Medical Device Clinical Studes in Сanada. Review

Medical Device Clinical Studies in Canada
Nancy Ruth
Director, Medical Devices
© Mapi 2014, All Rights Reserved
Agenda














Introduction
Agency
Medical Devices Regulations and Guidance
Ethics Board Approvals
ITA Submission Process
Health Canada Review
Post-Authorization Requirements
Importing ITA Devices
Inspections
Monitoring
Similarities/Differences between ITA, CTA
Drug, Device Combination Product Studies
Summary
Questions
2
© Mapi 2014, All rights
reserved
INTRODUCTION
Introduction

Medical Devices are regulated based on risk class
 Class IV – highest risk
 Class I - lowest risk

Manufacturers of Class II, III and IV medical devices must apply
for and receive a licence prior to marketing

Medical Device Licence applications include administrative
requirements, fee and evidence of safety and effectiveness based
on the risk of the device - may include clinical evidence

If a manufacturer wishes to conduct investigational testing of
a Class II, III and IV device on human subjects in Canada, they
must apply for and receive an Investigational Testing Authorization
(ITA)

Class I ITA does not require an ITA approval

May be for a new device to Canada or a change in intended use

Comparable to Clinical Trial Application for drugs
4
© Mapi 2014, All rights
reserved
AGENCY
Agency

Health Canada is the Federal department responsible for
helping Canadians maintain and improve their health

Therapeutic Products Directorate (TPD) is the Directorate
within Health Canada that regulates pharmaceutical drugs and
medical devices for human use

Health Products & Food Branch Inspectorate (HPFBI) is the
branch within Health Canada responsible to compliance and
enforcement for regulated products and establishments

Within the TPD, the Medical Devices Bureau (MDB) is
responsible for regulating all pre-market activities involving
medical devices to be manufactured or sold in Canada




Device Evaluation Divisions (more detail next slide)
Device Licensing
Special Access Program
Investigational Testing Authorization
6
© Mapi 2014, All rights
reserved
Agency Cont’d

Device Evaluations Divisions (within MDB)





Cardiovascular devices
Musculoskeletal devices
In vitro Diagnostic Devices (IVDD)
General and Restorative Devices
Scientific review for SAP, ITA and licensing is conducted
by the appropriate Device Evaluation Division listed above
7
© Mapi 2014, All rights
reserved
MEDICAL DEVICES REGULATIONS AND
GUIDANCE
Food & Drugs Act

Statutory basis for regulation

Governs the manufacture, distribution, advertising and
sale of foods, drugs, cosmetics, medical devices and
other therapeutic products in Canada

Federal government regulates what can be sold in
Canada & the level of control applied

Defines “medical device” and “labelling”

Specific regulations further define requirements
applicable to each type of healthcare product

Medical Devices Regulations
 http://laws.justice.gc.ca/eng/regulations/SOR-98-282/
9
© Mapi 2014, All rights
reserved
CMDR SOR/98/282

Section 1 – Definitions

Section 2-5 – General Applications

Sections 6-7 – Risk Classification
Part 1 – General

Sections 6-9 – Application & Manufacturer’s obligations

Sections 10-20 – Safety & Effectiveness requirements

Sections 21-24 – Labelling, Advertising

Section 25 – Class I devices
10
© Mapi 2014, All rights
reserved
CMDR SOR/98-282 Cont’d

Section 26-27 – Prohibitions re: import, sale, advertising

Section 26-31 – Definition of licencing type

Section 32 – Quality system requirements

Section 33 – Foreign manufacturers

Section 34 – Licence amendments

Sections 35-43 – Includes Licence Issuance, suspension,
annual renewal

Sections 44-51 – Establishment Licence

Sections 52-56 – Distribution records
11
© Mapi 2014, All rights
reserved
CMDR SOR/98-282 Cont’d

Sections 57-61 – Complaint handling & MPR reporting

Sections 63-65 - Recall

Sections 66-68 – Implant registration
Part 2 – Custom Made and SAP Devices
Part 3 – Investigational Testing
Part 4 – Export Certificates (medical devices manufactured
in Canada for export only)
Part 5 – Transitional, provisions, coming into force
12
© Mapi 2014, All rights
reserved
Part 3 Investigational Testing

Sections 79 & 80 – Application and Scope

Sections 81 – Records to be maintained

Sections 82 – ITA application requirements

Section 83 – Authorization

Section 84 – Additional information may be requested by
Health Canada during application review

Section 85 – Additional information may be requested by
Health Canada after issuance of ITA & authorization may
be cancelled
13
© Mapi 2014, All rights
reserved
Part 3 Investigational Testing Cont’d

Section 86 – Labelling requirements

Section 87 – Advertising of ITA devices

Section 88 – references Part I requirements for:
 Distribution records
 Complaint handling
 Mandatory Problem Reporting
 Recalls
 Implant registration (limited number of devices)
 (same requirements as for licensed devices)
14
© Mapi 2014, All rights
reserved
Guidance ?

1999 guidance documents for IVDD and non-IVDD
medical devices
 Provides application format and limited content requirements

Note: Health Canada is drafting a new guidance
document for ITA – in pipeline >2yr

Dr. Fred Lapner, Head of Investigational Testing (retired
this year) and his office have always been quite helpful
 Bisi Lawuyi has replaced him
15
© Mapi 2014, All rights
reserved
ETHICS BOARD APPROVALS
Research Ethics Board

Research Ethics Boards – REB-ERB, MECs, IRB etc. –
local (hospital or university based) – regional (like WIRB)
- example is IRB Services in Toronto

Similar setup - annual renewal of clinical studies

REB composition requirements the same as for drug studies
per ICH GCP guidelines:
 Occasionally will see approval for life of study
 Need annual report
 At least 5 persons – include both men and women and
consider other elements of diversity
 2 members with expertise in methods or area of research
covered by REB
 1 member knowledgeable in ethics
 1 member with no affiliation with the institution, from the
community served by REB
 1 member with knowledge in relevant law

Quorum to vote
17
© Mapi 2014, All rights
reserved
ITA SUBMISSION PROCESS
ITA Application Process

Who files?

When to file?

Which devices need ITA?
 Only the manufacturer of a device may file for an ITA (note
consultant, distributor or investigator may submit on
manufacturer’s behalf but manufacturer must sign application
form and the authorization is issued to the manufacturer.)
 Device has reasonable probability of safety and effectiveness
 Completion of appropriate pre-clinical testing, animal studies
- varies widely due to range of device types and classifications
 Novel devices/new technology – helpful to conduct a pre-ITA
meeting to obtain agency feedback/agreement with protocol,
end points
 Class II, III, IV

Class I does not require ITA Authorization from Health Canada
 Record requirements
 Ethics Board Approval is required
19
© Mapi 2014, All rights
reserved
ITA Submission

ITA Submission should include:
 Cover Letter and Table of Contents
 Executive Summary
 ITA Application Form(s)
— If investigational devices used in ITA study are manufactured by
different manufacturers, more than one submission will be required
— If more than one investigational device is used in ITA study, an
application form per device will be needed

Could require multiple application forms, however
generally one ITA submission (one supporting dossier)
per study protocol
20
© Mapi 2014, All rights
reserved
ITA Submission

Must advise Health Canada of:
 Number of devices to be used in the study (for use in
Canada, if the study is multijurisdictional)
 Number of subjects to be enrolled in Canada
— Protocol may state total number patients for all sites, all countries

ITA Application form does not include a field for these – advisable to
clearly state these numbers in your cover letter, Executive Summary
and Protocol Description Section
21
© Mapi 2014, All rights
reserved
ITA Submission Cont’d

Investigator Agreement(s) and Investigator CV(s)
 Class III, IV – submit with the ITA package
 Class II - maintain on file, provide only if requested by
Health Canada

Ethics Board approval-Ethics review can be concurrent
with Agency review
 Class III, IV – submit with ITA package
 Class II – maintain on file, provide only if requested by
Health Canada
22
© Mapi 2014, All rights
reserved
ITA Submission Cont’d

Background information or introduction

Manufacturer identification – this is the sponsor

Device description – sufficient information for
understanding of device, how used in study
 Material specifications
 Engineering drawings or photographs

Name of Institution(s) where the study will be conducted

Protocol and informed consent
 No prescribed format
 Include Case Report Forms
23
© Mapi 2014, All rights
reserved
ITA Labelling Requirements

Label includes: device marking, package labelling,
Instructions For Use, Investigator Brochure (if available)

CMDR Labelling requirements for medical devices
(Section 21-23) do not apply under ITA

Labelling of devices authorized under ITA must include
(at a minimum):
 Name of device
 Name of manufacturer
 2 or 3 required statements in both English and French
24
© Mapi 2014, All rights
reserved
ITA Labelling Requirements Cont’d

Required statements for all ITA devices
 “Investigational Device” and “Instrument de recherché”
“To be Used by Qualified Investigators Only” and “Réservé
uniquement à l’usage de chercheurs compétents”

In vitro diagnostic device to be used under ITA must also
include the following bilingual statements on labelling
 “The performance specifications of this device have not been
established” and “Les spécifications de rendement de
l’instrument n’ont pas été établies
25
© Mapi 2014, All rights
reserved
ITA Submission Cont’d
Class III and IV ITA applications also require:

Design philosophy
 Features of the device that permit it to be used for its
intended use
 Performance specifications should be linked with the
objectives of proposed testing
 Comparison to previous generations or competitive devices

Marketing history




Any previous Special Access requests in Canada
Status of the subject device in other jurisdictions
Volume of sales and any adverse event or recall information
If marketing history of subject device does not exist, provide
marketing data for earlier generation device may be helpful
in determining safety profile
26
© Mapi 2014, All rights
reserved
ITA Submission Cont’d
Class III and IV ITA applications also require:

Risk Analysis and Evaluation
 ISO 14971 may be referenced

Previous studies






Preclinical animal and bench studies
Biocompatibility studies
Medical Electrical safety
Clinical Studies in other jurisdictions
Literature review may be appropriate
Alternate treatments
 Methods currently used to diagnose and treat the medical
conditions that are the subject of the proposed study

Precautions
 Cautions, warnings, contra-indications and possible adverse
effects
 Should also be stated in labelling
27
© Mapi 2014, All rights
reserved
Specific to IVDD ITAs

REB must be submitted to Health Canada for Class II
IVDDs if ITA testing includes procedures that pose high
risk to the test subject.

Class II submission requirements apply to Class II or IV
IVDDs NOT for near patient use or NOT for patient
management decisions
 Less risk, less information

Additional bilingual investigational labelling statement
 “The performance specifications of this device have not been
established” and “Les spécifications de rendement de
l’instrument n’ont pas été établies »
28
© Mapi 2014, All rights
reserved
Submission Format
Application Form
Executive Summary
Table of Contents
1. Background Information
1.1 Device Description
1.2 Design Philosophy
1.3 Marketing History
2. Risk Assessment
2.1 Risk Analysis and Evaluation
2.2 Previous Studies
2.3 Alternate Treatments
2.4 Precautions
Note: some sections
not applicable to
Class II
Tip: list of definition
is helpful
3. Institutional Information
3.1 Investigator(s)
3.2 Name of Institution(s)
3.3 Research Ethics Board Approval(s)
4. Protocol
5. Device Label
6. Investigator Agreement(s)
29
© Mapi 2014, All rights
reserved
Submission to Health Canada

1 paper copy in three ring binder(s) and 1 electronic copy
(CD ROM copy preferred)

Electronic copy should be provided in a format from which
Health Canada can copy

Submission should be mailed or couriered to:
 Bisi Lawuyi Section Head, ITA and Special Access
Therapeutic Products Directorate
Medical Devices Bureau
2934 Baseline Road, Tower B
Address Locator: 3403A
Ottawa, ON K1A 0K9

No Fee
30
© Mapi 2014, All rights
reserved
HEALTH CANADA REVIEW
Review of ITA by Health Canada

Post submission, an auto-email received from
[email protected]
“This is to inform you that your application was received
and assigned reference #123456”

Six digit reference number is referenced on all
communications

30 day review target

No “default” timeline (different from drug trials)

Review is conducted by the ITA office with consult from
the Device Evaluation Division specific to the type of device
32
© Mapi 2014, All rights
reserved
Review of ITA by Health Canada Cont’d

Possible communications
 Screening Deficiency Letter-issued to manufacturer or
their regulatory correspondent who will have 15 days to
respond to question(s)
− Typically for a minor/administrative issue
− 30 day timeline starts again once Health Canada received
SD Response
 Additional Information Request-issued to manufacturer
or regulatory correspondent who will have 60 days to
respond to question(s)
− More significant question of safety & effectiveness regarding
device or planned study
− 30 day timeline starts again once Health Canada received
AI Response
 Also may receive informal call, email for clarification
- Issues that can be resolved within 1-2 days; clock doesn’t stop
33
© Mapi 2014, All rights
reserved
Review of ITA by Health Canada Cont’d

Possible communications (cont’d)
 Letter of Authorization-issued to manufacturer, investigators
will be listed on page 2
— May begin enrollment and initiate the trial

Refusal/Rejection Letter may be issued if:
— The device cannot be used safely for the study;
— The study is not in the best interest of the subjects, or
— The objectives cannot be achieved

A Refusal/Rejection Letter may be appealed

Must have letter of authorization to begin enrolling patients
 No default 30 days
 Different from CTA/drug studies
34
© Mapi 2014, All rights
reserved
POST-AUTHORIZATION REQUIREMENTS
Post Authorization

Additional sites
 No specific form - submit letter with site/investigator
information
 Class III, IV also submit investigator agreement, CV, REB
approval (Class II these are retained unless requested)
 Health Canada will issue new letter of authorization
 Different from CTA-drug ie:
— CTSI form submitted or implementation of CTA-A (amendment)
same form as submitted for sites prior to commencement of CTA
— Includes information from REB approval and Qualified Investigator
Undertaking (QIU)
— Information not typically available at time of CTA/CTA-A
submission
36
© Mapi 2014, All rights
reserved
Post Authorization Cont’d

Protocol amendment or significant device changes

Mandatory Problem Reporting-(“device incidents” aka Adverse
Events-definitions slightly different)-both expected and
unexpected
 Any change to the device which fails outside the risk
assessment of the protocol will require a new application
 A new authorization letter will be issued
 No specific form – letter with details, supporting information
varies according to nature of change
 Different from CTA (drug) – CTA-A amendment process
 different from drug – only unexpected AEs

Mandatory Problem Report is required if:
 Related to a failure of the device or deterioration in its
effectiveness; OR
 any inadequacy in its labeling or in its direction for use, AND
 Has lead 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
 Notified to Marketed Health Products Directorate
37
© Mapi 2014, All rights
reserved
Post Authorization Cont’d

Note: same criteria as marketed devices

Principal investigator must report to manufacturer within
72 hours

Manufacturer must report to Health Canada - 10 or 30 day
initial report, and closure report (same as marketed devices)

Records retention
 Keep ITA, procedures, distribution, complaints, mandatory
problem report, recall records
 Duration not defined, different from CTA (drug) - Canadian GCP
for drugs 25 year retention
 Recommended to follow this for ITA

Advertising-state:
 Device is subject of investigational testing
 Purpose of testing
38
© Mapi 2014, All rights
reserved
IMPORTING ITA DEVICES
Importing ITA Devices

Shipping documentation should clearly state - investigational
devices

Include a copy of the ITA Authorization with shipping
paperwork

Labelling should include ITA references prior to import
(required statements)
40
© Mapi 2014, All rights
reserved
INSPECTIONS
Inspections

Inspection Program for medical device clinical trials-not
developed yet
 Different from CTA (drug) – inspection process well developed

If importer/distributor/Class I manufacturer is being
inspected under the Medical Device Establishment Licence
inspection program, compliance with CMDR Part 3
is reviewed if ITA product inventory or activities are taking
place at the establishment

ITA approval letters, import date, labelling of ITA devices,
distribution records, mandatory problem reporting and
recall requirements reviewed

Different from drug clinical trials and FDA clinical trials
(IDE) involving medical devices

GCP should be followed (ICH guidelines)-not in ITA
regulations at present

Expected in future revisions of ITA regulations
42
© Mapi 2014, All rights
reserved
MONITORING
Monitoring

Clinical trial monitoring as for drug studies

PIPEDA and applicable provincial privacy legislation

GCP-not addressed in Medical Device Regulations BUT
adherence expected
 Follow ICH guidelines
 Critical for acceptability of study data in all jurisdictions

Sponsors are reminded to register studies in a publicly
available registry such as www.clinicaltrials.gov or similar
44
© Mapi 2014, All rights
reserved
Study Closure

Notification to Health Canada is required if study
discontinued because of safety issue

Closure-while there is no regulatory requirement, the ITA
office appreciates notification when an ITA is complete

Authorization letters are now requesting a copy of the
Final Study Report upon completion of the study (always
recommended, but a request we are seeing in ITA approvals
since late 2013)
45
© Mapi 2014, All rights
reserved
SIMILARITIES/DIFFERENCES Between ITA, CTA
Similarities to CTA

Agency authorization is required for device clinical trials
(exception for Class I)

Ethics Board Approval and investigator agreement are
required
 Not submitted for CTA but retained in case Health Canada
requests
 Submitted for Class III, IV devices, not for Class II but retained
in case Health Canada requests

GCP guidelines should be followed - Health Canada GCP, ICH
 Expected but not yet a regulatory requirement for device ITA

Registration with Clinical trial registry is now requested

Significant changes to study protocol (ie not editorial) or
device, and new sites must be submitted
 ITA-format for notification not prescriptive – no “amendment”
form, process
 New authorization must be issued before implementing device
study change
47
© Mapi 2014, All rights
reserved
Differences from CTA

Phases of drug studies are not typically referenced in
medical device studies; numbers of patients typically
lower with devices

Content of device studies is less prescriptive, more
variable – wide range of device types with different types
of supporting information eg software vs aortic valve vs
insulin pump vs dental implant

No default timeline to begin patient enrollment in device
studies, Investigational Testing Authorization letter must
be received prior to first patient enrollment

Manufacturer of a device must file/sign for the ITA, no
investigator sponsored studies
48
© Mapi 2014, All rights
reserved
Differences from CTA Cont’d

No Canadian Agent required for foreign manufacturers;
no in Canada Senior Scientific Officer or Medical Officer
signature needed

No differentiation between “expected” and “unexpected”
device incidents (adverse events)
 All are reported

Manufacturer of a device must file for the ITA, no
investigator sponsored studies

If two or more medical devices (manufactured by different
companies are) to be used in a study, each manufacturer
must apply for an ITA

Structure of submissions - CTA more prescriptive
(CTD format)
49
© Mapi 2014, All rights
reserved
DRUG, DEVICE COMBINATION
PRODUCT STUDIES
Scenarios
Combination Products - ITA Needed

Device incorporating a drug (eg injectable hyaluronic
implant with lidocaine or cortisone, orthopedic implant,
cement or wound product with antibiotic, drug eluting stent):
 Section10 of ITA application form must be completed (name of
drug, active ingredient, manufacturer and DIN if applicable)
 Submission may also require inclusion of drug quality information
in ITA (might include Quality Overall Summary-QOS if not
a DIN product)

Advisable to contact ITA office about the extent of information
required to support an ITA

Drug information will be reviewed by TPD (pharmaceutical)
or BGTD (Biologics and Genetic Therapies Directorate)- no
legislated timeline for this; delays are common – impact on
planning for authorization, enrolling patients etc

Reporting of adverse events-get clarification from Agency,
which Bureau wishes to receive reports
 Typically if product is subject of ITA, Mandatory Problem Reports
submitted to MHPD
— They communicate to other bureaux as relevant
51
© Mapi 2014, All rights
reserved
Combination Products – CTA Needed

Drug product incorporating a device:
 examples: drug delivery system (drug in prefilled syringe,
IV bag, vaginal ring, metered dose inhaler, implant)
 Device information may be incorporated into the CTA under
section Other Information (Section 1.2.9)
 Depending on the device/complexity, may be brief or
extensive
 Some cases, section is equivalent to technical content of ITA
 Medical Devices Bureau consultation review

Advisable to contact the Office of Clinical Trials about the
extent of device information required

May also need to contact the Medical Devices Bureau

Device information will be reviewed by Medical Devices
Bureau

Reporting of adverse events-get clarification from
Agency, which Bureau(x) wishes to receive reports
52
© Mapi 2014, All rights
reserved
Devices in Drug Studies - CTA and ITA Needed

A drug study which uses unlicensed devices, but not as
a combination product – example:
 in vitro diagnostic device for study subject evaluation licensed
in other jurisdictions where there are study sites-sponsor
wants consistency of results

Authorization needed to use the unlicensed device in the
drug CTA

Separate ITA must be filed in parallel with the drug CTA

Same protocol, even though the objective of the study/end
points are NOT about the device
 Must be signed by the device manufacturer, not the
drug CTA sponsor
53
© Mapi 2014, All rights
reserved
Devices in Drug Studies Cont’d

Other examples of unlicensed devices used in a drug
study:
 Photodynamic therapy – laser, fibre-optic used to activate
drug administered to patient
 Software used in dosing/determination or evaluation of
study patients
 Sometimes have been treated as separate ITA, other times
device information has been incorporated into the CTA
 Consult with the Office of Combination Products, Medical
Devices Bureau on current thinking, preference
54
© Mapi 2014, All rights
reserved
Devices in Drug Studies Cont’d

Where separate ITA must be filed in parallel with the drug
CTA:
 As noted, same protocol, even though the objective of the
study/end points are NOT about the device
 Must be signed by the device manufacturer, not the
drug CTA sponsor
 Can add complexity – device manufacturer may/may not be
willing to accept responsibility for their product used in a
clinical trial – may not agree to sign
 Alternatives:
— ask device manufacturer to file a Health Canada licence
application
— Issues - global strategy, CMDCAS certificate, etc.
— Choose an already-licensed equivalent product
— Issues: consistency in a global study, volume pricing etc.
55
© Mapi 2014, All rights
reserved
Devices in Drug Studies Cont’d

Licensed devices used in drug studies – acquired by
sponsor for the study sites



drug administration devices (syringes, needles)
Specimen collection devices (blood collection tubes, needles,
urine cups)
Near patient in vitro diagnostic devices (glucose meters, strips,
urinalysis strips)

May be imported from outside Canada or obtained from a
domestic source

Importation/distribution regulated through Medical Device
Establishment Licensing (MDEL)

Responsibility to hold MDEL may fall on sponsor

Regulatory obligations for licence application, fees, records,
recalls, HPFBI MDEL inspection

If no MDEL, could be cited in CTA HPFBI site inspection
 Order, pay, store, provide to site (or drop ship)
56
© Mapi 2014, All rights
reserved
Drugs in Device Studies Cont’d

Investigation device(s) used in study with approved drug(s):
 Two unlicensed devices, different manufacturers-continuous
glucose monitor/sensor, insulin pump – closed loop when used
together
 2 insulin products, Health Canada approved for use with the pump
 2 x ITA needed, no CTA (on-label use)
— Cite DIN(s), no other information provided
 One body of supporting information
— Proprietary information issue between the manufacturers
— Strategies to protect, ensure confidentiality
— Manufacturer copies, Health Canada

Patients used prescribed insulin(s) dosage

treatment with drugs integral to the execution of protocol, study
outcome but not part of the endpoints or study authorization
57
© Mapi 2014, All rights
reserved
Drugs in Device Studies Cont’d

Investigational device(s) used in study with approved drug(s):
 IT needed, no CTA (on-label use)
— Cite DIN(s)
 Study used software + continuous glucose monitor/sensor +
transmitter + insulin pump + glucose meter + ketone meter
+ 2 different insulin products
 Some devices licensed, some not licensed (including software
- also a device)
— 2 separate ITAs – we submitted on behalf of one manufacturer,
the other submitted by its manufacturer
— Licensed devices were citied with Health Canada MDL#s
— Drug DINs were citied




Patients use prescribed insulin(s) dosage
Software interfaces with other devices to adjust insulin dosing
according to blood glucose level detected, prevent nocturnal
hypoglycemia (dangerous)
No drug information in ITA submission, other than to cite insulin
names, DINs
Drugs integral to the execution of protocol, study outcome but
not part of the endpoints or study authorization
58
© Mapi 2014, All rights
reserved
SUMMARY
Summary

Similarities and differences between Investigational Device
Authorization, Clinical Trial Applications but goals of
regulations aligned
 Protect study subjects
 Permit collection of data to support marketing application,
further research, product development
 Ensure reasonable chance of success

Complexities where drugs and devices are used together
 Case by case, agency preferences, interpretations where
regulations do not address evolving technologies, treatments
 Planning should consider potential delays

Help is available!
 Medical Devices Bureau
 Office of Clinical Trials
 Experienced internal resources, consultants
60
© Mapi 2014, All rights
reserved
QUESTIONS
THANK YOU!
[email protected]