Collaboration Education and Test Translation Program cettprogram Giovanna Spinella, MD

1. Collaboration Education andTest Translation Program Collaboration Education and Test Translation Program www.cettprogram.org Giovanna Spinella, MD Science and Program Consultant NIH ORD CETT Program Quality, Access, and Sustainability of Biochemical Genetic Testing Working Meeting Atlanta, October 6-7, 2006

2. Quality Testing Rare Genetic Diseases:Steering Committee • CDC • NIH-ORD • EMORY • HRSA • ASHG • ACMG • SIMD • Genetic Alliance

3. How We Started • May 19–21, 2004 Atlanta, GA http://www.phppo.cdc.gov/dls/genetics/RareDiseaseConf.aspx • March 17, 2005 ACMG Satellite • September 26–27, 2005 Washington, DC

4. CETT Program Objectives • Promote new genetic test development • Translate from research to clinical practice • Educate about each rare genetic disease; research opportunities & clinical impact • Collect and Store clinical and genetic information

5. CETT Program Philosophy All parties benefit when: • Quality of testing for rare disorders meets or exceeds existing standards • Clinical laboratories, researchers, clinicians, and disease specific advocacy groups collaborate • High-quality educational materials explain what the test can and cannot tell you and how best to use the test

6. CETT Program • First applications accepted Feb-March 2006 • Facilitated application process • Constructive feedback • Applications • Accepted monthly • Reviewed in 2 month cycle • Progress • September 2006 – 10 approved, 8 in queue

7. Applicants = Collaborative Group • Clinical (CLIA-certified) laboratory • Researcher (laboratory and/or clinician) • Disease specific advocacy group

8. The CETT/NCBI Partnership What can NCBI (National Center for Biotechnology Info) do for CETT Collaborative Groups? Help develop a useful data collection scheme Put data in a broader context to help advance knowledge about the disorder

9. Advocate Mentors • Group of disease specific advocate leaders • Resource to each collaborative group • Assigned early in the process

10. Review Process Staff reviews for completeness One month goal Review Board evaluates quality One month goal

11. Review Board • 15 Members • Three teams of five members, one each from: • Laboratory genetics • Medical genetics • Research • Primary care • Disease specific advocacy

12. Review Board • Vet guidelines by which applications are evaluated • Evaluates quality of each application • Provides constructive feedback for each application

13. Scientific Evidence • How many genes cause the disorder? • What percentage of patients have mutations in the gene for which testing is proposed? • What percent will be detected compared to current testing?

14. Proposed Methodology • Is the approach efficient & cost effective? • How will unusual results be evaluated? • If mutation screening is used, how will negative results be evaluated? • Are other methods of diagnosis available? Replace / compliment?

15. Impact on Healthcare • What are the indications for testing? • How will proposed test change current diagnostic pathway? • Could correct diagnosis reduce unnecessary diagnostic testing/facilitate genetic counseling? • Could early diagnosis reduce morbidity/ mortality?

16. Laboratory Qualifications • Director’s certification • CLIA or other certification • Number of disorders tested • Staffing for the clinical-laboratory interface: genetic counselors?, physician consultants?

17. Data Collection • Clinical information necessary for test result interpretation collected on a SHORT form at the time test is ordered • Subset of clinical and genotype information entered in publicly accessible database • Multiple pathways suggested

18. Educational Materials Provided for three audiences: Medical geneticists, non-geneticist clinicians, patients • Test ordering • Test result interpretation for negative, positive, or indeterminate results • Uses of testing in diagnosis, management, genetic counseling • Create a GeneReview (first year)

19. Evidence of Collaboration • All have active roles • Interviews by staff to clarify roles • Referral of patients by clinical lab to researcher • Disease specific advocacy group: • Ensures appropriateness/dissemination of educational materials • Is resource for patients and families

20. Funding/Commitment • Based on complexity of the test process • Does not include equipment or institutional costs (or cost of patient test) • Collaborative group provides feedback to CETT Program for 5 years (from when genetic test is put in public domain)

21. Potential Outcomes • Improve understanding of CLIA and quality standards • Improve dialogue among stakeholders: Clinical laboratories, reference laboratories, researchers, clinicians, disease specific advocates, oversight bodies, payers • Collect genotype/clinical information: -improve test interpretations -genotype/phenotype correlations

22. Program Staff ORD Program Director: Project Coordinator: Scientific Advisor: Review Board Coordinator: NCBI Liaison: Giovanna Spinella, MD Andrew Faucett, MS Suzanne Hart, PhD Roberta Pagon, MD Lisa Forman, PhD

23. Rare Diseases Approved for Translations Molecular Genetic Tests: • Cherubism (Toronto Sick Children) • Cornelia de Lange Syndrome (U Chicago) )**Clinically Available • Infantile Neuroaxonal Dystrophy (Oregon Health and Science U) • Joubert Syndrome (Prevention Genetics) • Kallman Syndrome (Gene DX) • Progressive Familial Intrahepatic Cholestasis (8 diseases/3 genes) (Baylor U-Mitochondrial Lab) • X-Linked Periventricular nodular heteroptopia (Harvard U)

24. Rare Diseases Approved for Translations (cont.) Multiple Methodology Approach to testing: • X-Linked Chondrodysplasia- molecular genetic testing in collaboration with biochemical genetic sterol analysis-clinical mass spectrometry (U Chicago) • Silver Russel Syndrome-methylation (quantitative Taqman) assay and molecular genetic testing (Emory U)

25. Experience of CETT Program to Date • Variability in Collaborative Group Composition: • Advocacy-spectrum from fully formed organizations to individuals willing to help • Research-spectrum from full compliment of research laboratory expertise and clinical expertise to predominance of one or the other • Approved International research collaboration and advocacy collaboration

26. Experience of CETT Program to Date (cont.) • Need for templates of educational materials for understanding genetic test and rare diseases for clinicians and individuals and families • Need for report forms to be interpretable to non genetic clinicians (example language) • Need for test results to be understandable and provide limitations of test

27. Experience of CETT Program to Date (cont.) • Laboratory Issues-molecular genetic testing: • clinical significance of variance of unknown significance (VOUS) • appropriate control samples for test validation • reasonable turn around time from test submission to providing test results • Informed consent issues regarding testing and in placing non identifiable data in public databases

28. Expanding CETT Program Approaches (to biochemical) • Modify current application form to accommodate non molecular genetic testing approaches and multiple approaches • Add biochemical scientific advisor to CETT Program staff • Expand Review Board expertise • Develop guidelines for quality control, quality assurance • Identify guidelines for cost of test development (where possible)

29. THANKS TO Office of Rare Diseases (ORD) Stephen Groft, Pharm D, Director National Institutes of Health www.cettprogram.org