Response to Recommendations to Health Canada of the Coroner's Jury into the Death of Ashley Marie Atkinson

Prepared by:
Health Products and Food Branch
Health Canada
Updated July 29, 2003

Table of Contents

• EXECUTIVE SUMMARY
• INTRODUCTION
• OVERVIEW OF HEALTH CANADA ACTIVITIES
• Making Health Product Information More Readily Available
  • Improving Current Information Products
  • Enhancing Product Monographs
  • Exploring Mobile Wireless Technology
• Shared Responsibility for the Effective Dissemination and Use of Information
  • Increasing Focus on Post Market Surveillance
• Moving Forward
• CORONER'S JURY RECOMMENDATIONS AND HEALTH CANADA RESPONSES
• Recommendations of the Coroner's Jury
• Responses to Recommendations Directed at Health Canada
  • Recommendation # 1.5b
  • Recommendation # 1.6a
  • Recommendation # 1.6b
  • Recommendation # 3a
  • Recommendation # 4
  • Recommendation # 5
• APPENDIX I - GLOSSARY OF TECHNICAL TERMS

EXECUTIVE SUMMARY

On November 13, 2002 an inquest was concluded into the death of a 6-year-old New Brunswick girl who died in February 2001. The Coroner's Jury concluded that the child died of "influenza viral pneumonia combined with acute respiratory distress syndrome," not propofol toxicity. Irrespective of this conclusion, the Coroner's Jury has provided recommendations directed toward many partners in the health care delivery system including provincial government, health care institutions, health care professionals, manufacturers, the New Brunswick Coroner's Office and Health Canada. The majority of the recommendations of the Coroner's Jury focussed on suggestions for making health product and drug related information more readily and easily accessible to health care professionals and for improved use of that information by the health community.

Health Canada received the Coroner's Jury recommendations in early February 2003. Health Canada is submitting this document in response to them. The Department welcomes the recommendations, the insight they have provided and the opportunity to respond.

Health Canada is committed to ensuring that each of the recommendations are given careful consideration and implemented to the furthest extent possible. With this in mind, this document, as the official response to the recommendations of the Coroner's Jury, provides overall information on the issues covered by the Coroner's Jury. In addition, specific responses are provided for those recommendations which were, in the opinion of Health Canada officials, those most directly related to the Department and its mandate as the regulator of health products in Canada.

Currently, the Department provides information on health product safety to both health care professionals and the general public through the Health Canada website, Dear Health Care Professional Letters, Notices to Hospitals, the Canadian Adverse Reaction Newsletter, public advisories and warnings, information provided through many other Departmental publications and communications materials, and by attending professional conferences to disseminate information on adverse reaction reporting and Health Canada's sources of health product information. Decisions to communicate product health risk information are made by taking into account the strength of available evidence, the immediacy of the risk, the likelihood of harm, and how a product is used. Such decisions are taken on a case by case basis.

Ongoing efforts to enhance how safety and effectiveness information on health products is communicated has resulted in changes to the Health Canada website, new operating procedures for use in the development of advisories for health professionals, an enhanced and expanded product monograph template, and a redesigned Canadian Adverse Reaction Newsletter with improved distribution methods that will make it even more easily accessible to health care professionals (i.e. it is now distributed with the Canadian Medical Association Journal - the CMAJ). In addition, the Department is providing a coordinated approach to ensuring that those who wish to receive all up to date information on health products can do so through the electronic e-mail system or by mail.

Many different organizations and individuals contribute to health care in Canada including Health Canada, provincial and territorial governments, health care providers, manufacturers and consumers.

Many of the recommendations of the Coroner's Jury can best be implemented in a collaborative way involving all parties in the health care delivery system. The Department works in partnership with health care professionals, their associations, pharmaceutical companies, other industry, and consumer and patients groups to enhance both the collection and dissemination of information on the benefits and risks of marketed health products.

The Department is committed to collaborating closely with other parties to address those recommendations whose solutions can best be found in a cooperative, multi-jurisdictional approach in order for them to be implemented broadly, consistently and effectively.

Canada has a reputation for one of the best drug safety records in the world and in order to maintain its performance, continuous improvement is a priority.

.INTRODUCTION

Health Canada has placed ever increasing emphasis on enhancing its drug and health product safety system -- from research and clinical trials to the review, approval and oversight of products that are brought to market in Canada. It has put in place a directorate dedicated to the surveillance of marketed drugs and other health products, implemented a new regulatory framework for clinical trials in Canada and increased its efforts to provide more timely health risk information to health care professionals and the general public.

In 2002, the Report of the Coroner's Jury investigating the death of Vanessa Young brought many issues related to Canada's drug safety system to the forefront and gave the Department both support for its efforts and additional ideas for improvement. The recommendations received from the Coroner's Jury investigating Ashley Marie Atkinson's death are equally important and helpful. They provide additional objective insight and again, allow the Department to further strengthen work that is currently underway and enhance ongoing efforts to improve the drug and health product safety system in Canada.

Two of the most prominent themes covered in the report of the Coroner's parallel priority areas of work in the Department over the past 3 years:

1. Making health product safety information more readily available to health care professionals and the general public;
2. Enhancing partnerships and emphasising shared responsibility for the dissemination and use of new safety information on marketed drugs and other health products in Canada including their indications, contraindications, warnings and advisories;

Additionally, Health Canada agrees with the Coroner's Jury assertion that there is need for ever increasing focus on post-market surveillance and helping maximize the safety and effectiveness of marketed drugs and health products available to Canadians and has made this a large part of the mandate of the Marketed Health Products Directorate (MHPD).

This document provides general information on the work of Health Canada in the context of these themes and issues as well as information in response to specific recommendations from the Coroner's Jury. In this document, Health Canada has chosen to respond to the recommendations which, based on its understanding, fall within the Department's mandate and are most appropriately directed to the Department as the regulator of health products in Canada.

OVERVIEW OF HEALTH CANADA ACTIVITIES

Health Canada is aware that there is an increasing need and desire for health related information B particularly information related to health risks. For this reason the Department is continually looking for ways to improve the way in which health safety information is provided to health care providers and the general public. The following is a summary of both ongoing Departmental efforts to maintain and enhance Canada's drug safety efforts.

MAKING HEALTH PRODUCT RISK INFORMATION MORE READILY AVAILABLE

Health Canada is undertaking a number of initiatives to ensure that information is readily available to health care providers and the public.

Improving Current Information Products

Currently, the Department provides information on health product safety to both health care professionals and the general public through:

1. the Health Canada website;
2. Dear Health Care Professional Letters;
3. Notices to Hospitals;
4. the Canadian Adverse Reaction Newsletter;
5. public advisories and warnings; and,
6. information provided through many other Departmental publications and communications materials; and
7. attendance at professional conferences to disseminate information on adverse reaction reporting and Health Canada's sources of health product information.

Decisions to communicate product health risk information are made by taking into account the strength of available evidence, the immediacy of the risk, the likelihood of harm, and how a product is used. Such decisions are taken on a case by case basis. Signals (reported information on a possible causal relationship between an adverse event and a marketed product) and patterns of such signals are monitored and assessed. When a safety concern is identified the risks are assessed. After this analysis decisions are taken as to whether there is a need to communicate and the appropriate audience and mode of communication.

As an example, when Health Canada considers it necessary to inform health care professionals about time-sensitive issues regarding the safety and/or effectiveness of a marketed health product, manufacturers of the product are directed to prepare Dear Health Care Professional Letters. These are then approved by Health Canada. In some cases, Health Canada may issue these documents independently if many manufacturers are involved, the situation warrants it, or if the manufacturers is not proceeding within agreed upon time limits. The target for these letters could include physicians, dentists, veterinarians, pharmacists, hospitals, and others. The distribution list is tailored to the safety issue being addressed and the letters are easily accessible on the Health Canada Website.

Ongoing efforts to enhance how the Department communicates safety and effectiveness information on health products has also resulted in changes to the Health Canada website, new operating procedures for use in the development of advisories for health professionals and a redesigned Canadian Adverse Reaction Newsletter with improved distribution methods that will make it even more easily accessible to health care professionals (i.e. it is now distributed with the Canadian Medical Association Journal - the CMAJ).

In addition, the Department is providing a coordinated approach to ensuring that those who wish to receive all up to date information on health products can do so through the electronic e-mail system. Health care professionals and others can subscribe to a listserv service called Health_Prod_Info where they will receive up to date safety information on health products, electronically via e-mail as soon as it is available. The address for subscription is: http://www.hc-sc.gc.ca/dhp-mps/medeff/subscribe-abonnement/index_e.html. There are now over 6000 subscribers to the listserv service.

Enhancing Product Monographs

The product monograph is a key piece of information used by health care professionals in prescribing and administering drugs to patients. It is a factual, scientific document on a drug that, devoid of promotional material, describes the properties, claims, indications and conditions of use of the drug product and contains other information that may be required for the optimal, safe and effective use of the drug.

The product monograph is produced by the manufacturer and submitted to Health Canada as part of the New Drug Submission process (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/monograph/index_e.html). It contains all the representations to be made in respect of the new drug as required by the Food and Drug Regulations, fulfils the requirements for adequate directions for use for new drugs, and, serves as a standard against which all professional literature, promotional material, or advertising distributed or sponsored by the manufacturer about the drug can be compared.

The product monograph outlines the indications (uses) for which the drug has been approved, any contraindications (prohibited uses), warnings, precautions and adverse reactions, dosage and administration and other relevant information that might help health care professionals to most effectively prescribe and administer the medication.

Health Canada has recently undertaken a comprehensive revision of the format and content of the product monograph. The product monograph guidance document is being revised with an aim to emphasize clinically relevant information and to make information easy to retrieve. Under the revised format for the product monograph the Adverse Reaction (AR) section is being standardized and expanded to include comprehensive information about the risks posed by drugs. The new format also includes a more user-friendly consumer information section that has been expanded to take up approximately one third of the final document.

These changes to the product monograph are being implemented on a voluntary basis by manufacturers beginning in 2003 and will become mandatory sometime in the year 2004. A guidance document on the new product monograph format will be published in late summer 2003 along with information that addresses issues and questions resulting from the consultations held throughout the project. Half day training sessions will also be offered to complement the guidance document for interested parties.

Health Canada's goal is to make all product monographs publicly available and easy to access by having them posted on a single website.

Exploring Mobile Wireless Technology

Health Canada is currently undertaking a research project that will provide concrete information on the benefits and drawbacks of mobile wireless technology (e.g. palm pilots) in disseminating updated safety information to health care professionals.

Specifically, this project is interested in determining the potential of mobile wireless technology to:

1. Enable health professionals to promptly and more completely report adverse reaction and medication incidents to Health Canada through the implementation of customized forms and drop-down lists;
2. Enable Health Canada to broadcast warnings and advisories to health professionals in a medium that reaches the point-of-care;
3. Provide a feature to encourage physicians to review and comply with Health Canada advisories/guidelines by providing physicians with a reminder system or some constant indicator highlighting those products for which Health Canada has already issued a warning or advisory; and
4. Provide physicians with an automated search functionality to create a list of patients who may have been prescribed a product that has had a warning or advisory issued.

Programming is currently underway. Testing in a clinical environment is planned for Winter 2004.

SHARED RESPONSIBILITY FOR THE EFFECTIVE DISSEMINATION AND USE OF INFORMATION

Health Canada has made significant progress towards strengthening the way in which new health product safety information is communicated to health care professionals and the general public. However, many different organizations and individuals contribute to health care in Canada including Health Canada, provincial and territorial governments, health care providers, manufacturers and consumers.

More specifically their related mandates include the following:

• Health Canada's mandate is to maintain a regulatory system that ensures safety is maximized and health risk factors are minimized;
• Manufacturers have a responsibility to provide products consistent with the regulatory framework;
• Provincial and territorial governments have a responsibility for the administering the health care system and providing services to the public. They set direction, policy and provincial/territorial standards that ensure quality services;
• Health professionals are responsible for obtaining the most comprehensive information available to them and ensuring consumers receive appropriate information to allow them to use those products safely and effectively; and
• Consumers have a responsibility to make informed choices about their health and that of their dependent children based on the information made available to them.

Many of the recommendations of the Coroner's Jury can best be implemented in a collaborative way involving all parties in the health care delivery system. Because health care services and products are delivered through the provincial and territorial programs, pharmaceuticals management initiatives must be carefully integrated across and between jurisdictions. With this in mind, the Department is committed to collaborating closely with other parties to address those recommendations whose solutions can best be found in a cooperative, multi-jurisdictional approach in order for them to be implemented broadly, consistently and effectively.

In addition to working with provincial and territorial ministries and organizations, the Department works in partnership with health care professionals, their associations, pharmaceutical companies, other industry, and consumer and patients groups to enhance both the collection and dissemination of information on the benefits and risks of marketed health products. Further strengthening of this area will require partnerships with health care professionals, industry and consumer organizations to help with the timely development, dissemination and uptake of the information.

For example, the Marketed Health Products Directorate convened two invitational workshops focussing on sharing best practice and improving partnerships in the area of information dissemination. The workshops were held in November 2001 and March 2003.

In the first workshop, focussing on communicating drug safety information, representatives from the pharmaceutical industry, health professional associations, consumer interest groups and regulatory authorities discussed strategies and mechanisms for ensuring information is developed and disseminated in ways which meet the needs of all users and audiences, and that the information is used and integrated into daily practice by both health care professionals and consumers. Minutes for this workshop can be found on Health Canada's website at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/cdsi-dicim_sum_rep_e.pdf (PDF Version)

The objective of the second workshop was to work toward a framework for the development and dissemination of product safety information and its integration into daily practice and use. Participants identified the following priority areas in which to direct effort and resources:

• develop effective communication tool(s) for use by health care professionals and consumers;
• facilitate the use of these tools by all health care professionals;
• continue to develop working relationships and exchange information with professionals and associations;
• undertake awareness campaigns at all levels (directed toward health care professionals and consumers); and
• focus on building professional and public awareness regarding the importance of reporting adverse events.

In both cases, workshop participants demonstrated a commitment to a "shared responsibility" among Health Canada, the pharmaceutical industry, health care providers, and consumers to address these issues.

Increasing Focus on Post-Market Surveillance

The Marketed Health Products Directorate at Health Canada has a mandate to coordinate the surveillance and assessment of all health products on the market, to communicate risk information about health products and conduct active surveillance and drug effectiveness projects. More specifically, it:

1. monitors marketed health product safety data such as adverse reaction and medication incident reports, evaluates product effectiveness, conducts risk/benefit assessments, and recommends appropriate action when problems are identified;
2. looks for ways to ensure greater access to Canadian and foreign adverse reaction and medication incident information through national and international collaborations, and through increased use of expert scientific advice and consumer input;
3. partners with others to promote adverse reaction and medication incident reporting, studies product effectiveness, and communicates to health care professionals and the public; and,
4. disseminates risk-related information to health professionals and the public through means such as the Canadian Adverse Reaction Newsletter, health product advisories and warnings, the Health_Prod_Info electronic mailing list, and Health Canada's website.

The directorate promotes a consistent approach to monitoring, assessing and intervening with respect to all regulated marketed health products.

MOVING FORWARD

Protecting the Health of Canadians through an appropriately resourced drug safety system will remain a priority for Heath Canada and the Government of Canada.

While Canada has a reputation for one of the best drug safety records in the world, continuous improvement in this area is a priority.

In order to assist in the clarification of some technical terms, a glossary is included in Appendix I of this document.

.CORONER'S JURY RECOMMENDATIONS AND HEALTH CANADA RESPONSES

This section provides responses to the recommendations which are, in the view of Health Canada most appropriately directed toward the Department in relation to its mandate as the federal regulator of health products.

There may be some repetition in the responses to the individual recommendations. This was done in order to ensure a fulsome response to each individual recommendation.

RECOMMENDATIONS OF THE CORONER'S JURY OF THE ASHLEY MARIE ATKINSON INQUEST

The following recommendations were made by the Coroner's Jury of the Ashley Marie Atkinson Inquest:

1. Adopt the Atlantic Health Sciences Corporation recommendations to the Coroner's Jury dated November 12th, 2002 and referred to as Exhibit Z.1 as follows: 1, 2, 3, 4, 5 and 7 with the amendment to the wording in the recommendations to include "all health care institutions in New Brunswick"
   1. All health care institutions in New Brunswick must ensure that all Health Canada warnings are given the broadest dissemination within their institutions to the relevant staff, as well as being referred to the appropriate hospital committees, consistent with the procedure adopted by Atlantic Health Sciences Corporation.
   2. All health care institutions in New Brunswick ensure that all members of their Pharmacy Department be immediately made aware upon receipt of warnings and directed to ensure compliance with the directive.
   3. All hospitals/health care institutions in New Brunswick have in place a Pharmacy Information System to provide immediate alerts when pharmaceuticals are ordered, for which their has been a precaution, warning or contraindication issued by Health Canada.
   4. Propofol is not to be ordered/used as a sedative agent for any period longer than 8 hours for children under the age of 18 years in all health care institutions in New Brunswick until further Health Canada reviews are completed.
   5. (a) Usage of pharmaceuticals for medical purposes other than as originally approved by Health Canada is internationally recognized as necessary to a good medical/clinical practice. It is recommended that all health care institutions in New Brunswick develop and maintain policies that recognize this practice.
      (b) Health Canada must formally acknowledge and recognize off-label usage of regulated pharmaceuticals and must formally monitor that usage notwithstanding the fact that the approval for the usage has never been obtained from Health Canada.
   6. (a) The results of all clinical trials conducted by pharmaceutical manufacturers must be reported to Health Canada immediately.
      (b) All serious adverse reactions to any approved pharmaceutical used for any medical purpose that becomes known to the manufacturer must be reported to Health Canada immediately.
2. When a paediatric intensivist is available, that all Paediatric Intensive Care Units (PICU's) in New Brunswick Health Care institutions be operated as closed units.
3. (a) All serious adverse reactions to any approved pharmaceutical used for any medical purpose that becomes known to the physician and/or health care institution must be reported to the manufacturer and to Health Canada.
   (b) To enable this to become part of the "best practices" of health care professionals, information and training on adverse reaction reporting needs to be included in the curriculum of health care professionals in Canada.
4. All reports received by Health Canada from pharmaceutical manufacturers and/or from physicians, with respect to clinical trials and/or serious adverse reactions to any approved pharmaceutical used for any medical purposes, must be disseminated to health care professionals and institutions immediately.
5. Health Canada implement guidelines and means for pharmaceutical manufacturers to respond within reasonable time limits to required changes in pharmaceutical inserts.
6. All health care institutions in New Brunswick implement the following policy: Medication and therapy orders be co-signed by both the physician transferring the patient and the physician receiving the patient into their care.
7. The New Brunswick Coroner's Office review their criteria for the calling of inquests to determine whether inquests are called in an effective and timely fashion.
8. All health care professionals in New Brunswick ordering or administering medications with which they are unfamiliar, be required to research the drug prior to its use.
9. Review the efficacy of including lactate blood screening in all children who are prescribed propofol medication in the course of their treatment.

RESPONSES TO RECOMMENDATIONS DIRECTED TOWARD HEALTH CANADA

This section will provide individual, full responses to each recommendation that provides suggestions for improvement to the health product safety system that fall within the mandate of the Department or are directly related to the work of the Department's regulatory programs.

ATKINSON CORONER'S JURY RECOMMENDATION #1.5 b

Health Canada must formally acknowledge and recognize off-label usage of regulated pharmaceuticals and must formally monitor that usage notwithstanding the fact that the approval for the usage has never been obtained from Health Canada.

Health Canada Activities to Date

"Off-label" use refers to the use of a marketed health product outside of indications included in approved product labelling. In order for indications to be approved substantial and sound scientific information is provided by the manufacturer and submitted for review and approval by Health Canada.

Adverse Reaction Monitoring

The Food and Drug Regulations section C.01.016 indicates that manufacturers are responsible for monitoring their marketed health products and for continuous assessment of the benefits and risks. The manufacturer is mandated to report all information with respect to any serious adverse reactions and medication incidents that have occurred in Canada and any serious unexpected adverse reactions that have occurred outside of Canada, irrespective of whether adverse reaction resulted from on or off-label use. This must be done within 15 days after the information comes to the attention of the manufacturer. Manufacturers are also obliged to prepare and have available, on request, annual summary reports on such matters.

Role of Health Canada in Off-label Use

Health Canada recognizes that "off-label" use of marketed health products occurs. However, Health Canada's mandate does not include regulating decisions regarding the choice and administration of a health product to an individual patient. Health Canada cannot condone or authorize "off-label" use.

Health Canada regulates drug and other health products available to Canadians. Drugs manufactured and sold in Canada must go through a regulatory process to ensure there is substantial evidence of the products safety, quality and effectiveness before they can be sold. Each drug is approved for use for certain conditions, and this is referred to as its on-label use and/or its indication. If a drug is to be marketed for use for another indication the manufacturer must make a separate submission for approval to Health Canada.

Health Canada may require a manufacturer to include information recommending against an "unapproved" use of a drug if information suggests a concern (e.g. 1993 - propofol recommendations against use in children for sedation in ICU). Health Canada may request a manufacturer to include information contraindicating a product in an indication when definitive information becomes available (e.g. 2002 - propofol contraindication in children for sedation in ICU).

The manufacturer must ensure that a drug's contraindications and warnings against improper dosing or other misuse permit identified risks associated with the product to be adequately managed by the health care professional. If the manufacturer does not meet these requirements, Health Canada can compel the manufacturer to stop selling the drug.

While Health Canada oversees the regulation of drugs, it has no jurisdiction over how health care professionals prescribe drugs once they are approved. When prescribing, health care professionals use their own medical discretion and rely on information from medical journals, reports and peer reviewed studies. In Canada, a physician's decision to prescribe particular medication for an individual patient, be it for an indication listed on an approved drug's labelling or otherwise, is part of the "practice of medicine".

Provincial and territorial governments regulate such practices of medicine or pharmacy by health care professionals through, inter alia, the provincial Colleges of Physicians and Registrars of Pharmacy. These statutory bodies established by provinces and territories have the mandate to protect the public, monitor, evaluate and discipline its members, and to deal with patient complaints about regulated health professionals.

Risks of Off-Label Use

The main risk of using a drug off-label (i.e. for a condition for which it has not been approved) is that no official clinical trials have been done to determine the effect the drug will have on the condition. Without the benefit of clinical trials, there is no substantial scientific evidence that a drug will work and less is known about potential adverse reactions or drug interactions.

Clinical Trials and Off Label Use with Children

Children are rarely subjects in clinical trials for many reasons. Parents may be reluctant to expose their child to non-approved drugs. Pharmaceutical companies may be reluctant to fund costly clinical trials because of the difficulties in finding the number of participants necessary for meaningful results. As a result of this and because individual paediatric cases may require new approaches, off-label use of drugs in paediatrics is widespread. A recent study sponsored by Health Canada and the Canadian Paediatrics Society titled - Prescription medicine use by a population of Canadian children - published by Brogan Incorporated, an Ottawa-based healthcare research company, looked at the drug prescription information of more than 1,000,000 children between 1999 and 2000. The study has found that about 50% of Canadian children receive a prescription drug during the course of a year - up to 1,400 different medications. The study concludes that some of these drugs may have been dispensed without appropriate research about their effects on children, and without regulatory supervision or assistance. In other words, they were prescribed off-label without a specific Health Canada approval for use in children.

While off-label use in paediatrics is widely recognized as medically necessary and "practice of medicine" controls have been put in place by provincial and territorial governments as part of their jurisdictional responsibility, the lack of research in the area of paediatrics is a concern.

Although the practice of medicine and pharmacy are not part of Health Canada's jurisdictional mandate, the Department works with the provinces and territories, physicians, pharmacists and their Colleges, the academic community and others, to continuously improve the way it identifies, gathers and communicates information about the benefits and risks of on and off-label uses of marketed health products approved for sale in Canada.

For example, the proposed Canadian Paediatric Society Surveillance Program project will collect information from 2300 pediatricians and sub-specialists on a monthly basis. The focus of reporting is serious and life-threatening adverse reactions in children and youth 0-18 years of age. In addition, the partnership will encourage pediatricians to report adverse drug reactions through regular reminders and monthly feedback to reporters.

Additionally, Health Canada is committed to facilitating the timely entry of health products into the marketplace in a way that is safe and effective. Health Canada acknowledges the importance of research into the appropriate prescribing and testing of drugs in children, and has an on-going commitment to facilitate this effort by exploring mechanisms to encourage pediatric clinical research and consequently to improve drug labelling for children in Canada. It will continue to work with the Canadian Paediatric Society to further advance work in this area.

Health Canada has mechanisms in place to support the timely entry of safe drugs on the market. For example, if a submission proposed for children addresses a need that is not currently met, Health Canada is able to grant that drug a priority status in the drug evaluation process.

Health Canada also continues to work with other regulators to develop guidance documents for industry that will assist them in meeting the need for paediatric drug testing.

In the specific instance of propofol, in April 1992 Canadian health care professionals were advised of serious adverse events including fatalities from propofol paediatric sedation in ICU settings in a Dear Health Care Professional Letter issued by the manufacturer.

The product monograph has always reflected the most current verifiable information with respect to the use of propofol in children. In the case of propofol, adverse reactions in children were noted in the product monograph as early as 1993.

When new clinical information from the UK Committee on Safety in Medicines came to light that more clearly identified an issue with the use of propofol in the sedation of children it was considered carefully. Once an issue has been identified, Health Canada undertook to investigate further. The investigation included a survey of major paediatric hospitals in Canada regarding the use of propofol in ICU settings for sedation in children. Once reviewed, these results were considered along with a careful review of a Supplemental New Drug Submission from the manufacturer proposing that the product be approved for paediatric sedation in ICU. After careful consideration, Health Canada rejected the manufacturers request for approval and considered it appropriate to direct the manufacturer to amend the product's monograph to contraindicate against such use. This was done on July 10, 2002.

As was the case with propofol, manufacturers can only market a drug for a particular use of a drug once that use has been supported by substantial evidence demonstrating the safety and efficacy. Similarly, Health Canada directs manufacturers to include a contraindication for a particular use in a drug's product monograph when there is sufficient evidence to support such a contraindication.

.ATKINSON CORONER'S JURY RECOMMENDATION #1.6 a

The results of all clinical trials conducted by pharmaceutical manufacturers must be reported to Health Canada immediately.

Health Canada Activities to Date

Clinical Trials in Canada

The regulations amending the Food and Drug Regulations for Clinical Trials in Canada were implemented on September 1, 2001. The new regulations enhance the safety of participants in clinical trials by:

• refining the process and requirements of a Clinical Trial Application (Application)
• increasing the obligations of the sponsor of the Application; and
• expanding the oversight of Health Canada to ensure the accountability of clinical trial sponsors.

A Clinical Trial Application includes non-clinical and clinical information as well as the chemistry and manufacturing information to support the use of the drug in humans. Applications must contain the following elements:

1. The Investigator's Brochure - a comprehensive document which summarizes all the non-clinical and clinical knowledge of the drug including prior human experience and up-to-date safety information. Investigator Brochures are normally updated at least annually.
2. The Trial Protocol - a medical-legal document which details the rules of conduct of the clinical trial. It provides the background to and rationale for the objectives of the trial, the rationale for the dose and dose regimen, the criteria by which trial participants are selected, the procedures for monitoring patients during the trial (frequency of visits and assessments at the visits), measures for supportive care and/or dose adjustments, rules for premature discontinuation of a trial or a patient's participation (voluntary or protocol defined) and rules for the reporting of adverse events during a clinical trial.
3. Model informed consent forms and, if applicable, assent documents which fully inform the patient of the risks of participation and of their rights as well as other drug and trial specific information.

The sponsor of a clinical trial must receive authorization of the Application by Health Canada and approval by the local Research Ethics Board before the trial may be initiated. Once authorized by Health Canada, the sponsor has the following obligations:

1. initial and annual approval of the trial by the appropriate local Research Ethics Board;
2. reporting of Research Ethics Boards refusals to Health Canada;
3. submission of Site Activation forms to Health Canada as each trial site initiates the protocol;
4. retention of Qualified Investigator Statements and Research Ethics Board Approval forms;
5. reporting of all serious and unexpected adverse reaction reports to Health Canada and to the Research Ethics Board(s);
6. reporting the premature discontinuation of a clinical trial to Health Canada; and
7. preparation of annual (or, more frequently during early drug development) updates to the Investigator's Brochure.

The following requirements and activities ensure Health Canada receives important information about each clinical trial:

1. Safety results must be reported on an on-going basis throughout the trial(s) in Canada and from other trials around the world (see next page for more information);
2. Efficacy and safety results are routinely incorporated into the Investigator's brochure which is sent to Health Canada.
3. The regulations require Health Canada to be notified in writing if a clinical trial is prematurely discontinued. Health Canada must be notified within 15 days with a clear statement of the reason(s) for the discontinuance. Health Canada may then request more information about the clinical trial.

Health Canada has the right to request information about a clinical trial at any time.

Decision to Participate In Clinical Trials

The decision to participate in a clinical trial versus other available treatment options is made by the patient (or parent/legal guardian in the case of a child) after discussion with their physician or health care provider. In the case of children, parents must ensure that they have a full discussion with their child's health care provider with respect to the benefits and risks of the proposed trial so that they can make an informed decision and give their consent based on all the available information (informed consent).

Clinical Trials and Off Label Use with Children

Children are rarely subjects in clinical trials for many reasons. Parents may be reluctant to expose their child to non-approved drugs. Pharmaceutical companies may be reluctant to fund costly clinical trials because of the difficulties in finding the number of participants necessary for meaningful results. As a result of this and because individual paediatric cases may require new approaches, off-label use of drugs in paediatrics is widespread. A recent study sponsored by Health Canada and the Canadian Paediatrics Society titled study - Prescription medicine use by a population of Canadian children - published by Brogan Incorporated, an Ottawa-based healthcare research company, looked at the drug prescription information of more than 1,000,000 children between 1999 and 2000. The study has found that about 50% of Canadian children receive a prescription drug during the course of a year - up to 1,400 different medications. The study concludes that some of these drugs may have been dispensed without appropriate research about their effects on children, and without regulatory supervision or assistance. In other words, they were prescribed off-label without a specific Health Canada approval for use in children.

While off-label use in paediatrics is widely recognized as medically necessary and "practice of medicine" controls have been put in place by provincial and territorial governments as part of their jurisdictional responsibility, the lack of research in the area of paediatrics is a concern.

Health Canada acknowledges the importance of research into the appropriate prescribing and testing of drugs in children, and has an on-going commitment to facilitate this effort by exploring mechanisms to encourage paediatric clinical research and consequently to improve drug labelling for children in Canada. The Department will continue to work with the Canadian Paediatric Society to further advance work in this area.

Health Canada has mechanisms in place to support the timely entry of safe drugs on the market. For example, if a submission proposed for children addresses a need that is not currently met, Health Canada is able to grant that drug a priority status in the drug evaluation process.

Health Canada also continues to work with other regulators to develop guidance documents for industry that will assist them in meeting the need for paediatric drug testing.

Clinical Trial Reporting Requirement for Adverse Reactions

Events which qualify as adverse reactions for expedited reporting are required to be reported to Health Canada during a clinical trial (Food and Drug Regulations C.05.014). These are adverse reactions which are both serious and unexpected. The term serious is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning and is not to be confused with severity.

In the case of fatal and life-threatening adverse events the Initial Report is to be sent within 7 days and a comprehensive follow-up within the subsequent 8 calendar days. All other serious and unexpected events are to be comprehensively reported within 15 calendar days.

It is noted that all sponsors of clinical trials, from commercial firms to single investigators are required to report these events to Health Canada. The sponsor is also required to send this information to the Institutional Research Ethics Board.

Expected adverse events are usually not reported to Health Canada, except in the case of an increase in the expected rate of occurrence which is judged to be clinically important. Other information which is to be submitted is a significant hazard to the trial participants, for example lack of efficacy for a drug used to treat a life-threatening disease or a major safety finding from newly completed preclinical work.

.ATKINSON CORONER'S JURY RECOMMENDATION #1.6b

All serious adverse reactions to any approved pharmaceutical used for any medical purpose that becomes known to the manufacturer must be reported to Health Canada immediately.

Health Canada Activities to Date

The Food and Drug Regulations require that adverse events be reported both while the health product or drug is undergoing clinical trials or after it has been put on the market. For marketed health products, adverse events must be reported for both on and off-label use. Health Canada continually looks for ways to improve its surveillance and monitoring system to ensure that adverse reactions are reported and investigated appropriately.

Reporting Requirements for Adverse Reactions to Marketed Health Products

Mandatory reporting by manufacturers to Health Canada according to internationally accepted time frames have existed since 1995. Under section C.01.016 of the Food and Drugs Regulations, manufacturers are required to report all information with respect to any serious adverse drug reactions and medication incidents that have occurred in Canada and any serious unexpected adverse drug reaction (unexpected because it is not listed in a product's labelling) that have occurred outside of Canada within 15 days after the information is received.

Clinical Trial Reporting Requirement for Adverse Reactions

Events which qualify as adverse reactions for expedited reporting are required to be reported to Health Canada during a clinical trial (Food and Drug Regulations section C.05.014). These are adverse reactions which are both serious and unexpected. The term serious is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning and is not to be confused with severity.

In the case of fatal and life-threatening adverse events the Initial Report is to be sent within 7 days and a comprehensive follow-up within the subsequent 8 calendar days. All other serious and unexpected events are to be comprehensively reported within 15 calendar days.

It is noted that all sponsors of clinical trials, from commercial firms to single Investigators are required to report these events to Health Canada. The sponsor is also required to send this information to the Institutional Research Ethics Board.

Expected adverse events are usually not reported to Health Canada, except in the case of an increase in the expected rate of occurrence which is judged to be clinically important. Other information which is to be submitted is a significant hazard to the trial participants, for example lack of efficacy for a drug used to treat a life-threatening disease or a major safety finding from newly completed preclinical work.

.ATKINSON CORONER'S JURY RECOMMENDATION #3 a

All serious adverse reactions to any approved pharmaceutical used for any medical purpose that becomes known to the physician and/or health care institution must be reported to the manufacturer and to Health Canada.

Health Canada Activities to Date

Canadian Adverse Reaction Reporting System

Patients, health processionals, manufacturers and regulatory authorities work together to monitor adverse reactions and medication incidents. The Canadian reporting system which is similar to models used by most other countries internationally, consists of two components: reporting of serious adverse reactions by manufacturers on a mandatory basis; and, reporting by health professionals on a voluntary basis.

Health Canada continues to work with health care professionals and consumers to strengthen the adverse reaction reporting system in Canada while seeking more effective ways to strengthen its ability to detect safety problems in a timely manner. That ability largely depends on the timely reporting of suspected adverse drug reactions by health care professionals either through the drug manufacturer or directly to Health Canada.

Active surveillance projects to complement the current voluntary system of adverse reaction and medication incident reporting have been started. The focus of these projects is currently on areas (professions, specialists, health facilities, etc.) internationally recognized as having poor reporting rates. These projects involve the development of a targeted surveillance system to stimulate reporting by paediatricians regarding serious adverse reactions in children, development of a consumer reporting module to actively solicit reports from HIV/AIDS patients, and collaboration on development of a reporting system with patient interest groups in certain chronic diseases.

Health Canada continually examines the barriers to adverse reaction and medication incident reporting and attempts to find alternate strategies to increase reporting rates. These barriers (e.g. lack of awareness about adverse reaction and medication incident reporting) are a widely acknowledged international reality in the field of adverse reaction and medication incident reporting. Health Canada is collaborating with foreign regulators to use partnerships and information sharing, among other strategies, to counteract and overcome these barriers.

Health Canada works with academia to encourage inclusion of adverse reaction reporting in curriculum of health professional schools across Canada. Health Canada cannot, however, mandate the curriculum content of health professions in Canada.

Mandatory Reporting by Health Professionals

Based on a review of this issue, Health Canada does not yet have clear evidence that a mandatory reporting system by health care professionals would increase the number of adverse reaction reports or the quality of the information submitted.

The Department recently collected information on the effectiveness of mandatory reporting by health care professionals. The results of a questionnaire sent to contacts in foreign jurisdictions showed no significant increase in quantity or quality of adverse reaction reporting under a scheme of mandatory reporting.

Reporting by health care professionals is considered vital but the experiences of jurisdictions like France, Sweden and Italy indicate that the implementation of mandatory schemes had little impact on reporting rates. Any increase in reporting rates was attributed to better information about the importance of reporting and, in some countries, this increase was marked by a worsening of the quality of the information submitted.

The experience of these countries with mandatory systems is also notable in that they do not detect drug safety problems at a higher rate than countries with voluntary systems. Officials in these jurisdictions believe that promoting their programs and emphasizing the reasons for reporting rather than the sanctions is more important in their efforts to encourage physicians and pharmacists to report.

Health Canada is conducting a public and health professional survey to explore perceptions, attitudes & opinions regarding mandatory reporting of serious adverse reactions. The perceptions, attitudes & opinions of both the public and health professionals regarding mandatory reporting will help the Department understand whether the public feels that such requirements are desirable or necessary. Results are expected by the end of Summer, 2003.

Approaches to Stimulate Adverse Reaction Reporting

To prompt the reporting of adverse reactions, a monthly Health Canada journal advertisement has been published in the CMAJ since April 2002 to promote Health Canada toll-free telephone and fax lines specifically established for adverse reaction reporting. The advertisement also includes Health Canada's internet address to subscribe to the Canadian Adverse Reaction Newsletter, as well as to health professional/consumer advisories. This advertisement has since been picked-up by other journals. The address for subscription is:http://www.hc-sc.gc.ca/dhp-mps/medeff/subscribe-abonnement/index_e.html.

The proposed Canadian Paediatric Society Surveillance Program project will collect information from 2300 pediatricians and sub-specialists on a monthly basis. The focus of reporting is serious and life-threatening adverse reactions in children and youth 0-18 years of age. In addition, the partnership will encourage pediatricians to report adverse drug reactions through regular reminders and monthly feedback to reporters.

Role of Regional Adverse Reaction Centres

National reporting activities are coordinated by Health Canada's Marketed Health Products Directorate. Adverse reactions reported on a voluntary basis by health professionals and consumers are currently being collected by five Regional Adverse Centres (British Columbia, Saskatchewan, Ontario, Quebec and Atlantic) and the National Office.

The Regional Centres are also responsible for promotion of the adverse reaction reporting program across Canada and provide feedback to health care professionals as they collect and assess AR case reports. The objectives of the Regional Centres are to:

1. promote the program and improve its visibility;
2. increase health care professional awareness of the benefits of voluntary reporting;
3. provide guidance to health care professional with respect to adverse reaction reporting thereby enhancing the quality of the reports;
4. increase health care professional participation in reporting;
5. provide feedback and updates to those who report so they see that their efforts are worthwhile; and
6. facilitate the collection of adverse reaction case reports.

.ATKINSON CORONER'S JURY RECOMMENDATION #4

All reports received by Health Canada from pharmaceutical manufacturers and/or from physicians, with respect to clinical trials and/or serious adverse reactions to any approved pharmaceutical used for any medical purposes, must be disseminated to health care professionals and institutions immediately.

Health Canada Activities to Date

Health Canada has made numerous improvements in the dissemination of health safety information in the past 3 years and is continuing to look for ways to improve its efforts to disseminate safety information on drug and other health products to consumers and health professionals.

Decisions to communicate product health risk information are made by taking into account the strength of available evidence, the immediacy of the risk, the likelihood of harm, and how a product is used. Such decisions are taken on a case by case basis. Signals (reported information on a possible causal relationship between an adverse event and a drug) and patterns of such signals are monitored and assessed. When a safety concern is identified the risks are assessed. After this analysis decisions are taken as to whether there is a need to communicate and, if so, the appropriate audience and mode of communication.

Ongoing efforts to enhance how information on health products safety is communicated has resulted in changes to the Health Canada website, new operating procedures for use in the development of Dear Health Care Professional Letter, changes in format and content of the product monograph and a redesigned Canadian Adverse Reaction Newsletter with improved distribution methods.

In order to ensure the quality of the information disseminated by the Department, the information received must be validated and evaluated prior to its release.

Limitations of Disseminating AR Reports Without Analysis by Health Canada

Reports received by Health Canada represent the suspicion, opinion or observation of the individual reporter and cause and effect relationships have not been established in the vast majority of reports submitted. It is important to remember that this information must not be used to estimate the incidence of adverse reactions but rather to identify potential problem areas or trends that may need further investigation.

Potential safety problems or signals may be identified through the systematic review of adverse reaction reports and any other additional information on product safety. Potential signals need expert evaluation before any actions are undertaken. The subsequent preliminary evaluation of the signal determines the likelihood of the association between the reaction and the health product. Typical information which must be taken into account includes the frequency, severity, plausibility, quality of the information contained in the reports, amount of product used, time needed for appearance of the reaction, underlying diseases, simultaneous use of other medications, and evidence of disappearance or reappearance of the reaction once the product was discontinued or reintroduced. Additional investigative studies and consultations with other regulatory agencies are often necessary to confirm the health product-adverse reaction relationship.

Disseminating Health Product and New Safety Information

Currently, the Department provides information on health products and health product safety to both health care professionals and the general public through:

• the Health Canada website;
• Dear Health Care Professional Letters;
• Notices to Hospitals;
• the Canadian Adverse Reaction Newsletter;
• public advisories and warnings;
• information provided through many other Departmental publications and communications materials; and,
• by attending professional conferences to disseminate information on adverse reaction reporting and Health Canada's sources of health product information.

New safety and effectiveness information derived from the adverse reaction reporting system is disseminated in health product advisories issued by Health Canada and/or manufacturers to health professionals and the public. Notices to Hospitals are used to fax new information to all Canadian hospitals. Advisories to health care professionals and consumers are posted on the Health Canada website and an electronic mailing list (Health_Prod_Info) alerts registrants to new warnings. The news media also serves to disseminate information in a timely fashion through news wire releases picked up on television, radio, and newspapers.

The Canadian Adverse Reaction Newsletter, a quarterly publication, alerts health professionals and consumers to potential signals detected through the review of case reports submitted to Health Canada. It is a useful mechanism to disseminate information on suspected adverse reactions to health products occurring in humans before comprehensive risk-benefit evaluations and regulatory decisions are undertaken. The Newsletter is distributed free of charge to:

• Physicians, by mail, as a separate document with the Canadian Medical Association Journal;
• Health Care Professionals and other interested parties by mail;
• The general public on the Web at: http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/index_e.html; and
• by e-mail to subscribers of the Health_Prod_Info electronic mailing list (to join the Health_Prod_Info mailing list go to http://www.hc-sc.gc.ca/dhp-mps/medeff/subscribe-abonnement/index_e.html).

Communicating Drug Safety Information Workshops

Health Canada's Marketed Health Products Directorate convened two invitational workshops focussing on sharing best practice and improving partnerships in the area of information dissemination. The workshops were held in November 2001 and March 2003.

In the first workshop, focussing on communicating drug safety information, representatives from the pharmaceutical industry, health professional associations, consumer interest groups and regulatory authorities discussed strategies and mechanisms for ensuring information is developed and disseminated in ways which meet the needs of all users and audiences, and that the information is used and integrated into daily practice by both health care professionals and consumers. Minutes for this workshop can be found on Health Canada's website at: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/hpfb-dgpsa/pdf/medeff/cdsi-dicim_sum_rep_e.pdf (PDF Version)

The objective of the second workshop was to work toward a framework for the development and dissemination of product safety information and its integration into daily practice and use. Participants identified the following priority areas in which to direct effort and resources:

• develop effective communication tool(s) for use by health care professionals and consumers;
• facilitate the use of these tools by all health care professionals;
• continue to develop working relationships and exchange information with professionals and associations;
• undertake awareness campaigns at all levels (directed toward health care professionals and consumers); and
• focus on building professional and public awareness regarding the importance of reporting adverse events.

In both cases, workshop participants demonstrated a commitment to a "shared responsibility" among Health Canada, the pharmaceutical industry, health care providers, and consumers to address these issues.

Evaluation Underway

Health Canada is currently evaluating the effectiveness of its health product safety and risk communication tools and dissemination methods. Surveys currently underway will inform Health Canada of the effectiveness of current methods used to communicate drug safety information, provide guidance for future improvements, and allow for the collection of benchmark data to be used in the future to evaluate performance of Health Canada in safety and risk communication. These surveys and the workshops with stakeholders will help us better target our efforts and resources in developing the most effective communication tools for use by health professionals and consumers.

ATKINSON CORONER'S JURY RECOMMENDATION #5

Health Canada implement guidelines and means for pharmaceutical manufacturers to respond within reasonable time limits to require changes in pharmaceutical inserts.

Health Canada Activities to Date

Product Monograph and Labelling Information Requirements

Manufacturers are responsible under the current Food and Drug Regulations to update their product monograph if the benefit/risk profile of the drug has changed significantly from that which was originally submitted and approved by Health Canada.

Section 9(1) of the Food and Drug Act prohibits the labelling of any drug in a manner that is false, misleading or deceptive or likely to create an erroneous impression regarding its character, value, quantity, composition, merit or safety.

Section C.01.003 of the Regulations under the Food and Drug Act states "No person shall sell a drug that is not labelled as required by these Regulations".

Section C.01.004 (1)(c)(iii) states that "The label of a drug shall show on any panel adequate directions for use of the drug". The phrase "adequate directions for use of the drug" has been interpreted by Health Canada as the information necessary for the proper use of the drug including, indications for use, recommended dosage, route of administration as well as appropriate warnings and precautions.

Should the information indicated above not be available on the labelling of a drug product, enforcement action can be taken by Health Canada.

When new information comes to light which requires modification of the labelling material or product mongraph, manufacturers of the product are required to exercise due diligence in taking the steps necessary to amend the labelling in question. For new drugs this includes filing the information with Health Canada and obtaining authorization to use the proposed amendment. Should the manufacturer not proceed with a required amendment in a timely manner thus not addressing potential health risks, enforcement action can be taken under the legislative requirements outlined above.

If the new information that is to be added to the product monograph reflects a serious health or safety risk, the manufacturer may be required to issue a Dear Health Care Professional Letter, a public advisory and/or a Notice to Hospitals. In some cases, Health Canada may issue these documents independently if many manufacturers are involved, the situation warrants it, or if the manufacturers is not proceeding within agreed upon time limits. Any of these actions would not replace the need to update the product monograph, only ensure that timely information was available to health care professionals and the public while it was being revised.

.APPENDIX I - GLOSSARY OF TECHNICAL TERMS

Adverse Reaction
Adverse reactions are undesirable effects to health products. Health products include drugs, medical devices and natural health products. Drugs include both prescription and non-prescription pharmaceuticals; biologically-derived products such as vaccines, serums and blood derived products; cells, tissues and organs; disinfectants; and, radiopharmaceuticals.

Reactions may occur under normal use conditions of the product. Reactions may be evident within minutes or years after exposure to the product and may range from minor reactions like a skin rash to serious and life-threatening events such as a heart attack or liver damage.

Adverse Event
Any untoward medical occurrence that may present during use of a health product, but that does not necessarily have a causal relationship with the product.

Canadian Adverse Reaction Newsletter
The Newsletter alerts health professionals to potential signals detected through the review of domestic case reports submitted to Health Canada. It is a useful mechanism to disseminate information on suspected adverse reactions to Health products occurring in humans before comprehensive risk-benefit evaluations and regulatory decisions are undertaken.

Clinical trial
Division 5 of the Food and Drug Regulations defines a clinical trial as, "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."

Contraindication
A specific use, or indication, or any other condition where the specified drug product or its active ingredient should not be used or where the use presents hazard(s) which outweigh anticipated benefit(s).

Dear Health Care Professional Letter
Previously called Dear Doctor Letters or Dear Health Professional Letters, these advisory letters are used to inform health care professionals about time-sensitive issues regarding the safety and/or effectiveness of a marketed therapeutic product. It is a letter issued by the sponsor containing content approved by Health Canada. Distribution could include physicians, dentists, veterinarians, naturopaths, pharmacists, hospitals and others. The distribution list will be tailored to the safety issue being addressed. In some situations the letter will be issued by Health Canada

Drug
For the purposes of Canada's regulatory system, the definition of drugs includes both prescription and non-prescription pharmaceuticals; biologically-derived products such as vaccines, serums and blood derived products; cells, tissues and organs; disinfectants; and, radiopharmaceuticals

Health Care Professional
Health care professionals include, but are not limited to, physicians, nurses, pharmacists and other medical and support personnel involved in the delivery of health care.

Health Product
Health products include drugs, medical devices and natural health products. Drugs include both prescription and non-prescription pharmaceuticals; biologically-derived products such as vaccines, serums and blood derived products; cells, tissues and organs; disinfectants; and, radiopharmaceuticals.

Indication
The use(s) for which a drug or health product has been approved by Health Canada for sale in Canada.

Informed Consent
Written consent which has been given after information has been received and understood by a person.

Marketed Health Product
A health product that has met Health Canada regulatory requirements and can be sold in Canada.

Medication Incident
Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient or consumer. Medication incidents may be related errors in or problems with professional practice, drug products, procedures and systems; and include prescribing, order communications, product labelling/packaging/nomenclature, compounding, dispensing, distribution, administration, education, monitoring and use.

Off-Label
"Off-label" use refers to the use of a marketed health product outside of indications included in approved product labelling. In order for indications to be approved substantial and sound scientific information is provided by the manufacturer and submitted for review and approval by Health Canada.

Product Monograph
The product monograph (PM) is a key piece of information used by health care professionals in prescribing and administering medication to patients. It is a factual, scientific document on a drug that does not contain any promotional material. It describes the properties, claims, indications and conditions of use of the drug product and other information that may be required for optimal, safe and effective use of the drug.

Post-Market Surveillance
The continued monitoring for, and the study of effects and other safety and effectiveness related aspects of marketed health products.

Practice of Medicine
The provincial and territorial governments are responsible for administering the health care system and providing services to the public. As part of this mandate they put in place practice of medicine guidelines. These are a set of directions or principles to assist the health care practitioners with patient care decisions about appropriate diagnostic, therapeutic, or other clinical procedures for specific clinical circumstances.

In addition to the provincial government, practice of medicine guidelines may be developed by other government agencies at any level, institutions, organizations such as professional societies or governing boards, or by the convening of expert panels. They can provide a foundation for assessing and evaluating the quality and effectiveness of health care in terms of measuring improved health, reduction of variation in services or procedures performed, and reduction of variation in outcomes of health care delivered.

Research Ethics Board
Research ethics boards are put in place to ensure the ethical conduct of health research on human subjects.
More specifically, the mission of, for example, a Research Ethics Board of a health science organization could be is to ensure that health related research carried out within the organization is of the highest quality, is conducted to protect the interests of human subjects and of society, and is in conformity with the law and existing ethical codes of conduct.

Serious Adverse Reaction
A noxious or unintended response to a drug or health product which occurs at any dose and required in-patient hospitalization or prolongation of existing hospitalization, causes congenital malformation, results in persistent or significant disability or incapacity, is life-threatening or results in death.

Serious Unexpected Adverse Reaction
A serious adverse reaction that is not identified in nature, severity, or frequency in the risk information set out on the label of the drug or in the product monograph.