Evidence Review Workgroup Advisory Committee on Heritable Disorders in Newborns and Children Report November 2008

1. Evidence Review WorkgroupAdvisory Committee on Heritable Disorders in Newborns and ChildrenReport November 2008 James M. Perrin, MD Professor of Pediatrics, Harvard Medical School Director, MGH Center for Child and Adolescent Health Policy

2. Current Progress and Activities • Pompe Disease – Final report submitted • SCID – Discussion today • Krabbe Disease – Review in process

3. Key authors: Ellen Lipstein, MD Alix Knapp, MS Program director: James M. Perrin, MD Staff: Marsha Browning, MD, MPH Alex R. Kemper, MD, MPH, MS Nancy Green, MD Lisa Prosser, PhD Denise Queally, JD Jennifer DeZarn, BA Sienna Vorono, BA SCID Report

4. Severe Combined Immunodeficiency (SCID) • Group of disorders characterized by absence of both humoral and cellular immunity • Severe defect in T cell production and function, with additional defects in B-lymphocytes and/or NK cells depending on the mutated gene • At least 15 genes cause SCID when mutated • As protection from maternal antibodies wanes, infants with SCID develop infections due to both common and opportunistic pathogens

5. Rationale for Review • Without treatment SCID leads to death in early childhood • Earlier treatment, particularly before the onset of lung infection, may decrease mortality and morbidity associated with SCID and with treatment • Methods to screen infants for SCID using quantitative PCR for T-cell receptor excision circles (TREC) have been developed

6. Methods of Review • Systematic literature review, summarizing the evidence available from published studies • Assessment of critical unpublished data and data presented at meetings from key investigators

7. Key Review Questions • Incidence/prevalence • Natural history • Timing of clinical onset • Severity of disease and variations • Genotype/phenotype • Screening • Methods of screening • Accuracy of screening; sensitivity/specificity • Methods of diagnosis • Risks and costs

8. Key Review Questions II • Treatment • Methods • Does treatment help? • Does early treatment help? • Availability • Risks and costs • Critical information still needed

9. Materials Provided/Available • Draft review summary • Evidence table/abstracted articles • Bibliography of all identified articles • List of interviewees

10. Systematic Review • January 1988- October 2008: Medline, OVID In-Process and Other Non-Indexed Citations database • English language only • Human studies only • Eliminated: non-human data, reviews, editorials or other opinion pieces, case-series of <4 patients, only contained adult subjects or not addressing one or more of the key questions • References also from nomination form, reviews • 725 abstracts selected for initial review • 60 articles selected for review and abstraction • Quality assessment directed toward study design

11. Papers Meeting Review Criteria *Epidemiologic studies using retrospective record review (Jones et al. 1991) and telephone survey (Boyle & Buckley, 2007)

12. Additional Expert Communication • Determined by literature review, discussion with genetic experts • Included experts representing all major issues related to SCID

13. Experts Contacted • Mei Baker - Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin; Newborn Screening Program, Wisconsin State Laboratory of Hygiene • Tony (Francisco) Bonilla- Harvard Medical School and Children’s Hospital, Boston, Mass • Rebecca Buckley -Duke University Medical Center, Durham, North Carolina • Anne Comeau -Deputy Director New England Newborn Screening Program University of Massachusetts • Lisa Filipovich -Cincinnati Children's Hospital Medical Center • Alain Fischer -Pediatric Immunology Department and the INSERM Research Unit • Alan P. Knutsen -Pediatric Clinical Immunology Laboratory, St Louis University Health Sciences Center • Ronald Laessig -Population Health Sciences and Pathology, University of Wisconsin • Edward McCabe -Clinical Biochemical Genetics, Department of Pediatrics, Mattel Children’s Hospital at UCLA • Sean McGhee -Division of Pediatric Immunology, David Geffen School of Medicine at UCLA • Luigi Notarangelo -Division of Immunology, Children's Hospital Boston, Harvard Medical School • Hans Ochs -Pediatrics and Immunology, University of Washington • Sung-Yun Pai - Harvard Medical School and Children’s Hospital, Boston, Mass • Ken Pass -Molecular Medicine, New York State Department of Health, Albany, New York • Jennifer Puck -Department of Pediatrics, Institute for Human Genetics University of California, San Francisco • Robert Vogt -Centers for Disease Control and Prevention, Newborn Screening Quality Assurance Program, Atlanta, Georgia

14. Incidence • Chan/Puck 2005 • 1:105,000 live births • Extrapolation from XSCID samples sent to single lab • Stephan et al., 1993 • 1:100,000 live births • Based on 5 years of referrals to specialized units in France • Jones et al., 1991 • 52/100,000 births in Navajo families

15. Quality Assessment of Abstracted Natural History Literature Adapted from Pandor et al. 2004, Pollitt et al. 1997

16. Natural History • Except for children diagnosed early in life, because of affected sibling, most children are diagnosed after recurrent (pulmonary) infections • All SCID subtypes exhibit infection with opportunistic organisms, although timing of onset may vary • Without treatment of underlying immunodeficiency, children with SCID die in early childhood from infection • Known phenotype/genotype differences do not affect main findings related to infection and death

17. Quality Assessment of Abstracted Screening Test Characteristic Literature Adapted from Pandor et al. 2004, Pollitt et al. 1997

18. Main Screening Methods • Whole blood lymphocyte counts • Quantitative polymerase chain reaction • Enzyme-linked immunosorbent assay (ELISA) of dried blood spots

19. Accuracy of Screen; Sens/Spec. Study Population Screening Methods Screening Test *Calculation stated in article ^Our calculation using data provided in article

20. Wisconsin Screening Experience Courtesy of Dr. Mei Baker, presented at the Newborn Screening Symposium, November 2008

21. Treatment Methods • Over the last twenty years, three modes of treatment for SCID have been investigated: • Allogeneic hematopoietic stem cell transplant (HSCT) including bone marrow transplant (BMT) • Enzyme replacement therapy (ERT) for some patients with ADA-deficient SCID • Small trials of gene therapy

22. Quality Assessment of Abstracted Treatment Literature Adapted from Pandor et al. 2004, Pollitt et al. 1997

23. Quality of Evidence Study Population Significant Findings Does Treatment for SCID Help? • Efficacy of HSCT over time: Large case-series * Potential patient overlap with Stephan et al. 1993 and van Leeuwen et al. 1994

24. Quality of Evidence Study Population Significant Findings Does Treatment for SCID Help? • Survival after HSCT: Long-term follow-up

25. Quality of Evidence Study Population Significant Findings Does Treatment for SCID Help? • Additional Long-term follow-up studies

26. Quality of Evidence Study Population Significant Findings Does Early Treatment Help? • Efficacy of HSCT in neonates/infants * Potential patient overlap of Myers et al. 2002, Buckley et al. 1999

27. Early Treatment for SCID • 161 SCID infants transplanted over the past 26 years, overall survival rate of 125/161 (78%) Graph 1B. Transplanted after First 3.5 Months of Life Graph 1A. Transplanted in First 3.5 Months of Life Percent Surviving survival rate 96% survival rate 71% Years Post-Transplantation Years Post-Transplantation The Kaplan-Meier graphs from Dr. Buckley (with permission)

28. Treatment for SCID: Availability • From SCID expert interviews: • Dr. Buckley reports there are fifteen major and 34 minor centers in the U.S. and Canada currently performing stem cell transplantation for SCID. • Dr. Notarangelo, Bonilla, and Pai stated that an informal survey performed under the auspices of the NIAID/Rare Diseases workshop identified 34 centers in the United States and Canada that currently perform HCT for SCID

29. Harms and Cost-effectiveness • Screening and Diagnosis • No studies identified • Diagnosis • None identified • Treatment (2 studies) • 8/41 children undergoing HSCT developed auto-immune hemolytic anemia; 3 died from complications • 4 children (of the 9/10 who had successful gene therapy) developed leukemia between 30 and 68 months after gene therapy. 3/4 were successfully treated with chemotherapy and regained poly-clonal T-cell populations • Cost-effectiveness (1 study) • Using a deterministic decision-tree model, comparing universal and targeted screening approaches, the authors assessed the thresholds at which screening would be cost-effective from a health care system perspective. Study reported, at a threshold of $100,000 per quality adjusted life year, an 86% likelihood of screening being cost-effective

30. Summary • Key findings: • SCID affects at least 1/100,000 newborns in the US • Several population-based screening trials are underway (Wisconsin) or planned; to date no population-based screening trial has been completed • Without curative treatment, newborns develop severe, often opportunistic, infections which lead to early death • Treatment, most commonly with hematopoietic stem cell transplant, decreases morbidity and mortality associated with SCID • Some evidence supports the notion that earlier treatment may lead to better outcomes

31. Critical Needed Information • Prevalence of SCID • A systematic method of case finding is needed in order to determine prevalence accurately. The new consortium of treatment centers (USIDNET) may serve as a method of more systematic case-finding. • Accuracy of Screening • Initial pilot screening data from Wisconsin suggest that a relatively low false-positive rate. However, current data are limited. • Data regarding the accuracy of other screening methods in population-based protocols, are not available • Feasibility of Screening • Wisconsin’s experience provides at least pilot data re feasibility. Data are needed regarding the ability of other newborn screening laboratories to offer SCID screening

32. Critical Needed Information • Acceptability of Screening • No data describe consumer or physician acceptance of newborn screening for SCID • Is the evidence for early treatment enough? • Cost-effectiveness (of screening and treatment) • Cost-effectiveness analyses utilizing measured costs and utilities, as well as applicable sensitivity analyses, are needed • Adequacy of available treatment centers • No current data address variation in treatment success among centers or the number of centers in the United States and their capacity to provide treatment for SCID. Data from USIDNET and CIBMTR may, in the future, provide evidence on this topic

33. Thank you