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CLIA certification, cap accreditation – international experience in gaining accreditation for use of massively parallel sequencing in a clinical laboratory
ABSTRACTS
ORPHAN DISEASES: CHALLENGES, COSTS AND OPPORTUNITIES – THIS IS HOW WE MIGHT DO IT: POLICY AND RESOURCING Ron Trent Department of Molecular & Clinical Genetics, Royal Prince Alfred Hospital, Camperdown, and Sydney Medical School, University of Sydney, NSW, Australia Marketing: The webpage for Orphanet states: (1) It is the portal for rare diseases and orphan drugs, (2) rare diseases are rare but rare disease patients are common. These concepts can be confusing and so complicate the potential to engage the public and decisionmakers. Activities such as Rare Diseases Day, support groups including a move towards a National organization, and individual action such as the Steve Waugh Foundation are important, as is the recent joining of Orphanet by Australia. How we might do it? Fortunately, there are a number of models developed and funded in the EU and the USA to identify and address the many issues around rare diseases and orphan drugs, e.g., European reference portal for information (Orphanet) and NIH’s Office of Rare Disease Research. However, information alone is not enough. To progress implementation requires a champion. Policy and resourcing: Government intervention is needed, e.g., US Rare Diseases Act 2002. Our Therapeutic Goods Administration (TGA) facilitates the registration of orphan drugs. However, subsidising drugs through the Pharmaceutical Benefit Schedule (PBS) continues to be an issue. Support for rare diseases must rate high in terms of priorities for the proposed National Disability Insurance Scheme (NDIS) but we should not wait to get this aspect of patient and family care onto the national agenda. ORPHAN DISEASES: CHALLENGES, COSTS AND OPPORTUNITIES – THIS IS WHY YOU MUST DO IT: A VOICE FOR FAMILIES Tracy Dudding Rare Voices Australia Rare diseases refer to a heterogeneous group of conditions each with an estimated prevalence of less than 1 in 2000. However, low prevalence does not equal low burden of illness. Rare diseases often begin in childhood, are disabling or life threatening and can be difficult to diagnose. There is no effective treatment for many of these conditions, which are referred to as ‘health orphans’ because they are neglected with respect to research. There are 5000–8000 distinct rare diseases that are estimated to collectively affect 6–8% of the population during their lives. The paradox is that although each condition is rare, it is not uncommon to have or know an individual with a rare disease. So unity became the foundation stone for Rare Voices Australia, a national alliance established in February 2012 which represents the interests and concerns of all Australians living with a rare disease. I will discuss challenges and opportunities within the areas of rare disease diagnosis and management, surveillance and monitoring, research and Orphan drug treatment. YOU SAY GENOMICS AND I SAY GENETICS Charles (Buck) Strom Genetics, Quest Diagnostics Nichols Institute, and Department of Pediatrics, University of California, CA, United States
S31
Many articles in academic and lay publications have predicted that massively parallel whole genome sequencing (NGS) will quickly replace all molecular testing modalities currently in place. These pundits ignore some of the major obstacles that will be necessary to overcome before NGS becomes a routine part of molecular testing. These include issues of accuracy (sensitivity and specificity), pseudogenes, variants of unknown clinical significance, post-translational modifications, informatics, repeat expansion diseases, gene conversions, cost, through-put, sequence assembly, platform stability, reimbursement, reporting, consenting, and regulatory (USA). Subsequently I will review the current offerings of exome sequencing and more limited gene panels performed by advanced sequencing currently that are offered in US laboratories and reagent manufacturers for heritable conditions and cancer. This presentation will examine each of these issues in detail to provide the attendee with knowledge that will aid him or her in evaluating potential opportunities in this field. ACCREDITATION FOR NEW AND EMERGING TECHNOLOGIES Andrew Griffin National Association of Testing Authorities (NATA), Australia The NATA/RCPA Accreditation program in Medical Testing has been in operation since the 1980 s. During this time there have been many extraordinary advances made in the field of medical science for which accreditation has been sought. The challenge for technical assessors, laboratories and NATA staff alike has been how to apply existing standards to these new and emerging technologies. The organisations seeking accreditation may be one of the only facilities using such technology in Australia (or even worldwide) and therefore are the ones making their own rules in terms of performance and quality. I will attempt to show how the accreditation program adapts to these new technologies using the professional resources available and reviews guidelines and standards of practice in terms of their intent. CLIA CERTIFICATION, CAP ACCREDITATION – INTERNATIONAL EXPERIENCE IN GAINING ACCREDITATION FOR USE OF MASSIVELY PARALLEL SEQUENCING IN A CLINICAL LABORATORY Vanessa Tyrrell Translational & Clinical Genomics, Illumina Inc., San Diego, CA, USA Genetic testing is already well established in clinical pathology laboratories using the more traditional technologies associated with molecular genetic testing. The introduction and implementation of ‘next generation’ technologies in genetic pathology, while posing a set of potentially challenging issues, is the obvious next step in providing more comprehensive delivery of information to clinicians to facilitate improvements in patient management and outcomes. Illumina’s protocol for offering individual genome sequencing by massively parallel sequencing in a clinical laboratory was developed responsibly, using current professional and regulatory guidelines, in conjunction with an independent ethics advisory board.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
S32
PATHOLOGY 2012 ABSTRACT SUPPLEMENT
The Clinical Laboratory Improvement Amendments (CLIA) certified College of Americal Pathologists (CAP) accredited laboratory has been delivering clinical services since 2009. The framework around regulation and certification of clinical genetic testing laboratories using massively parallel sequencing will be discussed, in the context of the following key areas: • Quality process: Test definition, consent, and sample tracking. • Technical validity: Accuracy, precision, and limitations. • Delivery of information: Return of results, privacy, and data management. THE CLINICAL LABORATORY’S JOURNEY TOWARDS ACCREDITATION IN DIAGNOSTIC GENOMICS Andrew Fellowes1, Cliff Meldrum2, Anthony Bell1, Rodney Scott2, Stephen Fox1 1Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Vic, and 2Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia The sequencing of the human genome and the development of new genomic methods has resulted in an explosion in our understanding of the molecular basis of disease, and a consequent explosion in the complexity of molecular diagnostic tests. Clinical laboratories are naturally striving to implement molecular diagnostic tests based on genomic methods such as massively parallel sequencing in order to provide genetic diagnosis at the genome scale, while leveraging the parallel processing and nanoscale architecture inherent in these technologies to consolidate costs and maintain turnaround times. These very characteristics, however, challenge both laboratories and accrediting agencies, who must respectively provide and assess objective evidence of clinical utility, analytical performance and limitations for assays of exceeding analytical complexity. With reference to recent local and international guidelines, we will provide examples of the validation of massively parallel sequencing of targeted gene panels for the detection of germline and somatic sequence variation in the clinical cancer setting. Issues particular to the application of this technology to clinical testing, including the use of reference materials, the importance of bioinformatic validation, and the problem of secondary findings, will be reviewed and discussed. ALTERNATE FORMS OF MOLECULAR TESTING Charles (Buck) Strom Genetics, Quest Diagnostics Nichols Institute, and Department of Pediatrics, University of California, CA, United States This presentation will describe two groundbreaking techniques validated in our laboratory: Molecular Combing and SOMAmer Diagnosis. Molecular Combing, developed by Genomic Vision, allows the visualisation and size measurement of single DNA molecules for the purposes of molecular diagnostics. I will describe the technology and the validation of a molecular combing for the diagnosis of fascio-scapular-humeral dystrophy (FSHD). Potential future uses of this technology in the hereditary cancer syndromes will also be discussed. Developed by SomaLogic Inc., SOMAmers (slow off-rate modified aptamers) are a new generation of protein-binding aptamers. SOMAmer reagents are nucleic acid molecules of 40–80 bp that are capable of binding to single proteins. Using a proprietary method,
Pathology (2013), 45(S1)
high affinity SOMAmer reagents can be isolated for virtually any purified protein. By introducing modified bases, SOMAmer reagents can be selected that bind with high affinity and remain bound to proteins in solution long enough for a quantitative assay. I will discuss the development of the first ever clinical SOMAmerbased assay that measures unbound EGFR in serum. I will present the utility of a SOMAmer-based assay for the purposes of proteomics discovery and the translation into a clinical assay. COMPANION DIAGNOSTIC TESTS: BREAKTHROUGHS AND BLISTERS Cliff Meldrum Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia Tumour profiling for the purpose of targeted therapies and personalised medicine has seen a rapid rise in the availability of companion diagnostics. Companion diagnostics can be defined as ‘an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product’ (FDA website http://www.fda.gov). Clinical diagnostic laboratories in Australia are now faced with decisions on whether to develop an in-house in vitro diagnostic device (IVD) or implement where available a companion diagnostic. This choice can be difficult, particularly when a laboratory may have already invested much time and effort in developing, validating and gaining accreditation for an in-house IVD. Confounding factors in this decision making process can be clinical trials with predicated companion diagnostics, and limited evidence for efficacy of the companion diagnostic or an in-house IVD. Issues related to the role of companion diagnostics in the Australian clinical laboratory will be reviewed and, in particular, the role of the laboratory director in choosing an appropriate assay will be discussed. MUTATION TESTING IN CANCER – OPPORTUNITIES AND CHALLENGES FOR PATHOLOGISTS Sandra A. O’Toole Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney Medical School, University of Sydney, Camperdown, and The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia An essential part of personalised medicine is the development of suitable companion diagnostics to stratify patients by specific molecular lesions that are sensitive to targeted therapies. In recent years there have been impressive responses in a subset of patients with specific somatic changes in genes encoding tyrosine kinase receptors such as HER2 in breast cancer, ALK and EGFR in lung cancer and BRAF in melanoma. However, there are significant challenges in implementing high quality, timely and cost effective molecular testing in a routine diagnostic setting, often on very small tissue samples containing a mixture of normal and malignant cells with damaged DNA. Furthermore, the volume of data from new high through-put technologies and the subsequent identification of multiple new targets, which may occur at very low frequencies, imposes additional pressures. Our own experience at Royal Prince Alfred Hospital has highlighted that a multidisciplinary approach between radiologists, physicians, surgeons, tissue and genetic pathologists is essential to ensure optimal diagnosis and therapy of patients. We have also
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
ORPHAN DISEASES: CHALLENGES, COSTS AND OPPORTUNITIES – THIS IS HOW WE MIGHT DO IT: POLICY AND RESOURCING Ron Trent Department of Molecular & Clinical Genetics, Royal Prince Alfred Hospital, Camperdown, and Sydney Medical School, University of Sydney, NSW, Australia Marketing: The webpage for Orphanet states: (1) It is the portal for rare diseases and orphan drugs, (2) rare diseases are rare but rare disease patients are common. These concepts can be confusing and so complicate the potential to engage the public and decisionmakers. Activities such as Rare Diseases Day, support groups including a move towards a National organization, and individual action such as the Steve Waugh Foundation are important, as is the recent joining of Orphanet by Australia. How we might do it? Fortunately, there are a number of models developed and funded in the EU and the USA to identify and address the many issues around rare diseases and orphan drugs, e.g., European reference portal for information (Orphanet) and NIH’s Office of Rare Disease Research. However, information alone is not enough. To progress implementation requires a champion. Policy and resourcing: Government intervention is needed, e.g., US Rare Diseases Act 2002. Our Therapeutic Goods Administration (TGA) facilitates the registration of orphan drugs. However, subsidising drugs through the Pharmaceutical Benefit Schedule (PBS) continues to be an issue. Support for rare diseases must rate high in terms of priorities for the proposed National Disability Insurance Scheme (NDIS) but we should not wait to get this aspect of patient and family care onto the national agenda. ORPHAN DISEASES: CHALLENGES, COSTS AND OPPORTUNITIES – THIS IS WHY YOU MUST DO IT: A VOICE FOR FAMILIES Tracy Dudding Rare Voices Australia Rare diseases refer to a heterogeneous group of conditions each with an estimated prevalence of less than 1 in 2000. However, low prevalence does not equal low burden of illness. Rare diseases often begin in childhood, are disabling or life threatening and can be difficult to diagnose. There is no effective treatment for many of these conditions, which are referred to as ‘health orphans’ because they are neglected with respect to research. There are 5000–8000 distinct rare diseases that are estimated to collectively affect 6–8% of the population during their lives. The paradox is that although each condition is rare, it is not uncommon to have or know an individual with a rare disease. So unity became the foundation stone for Rare Voices Australia, a national alliance established in February 2012 which represents the interests and concerns of all Australians living with a rare disease. I will discuss challenges and opportunities within the areas of rare disease diagnosis and management, surveillance and monitoring, research and Orphan drug treatment. YOU SAY GENOMICS AND I SAY GENETICS Charles (Buck) Strom Genetics, Quest Diagnostics Nichols Institute, and Department of Pediatrics, University of California, CA, United States
S31
Many articles in academic and lay publications have predicted that massively parallel whole genome sequencing (NGS) will quickly replace all molecular testing modalities currently in place. These pundits ignore some of the major obstacles that will be necessary to overcome before NGS becomes a routine part of molecular testing. These include issues of accuracy (sensitivity and specificity), pseudogenes, variants of unknown clinical significance, post-translational modifications, informatics, repeat expansion diseases, gene conversions, cost, through-put, sequence assembly, platform stability, reimbursement, reporting, consenting, and regulatory (USA). Subsequently I will review the current offerings of exome sequencing and more limited gene panels performed by advanced sequencing currently that are offered in US laboratories and reagent manufacturers for heritable conditions and cancer. This presentation will examine each of these issues in detail to provide the attendee with knowledge that will aid him or her in evaluating potential opportunities in this field. ACCREDITATION FOR NEW AND EMERGING TECHNOLOGIES Andrew Griffin National Association of Testing Authorities (NATA), Australia The NATA/RCPA Accreditation program in Medical Testing has been in operation since the 1980 s. During this time there have been many extraordinary advances made in the field of medical science for which accreditation has been sought. The challenge for technical assessors, laboratories and NATA staff alike has been how to apply existing standards to these new and emerging technologies. The organisations seeking accreditation may be one of the only facilities using such technology in Australia (or even worldwide) and therefore are the ones making their own rules in terms of performance and quality. I will attempt to show how the accreditation program adapts to these new technologies using the professional resources available and reviews guidelines and standards of practice in terms of their intent. CLIA CERTIFICATION, CAP ACCREDITATION – INTERNATIONAL EXPERIENCE IN GAINING ACCREDITATION FOR USE OF MASSIVELY PARALLEL SEQUENCING IN A CLINICAL LABORATORY Vanessa Tyrrell Translational & Clinical Genomics, Illumina Inc., San Diego, CA, USA Genetic testing is already well established in clinical pathology laboratories using the more traditional technologies associated with molecular genetic testing. The introduction and implementation of ‘next generation’ technologies in genetic pathology, while posing a set of potentially challenging issues, is the obvious next step in providing more comprehensive delivery of information to clinicians to facilitate improvements in patient management and outcomes. Illumina’s protocol for offering individual genome sequencing by massively parallel sequencing in a clinical laboratory was developed responsibly, using current professional and regulatory guidelines, in conjunction with an independent ethics advisory board.
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
S32
PATHOLOGY 2012 ABSTRACT SUPPLEMENT
The Clinical Laboratory Improvement Amendments (CLIA) certified College of Americal Pathologists (CAP) accredited laboratory has been delivering clinical services since 2009. The framework around regulation and certification of clinical genetic testing laboratories using massively parallel sequencing will be discussed, in the context of the following key areas: • Quality process: Test definition, consent, and sample tracking. • Technical validity: Accuracy, precision, and limitations. • Delivery of information: Return of results, privacy, and data management. THE CLINICAL LABORATORY’S JOURNEY TOWARDS ACCREDITATION IN DIAGNOSTIC GENOMICS Andrew Fellowes1, Cliff Meldrum2, Anthony Bell1, Rodney Scott2, Stephen Fox1 1Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Vic, and 2Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia The sequencing of the human genome and the development of new genomic methods has resulted in an explosion in our understanding of the molecular basis of disease, and a consequent explosion in the complexity of molecular diagnostic tests. Clinical laboratories are naturally striving to implement molecular diagnostic tests based on genomic methods such as massively parallel sequencing in order to provide genetic diagnosis at the genome scale, while leveraging the parallel processing and nanoscale architecture inherent in these technologies to consolidate costs and maintain turnaround times. These very characteristics, however, challenge both laboratories and accrediting agencies, who must respectively provide and assess objective evidence of clinical utility, analytical performance and limitations for assays of exceeding analytical complexity. With reference to recent local and international guidelines, we will provide examples of the validation of massively parallel sequencing of targeted gene panels for the detection of germline and somatic sequence variation in the clinical cancer setting. Issues particular to the application of this technology to clinical testing, including the use of reference materials, the importance of bioinformatic validation, and the problem of secondary findings, will be reviewed and discussed. ALTERNATE FORMS OF MOLECULAR TESTING Charles (Buck) Strom Genetics, Quest Diagnostics Nichols Institute, and Department of Pediatrics, University of California, CA, United States This presentation will describe two groundbreaking techniques validated in our laboratory: Molecular Combing and SOMAmer Diagnosis. Molecular Combing, developed by Genomic Vision, allows the visualisation and size measurement of single DNA molecules for the purposes of molecular diagnostics. I will describe the technology and the validation of a molecular combing for the diagnosis of fascio-scapular-humeral dystrophy (FSHD). Potential future uses of this technology in the hereditary cancer syndromes will also be discussed. Developed by SomaLogic Inc., SOMAmers (slow off-rate modified aptamers) are a new generation of protein-binding aptamers. SOMAmer reagents are nucleic acid molecules of 40–80 bp that are capable of binding to single proteins. Using a proprietary method,
Pathology (2013), 45(S1)
high affinity SOMAmer reagents can be isolated for virtually any purified protein. By introducing modified bases, SOMAmer reagents can be selected that bind with high affinity and remain bound to proteins in solution long enough for a quantitative assay. I will discuss the development of the first ever clinical SOMAmerbased assay that measures unbound EGFR in serum. I will present the utility of a SOMAmer-based assay for the purposes of proteomics discovery and the translation into a clinical assay. COMPANION DIAGNOSTIC TESTS: BREAKTHROUGHS AND BLISTERS Cliff Meldrum Hunter Area Pathology Service, John Hunter Hospital, Newcastle, NSW, Australia Tumour profiling for the purpose of targeted therapies and personalised medicine has seen a rapid rise in the availability of companion diagnostics. Companion diagnostics can be defined as ‘an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product’ (FDA website http://www.fda.gov). Clinical diagnostic laboratories in Australia are now faced with decisions on whether to develop an in-house in vitro diagnostic device (IVD) or implement where available a companion diagnostic. This choice can be difficult, particularly when a laboratory may have already invested much time and effort in developing, validating and gaining accreditation for an in-house IVD. Confounding factors in this decision making process can be clinical trials with predicated companion diagnostics, and limited evidence for efficacy of the companion diagnostic or an in-house IVD. Issues related to the role of companion diagnostics in the Australian clinical laboratory will be reviewed and, in particular, the role of the laboratory director in choosing an appropriate assay will be discussed. MUTATION TESTING IN CANCER – OPPORTUNITIES AND CHALLENGES FOR PATHOLOGISTS Sandra A. O’Toole Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, Sydney Medical School, University of Sydney, Camperdown, and The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia An essential part of personalised medicine is the development of suitable companion diagnostics to stratify patients by specific molecular lesions that are sensitive to targeted therapies. In recent years there have been impressive responses in a subset of patients with specific somatic changes in genes encoding tyrosine kinase receptors such as HER2 in breast cancer, ALK and EGFR in lung cancer and BRAF in melanoma. However, there are significant challenges in implementing high quality, timely and cost effective molecular testing in a routine diagnostic setting, often on very small tissue samples containing a mixture of normal and malignant cells with damaged DNA. Furthermore, the volume of data from new high through-put technologies and the subsequent identification of multiple new targets, which may occur at very low frequencies, imposes additional pressures. Our own experience at Royal Prince Alfred Hospital has highlighted that a multidisciplinary approach between radiologists, physicians, surgeons, tissue and genetic pathologists is essential to ensure optimal diagnosis and therapy of patients. We have also
Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.