Draft Guidance Document: Submission of Pharmacogenomic Information: NOTICE

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Date: 2006-03-07

TABLE OF CONTENTS

• 1.0 INTRODUCTION
  • 1.1 Objectives
  • 1.2 Scope and Application
  • 1.3 Abbreviations and Definitions
    • 1.3.1 Abbreviations
    • 1.3.2 Definitions
  • 1.4 Background
• 2.0 SUBMISSION OF PHARMACOGENOMIC INFORMATION
  • 2.1 Information Requirements for Clinical Trial Applications
    • 2.1.1 Clinical Trial Applications Involving Pharmacogenomic Testing
    • 2.1.2 Pre-application Meetings
  • 2.2 Information Requirements for New Drug Submissions, Supplemental New Drug Submissions, Abbreviated New Drug Submissions
    • 2.2.1 NDS, SNDS, or ANDS involving Pharmacogenomic Tests
    • 2.2.2 Labeling Considerations
    • 2.2.3 Pre-Submission Meetings
• 3.0 POST-MARKET PHARMACOGENOMIC CONSIDERATIONS
• 4.0 ADDITIONAL INFORMATION

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March 15, 2006

Our file number: 06-105773-551

Release of Draft Guidance Document: Submission of Pharmacogenomic Information

Health Canada is pleased to announce the release of the draft Guidance Document Submission of Pharmacogenomic Information for a 60-day comment period.

The guidance document is intended to clarify how and when to submit pharmacogenomic information to Health Canada. The document applies to sponsors intending to submit pharmacogenomic information, either in support of an application or submission for a drug, biologic, or medical device intended for human use. The document also applies to the submission of pharmacogenomic information as part of ongoing post-market activities.

The draft document is available in both French and English on the Health Canada website at the following link: http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/pharmaco/draft_pharm aco_ebauche-eng.php

Comments on the draft guidance document should be submitted to Health Canada no later than May 15, 2006 in order to allow sufficient time for their assessment. For your convenience, please find attached a template for your comments.

Comments should be directed to the following contact:

Stephanie Hardy
Biologics and Genetic Therapies Directorate
Health Products and Food Branch
Building 7, Tunneys Pasture
Ottawa, ON K1A 0K9
Address Locator: 0702A
Fax number: (613) 952-5364
Email address: stephanie_y@hc-sc.gc.ca

Draft Guidance for Industry: Submission of Pharmacogenomic Information - Draft date: 2006/03/07

• Comments submitted by (full name, company/association name (if applicable))
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Submission of Pharmacogenomic Information

This guidance document is being distributed for comment purposes only.

Published by authority of the Minister of Health

Draft Date: 2006/03/07

Health Products and Food Branch

Our mission is to help the people of Canada maintain and improve their health. Health Canada

HPFB's Mandate is to take an integrated approach to the management of the risks and benefits to health related to health products and food by:

• Minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and,
• Promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.

Health Products and Food Branch

© Minister of Public Works and Government Services Canada 2006

Available in Canada through
Health Canada - Publications
Brooke Claxton Building, A.L. #0913A
Tunney's Pasture
Ottawa, Ontario
K1A 0K9
Tel: (613) 954-5995
Fax: (613) 941-5366

Également disponible en français sous le titre : Ébauche ligne directrice - Présentation de l'information pharmacogénomique

Catalogue No. E
ISBN

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.

Policy and regulatory initiatives of other jurisdictions were considered during the development of this guidance document. This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidances.

1.0 INTRODUCTION

1.1 Objectives

Health Canada, the federal regulatory authority that evaluates the safety, efficacy, and quality of health products available in Canada, recognizes that the application of pharmacogenomics is increasingly becoming an integral part of the drug discovery and development processes. This document is intended to provide guidance to sponsors on how and when to submit pharmacogenomic information to Health Canada.

1.2 Scope and Application

This guidance document applies to sponsors intending to submit pharmacogenomic information to Health Canada, either in support of an application or submission for a drug, biologic, or medical device intended for human use, or as part of ongoing post-market activities.

In this guidance document, "shall" is used to express a requirement, i.e., a provision that the user is obliged to satisfy in order to comply with the regulatory requirements; "should" is used to express a recommendation or that which is advised but not required; and "may" is used to express an option or that which is permissible within the limits of the guidance document.

1.3 Abbreviations and Definitions

1.3.1 Abbreviations

ADR

Adverse Drug Reaction

ANDS

Abbreviated New Drug Submission

BGTD

Biologics and Genetic Therapies Directorate

CTA

Clinical Trial Application

CTA-A

Clinical Trial Application Amendment

CTD

Common Technical Document

DNA

Deoxyribonucleic acid

IVDD

In Vitro Diagnostic Device

MAH

Market Authorization Holder

MDB

Medical Devices Bureau

MHPD

Marketed Health Products Directorate

NDS

New Drug Submission

SNDS

Supplemental New Drug Submission

SNP

Single Nucleotide Polymorphism

TPD

Therapeutic Products Directorate

1.3.2 Definitions

Adverse Drug Reaction:
A noxious and unintended response to a drug, which occurs at doses normally used or tested for the diagnosis, treatment or prevention of a disease or the modification of an organic function. [C.01.001]

Biologic Drug:
A drug listed in Schedule D to the Food and Drugs Act that is in dosage form, or a drug that is a bulk process intermediate that can be used in the preparation of a drug listed in Schedule D to the Act. [C.04.001]
Schedule D includes names of individual products (such as "insulin"), product classes (such as "immunizing agents"), references to particular sources (such as "drugs, other than antibiotics, prepared from microorganisms") and methodology (such as "drugs obtained by recombinant DNA procedures"). Drugs or biological preparations similar to those listed in Schedule D for which there are special safety, efficacy and quality concerns, are treated as biologics for regulatory purposes.

Biomarker¹: A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.

Device:
Any article, instrument, apparatus or contrivance, including any component,
part or accessory thereof, manufactured, sold or represented for use in

1. the diagnosis, treatment, mitigation or prevention of a disease, disorder or abnormal physical state, or its symptoms, in human beings or animals,
2. restoring, correcting or modifying a body function or the body structure of human beings or animals,
3. the diagnosis of pregnancy in human beings or animals, or
4. the care of human beings or animals during pregnancy and at and after birth of the offspring, including care of the offspring, and includes a contraceptive device but does not include a drug. [Section 2 of the Food and Drugs Act]

Drug:
Any substance or mixture of substances manufactured, sold or represented for use in:

1. the diagnosis, treatment, mitigation or prevention of a disease, disorder, or abnormal physical state, or its symptoms, in human beings or animals;
2. restoring, correcting or modifying organic functions in human beings or animals; or
3. disinfection in premises in which food is manufactured, prepared or kept. [Section 2 of the Food and Drugs Act]

In Vitro Diagnostic Device:
A medical device that is intended to be used in vitro for the examination of specimens taken from the human body. [Section 1 of the Medical Devices Regulations]

Pharmacogenomics:
Pharmacogenomics is the identification and study of genes and their corresponding products which influence individual variation in the efficacy or toxicity of therapeutic products, and the application of genomic information to help inform therapeutic product development and/or clinical application. This may include:

• choosing the most appropriate therapeutic product for a patient;
• selecting optimal dose; and/or
• identifying those at risk for atypical or more frequent adverse drug reactions.

Pharmacogenomic Test:
An in vitro diagnostic device intended to identify inter-individual variations in whole-genomes or candidate genes, single-nucleotide polymorphisms, haplotype markers, or alterations in gene expression that may be correlated with pharmacological function and therapeutic response.

Single Nucleotide Polymorphism²:
A chromosomal locus at which a single base variation exists stably within populations (typically defined as each variant form being present in at least 1-2% of individuals).

1.4 Background

There is a growing understanding of how genes and genetic variation contribute to drug responses, including non-response and toxicity. This understanding, coupled with the sequencing of the human genome and corresponding potential for understanding gene function/interaction, offer new opportunities for drug development and health care.

Many sponsors are considering integrating pharmacogenomics into the drug discovery and development processes, and there are increasing efforts by regulators to determine the most appropriate means of using pharmacogenomic information within the context of pre-market and post-market drug evaluation and regulatory decision-making.

Pharmacogenomics is a rapidly evolving field of research, and as such, it will take a concerted effort between sponsors and regulators to harness the benefits that it has to offer.

Pharmacogenomics may have utility in areas such as:

• the determination of drug disposition (such as metabolism, transport, receptor site) and response where genetic variation may affect the expression or activity of one or more critical components;
• identification of predisposition(s) to diseases having genetic components;
• the surveillance or monitoring of disease-based expression to determine disease stage and whether therapeutic intervention has an affect on disease progression;
• the identification of target patient population that may either have greater or reduced response to a drug (altered efficacy) or risk of developing a drug-related adverse reaction (altered safety); and
• the investigation of the genetic basis of rare adverse drug reactions (ADR) in the context of a risk management programme, particularly if such data was used in the nonclinical phases of drug development.

General Considerations for Pharmacogenomic Studies

Testing in clinical trials, including pharmacogenomic testing should be done without compromising the well-being of patients. When a drug is studied in one geographical area and/or specific subgroup(s), the intrinsic (e.g. pharmacogenomic) and extrinsic (e.g. diet) factors that could impact on the extrapolation of data to other geographical area(s) and/or specific subgroup(s) should be considered. Hence a study that stratifies or excludes patients on the basis of pharmacogenomics should be interpreted with caution. Special attention may be required for some issues such as: the nature of the subgroup involved (e.g. pediatric), interpretation and validation of tests, variable phenotypic expression of genotype, variation in haplotypes among different populations, complexity of multiple genetic expressions, environmental factors which may affect expression, re-evaluation of existing therapies in the pharmacogenomic context, re-labelling of currently marketed drugs, and education.

2.0 SUBMISSION OF PHARMACOGENOMIC INFORMATION

In Canada, drugs are regulated by the Therapeutic Products Directorate (TPD) and biologic drugs are regulated by the Biologics and Genetic Therapies Directorate (BGTD) in accordance with the Food and Drugs Act and Regulations. In vitro diagnostic devices (IVDD) are regulated by TPD's Medical Devices Bureau (MDB) in accordance with the Food and Drugs Act and the Medical Devices Regulations. This section provides guidance to sponsors on how the Food and Drugs Act and its associated regulations apply to the submission of pharmacogenomic information to Health Canada.

2.1 Information Requirements for Clinical Trial Applications

Part C, Division 5 of the Food and Drug Regulations defines specific Clinical Trial Application (CTA) and CTA-Amendment (CTA-A) requirements for the sale and importation of drugs for use in human clinical trials in Canada. CTAs should be submitted in accordance with Health Canada's Guidance for Clinical Trial Sponsors: Clinical Trial Applications.

In accordance with C.05.005 (e), sponsors are required to submit pharmacogenomic information from nonclinical studies that pertain to the pharmacological aspects, pharmacokinetics, and toxicological effects of the drug.

Any pharmacogenomic results from clinical pharmacokinetic studies of the drug as well as any information regarding drug safety, pharmacodynamics, efficacy and dose responses of the drug that were obtained from previous clinical trials in humans shall be submitted as part of the CTA in accordance with C.05.005 (e) (vi) and (vii).

If pharmacogenomic data are being used by the sponsor to support the design of the proposed clinical trial or animal study, to justify testing in humans, or to support the proposed indication(s)/labelling of the drug, it shall be submitted as part of the CTA.

Written informed consent shall be obtained from every person participating in a clinical trial. Informed consent is required for both the participation in the clinical trial as well as for any pharmacogenomic testing that is in any way related to a clinical trial. Consent forms for trials involving pharmacogenomic testing should clearly specify the pharmacogenomic testing that will be conducted, the precise reasons for the pharmacogenomic testing, the identification or otherwise of the specimens, their banking if the case may be, any provisions for future use and the extent to which, if at all, the specimen can be related in the future to the donor. Constraints and conditions set by each local Research Ethics Board must be respected in this regard.

As per C.05.009, Health Canada reserves the right to request any additional information that is required to assess the safety and risks of the drug intended for use in the proposed clinical trial, and which could include pharmacogenomic information.

2.1.1 Clinical Trial Applications Involving Pharmacogenomic Testing

At the clinical trial stage, pharmacogenomic testing can be achieved in two ways:

1. Using a pharmacogenomic test that is licenced for sale in Canada;
2. Obtaining authorization for investigational testing;

(i) Pharmacogenomic test that is licenced for sale in Canada
If a sponsor of a clinical trial intends to collect data using a pharmacogenomic test that is already licenced for sale in Canada, the sponsor should include in their CTA the name, description, and licence number of the IVDD and whether the device will be used for its intended purpose. If the device is to be used for a purpose that is different from the purpose for which it was licenced, the manufacturer/device sponsor shall obtain an authorization for investigational testing from Health Canada. Refer to item (ii) below.

(ii) Authorization for investigational testing
If a sponsor of a clinical trial intends to collect pharmacogenomic data using an IVDD that is not licenced by Health Canada, the manufacturer/device sponsor shall obtain an authorization for investigational testing from Health Canada³. The sponsor submitting a CTA for a drug in which therapeutic decisions will be based on the results of a pharmacogenomic test should include all available data that supports the safety and effectiveness of the test. This information will be reviewed by MDB. To obtain authorization, sponsors should refer to Part 3 of the Medical Devices Regulations and use the guidance document, Preparation of an Application for Investigational Testing - In Vitro Diagnostic Devices (IVDD) to guide the preparation of documents submitted to Health Canada.

CTAs that involve the use of an investigational IVDD with a drug/biologic shall be submitted to the applicable review Bureau/Centre within TPD or BGTD in duplicate and may be reviewed jointly with the MDB. Authorization for the CTA or CTA-A, will not be granted until authorization for the use of the investigational device has also been obtained. The lead Directorate will be responsible for communicating the regulatory decision to the sponsor⁴.

When dose selection, safety, or efficacy of a drug may be contingent upon the performance of a pharmacogenomic test, the sponsor should demonstrate the analytical validity of the test used. Once a sponsor has established the analytical validity of a test, its clinical validity and utility can be established only by testing in human populations. Every study based on pharmacogenomic data should provide evidence that the performance characteristics of the test used were satisfactorily validated.

2.1.2 Pre-application Meetings

Sponsors are encouraged to request consultation meetings with the relevant Directorates prior to submitting CTAs that contain pharmacogenomic information or that use a pharmacogenomic test. These consultations will enable sponsors and Health Canada to share information and knowledge pertaining to the integration of pharmacogenomics in the drug development and approval process and will help familiarize Health Canada staff with industry activities related to pharmacogenomics.

For drugs and biologics, pre-application meetings should be requested as per the process outlined in the Guidance for Clinical Trial Sponsors: Clinical Trial Applications. In the meeting request and Information Package, sponsors should indicate whether an associated application for an investigational pharmacogenomic test has been submitted to the MDB.

2.2 Information Requirements for New Drug Submissions, Supplemental New Drug Submissions, Abbreviated New Drug Submissions

Part C, Division 8 of the Food and Drug Regulations defines the requirements for the sale of new drugs in Canada and prohibits the sale of new drugs unless the manufacturer has filed a submission that is satisfactory to the Minister. Sections C.08.002., C.08.002.1, and C.08.003 outline the requirements for submission of a New Drug Submission (NDS), Abbreviated NDS (ANDS), and Supplemental NDS (SNDS) respectively. NDS should be submitted in accordance with the Health Canada guidance document, Preparation of New Drug Submissions in the CTD Format.

In order to comply with the above-mentioned sections, sponsors shall submit pharmacogenomic data if it provides evidence of the safety and/or clinical effectiveness of the new drug in the context of its proposed indications. Similarly, if pharmacogenomic data is being used to support the proposed dosage of the drug, the claims to be made for the drug, or the contra-indications and side effects of the drug, the data shall be submitted by the sponsor.

Part C, Division 8 of the regulations enables Health Canada to request any additional information or material respecting the safety and effectiveness of the new drug, which could include relevant pharmacogenomic information.

2.2.1 NDS, SNDS, or ANDS involving Pharmacogenomic Tests

Health Canada encourages sponsors intending to use a pharmacogenomic test to support a therapeutic decision (eg. the choice or dosing of a drug) to apply for a medical device licence as they progress through their drug development program if a licenced test is not already available for use in Canada.

If the sponsor used a pharmacogenomic test that is already licenced in Canada, the sponsor should indicate in their submission, the name, description, and licence number of the IVDD that was used.

In Canada, all devices intended to be used for pharmacogenomic testing are classified as Class III medical devices and require a pre-market scientific assessment of the safety and effectiveness by the MDB. The requirements for an application for a new Class III medical device are described in the guidance document: Preparation of a Premarket Review Document for Class III and Class IV Device Licence Applications, and in Section 32 of the Medical Devices Regulations.

Since these devices may have profound impact on the safety and effectiveness of the drug for which the assay/test is performed, data for pre-market review will be required. To ensure proper classification of the devices, sponsors are encouraged to contact MDB for further guidance.

2.2.2 Labeling Considerations

Sponsors shall comply with all of the applicable labeling requirements in the Food and Drugs Act and Regulations. Sponsors should refer to the Guidance for Industry: Product Monograph for guidance on the development of a product monograph. When developing the product monograph and labeling, sponsors should consider whether there is evidence to support the inclusion of pharmacogenomic information. For example,

• when pharmacogenomic data demonstrate that subgroups of patients have higher clinical efficacy, specific labeling may be warranted to identify and define the population subgroup(s) that may be at increased risk for ADR(s) and/or that may derive the greatest benefit;
• when there is sufficient evidence to support special dosage considerations for specific population subgroup(s), these should be defined (for example, when there is evidence to support dosage reductions for particular patient subgroups to avoid ADRs);
• when diagnostic testing is recommended or required in order to optimize the use of the drug (e.g. if testing is recommended prior to selecting or prescribing treatment).

When the medical and technical aspects of the submission have been evaluated, staff from the relevant review division will be available to discuss the development of an appropriate product monograph with the sponsor.

2.2.3 Pre-Submission Meetings

Sponsors are encouraged to request consultation meetings prior to submitting NDS that contain pharmacogenomic information.

For drugs and biologics, pre-submission meetings should be requested as per the process outlined in the Management of Drug Submissions Guidance. In the meeting request and Information Package, sponsors should indicate whether an associated medical device application has been submitted to the MDB.

3.0 POST-MARKET PHARMACOGENOMIC CONSIDERATIONS

Pharmacogenomics may enhance the ability to detect and prevent serious ADR(s) in the post-market setting, particularly drugs with variable pharmacokinetic/pharmacodynamic properties and narrow therapeutic indices.

Sponsors/MAHs are reminded of mandatory post-market reporting requirements for drugs under the relevant regulations, as well as mandatory problem reports for problems with licenced pharmacogenomic tests⁵,⁶.

Sponsors/MAHs are also encouraged to consult with MHPD regarding the integration of pharmacogenomics into post-market activities. Should pharmacogenomic safety issues involving therapeutic products arise in the post-market setting, both MHPD and the relevant pre-market directorate may discuss appropriate strategies to address the issue.

Pharmacogenomic information obtained post-market that triggers a change(s) to the drug is to be submitted to the relevant pre-market review directorate (e.g. changes to the indication or dosing recommendations would require the submission of an SNDS).

For the analysis of post-market safety issues arising from pharmacogenomic data, information required by Health Canada to assess the risk should at minimum include the ADR(s) in question, the suspected SNP/haplotype involved, and validation information on the pharmacogenomic test used. Additional contextual information may also be required in order to interpret the significance of the link between the safety issues and the SNP/haplotype. Such information may include, but is not restricted to, the following:

• information on related metabolic enzymes or transport proteins associated with the SNP/haplotype, particularly where more than one known or suspected biological pathway may be involved;
• non-genetic intrinsic and extrinsic factors that may be confounding variables, including age, gender, race/ethnicity, co-medications (including natural health products, supplements, and foods), smoking and alcohol use, co-morbidities, possible failure of compliance, weight/nutritional status, etc;
• summary information on other common characteristics of the patient population that may also explain the occurrence of the ADR(s) in question (e.g. pediatric population).

In addition, the sponsor/MAH should provide a summary analysis of the significance of this information on the overall safety of the product for its given indication(s). A risk management strategy should be proposed to ensure that risks associated with the health product are appropriately addressed.

It should be noted that Health Canada has initiated the process of implementing the ICH E2E guidance document on Pharmacovigilance Planning⁷. This document is intended to aid in planning pharmacovigilance activities, particularly during the early post-marketing period after a therapeutic product is licenced. Where feasible, sponsors/MAHs are encouraged to integrate pharmacogenomic testing as part of ICH E2E, Pharmacovigilance Planning.

4.0 ADDITIONAL INFORMATION

Pharmacogenomics is an emerging field. On an ongoing basis, Health Canada may update its guidance in response to new scientific knowledge and/or based on experience gained by the department.

Questions concerning the submission of pharmacogenomic information to Health Canada should be directed to:

For drugs:

Therapeutic Products Directorate
Regulatory Project Management Division
Office of Business Transformation
Building 2, Tunney's Pasture
Ottawa, Ontario K1A 0K9
Address Locator: 0202D2
Phone: (613) 954-6481
Fax: (613) 952-9310
E-mail: RPM_Division-GPR_n@hc-sc.gc.ca

For medical devices:

Therapeutic Products Directorate
Medical Devices Bureau
Licensing Services Division
Room 1605, Statistics Canada Main Building,
Tunney's Pasture
Ottawa, Ontario K1A 0L2
Address Locator: 0301H1
Phone: (613) 957-7285
Fax: (613) 941-4726
E-mail: mgr-lsd_d@hc-sc.gc.ca

For biologic drugs:

Biologics and Genetic Therapies Directorate
Centre for Policy and Regulatory Affairs Division
Regulatory Affairs Division
Building 7, Tunney's Pasture
Ottawa, Ontario K1A 0K9
Address Locator: 0701A
Phone: (613) 957-1722
Fax: (613) 941-1708
Email: BGTD_D_Enquiries@hc-sc.gc.ca

For marketed health products:

Marketed Health Products DirectorateBuilding 7, Tunney's Pasture
Ottawa, Ontario K1A 0K9
Address Locator: 0701C
Phone: (613) 954-6522
Fax: (613) 952-7738
Email: MHPD_C@hc-sc.gc.ca

References

1. Biomarkers Definitions Working Group. 2001. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework". Clin Pharmacol Ther. 69(3): 89-95.
2. Food and Drug Administration. Guidance for Industry: Pharmacogenomic Data Submissions. U.S. Department of Health and Human Services, 2005.
3. Health Canada. Guidance for Clinical Trial Sponsor: Clinical Trial Applications. Public Works and Government Services Canada, 2003.
4. Health Canada. Guidance for Industry: Product Monograph. Public Works and Government Services Canada, 2004.
5. Health Canada. Preparation of Drugs Submissions in the CTD Format. Public Works and Government Services Canada, 2003.
6. Health Canada. Preparation of an Application for Investigational Testing - In Vitro Diagnostic Devices (IVDD). Public Works and Government Services Canada, 1999.
7. Health Canada. Preparation of a Premarket Review Document for Class III and Class IV Device Licence Applications. Public Works and Government Services Canada, 1998.
8. Health Canada. Management of Drug Submissions Guidance. Public Works and Government Services Canada, 2005.
9. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Tripartite Guideline: Pharmacovigilance Planning E2E, 2004.
10. World Health Organization. Glossary of Technical Terms in Genetics, Report of the Advisory Committee on Health Research. Genomics and World Health, 2002.

Footnotes

• ¹ Biomarkers Definitions Working Group. 2001. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework". Clin Pharmacol Ther. 69(3): 89-95.
• ² World Health Organization. Glossary of Technical Terms in Genetics, Report of the Advisory Committee on Health Research. Genomics and World Health, 2002.
• ³ Part 3, Section 80 (2) of the Medical Devices Regulations states that no person shall import or sell a Class II, III or IV medical device to a qualified investigator for the purpose of conducting investigational testing unless the manufacturer or importer holds an authorization issued under subsection 83(1) and possesses records that contain all the information and documents required by section 81.
• ⁴ The lead Directorate is that defined as the Directorate responsible for the review of the product filed by the sponsor of the CTA or CTA-A
• ⁵ C.01.016 of the Food and Drug Regulations details post-market reporting requirements for drugs.
• ⁶ Part 1, Sections 59-61 of the Medical Devices Regulations detail the requirements for mandatory problem reporting for medical devices, which include pharmacogenomic tests (Class III devices).
• ⁷ ICH E2E: Pharmacovigilance Planning. Document can be found at: http://www.ich.org/LOB/media/MEDIA1195.pdf