Case Study I: Clinical Considerations When Establishing Release Specifications for Vaccines

1
Case Study I Clinical Considerations When
Establishing Release Specifications for Vaccines

• Luwy Musey
• Merck Research Laboratories

2
Major Paradigms

• Release specifications assure a safe and
  effective product through shelf-life
• Safety considerations drive upper release
  specification
• Efficacy/effectiveness at end-expiry and
  stability define minimum release
• Requires collaborative effort (pre-clinical and
  clinical development, manufacturing, statistics,
  and regulatory agencies)

3
Vaccine Development Process
4
Establish Clinical Limits

• Expiry window defined by
• Clinically derived lower specification
• Stability loss determined by formulation
• Testing and experimental variabilities

5
Strategies to Establish End-Expiry Dose

• Design options
• Dose ranging study
• Pivotal study performed at end-expiry dose
• Placebo controlled
• Relative efficacy/effectiveness
• Possible endpoints
• Direct measure of disease prevention or surrogate
• Indirect measure When marker is identified
  e.g., acceptable immunogenicity at lowest dose

6
Cases to Illustrate Different Clinical Approaches
for Live Virus Vaccines (LVV)

• ProQuad (combination vaccine of M-M-RII and
  VARIVAX) post-licensure data for me,mu,ru, dose
  ranging for VZV
• M-M-RII end-expiry for mumps
• Zoster Vaccine pivotal study at end-expiry
• RotaTeq dose ranging for efficacy

7
ProQuad Example

• M-M-RII components in ProQuad same or better
  immunogenicity as in M-M-RII no dose ranging
  for combination
• Definition of VZV end-expiry dose in ProQuad in
  VZV dose ranging trial
• Antibody titre 5 gpELISA units/ml correlates
  with efficacy (absence of breakthrough disease)
• End-expiry dose is a dose of ProQuad with a SCR
  of 76 (l.b. of 95 CI) 5 gpELISA units/ml

8
(No Transcript)
9
Dose Response Study (Protocol 011)Identification
of Minimum Dose
Varicella Responses 6 Weeks Postvaccination
10
M-M-RII Example

• Mumps end-expiry needed revision due to several
  assay changes over time
• Approach in-vitro age M-M-RII to target various
  potencies above, at and below previous end-expiry
  specification (target such that upper bound of
  95 CI was lt 4.0 log and lt 3.7 log TCID50)
• Test in clinic for acceptable seroconversion rate
  by mumps virus neutralizing antibody

11
Mumps End-Expiry Potency

• Incubation
• Low potency was achieved by storing product at
  25C.
• Two sets of samples were placed at 25C, approx.
  10 weeks apart.
• Clinical samples were pulled from the second set
  at 6.86 weeks, based on potency data from the
  first set.
• Potency
• Six vials were pulled and tested at weekly
  intervals.
• All results were adjusted to the House Standard
• Linear regression was fit to data from weeks
  3-10, to avoid non-linear portions of the
  degradation curve.
• 95 upper confidence bound was calculated to
  conservatively estimate the average clinical dose.

12
Mumps End-Expiry Potency
13
M-M-RII Protocol 007

• Double blind, randomized, study of
• M-M-RII at mumps expiry potency in healthy
  children 12 to 18 months of age

14
Study Design

• Objective To demonstrate similarity in
  immunogenicity between M-M-RII containing mumps
  at end expiry and at release potencies
• Sample size 1997 subjects randomly assigned to 3
  different treatment groups
• Study duration ? 1 year per subject
• Blood samples taken at baseline, 42 days and 1
  year postvaccination
• Immunogenicity measured by PRN assay and ELISA

15
Analysis of Similarity and Acceptability of Mumps
PRN Seroconversion Rates by Treatment Groups
16
Analysis of Similarity and Acceptability of Mumps
PRN Seroconversion Rates by Treatment Groups
17
Summary Mumps Expiry

• M-M-RII containing mumps virus potency 4.1
  log10 TCID50/dose induces acceptable levels of
  mumps-specific neutralizing antibodies similar to
  those elicited by M-M-RII containing mumps virus
  potency within the release potency range
• M-M-RII containing mumps virus potency of 3.8,
  4.1, or 4.8 log10 TCID50/dose is generally well
  tolerated.
• Mumps virus potency in M-M-RII should contain
  no less than 4.1 log10 TCID50/dose at end-expiry

18
Herpes Zoster Example

• Primary endpoints prevention/reduction of HZ
  burden of illness and post herpetic neuralgia
• Double-blind placebo controlled clinical trial
• Frequency of endpoint such that 40 000 patients
  needed with observation period of 3 years
• No surrogate marker identified

19
Herpes Zoster Example

• Question How to define minimum effective dose?
• Solution run pivotal trial at likely end-expiry
  dose
• Age material to reflect likely shelf-life,
  monitor stability of vaccine through
  administration in trial
• Trend analysis of case accrual through
  observation period to demonstrate stable efficacy
  across doses administered

20
RotaTeq Example

• Efficacy against rotavirus disease of any
  severity or any serotype

21
Assume Adequate Potency Through Shelf-Life

• Lower release limit is generated by
• Clinically derived lower specification
• Stability loss determined by formulation
• Testing and experimental variabilities

22
Assume Adequate Potency Through Shelf-Life

• Lower release limit is generated by
• Clinically derived lower specification
• Stability loss determined by formulation
• Testing and experimental variabilities

23
Opportunities to Reduce Variability

• Nested designs and variance component analysis
• e.g., Plate within Run within Technician within
  Laboratory

24
Opportunities to Reduce Variability

• Assay variability through replication

• Variance components from assay validation
• Reportable Value is the average

25
Opportunities to Reduce Variability

• Stability uncertainty through statistical design

26
Vaccine Development Process
27
Robust Manufacturing Process

• Manufacturing window is generated by
• Clinically derived upper specification
• Assay and Process variabilities
• Successful technology transfer

28
Strategies to Establish Upper Release
Specifications

• Safety data from clinical study in relevant
  cohort at high dose/dose ranging
• Post-licensure passive surveillance data

29
ProQuad Example

• Upper release specs for me, mu and ru defined by
  licensed M-M-RII experience (passive reporting
  system)
• Varicella safety in ProQuad - highest dose
  studied in clinical trial generally safe

30
Objective

• Assign Maximum Release Specifications for
  Measles, Mumps and Rubella in ProQuad by using
  the M-M-R II Safety Database

CBER agreement that M-M-R potencies in ProQuad
be based on experience with M-M-R II
31
Clinical Profile of M-M-R II

• More than 450 million doses distributed since its
  introduction in 1979
• Two-dose schedule in US Vaccine to be
  administered at 12-15 months, and 4-6 years
• Dramatically effective in decreasing the
  incidence of Measles, Mumps, Rubella by gt 99
• Excellent Tolerability and Safety profile

32
Strategy to Set Maximum Release Specification

• Determine range of Me, Mu, and Ru release titers
  for M-M-R II lots released on the U.S. market
• Evaluate reporting rates of Adverse Experiences
  associated with these lots
• Determine possible correlation between increase
  in Me, Mu, and Ru titers and reporting rates of
  Adverse Experiences associated with the
  administration of M-M-R II

33
Methodology (1)

• WAES (Worldwide Adverse Experience System,
  Passive reporting system) database
• (Adverse Experiences Fever, Febrile
  seizures, Rash, Serious AEs, Death)
• Vaccine lots Number and House Standard
  calibrated Release titers
• Evaluation limited to September 30, 1999 -
  December 1, 2001
• - Improvement in the reporting system since
  1990
• - Improvement in the accuracy of the virus
  titer measurement
• since September 1999 (Change in Assay
  format from 3x1 to 1x6 )
• - Change in the Filling target for Mumps
  from 4.9 to 5.2 log10
• TCID50/0.5 mL (minimum release titer
  increased from 4.3 to 5.0 log10)
• (September 1999)

34
Methodology (2)

• Analyses performed
• Compare frequency of reported adverse experiences
  by
• - Number of doses distributed
• - Measles, Mumps, and Rubella release
  potencies
• Linear regression analysis to assess possible
  correlation between increase in virus vaccine
  potency (for each virus separately) and reporting
  rates of different AEs.

35
Vaccines Analyzed
Inaccuracy in rubella titer for a subset of
lots due to incomplete mumps neutralization
36
Results (1)
Reporting rates per million doses (range across
the virus titers analyzed) Total of 4 deaths
(Measles 3.8, 3.9, 3,9 and 4.0) (Mumps 5.1, 5.1,
5.2 and 5.3) (Rubella 3.7, 3.8 and 4.0)
37
Reporting Rates of Fever Across Measles
Potencies (2002)
0.5M
2.3M
4.1M
6.2M
2.6M
3.8M
0.17M
38
Summary of Results

• No indication that reporting rate of any adverse
  experience increases as a function of Me, Mu, and
  Rubella potencies within range analysed
• Fever and Rash mostly assessed as mild,
  transient, and non-serious
• Deaths occurred in 4 subjects (all assessed as
  not related to the vaccine by the healthcare
  providers)

39
Clinical Safety Data Measles (1991-1995)

• WAES queried in 1997
• Vaccines released between 1991-1995
• Total number of doses 69 million (72 lots)
• Uncalibrated Titer range 3.5 to 4.3 log10
  TCID50/0.5mL
• Findings similar to those observed with more
  recent dataset (1999-2001)

40
Proportion of Subjects with Fever Across Measles
Potencies (Merck Clinical Trials)
N128
N329
N895
N1083
N30
N412
N520
N3397
41
Conclusions Post-marketing Safety Evaluation
(WAES Database) and Merck Clinical Trials

• Based on historical data available,
• No association between increase in Measles,
  Mumps, or Rubella potencies and reported AEs
• No evidence of increased AEs reporting rates
  across tested virus titers range
• No suggestion of correlation of reporting rates
  of AEs with potencies using Me, Mu, and Ru
  release titers for analyses.

42
Post-Marketing Safety Evaluation (WAES
Database) and Merck Clinical Trials

• No association between Mumps release potency and
  reporting rates of adverse experiences across the
  range of potencies that have been released to the
  market
• No evidence of trends towards increased reporting
  rates for serious AEs, fever, febrile seizure, or
  death in association with increasing mumps
  potencies (Query of WAES database and results
  from 8 clinical trials)
• Safety profile of M-M-RII does not appear to be
  affected by Mumps potencies up to 5.4 log10
  TCID50/dose

43
Clinical Recommendations

• After a thorough review of the WAES Safety
  Database and M-M-R II Clinical Trials, Clinical
  Research recommends the following House Standard
  Calibrated Maximum Release Specifications for
  ProQuad
• Measles 4.2 log10 TCID50 /Dose
• Mumps 5.4 log10 TCID50 /Dose
• Rubella 4.1 log10 TCID50 /Dose

44
Specification Development for a Stable Product

• Goals of developing specifications for a stable
  product are the same
• More emphasis on process capability at minimum
  release potency. Less rigorous post-release
  testing undertaken.
• Important to establish a lower expiry bound using
  clinical data
• Allow room in process for monitoring changes in
  stability or product consistency.

45
Concluding Remarks

• Successful vaccine development, manufacture, and
  quality control requires the collaboration of
  clinicians, clinical coordinators, scientists,
  engineers, auditors, data coordinators, computer
  specialists, regulators statisticians