Clinical Evaluation of Vaccines“The Long Haul”

Steve Self

Biostat 578 3/2/06

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

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

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

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 vectorViral vector + lipopeptidesDNA + proteinCanarypox + rgp120

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 doseSafety evaluation after second immunizationSystemic and local reactionsSafety outcomes specific to vaccineVery little information about immunogenicity

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

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

Optimization of vaccine regimen

• Large “parameter” space

• Multidimensional outcome space (immune responses)

• Uncertainty of outcomes– Statistical uncertainty– Biological uncertainty

• Potential (hope) for interactions

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 don’t fit paradigm at all (eg dose de-

escalation)

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 > 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

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

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

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?

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

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

()

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)

Required # Endpoints for 90% Power

Phase III TOC

VE1 VE0 = 30%,

= 0.025

VE0 = 0%,

= 0.025

VE0 = 0%,

= 0.05

VE0 = 0%,

= 0.10

VE0 = 0%,

= 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

Other Design Parameters that May Differ

Design

ParameterTest of Concept

DesignPivotal Trial

Design

Vaccine Prototype Product

Population Narrow(optimize for sensitivity, operational efficiency)

Representative (target for licensure)

Primary Endpoint

Biomarker(Distal)

Clinical Outcome

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

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 347:1645, 2002

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 0:41 split (V:C)

• Total (pers+trans) incident infection: 74 cases (6:68)

Koutsky et al., New Eng J Med 347:1645, 2002

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 4:36 split (V:C)

Villa et al., Lancet Oncology, 2005

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

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 7:111 split (V:C)

– HPV16-assoc CIN2-3: 12 cases with 0:12 split (V:C)

Mao et al., Obstet & Gyn 107(1): 18-27, 2006

Other supportive studies

• Adolescent immunogenicity and tolerability– >4500 boys and girls

• Mid-adult women’s efficacy and tolerability– Women age 24-45

• Nordic study – Durability of protection– Long-term safety– > 50,000 men and women

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 L:ancet 2004

GSK HPV VaccineTest of Concept Trial: ITT Results

010

2030

4050

6070

8090

100

HPV16 HPV18 HPV16/18

Incident InfectionsPersistent Infections

% Efficacy

Harper et al., The Lancet, 2004

*

* 100% efficacy in ATP analysis

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)

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

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

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)

= 0.025 (overall) NE = 100

Power of 90% to distinguish VES = 0% vs 53%

logVL = 0 vs 0.6-0.7 logs (depending on VES)

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 vaccineInfection endpoint: relative risk for infectionVL endpoint: difference in mean log-VL

– Power of tests depend on Number of infection endpoints among vaccineesPrevalence of high/low responders to vaccineMagnitude of difference between high/low responders

Minimum Detectable Effect Sizes (with 90% power)

Infection Endpoint logVL Endpoint

Total # Infections

VE0=30%

=0.025

VE0=0%

=0.025

VE0=0% =0.10

RR*(L,H) = 0 =0.025

**(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** mean logVL: Low immune responders – High immune responders

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?

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

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?

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

Series of TOC Trials?

– Trial-specific analysesPowerful inferences about vaccine effect on VL endpointModest 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?

Basis for licensure?

• Evidence for clinical benefit must be “compelling and robust”– Two-trial rule often referred to as standard

Two independent trialsEach trial delivers p-value < 0.025 for primary test of efficacy

– “Compelling” evidenceOverall false positive rate is small (0.000625 = 0.0252)

– “Robust” evidenceReplicated resultsEvidence for efficacy consistent across two trial settings (ie each

trial delivers p-value < 0.025)

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 testRobust evidence:

Representative study population Homogeneity of study population Uniformity of efficacy result over key study strata

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 trialStudy population includes three “strata” of pre-specified sizePrimary analysis plan includes overall analysis as well as pre-

specified stratum-specific analyses (with appropriate adjustment for multiplicity)

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?

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

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

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