Evaluating Emerging Technologies: Is the Future Now? (Text Version)

On September 27, 2010, Susan Tolivaisa made this presentation at the 2010 Annual Conference. Select to access the PowerPoint® presentation (4.2 MB).  

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Slide 1

Evaluating Emerging Technologies: Is the Future Now?

Susan Tolivaisa
Eunice Kennedy Shriver National Institute of Child Health and Human Development

Image: The MOMS—Management of Myelomeningocele Study logo. This logo appears in the lower right-hand corner of all subsequent slides.

Images: The Department of Health and Human Services and National Institutes of Health appear in the lower left-hand side of the slide; the Eunice Kennedy Shriver National Institute of Child Health and Human Development logo appears in the lower right.

Slide 2

The MOMS Trial and Its Development

MOMS Clinical Centers

• The Children's Hospital of Philadelphia
• University of California-San Francisco 
• Vanderbilt University Medical Center

Coordinating Center

• The George Washington University Biostatistics Center

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Pregnancy and Perinatology Branch

Slide 3

Background

• Obstetrical management, especially for high-risk patients, has often adopted practices without objective evaluation.

Image: A pregnant woman is shown.

Slide 4

Background

• Fetal surgery began for lethal conditions
• Risks involve two:
  • Mom
  • Baby
• Long term risks: future pregnancies

Image: A pregnant woman is shown.

Slide 5

Fetal surgery for myelomeningocele (MMC or spina bifida) moves beyond the typical paradigm

• Not a lethal condition

Slide 6

Myelomeningocele (MMC)

Open Neural Tube Defect

• Most common & severe CNS congenital anomaly
• Affects ~ 1500 fetuses in U.S. annually
• Severity varies depending on level of lesion
• Significant morbidity and mortality
• Life-long disabilities

Image: An illustrated image of an open neural tube defect on a fetus.

Slide 7

Complications

• Hydrocephalus
• Need for ventriculoperitoneal shunting
• Motor & cognitive impairments
• Bladder & bowel incontinence
• Social & emotional challenges

Images: A crying, newborn infant, a child walking with crutches, and a woman in a wheelchair are shown.

Slide 8

History of Trial
"NICHD Workshop: Current Scientific, Ethical & Clinical Considerations of Maternal-Fetal Surgery"

• Multidisciplinary workshop in July, 2000
• Examined the relevant issues
• Encouraged name of "maternal-fetal surgery"
• Myelomeningocele discussed
  • Clinically available
  • Limited follow-up
  • Unknown if outcome better

Slide 9

Human Fetal Myelomeningocele Repair

Images: Illustrated images of an open neural tube defect on a fetus, and of a fetus with a normally functioning neural tube are shown.

Slide 10

ACOG Committee Opinion

Maternal-fetal surgery for myelomeningocele should be evaluated in a multicenter RCT.

Images: The American College of Obstetricians and Gynecologists—Women's Health Care Physicians logo and the header image of I Number 252-2001 from the Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists—Women's Health Care Physicians are shown.

Slide 11

Why We Are Doing a Trial?

• Prior to 2002, data indicated some benefits regarding hindbrain herniation and shunting but:
  • No comparison group
  • Potential confounding
  • Potential risks to mom & baby
  • Short term data only
  • Incomplete follow-up

Slide 12

Development of MOMS Trial

Image: An illustration of a door with a red "X" on it.

• UCSF, CHOP, Vanderbilt held meetings
• Agreed to collaborate
• Other fetal surgery sites agreed to
  "no back door" policy
  • Cannot get maternal-fetal repair outside of the trial

Slide 13

Goal of the Trial

• To compare the safety and efficacy of in utero repair of open neural tube defects with that of the standard postnatal repair.

Slide 14

Primary Hypotheses

Midtrimester repair of fetal MMC compared with standard postnatal repair

• Reduces the risk of death or ventricular decompression shunting
• Results in an improvement in neurologic and neuromotor function

Slide 15

MOMS Primary Outcome
Dual Primary Outcome:

• Death, placement of or meeting criteria for ventricular shunt by age 1
• Composite of Bayley Scales of Infant Development MDI and motor function) assessed by independent team of examiners at 30 mos.

Slide 16

Basic Study Design

• Unmasked randomized trial
• Sample size 200
• Central screening
• Eligible and interested are assigned to a MOMS center
• Evaluated at MOMS center and if consenting, randomized
• Prenatal, postnatal repair & delivery at MOMS center
• 12 and 30 month follow-up

Slide 17

Reasons for Central Screening/Referral

• Consistent counseling
• Allows time to process information, consider options
• Consistent eligibility screening

Slide 18

Inclusion Criteria

• MMC starting at T1-S1 with evidence of hindbrain herniation
• Singleton pregnancy 19⁰ to 25⁶ weeks, normal karyotype
• U.S. resident
• Minimum 18 years old

Slide 19

Major Exclusion Criteria

• Increased risk for preterm delivery, e.g. prior spontaneous PTD
• Contraindication to surgery, e.g. previous classical cesarean or fetal surgery
• BMI ≥ 35

Slide 20

Screening at Clinical Site (2 days)

Image: A chart illustrates the process of screening at a clinical site:

• Travel & lodging arranged.
• Mother and support person.
• Paid by MOMS center.

Evaluation process

If requirements met, offered randomization.

• Comprehensive ultrasound
• MRI of fetus
• Fetal echocardiogram
• Psychological testing
• Meetings with evaluations team

• Fetal surgeon
• Neurosurgeon
• Nurse
• Neonatologist
• Social worker
• Anesthesiologist
• Perinatologist

Slide 21

Randomization to Neonatal Discharge

Image: A chart illustrates the following discharge process:

Moms and infants return to assigned center.

Prenatal group:

• Admitted to MOMS center
• In utero repair
• Remains near center until delivery
• Deliver by CD @ 37wks if undelivered

Postnatal group:

• Return home
• Return at 37wks to MOMS center for delivery by CD
• Postnatal closure within 48h

Slide 22

Human Fetal Myelomeningocele Repair

Image: Doctors engaged in a Human Fetal Myelomeningocele Repair operation are shown.

Slide 23

MOMS Follow-up

Image: A chart illustrates the MOMS Follow-up process:

Moms and infants return to assigned center.

12 months:

• Neurologic Exam
• Developmental Testing
• Urodynamics
• MRI of head & spine
• Spine x-ray

30 months:

• Neurologic Exam
• Developmental Testing
• Urodynamics

Slide 24

Primary Outcome Measure 1

• Need for ventricular decompressive shunting at 12 months defined by objective criteria
  • If shunt placed without meeting criteria, qualifies as primary outcome
  • Important for neurosurgeons to use criteria
• Independent committee of neurosurgeons, blinded to treatment assignment, determines whether criteria have been met

Slide 25

Primary Outcome Measure 2

• Composite score from the Bayley Scales of Infant Development MDI and the difference between the motor level and lesion level
  • Evaluated by independent examiners blinded to treatment assignment
  • Videotapes of physical exams reviewed by independent expert

Slide 26

Why Independent Review Committees/Examiners?

• Primary outcome 1 and urology both practice dependent
• Unmasked trial; therefore susceptible to bias (investigator, ascertainment)
• Ensure consistent outcome determination across centers

Slide 27

Data and Safety Monitoring Committee (DSMC)

• Appointed by NIH; no conflict of interest
• Multidisciplinary (Biostatistics, Epidemiology, Maternal-Fetal Medicine, Neonatology, Pediatrics, Neurosurgery, Urology, Ethics, Layperson)
• Reviews interim data and has the authority to recommend stopping trial:
  • Evidence of benefit
  • Evidence of harm
  • Futility
  • External influences and events

Slide 28

MOMS Status (9/7/2010)

• 1510 central contacts
• 1049 screened
  • 533 met exclusion criteria
  • 230 decided not to participate
  • 293 eligible & referred
• 178 randomized

Slide 29

Exclusion: Central Screening

Image: A bar chart shows the following statistics:

• Not spina bifida: 7%
• Non-U.S. resident: 10%
• Lesion <S1: 5%
• No ACM: 3%
• Fetal anomaly: 5%
• BMI ≥ 35: 20%
• prev sPTD: 7%
• Contraind to surg: 9%

(n=533)

Slide 30

Reasons for Non-participation

Image: A bar chart shows the following statistics:

• Risks too great: 27%
• Decided to terminate: 24%
• Travel/Follow-up/Finances: 25%
• Refused amnio: 4%
• Refused randomization: 3%
• Unknown: 17%

(n=230)

Slide 31

Screening & Enrollment

Image: A bar chart shows quarterly screening & enrollment statistics from the first quarter of 2003 to the third quarter of 2010. The numbers are at their lowest at the beginning and end of the chart: 24 in the first quarter of 2003 and 20 in the the third quarter of 2010. Between these two quarters, the numbers are mostly between 40 and 55, with the highest number being 62 at the third quarter of 2007.

Note: First patient randomized 3/6/03.

Slide 32

Randomization by Month

Image: A line graph shows the expected and actual number of participants from March 2003 to July 2010 at 4-month intervals. The Expected line rises sharply from just above 0 in March 2003 to 200 in July 2004 and remains at 200. The Actual line rises steadily from month to month, beginning at 0 and ending at 175 by July 2010.

Slide 33

Follow-up Visits

99% 30-month follow-up visits to date (n=129)

Slide 34

MOMS Publicity 2010

• Mass mailings—1,500 pieces
• Mass E-mails—4 (SMFM, NSGC, SBA Parents & Providers)
• Advertisements—2 (Green journal, Google)
• Meetings/Speaking engagements—21
• Association newsletters—16
• Links to Web site—10

Slide 35

Summary

• Challenging trial
• Slow recruitment
• Excellent follow-up
• No "back door" policy crucial
  • NAFTnet (North American Fetal Therapy Network) endorsed