General Session I. Genetic Testing for Rare Diseases, Oversight Issues, and Public Needs

The first general session, moderated by Dr. Carol Greene, Office of the Secretary, Department of Health and Human Services (HHS), included the following presentations:

Overview of Laboratory Testing for Rare Diseases       [Full Presentation]
Dr. Bin Chen and Andy Faucett, DLS, PHPPO, CDC, presented an overview of currently available rare disease tests and laboratories offering testing for rare diseases. A review of genetic tests listed in the GeneTests directory in 2000, conducted by OGDP and DLS, CDC, found that at least 95% of available genetic tests were performed for rare diseases and conditions. A more recent review of GeneTests indicated that, of the 1,039 diseases listed as of April 2004, clinical testing was available for 694 diseases, or 67%; whereas for the remaining 354 diseases, testing was for research purposes only. Among clinically available genetic tests, 78% are available from US laboratories and 22% are available only outside the US. Over the past 6 months, the net number of clinically available genetic tests has increased by 51, reflecting a combination of transition of "research only" tests to clinical testing, new tests offered by clinical laboratories, and tests that are no longer clinically available. In addition, changes were noted in laboratory services, including a significant increase in laboratories offering clinical confirmation for mutations identified by research laboratories. The analysis also revealed that the average growth rate of genetic tests over the past 6 months was less than 10 new tests per month; in contrast, an average of 20 new rare diseases are described in the medical literature every month, while 60-100 new entries related to genetic research findings appear in the Online Mendelian Inheritance In Man (OMIM) database per month.

CLIA Oversight for Rare Disease Testing       [Full Presentation]
Virginia Wanamaker, Deputy Director of Division of Laboratory Services, Centers for Medicare and Medicaid Services (CMS), provided an overview of the Clinical Laboratory Improvement Amendments (CLIA) regulations and the outcome-oriented survey process for laboratory performance. She specifically addressed CLIA compliance issues relating to genetic testing, and updated participants on the progress of the preparation of a Notice of Proposed Rule Making for establishing a genetic testing specialty under CLIA. In addition, she provided clarification on two "myths" regarding CLIA compliance - Myth 1 assumes that if a CLIA-certified laboratory sends a patient specimen to a research laboratory for testing and then confirms the test results of the research laboratory, the research laboratory does not need a CLIA certificate; and Myth 2 assumes that if a physician sends a patient specimen to a foreign laboratory, it is not subject to CLIA requirements regarding specimen referral and the foreign laboratory does not have to be CLIA-certified. Ms. Wanamaker emphasized that under CLIA, both the "research laboratory" in Myth 1 and the foreign laboratory in Myth 2 need to be CLIA-certified.

IRB Issues in Releasing Individual Test Results in Clinical Research       [Full Presentation]
Glen Drew, Office for Human Research Protections (OHRP), provided an overview of the work of OHRP in assuring safety and protection of human subjects in HHS-supported research through responsibilities of the Institutional Review Boards (IRBs). Every institution engaged in human subject research conducted or supported by HHS must obtain an assurance of compliance approved by OHRP; OHRP also evaluates complaints and indications of noncompliance, and determines regulatory actions needed based on results of the institutional investigation. He highlighted the top 10 information elements that should be included in the informed consent document for clinical research, and concluded that whether test results could be disclosed, as well as the extent and conditions of disclosure, should be explained as part of the informed consent and adhered to during clinical research. Regarding genetic testing in research studies, OHRP currently does not have specific guidelines regarding CLIA compliance. It is left to individual IRBs to determine whether or not testing needs to be performed by a CLIA-certified laboratory if individual test results will be released to research participants and/or their care providers.

HIPAA Privacy Rule and Rare Disease Clinical Research*       [Full Presentation]
Myra Moran, Office for Civil Rights (OCR), gave an overview of the HIPAA Privacy Rule and its implications for clinical laboratories, focusing on the requirements relating to the use and disclosure of protected health information by covered entities for research purposes, records subject to CLIA, and the rights of the individuals with respect to that information. She specifically clarified the relationship between the Privacy Rule and CLIA regarding the right of patients or research participants to access their laboratory records. The Privacy Rule does not require clinical laboratories that are also covered health care providers to provide an individual with access to information if CLIA prohibits them from doing so. CLIA permits clinical laboratories to provide clinical laboratory test records and reports only to "authorized persons," as defined primarily by State law. The individual who is the subject of the information is not always included as an authorized person. Therefore, the Privacy Rule includes an exception to individuals' general right to access protected health information about themselves if providing such access would be in conflict with CLIA. In addition, for certain research laboratories that are exempt from the CLIA regulations, the Privacy Rule does not require such research laboratories, if they are also a covered health care provider, to provide individuals with access to protected health information, because doing so would result in the research laboratory losing its CLIA exemption. Nonetheless, in most cases, individuals who receive clinical laboratory tests will be able to receive their test results or reports through the health care provider who ordered the test for them.

A question was presented as to whether a covered health care provider may disclose health information about a third party, such as a family member's medical history, as necessary to treat a patient. For example, the provider may need to provide a genetic testing laboratory with the disease information of the patient's parents for purposes of diagnosing the patient. The Privacy Rule allows a covered entity, without the patient's authorization, to use or disclose protected health information, such as X rays, laboratory and pathology reports, diagnoses, and other medical information for its own treatment purposes, as well as disclose the information for the treatment purposes to any health care provider. This includes sharing the information of a third party, such as a patient's family medical history, with another health care provider as necessary for the treatment of a patient. Additional information regarding the use and disclosure of protected health information to carryout treatment, payment or healthcare operations is contained in the HIPAA Rule. See 45 CFR § 164.506.

*This summary is approved and cleared by the Office for Civil Rights (OCR) HHS.

Rare Genetic Diseases: Former SACGT Workgroup and the NIH-DOE Task Force on Genetic Testing       [Full Presentation]
Dr. Michael Watson, Executive Director of the American College of Medical Genetics (ACMG), reviewed the recommendations on rare disease genetic testing under the NIH-Department of Defense (DOE) Task Force on Genetic Testing and the work of the Rare Disease Workgroup established by the previous Secretary's Advisory Committee on Genetic Testing (SACGT). He also summarized results of a CLIA compliance survey conducted among ASHG members in 2002, which indicated that among the 99 respondents, 35 were non-CLIA laboratories releasing patient test results. The survey revealed that these laboratories either assumed they were not performing clinical testing since they did not bill for their services, or thought it too difficult to obtain a CLIA certificate. Dr. Watson pointed out that the respondents expressed interest in obtaining assistance with CLIA compliance. Among the types of assistance needed were guidance for developing quality assurance programs, help to identify clinical laboratories willing to take on new tests, and educational workshops.

Clinicians' Perspective and Needs for Rare Disease Laboratory Testing       [Full Presentation]
Dr. William Gahl, Clinical Director of the National Human Genome Research Institute (NHGRI) and Director of the Intramural Program of ORD, NIH, presented a pilot approach co-sponsored by NHGRI and ORD to bring molecular diagnostic tests for specific rare diseases to clinical use. This pilot program will fund several CLIA-certified laboratories, including Greenwood Genetics Center, GeneDx, and the Emory University Molecular Genetics Laboratory, to set up genetic tests for a number of disorders studied by NHGRI. The first group of tests to be developed includes rare diseases with less complicated mutations and is anticipated to cost approximately $5,000 per gene. These laboratories are expected to make the tests publicly available and provide testing on a fee-for-service basis for at least 10 years.

Newborn Screening Systems: A Model for Translating Science into Practice       [Full Presentation]
Dr. Michele Puryear, Chief of Genetic Service Branch, Division of Services for Children with Special Health Needs, Maternal and Child Health Bureau (MCHB), Health Resources and Services Administration (HRSA), provided an overview of the vision and goals of the MCHB Strategic Plan to assure the highest quality of healthcare and to facilitate access to care. She summarized the present initiatives of the Genetic Service Branch and activities under Title XXVI of the Children's Health Care Act of 2000 to improve the ability of States to provide newborn and child screening for heritable disorders. Currently, HRSA is initiating projects to establish regional genetic service and newborn screening collaboratives for the 7 geographical regions in the country, which will strive to facilitate access to genetic expertise, services, and technology that providers and families need to diagnose and manage children identified with genetic disorders. Dr. Puryear also provided updates on the establishment of the Secretary's Advisory Committee on Heritable Disorders and the tasks of this Committee.

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General Session II: Approaches to Providing Quality Testing for Rare Diseases and Conditions

The second general session included examples of current approaches to providing and assuring quality laboratory testing for rare diseases. This session was moderated by Dr. David Ledbetter. (Note: Dr. Segolene Ayme, Director of Orphanet, France, was unable to attend the conference. A copy of her presentation at a February 2004 European Rare Disease Workshop was shared with participants to provide insights on European rare disease networks.)

Proposed Partnership between Research and CLIA-certified Laboratories       [Full Presentation]

Dr. David Ledbetter, Emory University School of Medicine, reviewed a proposal made to the former SACGT, in November 2001, on the potential for partnerships between research laboratories and CLIA-certified molecular genetics laboratories to improve clinical availability of genetic tests for rare diseases. Dr. Ledbetter pointed out that providing research participants and/or their healthcare providers with test results generated in non-CLIA-certified laboratories would present an above-minimal risk to research participants, due to the potential for errors in patient testing performed by non-credentialed laboratories lacking adequate quality assurance standards. He suggested that such a risk be considered a significant issue of human subjects' protection, which should be more carefully evaluated by OHRP at the national level and by IRBs at the local level. Dr. Ledbetter also described his efforts to establish a National Laboratory Network for Rare Disease Genetic Testing and proposed that this model be further discussed during the breakout discussion sessions of the conference.

The Johns Hopkins University Experience       [Full Presentation]
Dr. Patricia Charache, Johns Hopkins University, shared her experience establishing a process to ensure quality of laboratory testing for patient care at the Johns Hopkins University. Specific strategies included a laboratory review program and a credentialing program for laboratory directors, under the principle that all laboratories providing testing used in patient care must meet the standards of CLIA and the Joint Commission on Accreditation of Healthcare Organizations (JCAHO). The outcomes for the laboratories testing for rare heritable diseases included transfer of clinical testing from small research laboratories to CLIA-certified pathology laboratories, discontinuation of patient testing in laboratories without CLIA certification, and employment of qualified laboratory directors. This process has resulted in substantial improvement in CLIA and JCAHO inspections. Dr. Charache concluded that education was critical to the success of this process; among other key programmatic considerations were avoiding bias, utilizing evidence-based data and the academic structure to effect changes, and providing information and support to all laboratories within the institution evenly.

Rare Orphan Genetic Disease Diagnosis - The University of Chicago Experience       [Full Presentation]
Dr. Soma Das, Director of Molecular Genetics Laboratory, Department of Human Genetics, the University of Chicago, presented the experience of her laboratory in implementing, validating, and providing genetic tests for rare diseases since 1998. Her presentation highlighted specific issues on validation, quality control and result interpretation of testing for rare diseases. She indicated the increase in testing volume for rare orphan genetic diseases in her laboratory since its implementation. She discussed the costs of setting up testing for these disorders, and summarized factors important for laboratories to financially break even and to expand the number of tests available; which included implementation of a billing mechanism, increasing test volume, increasing testing personnel, and automation of testing technology. She also pointed out that the lack of funding and licensing conditions of gene patents could be factors negatively affecting laboratory growth.

The GeneDx Experience       [Full Presentation]
Dr. Sherri Bale, President and Clinical Director of GeneDx, described the process of setting up a commercial laboratory dedicated to diagnostic testing for rare diseases, which included securing financial support and space, obtaining CLIA certification and Maryland State licensure, selecting initial tests to offer, and building the test menu over time. Since 2000, the number of tests offered by the laboratory has grown from 16 to over 80, and the volume has increased from 166 in 2000 to an anticipated 4000 patient specimens for 2004. Dr. Bale suggested that the business model had worked successfully for her laboratory. She also shared problems encountered in offering rare disease testing, including obtaining proper informed consent, prenatal testing, lack of available proficiency testing program, significant increase in liability insurance costs, and licensing issues related to patented genes.

The Genetic Testing Quality Assurance Program in New York State       [Full Presentation]
Dr. Michele Caggana, Section Head, Genetic Testing Quality Assurance Program, Wadsworth Center, New York State Department of Health, provided an overview of the New York State oversight for laboratories performing genetic testing for New York State residents. As Section Head, Dr. Caggana's responsibilities include approval of certificate of qualification for laboratory directors and assistant directors, review and evaluation of method validation submissions, review of survey results, analysis of questionnaire data, and review of non-permitted laboratory requests. She emphasized that for genetic testing; New York State requires laboratories to have specific approval for each test they perform. For any test submitted by a licensed medical practitioner for which no laboratory is approved, laboratories must submit a "Non-permitted Laboratory Request" together with information regarding the test to be performed, the referring laboratory, and the referral laboratory, the CLIA number of the referral laboratory, the patient, the referral, and justification for testing. Approval of such requests is based on continuity of care, the need for additional testing, and other considerations, but not for financial reasons. Dr. Caggana summarized that 1,326 non-permitted laboratory requests have been reviewed during the past 5 years, among which a significant portion were for rare disorders.

The Hospital of Sick Children Experience       [Full Presentation]
Dr. Peter Ray, Director of the Molecular Diagnostic Laboratory of the Hospital for Sick Children, Toronto, Canada, described his laboratory's experience in providing genetic testing for rare diseases, with an emphasis on pediatric disorders. He shared issues of concern regarding result interpretation in mutation detection for Batten disease, mutation and carrier analysis for Duchenne muscular dystrophy, and sequencing-based testing methods. Dr. Ray pointed out that providing healthcare providers with adequate information on result interpretation was critical to assure appropriate understanding and use of test results in patient care. In light of this need, the Hospital for Sick Children has established a resource center for hospital physicians to provide information on testing availability, referral advice, and assistance with result interpretation and patient counseling.

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General Session III: Translation of Gene Findings to Clinical Tests

The third general session, moderated by Dr. Steve Groft, included a series of presentations on developing rare disease laboratory tests based on research findings and integrating new tests into practice.

Office of Rare Diseases Experience in Rare Disease Gene Testing       [Full Presentation]
Dr. Giovanna Spinella, Director of Extramural Research program, ORD, NIH, began her presentation with an overview of ORD's responsibilities under the Rare Disease Act of 2002, which include stimulating and coordinating research on rare diseases; developing information resources to meet the needs of the public, health professionals, patients and families; and preparing reports to Congress on rare disease research, education, and advances. She highlighted perspectives of the patient community and the research investigators in the process of finding disease genes and translating the findings into clinical testing - patients participating in research often desire to know their mutation status because they view gene discoveries as a critical first step towards understanding their disease and developing specific treatment; on the other hand, the small number of research investigators for each specific rare disease, who may become experts in test development, often feel responsible to provide testing information back to patients and families. However, the perceived difficulty in attaining CLIA compliance and barriers to transferring testing to clinical laboratories, due to the lack of CLIA-certified laboratories willing to take on low volume testing for rare diseases or burdens in establishing licensing agreements, could result in research laboratories releasing patient test information without a CLIA certificate. Dr. Spinella summarized additional issues raised by researchers to ORD, including whether a non-CLIA-certified research laboratory could provide information back to research participants, the role of IRBs in gate-keeping this issue, the lack of genetic tests for many rare diseases, and inconsistent access to testing even when it is available. She concluded the presentation by emphasizing the need to improve availability of rare disease gene testing and the importance of translating research findings into validated clinical testing.

The Office of Orphan Products Development Grant Program       [Full Presentation]
Dr. Janet Whitley, Office of Orphan Products Development (OOPD), the Food and Drug Administration (FDA), gave an overview of the Orphan Products Grant Program, which supports clinical research demonstrating promise for the diagnosis and treatment of rare diseases. Under this grant program, 36 biological products for rare diseases have been brought to market together with hundreds of scientific publications, abstracts, and presentations. Dr. Whitley also described OOPD's responsibilities in the evaluation of humanitarian use devices (HUDs), which are defined as medical devices intended to benefit patients in the diagnosis and/or treatment of a disease or condition that affects or is manifested in fewer than 4,000 individuals per year in the US. HUD applications are first reviewed by OOPD to determine the appropriateness of the rationale and the intended population; then the device must be evaluated for safety and probable benefit by another FDA program under the Center for Devices and Radiological Health (CDRH).

Humanitarian Device Exemptions (HDE) and Investigational Device Exemptions (IDE) Programs       [Full Presentation]
Dr. Elizabeth Mansfield, Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), CDRH, FDA, reviewed the responsibilities of her program for reviewing and approving device applications under the HDE and IDE regulatory provisions. She discussed a number of commonly expressed concerns regarding HDE approvals, including whether the 4,000 US patients per year is the right limit for both therapeutic drugs and diagnostic devices, whether the post-market requirements for IRB approval and non-profitability are appropriate, and why so few HDE applications have been submitted to FDA. Dr. Mansfield suggested that, because of the restrictions to HDE, test developers might not consider it an attractive option; they might instead choose to offer testing for rare diseases as laboratory-developed, or "home brew", tests to be able to make a profit.

Development of a Genetic test for Pseudoxanthoma Elasticum (PXE): Patients' Role in Research Translation       [Full Presentation]
Sharon Terry, President and CEO of the Genetic Alliance and Executive Director of PXE International, Inc., shared the process of developing a mutation detection assay for PXE, an inherited disorder affecting connective tissue in multiple organs, with the support and participation of PXE International, Inc., an international patient support organization. She highlighted a number of challenges and problems in rare disease research, including limited pools of participants, small collections of patient samples, competitive and fragmented research environment, poor confidentiality protection for patients, variable informed consent process, inaccurate disease characterization, limited reporting of test results to participants, and inadequate funding. To assist in research translation, the Genetic Alliance initiated a BioBank project in 2003 to establish a repository of biological samples associated with clinical data, to facilitate accelerated, coordinated, and ethical genetic research.

Genetic Testing for Rare Diseases: A Payer Perspective       [Full Presentation]
Dr. Morris Mellion, Associate Medical Director, Blue Cross and Blue Shield Association (BCBSA), presented issues considered by BCBSA in determining whether a rare disease test could be covered and reimbursed. In general, to be covered by the health plan, the test or technology must meet appropriate FDA and CLIA regulatory requirements and must be scientifically validated. He outlined 5 criteria that the BCBSA Technology Evaluation Center uses in conducting technology assessments, including 1) the technology must have final approval from the appropriate governmental regulatory bodies, 2) the scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, 3) the technology must improve the net health outcome, 4) the technology must be as beneficial as any established alternatives, and 5) improvement must be attainable outside of investigational settings. Subsequently, Dr. Margaret Piper, Technology Evaluation Center, BCBSA, explained how these criteria are used in evaluating and determining the clinical implementation of a number of genetic tests, including molecular genetic testing for the HFE gene related to hereditary hemochromatosis, BRCA 1/2 genes for inherited susceptibility to breast cancer, APC and mismatch repair genes for hereditary colon cancers, and ApoE testing for Alzheimer disease. She acknowledged the difficulty in gathering data for rare disease testing due to the low prevalence of rare diseases, but also pointed out the opportunities for assessment studies in this area. For example, the small sample size might be more representative of the affected population. Dr. Piper concluded with a summary of the payer's perspective for rare disease testing, emphasizing the following needs: 1) to agree on a workable definition for rare disease, 2) to apply regulatory standards to ensure quality, 3) to improve data collection to aid in evidence-based decision making, 4) to improve technology assessment, and 5) to handle exceptions on a case-by-case basis.