Comparing Regulation of IVD Medical Devices in Europe and Canada. By Ivor D. Barrett, PhD

Transcription

1 Comparing Regulation of IVD Medical Devices in Europe and Canada By Ivor D. Barrett, PhD 26 May 2011

2 In vitro diagnostic (IVD) medical devices are reagents and related instruments used to test specimens derived from the human body to obtain information regarding physiological and pathological conditions, congenital abnormalities, compatibility of potential recipients of blood transfusions and tissue transplants and effectiveness of therapy. As the results of these tests are used to inform crucial clinical decisions, regulation of IVD devices is seen in many regions of the world as an important requirement to protect patient safety. Major IVD markets have developed their own regulations that, although similar in many ways, also have fundamental differences. Manufacturers and suppliers of IVD products must be aware of the similarities and differences in regional regulations to avoid contravening local legislation when selling in these markets. Regulatory requirements have to be considered at an early stage of new product development because specific performance studies may be necessary to ensure compliance. Failure to schedule such studies could lead to delays in regulatory approval with consequential loss of sales and revenue. This article compares the IVD regulations in two major device markets: the EU (In Vitro Diagnostic Medical Devices Directive, IVDD 1 ) and Canada (Canadian Medical Device Regulations, CMDR 2 ). The level of intervention by European and Canadian authorities in the premarket approval process of IVD devices and the extent of product validation requirements are dependent upon the risk to the patient if the test produces false or inaccurate information. More stringent requirements are applicable to products where failure or misdiagnosis could result in serious deterioration in the health or even death of the patient. It is important to remember that under both EU and Canadian regulations, the legal manufacturer of a device is defined as the manufacturer named on the label. The legal manufacturer takes full responsibility for the product under the regulations, irrespective of whether it actually manufactured the product. For instance, an ownbrand label of an IVD product (whose name is on the label) is fully responsible for that device even if it is completely manufactured, packed, and labeled by another company on its behalf. In this article, the term manufacturer always refers to the legal manufacturer of the device. Device Classification In both markets, the level of regulation is defined by the classification of the product (Table 1). In EU, higher-risk products are listed in Annex II of the IVDD. These products are listed by analyte and type of use (e.g., screening, blood grouping and confirmatory test). Annex II List A products carry the highest risk to patients. They include screening and confirmatory tests for viral markers such as HIV and hepatitis. Reagents for ABO blood grouping also fall into this category. Annex II List B products are regarded as having an intermediate level of risk. This category includes tests for the less-important blood phenotypes, a range of other viral markers, and tests for the principal human leukocyte antigen (HLA) tissue groups and hereditary disorders. It also includes tests for prostate-specific antigen and self-test devices for blood sugar. All other products that are not specifically mentioned are classified as low risk, although any self-test products sold to the general public have more stringent requirements than the equivalent professional tests. The CMDR defines a much more systematic classification process. Products fall into one of four classes (I, II, III or IV) dependent upon the manufacturer s intended use of the product. The appropriate class is obtained by applying a series of nine rules described in the CMDR. This system is fully risk-based with highest-risk products falling in Class IV, which is subject to the most stringent requirements. The EU IVDD is currently being redrafted. It is anticipated that the revised directive will require IVD devices to be classified by a fully risk-based method based on the Global Harmonization Task Force (GHTF) guidelines 3 and similar to the Canadian system. However, the publication of the new directive is still a few years in the future. Registration of Products, Manufacturers and Device Licenses Generally, in both markets, products must be registered (Table 2) prior to making them available for sale, unless they fall into the lowest risk category. In the EU, all products have to be registered with the Competent Authority in the country in which they are to be sold. In the UK, this is the Medicines and Healthcare products Regulatory Agency (MHRA 4 ). The lowest-risk products are not registered individually but rather in terms of a group code based on analyte and assay technology. For higher classifications, products are assessed individually and certified by Notified Bodies accredited under the IVDD by the Competent Authority in the country in which they are based. Any European Notified Body may be used provided it has the necessary scope to assess and certify the product type. Manufacturers can check the scope of Notified Bodies on the European New Approach Notified and Designated Organisations (NANDO) website. 5 The UL Notified Body 6 has a comprehensive scope covering most IVD devices. Products approved by a Notified Body can subsequently be legally marketed in any country in the EU subject to the registration requirements above. In Canada, all products in Classes II, III and IV must be licensed by Health Canada, 7 which is Regulatory Focus 27

3 Table 1. IVD Device Classification Europe (IVDD) Canada (MDR) Device Example (Professional use) Class I IVD used to identify cultured microorganism Pregnancy test (self-test) Annex II List B I Blood glucose monitor Annex II List A Class IV HIV test kit accredited to the Standards Council of Canada (SCC). The requirements for Notified Body certification in Europe and product licensing in Canada increase in stringency with risk category and hence product classification. These requirements are summarized in the next section. All IVD manufacturers located in the EU have to be registered with the Competent Authority in the country where they are based. Manufacturers located in other parts of the world must, by law, appoint an Authorized Representative, resident in the EU, that is legally responsible for communications with the Competent Authority on behalf of the manufacturer. The Authorized Representative is often a distributor of the manufacturer s products, but can be a specialist independent company that represents several manufacturers. Any entity that imports or sells a medical device on the Canadian market requires an establishment license. However, manufacturers of Class II, III and IV devices (along with retailers and healthcare facilities) are exempted from this requirement. Manufacturers of Class I devices are not exempt unless they import or distribute the device solely through an organization that holds an establishment license. Health Canada requires manufacturers to have a regulatory correspondent. This is a named person authorized by the manufacturer to be its official contact with Health Canada with respect to its licensed devices. The regulatory correspondent can simply be an employee of the manufacturer or a local distributor. Alternatively, an independent service company may be used for convenience. The regulatory correspondent does not have to be based in Canada, as there is no requirement for foreign manufacturers to have a local authorized contact. Product Technical Documentation Product technical documentation for all classes of IVD devices (Table 3) must be available for inspection by the Competent Authority or Health Canada at any time. The EU and Canadian requirements for content are similar and include comprehensive data demonstrating that the product performs satisfactorily in meeting its claims for intended use, does not cause harm to the patient or user, and will retain its claimed performance characteristics following transportation and storage until its expiration date. In both the EU and Canada, the level of scrutiny of the technical information depends upon the classification of the product. In essence, the higher the class, the more carefully the performance data are assessed. In Europe, technical files for products that are not self-test or not listed in Annex II of the IVDD do not have to be independently assessed. The manufacturer simply makes a legal declaration of conformity, asserting that the product meets the requirements of the IVDD, and, following registration of the product with the Competent Authority, is free to sell it in the EU. Technical data for all other products (selftest and Annex II) must be independently assessed by a Notified Body with appropriate IVD scope, such as UL, for compliance with the requirements of the directive. This assessment takes the form of a review of the technical file for self-test and Annex II List B products, but any List A product requires a comprehensive assessment of the full design dossier. Additionally, Annex II List A products have to comply with applicable Common Technical Specifications 8 published in European Commission Decision 2009/886/EC. In Canada, Class I products do not require a product license, so no application needs to be made to Health Canada. For products, a senior member of management has to make a legal attestation that the product meets the requirements of the CMDR with emphasis on labeling, compliance with safety and effectiveness requirements and testing on human samples representative of its intended use. I products require submission of a technical file describing the device and materials used in its manufacture, and summarizing evidence to support safety and effectiveness claims. To license IVDs in the highest classification, Class IV, a full design dossier must be submitted to support the application. Files for I and IV devices are sent directly to Health Canada for assessment. There is no third-party system in Canada equivalent to the European Notified Bodies. 28 May 2011

4 Table 2. Registration of IVD Products, Manufacturers and Device Licenses Europe (IVDD) Canada (MDR) Classification Product Manufacturer Classification Product Manufacturer (Professional use) Annex II List B Annex II List A Registration of product group with Competent Authority (CA) Assessment by Notified Body Registration with CA Registration with Competent Authority If not based in Europe, Authorized Representative in Europe required Class I I Class IV No device license required Device license required Establishment license required unless importing/ distributing product solely through company with establishment license Establishment license not required Quality Management System (QMS) Requirements The majority of manufacturers of IVDs probably have an approved quality system certified to ISO9001:2008 and/or ISO13485:2003 (Table 4). However, manufacturers of Class I products destined for sale in Canada are not obliged to have a certified quality system. devices must be manufactured under an ISO13485:2003 quality system, although the requirements of Clause 7.3 (Design and Development) can be excluded. Manufacturers of I and IV devices must have full quality system certification to ISO13485:2003, including design and development. The registrar certifying that the quality system conforms to the requirements of ISO13485:2003 must be recognized by Health Canada under the Canadian Medical Devices Conformity Assessment System (CMDCAS) and the auditors used must be qualified under the CMDCAS program, as the auditing process includes the elements of the CMDR. The QMS requirements for manufacturers of IVDs for sale in the EU are noticeably different. Manufacturers of devices that are not listed in Annex II of the IVDD do not have to have an approved quality system. Devices that are listed Table 3. IVD Device Technical Submissions Europe (IVDD) Canada (MDR) Classification Product Submission Classification Product Submission (Professional use) Annex II List B Annex II List A Technical file must be available No submission Self-declaration that requirements of IVDD met Technical file assessed by Notified Body Design examination certificate issued; alternatively, full quality assurance route (like Annex II products) may be used Technical file and quality system assessed by Notified Body Full quality assurance certificate issued Design dossier and quality system assessed by Notified Body Design examination and full quality assurance certificates issued Class I I Class IV Technical file must be available No submission to Health Canada required No product license required. Attestation of compliance to MDR submitted to Health Canada Technical file must be available Product license issued Summary technical file submitted to Health Canada supporting compliance with MDR Product license issued Full design dossier submitted to Health Canada supporting compliance with MDR Product license issued Regulatory Focus 31

5 Table 4. Quality System Requirements for IVD Manufacture Europe (IVDD) Canada (MDR) Classification Product Submission Classification Product Submission (Professional use) No certified QMS requirement Class I No certified QMS requirement Annex II List B Annex II List A No certified QMS requirement Quality system assessed by Notified Body. EC full quality assurance certificate issued. No requirement for ISO13485:2003 certification Quality system assessed by Notified Body. EC full quality assurance certificate issued. No requirement for ISO13485:2003 certification. All batches of product must be verified by Notified Body prior to release I Class IV ISO13485:2003 certification under CMDCAS required (design and development can be excluded) ISO13485:2003 certification under CMDCAS required (design and development must be included) ISO13485:2003 certification under CMDCAS required (design and development must be included) No requirements under MDR for batch verification. in Annex II are normally manufactured under a full quality assurance system that must be audited and approved by a Notified Body. The requirements for this full quality assurance system are based upon those in ISO13485:2003 but also include quality elements of the IVDD. Certification by a Notified Body alone, however, does not permit automatic certification to ISO13485:2003. Conversely, ISO13485 certification alone is not sufficient to show compliance with the IVDD. For convenience and to minimize costs, many manufacturers have their quality system certified to ISO13485 and IVDD requirements by a combined registrar and Notified Body. However, the quality system may be certified to ISO13485 by one registrar and to IVDD requirements by a completely separate Notified Body. Under the IVDD, Annex II List B products can alternatively be certified by a combination of EC Type Examination and EC Verification by a Notified Body. EC Type Examination requires assessment of product technical documentation and physical examination/testing of initial samples of the device to confirm that they have been manufactured in accordance with that documentation and meet the essential requirements of the IVDD. EC Verification requires examination and testing of all batches of product to ensure continued compliance with the IVDD. Similarly, Annex II List A products can also be initially certified by EC Type Examination, but this certification has to be supplemented by assessment and continuing surveillance of the manufacturer s production quality assurance system. These certification routes have not been described in detail as they are complex and few manufacturers of Annex II products opt for them. Additionally, it must be emphasized that, to comply with IVDD requirements, all Annex II List A products are subject to batch verification prior to QC release for sale. Each batch has to be certified by the Notified Body as compliant with its quality control release specifications by a process of independent testing or witness testing arranged by the Notified Body. There is no similar requirement in the Canadian regulations for verification and release of each batch of high-risk products prior to sale. Conclusion I have pointed out the principal similarities and differences between the current European and Canadian regulations on in vitro diagnostic medical devices. Although differences exist, there are opportunities to simplify the process a little if manufacturers intend to sell in both markets. As the technical documentation requirements for Notified Body certification and Canadian device licensing are similar, there is considerable scope for manufacturers to present the data in a format suitable for their regulatory applications in both regions. Additionally, the manufacturer s quality system can be audited for both Canadian and European IVD regulatory compliance in the most efficient and economical way by using a CMDCAS-recognized ISO13485 registrar that is also a European IVD Notified Body. Nevertheless, regulatory professionals at companies that are planning to sell IVD products on these markets should study the details of the IVDD and the CMDR to ensure full compliance with the legislation. These documents are available on the European Commission and Canadian 32 May 2011

6 Department of Justice websites. Further help and information can be obtained from any European Competent Authority or Health Canada directly. References 1. Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices. European Commission website. eu/consumers/sectors/medical-devices/documents/. Accessed 19 March Medical Devices Regulations (SOR/98-282). Department of Justice, Canada website. SOR /. Accessed 19 March Global Harmonization Task Force (GHTF): Principles of In Vitro Diagnostic (IVD) Medical Devices Classification (2008). GHTF website. sg1final_n045.pdf. Accessed 19 March Medicines and Healthcare products Regulatory Agency, London, United Kingdom. MHRA website. mhra.gov.uk/. Accessed 19 March European Commission Nando (New Approach Notified and Designated Organisations) Information System. European Commission website. enterprise/newapproach/nando/index.cfm. Accessed 19 March Underwriters Laboratories. UL website. ul.com/. Accessed 19 March Medical devices Legislation and guidelines. Health Canada website. md-im/legislation/index-eng.php. Accessed 19 March Commission Decision of 27 November 2009 amending Decision 2002/364/EC on common technical specifications for in vitro diagnostic medical devices (2009/886/EC). European Commission website. Accessed 19 March Author Ivor Barrett has 27 years of experience in design and development, manufacturing, quality control and quality assurance within the IVD medical device industry. He is currently an IVD certification manager in the UL Notified Body with additional responsibilities as a quality system lead auditor for the European IVD Directive, ISO13485, ISO9001 and CMDCAS. He holds a postgraduate doctorate from the University of London (Institute of Cancer Research). Disclaimer This article is intended for general information purposes only and is not intended to provide specific legal or other advice with respect to its subject matter and UL disclaims any responsibility or liability therefor. Regulatory Focus 33