Kristi Watterberg, MDProfessor and Chief, Division of Neonatology
Vice-chair, Department of Pediatrics
Progress through collaboration: the story of the Neonatal
Research Network
Why do we need a Neonatal Network?
Preterm and critically ill newborns are a relatively small population in each NICUIn 2007, 54 – 180 infants/network center <1000g BW~1700 in the whole network
Answering questions takes a large populationStarted in 1986 by NICHD with 8 centers, now
16Purpose: to conduct multi-center clinical trials
and observational studies in neonatal medicine to decrease morbidity and mortality & promote healthy outcomes
PublicationsDoing the job right takes a lot of money and a lo-o-ong time!
Neonatal Research NetworkProtocol Development Process
Concept Stage
Approved by NICHD
Submit Concept title to NICHD (due at least 4-5 weeks
prior to Steering Committee Meeting)
Submit 2-5 page Concept overview for SC review (3 weeks prior to meeting)
Present at SC meeting(20-minute presentation, 40-minute discussion)
Steering Committee vote(by secret ballot)
Approved by ⅔ majority (11/16 sites)
Rejected (½- ⅔ vote)
Submit full protocol to Protocol Review Subcommittee (due within 6 months)
Rejected (less than 50% vote)
Rejected
Approved by Subcommittee
Revisions Requested(due within 6 months)
Present to Steering Committee(20-30 min. presentation, 30-40 min. discussion)
Steering Committee members present protocol to their site faculty and staff
Steering Committee vote within 6 weeks(by secret ballot)
Approved by ⅔ majority (11/16 sites)
Revisions Requested
Rejected
Development Stage Develop full protocol(form working group if needed)
Can revise and resubmit
Reviewed by outside advisory board and DSMCRevisions Requested
Steering Committee budget vote(by secret ballot as funds become available)
Prioritized forImplementation
Not Prioritized
Protocol Stage
Rejected
Subcommittee reports to SC on protocols in development and any
rejections
Stanford, Utah, New Mexico, UT-Dallas, UT-Houston, Iowa, Indiana, U Alabama Birmingham, Wayne State U, Case Western Reserve, Cincinnati, Duke, Tufts, Brown, Yale
Why do we need large RCTs?Reports of small studies often show positive
results –why?Negative studies often aren’t reportedReports of negative studies are much more often
rejected by journals – not exciting, harder to ‘prove a negative’
Therefore, early, small reports of new therapies or techniques are usually positive
Side effects often not seen in small studiesE.g., if an SAE is 1 vs. 2 in a 40 infant trial – is
that going to be 50 vs. 100 in a 1000 patient trial? Or 99 vs. 100?
The life cycle of a new therapy
Good
Bad
NEW!
Side effectsBen
efit
- R
isk
Multicenter trial results
Generic Data Base: detailed information on a large prospective cohort of VLBW infants Morbidities, mortality, outcomes at 18 – 22 monthsFactors associated with adverse outcomes, such as
BPD, NEC, postnatal steroidsChanges over time
Early onset sepsis – surveillance of pathogensEarly diagnosis of candidal sepsisGrowth of VLBW infantsOutcomes of infants born at the border of
viability
Contributions of the NRN: (1) Observational studies
Benefits of the Network (2): RCTs that stopped ineffective/harmful therapies
IVIG to prevent nosocomial infection – no benefit
Fanaroff, NEJM 1994
Indomethacin prophylaxis for improved neurodevelopment – no benefit
Schmidt, NEJM 2001
Glutamine supplementation in TPN – no benefit
Poindexter, Pediatrics 2004
iNO for preterm infants: no early or long term benefit
Van Meurs, NEJM 2005; Hintz, J Pediatr 2007
Etc…..
Benefits of the Network (3): RCTs that showed a positive effect of intervention
iNO for term/late preterm infants with PPHN – death or ECMO
NINOS study group, NEJM 1997
Vitamin A to reduce BPD - oxygen at 36 weeks Tyson, NEJM 1999
Hypothermia for hypoxic-ischemic encephalopathy - death or disability at 2 years
Shankaran, NEJM 2005
CPAP instead of intubation/surfactant in the delivery room
Finer, NEJM 2010
Etc…
NRN member 1991 – 2001 (Papile PI)Dexamethasone: early vs. late Rx for
extubationFaster extubation with early DEX, but no
difference in median time to extubationMore adverse effects in early DEX group
Papile, NEJM 1998
Erythropoietin: effects of EPO on transfusions in preterm infants
Epo Hct, but didn’t transfusions or improve long term outcomes
Ohls, Pediatrics 2001
Studies from New Mexico – (1st time)
2006 – 2011 (Watterberg PI)
Ongoing/completed:Hypotension in critically ill term and late preterm
infants – Phase I, observational study (Fernandez)Ancillary – effect of ethnicity/race on cognitive
and language testing at 18 – 22 months (Duncan/Lowe)
Ancillary – object permanence (Lowe/Duncan)In the pipeline:
RCT of hydrocortisone for extubation (Watterberg)Hydrocortisone for hypotension in term/late
preterm infants – Phase II, RCT (Fernandez – concept to be presented next month)
Studies from New Mexico (2nd time)
So in summary….The Neonatal Research Network has
contributedunique observational dataand important randomized trials to the neonatal
communityFulfilling its ongoing mission of decreasing
morbidity and mortality & promoting healthy outcomes in newborn infants
We’re proud to be a part of this vital endeavor!
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