1. health and fitness
2. disease
3. infertility

The Future of Clinical Trials
in Infertility
Richard S. Legro, M.D.
Professor of Obstetrics and Gynecology and
Public Health Sciences
Penn State College of Medicine
Hershey, PA 17033
Disclosure
Consultant
Euroscreen, Astrazenca, Ferring
U. S. National Institutes of Health (NIH), Food and
Drug Administration.
Grant Funding
NIH
PA Commonwealth Tobacco Settlement Funds
Board/Committee Member
ASRM
Endocrine Society
Androgen Excess/PCOS Society
Clinical Trials in InfertilityThe Rare Done by the Rarefied
Less than 10% of the articles that appear in
Fertility and Sterility and Human Reproduction
are clinical trials
– Personal communication Editors
Clinical trials are team based, cumbersome and
expensive
Scientific creativity is stifled: “Are you now a clinical
trialist?”
Individual credit is diluted: “No promotion to
Professor for the 23rd author”
We don’t really need randomized
clinical trials (RCTs) in infertility*
All breakthroughs were accomplished
without clinical trials: IVF, ICSI, FET,
Donor oocytes, Oocyte
Cryopreservation, Embryo Selection
* Subfertility or fertility may be substituted
We as a physician group, without
external supervision, are likely to
perform the most lucrative
procedure that is unique to our
specialty or subspecialty
“There is at bottom only one
genuinely scientific treatment for
all diseases, and that is to
stimulate the phagocytes.”
Sir Ralph Bloomfield Bonington, M.D.
In “The Doctor’s Dilemna” by
George Bernard Shaw (1909)
Increasing Utilization of IVF
as an Infertility Treatment
Time Period
Years
1978-2003
25
Million of
Babies
Born
1
2003-2013
10
5
Kamphuis et al, BMJ, 2014
Polycystic Ovary Syndrome
CDC Assisted Reproductive
Most common cause
Technology National Summary
of anovulatory
infertility
Using own
2005
2011
Eggs
Need for low cost,
Number of IVF 89,385 101,213
safe, and effective
cycles
infertility therapies
IVF, developed for
Tubal Factor Infertility
increasingly used for
Ovulatory Dysfunction
Ovulatory
Dysfunction
(%)
8%
14%
RCTs are required to establish
comparative effectiveness and
harms of infertility treatments
They form an important counterbalance
to the wholesale adoption of new
treatments or their drift to lesser
indications when simpler therapies (or
no therapy) is effective
Overutilized Infertility Therapies
GIFT
Multiple Embryo Transfer
Assisted Hatching
Routine Prenatal Genetic Screening of
Embryos
Metformin as first line infertility therapy for
PCOS
CAVEAT: By inadvertently focusing
on the pregnancy outcome of the
fresh transfer after an IVF cycle
(instead of the cumulative pregnancy
results of all transfers from that
cycle), National ART regulatory
agencies have contributed to
practices encouraging multiple
embryo transfer
Major Hurdles in Reproductive Trials
1) Involvement of three individuals: father, mother,
and fetus.
“Vulnerable” populations (reproductive age women and
fetus/infant)
2) Determining the primary outcome
Is it live birth?
3) Capturing harms of infertility treatment
At what point do we begin or stop surveillance for harms of
infertility treatment
– Louise Brown is only 36.
4) Limited Interest in Funding the Trials
The CONSORT Guidelines are
only written for a single
individual in a trial
How do you report on trials involving
multiple individuals with outcomes (i.e. live
birth) that can occur long after the study
intervention has ceased?
Clinical Trials involving
Multiple Individuals
Obstetric
Mother /Infant
Directed Donor Transplant (Kidney/Liver/Lung)
Donor/Recipient
Infertility
trials involve
three subjects
(ideally) :
mother,
father, and
Infant(s)
Or more…
Couples in Infertility Trials
A couple (not the gamete, embryo, cycle) is the
preferred unit of analysis
Both male and female confounding infertility factors are
screened out and both often participate to varying degree
Do you consent the secondary partner to participate?
Varying degree of burden if male (i.e. intercourse or
semen specimen) vs female (treatment plus pregnancy
risks)
How do you track outcomes and adverse events in
the secondary partner?
Brave New
World of
Complexity
in Analysis
Legro et al, Fertil
Steril, 2014
Why choose Live Birth as the
primary outcome versus ongoing
first trimester pregnancy
Ongoing pregnancy is an excellent surrogate
of Live Birth- pregnancy loss rates in clinical
trials are comparable between control and
intervention groups (~20% from clinical
pregnancy to live birth)
Clarke et al, Fertil Steril, 2010
No more Surrogate Outcomes
in Clinical Trials
A surrogate measure is an intermediate endpoint that
has been validated against some clinically meaningful
endpoint
Glycohemoglobin in type 2 diabetes as a marker for CVD
morbidity and mortality
– Rosiglitazone
– Intensive therapy of type 2 diabetes (ACCORD Trial)
HDL/LDL Cholesterol as a marker for prevention of
primary and secondary CVD morbidity and mortality
– CETP inhibitors (torcetatrib)
Pregnancy Loss: ? Increased
with Metformin in PCOS
CC
All pregnancy loss
16/62
MET
10/25
COMB
24/80
COMB Vs.
COMB
CC Vs.MET
MET
Vs. CC
0.35
0.58
0.19
0.15
0.74
0.10
(25.8%) (40.0%) (30.0%)
st
1 trimester
14/62
10/25
20/80
loss (22.6%) (40.0%) (25.5%)
Legro et al, NEJM, 2007
Reproductive Medicine Specialists,
Perinatologists and Neonatologists have
different views on what is the main outcome of
an infertility trial
The Perinatal
Division of
Labor
PreConception
Conception
8-10 24 weeks- 40 weeks Infant
weeks
Fetal
Term
Pregnant Viability Pregnancy
Reproductive Medicine
Network- 7 sites
Maternal Fetal Medicine
Network- 14 sites
Neonatal Research
Network- 20 sites
In the U.S., just as in perinatal
research, clinical care of the
infertile couple is fragmented
The patients are handed off from
Reproductive Endocrinologist and/or
Urologist to Obstetrician to
Neonatologist/Pediatrician
Are we missing the elephant?
Screening
to
Treatment
to
Pregnancy
to Live
Birth
Capturing all
Outcomes
means
Longer Flow
Charts
(Longer
Trials)
Primum Non Nocere
(First Do No Harm)
I will apply treatment for the benefit of the
sick. I will keep them from harm and
injustice.
3rd paragraph Hippocratic Oath
By not fully capturing adverse
events to participants during and
after infertility treatments in
clinical trials, we can not
adequately counsel patients
about the risk/benefit ratio of
treatments
Defining reproductive risk
is the largest hurdle in an infertility clinical
trial
Fetal/Infant
Does the intervention cause pregnancy loss?
Does it cause birth defects?
Does it cause potential infant developmental delays?
Maternal
Has it been studied in women of reproductive age (or
primarily men and older women)?
– What are the risks during treatment and during pregnancy?
Paternal
Rarely studied when the female is the treatment target.
Still Haunted by Thalidomide
Adverse Effects of Fertility Treatments (Many
long after the treatment was established)
DES
Reproductive tract
anomalies and cancers
Clomiphene
Multiple pregnancy
? Congenital anomalies
Gonadotropins
High order multiple
pregnancy
OHSS
IVF
Increased fetal sex
chromosomal aneuploidies
with ICSI
Increased rate SGA
singleton babies
? Increased risk perinatal
complications with fresh vs
frozen embryo transfers
? Increased Imprinting
Errors
Paternal Risk: Is Participation in an
Infertility Trial Hazardous to a Relationship?
Legro et al, NEJM 2007
What are the long term risks of
exposure to infertility treatments?
Implicit in the primary hypothesis
of every clinical trial is that the
treatment studied is effective and
safe
Without systematically and
prospectively collecting adverse
events there can be no
conclusions made about safety.
How do we design a trial to
capture the risks to mothers and
infants of infertility treatment?
Indication: Polycystic Ovary Syndrome
Pregnancy Outcome in PCOS
Meta-analysis: 720 women with PCOS vs 4505 controls
OR
95% CI
Pregnancy induced hypertension: 3.67
1.98-6.81
Pre-eclampsia
3.47
1.95-6.17
Gestational Diabetes:
2.94
1.70-5.08
Pre-term birth
1.75
1.16-2.62
Perinatal mortality
3.07
1.03-9.21
Boomsma et al, Human Reproduction Update 2006
Is letrozole (an aromatase
inhibitor), used as an ovulation
induction agent safe to the
fetus/infant
Is it teratagonic or does it pose
developmental issues to an infant?
FDA Guidelines for an IND
for Letrozole for Infertility
Serum pregnancy test at the beginning of each
menstrual cycle before being challenged with study
medication.
Examination of the infant within a month of birth by a
developmental pediatrician
Rule out congenital anomalies
Completion of a yearly standardized infant
developmental questionnaire by a parent up to age 3
Collection of CDC growth curves and infant medical
records
Collection of Safety Data During Trial
Male
Partner
Yes
Female Fetus/
Partner Infant
Yes
N.A
Yes
N.A.
Pregnancy/ Delivery
Repeat
QOL
N.A.
Yes
Yes
Puerperium/ Neonatal Period
N.A.
Yes
Yes*
Baseline QoL
Medication Treatment Phase
* Pregnancy Registry Mandated by FDA: Infant exam for
congenital anomalies, 3 year developmental follow up
Incomplete Reporting of Outcomes of
Infertility Trials
Dapuzzo et al,
Fertil Steril
2011
Reporting Clinical Trials in Infertility: A Modified
CONSORT Statement
The Harbin Consensus Conference Workshop Group*
*Conference Chairs: Xiaoke Wu (China), Richard S. Legro (USA)
Scientific Committee: Cynthia Farquhar (New Zealand), Ben Mol
(Netherlands), Bart Fauser (Netherlands), Kurt T. Barnhart (USA),
Invited Participants: Robert Silver, M.D. (USA), Seetha Shankaran
(USA) Craig Niederberger (USA), Juha Tapanainen (Finland),
Siladitya Bhattacharya (U.K.), Richard Reindollar (USA), Robert
Rebar (USA), Stefano Palumba (Italy), Heping Zhang (USA), Sheryl
Vanderpool (Switzerland), Hans Ever (Netherlands), Antonio
Pellicier (Spain), Robert Norman (Australia), Ernest Ng (China).
Goals of Harbin Consensus
Conference
To discuss and develop modifications in the
CONSORT checklist to improve the quality
(and reprorting) of infertility clinical trials
Produce a draft revised checklist
To develop a strategy to disseminate results
and determine its impact on infertility trials
Hot August
Days and
Nights, Harbin,
China 2013
Summary of Consensus
Recommendations
Topic
Current
Description
Numbers For each group,
Analyzed number of
participants
(denominator)
included in each
analysis and
whether the
analysis was by
original assigned
groups
Consensus Modification
The preferred unit of analysis is per
randomized individual/couple (and not cycles
or oocytes/embryos) for specified period of
time (preferably displayed with life table
analysis). Use of per cycle analysis should be
justified and, if used, must account for
individuals receiving multiple cycles.
Clearly describe what happens to all multiple
pregnancies, including fetal reduction and
vanishing gestations. Report multiple
pregnancy outcome both per woman and per
pregnancy. Separate out twin/triplets/quads/etc.
Summary of Consensus
Recommendations
Topic
Current Description
Outcomes Completely defined
pre-specified primary
and secondary
outcome measures,
including how and
when they were
assessed
Consensus Modification
In trials of fertility treatment the primary
outcome should be clearly defined and
reporting live birth (defined as a delivery ≥
20 weeks gestation) is preferred (including
gestational age, birth weight and sex of
infant).
Summary of Consensus
Recommendations
Topic
Current Description
Harms All important harms
or unintended effects
in each group (for
specific guidance,
see CONSORT for
harms [28])
Consensus Modification
All important harms or unintended effects in
each group (males, females, infants); during
treatment (including both male and female
partners), during pregnancy and around birth,
and in infants after birth.
To think about doing better
infertility trials
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Partners in Health:
Bring Multi-Agent
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eradicate MDRtuberculosis and
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“Foreign Clinics Cash In On
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Accessed 4/3/13
PPCOS II Investigators
Funding/Collaborators
Supported by NIH grants, K08 and K24 grant, The National Cooperative Program for Infertility
Research U54 HD 34449, U10 38992, Reproductive Medicine Network, 1R01HD056510 and A
General Clinical Research Center grant MO1 RR 10732 to Penn State
Northwestern
Andrea Dunaif, M.D.
Margrit Urbanek, Ph.D.
Virginia Commonwealth
Jerry Strauss, M.D.,Ph.D.,
John Nestler, M.D.
University of Pennsylvania
Christos Coutifaris, M.D., Ph.D.
Rich Spielman, Ph.D.
Anuja Dokras, M.D., Ph.D.
Penn StateJan McAllister, Ph.D.
Larry Demers, Ph.D.
Bill Dodson, M.D.
Rich Zaino, M.D.
Peter Lee, M.D., Ph.D.
Alex Vgontzas, M.D.
Allen Kunselman
Jami Ober
Kelly Stamets
Rawa Patsy
Emily George
Sandra Eyer
Christy Bartlebaugh
It does happen exceptionally that a
practicing doctor makes a contribution to
science; but it happens much oftener that
he draws disastrous conclusions from his
clinical experience because he has no
conception of scientific method, and
believes, that the handling of evidence
and statistics needs no expertness
George Bernard Shaw, Preface to
“The Doctor’s Dilemma”