Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.
Contact: Policy and Promotion Division
This document is also available in PDF format
Draft Guidance Document: Submission of Pharmacogenomic Information: NOTICE (PDF Version, 126 Kb)
March 15, 2006
Our file number: 06-105773-551
Health Canada is pleased to announce the release of the draft Guidance Document Submission of Pharmacogenomic Information for a 60-day comment period.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Comments on the draft guidance document should be submitted to Health Canada no later than May 15, 2006 in order to allow sufficient time for their assessment.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
Draft Date: 2006/03/07
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:
Health Products and Food Branch
© Minister of Public Works and Government Services Canada 2006Available in Canada through
╔galement disponible en franšais sous le titre : ╔bauche ligne directrice - PrÚsentation de l'information pharmacogÚnomique
Catalogue No. E
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.
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.
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.
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]
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.
Any article, instrument, apparatus or contrivance, including any component,
part or accessory thereof, manufactured, sold or represented for use in
Any substance or mixture of substances manufactured, sold or represented for use in:
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 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:
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).
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:
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.
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.
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.
At the clinical trial stage, pharmacogenomic testing can be achieved in two ways:
(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.
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.
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.
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.
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 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.
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.
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:
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.
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: