New Vaccine Candidates The Challenges of Clinical Trial Design

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New Vaccine Candidates The Challenges of
Clinical Trial Design
Dr David Woolner, Medical Director, Merck Sharp
Dohme (NZ) Ltd
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Pipeline Vaccines

• Measles, Mumps, Rubella and Varicella (MMRV)
• Shingles/Post Hepatic Neuralgia(PHN)
• Rotavirus
• Human Papilloma Virus (HPV)

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Rotavirus Leading Cause of Severe Diarrhea in
Infants and Young Children Worldwide

• Virtually all children are infected by 5 years of
  age
• Worldwide, approximately 1,000 children die every
  day from rotavirus
• Rotavirus accounts for over 2 million
  hospitalizations worldwide annually
  (55,000-70,000 in US)
• Rotavirus affects all children equally
• Regardless of socioeconomicstatus, environmental
  conditions, geographic area
• Severe symptoms equally commonin developed and
  developing world

Parashar et al., Emerging Infect Dis. 2003
9565-72. Parashar et al., 2005 IDSA Abstract
579.
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Structure of Rotavirus

• Nonenveloped icosahedral particle
• 11 segments of double-stranded RNA enclosed in a
  triple layer capsid
• Outer layer consists of VP7 and VP4, which are
  important for immunity
• Induce serotype-specific neutralizing antibodies
• Rotaviruses are classified by their G- and
  P-types
• VP7 determines G-type
• VP4 determines P-type

VP4 (P serotype)
VP7 (G serotype)
Figure adapted from Estes MK, J Infect Dis.
1996174(Suppl 1)S37-S46.
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G1, G2, G3, and G4 Account for gt90 of Rotavirus
Cases
P1a is Most Common P-Type
Other 2
G9 5
G4 1
G3 1
P3 lt1
Other lt1
P2a 2
G2 12
P1b 14
G1 79
P1a 83

• Prevalent G- and P-types in US,1996-2002

Griffin et al., J Clin Microbiol 2000
382784-7 and Santos et al., Rev. Med. Virol.
2005 1529-56.
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NZ Epidemiology

• Reflects global trends
• gt 1,100 hospitalisations per year, approx 657 per
  100,000 children under 3 years of age
• For each admission there may up to 11 times as
  many GP consults, and as many as 35 cases in the
  community without consultation

Grimwood K, Huang QS, Cohet C et al. Rotavirus
hospitalisation in New Zealand children under 3
years of age. Journal of Paediatrics and Child
Health 42 (2006) 196203
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Rotavirus the challenge

• To develop and test a multivalent rotavirus
  vaccine directed against the most prevalent
  rotavirus serotypes
• To demonstrate prevention of rotavirus
  gastroenteritis in infants and children caused by
  the serotypes G1, G2, G3, G4, and G-serotypes
  that contain P1a (e.g., G9)
• To be able to administer the vaccine to infants
  as young as 6 weeks of age

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RotaTeq Development
Dose-ranging Study, Monovalent (P1), Quadrivalent
(G1-4), Pentavalent (G1-4, P1) (005)
Study of Different Buffers (G1-2) (003)
Proof-of- Concept Study (G1-3, P1) (002)
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RotaTeq Development
Dose-ranging Study, Monovalent (P1), Quadrivalent
(G1-4), Pentavalent (G1-4, P1) (005)
Study of Different Buffers (G1-2) (003)
Proof-of- Concept Study (G1-3, P1) (002)
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The Challenge Grows
Dose-ranging Study, Monovalent (P1), Quadrivalent
(G1-4), Pentavalent (G1-4, P1) (005)
Study of Different Buffers (G1-2) (003)
Proof-of- Concept Study (G1-3, P1) (002)
Study Design Endorsed by FDA Advisory Committee
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REST Study Design

• Sample size 60,000 (randomized
  1V1P) Additional groups of 10,000 subjects
  enrolled until primary safety criteria met or
  100,000 subjects enrolled
• Age 6 to 12 weeks at first dose
• Regimen 3 oral doses, 1 every 4 to 10 weeks
• Sites Areas with good standard of care for
  intussusception
• Duration January 2001 to April 2005

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71,799 Subjects in 11 Countries
Vaccinated36,203 in Vaccine Group 35,596 in
Placebo Group
Finland
United States (50 of Enrollment) including
Navajo White Mt. Apache Nations
Sweden
Germany
Belgium
Italy
Taiwan
Puerto Rico
Mexico Guatemala Costa Rica
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REST Primary Safety Hypothesis

• Vaccine will not increase the risk of
  intussusception (IS) relative to placebo within
  42 days of any dose
• To satisfy the primary safety hypothesis, 2
  criteria must be met
• 1. Interim monitoring No increased IS risk (LB
  95 CI gt1) in vaccine recipients following any
  dose
• 1 to 7 days
• 1 to 42 days
• 2. End of study Upper bound of the 95 CI
  estimate of the relative risk of IS 10
• RR point estimates 2 would be needed to satisfy
  the safety criteria

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Overview of Safety Evaluationsin Phase III
Studies

• All serious adverse events (SAEs) including
  intussusception
• Vaccine-related SAEs and deaths were to be
  reported until studys end

Large-Scale Cohort N71,799 (36,203V35,596P)

• All adverse events (AEs)
• Other AEs of clinical interest
• Fever (temp 100.5F rectal equivalent),
  vomiting, diarrhea, irritability, and hematochezia

Detailed Safety Cohort N11,722(6143V5579P)

• Fecal vaccine-strain shedding was evaluated in 2
  ways
• Pre-specified time interval
• All rotavirus-positive potential acute
  gastroenteritis cases

NNumber vaccinated.
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Comprehensive Interim Monitoring for
Intussusception (IS)

• Active Surveillance at Study Sites
• Contacts on days 7, 14, and 42
• Up to 1 year after first dose

Independent SafetyEndpoint AdjudicationCommittee
- Adjudicated cases using specific case
definition
Independent Data andSafety Monitoring Board
(DSMB) - Unblinded each case and made
recommendations for continuation - Reviewed
safetydata every 6 months
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Efficacy Endpoints

• RotaTeq prevents 74 of any severity of
  rotavirus gastroenteritis and 98 of severe
  disease
• RotaTeq prevented healthcare encounters for
  rotavirus gastroenteritis
• 96 ? hospitalizations
• 93 ? emergency department visits
• 86 ? physician office visits
• Serotype-specific data indicate that RotaTeq is
  efficacious against the G serotypes in the
  vaccine and against G9 strains containing P1
• Efficacy persisted during the second rotavirus
  season postvaccination

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REST Study Design

• REST achieved the goals of the study design and
  the extensive safety monitoring which were to
  provide
• High probability that a study of a vaccine with
  increased intussusception risk would stop early
  and simultaneously
• High probability that a safe vaccine would meet
  the end-of-study criteria

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Case Definitionfor Rotavirus Gastroenteritis
Clinical and Laboratory Criteria

• Clinical Case Definition
• Forceful vomiting and/or 3 loose stools in 24
  hours
• Severity of cases assigned using a clinical
  scoring system
• Based on intensity and duration of fever,
  vomiting, diarrhea, and behavioral changes
  8mild gt8 16moderate gt16severe
• Laboratory Case Definition
• Rotavirus detection by EIA
• Serotype identification by PCR
• Vaccine-virus strain identification by plaque and
  electropherotyping

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Quadrivalent HPV the NZ Experience
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Objectives of Clinical Program

• A Quadrivalent HPV L1 VLP vaccine will reduce
  the incidence of vaccine-type specific
• Cervical cancer (via CIN 2/3 AIS)
• CIN
• External genital lesions
• AIN and anal cancer
• A Quadrivalent HPV L1 VLP vaccine will be
  effective and well tolerated in
• Adolescents aged 9 to lt18 years (both genders)
• Sexually active adults (both genders)

VLP Virus-like particle.
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Rationale for a Quadrivalent HPV (Types 6, 11,
16, and 18) L1 VLP Vaccine
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Mercks Quadrivalent HPV L1 VLP Vaccine1

• Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP
  vaccine
• VLPs manufactured in Saccharomyces cerevisiae
• Yeast-derived vaccines given to millions of
  children and adults.
• Aluminum adjuvant 225 µg per dose
• 0.5 mL injection volume IM
• 3 doses within 6 months (0, 2 6)

VLP Virus-like particle. 1. Villa LL, Costa
RL, Petta CA, et al. Lancet Oncol. 20056271278.
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How Do We Show Cancer Efficacy?
InitialHPV Infection
ContinuingInfection
CIN 2/3
Cervical Cancer
CIN 1
Cleared HPV Infection
CIN cervical intraepithelial neoplasia1.
Franco EL, Harper DM. Vaccine. 20052323882394.
2. Pagliusi SR, Aguado MT. Vaccine.
200423569578.
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Early Clinical Programme

• HPV 16 Vaccine, Proof of Principle Efficacy
  Study1
• Double-blind, placebo-controlled study, 2392
  women aged 16 to 23, followed for 4 years
• Primary Endpoint
• Persistent HPV 16 Infection
• HPV 16-related CIN
• Efficacy evaluation in women who are HPV 16-naïve
  at baseline
• Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP
  Vaccine
• Dose-Ranging and Efficacy Study, 155 women aged
  16 to 23 Followed for 3 years
• 3 formulations of HPV vaccine or Placebo given at
  enrollment, Month 2, and Month 6

1Koutsky et al. New Engl J Med 20023471645-51
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FUTURE Phase III study for the Prevention of
CIN Warts
Females United To Unilaterally Reduce Endo/ectocer
vical cancer
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FUTURE Study

• Phase III pivotal efficacy study of Quadrivalent
  Vaccine (HPV 6, 11, 16, 18)
• Thirteen countries and 53 Study Sites
• Total subject pool 11,000
• Consists of Three Studies
• Protocol 013 Efficacy and Safety Study
• Protocol 011 Hepatitis B Co-administration study
• Protocol 012 Immunogenicity comparison of
  Monovalent HPV 16 Vaccine and Quadrivalent
  Vaccine

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FUTURE Study Objectives

• Primary Efficacy Objectives
• A three dose regimen of Quadrivalent Vaccine (Day
  0, Month 2, Month 6) 11 ratio with placebo.
• Reduces the incidence of HPV 6, 11, 16, 18 -
  related
• Genital warts,
• ViN, VAiN,
• Vulvar Cancer
• Vaginal Cancer
• Cervical dysplasia (any grade),
• Adenocarcinoma in situ
• Cervical cancer compared with placebo
• ViN Vulval intraepithelial neoplasia or VAiN
  Vaginal Intraepithelial Neoplasia

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Subject Selection Challenges

• 16 to 23 year old women
• 0 4 lifetime male or female partners
• Not pregnant at time of enrolling in the study
• Agree to refrain from sexual activity 48 hours
  prior to a clinic visit where pelvic exam is
  planned.
• History of any abnormal smears, genital warts or
  treatment for warts
• Plans to permanently relocate during the study
• Not Immunocompromised

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Potential Recruitment Issues

• Discussing sex/STIs
• Direct questioning re sexual activity
• Positive pregnancy test
• Dealing with HPV positive serology at baseline
• Subject allowed refusal without stating why

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Investigators Selected

• Family Planning Association
• Helen Roberts and Sue Bagshaw
• Both practitioners well known for womans health
• FPA Christchurch and Auckland (4 sites)
• No research experience with pharma companies

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Recruitment

• Engaged Advertising Agency
• Defined a campaign to run for 6 weeks before
  First Patient In Date
• Theme of Women Helping Women
• Logo

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Media Campaign

• Poster Campaign
• Radio Advertising
• Free phone 0800 number
• Call Centre screening
• Magazine Advertising
• Web site
• www.hpv.co.nz (no longer active)

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Media Campaign

• Radio interview on BFM and Canterbury student
  radio
• Brochures to pick up
• University activity
• Auckland University
• Lincoln and Canterbury
• Next Magazine
• Lectures to Medical and Nursing Students

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What worked ?

• Posters
• Brochures
• Call centre to screen
• Friends referring friends
• Family Planning Nurses and Doctor awareness and
  referral to coordinators
• Modest remuneration (AFTER consent)
• Westfield vouchers 35 per Visit

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What Didnt Work

• Website not overly utilized
• Good for back up information
• Campus Activity
• Small amount of self-referral

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How did FUTURE Progress?

• 173 patients enrolled from July 2002 to March
  2003
• Retention NZ 94 vs. World-wide Retention 91
• Relocations !
• All participants who received placebo or
  monovalent vaccine were offered the vaccine free
  of charge

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• GARDASIL Quadrivalent Human Papillomavirus
  (Types 6, 11, 16, 18) Recombinant vaccine
  registered in New Zealand on July 20 2006.
• GARDASIL is indicated in females aged 9 to 26
  years for the prevention of cervical, vulvar,
  and vaginal cancer, precancerous or dysplastic
  lesions, genital warts, and infection caused by
  Human Papillomavirus (HPV) Types 6, 11, 16, and
  18 (which are included in the vaccine).
• GARDASIL is indicated in males aged 9 to 15 years
  for the prevention of infection caused by Human
  Papillomavirus (HPV) Types 6, 11, 16, and 18
  (which are included in the vaccine).
• Immunogenicity studies have been conducted to
  link efficacy in females aged 16 to 26 years to
  the younger populations.

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References Slide 30 Mercks Quadrivalent HPV L1
VLP Vaccine1 1. Villa LL, Costa RLR, Petta CA, et
al. Prophylactic quadrivalent human
papillomavirus (types 6, 11, 16, and 18) L1
virus-like particle vaccine in young women A
randomised double-blind placebo-controlled
multicentre phase II efficacy trial. Lancet
Oncol. 20056271278. 2. Clifford GM, Rana RK,
Franceschi S, Smith JS, Gough G, Pimenta JM.
Human papillomavirus genotype distribution in
low-grade cervical lesions Comparison by
geographic region and with cervical cancer.
Cancer Epidemiol Biomarkers Prev.
20051411571164. 3. Clifford GM, Smith JS,
Plummer M, Muñoz N, Franceschi S. Human
papillomavirus types in invasive cervical cancer
worldwide A meta-analysis. Br J Cancer.
2003886373. 4. Recombivax HB Hepatitis B
Vaccine (Recombinant) prescribing information.
Merck Co, Inc. Whitehouse Station, NJ.
1998. Slide 31 References Slide 31 How Do We
Show Cancer Efficacy? Franco EL, Harper DM.
Vaccination against human papillomavirus
infection A new paradigm in cervical cancer
control. Vaccine. 20052323882394. Pagliusi
SR, Aguado T. Efficacy and other milestones for
human papillomavirus vaccine introduction.
Vaccine. 200423569578. Moscicki AB, Shiboski
S, Hills NK, et al. Regression of low-grade
squamous intra-epithelial lesions in young women.
Lancet. 200436416781683. Östör AG. Natural
history of cervical intraepithelial neoplasia A
critical review. Int J Gynecol Pathol.
199312186192. Villa LL, Costa RLR, Petta CA,
et al. Prophylactic quadrivalent human
papillomavirus (types 6, 11, 16, and 18) L1
virus-like particle vaccine in young women A
randomised double-blind placebo-controlled
multicentre phase II efficacy trial. Lancet
Oncol. 20056271278. Koutsky LA, Ault KA,
Wheeler CM, et al. A controlled trial of a human
papillomavirus type 16 vaccine. N Engl J Med.
200234716451651.