Clinical Evaluation of Vaccines

1
Clinical Evaluation of VaccinesThe Long Haul

• Steve Self
• Biostat 578 3/2/06

2
Outline

• Introduction
• Phase I/II Trials HIV vaccines
• The End of Phase II
• Efficacy Evaluation
• Test of Concept (Phase IIB) Designs HPV
  vaccines
• Pivotal Trials HPV vaccines
• Multiple Test of Concept Trials HIV vaccines
• Post-Marketing Surveillance Rotovirus vaccines
• Conclusions

3
Introduction

• Development of an efficacious vaccine can easily
  take 20 years and cost ½ billion dollars
• Clinical evaluation alone can involve a dozen
  interlocking trials of different designs
  conducted over a decade
• Goals of this presentation
• Overview of clinical evaluation programs
• Particular emphasis on crux move of these
  programs the move to efficacy evaluation
• HIV vaccine development as context

4
Iterative Nature of Vaccine Development

• Vaccines as molecular machines
• Historical vaccines
• Modern vaccines
• Chicken and egg problem
• What immune response is protective?
• How to induce protective responses?
• Idiosyncratic nature of pathogens and vaccines

5
HIV-1 Vaccines in Clinical Trials in 2005

• 22 products
• 7 DNA vaccines naked, multiclade, adjuvanted,
  etc.
• 8 viral vectors Adeno, AAV, VEE, MVA, Fowlpox,
  Canarypox, Vaccinia, NYVAC
• 3 subunits or peptides V1-V2 deleted envelopes,
  lipopeptides, adjuvanted protein
• 4 prime-boost combinations
• DNA Viral Vectors (MVA, Fowlpox, Adeno)
• Viral Vector heterologous viral vector
• Viral vector lipopeptides
• DNA protein
• Canarypox rgp120

6
Phase IA Design

• First in humans safety is question one
• Dose escalation
• From dishwater to either
• maximum tolerable or
• feasibly manufacturable
• 10 vaccinees (2 placebos) per dose
• Safety evaluation after second immunization
• Systemic and local reactions
• Safety outcomes specific to vaccine
• Very little information about immunogenicity

7
Immunogen vs vaccine (regimen)

• Route of administration
• Tissue specificity intramuscular, intradermal,
  subcutaneous, mucosal
• Site specificity deltoid, gluteus, nasal, oral,
  intrarectal, intravaginal
• Multiple administration of immunogen
• Schedule (eg, 0,1,6 mo)
• Heterologous immunogens
• Schedule/route for each immunogen
• Co-administration timing and/or route

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Phase IA Design

• Heterologous combination regimen
• Each component immunogen assessed via dose
  escalation design before combination is evaluated
• Eg 2 components (V1, V2) each escalating over 3
  dose levels

P1 V1/D1 V1/D2 V1/D3
P2 1 2 3
V2/D1 1 4
V2/D2 2 5
V2/D3 3 6
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Optimization of vaccine regimen

• Large parameter space
• Multidimensional outcome space (immune responses)
• Uncertainty of outcomes
• Statistical uncertainty
• Biological uncertainty
• Potential (hope) for interactions

10
Ranking and Selection Trial Designs

• Direct comparision of multiple regimens
• Goal is to select best regimen to move forward
  for expanded evaluation
• Assumptions
• Indifference in case of tie
• Unambiguous empirical ranking based on primary
  outcome
• Efficient relative to standard superiority
  designs
• However
• Assumptions are rarely met precisely
• Some questions dont fit paradigm at all (eg dose
  de-escalation)

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Ranking and Selection Trial Designs

• Multiple group randomized design (Phase IB)
• 30-50/arm to reliably pick winner w/ binary
  outcome if response rates differ by 15
• No control arm required (unless concern about
  endpoint assay validity)
• Biased estimate of immune response to best
  vaccine
• Logistically difficult if gt 5 arms
• How to select a few regimens over which to
  optimize?
• Results may suggest other regimens worth of
  testing
• Multiple generations of trials to adequately
  explore potential

12
Phase II Designs

• Goals
• Characterization of immunogenicity
• Is efficacy plausible in target population?
• Comparative of regimens not amenable to
  ranking/selection approaches
• Expand safety evaluation
• Reduce upper bound of rate for SAEs
• Design
• Randomized, placebo controlled
• May be comparative trial
• Hundreds of vaccinees per arm
• Study population reflect target in efficacy
  evaluation
• Decision guidelines for go/no-go based on minimum
  immune response tied to efficacy trial goals

13
End of Phase II

• Formal meeting with US FDA
• Integrated analyses of all relevant clinical data
• Tiered approach for immunogenicity data
• Combined safety database
• Plan for efficacy evaluation
• Efficacy trial design
• Criteria for success
• Other aspects of evaluation program

14
Efficacy Evaluation

• Pivotal trial
• Goal is to provide robust and compelling
  evidence for net clinical benefit
• Does Phase I/II trial experience provide enough
  information to reliably design and conduct such a
  vaccine efficacy trial?
• Is there an intermediate step a trial that will
  test the concept of efficacy at much reduced
  time/cost?

15
TOC and Pivotal Trials

• Similarities
• Hypothesis-driven RCT
• Provide direct evaluation of vaccine efficacy
• Differences Goals
• Pivotal Trials Provide compelling and robust
  evidence of efficacy, define balance of clinical
  benefits and risks
• TOC Initial evaluation to provide sufficient
  information for
• Making a go/no-go decision for pivotal evaluation
• If go inform design (scientific, operational)
• If no-go inform direction of further development
  (if any)
• Must be conceptually coherent with plan for
  pivotal evaluation

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Statistical Design Parameters

Design Parameter Test of Concept Design Pivotal Trial Design
H0 VE 0 (minimum for continuing evaluation) VE 30 (minimum for clinical significance)
Type I Error (a) 0.025 or greater 0.025 or less
H1 (efficacy to distinguish from H0 with 90 power) VE 50 (Ex STEP) VE 60 (Ex VaxGen 003, 004)
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Required Endpoints for 90 Power
Phase III TOC TOC TOC TOC
VE1 VE0 30, a 0.025 VE0 0, a 0.025 VE0 0, a 0.05 VE0 0, a 0.10 VE0 0, a 0.20
30 - 350 292 227 158
40 1901 178 143 113 81
50 419 99 85 66 45
60 160 61 49 37 28
70 78 37 30 26 17
STEP 100 endpoints, VaxGen Phase III Trials
225/360 endpoints
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Other Design Parameters that May Differ

Design Parameter Test of Concept Design Pivotal Trial Design
Vaccine Prototype Product
Population Narrow (optimize for sensitivity, operational efficiency) Representative (target for licensure)
Primary Endpoint Biomarker (Distal) Clinical Outcome
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Example HPV Vaccine Evaluation

• Two vaccine development programs
• Merck
• GSK
• Both use TOC designs for early efficacy
  evaluation
• Both follow TOC trial with large pivotal
  evaluation
• HPV
• Sexually transmitted virus
• Chronic infection
• Multiple viral strains
• Strain-specific cause of cervical cancer, genital
  warts

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Merck HPV Vaccine Test of Concept Trial 1

• Monovalent (prototype) vaccine
• HPV16 L1 VLP vaccine with alum adjuvant
• 3 doses IM
• Placebo controlled trial of 2392 women (age
  16-23)
• Primary endpoint persistent HPV 16 infection
• Mean duration of follow-up 17.4 months
• Target number of endpoints 41

Koutsky et al., New Eng J Med 3471645, 2002
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Merck HPV Vaccine Test of Concept Trial 1
Results

• Analyzed 1533 women (ATP)
• fully vaccinated
• HPV negative throughout vaccination period.
• Primary result 41 endpoints with 041 split
  (VC)
• Total (perstrans) incident infection 74 cases
  (668)

Koutsky et al., New Eng J Med 3471645, 2002
22
Merck HPV Vaccine Test of Concept Trial 2

• Quadravalent vaccine (Gardasil)
• HPV (16, 18, 11, 6) L1 VLP vaccine with alum
  adjuvant
• 3 doses IM
• Placebo controlled trial of 552 women (age 16-23)
• Mean duration of follow-up 2.5 years
• Primary endpoint persistent HPV infection
  (vaccine types)
• Target number of endpoints 40
• Result 40 endpoints observed with 436 split
  (VC)

Villa et al., Lancet Oncology, 2005
23
Merck HPV Vaccine Gardasil Pivotal Trial

• Randomized, placebo controlled trial
• Study population
• 25,000 women (age 16-23)
• 33 countries, 150 study sites
• 3.5 years follow-up (post-vaccination)
• Primary efficacy endpoints
• HPV-associated CIN2-3
• Genital warts
• Results presented to US FDA VRBPAC 12/05

24
Merck HPV Vaccine Test of Concept Trial 1 Redux

• Long-term followup
• 48 months post-vaccination
• Blinding of treatment assignment maintained
• Endpoints
• Persistent HPV 16 infection
• HPV16-assoc CIN2-3
• Results
• Persistent HPV16 infection 118 cases with 7111
  split (VC)
• HPV16-assoc CIN2-3 12 cases with 012 split
  (VC)

Mao et al., Obstet Gyn 107(1) 18-27, 2006
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Other supportive studies

• Adolescent immunogenicity and tolerability
• gt4500 boys and girls
• Mid-adult womens efficacy and tolerability
• Women age 24-45
• Nordic study
• Durability of protection
• Long-term safety
• gt 50,000 men and women

26
GSK HPV Vaccine Test of Concept Trial

• Bivalent vaccine (Cervarix)
• HPV16/18 L1 VLP vaccine with AS04 adjuvant
• 3 doses (IM)
• Placebo controlled trial of 1113 young women
  (age15-25)
• Mean duration of follow-up 18 months.
• Primary endpoint persistent HPV16/18 infection

Harper et al., The Lancet 2004
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GSK HPV VaccineTest of Concept Trial ITT Results
Efficacy

100 efficacy in ATP analysis
Harper et al., The Lancet, 2004
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GSK HPV Vaccine Pivotal Trials

• GSK Cervarix trial
• Randomized controlled trial
• 18,000 young women (age 18-25)
• Efficacy endpoints HPV-assoc CIN2-3
• N. America, Latin America, Asia Pacific, Europe
• Expected EU filing in 06
• NCI Cervarix trial
• Randomized controlled trial
• 12,000 young women (age 18-25)
• Costa Rica (Guanacaste, Puntarenas)

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Summary

• TOC designs are integral components of a larger
  program for vaccine evaluation planned or not!
• Consistent, coherent goals
• Sequence/timing for data and decisions
• TOC designs are used to achieve multiple goals
• Initial testing of prototype vaccine
• Screening evaluation of vaccine product
• Basis for initial data on durability of effects
• TOC designs are not used as a substitute for
  pivotal trial designs

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HIV Vaccines

• Nature of vaccine effect highly uncertain
• Uncertain that any efficacy in humans will obtain
• If there is efficacy, it is uncertain how it will
  manifest
• Stronger rationale for effect on VL than
  acquisition endpoints for vaccines inducing
  primarily CMI responses
• However need appropriate due diligence in
  assessment of impact on acquisition
• Pivotal trial designs are large/long/expensive
• Ideal setting to consider TOC design for initial
  efficacy evaluation

31
STEP A HIV Vaccine TOC Trial

• MRK Ad5 Trivalent HIV-1 gag/pol/nef (0,1,6)
• Study population
• 3000 men and women (18-45 yo) at risk for HIV
  infection
• Sites with predominately subtype B virus
  throughout the Americas, Carribean and Asia
• Co-primary endpoints
• HIV infection
• Viral load (during early HIV infection)
• a 0.025 (overall)
• NE 100
• Power of 90 to distinguish
• VES 0 vs 53
• D logVL 0 vs 0.6-0.7 logs (depending on VES)

32
Immune Correlates of Protection

• Identification of immune correlates of protection
  is an important secondary trial objective
• Test for difference between high and low
  responders to vaccine
• Infection endpoint relative risk for infection
• VL endpoint difference in mean log-VL
• Power of tests depend on
• Number of infection endpoints among vaccinees
• Prevalence of high/low responders to vaccine
• Magnitude of difference between high/low
  responders

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Minimum Detectable Effect Sizes (with 90 power)
Infection Endpoint Infection Endpoint Infection Endpoint Infection Endpoint logVL Endpoint logVL Endpoint
Total Infections VE030 a0.025 VE00 a0.025 VE00 a0.10 RR(L,H) D0 0 a0.025 D(H,L)
50 76 64 56 20.0 0.85 0.30
100 66 49 43 5.9 0.68 0.24
150 61 42 36 3.8 0.55 0.21
200 57 38 32 3.1 0.47 0.19
250 55 34 29 2.6 0.42 0.18
Relative risk for infection among low immune
responders to vaccine relative to high
resonders D mean logVL Low immune responders
High immune responders
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The Problem of Heterogeneity

• Important theme involves human and viral
  variation
• At risk populations span large geographic regions
  with different viral and human factors that
  plausibly can affect vaccine efficacy
• Impact of human and viral variation on vaccine
  efficacy uncertain
• How to design an HIV vaccine evaluation program
  that rationally assesses efficacy across this
  heterogeneity?

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What pivotal trial design?

• If first TOC demonstrates efficacy in MSM with
  subtype matched virus is efficacy plausible for
• Heterosexual men?
• Heterosexual women?
• Injection drug users?
• Subtype mismatched viral populations?
• A global vaccine would require evaluation across
  this heterogeneity yet it is a large leap from
  efficacy results in a single narrow TOC design to
  such an extensive evaluation
• Remember primary goals of a TOC trial are to
  inform
• a data-driven go/no-go decision and
• how to proceed with next step in evaluation

36
Two TOC Trials before Pivotal Trials?

• Because of heterogeneity, there are two basic
  concepts to test in earliest stage of evaluation
  
• Is there any efficacy?
• Is there any robustness of efficacy?
• With a positive test of each of these concepts
  then ready to design and conduct pivotal
  trial(s).
• Example STEP HVTN 503
• First TOC assesses efficacy in optimized (viral
  subtype matched) setting
• Second TOC
• assesses robustness to different viral challenge,
  
• strengthens inference in women, hetero men
• What pivotal trials would follow if both TOCs are
  positive?
• Would efficacy in an IDU population be evaluated
  in a third TOC trial?

37
Continue Series of TOC Trials?

• Harmonized TOC designs (same vaccine regimen,
  same control, same endpoints)
• Trial settings to cover specified set of major
  human/viral heterogeneities
• Joint assessment of impact on acquisition and VL
  endpoints as in STEP/503 designs
• Allow enough flexibility to consider conducting
  trials both in parallel and in series
• Science and art of bridging
• Equipoise, ethics and perceptions
• Logistics and operational capacity

38
Series of TOC Trials?

• Trial-specific analyses
• Powerful inferences about vaccine effect on VL
  endpoint
• Modest power to assess vaccine effect on
  acquisition endpont
• Secondary analyses of pooled data across trials
• Power to assess overall impact on acquisition
  endpoint
• Power to assess pre-specified subgroup effects on
  VL (eg, gender)
• Power to assess immune correlates of protection
• What are the risks with this strategy with
  respect to licensure?

39
Basis for licensure?

• Evidence for clinical benefit must be compelling
  and robust
• Two-trial rule often referred to as standard
• Two independent trials
• Each trial delivers p-value lt 0.025 for primary
  test of efficacy
• Compelling evidence
• Overall false positive rate is small (0.000625
  0.0252)
• Robust evidence
• Replicated results
• Evidence for efficacy consistent across two trial
  settings (ie each trial delivers p-value lt 0.025)

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Spirit not the letter

• Other ways to develop evidence for efficacy that
  is considered compelling and robust
• A single trial instead of two?
• Compelling evidence
• Use size of the single primary test for efficacy
  of 0.000625?
• Or negotiate to use size of test of 0.004
  (.0251.5), say
• Larger trial size required to maintain power with
  smaller size of test
• Robust evidence
• Representative study population
• Homogeneity of study population
• Uniformity of efficacy result over key study
  strata

41
Spirit not the letter

• Three positive TOC trials as basis for licensure?
• How to balance strength of overall evidence
  required with strength of evidence required from
  each trial?
• Fix maximum size of overall p-value at standard
  0.000625
• Then each of 3 trials would be required to
  deliver a p-value no greater than 0.085
  (0.0006251/3)
• Comparable strategy to a single large pivotal
  trial
• Study population includes three strata of
  pre-specified size
• Primary analysis plan includes overall analysis
  as well as pre-specified stratum-specific
  analyses (with appropriate adjustment for
  multiplicity)

42
PAVE 100 Going Global?

• NIH VRC Multivalent Vaccine
• Subtypes A, B, C env
• Subtype B gag/pol/nef
• Want to test two concepts
• Any efficacy
• Robustness of efficacy across 3 viral populations
• Strategy under discussion
• Three simultaneous TOC trials (one stratified Ph
  III trial?)
• Balance of overall vs study specific analyses?
• Implications for licensure if uniformly positive?
• Larger evaluation plan eg, non-matched virus,
  IDU?

43
Post-Marketing Surveillance

• Even largest efficacy trials not large enough to
  define adverse events caused by vaccine that
  occur in low but important frequency
• VAERS system for passive surveillance of adverse
  events but lacks ability to estimate rates of
  events
• Very large (post-marketing) epidemiologic studies
  of AEs associated with vaccine
• Statistical issues of design, analysis,
  interpretation

44
Rotovirus vaccine

• Wyeth vaccine licensed in late 90s
• Highly efficacious in preventing severe
  gastroenteritis and death esp in developing world
• Small but real risk of intussesception identified
  in Phase IV studies
• Wyeth pulled vaccine from market
• Merck recently received license for their
  rotovirus vaccine
• Highly efficacious
• Theoretical reasons to believe risk of
  intussesception lower than that for Wyeth vaccine
• Data from efficacy trial showed somewhat lower
  rate and different temporal pattern of
  intussesception cases
• Very large (60-80,000) person Phase IV studies
  planned to define risk

45
Conclusions

• Clinical development and evaluation of vaccines
  is a long haul
• Statistical reasoning is involved at every step
  along the way
• Measurement technologies
• Study design
• Data analysis
• Statistical reasoning is also involved at a
  programmatic level