Unexplained Infertility Treatment Successes Mean Reported

1
Outcome Measurement for Assisted Reproductive
Technology
DAVID L. KEEFE, M.D. Tufts New England Medical
Center, Boston, Massachusetts Laboratory for
Reproductive Medicine, Marine Biological
Laboratory, Woods Hole, MA Brown University, and
Women Infants Hospital, Providence, RI
2
Overview of Presentation

• Introduction to ART procedures
• Study population
• How factor in study populations for ART studies
• How should IVF/ICSI/Donor Egg be factored in?
• Study Design
• Efficacy measures Primary and secondary
  endpoints
• How should success be defined?
• Safety endpoint measures
• A look into the future of ART outcome measurement

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Assisted Reproductive Technologies

• In Vitro Fertilization/Embryo Transfer (IVF-ET),
  w/ or w/o ICSI
• Gamete Intrafallopian Tranfer (GIFT)
• Zygote Intrafallopian Transfer (ZIFT)
• Tubal Embryo Transfer (TET)
• Controlled Ovarian Hyperstimulation (COH) w/
  Intrauterine Inseminations

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IVF Steps

• Ovarian down-regulation w/ OCP, GnRH agonist or
  antagonist
• Controlled ovarian hyperstimulation with
  gonadotropins U/S, E2 monitoring
• Trigger maturation with hCG
• Retrieval
• Fertilization by IVF or ICSI
• Culture embryos
• Transfer embryos w/ or w/o hatching
• Luteal support

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IVF- Clinical Processes
Sperm collection
Assess sperm quality and count
Wash sample
Egg equilibration
Assessment of fertilization
Wash/remove excess sperm
Incubate
Assess Transfer
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IVF- Laboratory Processes
Sperm collection
Eggs retrieved
Eggs stripped and cleaned
Wash sample
Egg equilibration
Assess sperm quality and count
Fertilization- IVF or ICSI
Wash/remove excess sperm
Assess fertilization
Assess Transfer Embryos
Incubate
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Controlled Ovarian Hyperstimulation Regimens for
Assisted Reproductive Technology
Day of hCG
Day 1 FSH/HMG
GnRH Antagonist Protocols
Day 6 of FSH/HMG
225 IU per day (150 IU Europe)
Individualized Dosing of FSH/HMG
250 mg per day antagonist
Day 2 or 3 of menses
GnRH Agonist Protocols
Day 1 of FSH/HMG
Day 6 of FSH/HMG
Day of hCG
7 8 days after estimated ovulation
Individualized Dosing of FSH/HMG
225 IU per day (150 IU Europe)
GnRHa 1.0 mg per day up to 21 days
0.5 mg per day of GnRHa
OCP
Down regulation
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Overview of Presentation

• Introduction to ART procedures
• Study population
• How factor in study populations for ART studies
• How should IVF/ICSI/Donor Egg be factored in?
• Study Design
• Efficacy measures Primary and secondary
  endpoints
• How should success be defined?
• Safety endpoint measures
• A look into the future of ART outcome measurement

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Differences in Study Populations be Factored Into
ART Studies

• IVF/ICSI/Donor Egg patients differ in underlying
  disease
• Differ in rate of egg dysfunction IVFgtICSIgtEgg
  donor
• Egg dysfunction (a.k.a. ovarian reserve, age,
  etc.) best predictor of outcome (can determine
  log-order differences in pregnancy rates among
  groups of patients)
• Studies should control for study population
  differences through inclusion/exclusion criteria,
  case-control or stratification

10
Overview of Presentation

• Introduction to ART procedures
• Study population
• How factor in study populations for ART studies
• How should IVF/ICSI/Donor Egg be factored in?
• Study Design
• Efficacy measures Primary and secondary
  endpoints
• How should success be defined?
• Safety endpoint measures
• A look into the future of ART outcome measurement

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Outcome Measures for ART

• Deliveries/initiated cycles- the gold standard
• Surrogate clinical outcomes
• Ongoing viable pregnancy (FH)
• Clinical pregnancy rate (FH)
• Biochemical pregnancy rate
• Surrogate biologic outcomes
• Number of follicles
• Peak E2
• Number eggs aspirated
• Fertilization rate
• Embryo cleavage and morphology rates

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Outcome Measures for ART-Deliveries/Initiated
Cycles

• The gold standard
• Large power needed
• Expensive
• Difficult-to-measure, but important patient
  differences have greater impact than drug therapy
  on this outcome

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Outcome Measures for ART-Surrogate Clinical
Outcomes

• Close to gold standard
• Less power needed
• Clinically important outcome
• May miss clinically-important differences, e.g.
  miscarriage rates
• Contaminated by clinic practices, e.g.
  cancellation policies

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Outcome Measures for ART-Surrogate Biologic
Outcomes

• Far from gold standard
• Much less power needed
• May not reflect clinically important outcome,
  e.g. young women with low response to COH still
  have excellent outcomes subtle differences in
  drug potency on egg yield and E2 can be managed
  by altering dosing

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How Should Success be Defined?

• Superiority to comparator (placeboactive
  control)
• Equivalence to active comparator
• Non-inferiority to active comparator
• Success should be defined not only according to
  pregnancy rate or its surrogate, but also
  according to convenience and discomfort level

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Success Should be Defined Based on Equivalence or
Non-Inferiority to Comparator

• Superiority to comparator (placeboactive
  control)- not necessary for new drug to prove
  useful for patient care
• Equivalence or Non-inferior drugs would
• Spur competition in market
• Allow multiple options affecting
  convenience/comfort, which differ according to
  patient preference, e.g. vaginal vs. IM route for
  progesterone therapy

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Example- Antagonist improves convenience w/o
improving pregnancy outcome (also, vag. prog,
s.q. gts.)

• Antagonist

Agonist
vs.
Based on median duration of use. North
American Ganirelix study.
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Safety Endpoints

• Ovarian hyperstimulation syndrome
• Miscarriage rate
• Multiple pregnancy rate
• Ectopic pregnancy rate

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Safety Endpoints- Ovarian Hyperstimulation
syndrome

• Life-threatening
• Risk sets upper limit on COH
• Risk may be modified by lowering peak estradiol
  e.g. aromatase inhibors, LH

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Safety Endpoints-Miscarriage Rate

• Common (15-70)
• Affected by patient-specific factors (e.g. age,
  ovarian reserve)
• May be influenced by all stages of ART, e.g.
  stimulation regimens, luteal phase support,
  culture media, etc.

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Multiple Gestations and ART

• Common (15-50)
• Major obstetric, pediatric and public health
  concern (prematurity, C.P., C/S rate,
  preeclampsia, gestational diabetes)
• Affected by patient-specific factors (e.g. age,
  ovarian reserve)
• Affected by (elusive ) clinician practices, e.g.
  number of viable embryos transferred
• Monozygotic twinning also should be considered,
  since is related to COH, increased in ART and
  causes significant morbidity (twin-twin tx)
• Should imprinting abnormalities
  (Beckwith-Wiedemann, Angelmann Sydromes, PIH) be
  considered an ART risk (DeBaun et al, AJHG,
  2001)?

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Overview of Presentation

• Introduction to ART procedures
• Study population
• How factor in study populations for ART studies
• How should IVF/ICSI/Donor Egg be factored in?
• Study Design
• Efficacy measures Primary and secondary
  endpoints
• How should success be defined?
• Safety endpoint measures
• A look into the future of ART outcome measurement

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The Future of IVF Outcome Measurement

• Multicenter network to facilitate RCTs
• Greater racial and ethnic diversity in clinical
  studies to ensure generalizability of data, as
  mandates increase access of working and middle
  class Americans to ART
• Improve biological surrogate outcomes

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The Future of IVF Outcome Measurement-Improving
Biological Surrogate Outcomes

• Aneuploidy ubiquitous and related to ART failure,
  through increased embryo apoptosis, implantation
  failure and miscarriage
• Thus, may provide a meaningful biologic surrogate
  outcome
• Safety problems with IVF stem from attempts to
  overcome egg aneuploidy through COH, e.g. OHSS
  and multiple gestations
• May be increased by COH (e.g. by short-cutting
  normal selection process, altering follicular
  environment)
• New technologies to dx aneuploidy e.g. CGH, SKY
• May be able to dx predisposition to aneuploidy

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Aneuploid Embryos Can Develop Normally Until Day
5 of Life!
Development of Embryo with Trisomy 21, determined
by PGD on day 3, with develoment to
normal-appearing blastocyst
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Preimplantation Genetic Diagnosis (PGD) Can
Improve Implantation Rate

• Identification of chromosomes X,Y,13,18,21,15,16,2
  2
• Implantation Rate
• PGD 24.2
• Controls 12.4 (plt0.001)
• Gianaroli et al FS, 1999

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Preimplantation Genetic Diagnosis (PGD) Predicts
IVF Outcome

• Age gt37
• gt 2 failed cycles of IVF
• 216 couples
• 3 groups, depending on normal embryos available
  after PGD
• 0 normal 1 normal gt1 normal
• patients 27 26 55
• embryos 114 118 322
• transfers 8 14 48
• Births/patient 4 15 31
• Ferraretti, et al World Congress IVF, 2002

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Preimplantation Genetic Diagnosis (PGD) in
Patients with Repeated Miscarriages

• 76 of embryos from patients with Recurrent
  Pregnancy Loss have aneuploidy
• Pellicer, et al FS 711033, 1999

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Gt.s Play Key Role in Meiosis
FSH then LH (Gonal F, Repronex, Follistim,
Bravelle, then hCG)
Immature Oocytes w/I Follicles
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Eggs From Older Women Have Abnormal Spindles
Age (years) Abnormal Spindles 20-35
17 40-45 79
Battaglia et al, Hum Reprod. 1996112217.
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Spindle Function Imaged by Polscope
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Eggs With Normal Spindles Develop Better
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Telomere Shortening Explains Effects of Age on
Aneuploidy

• Late exit from the Production Line (Henderson and
  Edwards, 1968)
• The effects of low levels of MtDNA deletions
  (Keefe, 1995)
• Spindle abnormalities (Battaglia,1997)
• Reactive oxygen species (Tarin, 1998)
• Increased embryo arrest
• Increased embryo death