Collaboration Education and

Test Translation Program

www.cettprogram.org

Giovanna Spinella, MDScience and Program Consultant

NIH ORD CETT ProgramQuality, Access, and Sustainability of Biochemical Genetic

Testing Working MeetingAtlanta, October 6-7, 2006

Collaboration Education andTest Translation Program

Quality Testing Rare Genetic Diseases:Steering Committee

CDC NIH-ORD EMORYHRSA

ASHGACMGSIMD Genetic Alliance

How We Started

May 19–21, 2004 Atlanta, GAhttp://www.phppo.cdc.gov/dls/genetics/RareDiseaseConf.aspx

March 17, 2005 ACMG Satellite

September 26–27, 2005 Washington, DC

CETT Program Objectives

Promote new genetic test development Translate from research to clinical practiceEducate about each rare genetic disease;

research opportunities & clinical impactCollect and Store clinical and genetic

information

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

CETT Program

First applications accepted Feb-March 2006Facilitated application process

• Constructive feedbackApplications

• Accepted monthly• Reviewed in 2 month cycle

Progress• September 2006 – 10 approved, 8 in

queue

Applicants = Collaborative Group

Clinical (CLIA-certified) laboratoryResearcher (laboratory and/or clinician)Disease specific advocacy group

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

The CETT/NCBI Partnership

Advocate Mentors

Group of disease specific advocate leadersResource to each collaborative groupAssigned early in the process

Review Process

Staff reviews for completenessOne month goal

Review Board evaluates qualityOne month goal

Review Board

15 MembersThree teams of five members, one each

from:• Laboratory genetics• Medical genetics• Research • Primary care• Disease specific advocacy

Review Board

Vet guidelines by which applications are evaluated

Evaluates quality of each applicationProvides constructive feedback for each

application

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?

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?

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?

Laboratory Qualifications

Director’s certificationCLIA or other certificationNumber of disorders tested Staffing for the clinical-laboratory interface:

genetic counselors?, physician consultants?

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

Educational Materials

Provided for three audiences: Medical geneticists, non-geneticist clinicians, patients

Test ordering Test result interpretation for negative,

positive, or indeterminate resultsUses of testing in diagnosis,

management, genetic counselingCreate a GeneReview (first year)

Evidence of Collaboration

All have active rolesInterviews by staff to clarify rolesReferral of patients by clinical lab to

researcherDisease specific advocacy group:

• Ensures appropriateness/dissemination of educational materials

• Is resource for patients and families

Funding/Commitment

Based on complexity of the test processDoes 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)

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

ORD Program Director: Project Coordinator:

Scientific Advisor:Review Board Coordinator:

NCBI Liaison:

Program Staff

Giovanna Spinella, MDAndrew Faucett, MSSuzanne Hart, PhDRoberta Pagon, MDLisa Forman, PhD

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)

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)

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

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

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

Experience of CETT Program to Date (cont.)

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 expertiseDevelop guidelines for quality control,

quality assuranceIdentify guidelines for cost of test

development (where possible)

THANKS TO

Office of Rare Diseases (ORD)

Stephen Groft, Pharm D, Director

National Institutes of Health

www.cettprogram.org