Pilot NBS project to prospectively identify

and follow infants with SMA

Kathryn Swoboda, Marci Sontag,

Jeff Botkin, Steve Dobrowolski,

NBSTRN: Amy Hoffman and the

Bioethics Work Group, Amy Brower

and the Clinical Centers Workgroup

SPINAL MUSCULAR ATROPHY (SMA)

• Most common recessive cause of infant lethality

• Incidence 1 in 6,000-10,000 births

• Motor neuron degeneration results in progressive

muscular atrophy, weakness, bulbar insufficiency and

premature death in majority of those affected

• Natural history study data suggest that early

intervention necessary to improve outcomes for the

severe infantile phenotype (50% of cases)

SMA Genetics

• SMN1 and SMN2 reside in an inverted

duplicated region on chromosome 5q13

• Critical bp change in exon 7 alters splicing, resulting

in truncated protein deleted for that exon

• But 10% fl product from SMN2 identical to that from

SMN1

• 95% of SMA subjects have a homozygous

deletion of exon 7 in SMN1

SMN2 dosage predicts phenotype

From Utah SMA Natural History Database

N=301

SMA type I accounts for 50% of cases

•Infantile onset

•Respiratory and bulbar

insufficiency

•Generalized weakness,

hypotonia

•Premature death in majority

by age 2 yrs

SMA type II accounts for 20-30%

•Significant respiratory morbidity,

scoliosis, hip dislocation, joint

and muscle contractures, early

mortality

Conceptual Framework: NBS in SMA • Pilot data from STOP SMA study suggests

early vs later intervention may substantially

improve outcomes

• Evidence-based process may not be adequate

to prove efficacy first due to early and severe

disease progression

• Early screening provides opportunity to assess

hypothesis that early identification will

improve outcomes with emerging new

therapies

“Real time” DNA-based NBS pilot for SMA in Utah and Colorado

• Births: 55,000/yr in Utah, 70,000/yr Colorado

– Subset of infants will be screened, due to challenges with

acceptance of DOH programs with an opt-out process, in

spite of broad public support in both states

• Goal: confirmation of diagnosis within three days of

obtaining newborn spot, first face to face contact

within 3 weeks of birth

• Prospective followup of infants with data entered

onto CRFs on forms designed in collaboration with

NBSTRN LTFU workgroup

Background – SMA Pilot in Colorado

• Initial pilot study was planned to be implemented through Department of Health using newborn screening dried blood spots – Approval was obtained through Colorado Multiple

Institutional Review Board (COMIRB) at University of Colorado

• After 2 years of discussion it was decided that there were challenges that would not allow the study to proceed through the Department of Health

Background – SMA Pilot in UT

• Initial plan to implement pilot though the Utah Department of Health using dried blood spots using an opt-out consent model

– Initial IRB approval by University of Utah

• However, in spite of broad population support, DOH IRB rejected this proposal

• Ultimately, after extensive discussion, IRB approved by DOH using opt-in consent model

Revised Plan- Colorado

• Infants will be screened with a separate dried blood spot, following state mandated NBS

• Sample will be sent to ARUP through research coordinators at the Colorado School of Public Health (CSPH)

– Coordinators will initially pick up samples personally. Later samples will be shipped to CSPH for logging and tracking before shipping to ARUP

Revised Plan- Utah • Infants will be screened using residual sample

from state-mandated NBS, but only following a witnessed opt-in consent documented directly on the card prior to collection

• Sample will be sent to the UTAH DOH laboratory, then deidentified prior to sending to ARUP for screening using the wave-melt technology

• Sample will be reidentified only if positive; investigators and DOH followup program will collaborate closely to contact families

Study Oversight and Consent

• Institutional Review Board Approval required through each major hospital system, therefore only larger systems are to be included

• Mothers provided brochure in hospital explaining study and opt-out procedures (CO)

• Mothers provided brochure in hospital and opt-in procedure (UT)

• Mother has 2 weeks from the time of baby’s birth to opt-out of participation

Opt-Out of Participation: CO

• Opt-out most closely matches the model used in Colorado for Newborn Screening

– Deemed to be minimal risk by COMIRB

– Full consent not feasible

• To opt-out, mother can:

– Call a toll free number

– Visit a secure website (REDCap database structure)

– Tell nurse at hospital (card will be marked as opt out for tracking purposes only)

Current status: CO

• IRB approval in place for hospitals covered by COMIRB (2 birthing hospitals, regional children’s hospital)

• IRB approval pending at largest birthing system – expected by June 2013

• Additional hospital systems are identified

• Training has occurred in first hospital and initial screening will begin in April 2013 – used as a pilot to streamline procedures

• Anticipate ~42,000 births/year to be eligible for screening (out of ~70,000 in state)

Current Status: UT

• IRB approval in place for the University of Utah

• Awaiting approval for other major hospital systems, expected to occur sequentially over next several months

• Anticipate maximum uptake ~ 35K births (as opposed to 55K had we been able to use an opt-out model

Critical Contributions from NBSTRN

• Provision of bloodspots via Michigan biobank (Steve Dobrowolski PI) to confirm performance of wave melt screening technology

• Referral and support for other newborn screening programs interested in collaboration (discussions ongoing with Wisconsin program)

• Support for design of CRFs for LTFU (now completed)

Acknowledgements • Funding source: NICHD

• Rodney Howell and Tiina Urv

• Steve Dobrowolski

• NBSTRN especially Amy Brower, Amy Hoffman, Mike Watson

• CHOP especially Jennifer Loutrel and Stacey Wrazien

• Colorado team, led by Marci Sontag

• University of Utah team, led by Kathryn Swoboda, Jeff Botkin

– THANK YOU FOR YOUR ATTENTION