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Background Analysis: US HHS Advisory Committee to Vote on Adding Newborn Screening for Spinal Muscular Atrophy to the Recommended Uniform Screening Panel; Will Discuss Additional Topics Related to Newborn Screening – FEB 8, 2018 (ACHDNC)


The US Department of Health and Human Services (HHS) has scheduled an Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) meeting for Thursday, February 8, 2018. The meeting will address several topics related to heritable disorders and newborn screening.


The Agenda involves the following topics:

·      Final evidence review and expected vote on whether to recommend adding spinal muscular atrophy (SMA) to the Recommended Uniform Screening Panel (RUSP);

·      States’ activities to achieve newborn screening (NBS) timeliness goals;

·      Cutoff determinations and risk assessment methods for dried bloodspot NBS; and

·      Workgroup updates.

Background - Recommended Uniform Screening Panel

Newborn screening involves the testing of every newborn for certain conditions, such as hearing loss and certain genetic, endocrine, and metabolic disorders that may not be apparent at birth. It is a State-based public health system that includes education, screening, diagnostic follow-up, and treatment. More than 98% of newborns in the United States are screened annually.

In 2006, the American College of Medical Genetics (ACMG) and the Health Resources and Services Administration (HRSA) brought experts together to provide advice on the standardization of the list of disorders for newborn screening. They recommended a uniform screening panel of 29 core/primary conditions to be included in state newborn screening panels: 20 inborn errors of metabolism, three hemoglobinopathies, and six other conditions. This panel was endorsed by ACHDNC and designated by the Secretary of HHS as a national standard for newborn screening programs. It is now known as the Recommended Uniform Screening Panel (RUSP). Since 2006, other disorders have been added to the RUSP.

The RUSP is recommended by the Secretary of HHS for States to screen as part of their State universal newborn screening (NBS) programs. It is recommended that every newborn be screened for all disorders on the RUSP. In practice, most states screen for the majority of disorders on the RUSP, and some states also screen for additional disorders.

Nominations of additional conditions for inclusion in the uniform panel can come from individuals and organizations with expertise on the nominated condition. ACHDNC reviews the nominations, following a systematic, evidence-based protocol. The overarching criteria are: there is a potential benefit of routinely screening all newborn babies for the disorder; public health laboratories have the ability to perform the test for the disorder; and there is the availability of effective treatments for the disorder. The ACHDNC provides recommendations to the Secretary of HHS, who makes the final determination on additions of disorders to the RUSP.

Background - Spinal Muscular Atrophy

At the upcoming meeting, the Committee will review and vote on whether to recommend adding SMA to the RUSP. SMA has been undergoing an evidence review process that started in May 2017. The process is a nine month process that is expected to conclude with the vote at the upcoming meeting.

As mentioned previously, the evidence review process started in May 2017. At the May 11-12, 2017 ACHDNC meeting Beth Tarini, MD, MS, a member of the ACHDNC’s Nomination and Prioritization Workgroup, presented on the condition, which was nominated for the RUSP by Cure SMA and cosponsored by the Muscular Dystrophy Association (MDA) and the SMA NBS Working Group. The SMA NBS Workgroup recommended the addition of SMA to the RUSP, focusing on SMA type I.

There are 5 SMA types (0, I, II, III, and IV). The types range in severity from type 0, in which individuals rarely survive past 6 months of age, type I, with a median life expectancy of 24 months, through types III and IV, which have some impairment but normal life expectancies.  SMA has an autosomal recessive inheritance and an incidence of 1 in 10,000 births. The Working Group based their recommendation on the following criteria:

·      The condition is medically serious, its definition and spectrum is well-described, and individuals with SMA are readily identifiable.

·      There is data from pilot SMA screening programs in New York and Taiwan.

·      The screening systems in both pilot programs have low (5%) false negative rates; however, there is no detection of compound heterozygous cases.

·      There is a widely-available confirmatory diagnostic process, described by Wang etal, J Child Neurol. 2007 Aug;22(8):1027-49, with a decision tree that utilizes clinical findings, gene sequencing data, and biopsies.

·      There are defined treatment protocols, including pulmonary, gastrointestinal, and orthopedic care. In addition, the first drug in the US for SMA, Spinraza (nusinerin), was approved by the FDA in December 2016.

There was a motion to approve SMA for evidence review, the next step toward placing the condition on the RUSP. All of the voting Committee members voted Yes, with 4 other members recused from voting.

At the August 3-4, 2017 ACHDNC meeting, Alex Kemper, MD, MPH, MS, leader of the Evidence-based Review Group, presented the group’s report on Phase 1 of the evidence review for SMA to be added to the RUSP. Dr. Kemper reminded the Committee that there are three phases to the evidence review, with phase 2 findings to be presented at the November 8-9, 2017 ACHDNC meeting; and the final report to be presented at the February 8-9, 2018 ACHDNC meeting. He listed the key topic areas that guide the evidence review as: epidemiology, clinical detection and usual care; screening; confirmatory testing and diagnosis; benefits and harms of screening and diagnosis; treatment and long-term follow-up care; treatment outcomes; benefits and harms of treatment and long-term follow-up; and impact on public health and healthcare systems.

Dr. Kemper reviewed the status of NBS for SMA, describing the pilot screening for SMA in three New York City (NYC) hospitals. In addition, he noted that the State legislature in Missouri has approved an SMA pilot, and three other States (Massachusetts, North Carolina, and Wisconsin) are considering SMA screening or pilots. He also noted that the Centers for Disease Control and Prevention (CDC) is developing quality assurance/quality control and proficiency testing materials for SMA. The NYC pilot, sponsored by Biogen, Inc., uses a recruiter to approach new mothers to consent to the screening; 93% have agreed to participate. The pilot uses first- and second-tier screening methods, plus confirmatory testing by a New York State laboratory. The pilot results show low false-positive rates, uncertain false-negatives, high carrier rates, and high scalability for the screening.

Dr. Kemper explained that the next steps in the SMA evidence review (Phase 2) would be to convene the technical expert panel. The panel will complete the systematic evidence review, develop the decision analysis structure, and assess the impact on the public health system, including the effect on States’ screening resources.

At the ACHDNC meeting on November 8-9, 2017, Dr. Kemper provided the Committee with the progress on the SMA Evidence Review. To that date, they had surveyed the literature regarding SMA (focusing on Type 1, or most severe, SMA), examined the screening and confirmatory tests for diagnosis of SMA, and examined the results of treatment options, including FDA-approved nusinersen. The remaining steps would be to develop estimates for the modeling parameters, reconvene the SMA Technical Expert Panel to review the parameter results, and gather estimates of cost of the program.

Background - State Timeliness

At the upcoming meeting, the Committee will hear presentations on States’ activities to achieve NBS timeliness goals. The ACHDNC’s recommended goals for timeliness are listed below.

·      Presumptive positive results for time-critical conditions should be communicated immediately to the newborn’s healthcare provider, but no later than five days of life.

·      Presumptive positive results for all other conditions should be communicated to the newborn’s healthcare provider as soon as possible, but no later than seven days of life.

·      All NBS tests should be completed within seven days of life, with results reported to the healthcare provider as soon as possible.

·      In order to achieve these goals, initial NBS specimens should be collected in the appropriate time frame for the newborn’s condition, but no later than 48 hours after birth; and

·      NBS specimens should be received at the laboratory as soon as possible, ideally within 24 hours of collection.

Background – Dried Bloodspot Screening

Some States vary in the levels and methods they use to determine cut-offs for distinguishing between normal and out-of-range test results. At the upcoming meeting, the ACHDNC will be presented with a review of cutoff determinations and risk assessment methods for dried bloodspot newborn screening. Following this review, the Committee will vote on whether to support the development of a guidance document on this topic.

Workgroup Updates

At the upcoming meeting, the Committee will hear workgroup updates from the Laboratory Standards and Procedures workgroup; the Follow-up and Treatment workgroup, including a presentation of the final draft of a report on Quality Measures in Newborn Screening; and the Education and Training workgroup, including a presentation of the final draft of a Communication Guide for relaying NBS results.

 What’s Next?

Tarius will send a Results Wire soon after the meeting. This report will include the voting outcomes, if applicable, and key outcomes of the discussion.

METADATA: Sponsor: none Drug Name: none Drug Class: none Indication: none

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DISCLAIMER: The information in this document is for informational purposes only. The SAC Tracker Background Analysis contains information from publicly available sources, including FDA, sponsor, scientific, and clinical websites. Tarius A/S assumes no liability for any inaccurate or incomplete information, or for any actions taken in reliance thereon. © Tarius A/S. All rights reserved.