	

- Safety assessment of vaccines is an ongoing process throughout the product life cycle.
- At each stage the study design (endpoints, sample size, and duration) should be driven by clear objectives, hypotheses, and prespecified criteria for success.
- Coordinated efforts on post-licensure surveillance studies provide the potential for rapid detection of potential risks.
- Ongoing discussions with regulatory agencies and the medical/scientific community is important to gain acceptance of study results.

## Outline

- Review of 2000 vaccine safety workshop
- Design features of REST
- Safety monitoring in REST
- Overview of post-licensing activities
- Concluding remarks

## Evaluating the Safety of New Vaccines(Ellenberg et al., 2005)

- Workshop (2000) addressed current standards and approaches for new vaccine evaluation pre and post-licensure.
- Extensive discussion on the advantages and disadvantages of conducting large controlled trials before licensure or widespread use.
- Rationale for larger prelicensure clinical trials
- Trial design and sample size usually focused on efficacy
- Unexpected rare but serious adverse outcomes
- Concerns over large trials
- Cost and time
- Spurious associations (multiplicity)

## Design Considerations for a Pentavalent Human-Bovine Reassortant Rotavirus Vaccine (PRV)(Sadoff, 2000)

- Demonstrate a high level of confidence that the vaccine is safe
- Minimize risk to participants using continuous data monitoring and early termination for unsafe vaccine
- Potential for a result that will support acceptance by regulatory agencies and medical community

## Factors That Made Ongoing Rotavirus Vaccine Development Feasible

- Had a specific endpoint to be tested (intussusception)
- Allowed for formulation of safety hypothesis with pre-established criteria for success
- Had specific time intervals during which potential risk of intussusception is greatest, which could be used to guide safety monitoring
- Reported increase in risk of intussusception with RRV-TV  was during first 2 weeks after Dose 1 and first week after Dose 2
- Intussusception has a clear case definition
- High level of confidence that it will be detected

## Challenges of Rotavirus Vaccine Development in Face of Intussusception

- Design a study that is large enough to provide a meaningful evaluation of an uncommon event, yet feasible to implement prelicensure.
- Develop a safety monitoring system to detect a potential increased risk of intussusception early and minimize risk to trial participants.
- Decide on safety criteria for demonstrating that the vaccine is clinically acceptable for licensure.
- Conduct a study that would be acceptable to regulatory agencies and the medical community.
- Rotavirus Efficacy and Safety Trial (REST) was launched.

## Rotavirus Efficacy and Safety Trial (REST)(NEJM, 2006)

- REST was a blinded, placebo-controlled study of RotateqTM, a pentavalent human-bovine rotavirus vaccine (PRV).
- Study involved >70,000 subjects at >500 sites in 11 countries.
- Risk of intussusception was similar for PRV and placebo recipients
- PRV was efficacious in reducing rotavirus gastroenteritis, severe disease and health care utilization.
- RotateqTM was licensed in February 2006 and was recommended for routine use by the ACIP.

## Study Design Features of REST

- Specific primary safety hypothesis
- Prespecified safety monitoring boundaries with established statistical properties
- Prespecified criteria for study conclusions regarding intussusception
- Group sequential design with sample size of at least 60,000 subjects
- Ongoing interaction with regulatory agencies, public health agencies, and advisory committees

## Safety Considerations

- Overseen by independent Data Safety Monitoring Board (DSMB)
- Active and passive safety surveillance of all participants through study duration
- Parent / legal guardian instructed to report potential IS cases to site
- Regularly scheduled contacts,  or home visits
- Centralized computer tracking system
- Potential IS cases reviewed by Safety Endpoint Adjudication Committee and reported to DSMB
- Minimal lost to follow-up (>99% subjects with complete follow-up)

## Overview of Safety Outcome

- Can never prove the absence of risk
- Study used a threshold based on an expected low background rate
- Analysis was based on simultaneously satisfying two components
- Continuous safety monitoring, based on boundaries defining increased risk
- End of study criterion, based on the upper bound of relative risk

## Safety Monitoring Boundaries

## Monitoring End of Study Criterion

## Statistical Properties of REST Study Design

- The goal of the REST study design and the extensive safety monitoring was to provide:
- High probability that a vaccine with increased intussusception risk would stop early due to ongoing safety monitoring, and simultaneously
- High probability that a safe vaccine would meet the end of study criteria
- The statistical operating characteristics of REST were estimated using Monte Carlo simulation

## Statistical Operating Characteristics for REST

## Statistical Operating Characteristics of REST*

- *	Assumes background intussusception rate of 1/2000 infant years and102 days of safety follow-up over three doses.
- ** RRV-TV = rhesus rotavirus tetravalent vaccine; Murphy et al, New Engl J Med. 344(2001): 564-572.

## Pharmacovigilance Plan to Monitor the Safety of RotaTeq®

- Clinical studies
- Safety Database of completed Phase III studies
- Current and future clinical studies
- Merck-sponsored pharmacovigilance activities
- Global routine pharmacovigilance, spontaneous reporting and PSURs
- Enhanced passive surveillance (US)
- Telephone follow-up of all IS cases
- Prompt reporting to FDA
- Active surveillance (US)
- Structured coordination and communication with regulatory and public health agencies

## Proposed Study Design

- Design:	Prospective surveillance study
- Outcomes:	Intussusception and General Safety
- Hypotheses: 	No hypotheses, protocol provides 	additional safety monitoring data
- Monitoring:	Sequential monitoring for intussusception
- Sample size:	44,000 vaccinated children
- Follow-up period:	Primary analysis: 30 days post each dose
- 	Secondary analysis: alternate intervals
- Committees:	Adjudication and Safety Monitoring

## Subjects and Database for Merck PLS Study

- Study Population:
- Large insured population in US (birth cohort ~ 100,000)
- Complementary to separate CDC studies
- Databases (large and linkable):
- Automated medical claims data of diagnoses from health events that result in hospitalization or emergency department visits
- RotaTeqTM vaccination information for each subject
- Subjects:
- All infants receiving RotaTeqTM during study period

## Study Design:  Control Groups

**Objective**

**Control Groups**

**Intussusception**

** ****Monitoring Boundary**
** ****Concurrent unvaccinated **

**General Safety**

** ****Self-controls**
** ****Historical controls**

## Monitoring Boundary for Proposed Post-Licensure Study of ROTATEQ® Assumes N=44,000 Subjects and 10,850 Person Years=0.05 Overall Adjusted for Sequential Design 

- Monitoring Boundary for Proposed Post-Licensure Study of ROTATEQ® Assumes N=44,000 Subjects and 10,850 Person Years=0.05 Overall Adjusted for Sequential Design

- Rate to be confirmed in retrospective study

## Examples of Power for Early Detection of Increased Relative Risk for IS Among Vaccinees in a 44,000 Subject Post-Licensure Study of RotaTeq®

## General Comments

- Safety evaluation of vaccines needs to be on a case-by-case basis.
- Do not advocate prelicensure studies of >70,000 routinely for new vaccines.
- REST was designed to study a specific rare event based on prior experience.
- Safety objectives need to be established at each stage of vaccine development and post-licensure.

## Safety Database

| Vaccine | Year Licensed | Number of Subjects* |  |
| --- | --- | --- | --- |
|  |  | Prelicensure | Postlicensure† |
| Varicella | 1995 | ~11,000 | 25,000 |
| Hepatitis A | 1996 | ~10,000 | 10,000 |
| Hib/HepB | 1996 | ~5,000 | 5,000 |
| MMRV | 2005 | ~5,000 | 25,000 |
| Rotavirus | 2006 | ~71,000 | 44,000 |
| HPV | 2006 | ~21,000 | 44,000 |
| Zoster | 2006 | ~38,000 | 20,000 |

- *Include controls/placebo recipients
- † Vaccinated subjects planned in protocol

## Concluding Remarks	

- Safety assessment of vaccines is an ongoing process throughout the product life cycle.
- At each stage the study design (endpoints, sample size, and duration) should be driven by clear objectives, hypotheses, and prespecified criteria for success.
- Coordinated efforts on post-licensure surveillance studies provide the potential for rapid detection of potential risks.
- Ongoing discussions with regulatory agencies and the medical/scientific community is important to gain acceptance of study results.