Early Check: A Collaborative Innovation to Facilitate Pre-Symptomatic Clinical Trials in Newborns

简要总结

详细描述

"Background" Newborn screening (NBS) is a state-based public health program that screens babies for a panel of over 30 conditions. It is estimated that about 12,500 newborns each year in the United States are identified with one of the conditions screened in NBS, with each child receiving the benefit of early treatment. For inclusion in newborn screening there must be evidence that pre-symptomatic treatment is more effective than treatment after clinical presentation. Most conditions proposed for newborn screening are rare, however, and researchers have difficulty identifying sufficient numbers of babies to test the benefits of pre-symptomatic identification and treatment. This lack of data is central to challenges that the U.S. Department of Health and Human Services Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC) faces when making federal recommendations to states on which conditions should be included in newborn screening programs. ACHDNC is often asked to consider conditions for inclusion in newborn screening for which there is limited evidence of the natural history, prevalence, and especially about the benefit of early treatment. "Rationale" That evidence gap, especially in the rare disease context, makes it important to develop and test a system to efficiently generate high-quality data about conditions that have the potential to be candidates for state newborn screening. The Early Check program will address this gap through screening newborns for a carefully selected panel of conditions, offered under a research protocol with biological maternal permission, except in cases where there is a transfer or loss of custody. In cases with a transfer/loss of custody, a legal guardian can grant permission for the infant to join Early Check. Early Check will identify pre-symptomatic infants with rare disorders, accelerate the acquisition of data on the early natural history of rare disorders, and demonstrate the feasibility of a statewide program to offer voluntary opt-in newborn screening for a panel of conditions not currently included in states' standard newborn screening. Further, Early Check will facilitate the public health 'on-boarding' of conditions that are ultimately recommended for state newborn screening programs. The initial panel of conditions screened in the Early Check program will change over the course of the study. Previously screened conditions have included spinal muscular dystrophy (SMA), fragile X syndrome (FXS), and Duchenne muscular dystrophy (DMD) and related neuromuscular conditions that result in increased levels of creatine kinase (CK-MM). SMA has an approved treatment, nusinersen, which has been demonstrated to improve outcomes in infants with infantile-onset SMA. In addition, infants with a shorter disease duration compared to a longer disease duration had improved outcomes after the start of treatment with nusinersen, suggesting that earlier identification of SMA would benefit affected infants. There is also an approved gene therapy, Zolgensma, for SMA. FXS does not have an approved treatment, although there is evidence that early behavioral intervention services may improve outcomes. Given that the diagnosis of FXS is made on average after the child is three years old, early identification through the screening of newborns may provide benefit to the child. These conditions are rare; SMA has an estimated incidence of 1 in \~10,000, DMD has an estimated incidence of 1 in 4000-5000 males, and FXS has an estimated incidence of 1 in \~4,000 males and 1 in \~4,000-6,000 females. We also completed a sub-study with a secondary permission process that offers mothers the choice to obtain additional data about the gene that causes FXS: specifically, whether the infant has a premutation in the gene, which has an uncertain impact on the infant's learning and development. This uncertainty is the reason why premutation results are offered separately under a sub-study. DMD causes progressive inflammation, fibrosis, and muscle fiber degradation, and weakness. DMD has traditionally been treated with physical therapy, corticosteroids, and ACE inhibitors to delay the progression of skeletal muscle and cardiac damage. In 2016, the FDA approved Eteplirsen (Exondys, 51) a promising treatment for a subset of patients with DMD. In 2017 the FDA approved Emflaza, a corticosteroid also known as deflazacort. In 2019 the FDA approved Vyondys 53 and in 2020 the FDA approved Viltepso for mutations amenable to exon 53 skipping. Early diagnosis allows for treatments that might work best if used presymptomatically. The current screening panel includes 182 genes for rare conditions that are highly actionable by age 2. An optional secondary panel includes 32 genes that are less actionable, or for which there are treatments under trial, with an additional optional third panel that screens for genetic risk for Type 1 Diabetes. For a wide range of rare disorders there is evidence that a delayed diagnosis (i.e., the frequently-described diagnostic odyssey as parents search for a diagnosis) can have negative health outcomes on children who miss out on treatments or interventions and on families who experience negative psychosocial impact In the future, Early Check will continue to integrate new conditions to the screening platform as science advances and funding is secured, and conditions may be removed from the screening platform as associated research questions are answered and/or conditions achieve inclusion in state newborn screening programs (as was the case with SMA and FXS). The overall research question is whether Early Check is an effective onboarding program to inform newborn screening policy decision-making. Early Check will also provide the infrastructure to facilitate translational research studies and clinical trials. A dilemma in research in rare diseases is a lack of sufficient numbers of presymptomatic patients. New treatments are being developed for rare diseases at a rapid pace. Presymptomatic treatment often has the best potential for effective treatment. Currently, early identification and intervention is based on the prenatal or early diagnosis of a sibling of a patient with known disease, which greatly limits the numbers of presymptomatic patients available for trials. Newborn screening has the greatest potential to identify presymptomatic infants. Ultimately the research program should more rapidly advance understanding of diseases and treatments, reducing the length of time for appropriate conditions to be added to the recommended panel for inclusion in state newborn screening programs, and provide early identification of affected newborns. Overall, this project will provide important information about the success of Early Check to feasibly and acceptably implement a large scale, electronically-mediated research approach to accurately identify affected infants. Results of the research activities and the ongoing quality assessment will be used to inform the most efficient and judicious translation of expanded newborn screening into public health in ways that maximize benefit and minimize potential risk of harm to children and families.

主要结局

次要结局

• Impact of Screening: Semi-structured parent interviews.(Measured within 6 months of participant screening results)