Public Release of Clinical Information: guidance document

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective.

Guidance documents are administrative instruments. They do not have force of law and as such they allow for flexibility. Alternate approaches to the implementation of the principles, considerations and requirements described in this document may be acceptable provided they comply with relevant laws. Discussion with the relevant program area in advance is encouraged to determine whether an alternative approach meets applicable statutory or regulatory requirements.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this document. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

Document change log
Version	Date
1.0	March 12, 2019

1. Introduction
2. Scope and Application.
3. General Guidance on Implementation
4. Procedures for Clinical Information in Drug Submissions and Medical Device Applications
5. Requirements for the Redaction of Confidential Business Information
6. Anonymization of Personal Information
- 6.1 Principles of Protecting Personal Information
- 6.2 Anonymization Process.
7. Contact Information
8. References
9. Appendices

1. Introduction

1.1 Policy Objective

Health Canada's objective is to make anonymized clinical information in drug submissions and medical device applications publicly available for non-commercial purposes following the completion of Health Canada's regulatory review process, while adhering to Canada's Privacy Act.

Health Canada receives clinical information to evaluate the safety and efficacy of drugs and medical devices that are submitted for approval for sale in Canada. Providing public access to this clinical information can enable independent re-analyses of data, foster new research questions, and benefit Canadians by helping them to make informed decisions about their health.

This document is designed to help the public, industry, healthcare professionals and other stakeholders better understand the implementation of Health Canada's Public Release of Clinical Information (PRCI) initiative, including: the procedures to prepare information for release; the categories of information that continue to be subject to the definition of confidential business information (CBI) and that may be eligible for redaction; and protection of personal information.

1.2 Terminology and Definitions

Anonymization:

Means the process through which personal information is modified by removing direct identifiers and any related code that would enable linkage with identifying information; and by ensuring that the remaining indirect identifiers no longer present a serious possibility of re-identifying an individual.

CBI:

Confidential Business Information, as defined in Section 2 of the Food and Drugs Act:

"confidential business information", in respect of a person to whose business or affairs the information relates, means - subject to the regulations - business information:

that is not publicly available,
in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available, and
that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitors.

CTD:

Common Technical Document submission format of the International Conference on Harmonisation (ICH)

eCTD:

Electronic Common Technical Document submission format of International Conference on Harmonisation (ICH)

Clinical Information:

Means information in respect of a clinical trial, as per the meaning in C.08.009.1 (1) of the Food and Drug Regulations (FDR), or information in respect of clinical studies or investigational testing, as per the meaning in s43.11 of the Medical Devices Regulations (MDR). For greater clarity, this includes the clinical overviews, clinical summaries, and clinical study reports for drugs, and the summaries and detailed information of all clinical studies and investigational testing that provided evidence of safety and effectiveness for medical devices.

Clinical Study Report:

Means an "integrated" full report of an individual study of any therapeutic, prophylactic or diagnostic agent (referred to herein as drug, or treatment) conducted in patients, in which the clinical and statistical description, presentations, and analyses are integrated into a single report, incorporating tables and figures into the main text of the report, or at the end of the text, and with appendices containing the protocol, sample case report forms, investigator related information, information related to the test drugs/investigational products including active control/comparators, technical statistical documentation, related publications, patient data listings, and technical statistical details such as derivations, computations, analyses, and computer output.

Directly-identifying Variable:

Means identifying information that is replicable, distinguishable and knowable.

FDA:

Food and Drugs Act

FDR:

Food and Drug Regulations

Generalization:

Means a technique of anonymization that uses re-categorization within a range for the purpose of enlarging the number of "like" individuals.

ICH:

International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

IMDRF ToC:

International Medical Device Regulators Forum Table of Contents

Indirectly-identifying Variable:

Means identifying information that can identify an individual through a combination of indirect identifiers.

Manufacturer:

For drugs has the same meaning as in Section A.01.010 of the Food and Drug Regulations.

For medical devices has the same meaning as in Section 1 of the Medical Devices Regulations.

Medical Device:

Has the same meaning as in the Medical Devices Regulations.

For information on the classification of medical devices, please refer to guidance document - Guidance for the Risk-based Classification System for In Vitro Diagnostic Devices (IVDDs) and guidance document - Guidance on the Risk-based Classification System for Non-In Vitro Diagnostic Devices (non-IVDDs).

MDR:

Medical Devices Regulations

Non-commercial Purpose:

Means the information will not be used to support a marketing authorization application anywhere in the world, or sold or traded to another person.

Offsetting:

Means a technique of anonymization that replaces numerical data through the addition or subtraction of a fixed quantity.

Personal Information:

Has the same meaning as in Section 3 of the Privacy Act.

PIM:

Process Initiation Meeting

Pseudonymization:

Means a technique of anonymization whereby personal information (e.g. subject identification number) is re-coded for the purpose of disassociating the variable from the patient.

Randomization:

Means a technique of anonymization that applies a random small change to variables to reduce the ability of the data to identify a person.

Redaction:

Means a technique that places an opaque box over text or image to conceal confidential business information, personal information or other information in a document that is otherwise legible.

Reference Population:

Means the group of individuals used to determine the risk of re-identification.

Re-synthesis:

Means a technique applied following generalization that converts a general data range to a specific data point within the original generalized range.

Rx-switch:

Submissions to switch an authorized medical ingredient to non-prescription status.

1.3 International Alignment

Health Canada recognizes the importance of international alignment in clinical information sharing, particularly regarding the release of clinical information that is available in other jurisdictions. Its implementation of the public release of clinical information seeks to align with international best practices, where these conform with Canadian legal requirements and help to advance Canadian policy objectives. Collaboration with the clinical information publication programs of our regulatory partners will help to reduce administrative burden and promote consistency in the protection of personal information.

2. Scope and Application

2.1 General scope and application

This document applies to amendments to the Food and Drug Regulations and the Medical Devices Regulations, which came into force on February 28, 2019. These regulatory amendments specify the clinical information in drug submissions and medical device applications that cease to be confidential business information following a final regulatory decision and authorize Health Canada to publicly release this information. This guidance describes the scope of clinical information eligible for public release and the procedures to remove information that remains CBI and to protect personal information prior to public release.

The regulatory amendments apply to clinical information submitted to Health Canada in the past as well as in the future. Health Canada intends to publish on a proactive basis the information in drug submissions and medical device applications that receive a final regulatory decision following the coming into force of the regulations (new submissions). Proactive publication of this information will be phased in over four years, as described in section 3.3 of this guidance. Health Canada intends to make available on request the information in drug submissions and medical device applications that received a final regulatory decision prior to the coming into force of the regulations (past submissions).

This document does not apply to the CBI disclosure authority under section 21.1(3)(c) of the Food and Drugs Act, which permits the Minister to disclose CBI to certain persons for the purpose of protection or promotion of human health or the safety of the public. Information on this authority can be found in guidance document - Disclosure of Confidential Business Information under Paragraph 21.1(3)(c) of the Food and Drugs Act.

2.2 Clinical Information in Drug Submissions

Paragraph C.08.009.2 of the FDR describes the circumstances when clinical information within drug submissions ceases to be CBI. These are:

the issuance of a notice of compliance (NOC),
the issuance of a notice of non-compliance-withdrawal (NON-W), or
the issuance of a notice of deficiency-withdrawal (NOD-W).

Paragraph C.08.009.3 of the FDR provides the Minister with the authority to disclose, without notification or consent, clinical information once it has ceased to be CBI under the above circumstances.

Clinical information for drugs is submitted under Division 8 of the FDR and is provided to Health Canada in the internationally-harmonized electronic Common Technical Document (eCTD) structure. Health Canada will release clinical information contained in eCTD modules 2.5 (Clinical Overviews), 2.7 (Clinical Summaries) and 5.3 (Clinical Study Reports). See Appendix A for greater detail. In addition, Health Canada will release clinical information in the following appendices to clinical study reports: 16.1.1 (Protocol and Protocol Amendments), 16.1.2 (Sample Case Report Forms) and 16.1.9 (Statistical Analysis Plan). See Appendix B for greater detail.

Clinical information may be found in the following drug submission types:

New Drug Submissions (NDS)
Supplemental New Drug Submissions (SNDS)
Abbreviated New Drug Submissions (ANDS)
Supplemental Abbreviated New Drug Submissions (SANDS)
Extraordinary Use New Drug Submissions (EUNDS)
Supplemental Extraordinary Use New Drug Submissions (SEUNDS)

Regardless of its location in a drug submission, chemistry, manufacturing, and other non-clinical information will remain subject to the FDA definition of confidential business information.

Health Canada intends to proactively publish clinical information in new drug submissions beginning in 2019. Proactive publication will be phased in by submission type, as described in section 3.3 of this guidance. Information in drug submissions not subject to proactive release is available on request.

2.3 Clinical Information in Medical Device Applications

Section 43.12 (1) of the MDR describes the circumstances when clinical information within medical device applications that is CBI ceases to be CBI. These are:

the issuance of a medical device license,
the issuance of a medical device license amendment, or
the issuance of a refusal letter.

Section 43.13 of the MDR provides the Minister with the authority to disclose, without notification or consent, clinical information once it has ceased to be CBI under the above circumstances.

For Class III and IV medical devices, clinical information is currently received under section 32 (3), and (4) of the MDR. Class I and II medical devices are out of scope. Class I medical devices are exempt from device licensing. Clinical evidence for Class II medical devices is not required to be submitted upon application for a medical device licence, except in certain circumstances.

Clinical information may be found in the following medical device application types:

Class III Medical Device Application
Class III Medical Device Application Amendment
Class IV Medical Device Application
Class IV Medical Device Application Amendment

Regardless of its location in a medical device application, manufacturing and other non-clinical information will remain subject to the FDA definition of confidential business information.

Health Canada intends to proactively publish clinical information in new medical device applications beginning in 2021. Proactive publication will be phased in by application type, as described in section 3.3 of this guidance.

2.4 Summary

The table below summarizes how the regulations apply to drug submissions and medical device applications, and how Health Canada intends to implement public release of the clinical information they contain.

Table: Application and Implementation of Regulations
	Application of regulations		Implementation
	Drug submissions	Medical device applications	Drug submissions	Medical device applications
New submissions/ applications	✔	✔	Begin proactive publication in 2019*	Begin proactive publication in 2021*
Past submissions/ applications	✔	✔	Available on request from March 20, 2019	Available on request from March 20, 2019
* see phase-in schedule for proactive publication in section 3.3 of this guidance

3. General Guidance on Implementation

3.1 Consideration Regarding Interim Analyses

An interim analysis is defined in ICH guidance: E9: Statistical Principles of Clinical Trialsas any analysis intended to compare treatment arms for efficacy or safety, at any time prior to the formal completion of a trial.

Premature disclosure of clinical information prior to the finalization of a clinical trial risks jeopardizing the reliability of the trial data by affecting patient recruitment, biasing data collection and analysis or weakening confidence in the study conclusions. Disclosure of interim analyses will be balanced with the need to retain the scientific integrity of clinical studies.

The decision to disclose clinical information within interim analyses will be taken case-by-case based on the following considerations:

Table: Considerations Regarding Interim Analyses
Situation involving an interim analysis:	Clinical Study Status	Disclosure
An interim analysis that established clear superiority of the treatment for the condition(s) of use and that is used to stop the trial early	Clinical study is not ongoing	Interim analysis will be considered for release
An interim analysis of a clinical study that has been either completed or discontinued	Clinical study is not ongoing	Interim analysis will be considered for release
An interim analysis of an ongoing trial that, if released, may impact the integrity of the study results and possibly weaken confidence in the conclusions drawn	Clinical study is ongoing	Interim analysis will not be considered for release

3.2 Individual Patient Records (Individual Patient Listings and Case Report Forms)

Clinical case report forms (e.g. ICH E3 16.3) are documents designed to record information on each trial subject as required by the clinical study protocol. Individual patient listings (e.g. ICH E3 16.2) include demographic data, individual efficacy response data, and listings of individual laboratory measurements by patient. As multiple records are provided for each trial participant, this information represents a large portion of a typical drug submission.

Because individual patient records include a large amount of structured and unstructured personal information, extensive modification is required to anonymize this information. Applying currently available methods for anonymization requires considerable resources and significantly reduces the research value of the information. Consequently, individual patient records will not be publicly released with other clinical information.

Researchers interested in obtaining individual patient records related to information for therapeutic products for the purpose of research or statistical analysis may do so under the Privacy Act in accordance with applicable provisions.

Adverse events and other significant participant-level results are reported in the main body of the clinical study report that is subject to release under this authority. Section 6 of this guidance sets out procedures for anonymizing personal information contained in clinical study reports prior to public release.

3.3 Implementation Schedule for the Proactive Disclosure of Clinical Information in Drug Submissions and Medical Device Applications

Health Canada plans to phase-in the proactive release of clinical information in drug submissions and medical device applications that receive a final regulatory decision following the coming into force of these regulations (new submissions). Proactive publication of this information is expected to be implemented on the following schedule:

Table: Implementation Schedule
Stage	Proposed Phase-in	Scope of Application Types
1	Year 1	NDS-NAS + SNDS-c + Rx-switch
2	Year 2	All NDS + SNDS-c + Rx-switch
3	Year 3	All NDS, all SNDS & Class IV devices
4	Year 4	All NDS, SNDS, ANDS, SANDS + Class III & IV devices

Implementation Stage 1

In the first stage of implementation of proactive public release, Health Canada aims to publish the clinical information within drug submissions for:

new active substances (NDS-NAS), representing submissions for drugs that are not variations of previously approved medicinal ingredients in Canada, i.e. "innovative" drugs;
supplemental new drug submissions containing confirmatory trials (SNDS-c) following the issuance of a notice of compliance with conditions as agreed to in the Letter of Undertaking; and
submissions to switch an authorized medicinal ingredient to non-prescription status (Rx-switch for full switch and partial switch submissions).

Implementation Stage 2

In stage two, Health Canada intends on adding the proactive publication of clinical information within all new drug submissions (both NDS-NAS and those not categorized as new active substances).

Implementation Stage 3

In stage three, Health Canada intends on adding the proactive publication of clinical information within all supplemental new drug submissions (SNDS) (e.g. submissions for new indications to a marketed product), and in-scope clinical information within Class IV medical device applications.

It is anticipated that the timing of stage three will align with the adoption of the IMDRF-ToC application structure for medical device applications, to permit the efficient publication of Class III and IV clinical information.

Implementation Stage 4

In stage four, Health Canada intends on adding the proactive publication of clinical information from abbreviated new drug submissions (ANDS; i.e., generic drug), and from Class III medical device applications.

3.4 On-request Release of Clinical Information in Past Drug Submissions and Medical Device Applications

Clinical information from past drug submissions and medical device applications (which received a final regulatory decision prior to the coming into force of the regulations on March 20, 2019) may be requested through Health Canada's clinical information portal. Information in submissions and applications that received a final decision after that date but which was not yet subject to proactive publication is also available on request.

The information in the following submission and application types is available on request:

New Drug Submissions (NDS)
Supplemental New Drug Submissions (SNDS)
Abbreviated New Drug Submissions (ANDS)
Supplemental Abbreviated New Drug Submissions (SANDS)
Extraordinary Use New Drug Submissions (EUNDS)
Supplemental Extraordinary Use New Drug Submissions (SEUNDS)
Class III Medical Device Application
Class III Medical Device Application Amendment
Class IV Medical Device Application
Class IV Medical Device Application Amendment

A request for clinical information from past submissions should be submitted using the online request form on Health Canada's clinical information portal, as described in Section 4.3 of this guidance.

4. Procedures for Clinical Information in Drug Submissions and Medical Device Applications

The publication of clinical information under the Public Release of Clinical Information initiative proceeds through five distinct phases - initiation, submission, review, finalization, and publication.

Health Canada aims to upload a final redacted and anonymized clinical information package onto Health Canada's clinical information portal within 120 calendar days from initiation of the process. In the event that a request is received for clinical information that is not currently in an electronic format, additional time may be required for digitization of paper records.

4.1 PRCI Process Initiation Meeting

Prior to the initiation of the publication of clinical information, a sponsor may elect to attend a one-on-one process initiation meeting (PIM).

The purpose of the PIM is to allow a sponsor to consult with Health Canada on the clinical documents in scope of release under PRCI, and provide an opportunity to clarify Health Canada's requirements and process.

Sponsors new to this initiative are encouraged to request a PIM prior to starting the process. A PIM may be requested within the period of time 120 calendar days prior to the final regulatory decision, and up to 20 calendar days following the final regulatory decision.

Requests for a PIM should be submitted to hc.clinicaldata-donneescliniques.sc@canada.ca.

Requests should propose several dates and times within the eligible period of time for the PIM consultation. A request for a PIM should also be accompanied by the following information:

An agenda or brief meeting outline;
A list of questions, if any, to be addressed by the PRCI team during the meeting.

Health Canada will acknowledge the request and confirm the meeting date.

PIMs will be conducted via teleconference only.

4.2 Health Canada Initiation of the Publication of Clinical Information

Positive Regulatory Decisions

Publication of clinical information is initiated upon issuance of the qualifying regulatory decision on the drug submission or medical device application; initiation triggers an email notification to the manufacturer, though manufacturers may start to prepare clinical information for publication prior to receiving the Health Canada notification.

The notification email identifies the drug submission or medical device application, and lists the documents Health Canada will publicly release. Appendices A and B specify the sections of a drug submission eligible for release, based on the eCTD format. As medical device applications currently vary in structure, the sections eligible for public release will be determined by Health Canada on a case by case basis. Future guidance on medical device applications will be developed to align with transparency initiatives of other regulatory agencies and with a new internationally harmonized format that is currently under development (IMDRF ToC).

Health Canada requests that within 60 calendar days the manufacturer submit the de-identified documents with proposed redaction(s). A proposed redaction control sheet (in.CSV file format, see template in appendix E) and anonymization report (see template in appendix F) must also be submitted, as described below.

Negative Regulatory Decisions

In the event a drug submission is found to not comply with the FDR, Health Canada will initiate publication 31 calendar days after the date of the notice, unless a Letter of Intent for Reconsideration has been received from the manufacturer.

In the event the manufacturer submits a Letter of Intent for Reconsideration, Health Canada will initiate publication upon completion of the reconsideration process, as described in the guidance "Reconsideration of Final Decisions Issued for Human Drug Submissions". This is expected to require 70-140 calendar days, depending on whether the request is referred for internal or external review.

In the event a medical device application is found to not comply with the MDR and the manufacturer submits a Letter of Intent to Appeal, Health Canada will initiate publication upon issuance of a decision of the appeal process, in accordance with the guidance "Management of Applications for Medical Device Licences and Investigational Testing Authorizations".

In the case of a first-level appeal, should the manufacturer not submit the necessary information supporting the appeal, Health Canada will initiate publication 21 days after receipt of a manufacturer's Letter of Intent to Appeal to the Bureau Director. In the case of a second-level appeal, Health Canada will initiate publication upon notification to the manufacturer of the Directorate's decision on the appeal.

Manufacturers will be notified by email when Health Canada initiates publication of clinical information related to a negative decision. The notification will include the same information and procedures as in the case of positive decisions (see above).

4.3 How to Request Clinical Information from Past Drug Submissions and Medical Device Applications

Health Canada plans to publish clinical information from past drug submissions and medical device applications upon receipt of a request from the public and within the limits of its administrative capacity. Requests made for multiple submissions or applications will be processed in sequence and subject to prioritization.

Members of the public may request clinical information from past submissions and applications through Health Canada's clinical information portal with an electronic request form identifying the product name, the name of the manufacturer, the related indication, the information being requested (e.g. clinical study report, clinical overview, clinical summary), the reason for the request, and the requester's contact information.

Where possible, the requester should provide Health Canada with the submission/application control number. This additional information is available within Health Canada's Summary Basis of Decision and Regulatory Decision Summary documents associated with the drug submission or medical device application.

Health Canada will confirm receipt of requests by direct notification to individual requesters. It will also regularly update a list of requests on its web portal.

Prioritization of Requests

In the event requests for information exceed Health Canada's administrative capacity, Health Canada will process requests for clinical information in priority sequence. Health Canada's prioritization of requests will consider metrics that identify products and information with high health system impact. These considerations include prioritizing drugs and medical devices that are subject to ongoing queries by health system organizations, products that are abundantly used, and products that have been demonstrated to be of high public interest.

Where there are multiple requests for submissions from a single manufacturer they may be sequenced to avoid excessive requirements to review information prior to release. Health Canada will notify requesters when it initiates processing of their request, and will regularly update the web portal to indicate which requests are currently being processed.

4.4 Submission of Annotated Documents with Proposed CBI Redaction(s) and Anonymization

Health Canada has described limited and specific circumstances, prescribed in regulations, where information found within the clinical component of a drug submission or medical device application may have ongoing commercial value following the final regulatory decision. The specific categories of information in drug submissions that Health Canada will consider for redaction (with sufficient justification) are described in Section 5 of this guidance document.

Future guidance will specify these categories for medical device applications based on the IMDRF TOC standardized format, which is currently under development. In the interim, medical device manufacturers should refer to Section 5 for guidance in proposing redactions consistent with the exceptions specified in the Medical Device Regulations section 43.12(2).

The justification of certain redactions may require the manufacturer to draw on information within their internal corporate plans (e.g. future development of new indications based on secondary outcome data). Consequently, Health Canada requests that the manufacturer submit an annotated version of all clinical information in scope of publication with any and all proposed redactions highlighted. Any text the manufacturer proposes to redact must remain readable, and all proposed redactions should be accompanied by specific and detailed justification recorded using the "Proposed Redaction Control Sheet" in.CSV format. Please refer to Appendix E for the control sheet template.

The annotated documents in drug submissions and medical device applications must also be anonymized in accordance with the process outlined in Section 5 of this Guidance document. The process of data anonymization should be detailed in a separate Anonymization report (see Appendix F for the Anonymization Report Template).

Once the manufacturer has prepared the above documents, Health Canada requests that the documents be transmitted through the Common Electronic Submissions Gateway (CESG). Documents submitted via the CESG must follow the defined naming convention outlined in Appendix D.

Health Canada may return to the manufacturer on one additional occasion to seek additional justification. The final decision on what clinical information is publicly released rests with Health Canada.

Relying on Previously Redacted Information

With appropriate certification, the manufacturer may submit to Health Canada final redacted documents of a drug submission that were previously accepted by the European Medicines Agency (EMA). Upon receipt of a Health Canada notification to prepare annotated documents for public release, in the case that this clinical information was previously released by the European Medicines Agency policy on publication of clinical data for medicinal products for human use (EMA Policy 0070), the manufacturer can choose this alternative pathway.

Manufacturers must submit final redacted documents using the CESG, as above.

Health Canada requests that manufacturers submit their certification using the template certification form found in Appendix G. Submission of this form attests that the clinical information in scope of Health Canada's Public Release of Clinical Information is identical to the clinical information published under EMA Policy 0070.

In circumstances where only a component of the information requested for release by Health Canada was previously redacted for the EMA, manufacturers may resubmit the same information with certification, and only redact the outstanding components for Health Canada.

4.5 Health Canada Review of Annotated Documents

Health Canada will review the manufacturer's justifications for each proposed redaction within the annotated documents. All proposed redactions will be assessed against the exceptions permitted under the regulations (see Section 5). Following review, proposed redactions will be accepted or rejected prior to finalization of the clinical information for public release.

Proposed redactions may be rejected for the following reasons:

When the manufacturer fails to adequately demonstrate that the information was not used to support the conditions of use or purpose for the drug or medical device, as set out in the submission or application;
When the manufacturer fails to adequately justify that the proposed information describes a test, method, or assay that is used exclusively by the manufacturer;
When the manufacturer fails to demonstrate that the proposed information is out of scope of the regulations;
When the proposed redaction pertains to information already in the public domain.

Health Canada will inform the manufacturer of any proposed redactions that the Department rejects. Manufacturers will be given one additional opportunity to further justify a redaction following Health Canada's review.

As outlined in Section 6, Health Canada requests the manufacturer to anonymize the clinical information using a risk-based anonymization process. Health Canada's review will reject the transformation of any data that is not accompanied by adequate justification. Health Canada retains final decision on what information is publicly released.

4.6 Finalization of Documents

Following Health Canada's review, the manufacturer must submit a final version of the documents, according to Health Canada instructions:

All accepted proposed redactions must be converted into non-readable text; redacted text should not be machine-readable or searchable. Redactions must be clearly visible (typically using an opaque box) and should be labeled to distinguish between CBI and personal information. Alternatively, EMA specifications on redacted text are permissible.
All proposed data transformations for the purposes of anonymization should be finalized; a revised Anonymization report which excludes any personal information will be prepared to accompany the final anonymized clinical documents (see Section 5 for more information on the requirements for the Anonymization report).
The final documents should be named in accordance with the naming conventions identified in Appendix D, and submitted to Health Canada via the CESG.

4.7 Publication of Final Documents

Final documents will be made publicly available for non-commercial purposes through Health Canada's clinical information portal. All pages within the final documents will bear a non-machine-readable watermark to notify users of the Terms of Use and indicate the information was disclosed by Health Canada for non-commercial purposes. Health Canada aims to publish clinical information 120 calendar days following the initiation of the process.

5. Requirements for the Redaction of Confidential Business Information

Two categories of clinical information will remain subject to the FDA definition of CBI. With valid justification by the manufacturer, Health Canada will protect the following from public release:

Clinical information that was not used by the manufacturer in the drug submission or supplement, or medical device application to support the proposed conditions of use or the purpose for which the drug or medical device is recommended; or
Clinical information that describes tests, methods or assays used exclusively by the manufacturer.

1) As per C.08.009.2(2)(a) of the FDR, clinical information submitted by the manufacturer but that did not support the proposed conditions of use for the drug, or the purpose for which the drug is recommended, does not cease to be confidential business information following Health Canada's final regulatory decision.

Similarly, as per section 43.12(2)(a) of the MDR, clinical information submitted by the manufacturer that did not support the features of the device that permit it to be used for the medical conditions, purpose and uses for which it is manufactured, sold or represented, does not cease to be confidential business information following Health Canada's regulatory decision.

As an example, a manufacturer may be using secondary or exploratory outcome measure data described in the clinical information to support future trials to gain approval for a new indication of use. Release of this information could provide a competitor with insight about the drug's future uses.

Clinical study reports, overviews, and summaries may contain data and discussion about secondary or exploratory end points that do not support the conditions of use or purpose of the product for which the submission or application seeks market authorization. In the rare instance where this information may form a component of an on-going development program for new claims, given adequate justification Health Canada will protect this information from public release.

2) As per C.08.009.2(2)(b) of the FDR and section 43.12(2)(b) of the MDR, clinical information in respect of tests, methods or assays that are used exclusively by the manufacturer do not cease to be CBI following Health Canada's final regulatory decision.

As an example, a manufacturer may develop novel modifications to a bioassay that is then used to collect clinical data. In certain instances, such modifications may rely on considerable effort and investment by the manufacturer and may be used for other ongoing studies or other routine use. Such modifications may be considered to be exclusively used by the manufacturer.

Clinical study reports, overviews, and summaries may include details, specifications, and validation information on assays and/or test methods developed exclusively by the submission sponsor or another third party and used exclusively by the submission sponsor. In the event that these methodological details have not been published in the public domain, and with adequate justification, Health Canada will protect this information from public release.

Regardless of its location in a drug submission, chemistry, manufacturing, and other non-clinical information will remain subject to the FDA definition of confidential business information.

6. Anonymization of Personal Information

6.1 Principles of Protecting Personal Information

The federal Privacy Act defines "personal information" as information about an identifiable individual that is recorded in any form; specific and non-exhaustive examples are then listed. Clinical information contains information that falls under this definition of personal information.

The Federal Court has adopted the "serious possibility" test to determine when information is about an identifiable individual (Gordon v. Canada (Health), 2008 FC 258). Clinical information must be adequately anonymized prior to public disclosure to avoid the serious possibility of identifying individual clinical trial patients; this requires the application of an objective, systematic, and documented process of anonymization.

In order to maximize the release of analytically-valuable information and to retain the most utility of the published clinical information, the anonymization of clinical information should be guided by the following principles:

1 - All transformation of data should be conducted for the sole purpose of preventing the disclosure of personal information;
2 - All data transformations should be accompanied by robust justification, and be applied to limited variables that risk re-identification, not to broad sections of clinical information; and
3 - Data transformation should favour methods that retain analytical value, e.g. generalization, randomization and offsetting, as opposed to redaction.

6.2 Anonymization Process

Many anonymization frameworks currently exist and are publicly available. Health Canada encourages a 3-step process adapted from the 2016 Information and Privacy Commissioner of Ontario De-identification Guidelines. The process of anonymization should broadly follow the following three steps:

Step 1: Identify and classify the variables
Step 2: Measure the re-identification risk
Step 3: Anonymize the data

By adopting an anonymization process that follows these steps, the risk of disclosing personal information can be reliably reduced. An anonymization approach which includes objective risk measurement and appropriate reference population selection provides further benefits by maximizing data utility while inherently adjusting for variable sensitivities of certain study populations.

Step 1: Identify and Classify the Variables

Directly-identifying and indirectly-identifying variables must be classified prior to processing the clinical information for anonymization.

Directly-identifying variables are commonly described as information that meets the test of being:

A - Replicable, in the sense that the variable is unlikely to frequently vary over time;
B - Distinguishable, in the sense that individual patients may have distinct recognizable values; and
C - Knowable, in the sense that someone knows the variable associated with a certain individual.

Directly-identifying variables can be either uniquely identifying (e.g. a patient's social insurance number), or not uniquely identifying (e.g. patient name). Some variables classified as directly-identifying may not be necessary for the purposes of understanding the clinical information (e.g. patient initials), while others may be necessary (e.g. subject identification numbers). The disclosure of directly-identifying variables presents a serious possibility of re-identifying an individual.

Indirectly-identifying variables are other identifying variables that fall within the definition of 'personal information' within Canada's Privacy Act. In order for an indirectly-identifying variable to require anonymization, its disclosure must present a serious possibility of re-identifying an individual when combined with other available information (e.g. demographic data). Indirectly-identifying variables may be necessary for the purpose of understanding the clinical information, and therefore their anonymization must be carefully justified, in line with the guiding anonymization principle number 2.

Step 2: Measure the Re-identification Risk

Once the variables have been classified, the data risk needs to be measured. This risk measurement provides justification for any data transformation that may follow. Variables which do not present a serious possibility of re-identifying an individual, alone or in combination with other information, are not considered personal information and should not be transformed.

The overall risk of re-identification associated with the disclosure of clinical information is the product of the risk inherent to the data and the risk associated with the context of the release. For the public release of clinical information (to the general public), the calculation of risk of re-identification needs to reflect this environment; in a public release environment, the context risk is unreducible, so the overall risk of re-identification is equivalent to the risk inherent to the data (as opposed to the release of information to a small and select group of individuals, which would constitute a lower context risk, and therefore a lower risk of re-identification).

Measurement of Re-identification Risk for Directly-identifying Variables

Directly-identifying variables possess a serious risk of identifying a trial participant, and should be assumed to carry a 100% risk of re-identification (risk=1.0); invariably these variables require anonymization in order to sufficiently reduce the risk of trial participant re-identification.

Measurement of Re-identification Risk for Indirectly-identifying Variables

The risk of re-identification for indirectly-identifying variables associated with a patient needs to be calculated on a patient level. One straightforward method of calculating the risk of re-identification for indirectly-identifying variables is to measure the cell size.

Cell size is defined as the number of patients with the same indirectly-identifying variable values. Adopting a risk threshold of risk=0.09 equates to a target cell size of 11 patients. Once indirectly-identifying variables in need of anonymization are identified, the data for the corresponding patients should be anonymized in order to achieve a cell size of 11.

Reference Population for Indirectly-identifying Variables

The selection of the appropriate reference population determines the total patient group size and the amount of anonymization (i.e. data transformation) that is necessary to reduce the risk of patient re-identification. The reference population can be informed from patients in the single trial in question (smallest population), all patients in similar trials by a specific study sponsor, all patients in similar trials (e.g.. by disease or therapeutic intervention category), or all patients in a geographic area (largest population).

When the appropriate reference population is one other than the single trial in question, an extrapolation of the trial population can be applied to achieve an estimate of the population size. In keeping with the first and second guiding principle, risk of re-identification should be informed not only by the number of individuals in a single study, but also by the number that reflects real-world risk.

Risk Threshold

Health Canada encourages adopting a 9% re-identification risk threshold (risk=0.09). This aligns with the risk threshold cited in the EMA Policy 0070 External Guidance and is in agreement with other public data disclosure risk thresholds. While a qualitative approach to risk measurement can be taken, a quantitative approach has the advantage of being based on empirical measurement and consequently is more precise, less subjective, and typically retains more data utility. In the event a qualitative approach to re-identification risk measurement is adopted, following anonymization the clinical information should no longer pose a serious possibility of identifying a person.

Step 3: Anonymize the Data

Data Utility

The methodology used to anonymize clinical information can have a detrimental effect on its utility. Data that is preserved retains the greatest utility. Consequently, it is advisable to not transform (anonymize) variables that do not contribute to the risk of re-identification, and to adopt methods that have the lowest impact on data utility.

Anonymization of Directly-identifying Variables

Directly-identifying variables may be anonymized through the process of redaction, pseudonymization, or randomization. Directly-identifying variables may be redacted if the removal of the variable will not be detrimental to the understanding of the clinical information. When a directly-identifying variable is critical to the understanding of the clinical information, other anonymization methods should be selected. For example, in the case of subject identification numbers, the use of pseudonymization ensures that the capacity to link clinical trial participant data throughout the study records is preserved.

Examples of directly-identifying variables that may be redacted include:

names
initials
signatures
job titles/positions
addresses
fax numbers
email addresses
health plan beneficiary numbers
batch/serial numbers
telephone numbers

Anonymization of Indirectly-identifying Variables

Health Canada encourages the generalization of indirectly-identifying variables. These variables may include: city, state/province, zip/postal code, demographic data (race, gender, etc.), medical history, serious adverse events, dates, height, weight, and BMI.

In certain circumstances, following generalization, the variables should be re-synthesized to avoid the appearance of anonymization. The subsequent re-synthesis is expected to achieve further risk reduction due to inability to identify leaked identifiers.

Documenting the Anonymization Process and Governance

The process of anonymization should be thoroughly documented to provide the necessary audit trail. Health Canada requests that the manufacturers submit a completed Anonymization Report (template provided in Appendix F) with the submission of all anonymized clinical information.

7. Contact Information

Mailing address:

Information Science and Openness Division
Resource Management and Operations Directorate
Health Products and Food Branch
Health Canada
Graham Spry Building
250 Lanark Avenue
Ottawa, Ontario
K1A 0K9

Telephone:
613-960-4687

Email:
hc.clinicaldata-donneescliniques.sc@canada.ca

8. References

Health Canada's clinical information portal

Food and Drugs Act

Food and Drug Regulations

Medical Devices Regulations

9. Appendices

Appendix A: Structure and Content of ICH CTD/eCTD M2.5, M2.7 and M5
Section	CBI	Proactive release
2.5 Clinical Overview	Not CBI	Yes
2.5.1 Product Development Rationale	Not CBI	Yes
2.5.2 Overview of Biopharmaceutics	Not CBI	Yes
2.5.3 Overview of Clinical Pharmacology	Not CBI	Yes
2.5.4 Overview of Efficacy	Not CBI	Yes
2.5.5 Overview of Safety	Not CBI	Yes
2.5.6 Benefits of Risks Conclusions	Not CBI	Yes
2.5.7 Literature References	Not CBI	Yes
2.7.1 Summary of Biopharmaceutics and Associated Analytical Methods	Not CBI	Yes
2.7.1.1 Background and Overview	Not CBI	Yes
2.7.1.2 Summary of Results of Individual Studies	Not CBI	Yes
2.7.1.3 Comparison and Analyses of Results Across Studies	Not CBI	Yes
2.7.1.4 Appendix	Not CBI	Yes
2.7.2 Summary of Clinical Pharmacology Studies	Not CBI	Yes
2.7.2.1 Background and Overview	Not CBI	Yes
2.7.2.2 Summary of Results of Individual Studies	Not CBI	Yes
2.7.2.3 Comparison and Analysis of Results Across Studies	Not CBI	Yes
2.7.2.4 Special Studies	Not CBI	Yes
2.7.2.5 Appendix	Not CBI	Yes
2.7.3 Summary of Clinical Efficacy	Not CBI	Yes
2.7.3.1 Background and Overview of Clinical Efficacy	Not CBI	Yes
2.7.3.2 Summary of Results of Individual Studies	Not CBI	Yes
2.7.3.3 Comparison and Analyses of Results Across Studies	Not CBI	Yes
2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations	Not CBI	Yes
2.7.3.5 Persistence of Efficacy and/or Tolerability Effects	Not CBI	Yes
2.7.3.6 Appendix	Not CBI	Yes
2.7.4 Summary of Clinical Safety	Not CBI	Yes
2.7.4.1 Exposure to the Drug	Not CBI	Yes
2.7.4.1.1 Overall Safety Evaluation Plan and Narratives of Safety Studies	Not CBI	Yes
2.7.4.1.2 Overall Extent of Exposure	Not CBI	Yes
2.7.4.1.3 Demographic and Other Characteristics of Study Population	Not CBI	Yes
2.7.4.2 Adverse Events	Not CBI	Yes
2.7.4.2.1 Analysis of Adverse Events	Not CBI	Yes
2.7.4.2.2 Narratives	Not CBI	Yes
2.7.4.3 Clinical Laboratory Evaluations	Not CBI	Yes
2.7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety	Not CBI	Yes
2.7.4.5 Safety in Special Groups and Situations	Not CBI	Yes
2.7.4.5.1 Intrinsic Factors	Not CBI	Yes
2.7.4.5.2 Extrinsic Factors	Not CBI	Yes
2.7.4.5.3 Drug Interactions	Not CBI	Yes
2.7.4.5.4 Use in Pregnancy and Lactation	Not CBI	Yes
2.7.4.5.5 Overdose	Not CBI	Yes
2.7.4.5.6 Drug Abuse	Not CBI	Yes
2.7.4.5.7 Withdrawal and Rebound	Not CBI	Yes
2.7.4.5.8 Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability	Not CBI	Yes
2.7.4.6 Post-Marketing Data	Not CBI	Yes
2.7.4.7 Appendix	Not CBI	Yes
2.7.5 Literature References	Not CBI	No
2.7.6 Synopses of Individual Studies	Not CBI	No
5.1 Table of Contents of Module	Not CBI	No
5.2 Tabular Listing of All Clinical Studies	Not CBI	No
5.3.1.1 Bioavailability (BA) Study Reports	Not CBI	Yes
5.3.1.2 Comparative BA and Bioequivalence (BE) Study Reports	Not CBI	Yes
5.3.1.3 In vitro - In vivo Correlation Study Reports	Not CBI	No
5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies	Not CBI	No
5.3.2.1 Plasma Protein Binding Study Reports	Not CBI	Yes
5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies	Not CBI	Yes
5.3.2.3 Reports of Studies Using Other Human Biomaterials	Not CBI	Yes
5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports	Not CBI	Yes
5.3.3.2 Patient PK and Initial Tolerability Study Reports	Not CBI	Yes
5.3.3.3 Intrinsic Factor PK Study Reports	Not CBI	Yes
5.3.3.4 Extrinsic Factor PK Study Reports	Not CBI	Yes
5.3.3.5 Population PK Study Reports	Not CBI	Yes
5.3.4.1 Healthy Subject PD and PK/PD Study Reports	Not CBI	Yes
5.3.4.2 Patient PD and PK/PD Study Reports	Not CBI	Yes
5.3.5.1 Study Reports of Controlled Clinical Pertinent to the Claimed Indication	Not CBI	Yes
5.3.5.2 Study Reports of Uncontrolled Clinical Studies	Not CBI	Yes
5.3.5.3 Reports of Analysis of Data from More than One Study	Not CBI	Yes
5.3.5.4 Other Study Reports	Not CBI	Yes
5.3.6 Reports of Post-marketing Experience	Not CBI	No
5.3.7 Case Report Forms and Individual Patient Listings, when Submitted	Not CBI	No
5.4 Literature References	Not CBI	No
*For a description of the submission elements please refer to the ICH M4E(R2) Guideline

Appendix B: Structure and Content of ICH CTD/eCTD Module 5.3 Clinical Study Reports
Section	Description	CBI	Public Proactive Release
1	Title Page	Not CBI	Yes
2	Synopsis	Not CBI	Yes
3	Table of Contents for the Individual Clinical Study Report	Not CBI	Yes
4	List of Abbreviations and Definition of Terms	Not CBI	Yes
5	Ethics	Not CBI	Yes
5.1	Independent Ethics Committee (IEC) or Institutional Review Board (IRB)	Not CBI	Yes
5.2	Ethical Conduct of the Study	Not CBI	Yes
5.3	Patient Information and Consent	Not CBI	Yes
6	Investigators and Study Administrative Structure	Not CBI	Yes
7	Introduction	Not CBI	Yes
8	Study Objectives	Not CBI	Yes
9	Investigational Plan	Not CBI	Yes
9.1	Overall Study Design and Plan - Description	Not CBI	Yes
9.2	Discussion of Study Design, Including the Choice of Control Groups	Not CBI	Yes
9.3	Selection of Study Population
9.3.1	Inclusion criteria	Not CBI	Yes
9.3.2	Exclusion criteria	Not CBI	Yes
9.3.3	Removal of Patients from Therapy or Assessment	Not CBI	Yes
9.4	Treatments
9.4.1	Treatments Administered	Not CBI	Yes
9.4.2	Identity of Investigational Product(s)	Not CBI	Yes
9.4.3	Method of Assigning Patients to Treatment Groups	Not CBI	Yes
9.4.4	Selection of Doses in the Study	Not CBI	Yes
9.4.5	Selection and Timing of Dose for Each Patient	Not CBI	Yes
9.4.6	Blinding	Not CBI	Yes
9.4.7	Prior and Concomitant Therapy	Not CBI	Yes
9.4.8	Treatment Compliance	Not CBI	Yes
9.5	Efficacy and Safety Variables
9.5.1	Efficacy and Safety Measurements Assessed and Flow Chart	Not CBI	Yes
9.5.2	Appropriateness of Measurements	Not CBI	Yes
9.5.3	Primary Efficacy Variable(s)	Not CBI	Yes
9.5.4	Drug Concentration Measurements	Not CBI	Yes
9.6	Data Quality Assurance	Not CBI	Yes
9.7	Statistical Methods Planned in the Protocol and Determination of Sample Size
9.7.1	Statistical and Analytical Plans	Not CBI	Yes
9.7.2	Determination of Sample Size	Not CBI	Yes
9.8	Changes in the Conduct of the Study or Planned Analyses	Not CBI	Yes
10	Study Patients
10.1	Disposition of Patients	Not CBI	Yes
10.2	Protocol Deviations	Not CBI	Yes
11	Efficacy Evaluation
11.1	Data Sets Analysed	Not CBI	Yes
11.2	Demographic and Other Baseline Characteristics	Not CBI	Yes
11.3	Measurements of Treatment Compliance	Not CBI	Yes
11.4	Efficacy Results and Tabulations of Individual Patient Data	Not CBI	Yes
11.4.1	Analysis of Efficacy	Not CBI	Yes
11.4.2	Statistical/Analytical Issues	Not CBI	Yes
11.4.2.1	Adjustments for Covariates Selection	Not CBI	Yes
11.4.2.2	Handling of Dropouts or Missing Data	Not CBI	Yes
11.4.2.3	Interim Analyses and Data Monitoring	Not CBI	Yes
11.4.2.4	Multicentre Studies	Not CBI	Yes
11.4.2.5	Multiple Comparison/Multiplicity	Not CBI	Yes
11.4.2.6	Use of an "Efficacy Subset" of Patients	Not CBI	Yes
11.4.2.7	Active-Control Studies Intended to Show	Not CBI	Yes
11.4.2.8	Examination of Subgroups	Not CBI	Yes
11.4.3	Tabulation of Individual Response Data	Not CBI	Yes
11.4.4	Drug Dose, Drug Concentration, and Relationships to Response	Not CBI	Yes
11.4.5	Drug-Drug and Drug-Disease Interactions	Not CBI	Yes
11.4.6	By-Patient Displays	Not CBI	Yes
11.4.7	Efficacy Conclusions	Not CBI	Yes
12	Safety Evaluation
12.1	Extent of Exposure	Not CBI	Yes
12.2	Adverse Events (AES)	Not CBI	Yes
12.2.1	Brief Summary of Adverse Events	Not CBI	Yes
12.2.2	Display of Adverse Events	Not CBI	Yes
12.2.3	Analysis of Adverse Events	Not CBI	Yes
12.2.4	Listing of Adverse Events by Patient	Not CBI	Yes
12.3	Deaths, Other Serious Adverse Events, and Other Significant Adverse Events	Not CBI	Yes
12.3.1	Listing of Deaths, Other Serious Adverse Events and Other Significant Adverse Events	Not CBI	Yes
12.3.1.1	Deaths	Not CBI	Yes
12.3.1.2	Other Serious Adverse Events	Not CBI	Yes
12.3.1.3	Other Significant Adverse Events	Not CBI	Yes
12.3.2	Narratives of Deaths, Other Serious Adverse Events and Certain Other Significant Adverse	Not CBI	Yes
12.3.3	Analysis and Discussion of Deaths, Other Serious Adverse Events and Other Significant Adverse Events	Not CBI	Yes
12.4	Clinical Laboratory Evaluation	Not CBI	Yes
12.4.1	Listing of Individual Laboratory Measurements by Patient (16.2.8) and Each Abnormal Laboratory Value (14.3.4)	Not CBI	Yes
12.4.2	Evaluation of Each Laboratory Parameter	Not CBI	Yes
12.4.2.1	Laboratory Values Over Time	Not CBI	Yes
12.4.2.2	Individual Patient Changes	Not CBI	Yes
12.4.2.3	Individual Clinically Significant Abnormalities	Not CBI	Yes
12.5	Vital Signs, Physical Findings and Other Observations Related to Safety	Not CBI	Yes
12.6	Safety Conclusions	Not CBI	Yes
13	Discussion and Overall Conclusions	Not CBI	Yes
14	Tables, Figures and Graphs Referred to but not Included in the Text
14.1	Demographic Data	Not CBI	Yes
14.2	Efficacy Data Summary Figures and Tables	Not CBI	Yes
14.3	Safety Data Summary Figures and Tables	Not CBI	Yes
14.3.1	Displays of Adverse Events	Not CBI	Yes
14.3.2	Listings of Deaths, Other Serious and Significant Adverse Events	Not CBI	Yes
14.3.3	Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events	Not CBI	Yes
14.3.4	Abnormal Laboratory Value Listing (Each Patient)	Not CBI	Yes
15	Reference List	Not CBI	Yes
16	Appendices	Not CBI	Yes
16.1	Study Information	Not CBI	Yes
16.1.1	Protocol and Protocol Amendments	Not CBI	Yes
16.1.2	Sample Case Report Form (Unique Pages Only)	Not CBI	Yes
16.1.3	List of IECs or IRBs (Plus the Name of The Committee Chair if Required by the Regulatory Authority) - Representative Written Information for Patient and Sample Consent Forms	Not CBI	No
16.1.4	List and Description of Investigators and Other Important Participants in the Study, Including Brief (1 page) CVs or Equivalent Summaries of Training and Experience Relevant to the Performance of the Clinical Study	Not CBI	No
16.1.5	Signatures of Principal or Coordinating Investigator(s) or Sponsor's Responsible Medical Officer, Depending on the Regulatory Authority's Requirement	Not CBI	No
16.1.6	Listing of Patients Receiving Test Drug(s)/Investigational Product(s) from Specific Batches, where More than one Batch was Used 28 Structure and Content of Clinical Study Reports	Not CBI	No
16.1.7	Randomisation Scheme and Codes (Patient Identification and Treatment Assigned)	Not CBI	No
16.1.8	Audit Certificates (if Available)	Not CBI	No
16.1.9	Documentation of Statistical Methods	Not CBI	Yes
16.1.10	Documentation of Inter-Laboratory Standardisation Methods and Quality Assurance Procedures if Used	Not CBI	No
16.1.11	Publications Based on the Study	Not CBI	No
16.1.12	Important Publications Referenced in the Report	Not CBI	No
16.2	Patient Data Listings
16.2.1	Discontinued Patients	Not CBI	No
16.2.2	Protocol Deviations	Not CBI	No
16.2.3	Patients Excluded from the Efficacy Analysis	Not CBI	No
16.2.4	Demographic Data	Not CBI	No
16.2.5	Compliance and/or Drug Concentration Data (if Available)	Not CBI	No
16.2.6	Individual Efficacy Response Data	Not CBI	No
16.2.7	Adverse Event Listings (Each Patient)	Not CBI	No
16.2.8	Listing of Individual Laboratory Measurements by Patient, when Required by Regulatory Authorities	Not CBI	No
16.3	Case Report Forms
16.3.1	CRFs for Deaths, Other Serious Adverse Events and Withdrawals for AE	Not CBI	No
16.3.2	Other CRFs Submitted	Not CBI	No
16.4	Individual Patient Data Listings (U.S. Archival Listings)	Not CBI	No

Appendix C: Process Flow Chart

Appendix D: Document Naming Convention for Submissions Through the CESG

Anonymized clinical information with proposed redactions, the accompanying redaction control sheets, and anonymization reports should be submitted via the CESG using node extension titles that are the same as the parent submission.

The file format in which documents must be submitted is PDF format.

The file naming convention for all documents with proposed redactions should follow the original file naming convention used in the original submission with the addition of "-pr" as a suffix. It is assumed that the original file naming convention was chosen in accordance with Health Canada's guidance document: Preparation of Drug Regulatory Activities in the Electronic Common Technical Document Format.

"-pr" = proposed redaction

E.g. clinical-overview-pr.pdf, summary-clin-safety-pr.pdf, study-XXXXXX-pr.pdf

Once redactions are finalized, Health Canada will apply the "-red" suffix, to the final anonymized documents prior to publication.

"-red" = final redaction

E.g. clinical-overview-red.pdf, summary-clin-safety-red.pdf, study-XXXXXX-red.pdf

Appendix E: Proposed Redaction Control Sheet
Document Name	Page Number(s)	Text Proposed for Redaction	Qualifying Exception for Regulations	Not Clinical Information	Detailed Justification of Proposed Redaction	Health Canada's Response to Proposed Redaction	Health Canada's Rationale
E,g, CSR-1.pdf	E.g. 122	(Copy and paste the text that is proposed to be redacted here. E.g. specific modifications to a bioassay which qualify for redaction.)	E.g. exceptions: C.08.009.2 (2)(a) or C.08.009.2 (2)(b)	E.g. chemistry, manufacturing information	E.g. The proposed text constitutes a proprietary modification to the bioassay developed by company A in collaboration with the Manufacturer. This information, if published will undermine the commercial interests of the Manufacturer by …)	Rejected / Partially Accepted / Accepted	E.g. The redaction has been rejected as the proposed text is information available in the public domain.

Appendix F: Anonymization Report Template

1. Anonymization methodology

Describe the approach taken, the risk threshold used and the rationale for the chosen approach.

2. Identification of data variables (direct and indirect identifiers)

Classify the variables considered personal information into directly‐identifying and indirectly‐identifying categories.
State and justify the reasons for describing information as personal information.

3. Measurement of disclosure risk

State and justify the reference population used and provide summary of the dataset used to perform risk assessment.
Describe the risk analysis in context of assumptions made on plausible re-identification attacks.
Evaluate the actual risk of re-identification associated with individual trial subjects.
Discuss how the data was transformed to reduce the risk of re-identification.
Provide evidence that the re-identification risk following the anonymization process is below the specified threshold.

4. Data utility considerations

State the efforts made to maximize the utility of the anonymized information.

5. Deviations

Any deviations from the suggested anonymization procedures should be justified and thoroughly documented.

6. Attestation

Statement that the criteria for anonymization has been fulfilled as per Health Canada requirements.
I, [name of the official of the company who has the authority to sign on behalf of the company] on behalf of [name of the company], certify that the Anonymization report has been prepared as per the Guidance made available by Health Canada.

Appendix G: Certification Letter with Table of Previously Redacted Information

Certification Form

Drug Product Name:

Company:

I certify that the information submitted to the European Medicines Agency under Policy 0070, and listed in the appendix to this form, is identical to the information submitted to Health Canada.

☐ The submission content is identical

☐ The submission content is identical other than the following information provided to Health Canada, but not to the European Medicines Agency:

Module 2:

Section 2.5 document 1 (pages xxx to xxx)

Section 2.7 document 1 (pages xxx to xxx)

Module 5

Clinical study document 1 (pages xxx to xxx)

Clinical study document 2 (pages xxx to xxx)

Signature of the responsible officer of the company certifying the accuracy of this document.

Signature Date

Name Position Title

____________________________________

Company

It is prohibited for a person to knowingly make false or misleading statements or provide false or misleading information to the Minister in connection with any matter under the Act concerning a therapeutic product. (Food and Drugs Act, 21.6)

Appendix H: Terms of Use

These Terms of Use govern the access and use of Clinical Information released by Health Canada for non-commercial purposes. By clicking the button "I agree" and accepting these Terms of Use and upon being granted access to the Clinical Information, you, and, if applicable, the organization on behalf of which you are accessing the Clinical Information, are expressly agreeing to be bound by these Terms of Use.

IT IS IMPORTANT TO READ THESE TERMS OF USE CAREFULLY

1. Definitions

"Clinical Information" means the information obtained from this site.

"Manufacturer" means the person or business issued a Drug Identification Number (DIN) or a medical device licence in respective of which the Clinical Information pertains.

"Re-identification" is the practice of matching anonymous data with other information to discover the individual to which the data relates.

"You" means you personally and, as applicable, if you are accessing and using the information on behalf of your employer, that employer, and its affiliates.

2. Representations and Warranties

You represent and warrant:

that if you are accessing Clinical Information on behalf of your employer, that you have the full legal authority to bind your employer.
that your access to Clinical Information is solely for non-commercial purposes.

3. Use of Clinical Information

3.1 You acknowledge that Clinical Information may be protected by copyright or other intellectual property rights of the Manufacturer or a third party. The permission granted through this site does not grant any intellectual property or other commercial rights in relation to Clinical Information other than as expressly set out herein.

3.2 Permission is hereby granted to you to download, save, print and share or otherwise use, reproduce or communicate Clinical Information for non-commercial purposes, which without limiting the foregoing, expressly excludes the use of the information to support a marketing authorization application anywhere in the world or the selling or trading of the information to another person.

3.3 If you notice any inadvertent disclosure of personal information in the Clinical Information obtained from this site, report this occurrence immediately to Health Canada. Clinical Information may not be used to identify trial subjects or other individuals through re-identification or to publish any personal information resulting from re-identification. If you know information is available that in combination with Clinical Information could reasonably be expected to lead to re-identification, immediately report this information to Health Canada.

3.4 You agree not to provide any copy of Clinical Information to any other entity or person without an undertaking to the benefit of Health Canada that the other entity or person will use the information solely for non-commercial purposes and otherwise in accordance with these Terms of Use.

3.5 When reproducing Clinical Information, you agree to not misrepresent the source of the Clinical Information and to acknowledge that the source of the information is the Manufacturer and not use the information in a way that suggests that the Manufacturer endorses your use of the Clinical Information for any other purpose other than non-commercial purposes.

3.6 You agree to notify Health Canada of any possible unauthorized uses of Clinical Information.

3.7 Health Canada reserves the right to revoke access and/or any permission hereby granted from any person who breaches these Terms of Use or who provides false or misleading information in association with any request for Clinical Information.

4. Amendments

4.1 Health Canada reserves the right to modify these Terms of Use at any time without advanced notice. Such modification(s) shall be effective immediately upon notice of the change or on such other date as it may be specified in the notice.

4.2 Your acceptance of the modified Terms of Use will indicate your agreement to the modifications which will extend to your use, after the date of acceptance, of Clinical Information previously accessed, downloaded, saved or printed by you.

5. Limitation of liability and Indemnification

5.1 Health Canada accepts no liability for your compliance with these Terms of Use or otherwise arising in any manner whatsoever from your acts, omission or conduct in the use of Clinical Information.

5.2 You agree to indemnify and hold harmless Health Canada, Her Majesty the Queen in Right of Canada, her assigns and successors, officers, employees, or agents, from and against all claims, actions, injury, losses, expenses, damages, and costs, including reasonable attorney's fees, resulting from any violation of these Terms of Use or other proceeding arising in any manner whatsoever from your acts, omission or conduct in the use of Clinical Information.

6. Disclaimer

Without prejudice to any of the obligations of the Manufacturer under the laws of Canada, Clinical Information is provided on an "AS IS" and "AS AVAILABLE" basis. By accessing and using Clinical Information, you agree that said access and use is entirely at your own risk. Health Canada excludes all representations, warranties, obligations and liabilities in relation to Clinical Information as made accessible to you to the maximum extent permitted by law. Neither Health Canada nor the Manufacturer are liable for any errors or omissions in Clinical Information as made accessible to you and shall not be liable for any loss, injury or damage of any kind caused by its use.

7. Severability

If any provision of these Terms of Use is declared by an arbitrator or a court of competent jurisdiction to be invalid, illegal or unenforceable, such provision shall be severed from these Terms of Use and all other terms shall remain in full force and effect.

8. Governing Laws and Jurisdiction

All matters relating to your access to, or use of, the Clinical Information shall be governed by the laws of the Province of Ontario, exclusive of its rules of private international law, and the laws of Canada applicable therein. The exclusive jurisdiction and venue with respect to any action or suit arising out of or in connection with these Terms of Use or their subject matter or formation (including non-contractual disputes or claims) shall be the courts of competent jurisdiction located in the Province of Ontario, except that if you or another party to the dispute reside outside of Canada, Health Canada may elect, at its sole discretion, that the courts located in the jurisdiction where you or such other party resides will have jurisdiction.

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Date modified:: 2019-04-01