Guidance for Clinical Trial Sponsors: Clinical Trial Applications
Published by authority of the
Minister of Health
Date Adopted |
2003/06/11 |
Effective Date |
2003/06/25 |
Health Products and Food Branch
Guidance Document
Our mission is to help the people of Canada maintain
and improve their health.
Health Canada |
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Également disponible en français sous le titre:
Ligne directrice à l'intention des promoteurs d'essais cliniques: Demandes
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Catalogue No. H49/168-2002E-IN
ISBN 0-662-33127-3
FOREWORD
Guidance documents are meant to provide assistance to industry and health
care professionals on how to comply with the
policies and governing statutes and regulations. They also serve to provide
review and compliance guidance to staff, thereby ensuring that mandates
are implemented in a fair, consistent and effective manner.
Guidance documents are administrative instruments not having force of
law and, as such, allow for flexibility in approach. Alternate approaches
to the principles and practices described in this document may
be acceptable provided they are supported by adequate scientific
justification. Alternate approaches should be discussed in advance with
the relevant program area to avoid the possible finding that applicable
statutory or regulatory requirements have not been met.
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 guidance, in order to allow
the Department to adequately assess the safety, efficacy or quality of
a therapeutic product. Health Canada is committed to ensuring that such
requests are justifiable and that decisions are clearly documented.
This document should be read in conjunction with the accompanying notice
and the relevant sections of other applicable guidances.
TABLE OF CONTENTS
1. PURPOSE
2. DEFINITIONS
3. REGULATORY OVERVIEW
4. PRE-CTA CONSULTATION MEETING
4.1 Pre-CTA Information Package
4.2 Pre-CTA Consultation Meeting Record
5. CLINICAL TRIAL APPLICATIONS (CTAs)
5.1 Filing a CTA
5.2 CTA Requirements
Module 1: Administrative / Clinical
Information
Module 2: Common Technical Document
Summaries
Module 3: Quality
5.3 CTA Requirements for Institution
/ Investigator-initiated Clinical Trials
5.4 Comparative Bioavailability Trial
Application Requirements
6 CTA AMENDMENTS
6.1 CTA-As: Clinical
6.1.1 Filing a CTA-A: Clinical
6.1.2 CTA-A Requirements: Clinical
6.2 CTA-As: Quality (Chemistry and Manufacturing)
6.2.1 Filing a CTA-A: Quality (Chemistry
and Manufacturing)
6.2.2 CTA-A Requirements: Quality (Chemistry
and Manufacturing)
7 CTA and CTA-A REVIEW PROCESS
7.1 Screening of CTAs and CTA-As
7.1.1 Requests for Clarification
7.1.2 Screening Rejection Letter
7.2 Review of CTAs and CTA-As
7.3 Filing of Trial Commencement Information
8 NOTIFICATION
9 LABELLING REQUIREMENTS
10 CLINICAL TRIALS INVOLVING INVESTIGATIONAL MEDICAL DEVICES
AND A DRUG (PHARMACEUTICAL OR BIOLOGICAL / RADIOPHARMACEUTICAL)
11 CLINICAL TRIALS INVOLVING A PHARMACEUTICAL AND A BIOLOGICAL
/ RADIOPHARMACEUTICAL DRUG
12 CONTINUOUS ASSESSMENT
12.1 Research Ethics Board Refusals 12.2 Premature Discontinuation of a
Trial 12.3 Adverse Drug Reactions (ADRs) 12.4 Updated Investigator's Brochure
13 RECORDS RELATED TO CTAs AND CTA-As
14 RESEARCH ETHICS BOARD REVIEW
15 QUALIFIED INVESTIGATORS
16 INDEX OF APPENDICES
Appendix 1: List of Abbreviations
Appendix 2: Useful Internet Website
Addresses
Appendix 3: Outline of a CTA / CTA-A
Appendix 4: Guidance Notes for Protocol
Synopsis (PCERT)
1. PURPOSE
This is a guidance document for the administration of the Food and
Drug Regulations Amendment (Schedule No. 1024) Clinical Trial Framework
[SOR/2001-203] (also referred to as the Regulations). This guidance
document is not an exhaustive description or explanation of Part C, Division
5 of the Regulations, but rather, outlines the application requirements
for sponsors wishing to conduct clinical trials with drugs in humans.
The format outlined in this guidance for Clinical Trial Applications (CTAs)
is consistent with that used for other types of drug submissions filed
in Canada, based on the format of the International Conference on Harmonization
(ICH) Common Technical Document (CTD). Although the scope of ICH's CTD
does not include applications at the clinical research stage of development,
the modular format of the CTD is being extended to CTAs that are filed
with Health Canada. This approach is intended to facilitate the preparation
of drug submission information throughout the lifecycle of a drug (e.g.,
from Clinical Trial Application to the New Drug Submission stage).
This guidance document supercedes the Clinical Trials Review and Approval
Policy (1997), the Preparation of Investigational New Drug Submissions
(1991) and the Conduct of Clinical Investigations (1989).
This document does not constitute part of the Regulations and
in the event of any inconsistency or conflict, the Regulations
take precedence over this guidance document.
2. DEFINITIONS
Most of the definitions listed below were taken from the Food and
Drug Regulations Amendment (Schedule No. 1024) Clinical Trial Framework,
Health Canada / ICH Guidance Documents E6: Guideline for Good Clinical
Practice: Consolidated Guideline and E8: General Considerations
for Clinical Trials.
Adverse Drug Reaction - Any noxious and unintended
response to a drug that is caused by the administration of any dose of
the drug.
Adverse Event - Any adverse occurrence in
the health of a clinical trial subject who is administered a drug, that
may or may not be caused by the administration of the drug, and includes
an adverse drug reaction.
Clinical Trial - An investigation in respect
of a drug for use in humans that involves human subjects and that is intended
to discover or verify the clinical, pharmacological or pharmacodynamic
effects of the drug, identify any adverse events in respect of the drug,
study the absorption, distribution, metabolism and excretion of the drug,
or ascertain the safety or efficacy of the drug.
Date of Commencement of a Clinical Trial
- For the purpose of the Clinical Trial Site Information Form, this is
defined as the date when the clinical trial site will be ready to enrol
patients in the clinical trial1.
Comparative Bioavailability Studies - For
the purpose of this document, studies comparing the pharmacokinetics of
two drug formulations in healthy adult volunteers.
Drug - For the purpose of this document,
a drug for human use that is to be tested in a clinical trial.
Good Clinical Practices - Generally accepted
clinical practices that are designed to ensure the protection of the rights,
safety and well-being of clinical trial subjects and other persons, and
the good clinical practices referred to in section C.05.010 of Division
5 of the Food and Drug Regulations.
Import - To import a drug into Canada for
the purpose of sale in a clinical trial.
Importer - The sponsor or person designated
by the sponsor who is responsible for the import of the drug into Canada
for the purpose of sale in a clinical trial. Individual investigators
at the clinical trial sites in Canada may serve as Canadian Importers.
Informed Consent - Written informed consent,
given in accordance with the applicable laws governing consent is obtained
from every person before that person participates in a clinical trial
but only after that person has been informed of:
- the risks and anticipated benefits to his or her health arising from
participation in the clinical trial; and
- all other aspects of the clinical trial that are necessary for that
person to make the decision to participate in the clinical trial.
Investigator's Brochure - In respect of a
drug, a document containing the preclinical and clinical data on the drug
that are described in section C.05.005(e) of Division 5 of the Food
and Drug Regulations.
Phase I - Initial safety studies on a new
drug, including the first administration of the drug into humans, usually
conducted in healthy volunteers. These trials may be conducted in patients
when administration of the drug to healthy volunteers is not ethical.
Phase I trials are designed mainly to determine the pharmacological
actions of the drug and the side effects associated with increasing doses.
Pharmacokinetic as well as drug-drug interaction studies are usually considered
as Phase I trials regardless of when they are conducted during drug development
as these are generally conducted in healthy volunteers. Phase I trials
also include trials in which new drugs are used as research tools to explore
biological phenomena or disease processes.
Phase II - Clinical trials to evaluate the
efficacy of the drug in patients with medical conditions to be treated,
diagnosed or prevented and to determine the side effects and risks associated
with drug. If a new indication for a marketed drug is to be investigated,
then those clinical trials may generally be considered Phase II trials.
Phase III - Controlled or uncontrolled trials
conducted after preliminary evidence suggesting efficacy of the drug has
been demonstrated. These are intended to gather the additional information
about efficacy and safety that is needed for further risk/benefit assessment
of the drug. In this phase, clinical trials are also conducted in special
patient populations (e.g., renal failure patients), or under special conditions
dictated by the nature of the drug and disease.
Phase IV - All studies performed after the
drug has been approved by the regulator for the market, and related to
the approved indication. These studies are often important for optimizing
the drug's use. They may be of any type but must have valid scientific
objectives. Commonly conducted studies include safety studies and studies
designed to support use under the approved indication such as mortality
and morbidity studies, or epidemiological studies.
Protocol - A document that describes the
objectives, design, methodology, statistical considerations and organization
of a clinical trial.
Qualified Investigator - The person responsible
to the sponsor for the conduct of the clinical trial at the clinical trial
site, who is entitled to provide health care under the laws of the province
where that clinical trial site is located, and who is
- in the case of a clinical trial respecting a drug to be used for
dental purposes only, a physician or dentist and a member in good standing
of a professional medical or dental association; and
- in any other case a physician and a member in good standing of a
professional medical association.
Research Ethics Board - A body that is not
affiliated with the sponsor, and
- the principal mandate of which is to approve the initiation of, and
conduct periodic reviews of, biomedical research involving human subjects
in order to ensure the protection of their rights, safety and well-being;
and
- that has at least five members, that has a majority of members who
are Canadian citizens or permanent residents under the Immigration Act,
that is composed of both men and women and that includes at least:
- two members whose primary experience and expertise are in scientific
discipline, who have broad experience in the methods and areas of
research to be approved and one of whom is from a medical discipline
or, if the clinical trial is in respect of a drug to be used for
dental purposes only, is from a medical or dental discipline,
- one member knowledgeable in ethics,
- one member knowledgeable in Canadian laws relevant to the biomedical
research to be approved,
- one member whose primary experience and expertise are in a non-scientific
discipline, and
- one member who is from the community or is a representative of
an organization interested in the areas of research to be approved
and who is not affiliated with the sponsor or the site where the
clinical trial is to be conducted.
Senior Medical or Scientific Officer - A
scientific or medical officer residing in Canada, representing the sponsor,
who is responsible for providing an attestation with respect to the Clinical
Trial Application/Amendment at the time of filing, as outlined in Appendix
3 of the Drug Submission Application Form (HC/SC 3011).
Serious Adverse Drug Reaction - An adverse
drug reaction that requires in-patient hospitalization or prolongation
of existing hospitalization, that causes congenital malformation, that
results in persistent or significant disability or incapacity, that is
life threatening or that results in death.
Serious Unexpected Adverse Drug Reaction
- A serious adverse drug reaction that is not identified in nature, severity
or frequency in the risk information set out in the investigator's brochure
or on the label of the drug.
Sponsor - An individual, corporate body,
institution or organization that conducts a clinical trial.
1 Before commencement of a trial, the
sponsor should ensure that Health Canada and the Research Ethics Board
have raised no objections to the Clinical Trial Application.
3. REGULATORY OVERVIEW
The Food and Drugs Act and Regulations provide authority to
Health Canada to regulate the sale of drugs for the purposes of use in
human clinical trials. Part C, Division 5 of the Regulations
defines specific Clinical Trial Application (CTA), and Clinical Trial
Application Amendment (CTA-A), requirements for the sale and importation
of drugs for use in human clinical trials in Canada.
The Regulations are consistent with the principles, definitions
and standards found in the Health Canada / ICH Guidance Documents E6:
Good Clinical Practice: Consolidated Guideline, E8: General Considerations
for Clinical Trials and E2A: Clinical Safety Data Management: Definitions
and Standards for Expedited Reporting. These guidance documents,
developed through the International Conference on Harmonisation2
(ICH) process have been adopted by Health Canada. Together, they define
parameters for the design, conduct, performance, monitoring, auditing,
recording, analysis and reporting of clinical trials.
A CTA must be filed prior to the initiation of a clinical trial in Canada.
Health Canada must review the application and notify the sponsor within
30 days if the application is found to be deficient [C.05.006(1)].
Sponsors must file applications to conduct clinical trials in Phases
I through III of drug development and comparative bioavailability trials.
This includes applications to conduct clinical trials involving marketed
products where the proposed use of the product is outside the parameters
of the approved Notice of Compliance (NOC) or Drug Identification Number
(DIN) application.
Sponsors conducting clinical trials in Canada with products that have
received a Notice of Compliance with Conditions (NOC/c) are required to
file a CTA. In this case, studies conducted within the parameters of the
NOC/c would be subject to review and authorization.
Applications to conduct Phase IV trials are not subject
to filing with Health Canada.
Health Canada targets to review applications to conduct comparative bioavailability
trials and Phase I trials in healthy adult volunteers within 7 days, with
the exception of applications for Phase I trials using somatic cell therapies,
xenografts, gene therapies, prophylactic vaccines or reproductive and
genetic technologies. Trials which do qualify for
the expedited review process can only proceed if:
- a No Objection Letter (NOL) is received from
Health Canada prior to the 30 day default period; or
- within 30 days after the date of receipt of the application,
a notice in respect of the drug, indicating that the sponsor may not
sell or import the drug, has not been received.
2 For more information on the International
Conference on Harmonisation, consult the ICH website: http://www.ich.org
4. PRE-CTA CONSULTATION MEETING
Health Canada invites sponsors to request a pre-CTA consultation meeting.
Such consultations may be particularly useful for new active substances
or applications that will include complex issues that may be new to Health
Canada.
The pre-CTA consultation meeting provides an opportunity for the sponsor
to present relevant data, discuss concerns and resolve issues regarding
drug development. It also gives Health Canada an opportunity to provide
guidance on the acceptability of the proposed trial(s). Sponsors may invite
the qualified investigator(s) who will be involved in the proposed trial(s)
in Canada to attend the meeting.
4.1 Pre-CTA Information Package
Requests for a pre-CTA consultation meeting should be submitted in writing
by the sponsor to the appropriate Directorate at the addresses identified
in Section 5.1. Requests should include a cover letter proposing 4 dates
and times suitable for a pre-CTA consultation meeting. A pre-CTA consultation
meeting may be scheduled in advance, however the information package should
be provided to the appropriate Directorate 30 days prior to the meeting
date. The Directorate will acknowledge the request for consultation, indicate
the number of copies of the information package to be provided and confirm
the pre-CTA consultation meeting date.
The Information Package should contain:
- a brief summary of all data including:
- a tabular listing of completed preclinical and clinical studies,
- an outline of the observed toxicological manifestations and a
discussion of their impact on the use of the drug in humans,
- an outline of the observed adverse events and a discussion of
potential safety problems;
- a proposed global clinical plan for the current stage of drug development
including regulatory status in other countries;
[It is recognized that this plan is subject to change as new
information becomes available.]
- details of the proposed clinical trials to be conducted in Canada,
within the scope of the intended CTA, including:
- a statement of trial design,
- parameters, values, ranges or limits for indication(s) and clinical
use(s), patient study population(s) and routes of administration,
- parameters, values, ranges or limits for dosage form(s), dosage
regimen(s) and formulation(s),
- proposed procedures and/or criteria for patient monitoring, clinical
efficacy and safety assessments, alternative treatments, premature
patient discontinuation and other considerations, as appropriate;
- a summary of significant Quality (Chemistry and Manufacturing) aspects
of the drug;
- for Biologicals (Schedule D) and Radiopharmaceuticals (Schedule C):
- a listing of all production site(s),
- a summary of the method of manufacture for both drug substance
and dosage form,
- relevant flow charts,
- a listing of quality control procedures and specifications, and
- a summary of product characteristics.
4.2 Pre-CTA Consultation Meeting Record
The sponsor should prepare and send to the appropriate Directorate a
written record of the discussions and conclusions of the consultation
meeting within 14 days of the consultation date. All records of this consultation
will be added to the Central Registry (CR) file for the drug.
5. CLINICAL TRIAL APPLICATIONS (CTAs)
Applications must be filed by the sponsor prior
to the initiation of the trial [C.05.006(1)]. Sponsors must conduct all
clinical trials, including Phase IV trials, in accordance with the principles
of Good Clinical Practices [C.05.010].
5.1 Filing a CTA
Sponsors must file a CTA for human drug clinical trials in Phases I
through III of development and comparative bioavailability trials [C.05.006].
This includes trials involving marketed drugs, where the proposed trial
is outside of the parameters of the approved NOC or DIN application, e.g.,
one or more of the following is different:
- indication(s) and clinical use;
- target patient populations(s);
- route(s) of administration; or
- dosage regimen(s).
Sponsors are not required to file a CTA
for clinical trials involving marketed drugs where the investigation is
to be conducted within the parameters of the approved NOC or DIN application.
These trials are referred to as Phase IV clinical trials.
CTAs and CTA-As should be sent directly to the
applicable review Directorate as follows:
Pharmaceutical Drugs
Therapeutic Products Directorate
Office of Clinical Trials
5th Floor, Holland Cross, Tower B
A/L 3105A
1600 Scott Street
Ottawa, Ontario
Canada K1A 0K9
Biological and Radiopharmaceutical Drugs
Biologics and Genetic Therapies Directorate
Regulatory Affairs Divison
Health Canada Building #7, 1st Floor
A/L 0701A
Tunney’s Pasture
Ottawa, Ontario
Canada K1A 0K9
The outer label should be clearly identified with "Clinical Trial
Application".
5.2 CTA Requirements
Information for a CTA should be formatted as outlined below (refer to
Appendix 3 for an outline of the CTA sections, as well as to the draft
Health Canada guidance: Preparation of New Drug Submissions in the
CTD Format, and to the ICH M4 guidance: Organisation of the Common
Technical Document3 for more general
guidance regarding CTD- formatted submissions). Each Module should be
submitted in a separate binder.
For Biologicals and Radiopharmaceuticals:
if the CTA contains both Clinical and Quality (Chemistry and Manufacturing)
information, Module 1 (Administrative / Clinical Information) should be
submitted in duplicate.
3 The format described in these documents
should be followed to the extent possible for CTAs and for CTAAs, if appropriate.
These CTD- related guidances may undergo further changes based upon practical
experience gained through the use of the CTD and with efforts to further
harmonise internationally. During the transition period of implementing
the CTD format, a certain level of discretionary flexibility may be exercised
by Health Canada with respect to format changes.
Items marked with an asterisk (*) should be submitted in hard copy and
in electronic format accepted by Health Canada (e.g., CD-ROM).
Note: Module 1 should include the cover letter.
Module 1: Administrative / Clinical
Information
The Administrative / Clinical Information Module should include:
1.1 Table of Contents
a listing of the contents of Module 1 (Administrative / Clinical Information),
Module 2 (Common Technical Document Summaries) and Module 3 (Quality),
if applicable;
1.2 Application Information
1.2.1 Drug Submission Application Form (HC/SC
3011)
a completed and signed Drug Submission Application Form (HC/SC 3011) including
Appendix 3, signed by the Senior Medical or Scientific Officer in Canada
and the Senior Executive Officer (Appendices 1 and 2 should be completed
and submitted if applicable);
1.2.2 Information on Prior-related Applications
a list of ongoing clinical trials in Canada for which approval has been
granted by Health Canada, if applicable;
1.2.3*Investigator's Brochure
a copy of the current Investigator's Brochure, supplemented as appropriate
with up-to-date safety, pre-clinical and clinical data;
The Investigator's Brochure containing all information regarding the
product to date should be prepared in accordance with the Health Canada
/ ICH Guidance Document E6: Good Clinical Practice: Consolidated Guideline,
and updated annually. Sectional reports should not be submitted.
For products marketed in Canada, a copy of the Product Monograph may
be submitted in lieu of the Investigator's Brochure.
For Biologicals and Radiopharmaceuticals:
if the Investigator's Brochure has been updated relative to a version
contained within a previously approved CTA/CTA-A, a summary of the changes
should be provided.
1.2.4* For Pharmaceuticals:
Protocol Synopsis (PCERT)
a Protocol Synopsis in the format of the Pre-clinical and Clinical Evaluation
Report Template (PCERT)4 [see Appendix
4 for further guidance]. A submission rationale and a brief summary is
included in the PCERT;
For Biologicals and Radiopharmaceuticals:
Submission Rationale/Brief Summary of the Drug
Product
a Submission Rationale and a Brief Summary of the Drug Product being proposed
for use in the clinical trial;
1.2.5*Study Protocol(s)
a copy of the final proposed protocol(s);
1.2.6 Informed Consent Document(s)
a copy of the Informed Consent documents(s) to be used in conjunction
with the clinical trial(s), including a statement regarding the risks
and anticipated benefits to the clinical trial subjects as a result of
their participation in the clinical trial(s);
Informed Consent document(s) to be used in conjunction with the
clinical trial(s) should be prepared in accordance with the Health Canada
/ ICH Guidance Document E6: Good Clinical Practice: Consolidated Guideline.
1.2.7 Clinical Trial Site Information
a completed Clinical Trial Site Information
Form for each proposed clinical trial site, if known at the time of the
application;
Please do not provide forms until all fields are completed.
For all clinical trial site information which becomes available after the
time of application, a completed Clinical Trial Site Information Form must
be provided to the appropriate Directorate. The forms may be faxed or mailed
to the addresses below prior to the commencement of the trial at that site.
For Pharmaceuticals, the forms may be sent electronically
in WordPerfect or unlocked PDF format to:
clinical_trials_site@hc-sc.gc.ca
4 The Pre-clinical and Clinical Evaluation
Report Template (PCERT) is the current standard for providing a synopsis
of the proposed protocol(s).
Pharmaceutical Drugs
Therapeutic Products Directorate
Office of Clinical Trials
5th Floor, Holland Cross, Tower B
A/L 3105A
1600 Scott Street
Ottawa, Ontario
Canada K1A 0K9
Fax #: (613) 946-7996
Biological and Radiopharmaceutical Drugs
Biologics and Genetic Therapies Directorate
Regulatory Affairs Divison
Health Canada Building #7, 1st Floor
A/L 0701A
Tunney’s Pasture
Ottawa, Ontario
Canada K1A 0K9
Fax #: (613) 941-1708
If any changes are made to the Clinical Trial Site Information Form
(e.g., change of qualified investigator) a revised form should be submitted.
Receipt of the Clinical Trial Site Information Form will not be subject
to an acknowledgment letter.
1.2.8 Canadian Research Ethics Board(s) Refusals
the name, address and telephone number and, if applicable, the fax number
and electronic mail address of any Research Ethics Board in Canada that
has previously refused to approve the clinical trial protocol, its reasons
for doing so and the date on which the refusal was given, if known at
the time of submitting the application;
1.2.9 Foreign Refusals
information regarding refusals by regulatory authorities outside Canada,
if applicable;
1.2.10 Letters of Access
letters authorizing Health Canada to access related Master Files (e.g.,
Drug Master Files, Site Reference Files), if applicable;
For Pharmaceuticals: The CTA sponsor should
ensure that the supporting Drug Master File has been submitted to and
accepted by Health Canada prior to filing a CTA.
For Biologicals and Radiopharmaceuticals:
Any supporting Master File information should be submitted or resubmitted
simultaneously with the related CTA to Health Canada.
1.2.11 Other Application-related Information
including e.g., a copy of the record of the discussions and conclusions
of the pre-CTA consultation meeting, if applicable.
1.3 Electronic Review Documents
Health Canada is developing a plan for the electronic Clinical Trial
Application (eCTA) that will be consistent with the standard for
the electronic Common Technical Document (eCTD) being developed
at ICH. Applicants should consult the Health Canada website for CTD/ eCTD
update Notices for guidance on the filing of electronic review documents.
Items marked with an asterisk (*) should be submitted in hard copy and
in electronic format accepted by Health Canada (e.g., CD-ROM).
For Pharmaceuticals: Module 1 electronic
files should be placed under this section, whereas Module 2 electronic
files should be placed at the beginning of Module 2.
For Biologicals and Radiopharmaceuticals:
All electronic files (i.e., Modules 1 and 2) should be placed under this
section.
Module 2: Common Technical Document
Summaries
For a CTA, this module reflects Quality (Chemistry and Manufacturing)
Information only.
The Common Technical Document Summaries Module should include:
2.1 Common Technical Document Table of Contents
a listing of the contents of Modules 2 and 3, if applicable;
2.2 CTD Introduction:
Not applicable to CTAs.
This section has been reserved for use during the preparation of drug
submissions at later stages of development (e.g., New Drug Submissions)
and maintained to ensure consistent numbering of subsequent sections (e.g.,
Section 2.3);
2.3* Quality Overall Summary
This section does not apply if the drug product to
be used in the clinical trial has received a NOC and/or DIN.
Items marked with an asterisk (*) should be submitted in hard copy and
in electronic format accepted by Health Canada (e.g., CD-ROM).
- * For Pharmaceuticals: (refer to Quality
Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals
for additional information).
Depending on the phase of the clinical trial, the completed applicable
"Quality Overall Summary - Chemical Entities (QOS-CE)" template, as
well as additional Quality information as outlined in the template,
should be submitted;
- Clinical Trial Applications - Phase I: QOS-CE (CTA - Phase I);
- Clinical Trial Applications - Phase II or III: QOS-CE (CTA - Phase
II or III);
If the Quality information was previously submitted to and approved
by Health Canada and has not changed, re-submission
of the applicable Quality Summary is not required. Sponsors should,
however, refer to the control number of the prior application.
Note: i) Quality for Phase II trials cannot be
cross-referenced to the Quality information submitted with Phase I trials;
and
ii) Quality for Phase III trials cannot be cross-referenced to the
Quality information submitted with Phase II trials.
- * For Biologicals and Radiopharmaceuticals:
If the Quality information was previously submitted to and approved
by Health Canada and has not changed, re-submission
of the applicable Quality Summary is not required. Sponsors should,
however, refer to the control number of the prior application.
The completed Quality Summary (i.e., check marked sections of an acceptable
and appropriate version available, based upon the product type), should
be provided. Sponsors should also refer to the applicable Health Canada
Quality guidances and updated notices for additional information.
- For Placebo-controlled studies: a qualitative
list of the ingredients in the placebo should be submitted.
Module 3: Quality
The Quality Module should include:
3.1 Table of Contents of Module 3
a listing of the contents of Module 3 (Quality);
3.2 Body of Data
Where there is additional supporting Quality information to that provided
in Module 2.3, this information should be provided separately in the appropriate
Module 3 section and cross-referenced under Module 2.3. The extent of
available supporting information may vary depending upon the stage of
drug development (e.g., Phase I-III studies). Sponsors should also refer
to the applicable Health Canada Quality guidances for additional information.
For Biologicals and Radiopharmaceuticals only:
3.2.R.1 Production Documentation
3.2.R.1.1 Executed Batch Records
Executed Batch Records should be provided if available,
depending upon the stage of drug development (e.g., Phase I - III studies).
3.3 Literature References
For Biologicals and Radiopharmaceuticals only:
Literature references related to Quality information should be provided
here if applicable.
5.3 CTA Requirements for Institution / Investigator-initiated
Clinical Trials
The regulatory requirements for CTAs outlined in Part C, Division 5
of the Food and Drug Regulations also apply to institution /
investigator-initiated clinical trials. These include the following:
- the use of a product not approved for marketing in Canada; and
- a product marketed in Canada, where the use of the product in the
clinical trial is outside the parameters of the NOC and/or DIN.
For such trials, the institution / investigator is considered to be
the sponsor of the trial and therefore, must fulfill all the regulatory
obligations of the sponsor as outlined in Part C, Division 5 of the Food
and Drug Regulations.
CTA filing requirements for these types of trials should include the
information as described in Section 5.2, with the following modifications:
- Appendix 3 of the Drug Submission Application Form (HC/SC 3011) may
be signed by the appropriate Department Head in lieu of the Senior Executive
Officer, and the Qualified Investigator may sign in lieu of the Senior
Medical or Scientific Officer (Appendices 1 and 2 should be completed
and submitted if applicable);
- For products not marketed in Canada, the
Investigator's Brochure and data on Quality (Chemistry and Manufacturing)
must be submitted [C.05.005].
If the manufacturer of that product has previously submitted information
to Health Canada that meets the regulatory requirements for CTAs, a letter
authorizing cross reference to their information on file may be submitted
in lieu of:
- Investigator's Brochure; and/or
- Quality (Chemistry and Manufacturing) Information.
5.4 Comparative Bioavailability Trial Application
Requirements
A separate guidance document "Clinical Trial Applications for Comparative
Bioavailability Studies for Pharmaceuticals" and the "Quality Overall
Summary template QOS-CE (CTA-BA)" are located on the website.
6 CTA Amendments (CTA-As)
CTA-As are applications in which a sponsor proposes information to support
changes to a previously approved application
[C.05.008]. CTA-As may involve changes to clinical trial drug supplies
(e.g., the manufacturing process for the drug has changed), changes to
an approved protocol (e.g., a revised dosing regimen), or both.
CTA-As must be approved by Health Canada prior to implementation of the
changes [C.05.008]. Amendments submitted with a CTA or when the CTA is
under review will not be accepted. This does not apply when a protocol
is amended prior to the initial filing of the CTA.
Where a sponsor wishes to make changes to the CTA under
review, the sponsor should withdraw the active CTA and submit a new CTA.
Amendments filed to Investigational New Drug Submission(s) submitted
prior to September 1st, 2001 should be filed in accordance
with the requirements of Part C, Division 5 of the Regulations.
If the sponsor is required to immediately make one
or more of the amendments referred to in subsection (2) of C.05.008 because
the clinical trial or the use of the drug for the purposes of the clinical
trial endangers the health of a clinical trial subject or other person,
the sponsor may immediately make the amendment without prior review by
Health Canada. A corresponding CTA-A which provides the information
required below, and which clearly identifies the change and the rationale
for immediate implementation of the change must be filed within 15 days
after the date of implementation of the amendment [C.05.008(4)]. This
is subject to a 30 day review period.
6.1 CTA-As: Clinical
Sponsors must file a CTA-A when the proposed changes to the protocol:
- affect the selection, the criteria for selection, monitoring, or dismissal
of a clinical trial subject;
- affect the evaluation of the clinical efficacy of the drug;
- alter the risk to health of a clinical trial subject;
- affect the safety evaluation of the drug; or
- extend the duration of the clinical trial.
6.1.1 Filing a CTA-A: Clinical
A single copy of the application should be filed directly to the appropriate
Directorate, at the addresses previously identified in Section 5.1. The
outer label should be clearly labelled with "Clinical
Trial Application - Amendment".
6.1.2 CTA-A Requirements: Clinical
Items marked with an asterisk (*) should be submitted in hard copy and
in electronic format accepted by Health Canada (e.g., CD-ROM).
Note: A cover letter, indicating the original CTA(s) with
file number and control number(s), should be included.
Module 1: Administrative / Clinical Information
The Administrative / Clinical Information Module should include:
1.1 Table of Contents
a listing of the contents of Module 1 (Administrative / Clinical Information),
Module 2 (Common Technical Document Summaries) and Module 3 (Quality),
if applicable;
1.2 Application Information
1.2.1 Drug Submission Application Form (HC/SC
3011)
a completed and signed Drug Submission Application Form
(HC/SC 3011) including Appendix 3, signed by the Senior Medical or
Scientific Officer in Canada and the Senior Executive Officer
(Appendices 1 and 2 should be completed and submitted if applicable);
For Institution/Investigator-initiated clinical trials, Appendix 3 of
the Drug Submission Application Form (HC/SC 3011) may be signed by the
appropriate Department head in lieu of the Senior Executive Officer and
the Qualified Investigator in lieu of the Senior Medical or Scientific
Officer.
1.2.5*Study Protocol(s)
a copy of the amended or working protocol
and a clear description of the changes that are being proposed (i.e.,
original wording vs. revised
wording);
This should include a copy of the most recently
approved protocol and a rationale for each
proposed change. Cross-referencing is not acceptable.
1.2.6 Informed Consent Document(s)
revised statements, regarding the protocol amendments being made, to be
included in the Informed Consent document, if applicable;
1.2.7 Clinical Trial Site Information
a completed Clinical Trial Site Information
Form for each clinical trial
site respecting the amendment;
Please do not provide forms until all fields are completed.
For all clinical trial site information which becomes
available after the time of the filing of the CTA-A, a completed Clinical
Trial Site Information Form must be provided to the appropriate Directorate.
The forms may be faxed or mailed to the addresses identified in Section
5.2 prior to the commencement of the trial at that site.
For Pharmaceuticals, the forms may be sent electronically
in WordPerfect or unlocked PDF format to:
clinical_trials_site@hc-sc.gc.ca
If any changes are made to the Clinical Trial Site Information Form,
a revised form should be submitted.
Receipt of the Clinical Trial Site Information Form will not be subject
to an acknowledgment letter.
1.2.8 Canadian Research Ethics Board(s) Refusals
the name, address and telephone number and, if applicable, the fax number
and electronic mail address of any Research Ethics Board in Canada that
has previously refused to approve the clinical trial protocol or amendment,
its reasons for doing so and the date on which the refusal was given,
if known at the time of submitting the CTA-A;
1.2.9 Foreign Refusals
information regarding refusals by other regulatory authorities outside
Canada, if applicable.
1.3 Electronic Review Documents
Refer to section 5.2 (Module 1) for guidance.
6.2 CTA-As: Quality (Chemistry and Manufacturing)
Sponsors must file a CTA-A to a previously approved application when
changes that may affect the quality or safety of the clinical trial drug
supplies are proposed. Changes to the Quality summary subsections of Module
2.3 and Module 3 (if applicable) including, but not limited to those listed
below, warrant the filing of a CTA-A.
- For Pharmaceuticals:
- S.2 MANUFACTURE (Drug Substance), where new ingredients are used,
including ingredients which do not appear in the final drug substance;
- S.3.2 IMPURITIES, where a new impurity or degradation product
has been identified;
- S.4 CONTROL OF DRUG SUBSTANCE, where a test is removed from the
specification and/or the test methods or limits are relaxed;
- P.3 MANUFACTURE (Drug Product), where new ingredients are used,
including ingredients which do not appear in the final product;
- P.3.3 DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS CONTROLS,
for sterile products only where the sterilization process is changed;
and
- P.5 CONTROL OF DRUG PRODUCT where a test is removed from the specification
and/or the test methods or limits are relaxed.
- For Biologicals and Radiopharmaceuticals:
- S.2 MANUFACTURE, regarding raw materials, where a new medicinal
or non-medicinal ingredient is used, including ingredients not appearing
in the final formulation;
- S.4 CONTROL OF DRUG SUBSTANCE, where a test method is altered
and/or the test limits are relaxed;
- P.3 MANUFACTURE, where minor changes to the formulation process
are proposed;
- P.5 CONTROL OF DRUG PRODUCT, where a test method is changed and/or
test limits are relaxed;
- P.8 STABILITY, where an extension of the shelf life for drug product
is proposed, and the original expiry date granted was ≤ 18
months; and
- A.1 FACILITIES AND EQUIPMENT, where modifications to an existing
facility are proposed.
It should be noted that for Biologicals and Radiopharmaceuticals, certain
changes relating to the production of a given drug may be considered beyond
the scope of an approved CTA. If such changes are submitted as
CTA-As they will be subject to reclassification as a CTA.
These changes include, but are not limited to:
- use of a new or alternate facility for any stage of production except
those used for packaging,
- changes in biological source material,
- changes to genetic expression systems,
- changes to the purification process,
- changes in drug substance and/or final product dosage form (e.g.,
liquid to lyophilized formulation),
- significant changes to product release specifications, and
- changes in drug substance and/or final product strength.
6.2.1 Filing a CTA-A: Quality (Chemistry and Manufacturing)
Submit one (1) copy of the following information to the appropriate
Directorate at the addresses identified in Section 5.1. Clearly identify
the submission on the outer label with "Clinical
Trial Application - Amendment".
6.2.2 CTA-A Requirements: Quality (Chemistry and
Manufacturing)
Items marked with an asterisk (*) should be submitted in hard copy and
in electronic format accepted by Health Canada (e.g., CD-ROM).
Note: A cover letter, indicating the original CTA(s)
with file number and control number(s), should be included.
All CTA-As: Quality should contain the following:
Module 1: Administrative / Clinical Information
The Administrative / Clinical Information Module should include:
1.1 Table of Contents
a listing of the contents of Module 1 (Administrative / Clinical Information),
Module 2 (Common Technical Document Summaries) and Module 3 (Quality),
if applicable;
1.2 Application Information
1.2.1 Drug Submission Application Form (HC/SC
3011)
a completed and signed Drug Submission Application Form (HC/SC 3011) including
Appendix 3, signed by the Senior Medical or Scientific Officer in Canada
and the Senior Executive Officer (Appendices 1 and 2 should be completed
and submitted if applicable);
1.2.3* Investigator's Brochure
For Biologicals and Radiopharmaceuticals only:
a revised Investigator's Brochure or an Addendum to the Investigator's
Brochure describing any new Quality (Chemistry and Manufacturing) information,
including supporting data as required, if applicable;
1.3 Electronic Review Documents
Refer to section 5.2 (Module 1) for guidance.
Module 2: Common Technical Document Summaries
The Common Technical Document Summaries Module should include:
2.1 Common Technical Document Table of Contents
a listing of the contents of Modules 2 and 3, if applicable;
2.3* Quality Overall Summary
applicable updated Quality Summary. Revised information should be clearly
identified.
Module 3: Quality (if applicable)
The Quality Module should include:
3.1 Table of Contents of Module 3
a listing of the contents of Module 3 (Quality);
3.2 Body of Data
Additional supporting Quality information to that provided in Module 2.3,
if applicable and available. (Refer to section 5.2 (Module 3) for additional
guidance.)
3.3 Literature References
For Biologicals and Radiopharmaceuticals only:
Literature references related to Quality information should be provided
here, if applicable.
7 CTA and CTA-A REVIEW PROCESS
All CTAs and CTA-As are subject to a 30-day default review period from
the date of receipt in Health Canada. An acknowledgement letter will be
issued to indicate the start of the review period.
Health Canada targets to review applications to conduct comparative bioavailability
trials and Phase I trials in healthy adult volunteers within 7 days (for
both CTA and CTA-As), with the exception of Phase I trials using somatic
cell therapies, xenografts, gene therapies, prophylactic vaccines or reproductive
and genetic technologies.
7.1 Screening of CTAs and CTA-As
All CTAs and CTA-As will be screened for acceptability, and deficiencies
identified at screening will be addressed by:
- Request for Clarification (Clarifax), or
- Screening Rejection Letter.
7.1.1 Requests for Clarification
Requests for clarification that are issued during screening should be
responded to within 2 calendar days [C.05.009]. A Rejection Letter will
be issued if a timely response to a Clarifax has not been provided.
7.1.2 Screening Rejection Letter
A Screening Rejection Letter will be issued when significant information
requirements have not been included in the CTA or CTA-A. Sponsors will
be issued a letter itemizing each deficiency. If the sponsor wishes to
resubmit the information and material at a future time, it will be processed
as new information and material, and will be assigned a new control number
as per the Management of Drug Submissions Guidance5.
7.2 Review of CTAs and CTA-As
The sponsor is responsible for resolving issues identified by Health
Canada. Sponsors must provide the information requested by Clarifax within
2 calendar days [C.05.009].
A Not Satisfactory Notice (NSN) will be issued if significant deficiencies
are identified during the review of the CTA or CTA-A, or if a timely response
to a Clarifax issued has not been provided. If the sponsor wishes to resubmit
the information and material at a future time, it will be processed as
new information and material, and will be assigned a new control number
as per the Management of Drug Submissions Guidance5.
If there have not been any deficiencies identified and the CTA or CTA-A
is deemed acceptable, a No Objection Letter (NOL) will be issued within
the review period. Sponsors of trials which
qualify for the expedited review process can only proceed if:
- a No Objection Letter (NOL) is received from
Health Canada prior to the 30 day default period, or
- within 30 days after the receipt of the application,
a notice in respect of the drug, indicating that the sponsor may not
sell or import the drug, has not been received.
7.3 Filing of Trial Commencement Information
Prior to commencement of the Clinical Trial or implementation of a Clinical
Trial Amendment, sponsors are required to complete and submit a Clinical
Trial Site Information Form. Receipt of this form will not be subject
to an acknowledgement letter.
5 Management of Drug Submissions Guidance
2003/04/04 is located on the Health Canada website.
8 NOTIFICATION
Notifications, as described below, must be provided for changes to CTAs
and CTA-As. The changes may be implemented immediately, but Health Canada
must be informed in writing, within 15 calendar days after the day of
the change [C.05.007]. Notification changes include the following changes
to CTAs and CTA-As:
- changes to the protocol that do not affect the safety of the trial
participants and which would not be considered an amendment under section
6;
- information on site closure or completion of the Clinical Trial;
- when the Clinical Trial has been discontinued in its entirety or at
any clinical trial site for reasons not related to the safety of clinical
trial participants (e.g., for administrative purposes, lack of recruitment,
etc); and
- changes to Quality (Chemistry and Manufacturing) information that
do not affect the quality or safety of the drug, for example:
- for Pharmaceuticals: production scale-ups with no changes in the
process,
- tightening of existing test specifications,
- changes in contract testing laboratories,
- changes in packaging material,
- for Pharmaceuticals: extension of shelf life, and
- for Pharmaceuticals: changes not listed under 6.2 (a).
Updated information regarding the change should be submitted in the form
of a cover letter and any supporting documentation. This information will
be reviewed and added to the file.
9 LABELLING REQUIREMENTS
Labelling of clinical trial drug supplies must conform with Section C.05.011
of the Food and Drug Regulations. Labels of CTAs should not be
submitted unless requested by the appropriate Directorate.
10 CLINICAL TRIALS INVOLVING INVESTIGATIONAL MEDICAL
DEVICES AND A DRUG (PHARMACEUTICAL OR BIOLOGICAL / RADIOPHARMACEUTICAL)
Applications that involve the use of a medical device with a drug must
be submitted to the lead Bureau / Directorate6
in duplicate.
Authorization for the CTA or CTA-A, as well as authorization for the
use of the investigational medical device, must be obtained prior to the
initiation of the clinical trial or implementation of the protocol amendment.
The lead Bureau / Directorate will be responsible for communicating the
regulatory decision to the sponsor.
11 CLINICAL TRIALS INVOLVING A PHARMACEUTICAL AND
A BIOLOGICAL / RADIOPHARMACEUTICAL DRUG
CTAs or CTA-As that involve the use of pharmaceuticals and
biologicals or radiopharmaceuticals must be submitted to the appropriate
lead Directorate6 in
duplicate.
The lead Directorate will be responsible for communicating the regulatory
decision to the sponsor.
6 The lead Bureau / Directorate
is that defined as the Bureau / Directorate responsible for the review
of the product filed by the sponsor of the CTA or CTA-A.
12 CONTINUOUS ASSESSMENT
12.1 Research Ethics Board Refusals
Following regulatory approval of a CTA or CTA-A, information regarding
refusals by other regulatory authorities or Research Ethics Board(s),
should be submitted as a notification. This information will be added
to the file, but will not be subject to an acknowledgement letter, nor
will a No Objection Letter (NOL) be issued.
12.2 Premature Discontinuation of a Trial
In the event of the premature discontinuation of a trial in its entirety
or at a clinical trial site for which a CTA or CTA-A has been filed in
Canada, the responsible Directorate must be notified as soon as possible,
but no later than 15 calendar days after the date of discontinuance [C.05.015(1)].
This notification should include:
- detailed rationale for this action;
- description of the impact on the proposed or ongoing trials, in respect
of the drug, conducted in Canada;
- confirmation that all qualified investigators have been notified of
the discontinuation and the reasons for the discontinuance and have
been advised in writing of any potential risks to the health of clinical
trial subjects or other persons;
- confirmation that the sale or importation of the drug to all sites
involved has been stopped; and
- confirmation that reasonable measures to ensure the return of all
unused quantities of the drug will be taken.
Note: Notification of a premature discontinuation of
a Clinical Trial outside Canada, for which there are ongoing trials in
Canada, should also be submitted to the appropriate Directorate.
The sponsor may resume the trial in its entirety or at a site that was
previously discontinued if the sponsor submits the following information
[C.05.015(2)]:
- the name, address and telephone number, and if applicable, the fax
number and electronic mail address of the qualified investigator for
each site and of the REB that approved the re-initiation of the trial
at each site;
- the name, address and telephone number and, if applicable, the fax
number and electronic mail address of any REB that has previously refused
to approve the re-initiation of the trial, if applicable;
- the proposed date of re-initiation of the clinical trial at each clinical
trial site.
This information will be subject to review, and should be submitted
as a CTA-A (see Section 6), in conjunction with the information submitted
at the time of notification of trial suspension. Sponsors may only resume
a trial when a No Objection letter (NOL) has been issued from the appropriate
Directorate within 30 days of the submission of information.
12.3 Adverse Drug Reactions (ADRs)
Only adverse drug reactions that are both
serious and unexpected are subject to expedited reporting to Health Canada.
Expedited reporting of reactions which are serious but expected is not
required. Expedited reporting is also inappropriate for serious events
from clinical investigations that are considered unrelated to the study
product, whether or not the event is expected.
During a clinical trial the sponsor is required to inform Health Canada
of any serious, unexpected adverse drug reaction that has occurred inside
or outside Canada:
- where it is neither fatal nor life-threatening, within 15 days after
becoming aware of the information;
- where it is fatal or life-threatening, immediately where possible
and, in any event, within 7 days after becoming aware of the information;
and
- within 8 days after having informed Health Canada of the ADR, submit
as complete a report as possible which includes an assessment of the
importance and implication of any findings.
Each ADR which is subject to expedited reporting should be reported
individually in accordance with the data element(s) specified in the Health
Canada / ICH Guidance Document E2A: Clinical Safety Data Management:
Definitions and Standards for Expedited Reporting.
Further definitions and standards for expedited reporting of adverse
drug reactions are described in the Health Canada / ICH Guidance Document
E2A: Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting. In situations when causality assessment and
determination of expectedness is not straightforward, the report should
be submitted in the expedited manner and the relevant issues addressed
in a cover letter.
Final reports of fatal or life-threatening reactions must
include an assessment of the importance and implication of the findings,
including relevant previous experience with the same or similar drugs.
There are situations in addition to the above that may necessitate rapid
communication to Health Canada, and appropriate scientific and medical
judgment should be applied to each situation. For example, information
that might influence the risk-benefit assessment of a drug, or that would
be sufficient to consider changes in drug administration, or in the overall
conduct of a clinical trial, represent such situations; including:
- for an "expected" serious ADR, an increase in the rate of occurrence
which is judged clinically important;
- a significant hazard to the patient population, such as lack of efficacy
with a drug used in treating a life-threatening disease; and
- a major safety finding from a newly completed animal study.
A completed ADR Expedited Reporting Summary Form should be attached
to the front of the report and reports should be submitted, by fax to:
Therapeutic Products Directorate
Pharmaceuticals (613) 941-2121
Biologics and Genetic Therapies Directorate
Biologics and Radiopharmaceuticals (613) 957-0364
Ongoing safety information respecting a drug should be conveyed to Investigator(s)
and their Research Ethics Board(s). For further information refer to the
Health Canada / ICH Guidance Documents E6: Guideline for Good Clinical
Practice and E2A: Clinical Safety Data Management: Definitions and Standards
for Expedited Reporting.
12.4 Updated Investigator's Brochure
Updated Investigator's Brochures, including all safety information and
global status should be submitted annually. Additional
information and any changes that have been incorporated in the updated
Investigator's Brochure should be highlighted for ease of review and evaluation.
If an Investigator's Brochure is updated more frequently, it should be
submitted as required.
13 RECORDS RELATED TO CTAs AND CTA-As
As required in Part C, Division 5 of the Food and Drug Regulations
[C.05.012]:
- the sponsor shall record, handle and store all information in respect
of a clinical trial in a way that allows its complete and accurate reporting
as well as its interpretation and verification.
- the sponsor shall maintain complete and accurate records to establish
that the clinical trial is conducted in accordance with good clinical
practices and these Regulations.
- the sponsor shall maintain complete and accurate records in respect
of the use of a drug in a clinical trial, including:
- a copy of all versions of the Investigator's Brochure for the
drug;
- records respecting each change made to the Investigator's Brochure,
including the rationale for each change and documentation that supports
each change;
- records respecting all adverse events in respect of the drug that
have occurred inside or outside Canada, including information that
specifies the indication for use and the dosage form of the drug
at the time of the adverse event;
- records respecting the enrolment of clinical trial subjects, including
information sufficient to enable all clinical trial subjects to
be identified and contacted in the event that the sale of the drug
may endanger the health of the clinical trial subjects or other
persons;
- records respecting the shipment, receipt, disposition, return
and destruction of the drug;
- for each clinical trial site, an undertaking from the qualified
investigator that is signed and dated by the qualified investigator
prior to the commencement of his or her responsibilities in respect
of the clinical trial, that states that:
- the qualified investigator will conduct the clinical trial
in accordance with good clinical practices, and
- the qualified investigator will immediately, on discontinuance
of the clinical trial by the sponsor, in its entirety or at
a clinical trial site, inform both the clinical trial subjects
and the Research Ethics Board of the discontinuance, provide
them with the reasons for the discontinuance and advise them
in writing of any potential risks to the health of clinical
trial subjects or other persons;
- for each clinical trial site, a copy of the protocol, informed
consent form and any amendment to the protocol or informed consent
form that have been approved by the Research Ethics Board for that
clinical trial site; and
- for each clinical trial site, an attestation, signed and dated
by the Research Ethics Board for that clinical trial site, stating
that it has reviewed and approved the protocol and informed consent
form and that the board carries out its functions in a manner consistent
with good clinical practices.
- The sponsor shall maintain all records referred to in this Division
for a period of 25 years
Records must be made available to the relevant Directorate within 2
days if there is a concern regarding the use of the drug for the purposes
of a clinical trial and a risk to health of the subjects involved in
that trial. In any other case, records must be provided within 7 days
of a request [C.05.013].
14 RESEARCH ETHICS BOARD REVIEW
Prior to initiating a clinical trial or implementing an amendment to
a clinical trial at a site, the proposed trial protocol and informed consent
must be reviewed and approved by a Research Ethics Board (REB) as defined
in the Regulations.
As described previously, the sponsor must:
- submit the name of the REB that approved the trial or trial amendment
prior to the commencement of the trial or trial amendment at that site
(see Clinical Trial Site Information Form);
- retain as records a Research Ethics Board Attestation, signed by the
REB that approved the protocol or protocol amendment at each site, that
it carries out its functions in a manner consistent with Good Clinical
Practices. Research Ethics Board(s) may wish to use the Research Ethics
Board Attestation(s) or develop similar documentation that meets the
requirements of Part C, Division 5 of the Food and Drug Regulations;
and
- submit information pertaining to the refusal of the protocol for any
reason by an REB.
Please note that the Research Ethics Board Attestation should not be
submitted unless requested by Health Canada.
The information required on the Qualified Investigator Undertaking, Research
Ethics Board Attestation, HC/SC 3011, and Clinical Trial Site Information
Form, is necessary due to differences in signing authority and attestation.
15 QUALIFIED INVESTIGATORS
There must be no more than one (1) qualified investigator at each site.
These restrictions do not apply to co-investigators.
Qualified Investigator(s) may wish to use the Qualified Investigator
Undertaking(s) or develop similar documentation that meets the requirements
of Part C, Division 5 of the Food and Drug Regulations.
Please note that the Qualified Investigator Undertaking(s) should not
be submitted unless requested by Health Canada.
The information required on the Qualified Investigator Undertaking, Research
Ethics Board Attestation, HC/SC 3011, and Clinical Trial Site Information
Form, is necessary due to differences in signing authority and attestation.
16 INDEX OF APPENDICES
Appendix 1: List of Abbreviations;
Appendix 2: Useful Internet Website Addresses;
Appendix 3: Outline of a Clinical Trial Application;
Appendix 4: Guidance Notes for Protocol Synopsis (PCERT).
Appendix 1: List of Abbreviations
Adverse Drug Reaction |
ADR |
Clinical Trial Application |
CTA |
Clinical Trial Application Amendment |
CTA-A |
Common Technical Document |
CTD |
Drug Identification Number |
DIN |
Good Clinical Practice |
GCP |
International Conference on Harmonization |
ICH |
Notice of Compliance |
NOC |
No Objection Letter |
NOL |
Not Satisfactory Notice |
NSN |
Pre-clinical and Clinical Evaluation Report Template |
PCERT |
Quality Overall Summary-Chemical Entities (Clinical Trial Applications) |
QOS-CE(CTA) |
Research Ethics Board |
REB |
Appendix 2: Useful Internet Website Addresses
Biologics and Genetic Therapies Directorate
www.hc-sc.gc.ca/dhp-mps/brgtherap/index_e.html
Canadian Institutes of Health Research
http://www.cihr.ca
Health Canada
http://www.hc-sc.gc.ca
Health Products and Food Branch
http://www.hc-sc.gc.ca/hpfb-dgpsa
International Conference on Harmonization
http://www.ich.org
National Council on Ethics in Human Research
http://www.ncehr-cnerh.org
Therapeutic Products Directorate
www.hc-sc.gc.ca/dhp-mps/prodpharma/index_e.html
Appendix 3: Outline of a CTA / CTA-A
Module |
Pharmaceuticals |
Biologicals and Radiopharmaceuticals |
1 |
Administrative / Clinical Information |
1.1 |
Table of Contents (Modules 1-3) |
1.2 |
Application Information |
1.2.1 |
Drug Submission Application
Form (HC/SC 3011) |
1.2.2 |
Information on Prior-related
Applications |
1.2.3* |
Investigator's Brochure |
1.2.4* |
Protocol Synopsis
(PCERT) |
Submission Rationale /
Brief Summary of the Drug Product |
1.2.5* |
Study Protocol(s) |
1.2.6 |
Informed Consent Document(s) |
1.2.7 |
Clinical Trial Site Information |
1.2.8 |
Canadian Research Ethics Board(s)
Refusals |
1.2.9 |
Foreign Refusals |
1.2.10 |
Letters of Access |
1.2.11 |
Other Application-related Information |
1.3 |
Electronic Review Documents |
2 |
Common Technical Document Summaries |
2.1 |
Common Technical Document Table of Contents |
2.2 |
---- |
2.37* |
Quality Overall Summary |
3 |
Quality (if submitted) |
3.1 |
Table of Contents of Module 3 |
3.2 |
Body of Data |
3.2.R.1 |
---- |
Production Documentation |
3.2.R.1.1 |
---- |
Executed Batch Records |
3.3 |
---- |
Literature References |
* These items should be submitted in hard copy and in electronic format
accepted by Health Canada (e.g., CD-ROM).
7 Refer to related Quality guidances for
drug submissions in the CTD format for additional, specific information
on the other available options under Module 2.3
Appendix 4: Guidance Notes for Protocol Synopsis
(PCERT)
GUIDANCE NOTES: "PROTOCOL SYNOPSIS"
The following information should be included in the Protocol Synopsis
(PCERT):
Trial Title and Number
Background / Rationale
Background: A brief, concise introduction
into the clinical problem and previous treatments and developments, i.e.,
pertinent data from previous preclinical/clinical pharmacology studies
and therapeutic exploratory studies taking into account relevant scientific
literature (citations by consecutive numbering, with list at end of
this section; important or not readily available references may be included
with the paper submission, if appropriate). This section should also
contain information on the new drug.
Rationale: Reasoning and justification for
the proposed new approach/ therapy.
Trial Objectives
Statement of the precise goal(s) of the trial (may be subdivided into
primary and secondary objectives) which may including testing of the null
hypothesis (Ho), i.e., testing a new drug population/ indication
etc., as applicable.
Study Design & Duration
- The statement of study design should include the method of randomization,
blinding and the comparative agent, if applicable.
- A "Brief outline of the study conduct" should be included, if applicable.
- The design of the study should be able to support any claims related
to the proposed study.
- Total study duration (anticipated starting/ finishing dates).
- Duration for each subject including post treatment period etc.
Number of Centres
Total number of trial sites with list of countries/geographical areas
and number of sites in Canada.
List of Investigators
Principal Investigators at each Canadian site.
Sample Size
Rationale and calculation for sample size requirement, anticipated drop-out
rate etc. The sample determination may include Ho testing and
desired power of the study.
Patient Population (Target population)
Description of specific characteristics of trial participants re. disease/
stage/ indication/ conditions/ treatment etc., as applicable. Description
of diagnostic criteria and assessment.
Inclusion Criteria
Enumeration of conditions determining participation in the proposed clinical
trial.
Exclusion Criteria
Enumeration of conditions determining exclusion from the proposed trial.
Drug Formulation
Brief description of the study drug(s) and formulation to be used in the
clinical trial. The relationship to the formulations used in the preclinical
and/or other clinical trials should be delineated, as applicable. This
may also include disclosure of the formulation intended to be marketed
and/or any bridging studies which may be necessary, planned, initiated
and/or already performed if different formulations have been used during
clinical development.
Instructions for safe handling.
Dosage Regimen
Rationale for dose selection.
Description of the schedule(s) for using the study drug(s) including escalations/
maintenance / reductions / discontinuation, as applicable.
Description of other supportive measures and dose modifications for specific
adverse events (anticipated toxicities), as applicable.
Washout Period
Description for pre-, during- and post-trial, as applicable.
Pre-study Screening and Baseline Evaluation
Description of the process of clinical validation for participation in
the clinical trial, including methodology / schedule of events.
Treatment Visit
Schedule of all events / visits / procedures during the clinical trial.
Premature Withdrawal/Discontinuation Criteria
Enumeration of all conditions / criteria and management for drug/ patient's
withdrawal or (premature) discontinuation, including voluntary withdrawal
by subject without prejudice to future treatment by the physician.
Early stopping rules for the trial.
Rescue Medication and Risk Management
Description of antidotes/ medications/ dosages / procedures used to help
reverse untoward effects or lack of efficacy resulting from any applications
of drug(s)/ procedures in connection with the clinical trial. This section
should include any risks, for example, dose dumping from slow release
formulations.
Concomitant Medication
Enumeration and description of all dis-/allowed drug/ medications, in
addition to the study drugs.
Efficacy Variables & Analysis
Description and validation of primary endpoint(s), ie. responses/changes
from baseline over time in relation to clinical trial events. Description
and validation of related secondary changes (secondary endpoints) following
from clinical trial events.
Safety Variables & Analysis
Monitoring/ assessing adverse drug reactions/ adverse events/ toxicities/
clinical laboratory parameters etc. in relation to clinical trial events.
Statistical Analysis
(The following points are presented for consideration while completing
this section)
- Analysis of trial parameters (primary/ secondary endpoints), population,
demographics, as applicable.
- Efficacy analysis methods and results of efficacy end-point analysis.
- Safety analysis methods and results of safety end-point analysis.
- Exploratory end-point analysis: evaluation effect(s) (or lack of
effects) of relevant biochemical/ pharmacological etc parameters, as
applicable.
- Pharmacokinetic endpoint analysis, as applicable.
- Interim analysis and role of Data Safety Monitoring Board, as applicable.
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