Device Registration Pathways in Canada

Transcription

1 Device Registration Pathways in Canada By Nancy Ruth, RAC, CQA (ASQ) 32

2 In Canada, medical devices are regulated by Health Canada s Therapeutic Products Directorate and are subject to the Canadian Medical Devices Regulations (CMDR) in force since 1998, with subsequent amendments, under the Food and Drugs Act (F&D Act). The Canadian medical device program combines some of the best features of other major jurisdictions, notably the EU and US. Like the EU, risk-based classification rules incorporated into the regulations assist in assigning class and determining requirements of evolving technology, and manufacturer quality systems are reviewed by third parties. Similar to the US, publicly available databases allow visibility of products licensed by the regulator as well as licensed medical device establishments. However, the definition of a medical device in Canada does not articulate mechanism of action as physical, i.e., nonpharmacologic, nonchemical or nonimmunologic, as is the case with the US and EU definitions. This can result in positioning some products, which are marketed elsewhere as medical devices, as drugs or natural health products in Canada. Further, Health Canada s definition of a manufacturer in the CMDR and its interpretation of trademark control issues differ from some regulators and may create issues for global companies in product registration and labeling. While delegating responsibility for premarket and postmarket manufacturer quality system activities, Health Canada retains control over licensing and related oversight of product safety and effectiveness, which lends consistency in the review of technical documentation. The agency participates in a third-party audit program (Canadian Medical Device Conformity Assessment System or CMDCAS), recognizing ISO 13485:2003 as a global standard for medical device quality systems. This is expected to lead to mutual recognition of quality systems in other jurisdictions worldwide that acknowledge the standard. Searchable databases of licensed products (Medical Device Active Licence Listing) and establishments (Medical Device Establishment Licence Listing) are useful to healthcare professionals and consumers, who would like to know what products have been registered. The licensed product database is also a tool for companies to determine classification and licensing status of comparator products in Canada. Defining a Medical Device The F&D Act defines medical device as any article, instrument, apparatus or contrivance, including any component, part or accessory thereof, manufactured, sold or represented for use in: a. the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, in human beings or animals, b. c. d. restoring, correcting or modifying a body function or the body structure of human beings or animals, the diagnosis of pregnancy in human beings or animals, or the care of human beings or animals during pregnancy and at and after birth of the offspring, including care of the offspring, and includes a contraceptive device but does not include a drug. 1 The CMDR further clarifies this definition by stating it does not include devices intended for use in animals, but does include in vitro diagnostic devices that may contain drugs. Devices for investigational use, special access and custom use are also addressed in the regulations. Defining a Manufacturer The CMDR defines manufacturer as the person who sells the medical device under his or her own name or under a trademark, design, trade name or other name or mark owned or controlled by the person. The manufacturer is the party who is deemed responsible for designing, manufacturing, assembling, processing, labeling, packaging, refurbishing or modifying the device, or for assigning it a purpose, whether those tasks are performed by that person or on his or her behalf. Note that a person includes a partnership, firm or association. 2 Product labeling, license application and quality system certificates must all uniformly reflect the responsible, legal manufacturer. Premarket Regulation Health Canada s Medical Devices Bureau delivers the premarket portion of the medical devices program, which includes: product assessment and device classification quality systems medical device licensing Classification Medical devices are assigned to Class I, II, III or IV using rules set out in Schedule 1 of the CMDR, with Class I representing the lowest risk and Class IV the highest. Separate sets of rules address in vitro diagnostic devices. Risk factors for most medical devices include: degree of invasiveness duration of contact with patient body system affected local versus systemic effects energy transmission hazard (powered devices) consequences of device malfunction or failure Risk factors for in vitro diagnostic devices include: intended use, indications for use Regulatory Focus 33

3 Table 1. Medical Device Classification Examples and Regulatory Requirements Device Class Risk Examples: Non-IVDD Examples: IVDD License Requirements Class I Lowest Manual reusable surgical instruments, hospital beds, stretchers, wheelchairs, adhesive bandages, surgical drapes, cell culture media Class II Low Daily wear contact lenses, endoscopes, hydrogel dressings, blood bags, surgical drills Class III Moderate Orthopedic, dermal and dental implantables, hemodialysis machines surgical lasers, electrocautery units, bone cement Class IV High Cardiac pacemakers, angiography catheters, cranial shunts, replacement heart valves, pacemakers, closed loop therapeutic systems, cardiac sutures, CNS shunts Microbiology and cell culture media, general diagnostic reagents Home use pregnancy kits, laboratory use assays for glucose, complete blood counts and therapeutic drug monitoring Near patient blood glucose monitors and test strips; near patient drugs of abuse screening; some infectious disease assays; diagnostic cancer markers Transmissible disease markers for life-threatening diseases and donor screening, e.g., hepatitis, HIV Medical Device Establishment License: Manufacturer Importer Distributor Annual application, fees Medical Device License Manufacturer Medical Device Establishment License Importer Distributor Annual renewal, fees application, such as screening, patientbased testing, diagnosis, monitoring technical/medical/scientific expertise of user, i.e., testing laboratory versus home use importance of information to diagnosis sole determinant or one of several impact of result (true and false) to patient and/or public health The level of control applied by Health Canada reflects the risk classification. Class I devices present minimal risk and are exempt from the medical device licensing requirement. However, manufacturers of Class I devices are required to obtain a medical device establishment license. Class II, III and IV devices require the manufacturer to obtain a medical device license as well as an establishment license prior to advertising, import or sale of a device. Table 1 provides examples of product classification and licensing requirements. Quality Systems Manufacturers of Class II, III and IV devices must submit to Health Canada an ISO 13485:2003 quality systems certificate with medical device license applications. This must be issued by a by a registrar recognized by the Standards Council of Canada according to the CMDCAS. The registrar conducts a third-party audit for compliance with the standard and CMDR and issues the certificate with requirements specific to the CMDCAS program. Registration to the standard is an ongoing process, and related expenses are borne by the manufacturer. Manufacturers of Class I, special access, custom made and investigational devices are exempt from this requirement. Medical Device Licensing Products and Establishments All medical devices sold in Canada must meet the safety and effectiveness requirements of CMDR and must be labeled in compliance with the regulations. An application for a medical device license must be submitted to Health Canada for Class II, III and IV medical devices, and the license issued, before the devices can be placed on the market. Health Canada controls importers and distributors of all classes of medical devices, and manufacturers of Class I, through Medical Device Establishment Licencing. License Medical Device Licenses Manufacturers of all Class II, III and IV medical devices must apply for and obtain a medical device license from Health Canada prior to advertisement, import or sale of the product. A license may be issued for a single device or several devices bundled into a system, test kit, group, family or group-family. 3 Definitions and interpretation of what constitutes each of these bundles and how devices may or may not be sold outside the bundles are provided in a guidance document, 4 as these are not defined in the CMDR. 34

4 Table 2. Interim Target Performance Standards for Management of Applications for Medical Device Licenses and Investigational Testing Authorizations 8 Performance Standards (in calendar days) Application Type Screening 1 Review 1 Screening 2 Review 2 Investigational Testing Class II License Class III License Class IV License Priority Review Class III & IV License License Amendment i) Significant Change (Class III and IV) ii) Significant Change (Class IV) iii) Administrative Change Faxback Forms (all classes) TARGET=90% of the submissions in a category to be processed within the time shown. (Screening 2 and Review 2: the screening and review of additional information requested during the review of an application or amendment) All medical device licenses must be renewed annually by 1 November and are subject to a $100 renewal fee. Note that Class I medical devices are exempt from the medical device licensing requirement, but must meet safety and effectiveness requirements (CMDR, Sections 10 20) and labeling requirements (CMDR, Section 21). Class II Medical Devices The Class II Medical Device License Application includes attestations that the manufacturer possesses evidence of the device s safety and effectiveness, which is not submitted but must be available if requested. A statement that labeling complies with the regulations, although not required, should be included. It is advisable to include copies of device labeling in the Class II submission package to ensure Health Canada has sufficient information about the device. An ISO 13485:2003 quality system certificate noting fulfillment of particular requirements for CMDCAS, issued by a registrar recognized by Health Canada and the Standards Council of Canada, must be submitted with the application. The application fee of $200 (CDN) must be submitted. Target time to process the application is 15 calendar days. Class III Medical Devices A Class III Medical Device License Application must be accompanied by a premarket review document containing detailed information about the product including description, design philosophy, marketing history, summary reports of all preclinical and clinical studies, testing, packaging and labeling. An ISO 13485:2003 (CMDCAS) quality system certificate is required. 5 The application fee for Class III devices is approximately $1,980 but can vary depending upon the complexity of the device and review components needed. Target screening and review times are 15 and 60 calendar days, respectively. Class IV Medical Devices A Class IV Medical Device License Application includes, in addition to the information needed for a Class III premarket review document, a risk assessment, quality plan, material and manufacturing specifications, complete preclinical and clinical study reports with data, test reports and process validation studies. As with Class II and III applications, an ISO 13485:2003 CMDCAS quality system certificate is required. 6 The application fee for Class IV devices varies with the complexity of the device, but generally begins in the area of $10,000. Target screening and review times are 15 and 75 calendar days, respectively. Amendments Changes to a licensed medical device or its intended use must be considered by the manufacturer to determine whether they are significant and require a Health Canada amendment. An application for an amended license must be made before the change is effected. Administrative changes such as changes to manufacturer name, device name, device identifier and additions or deletions of catalog numbers can be submitted by fax-back amendment. Health Canada s target time to process these is seven days. Health Canada recently implemented notification of amendment to manufacturers by rather than fax. 36

5 For Class II licenses, a change in intended use requires submission of an administrative amendment application form, with a turnaround target of 15 days. For Class III and IV device licenses, significant changes require the submission of evidence of safety and effectiveness. Examples of such changes include change in design or performance specifications, materials, manufacturing methods or quality control procedures, and intended use. Guidance is available from Health Canada to determine whether a change is significant. 7 An application form and supporting dossier relevant to the change must be submitted; fees are calculated based upon the number and type of dossier components. Review targets are the same as for original license submissions. The amended license must be issued prior to importation or sale of the modified device. Practical Tips for License and Amendment Applications Identification of missing or incomplete information can result in screening deficiencies and requests for additional information by Health Canada. These lead to significant increases in review times and additional review cycles. See Health Canada policy, Management of Applications for Medical Device Licences and Investigational Testing Authorizations. Efforts should be made to determine Health Canada s expectations, especially safety and effectiveness requirements, where most deficiencies are encountered. Health Canada has few guidance documents to define required information for safety and effectiveness for specific product types. The guidance, Preparation of a Premarket Review Document for Class III and Class IV Device Licence Applications, released in 1998, does not provide enough information to ensure a comprehensive submission; it does not reflect the evolution of technology and regulatory thinking. Some US Food and Drug Administration guidance documents for specific product types are useful. Standards recognized by Health Canada and other agencies can indicate needed information and testing. Dialogue with agency reviewers is also helpful to determine requirements. A good narrative helps the reviewer understand the device. Health Canada has no substantial equivalence process; however, comparison of new devices with Canadian licensed products is expected. This is particularly important with performance and clinical testing for in vitro diagnostic devices. For amendment applications, provide a description and rationale for the changes with a clear explanation of previous versions of the device; a tabulated summary is preferred. An electronic copy of the submission in Microsoft Word or searchable pdf format in addition to the paper copy should be provided as a courtesy. Health Canada uses this source material to copy/paste into the review documentation. Medical Device Establishment License (MDEL) The manufacturer of a Class I device must hold a medical device establishment license (MDEL) unless sales are solely through establishment(s) that hold an MDEL. Class II, III and IV manufacturers are not required to hold an MDEL. Importers and distributors of all classes of devices are required to hold an MDEL. Exceptions are made for healthcare professionals, dispensers, institutions, retailers and those who import devices for personal use. License applications must be made annually, and the applicant must provide information related to company activities, sites, classes and medical specialties of devices sold and their manufacturers. Attestations are made and signed by a senior company official to confirm the accuracy of the information and the existence of documented procedures to meet regulatory obligations. These procedures include complaint handling, records distribution and recall. In addition, depending upon the activities and products handled, procedures for mandatory problem reporting, corrective action, product handling, delivery and service may be required. The application fee is $2,120; licenses expire annually on 31 December. 9 There is no performance target for application processing, which may require several weeks. Licensed establishments are subject to the Medical Device Inspection Program. Inspections are not performed before establishment licenses are issued. There is not a defined schedule for the inspections, and a reinspection cycle has not been established. Review Process Priority Review A manufacturer may apply for priority review for a Class III or IV medical device license intended for the diagnosis or treatment of a serious, life-threatening or severely debilitating disease or condition. The device must offer effective treatment or diagnosis of a disease or condition for which no medical device is currently licensed in Canada, or significant risk/ benefit improvement over existing licensed devices. The manufacturer s request must include substantial supporting clinical evidence. The policy provides for a review and screening target of 45 days from date of receipt by the Medical Devices Bureau. This path can provide a Regulatory Focus 37

6 inadequacy in its labeling or in its direction for use; and b. has led to the death or a serious deterioration in the state of health of a patient, user or other person, or could do so were it to recur Both manufacturers and importers must submit Mandatory Problem Reports to Health Canada within 10 days if the incident has led to death or serious deterioration of health or within 30 days if the incident has not led to death or serious deterioration of health, but could do so were it to recur. Duplicate reporting between manufacturers and importers can be avoided as the manufacturer can authorize (in writing to Health Canada) the importer to report on its behalf. 10 substantial advantage when there are prolonged review times due to a backlog of submissions. Submission Review Times Table 2 shows target timeframes for review of Medical Device License Applications, but submission screening and review times are currently backlogged in all sections of the Device Evaluation Division, with an average delay of approximately six months for Class III and IV submissions. To forecast the time to market, it is advisable to contact the Medical Devices Bureau when planning a submission. Postmarket Regulation Health Canada s Health Products and Food Branch Inspectorate conducts postmarket activities such as regulatory inspections for establishment licensing, mandatory problem report management and recalls. Manufacturers, importers and distributors of all classes of devices are subject to postmarket regulations, which include procedures for records distribution, complaint handling and recall. Manufacturers and importers are also responsible for mandatory problem reporting. The Medical Device Inspection Program reviews compliance with these requirements. Mandatory Problem Reporting This requirement applies to any incident (expected or unexpected) involving a legally marketed or investigational device that: a. is related to a failure of the device or a deterioration in its effectiveness, or any Recalls Health Canada defines recall as any action taken by the manufacturer, importer or distributor of the device to recall or correct a device or to notify owners and users of its defectiveness or potential defectiveness after becoming aware that the device may: be hazardous to health fail to conform to any claim made by the manufacturer or importer relating to its effectiveness, benefits, performance characteristics or safety may not meet the requirements of the F&D Act or the Medical Devices Regulations 11 This definition is broader than in some jurisdictions; actions not considered a recall in some countries may constitute a recall in Canada. Complaint Handling Health Canada requires the manufacturer, importer and distributor of a medical device to establish and implement documented procedures that will enable them to investigate problems and recall devices when necessary in an effective and timely manner. 12 Distribution Records Information to be contained in the records must be sufficient to permit complete and rapid withdrawal of the medical device from the market. Records must be accessible and retrievable quickly, and retained for the longer of these time periods: the device s useful life or two years after the date of shipment. Retailers and healthcare facilities are not subject to these requirements. 13 On the Horizon Canada is a founding member of and participant in the Global Harmonization Task Force (GHTF) and is moving toward implementation of some of the group s published documents. Guidance on the use of the Summary Technical Document 38

7 (STED) format in Canadian Medical Device License Applications is expected in mid Substantial fee increases for all license types are anticipated. These have been under discussion with industry for the past two years. Backlogs for review of medical device licenses are expected to continue. Declaration of information on Bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) is now included on license application forms. No minimum allowable levels have been set by Health Canada at present. Legislation respecting updates to the Food and Drugs Act (formerly Bills C-51 and C-52) is expected to be reintroduced and will affect regulation of medical devices. References 1. Food and Drugs Act of Canada, R.S., c. F-27, s. 1, Interpretation, Definitions. 2. Medical Devices Regulations, SOR/98-282, Interpretation. 3. Guidance For the Interpretation of Sections 28 to 31: Licence Application Type. Health Canada. January Ibid. 5. Guidance on Preparation of a Premarket Review Document for Class III and Class IV Device License Applications. Health Canada. April Ibid. 7. Draft Guidance for the Interpretation of Significant Change of a Medical Device. Health Canada. March Management of Applications for Medical Device Licenses and Investigational Testing Authorizations. Health Canada 9. Guidance on Medical Device Establishment Licensing. Health Canada. November Medical Devices Regulations, SOR/98-282, Sections Medical Devices Regulations, SOR/98-282, Interpretation. 12. Medical Devices Regulations, SOR/98-282, Sections Medical Devices Regulations, SOR/98-282, Sections Additional Resources Canadian Medical Devices Regulations CMDR SOR / Interpretation, Application and Classification CMDR SOR / Part 1: General CMDR SOR / Part 2: Custom Made Devices and Medical Devices to be Imported or Sold for Special Access CMDR SOR / Part 3: Medical Devices for Investigational Testing involving Human Subjects Medical Devices Regulations, SOR/98-282, Part 3: Medical Devices for Investigational Testing Involving Human Subjects & Health Canada Guidance: Preparation of an Application for Investigational Testing Medical Devices. Medical Devices Regulations, SOR/98-282, Part 2: Custommade Devices and Medical Devices to be Imported or Sold for Special Access & Health Canada Guidance: How to Apply for Authorization to Obtain Custom-made or Special Access Devices. Food and Drugs Act of Canada Medical Devices Bureau website Health Products Food Branch Inspectorate: Health Canada s Compliance & Enforcement, Medical Devices ISO 13485:2003 Medical devices Quality management systems Requirements for regulatory purposes Author Nancy Ruth, RAC, CQA (ASQ), is director, medical devices at CanReg Inc. and can be reached at nruth@canreginc.com. Co-authors were CanReg colleagues Kathryn Ronalds, RAC, associate director, medical devices and Shirley Furesz, RAC, senior regulatory affairs consultant. Regulatory Focus 39