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Contact Policy Bureau Enquiris

July 25, 2007

Our file number: 07-116254-984

Release of Discussion Paper for Consultation: Proposed Changes to the Regulatory Framework for Investigational Testing of Medical Devices

Health Canada is pleased to share with you the following discussion paper on proposed changes to the regulatory framework for Investigational Testing of Medical Devices. Health Canada is considering the proposed changes as a means to better manage the risks related to the conduct of investigational testing of medical devices, and to support Health Canada's interest in applying a risk management approach that is consistent with the approaches applied by other regulators, including the regulatory framework that Health Canada applies for clinical trials of drugs. This is consistent with the Auditor General's March 2004 Report, which recommended that Health Canada review its approach for managing the risks related to the conduct of investigational testing of medical devices, and take appropriate action to manage these risks.

The purpose of this consultation is to obtain feedback from stakeholders on the issues, analysis and recommended option as presented in the discussion paper. The discussion paper also presents important information for consideration, including updates on other Health Canada initiatives which may have an impact on investigational testing of medical devices in the future.

Comments provided to Health Canada should be submitted no later than October 25, 2007 in order to allow sufficient time for their assessment.

Comments should be directed to:
Investigational Testing Consultation
Bureau of Policy, Science and International Programs
Therapeutic Products Directorate
Holland Cross, Tower B, 2 nd Floor, A.L. 3102C5
1600 Scott Street
Ottawa ON K1A 0K9

Email: policy_bureau_enquiries@hc-sc.gc.ca
Telephone: 613-948-4623
Fax: 613-941-1812

Thank you for your interest and contribution. The input received through these public consultations will help guide our work to strengthen the risk management approach for investigational testing in order to minimize risks to participants while also encouraging research in Canada.

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Discussion paper for consultation

Investigational Testing of Medical Devices

Therapeutic Products Directorate

July 2007

Contents

1. ISSUE
2. PURPOSE
3. BACKGROUND
4. ISSUE ANALYSIS
5. OPTIONS ANALYSIS
6. CONSIDERATIONS
7. RECOMMENDATIONS
8. NEXT STEPS
Appendix: Terms and Abbreviations

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1. Issue:

There is a need for ongoing assessment of the regulatory environment and oversight of investigational testing in order to ensure that risks to participants are minimized while research, which may lead to health benefits for Canadians, is encouraged. The current regulatory framework for investigational testing is inconsistent with the approaches that are applied by other jurisdictions, including the regulatory framework that Health Canada applies for clinical trials of drugs.

2. Purpose:

The purpose of this discussion paper is to:

• present an analysis of the current Medical Devices Regulations, Part III - Medical Devices for Investigational Testing using Human Subjects, as they relate to potential health risks associated with investigational testing (IT);
• identify other initiatives that are currently linked to the review of the regulatory framework for investigational testing;
• consider options for strengthening the current regulatory framework for investigational testing, which includes addressing the issues identified in the March 2004 Auditor General's Report; and,
• obtain input from stakeholders on the issues, analysis and recommended option.

3. Background:

3.1 Introduction

In March 2004, the Auditor General of Canada noted, inter alia, that Health Canada's approach to managing the risks associated with investigational testing of medical devices was inconsistent with the approach it applies to clinical trials of other therapeutic products, as well as with the approaches taken by other international regulatory authorities¹. The Auditor General also cited various operational inconsistencies.

Health Canada regulates both clinical trials involving drugs and investigational testing involving medical devices. Drugs are consumed and typically have a systemic effect. Clinical trials for drugs follow a progressive path that begins only once extensive animal studies have been conducted, and often involve complex study designs. For example, an efficacy trial could involve the use of a placebo or another drug as a comparator. The study would typically involve blinding so the participant and, in the case of a double-blind study, the investigator would be unaware of which treatment is being administered. Investigational testing of medical devices, on the other hand, involves the use of mechanical devices and most often surgical procedures. The use of placebos or study designs involving blinding is much more challenging, complicated, and sometimes impossible for medical device trials.

Investigational testing, sometimes called clinical trials or clinical investigations, determines the safety and therapeutic effectiveness of a medical device through controlled testing on human subjects. An investigational test is generally designed to:

• verify that under specific indications for use, the device performs as intended by the manufacturer; and
• identify any risks and adverse events under normal conditions of use to allow assessment of whether these events are acceptable when assessed against the intended benefits of the medical device.

The Food and Drugs Act (FDA) sets out the legislative framework under which medical devices are regulated. Section 30(1) of the FDA provides for the subject matter within which the Governor in Council is authorized to make regulations with respect to medical devices, among other things. The regulations governing medical devices for investigational testing involving human subjects are contained in Part 3 of the Medical Device Regulations (MDR). These include requirements that need to be met by an importer or manufacturer in order to receive authorization from Health Canada to sell a device to a qualified investigator for the purpose of conducting investigational testing. Specifically, subsection 83(1) states that a medical device can be used for investigational testing only if Health Canada determines that it will not endanger the life, health or safety of patients or other persons, it is not contrary to the best interests of the participants, and the objective of the investigational testing will be met. Failure to safely conduct investigational testing could result in harm to participants, and failure to conduct effective tests could result in inaccurate results about the safety and therapeutic effectiveness of medical devices.

Responsibilities relating to the management of risks associated with medical device IT are cross-cutting. The following players involved in IT share and contribute in these responsibilities: Health Canada, manufacturer/importer (usually the sponsor and henceforth used interchangeably), qualified investigator(s), Data Safety Monitoring Board² (DSMB), ethics committee (at the health care facility at which the IT is being conducted), and the health care institution where the trial is taking place.

1 Report of the Auditor General of Canada, March 2004: Health Canada - Regulation of Medical Devices; Sections 2.47 - 2.53. Available online: http://www.oag-bvg.gc.ca/domino/reports.nsf/html/20040302ce.html

2 Data Safety Monitoring Board review is not required for low-risk studies

3.2 Related Initiatives

The goal of this initiative is to strengthen the risk management approach for investigational testing in Canada by specifically addressing the issues that are identified in the March 2004 Auditor General's Report, however, a number of current Health Canada initiatives are also examining issues that are linked to the regulatory framework for investigational testing. While this initiative will focus on the recommendations made by the Auditor General, other issues related to investigational testing will be addressed through these separate initiatives, including the following:

• Review of the 2001 Clinical Trials Regulatory Framework:
  Part C, Division 5 of the Food and Drug Regulations
  Presently, Health Canada is conducting a review of Division 5 of the Food and Drug Regulations for clinical trials. While the short-term outcomes of this review are mainly administrative and are not expected to impact the Medical Device Regulations, some long term recommendations and other issues resulting from this review will need to be considered from both a drug and medical device perspective. More information about this initiative can be found on the Health Canada website, and details regarding next steps will be available in late Summer 2007:
  http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/consultation/clini-rev-exam/index-eng.php

• The Health Products and Food Branch (HPFB) Blueprint for Renewal initiative
  The Blueprint for Renewal initiative was launched in 2006 with the goal to modernize the way HPFB regulates health products and food, including medical devices. More information on Blueprint for Renewal and its supporting initiatives can be found on the Health Canada website at:
  http://www.hc-sc.gc.ca/ahc-asc/branch-dirgen/hpfb-dgpsa/blueprint-plan/index-eng.php

• Registration and Disclosure of Clinical Trial Information
  The aim of this Health Canada initiative is to develop a Canadian approach for improving the public availability of information about clinical trials for drugs and investigational testing for medical devices. Registration in a publicly accessible registry would improve transparency, making information about clinical trials and investigational testing available to patients, researchers, physicians, and other interested stakeholders. For more information about this initiative, please see the Health Canada website at:
  http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/proj/enreg-clini-info/index-eng.php

• Therapeutic Combination Products
  The Health Products and Food Branch (HPFB) has convened a working group to review and assess Health Canada's current framework for therapeutic combination products involving medical devices and drugs (including pharmaceuticals, biologics, radiopharmaceuticals and natural health products). The aim of the working group is to develop a comprehensive, transparent and efficient system for the assessment of therapeutic combination products including those intended for investigational testing or clinical trial. A consultation document is forthcoming in 2007.

• Review of the Special Access Programme
  Health Canada is currently conducting a comprehensive review of the Special Access Programme (SAP) in order to modernize the regulatory framework supporting the Programme. The SAP provides Canadians with limited access to drugs and medical devices that cannot otherwise be sold or distributed in Canada. Authorization for access is provided to health care practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, unavailable or offer limited options.

  The regulatory framework to support the Programme was established in 1966 and a comprehensive review is required to modernize the framework and further define authorities. Moreover, a different special access scheme was created under the Medical Devices Regulations (established in 1998). This review will additionally seek to reconcile the relevant differences between the regulations supporting the two special access programs.

  The comprehensive review of the SAP is multi-faceted, involving an operational review to evaluate how the Programme is functioning within its existing framework, and an ethics review to study the ethical context of the mandate and activities of the SAP. These projects, as well as ongoing work on a regulatory amendment to permit the block release of non-marketed drugs for health emergency or bio-defence situations, will inform a broad policy/regulatory review aimed at modernizing the Programme. This review will involve the development of options to address the various challenges associated with the SAP. Health Canada will provide opportunities for stakeholders and the Canadian public to contribute to this review through consultations.

• Accreditation of Human Research Protection Programs
  The Health Policy Branch (HPB) is participating in the Sponsors' Table for Human Research Participant Protection in Canada. The Sponsors' Table is a group of organizations that shares a common interest in promoting research involving humans that meets the highest standards in excellence and ethics. T he Sponsors' Table has come together to facilitate a process to develop and assess an accreditation or alternative system for human research participant protection taking into consideration all relevant sectors and players in Canada. An Experts Committee has been established to provide expert advice, from relevant disciplines and fields, on the development and assessment of a model accreditation (or comparable) system for human research participant protection in Canada.
  For more information please the Sponsors' Table website at:
  www.hrppc-pphrc.ca.

• Development of a Standard for Research Ethics Boards Reviewing Clinical Trial Applications
  Health Canada has reached an agreement with the Canadian General Standards Board (CGSB) to facilitate the development of a voluntary standard for Research Ethics Boards (REBs) that review clinical trial applications. The voluntary standard initiative is a way of providing guidance to REBs that are required to review clinical trial applications under the regulatory framework for clinical trials. The goal of this initiative is to bring stakeholders together in a process to develop operational support and guidance for REBs in the form of voluntary standards. The standards will also aim to enhance harmonization by providing REBs that review clinical trial applications with a common approach to functioning. An organizing meeting was held with stakeholders in March 2007 where broad support for the project was received. The next step is to establish a technical committee, which will then be responsible for drafting the standard.

3.3 Current Procedures and Requirements

Investigational testing of medical devices in human subjects has become a growing area for research and development in Canada since the establishment of the new Medical Device Regulations in May 1998. There has subsequently been an increase in the number of submissions received by Health Canada for medical devices.³

An investigational testing application (ITA) to Health Canada is indicated when a medical device has been shown to have a reasonable probability of safety and effectiveness after the completion of all appropriate preclinical and animal studies. For some novel medical devices it is not possible to establish effectiveness unless investigational testing is carried out on humans⁴. Upon completion of the preclinical and animal studies, the sponsor (who is also the manufacturer/importer) must establish an investigational testing idea/concept for the involvement of humans, which leads to the investigational plan.

The Medical Devices Regulations (MDR) are made under the FDA and are directed at regulating the safety and effectiveness of medical devices sold in or imported into Canada. The MDR are divided into five parts, with Part 3 being dedicated to the subject of investigational testing. Health Canada's regulatory requirements for medical devices IT involving human subjects are contained in Part 3 of the MDRs, sections 79 to 88. These requirements focus on the essential data that a sponsor must present to Health Canada in order to obtain authorization to conduct investigational testing. Section 80 of the MDR prohibits the sale and import of devices for investigational testing unless a manufacturer/importer is selling the device to a qualified investigator for the purpose of investigational testing as described in 80 (2) or (3).

A risk classification scheme has been developed to categorize medical devices according to their potential risk; the degree of regulation imposed on any device is proportional to its risk. The rules for classification are based on the following indicators: degree of invasiveness, duration of contact, body system affected, and local versus systemic effects. While Class I medical devices present the lowest potential risk and are not required to submit applications for investigational testing to Health Canada, Class IV devices present the greatest potential risk; an Investigational Testing Application (ITA) must be submitted to Health Canada for investigational testing involving Class II, III and IV devices⁵. Pursuant to section 80 of the MDR, no person shall import or sell a medical device for investigational testing without authorization from HC, which is given following compliance with all of section 81.

Section 81 (Records) includes the following requirements for Class III and IV devices: the name and contact information for the manufacturer and importer; information about the device (including name, class, identifier, description of materials and features, market history); a risk assessment; the names and qualifications of all qualified investigators; information about the institution(s) where the investigational testing will be conducted; the protocol; a copy of the device label; and, written undertaking from each qualified investigator. F or Class II devices, only the requirements set out in paragraphs 81(a), (b), (h), (i), and (j) apply: the name and contact information for the manufacturer and importer; information about the device (name, class, identifier); information about the institution(s) where the investigational testing will be conducted; the protocol; and, a copy of the device label.

Additionally, sections 82 and 83 address Authorization; sections 84 and 85 address Additional Information; section 86 addresses Labelling; section 87 addresses Advertising; and section 88 addresses Other Requirements covering the requirements for distribution records, complaint handling, mandatory problem reporting, recalls, and implant registration.

The manufacturer/importer is responsible for submitting the ITA (which includes the information listed above) to Health Canada for review. In some circumstances, the ITA is submitted to Health Canada without the final REB approval; however, Health Canada cannot authorize the ITA until the REB approval is submitted. The role of the REB, established at the health care institution where the IT will be conducted, is to safeguard the rights, safety and well-being of all research participants by reviewing and approving research projects that meet acceptable ethical and scientific standards⁶.

ITAs are screened by Health Canada prior to the commencement of a review, and the screening period is included in the thirty (30) calendar day target review time. If an ITA is accepted for review, a Screening Acceptance Letter is issued to the manufacturer/importer. Upon review of the ITA, if all information is acceptable, the IT manufacturer/importer will receive authorization from Health Canada⁷.

If the information provided in the ITA is not adequate, the manufacturer/importer will either receive a Screening Deficiency Letter, an Additional Information (AI) Letter, or a Refusal Letter. Manufacturers/importers have fifteen (15) calendar days to respond to Screening Deficiency requests, and sixty (60) days to respond to AI requests⁸.

For AI Letters, the manufacturer/importer is given sixty (60) calendar days from the date of the letter in which to submit the requested information in question and answer format. The review clock is stopped from the date of the AI Letter. Upon receipt of the response to the AI Letter, a facsimile acknowledging the receipt of the additional information will be issued to the manufacturer/importer and a new thirty (30) calendar day review period begins. A Refusal Letter will be issued by the Bureau Director in the following circumstances:

• failure to submit the requested information in response to an AI Letter within the sixty (60) calendar days specified, or submission of an incomplete or deficient response;
• failure of the manufacturer/importer to meet the requirements of the Medical Devices Regulations or any provisions of the Act; or
• the manufacturer/importer has made a false or misleading statement in the application.

The Refusal Letter will contain the specific reasons or deficiencies that resulted in the decision to refuse issuance of the authorization for IT.

Once the manufacturer/importer receives authorization for the ITA, the qualified investigator(s) may begin the implementation phases included in the plan. When the IT is set up, the qualified investigator(s) may begin conducting the IT. In the case of ITs of high risk devices, the manufacturer/importer may establish a Data Safety and Monitoring Board (DSMB), also known by other names (e.g., data monitoring committees), as a mechanism for monitoring interim data in clinical trials in order to ensure the safety of the participating subjects by analyzing adverse events and by performing interim analyses of the clinical outcome data. DSMBs are commonly composed of biostatisticians, scientists, bioethicists, and clinicians who are knowledgeable about the question being studied.

When an IT results in negative findings, the study may be either discontinued by the manufacturer/importer or suspended by Health Canada. Conversely, when an IT results in positive findings, the manufacturer/importer typically submi ts a medical device license application which would include the findings from the IT for review by Health Canada.

3 Health Products and Food Branch: Regulatory Review of Drugs, Biologics and Medical Devices - 2005 Annual Summary of Performance; p.8. Available online at: http://www.hc-sc.gc.ca/ahc-asc/alt_formats/hpfb-dgpsa/pdf/pubs/performance_rendement_2005-eng.pdf

4 Therapeutic Products Directorate Guidance Document: Preparation of an Application for Investigational Testing - Medical Devices; Section 4.0. Available online at: http://www.hc-sc.gc.ca/dhp-mps/md-im/applic-demande/guide-ld/test_md3_im3-eng.php.

5 Therapeutic Products Directorate Guidance Document: Preparation of an Application for Investigational Testing - Medical Devices. Available online: http://www.hc-sc.gc.ca/dhp-mps/md-im/applic-demande/guide-ld/test_md3_im3_main_principal-eng.php#61

6 Regulations Amending the Food and Drug Regulations (1024 - Clinical Trials), Regulatory Impact Analysis Statement; p.25. Available online at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/compli-conform/1024-eng.pdf

7 Therapeutic Products Directorate Guidance Document: Preparation of an Application for Investigational Testing - Medical Devices; Section 2.2. Available online at: http://www.hc-sc.gc.ca/dhp-mps/md-im/applic-demande/guide-ld/test_md3_im3-eng.php.

8 Ibid. Section 8.0

3.4 Areas to be addressed

The conduct of IT is not required by regulations to conform with the principles of Good Clinical Practices (GCPs); there are no requirements for interim/final reporting of results to Health Canada for monitoring purposes; there is no inspection program in place to ensure that the qualified investigator(s) are following the approved protocol and conducting the IT in accordance with GCPs. In order to mitigate the risks associated with medical device IT, Health Canada is examining how to best address these gaps.

>4. Issue analysis:

While medical device trials are not formally classified by phase (as for drugs), there are similarities between the stages of medical device development and medicinal/drug development. The concept of a new medical device is often subject to extensive preclinical testing (such as bench testing and immunogenicity testing) and, when appropriate, animal testing. The invasive nature of many medical devices precludes testing in healthy volunteers, necessitating the use of animal model testing to help assess biocompatibility, safety and efficacy. Manufacturing feasibility studies may also be conducted in order to ensure that the device can be made repeatedly; these studies may look at lot or formulation variability, design improvements, materials specifications, etc⁹. Initial IT of devices involves a pilot study in small groups of patients. If the feasibility of the concept is proven, larger studies with well-designed protocols and a sound statistical basis are undertaken.

The following analysis identifies the differences between the medical device trial/investigational regulatory requirements of foreign agencies [U.S. Food & Drug Administration (FDA), the European Union (EU), and the Australian Therapeutic Goods Administration (TGA)] and Health Canada's (HC's) present requirements in the MDR. Also identified are the gaps between HC's drug clinical trial regulatory framework and HC's medical device IT regulatory framework.

9 Stark, N.J. Clinical Trial Design, Third Edition, Clinical Design Group Inc 2000. ISBN: 1-889160-02-4.

4.1 Good Clinical Practices

Good Clinical Practices (GCPs) are an essential risk management tool. GCPs are international ethical and scientific quality standards for the design, conduct, monitoring, recording, auditing, analysis, and reporting of studies. GCPs ensure that the data reported are credible and accurate, and that subjects' rights and confidentiality are protected. The International Conference on Harmonisation (ICH) for drugs is comparable to t he Global Harmonization Task Force (GHTF) for medical devices; the ICH has developed guidelines for GCPs (ICH E6) and the GHTF recognizes ISO 14155 as the standard addressing the requirements for good clinical practices. Although ICH E6 and ISO 14155 were developed by different organizations and different fora, each addresses the objectives for good clinical practices:

• ISO 14155 ( Clinical Investigation of Medical Devices for Human Subjects) defines procedures for the conduct and performance of clinical investigations of in vivo medical devices (not for in vitro devices). It specifies general requirements intended to:

  • protect human subjects;
  • ensure the scientific conduct of the clinical investigation;
  • assist sponsors, monitors, investigators, ethics committees, regulatory authorities and bodies involved in the conformity assessment of medical devices.

• ICH E6 - Good Clinical Practice: Consolidated Guideline¹⁰, which has been adopted by Health Canada for drug clinical trials, defines GCPs as an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

A comparison of the medical devices frameworks of the FDA, EU and TGA shows that HC is the only jurisdiction that does not require in regulation that medical device IT conforms to GCPs. The FDA included the requirement to conduct IT in accordance with the principles of GCPs into regulation (21 CRF 812.40 and 21 CFR 812.100(e)); FDA has set up the Bioresearch Monitoring (BIMO) which is an agency-wide program that inspects trial sites against conformance with GCPs; ICH GCP guidelines are also referenced and followed for drug clinical trials, but not for medical device IT. Similarly, t he EU's regulations requiring GCP conformance came into force in May 2004. The TGA has regulatory requirements established for the conduct of medical device trials in accordance with the National Statement on Ethical Conduct in Research Involving Humans, which states that the ethics committee and the researcher must follow the requirements of ISO 14155 Clinical Investigation of Medical Devices on Human Subjects.

In Canada, the human drug clinical trial requirements are set out in Division 5 of the Food and Drug Regulations and GCPs are captured under section C.05.010; HC has adopted ICH GCP guidelines for additional guidance on the subject. There are no regulatory requirements or guidelines specific to medical device GCPs in place.

10 International Conference on Harmonisation (ICH) E6 - Good Clinical Practice: Consolidated Guideline. Available online at: http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/efficac/e6-eng.php

4.2 Trial Inspection Program

Inspection programs are essential as a compliance and enforcement tool. Presently, there is no inspection program in place for medical device IT in Canada. The U.S. FDA completes clinical trial inspections for drugs and medical devices at approximately 1 to 2 percent of the total number of clinical trials per year. The EU has an audit program (or GCP inspection program) in place for drugs but does not have an inspection program in place for medical device clinical trial sites. The TGA is considering implementing an inspection program within 3 years, and is aiming to inspect 1 to 3 percent of drug and medical device trial sites.

In Canada, drug clinical trial sites are inspected by the Health Products and Food Branch Inspectorate (HPFBI). The inspection program covers approximately 2% of all drug clinical trial sites per year. There is no inspection program for medical device IT.

4.3 Interim and Final Reporting to the Regulatory Agency

Reporting the progress of an IT to the reviewing regulatory agency, in terms of interim and final results, is an important monitoring tool which ensures that the trial is being conducted in accordance with the protocol, and that the expected results are being observed. Reporting interim and/or final results is also a mechanism which captures negative or potentially hazardous occurrences. Interim and/or final reporting would provide information to HC which may mitigate risks associated with similar ITs, particularly where the IT does not result in a premarket application.

Currently, the sponsor is not required to submit interim and/or final reports on medical device IT results to HC for review. The only reports required by HC are in accordance with section 81(v) of the MDR, which states that the qualified investigator must report a failure of the device or a serious adverse event related to a medical device to the manufacturer or importer and to HC within 72 hours after it comes to the attention of the qualified investigator.

In the U.S., clinical studies of medical devices are categorized as exempt, non-significant risk, or significant risk. Exempt studies are not regulated by FDA. These studies are conducted using devices that already have marketing approval in the U.S. and are being used according to their approved directions for use, or involve in vitro diagnostic devices where the diagnosis can be confirmed by another accepted method. Non-significant risk studies are those that do not pose a significant risk to subjects. They are subject to Institutional Review Board (IRB) approval; the IRB also makes the determination of non-significant risk, and considers both the device and protocol in doing so. Significant risk studies are those that present a significant risk to subjects and typically involve an implant, a life-supporting or life-sustaining device, or a device that presents the potential for serious risk. Before they begin, significant risk studies must first be approved by the IRB and receive an Investigational Device Exemption (IDE) from the FDA¹¹.

Section 812.150 of the U.S. Code of Federal Regulations (CFR) outlines the various types of reports that the sponsor is responsible for, and to whom the reports should be submitted, depending upon the risk classification of the device:

• Sponsor reports include the following:
  • unanticipated adverse device effects (to the FDA and ethics committee/IRB);
  • withdrawal of ethics committee approval (to the FDA);
  • withdrawal of FDA approval (to the ethics committee);
  • current investigator list (to the FDA) in 6 month intervals;
  • progress reports (to ethics committee if nonsignificant risk device; to ethics committee and FDA if significant risk device) semi-annually;
  • recall and device disposition (to FDA and ethics committee);
  • final report (to the ethics committee if nonsignificant risk device; to FDA and ethics committee if significant risk device) within 6 months of completion or termination of the investigation;
  • informed consent (to FDA if informed consent not properly obtained);
  • significant risk device determinations (to the FDA if the sponsor does not agree with the ethics committee on the determination); and others.

The EU's Medical Devices Directive allows the Competent Authorities to request a final report of a clinical investigation of a medical device; requirements are also established for adverse event reporting, requesting that all serious device and non-device related adverse events are reported to the Competent Authority.

In Australia, clinical trials are conducted under one of two schemes based on the risks associated with the trial [Clinical Trial Exemption (CTX) and Clinical Trial Notification (CTN)]. Under both schemes, the ethics committee of the institution in which the trial is to be conducted is primarily responsible for the approval and monitoring of the trial, and for setting any conditions which, for example, may include the reporting of interim and/or final results to the ethics committee. The TGA does not have requirements in regulation for submitting interim and/or final reports of medical device trial results. Like HC, the TGA requires that the investigational information be included in the premarket submission.

In Canada, interim reporting of clinical trials of drugs is accomplished through updates to the Investigator's Brochure (IB). Division 5 of the Food and Drug Regulations requires that an updated Investigator's Brochure (IB) be submitted to HC annually for all Clinical Trial Applications (CTAs); IBs are also submitted to HC if they are re-written or updated. As described in ICH Guidance E6: Good Clinical Practice, the IB is a compilation of the clinical and non-clinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects and includes the following information:

• Title page (e.g., sponsor name, identity of each investigational product, the release date);
• Confidentiality statement (optional);
• Table of Contents;
• Summary (i.e., highlighting the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product);
• Introduction;
• Physical, Chemical, and Pharmaceutical properties and formulation;
• Non-clinical studies (i.e., discussion of the most important findings);
• Effects in Humans (including safety, efficacy, pharmacodynamics, dose responses); and
• Summary data and Guidance for the Investigator (overall discussion of the non-clinical and clinical data, as an informative interpretation of the available data).

The annual IB updates that are submitted to Health Canada may also include final results of completed clinical trials if these provide new safety information that is relevant to an ongoing trial. In addition, t he clinical trial reviewer at HC may request more specific information than is listed above (e.g., interim analysis reports, DSMB findings, etc.). AE reporting is also a requirement for drugs. There are no requirements relating to interim and/or final trial reporting for medical devices at HC apart from AE reporting.

11 Stark, N.J. Clinical Trial Design, Third Edition, Clinical Design Group Inc 2000. ISBN: 1-889160-02-4.

4.4 Ethics Committee Roles and Responsibilities

It should be noted that ethics committees are referred to by HC as Research Ethics Boards (REBs); by the TGA as Institutional Review Boards (IRBs) and Human Research Ethics Committees (HRECs); by the EU as IRBs and Ethics Committees (ECs); and by the FDA as IRBs.

Ethics committees play an important role in protecting human research participants. The impact of ethics committees on the management of risks associated with ITs varies depending on their responsibilities.

Following is a summary of the roles and responsibilities of the ethics committees in Canada, U.S., Europe, and Australia:

• Canada: There are a number of different types of REBs, such as those affiliated with universities and hospitals, private REBs that operate on a for-profit basis, and REBs affiliated with private research organizations. The current overall governance of research ethics involving humans and REBs in Canada is covered by a combination of guidelines, policies, and regulations, the most prominent of which being the Tri-Council Policy Statement (TCPS),¹² which is the national research ethics guidance document in Canada, and ICH Guidance E6 - Good Clinical Practice: Consolidated Guideline, which is the international regulatory guidance document.

  While many REBs function within public health institutions, and as such are accountable to the governing boards of these institutions, accountabilities of private REBs are unclear. REBs are not within the regulatory jurisdiction of HC. REBs are meant to be independent of the regulator, but the lack of a governance structure for REBs continues to raise concern,¹³ particularly with regards to private REBs since these not under the purview of a hospital or other governing body.

  REB involvement in investigational testing is captured under section 81(h) of the MDRs; f or Class III and IV ITAs, written approval from each proposed institution's REB must be provided with the application. REBs function as a safeguard of the rights, safety and well-being of all research participants by reviewing and approving research projects that meet acceptable ethical and scientific standards¹⁴.

• United States: The IRBs are responsible for trial approval, including the protocol. IRBs conduct continuing review of research covered by the FDA's regulations at intervals appropriate to the degree of risk, but no less than once per year. FDA also allows independent or non-institutional IRB review, which is referred to as "non-local IRB review." A written agreement must be in place in order to clarify the IRB's role and responsibility for the oversight and ongoing review of the research.¹⁵

• Europe: The EU's new Clinical Trials Directive requires that a single favourable ethical opinion must be given for each Member State in which the trial has been authorized.¹⁶ This method results in varying responsibilities for IRBs/ECs in member states. However, all IRBs/ECs are responsible for trial approval, on-going risk/benefit assessments, and trial monitoring. The EU is currently looking to increase the responsibilities of the ethics committees.

• Australia: The HRECs/IRBs are responsible for trial approval, including the protocol. IRBs/HRECs receive progress reports at specified intervals and a final report from principal researchers.

  The TGA applies two different schemes for trials of therapeutic goods. Under the Clinical Trial Notification (CTN) Scheme, the TGA does not need to approve the trial but must receive notification and the required notification fee prior to the trial commencing. For CTN trials, the IRB/HREC is responsible for assessing the scientific validity of the trial design, the safety and efficacy of the medicine or device and the ethical acceptability of the trial process, and for approval of the trial protocol. The institution or organization at which the trial will be conducted, referred to as the 'Approving Authority', gives the final approval for the conduct of the trial at the site, having due regard to advice from the IRB/HREC.

  The Clinical Trial Exemption (CTX) Scheme is an approval process that involves an application to the TGA as well as approval from an ethics committee. During the initial application stages, the TGA reviews the product information submitted by the clinical trials sponsor and provides written advice regarding the accuracy or interpretation of the data. If the TGA has no objection, the sponsor submits a data package to the HREC. The sponsor must secure approval from the HREC in order for a clinical trial to be carried out.

  The HREC's main role is to approve proposed trial protocols after reviewing the summary information received from the sponsor and comments from the TGA. Furthermore, the HREC has the ability to request any additional information from the sponsors to carry out their evaluation. HREC provides advice to the sponsor before and during the course of a trial to ensure that both CTN and CTX trials are carried out in accordance with Good Clinical Practice guidelines and the Australian National Statement on Ethical Conduct in Research Involving Humans, 1999. In signing a notification form submitted by the sponsor and approving their clinical trial protocols, the HREC accepts responsibility for monitoring the progress and conduct of the trials.¹⁷

12 Tri-Council Policy Statement (TCPS): Ethical Conduct for Research Involving Humans. Available online at:
http://www.pre.ethics.gc.ca/english/pdf/TCPS%20October%202005_E.pdf

13 Health Products and Food Branch: Clinical Trials Regulatory Review - Results of 2006 E-Consultation, December 2006; p.18. Available online at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/prodpharma/e-consultation-eng.pdf

14 Regulations Amending the Food and Drug Regulations (1024 - Clinical Trials), Regulatory Impact Analysis Statement, June 2001; p.25. Available online at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/compli-conform/1024-eng.pdf

15 U.S. Food and Drug Administration: Information Sheets - Guidance for Institutional Review Boards and Clinical Investigators, 1998 Update: Non-Local IRB Review. Available online at: http://www.fda.gov/oc/ohrt/irbs/nonlocalreview.html.

16 Official Journal of the European Communities: Directive 2001/20/EC [Clinical Trials], Issue 121; p.39. Available online at: http://europa.eu.int/eur-lex/pri/en/oj/dat/2001/l_121/l_12120010501en00340044.pdf.

17 Therapeutic Goods Administration: Human Research Ethics Committees and the Therapeutic Goods Legislation, January 2001; pp 7-12. Available online at: http://www.tga.gov.au/docs/html/hrec.htm

4.5 Comparison Tables

Table 1 below illustrates the similarities and differences of the investigational regulatory requirements included in the general application forms established by HC, FDA, EU, and the TGA. Major gaps are apparent: HC is the only regulatory body which does not require conformance with Good Clinical Practices ( GCPs); there are no monitoring requirements in terms of interim and/or final reporting; and there are no inspections of trial sites.

Table 2 below illustrates the similarities and differences of the investigational regulatory requirements between HC's drug and medical device areas. Gaps are evident in this case as well: the medical device framework does not include conformance with GCPs; there are no monitoring/reporting requirements; and there are no inspections of trial sites. The drug area does not require labelling to be submitted.

The gaps and differences relating to the regulatory requirements and frameworks for medical device investigational testing/clinical trials, established by HC and other regulatory jurisdictions, are outlined above and in the tables below.

Finally, HC is considering changing the term "investigational testing" to "clinical investigation," which is the term used in ISO standard 14155 for GCPs.

Table 1: Comparison of the medical device investigational requirements for HC/FDA/EU/TGA

	HC/MDB Investigational Testing Authorization (ITA)	FDA/CDRH Investigational Device Exemption (IDE - SR)18	EU Clinical Trial (CT)	TGA Clinical Trial (CT) CTN19 and CTX20
General Requirements of Application Form (rearranged for comparison)	- Intro Manufacturer info Device info Institutional info - Risk Assessment - Protocol - Device Label - Investigator info - Ethics approval - No requirements for maintenance of records	- Intro Manufacturer info Device info Institutional info - Risk Assessment - Protocol - Device Label - Investigator info - Ethics approval - Maintain records for 2 years upon completion of trial	- Intro Manufacturer info Device info Institutional info - Risk Assessment - Protocol - Device Label - Investigator info - Ethics approval - No requirements for maintenance of records	- Intro Manufacturer info Device info Institutional info - Risk Assessment - Protocol - Device Label - Investigator info - Ethics approval - Maintain records for 15yrs
GCP requirements	NO	YES ICH	YES Compliance with ISO 1415521	YES Compliance with ISO 14155
Interim and/or final reporting	NO	YES Also developed the Bioresearch Monitoring Program	YES	YES
Ethics Approval	REB22	IRB23	IRB, EC24	HREC25, IRB
Inspection of Trial sites	No inspection program.	~1 to 2% of sites are inspected yearly. Also do compliance inspections when AEs reported.	Inspect both commercial and non-commercial trial sites according to GCP requirements.	Proposing to inspect ~1 to 3% of trial sites

Note: At HC, only the following sections of the MDRs are required for Class II medical devices - sections 81 (a), (b), (h), (i) and (j).

18 IDE: An Investigational Device Exemption (IDE) application must be submitted to the FDA before investigational testing can be conducted on a medical device. IDE applications are only required if the medical device has been determined to be a "significant risk" (SR) device.

19 CTN: A Clinical Trial Notification (CTN) must be submitted to the TGA upon commencement of an investigational testing of a medical device - no formal application required.

20 CTX: A Clinical Trial Exemption (CTX) application must be submitted to (and approved by) the TGA before investigational testing can be conducted on a medical device.

21 ISO 14155: Standard for "Clinical Investigation of medical devices for human subjects"

22 REB: Research Ethics Board - HC. Equivalent to EC, IRB and HREC.

23 IRB: Institutional Review Board - FDA & EU & TGA & HC. Equivalent to EC, REB and HREC.

24 EC: Ethics Committee - Equivalent to REB, IRB, HREC.

25 HREC: Human Research Ethics Committee - TGA. Equivalent to EC, REB and IRB.

Table 2: Comparison of Health Canada requirements - Clinical Trials of Drugs vs. Investigational Testing of Medical Devices

	HC/Medical Devices Investigational Testing Authorization (ITA)	HC/Drugs Clinical Trial Application (CTA)
General Requirements of Application Form (rearranged for comparison)	- Intro Manufacturer info Device info Institutional info - Risk Assessment - Protocol - Device Label - Investigator's info - Ethics approval prior to authorization - No requirements for maintenance of records - No requirements for Quality Management System (QMS)	- Intro Manufacturer info Drug info Institutional info - Risk Assessment - Protocol - Label not required (unless requested) - Investigator info - Ethics approval after receiving No Objection Letter (NOL) - Maintain records for 25yrs - Requirements for Quality (Chemistry & Manufacturing) and Good Manufacturing Practices (GMP)
Good Clinical Practice requirements	NO	YES
Monitoring/reporting requirements	NO	YES
Ethics Approval	Research Ethics Board (REB)	Research Ethics Board (REB)
Inspection of Trial sites	No inspection programme.	Up to 2% of sites are inspected, along with the REBs that approved the studies. Also do compliance inspections when problems or concerns are brought to our attention.

Note: At HC, only the following sections of the MDRs are required for Class II medical devices - sections 81 (a), (b), (h), (i) and (j).

5. Options analysis

This is not an acceptable option as the analysis demonstrates that the present regulatory framework requires improvement to more thoroughly address health risk issues associated with medical device IT. Also, HC has made commitments to address the risk management issues outlined in the Auditor General's report.

Pros:

• No financial cost would incur.

Cons:

• The present regulatory framework does not include GCPs, interim and/or final reporting to HC, or inspection of trial sites, and therefore does not adequately address the risks to health associated with IT.
• Commitments following the Auditor General's recommendations would not be met.
• The present regulatory framework is not aligned with other regulatory jurisdictions or with the regulatory framework for clinical trials of drugs in Canada. Failure to address this may undermine the credibility of the Canadian regulatory system for investigational testing, which may discourage the conduct of investigational testing in Canada and put medical devices approved in Canada at a disadvantage with respect to international trade.

The guidance documents may be updated or newly developed, and/or internal Standard Operating Procedures (SOPs) may be developed. For example:

• Requesting data safety monitoring
• Adopting the ISO 14155 Standard (GCP)
• Updating the current guidance on medical device IT, etc.

Pros:

• The risks associated with IT may be reduced as sponsors would have more understanding of what must be submitted, monitored, and followed.
• This option would more closely link the device IT requirements and guidances with HC's clinical trial requirements and guidances for drugs.
• HC would be more in line with other regulatory jurisdictions.
• Increased awareness by stakeholders/sponsors/ethics committees of regulatory expectations.
• Improved level of expertise in application of "best practices".

Cons:

• Resources, including funding, would be required to implement this option.
• Guidances do not have the force of law and therefore, where regulatory authorities are absent, HC would rely on voluntary compliance.
• Limited impact on achieving the goal to ensure that risks to participants are being minimized.

Pros:

• Conformance with GCPs would greatly improve risk management related to ITs. There would be more confidence in IT procedures and results if GCPs were a regulatory requirement.
• Interim and/or final reporting of significant risk ITs would provide information to HC which may mitigate risks associated with other similar ITs, particularly where the IT does not result in premarket application.
• Improved reporting processes would provide information (e.g., historical) that may be beneficial in addressing AEs once the medical device is on the market.
• This would bring HC in line with other regulatory agencies, which would better position Canadian manufacturers to promote their products on the international market.
• This would provide a clear mandate to inspect for conformity with the requirements.

Cons:

• This option would require more resources, as there would be more information submitted for review, and enforcement strategies would need to be established.
• Criteria would need to be developed in order to determine which types of investigational testing would qualify as significant risk studies (i.e., Class IV and some Class III).

Pros:

• An inspection program would monitor ITs so that they are conducted in accordance with GCPs and other relevant standards, and that proper procedures are being followed.
• Having a program established for the inspection of both investigational testing and clinical trial sites would be most cost-effective.
• Expertise already exists within the Health Products and Food Branch Inspectorate.

Cons:

• HPFBI has never done an inspection of a medical device IT site; training, funding, and time to develop strategies and supporting documents would be necessary.
• Regulatory changes would be required and necessitate time and resources.

• Funding would be required for more reviewers, an inspection system, training, and information gathering and reporting.

Pros:

• This option provides a comprehensive solution and addresses all identified major concerns associated with the management of risks related to medical device investigational testing.
• It harmonizes the Canadian requirements with those of other international regulatory jurisdictions, which may lead to the promotion of investigational testing in Canada.
• It better positions Canadian manufacturers to promote their products on the international market.
• Cons:
• Requires funding for more reviewers, inspection system, training, and information gathering and reporting.

6. Considerations

• Additional resources will be needed within Health Canada to implement the recommended option.
• Given the numerous players and responsibilities involved in the investigational testing of medical devices in Canada, it is essential that a teamwork approach be emphasized and promoted. The team includes the device sponsor; the investigator(s); the institution where the IT is being conducted, and REB; the DSMB; and Health Canada.
• FDA is currently trying to accept/recognize data from foreign jurisdictions, and one important stipulation made by the FDA is that the data must go through a DSMB. Although HC does not currently have the authority to require DSMB involvement, it should be encouraged.
• Harmonization with the requirements and processes of other regulatory jurisdictions is in Canada's best interest, and is a priority for Health Canada. As an initial step towards international collaboration and coordination, Health Canada participates in the Global Harmonization Task Force (GHTF) as a leading member.

7. Recommendation:

It is recommended that Option #5 be implemented.

This combination of options 2, 3 and 4 would provide a comprehensive approach for addressing the issues identified with the current framework for investigational testing of medical devices. This option is in line with Health Canada's focus on transparency and openness, and addresses the concerns outlined in the Auditor General's Report.

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8. Next steps based on the recommendation that option #5 be chosen:

• Conduct resource estimates for Health Canada, followed by full costing
• Propose to amend MDRs to include the appropriate requirements for IT monitoring
• Develop guidance document(s) and SOPs
• HPFBI would need to establish a medical device trial site inspection programme, including training and SOPs
• Develop or adopt suitable electronic information technology to capture and report pertinent information (e.g., databases, registries, etc.)
• Set up a review program for interim/final reports
• Appropriate funding must be established to implement and maintain these activities

Appendix: Terms and Abbreviations

TERMS:

Adverse Drug Reaction (Division 1, C.01.001, Food and Drug Regulations): Any noxious and unintended response to a drug caused by the administration of any dose of the drug.

Adverse Event (Division 5, C.05.001, Food and Drug Regulations):
Any adverse occurrence in the health of a clinical trial subject who is administered a drug, which may or may not be caused by the administration of the drug, and includes an adverse drug reaction.

Clinical Trial (Division 5, C.05.001, Food and Drug Regulations):
An investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.

Protocol (Division 5, C.05.001, Food and Drug Regulations):
A document that describes the objectives, design, methodology, statistical considerations and organization of a clinical trial.

Qualified Investigator (Interpretation, Section 1, Medical Devices Regulations):
A person who is a member in good standing of a professional association of persons entitled under the laws of a province to provide health care in the province and who is designated, by the ethics committee of the health care facility at which investigational testing is to be conducted, as the person to conduct the testing.

Research Ethics Board (Division 5, C.05.001, Food and Drug Regulations):
A body that is not affiliated with the sponsor, and

1. the principal mandate of which is to approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being; and
2. that has at least five members, that has a majority of members who are Canadian citizens or permanent residents under the Immigration Act, that is composed of both men and women and that includes at least:
   1. two members whose primary experience and expertise are in scientific discipline, who have broad experience in the methods and areas of research to be approved and one of whom is from a medical discipline or, if the clinical trial is in respect of a drug to be used for dental purposes only, is from a medical or dental discipline,
   2. one member knowledgeable in ethics,
   3. one member knowledgeable in Canadian laws relevant to the biomedical research to be approved,
   4. one member whose primary experience and expertise are in a non-scientific discipline, and
   5. one member who is from the community or is a representative of an organization interested in the areas of research to be approved and who is not affiliated with the sponsor or the site where the clinical trial is to be conducted.

Sponsor (Division 5, C.05.001, Food and Drug Regulations):
An individual, corporate body, institution or organization that conducts a clinical trial.

ABBREVIATIONS:

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