Health Canada needs to act on laboratory-developed diagnostics

Kelly Holloway; Fiona A. Miller; François Rousseau; Alberto Gutierrez; Stuart Hogarth

doi:10.1503/cmaj.190550

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RE: Response from the CSA Technical Committee Z252.11 Lab-developed Tests
Edward Dunn and Robert Rennie

Posted on: 29 July 2020
RE: Responses to Health Canada needs to act on laboratory-developed diagnostics
Kelly Holloway, Fiona A Miller, François Rousseau, Alberto Gutierrez and Stuart Hogarth

Posted on: 19 January 2020
RE: Health Canada needs to act on laboratory-developed diagnostics
Michele D'Elia

Posted on: 29 November 2019
RE: Health Canada needs to act on laboratory-developed diagnostics
Donna M Berry, Rulan S Parekh and Meredith S Irwin

Posted on: 02 October 2019

Posted on: (29 July 2020)

RE: Response from the CSA Technical Committee Z252.11 Lab-developed Tests
Edward Dunn, Director Product & Service Dev, Dynacare Company
Other Contributors:
Robert Rennie, Provincial Microbiology Consultant
The Canadian Standards Association (operating as “CSA Group”) is a private, not-for-profit company that publishes voluntary standards, and related documents, through a consensus-based standards development process approved by the Standards Council of Canada. This process brings together volunteers representing varied viewpoints and interests to achieve consensus.
The first edition of CSA Z316.8:18 Requirements for the design, development, and validation of laboratory-developed tests used for the screening, diagnosis, and management of clinical conditions assists in achieving harmonization of the management of laboratory-developed tests (LDTs). The standard provides guidance to laboratories and assists accreditation bodies in the establishment of a standardized validation process.

Members of CSA Technical Committees (TCs) and Subcommittees (TSCs) provide technical expertise in the content development of standards; they do not act on behalf of the association or organization where they are employed. Financial support to develop the standard was provided in part from the governments of the provinces and territories, as administered by CADTH, CSMLS, Alere ULC, Siemens and Roche, and developed in accordance with CSA Group’s accredited process. The standard was developed by voluntary members of the TSC for LDTs, and approved by the TC. Members represent their respective stakeholder groups and are chosen based on their experience relevant to such stakeholder group....
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The Canadian Standards Association (operating as “CSA Group”) is a private, not-for-profit company that publishes voluntary standards, and related documents, through a consensus-based standards development process approved by the Standards Council of Canada. This process brings together volunteers representing varied viewpoints and interests to achieve consensus.
The first edition of CSA Z316.8:18 Requirements for the design, development, and validation of laboratory-developed tests used for the screening, diagnosis, and management of clinical conditions assists in achieving harmonization of the management of laboratory-developed tests (LDTs). The standard provides guidance to laboratories and assists accreditation bodies in the establishment of a standardized validation process.

Members of CSA Technical Committees (TCs) and Subcommittees (TSCs) provide technical expertise in the content development of standards; they do not act on behalf of the association or organization where they are employed. Financial support to develop the standard was provided in part from the governments of the provinces and territories, as administered by CADTH, CSMLS, Alere ULC, Siemens and Roche, and developed in accordance with CSA Group’s accredited process. The standard was developed by voluntary members of the TSC for LDTs, and approved by the TC. Members represent their respective stakeholder groups and are chosen based on their experience relevant to such stakeholder group.

The TSC took into account the needs of regulatory authorities, consumers, contractors, providers of related services, and other users when developing the technical content of the standard. The standard was developed in such a way that it could be adopted by regulators and to lay the groundwork for potential future development. When the TSC developed requirements in the standard they determined the best technical resolution to provide the minimum guidelines that any stakeholder impacted can implement to ensure best safety practices. At the time of development, this standard was intended to provide a basis for the implementation of a consistent lab-developed testing development process across Canada. The TSC is currently discussing the potential for additional standard development in the genetic topic area.

Health Canada’s jurisdiction does not extend to tests developed within Canadian clinical laboratories, not intended for sale or distribution to other laboratories. Regulation at this level rests with each provincial Department of Health and each province has its own system for regulation of clinical laboratories.

At the time of development, this standard was intended to provide a basis for the implementation of a consistent lab-developed testing development process across Canada. It provides guidance to both the laboratories developing tests for use in their own laboratories, as well as for accreditation bodies.
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Competing Interests: None declared.
References
Kelly Holloway, Fiona A. Miller, François Rousseau, et al. Health Canada needs to act on laboratory-developed diagnostics. CMAJ 2019;191:E1067-E1069.
Posted on: (19 January 2020)

RE: Responses to Health Canada needs to act on laboratory-developed diagnostics
Kelly Holloway, Postdoctoral Fellow, Institute of Health Policy, Management and Evaluation, University of Toronto
Other Contributors:
Fiona A Miller, Professor

François Rousseau, Professor

Alberto Gutierrez, Partner

Stuart Hogarth, Lecturer
We appreciate the responses to our article entitled, “Health Canada needs to act on laboratory-developed diagnostics.” Michele D’Elia from Roche Diagnostics offers an update by indicating that the company’s NIPT test was approved by Health Canada as our article was under review. Roche volunteered to submit an application for their test after it had been on the Canadian market for several years, demonstrating our point that Health Canada does not require pre-market approval for laboratory-developed tests. Further, we agree that the voluntary standard Roche helped to develop through the Standards Council of Canada could be a useful first step to set minimal requirements for these tests. We reiterate that this voluntary standard does not require any manufacturer to submit their test for an external evaluation for safety and efficacy.

We also acknowledge the position advanced by Donna M. Berry and colleagues, that in some cases it may be necessary to balance the need for regulatory guidelines and oversight with the importance of access to novel tests for patients that have no other options. Our paper touches on the EU’s approach to regulation, where a health institution exemption would require reduced but enhanced oversight for tests that are used within individual hospital laboratories. Health Canada should look to this type of international leadership on medical devices to improve the regulation of laboratory-developed diagnostics in Canada.

Competing Interests: None declared.
Posted on: (29 November 2019)

RE: Health Canada needs to act on laboratory-developed diagnostics
Michele D'Elia, Director Medical Affairs, Roche Diagnostics - Division of Hoffmann-La Roche Limited
We wish to acknowledge the work of Holloway et al. for highlighting the current regulation gap that exists in Canada with laboratory-developed tests and identifying the role of regulators such as Health Canada in ensuring that licensed tests undergo a rigorous review process to evaluate their safety and efficacy. The article mentions that the non-invasive Harmony prenatal test was neither evaluated nor approved by Health Canada. This is no longer the case as Harmony became, on September 4th 2019, the first non-invasive prenatal test (NIPT) to meet the Health Canada Medical Devices Bureau's requirements of safety, effectiveness and quality1. The authors also identify a voluntary standard introduced in April 2018 by Standards Council of Canada (Z316.8-18 on Requirements for the Design, Development and Validation of Laboratory-Developed Tests)2. While the standard, as a stand-alone document does not recognize the safety and efficacy of a test, its application by a laboratory-accreditation organization such as Institute for Quality Management in Healthcare (IQMH)3 or its inclusion in Institut National d'Excellence en Santé et Services Sociaux (INESSS) review process4 may serve as a first step to set the minimal requirements for such tests.

1. https://health-products.canada.ca/mdall-limh/information.do?lang=eng&lic...
2....
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We wish to acknowledge the work of Holloway et al. for highlighting the current regulation gap that exists in Canada with laboratory-developed tests and identifying the role of regulators such as Health Canada in ensuring that licensed tests undergo a rigorous review process to evaluate their safety and efficacy. The article mentions that the non-invasive Harmony prenatal test was neither evaluated nor approved by Health Canada. This is no longer the case as Harmony became, on September 4th 2019, the first non-invasive prenatal test (NIPT) to meet the Health Canada Medical Devices Bureau's requirements of safety, effectiveness and quality1. The authors also identify a voluntary standard introduced in April 2018 by Standards Council of Canada (Z316.8-18 on Requirements for the Design, Development and Validation of Laboratory-Developed Tests)2. While the standard, as a stand-alone document does not recognize the safety and efficacy of a test, its application by a laboratory-accreditation organization such as Institute for Quality Management in Healthcare (IQMH)3 or its inclusion in Institut National d'Excellence en Santé et Services Sociaux (INESSS) review process4 may serve as a first step to set the minimal requirements for such tests.

1. https://health-products.canada.ca/mdall-limh/information.do?lang=eng&lic...
2. https://www.csagroup.org/article/new-standard-for-medical-laboratory-dev...
3. https://iqmh.org/Resources/News/Post/7013/New-CSA-Group-Standard-Z316-8-...
4. https://www.msss.gouv.qc.ca/professionnels/soins-et-services/biologie-me...
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Competing Interests: Michele D’Elia is an employee of Roche Diagnostics who commercializes the Harmony Prenatal test.
Posted on: (2 October 2019)

RE: Health Canada needs to act on laboratory-developed diagnostics
Donna M Berry, Program Manager, Research Operations, Hospital for Sick Children
Other Contributors:
Rulan S Parekh, Staff Physician, Associate Chief of Clinical Research

Meredith S Irwin, Staff Oncologist, Associate Chair of Research, Department of Paediatrics
We read with interest the CMAJ commentary “Health Canada needs to act on laboratory-developed diagnostics” and agree enthusiastically with the authors’ assertation that the Canadian regulatory system must be updated to address issues arising as molecular diagnostic technologies are developed and adopted. However, we wish to highlight another class of tests, which need to be considered, especially in precision health and the context of rare diseases, a common issue in children. These are tests performed in specialized research laboratories which due to the complexity of specific assays and/or the low number of cases, cannot currently be feasibly implemented in clinical laboratories or developed as a laboratory developed test (LDT). As an example, RNA sequencing can detect fusions between two unrelated genes in a tumour. The detection of certain rare fusion proteins may support the use of molecularly targeted drugs in otherwise chemotherapy-resistant deadly tumours. Not all genetic findings can be validated due to technique, especially when variants are rare or unique to an individual. Moreover, retesting and validation adds a considerable financial burden. Under the current Ontario regulations (1) this type of research testing would be unavailable to patients as the results must be validated in an accredited clinical laboratory before use for diagnosis or treatment. While we recognize the need for regulatory guidelines and oversight, we also need to acknowledge the import...
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We read with interest the CMAJ commentary “Health Canada needs to act on laboratory-developed diagnostics” and agree enthusiastically with the authors’ assertation that the Canadian regulatory system must be updated to address issues arising as molecular diagnostic technologies are developed and adopted. However, we wish to highlight another class of tests, which need to be considered, especially in precision health and the context of rare diseases, a common issue in children. These are tests performed in specialized research laboratories which due to the complexity of specific assays and/or the low number of cases, cannot currently be feasibly implemented in clinical laboratories or developed as a laboratory developed test (LDT). As an example, RNA sequencing can detect fusions between two unrelated genes in a tumour. The detection of certain rare fusion proteins may support the use of molecularly targeted drugs in otherwise chemotherapy-resistant deadly tumours. Not all genetic findings can be validated due to technique, especially when variants are rare or unique to an individual. Moreover, retesting and validation adds a considerable financial burden. Under the current Ontario regulations (1) this type of research testing would be unavailable to patients as the results must be validated in an accredited clinical laboratory before use for diagnosis or treatment. While we recognize the need for regulatory guidelines and oversight, we also need to acknowledge the important balance of enabling access to novel tests that may provide new or refined diagnoses and treatments impacting patients with no other options.
At the Hospital for Sick Children, a multi-disciplinary group of clinicians, scientists, legal experts and ethicists have formed the ENACT (ENAbling Clinical Translation) committee, which is developing institutional guidelines and policies to address issues related to return of research results and regulatory gaps. We believe this type of local oversight is a critical first step and that new systems of federal or provincial regulatory oversight for research tests and LDTs should be nimble and capable of rapid adjustment to the ever-changing landscape of advancing health care technologies, similar to the concept of a “regulatory sandbox” proposed for innovative health care products in the 2019 federal budget (2) (https://www.budget.gc.ca/2019/docs/plan/toc-tdm-en.html). Our collective goal is to foster rapid changes in health care and provide an agile, innovative and safe healthcare system in Canada that provides access to state of the art diagnostics and therapies for all Canadian children and adults.

(1) Laboratory and Specimen Collection Centre Licensing Act, R.S.O. 1990, c. L.1
(2) Investing in the Middle Class, Canadian Federal Budget 2019, Tabled in the House of Commons by the Honourable William Francis Mourneau, P.C., M.P, Minister of Finance, March 19, 2019, Chapter 2, Part 5.
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Competing Interests: None declared.