Medicines that Work for Canadians: Business Plan for a Drug Effectiveness and Safety Network

Prepared by Gary Fox and Nicolaas Otten, Donna Cona Inc.
for Health Canada
February 2007

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Table of Contents

• Executive Summary
• 1.0 Introduction
  • 1.1. Mandate
  • 1.2. Background
  • 1.3 Business Plan
  • 1.4 Guiding Principles for the Plan
  • 1.5 Approach and Methodology
  • 1.6 Priority Projects
• 2.0 Drug Safety and Effectiveness In Canada Today
  • 2.1 Organizations Involved in Drug Assessments
  • 2.2 Current Evaluation Processes
  • 2.3 Recent Trends
  • 2.4 Centres of Research in Canada Today
• 3.0 Issues with Drug information in Canada (RWS&E)
  • 3.1 Approval Process
  • 3.2 Post-Market Surveillance of Effectiveness and/or Safety
  • 3.3 Research
  • 3.4 Capacity
  • 3.5 Data
• 4.0 International Experience
  • 4.1 Centers for Education and Research on Therapeutics (CERTS) - USA
  • 4.2 Developing Evidence to Inform Decisions re Effectiveness (DeCIDE) - USA
  • 4.3 Intensive Medicine Monitoring Program (IMMP) - New Zealand
  • 4.4 Web-based Visual Data Mining Environment (WebVDME)- USA
  • 4.5 Research on Adverse Drug Events and Reports (RADAR) - USA
• 5.0 A Canadian Solution
  • 5.1 Vision
  • 5.2 Mission
  • 5.3 Program Objectives
  • 5.4 Differentiators
  • 5.5 Structure Components
  • 5.6 Operational Flow
  • 5.7 Priority Setting Processes
  • 5.8 Program Evaluation
  • 5.9 Compelling Cases
• 6.0 Funding Concepts
  • 6.1 Funding Elements
  • 6.2 Funding Parameters
  • 6.3 Growth
• 7.0 Organizational Options
  • 7.1 Overview
  • 7.2 Organization Options
  • 7.3 Recommendation
  • 7.4 Options for the Host
• 8.0 Priority Projects
  • 8.1 Background/Purpose
  • 8.2 Priority Criteria
  • 8.3 Projects Identified
• 9.0 Summary Costs and Next Steps
  • 9.1 Estimated Annual Costs - Full Program
  • 9.2 Next Steps
  • 9.3 Estimated 5 Year Cost
• Appendix 1: Project Participants
• Appendix 2: Compelling Cases
• Appendix 3: Scientific Director Office Salary Costing Assumptions
• Appendix 4: Approach and Methodology
• Notes

Executive Summary

The Situation

Drugs are the fastest growing component of health care costs in Canada. According to the Canadian Institute for Health Information (CIHI), over $21 billion was spent on drugs in Canada in 2004. Prescription drugs represented over 82% of this cost, and publicly funded programs (for the elderly and those on social assistance) paid over 37% of the total. CIHI forecasts that the total cost will have increased to more than $24 billion in 2006.

Health Canada has a clear regulatory responsibilityregarding the safety and efficacy of medicines and their use in Canada. This includes both pre-market approval and, following market authorization, post-market safety surveillance. The provinces and territories administer the publicly funded drug plans, and also have a keen interest in the safety and effectiveness of medications. Clinicians recommend, and patients take, many drugs, often based upon limited information about drugs' long-term benefits and risks. Pharmaceutical companies have a keen interest in the regulatory and clinical environment in Canada that may impact the marketability of their products. Thus, many groups have an interest in high quality evidence about drug safety and effectiveness.

The Problem

There are critical issues for Canada and Canadians regarding real world safety and effectiveness of medicines, post-market:

• Current evidence gaps may harm Canadians: There are large gaps in the evidence available on the safety and effectiveness of medicines used in the long term in a real world environment. These gaps impact negatively upon the mortality and quality of life of Canadians. Canadians' experience with Vioxx, gatifloxacin and estrogen therapy provide compelling examples of these gaps and the related impacts (see Section 5.9 and Appendix 2 Compelling Cases.)
• No organization has the mandate and capacity to rectify the evidence gap: Currently, no organization in Canada has both the mandate and capacity to proactively assess the real world safety and effectiveness of drugs once they enter the market.
• Shortage of highly trained personnel: There is limited human resource capacity across Canada to take on substantial new post market surveillance research initiatives. There is a need for significant investment in people, training programs and time to build that capacity.
• Need for rapid response to important policy or safety concerns: There is limited capacity to address urgent research requests in a timely manner to assess specific issues when they arise.

Canada is not alone with these problems. Many countries are faced with similar issues but few have the tools and databases to address these shortcomings.

The Business Plan

This Business Plan is intended to address critical aspects of the Real World Safety and Effectiveness of medicines in Canada. The plan proposes a national network of pharmaceutical research centres of excellence, in conjunction with a national oversight body comprised of key stakeholders which will establish priorities for research. The network will build upon existing strengths in post-marketing surveillance in Canada, and will expand the body of evidence on the safety and effectiveness of medicines, providing timely and high quality information upon which policy makers, healthcare providers and patients may make reasoned decisions about the prescribing and use of medicines.

At the Working Conference on Strengthening the Evaluation of Real World Drug Safety and Effectiveness held in September 2005, two over-riding characteristics of a governance model for the proposed network and oversight body were identified.

• Build on what already exists and learn from existing models [e.g. the Canadian Agency for Drugs and Technologies in Health (CADTH) and the Canadian Patient Safety Institute (CPSI)].
• Structure a governance model that includes a national / central governing body with coordination and extensive involvement, commitment and collaboration by research centres, regulatory bodies, patients, health care providers, industry and governments.

This Business Plan has been developed as part of the National Pharmaceuticals Strategy. The project was a collaborative effort among the National Pharmaceuticals Strategy (NPS), the Canadian Institutes of Health Research (CIHR) and the Canadian Drug Policy Development Coalition (CDPDC). The development of this Business Plan was overseen by a Project Authority Advisory Committee comprised of representatives of the above partners and also included representation from the patient and health care provider communities.

The Uniqueness of the Canadian Environment

Canada is uniquely positioned to take a leadership role internationally in the post-market surveillance of medicines. While Canada represents approximately 2% of the total drug market world wide, it provides a unique opportunity for research into the effectiveness and safety of drugs:

1. Information on Prescription Purchases
   • Canadian Provinces and Territories collect drug usage data as part of administering provincial health care.
   • This data can be (and is in many jurisdictions) linked to information from hospitals and clinics to create databases which may be used to answer such questions as "Did the patients suffer a heart attack after taking the drug?" Some of these databases are the most comprehensive in the world.
   • CIHI is building a secure database (NPDUIS) to hold data from all provinces and territories.
     
     

     International Interest Many international researchers already take advantage of our resources. However, within Canada, there is infrequent collaboration and little transfer of knowledge to address therapeutic issues locally.

2. Provincial Variations on Formularies
   Provinces take differing positions on funding for specific drugs, based on the needs of their respective populations. This provides a unique opportunity to compare the results of different treatments of a specific disease between jurisdictions.

International researchers already take advantage of our unique resources, working closely with specific provinces such as British Columbia and Saskatchewan. However, Canada, in spite of having researchers who are world leaders in analyzing drug databases and have sophisticated expertise in the conduct of clinical trials, has no co-ordinated plan to maximize the use of these resources nor are there many collaborative efforts to enhance the quality of information or compare drug utilization, safety and effectiveness.

This Business Plan proposes to address some of the issues noted by taking advantage of the unique resources available to Canadian researchers. The plan was developed following an extensive environmental scan conducted both nationally and internationally of key stakeholders.

The Proposed Solution

In concept, this plan proposes a national network of pharmaceutical research centres of excellence which will develop trusted, timely and nonbiased evidence to inform pharmaceutical policy decisions and treatment practices. The program will be under the guidance of a national oversight body, which will identify gaps in knowledge, evidence and information, and prioritize areas for research.

The objectives of the program would be to:

• Identify important gaps in information on the safety and effectiveness of medicines

  Knowledge Transfer
  Knowledge Transfer is a critical component of this program. However, there are many organizations in Canada which currently build, support and provide tools for transfer of health care information to the public, health care practitioners and to policy makers. It is planned that a separate business plan will be undertaken to look at the development and implementation of a comprehensive resource for Knowledge Transfer, combining the material from all the related organizations. In anticipation of that initiative, this business plan does not address Knowledge Transfer fully..

• Research and make available evidence on the safety and effectiveness of medicines to health care practitioners, patients and policy makers.
• Provide a streamlined process such that critical issues can be addressed promptly.
• Develop research capacity throughout the country, including
  • Additional researchers, clinicians and analysts.
  • Enhanced training and mentoring programs to develop highly qualified personnel with the needed skills.
  • Potential new research centres in the longer term (eg. a centre based in the Atlantic Provinces; a centre focused on the unique needs of the First Nations people).
• Develop new and enhance existing national and international partnerships to share information and research
• Improve the effectiveness of the national research effort through expanded collaboration

Program Components

As envisaged in the plan, the program would consist of a number of components:

Stakeholders: The Stakeholders represent the parties in Canada which would have a vested interest in the success and usefulness of the program. The stakeholders would suggest topics for research and would seek the results of the projects undertaken.

Oversight Committee: The Oversight body is a committee of representatives of the stakeholders (approx. 15 in total). Among other duties, it would set the strategic direction for the network; establish criteria for research project selection; establish priorities for research; direct funding; and evaluate the performance of the network over time. It would ensure the coordination and collaboration of drug research that is missing in Canada today.

Scientific Director and Secretariat: The Scientific Director would, among other things, implement a vision for research in safety and effectiveness of medicines in Canada; develop and administer the network of centres; manage the research projects on behalf of the Oversight Committee; ensure the quality of the research done by the network, monitor drug focused research and issues in Canada and internationally; and provide financial accountability.

Network: There are numerous research centres and informal networks in place across Canada that are capable of undertaking post market research into the safety and effectiveness of medicines. What is missing today and addressed in this Business Plan is capacity and coordination and collaboration among these centres. For this program, the centres will be classed into to two groups:

• Primary Funded Research Centres: These centres will be selected through a Request For Application process and will be funded for up to a five year period. These centres will undertake direct responsibility for research, for the critical component of capacity building, and collaboration. They will be accountable for meeting agreed objectives in each area. At the outset there would be 4 to 5 Primary Funded Centres. This may grow over time.
• Project Funded Research Centres: Project Funded Centres are those centres which do not seek or are not selected as a Primary Funded Research Centres. These centres may have specialized expertise and may be asked to undertake discrete projects or to participate in a larger project undertaken by a funded centre. These centres would be provided project funding as needed to fulfill the specific project requirements.

What is Unique About this Plan?

While the details appear in the text of this document, the key features that make this proposal unique include: the focus on consensus driven priorities for research versus the current non-prioritised and competitive process; the emphasis on building upon and strengthening the current research and researcher capacity in Canada (i.e., investing in Canadian knowledge and talent); the opportunity to collaborate with international partners; the development of evidence-based information that will be of use to patients, providers and regulators at all levels; and finally, a significant focus on effectiveness research which has been clearly identified as a significant gap in the efforts to ensure rational use of medicines in Canada.

The Cost and Time Frame

The estimated annual cost of this program would be just under $21 million per year or less than 0.1% of the total annual Canadian expenditure on drugs. This total expenditure can be viewed as consisting of two parts - fixed and variable.

Estimated Annual Operating Costs

No.	Funding Element	Cost
1	Office of the Scientific Director	$1,245,800
2	Oversight Committee	$120,000
3	Board	$60,000
4	Primary Funded Research Centres (4 Centres at the outset)	$3,200,000
5	Project Funding	$16,000,000
Total Annual Cost		$20,625,800

• The fixed costs include program administration (the Office of the Scientific Director, the Oversight Committee and the Board) and the Primary Funded Centres. Note that the costs of administering the program would be less than 15% of the total annual operating cost. The Primary Funded Research Centres would cost approximately $800,000 each per year - that cost principally covering project management, collaboration, capacity development, database access, and some project funding.
• The variable cost is the Project Funding. Total project funding will vary depending on the research undertaken - the number of projects and the protocol required to address the question. The number of projects to be undertaken could vary and will certainly grow over time as the program proves of value. The protocol or study method will also vary depending on the question. The cost to analyse administrative databases in response to a question would be significantly lower than the cost of a randomized controlled trial. During the first, and possibly the second year, funds allocated to projects will be lower than shown as the program is being established.

Recommendation: The program should be initially funded for a five year period with an independent evaluation performed in the fifth year to determine whether the return on the investment would justify on-going funding and potentially the addition of more Primary Funded Centres.

Organization Options

There has been considerable concern expressed over the number of organizations in Canada with overlapping mandates with respect to the management, surveillance and reporting on drugs. For that reason, it is proposed that this program become associated with or a part of an existing organization with a closely related mandate. A number of organizations were considered and three were interviewed, as detailed in the plan. Based on criteria established by the Project Authority Advisory Committee, it was determined that any one of these organizations would be a viable host.

Recommendation: Based on its focus on research; available clinical skills; experience in managing the funding of research as well as capacity development; and its international and national reputation, CIHR should be the first choice.

The Benefits

Why do this?

Better and more timely information on the benefits and harms of drugs:

There are many examples of drug therapies which had unexpected and negative results when introduced to a real world environment - an environment unlike that under which clinical trials are conducted; an environment where drugs are taken for longer periods of time, for differing sub-populations of patients (gender, age, co-morbid diseases, etc.) and for indications not initially evaluated. As detailed in the body of this report. one need only consider the impact of Vioxx, gatifloxacin and estrogen therapy to understand the potential human and financial impacts, and the reality that all drugs have risks as well as benefits. These are but three examples. There are many more drug therapies where filling the gaps in essential available information, as proposed in this plan, represents a significant opportunity to decrease the risks and increase the benefits of medicine use for Canadians.

Better access to new drugs for Canadians

Inasmuch as drugs will be more carefully scrutinized post-market, drug plans would likely be more willing to pay for new drugs than is currently the case. This would improve access to new drug therapies for all Canadians.

Creation of a trusted source of drug information:

The involvement of stakeholders from a broad cross section of involved and interested parties (from patients to regulators) on the Oversight Committee will make the drug system more transparent and responsive to the legitimate needs of the various stakeholders.

A co-ordinated national network will increase collaboration among research centres and expand the available data sources for study, resulting in improved analyses and more complete results.

Ability to respond promptly to urgent questions:

The availability of a network of funded research centres, highly skilled researchers, linked health and drug databases, and a priority setting process for research would increase the ability of Canada to respond promptly to urgent questions. The international contacts that could be made through this network would increase Canadian awareness of important issues with drugs sooner.

Greater value for research dollars:

A co-ordinated national network will reduce or eliminate the duplication of research across jurisdictions, thereby permitting the same budget to support more projects.

International Recognition

A coordinated, priority driven program of post market drug research which would take advantage of existing information and skills in Canada would bring international attention to Canada. This would also raise the possibility of investment in Canadian research from international sources.

The Business Plan recommends:

• The development of a national co-ordinated network for post market surveillance and research into the real world safety and effectiveness of medicines.
• The maximization of the benefits afforded by the unique data resources available in Canada.
• The development of research capacity, including people, education and training to permit prompt response to real needs for information in a timely fashion.

The network as outlined in the Business Plan is not intended to be the ultimate and sole source of new evidence to fill gaps in information on the safety and effectiveness of medicines. Rather it is intended to augment and strengthen the work being done today; to improve the effectiveness of the dollars being spent on research through greater collaboration, and to provide a focus on developing the talent needed to undertake this important work.

1.0 Introduction

1.1 Mandate

At the First Minister's Meeting on the Future of Health Care 2004, the Provincial and Territorial Ministers of Health were directed to establish a Ministerial Task Force to develop and implement the National Pharmaceuticals Strategy (NPS).

The NPS is a collaborative, integrated, and comprehensive approach to addressing many issues related to the use of pharmaceuticals in Canada. It is a multi-year strategy that is national in scope and responsive to provincial / territorial needs, with the intent to better integrate the use of pharmaceuticals into Canada's publicly funded health care system. Among several initiatives, First Ministers directed that the Strategy include strengthening the evaluation of real-world drug safety and effectiveness.

1.2 Background

Drugs approved by Health Canada must undergo rigorous pre-market clinical testing. However, the evidence may not be sufficient in determining if the drug will ultimately be of clinical benefit. For example, most trials are relatively short in duration (usually less than 3 to 4 months) which is too short in determining some clinical outcomes. Further, many of these trials involve carefully selected patient groups that may not totally reflect the patient population that will eventually use the drug. This type of trial, which often uses placebo as the comparator, has limited ability to predict a drug's safety and effectiveness ¹ in the "real world" where it may be used in different population groups, at varying doses, and for longer periods of time and for purposes that were not originally tested in trials i.e. 'slippage of indications'.. The performance of a drug can only be fully assessed based on real world clinical outcomes and/or when directly compared to alternatives.

While the federal government has a clear regulatory role regarding post-market safety surveillance, a comprehensive approach to addressing the issues of safety and effectiveness requires the participation of many players, and the need for national oversight and planning. A system for prioritizing drugs and drug classes for surveillance based on their impact on health outcomes and on Canada's publicly funded health care system is also needed.

The Real World Safety and Effectiveness (RWS&E) element of the National Pharmaceuticals Strategy embodies four key strategies:

• Support collaboration and priority-setting, through a national oversight body, composed of key stakeholders and all jurisdictions, with the mandate to plan, set priorities, coordinate and budget for answering real world safety and effectiveness questions; while respecting the federal regulatory responsibility for post-market safety..
• Strengthen existing capabilities, through the development of a network of research centres, hospital-based teams and enhanced regional Adverse Drug Reaction Reporting (ADR) centres. Together, this network of networks would focus on developing strong education and outreach to local providers and patients.
• Build "front-line" participation and new opportunities, through active engagement of primary care and hospital based teams, development of education programs to build drug knowledge, harnessing of the electronic health record and use of other approaches to support creation of data by patients and providers.
• Establish clear standards and transparency of evidence, through strengthening of linkages among regulatory and health system decision-making experts, frameworks and processes; supporting dialogue and guideline development on the levels and standards of medical evidence; making evidence and its interpretation by regulatory and health system decision-making experts publicly available.

A comprehensive approach to safety and effectiveness must also consider international approaches to similar issues and opportunities to leverage and align with international practice. This Report addresses the international context in Section 4 and speaks to alignment and leveraging in Section 5. In addition, there is current research underway via a separate contract specifically looking at lessons learned from international programs in safety and effectiveness.

1.3 Business Plan

The Real World Safety and Effectiveness Working Group is working with the Canadian Institutes of Health Research and the Canadian Drug Policy Development Coalition on the development of a business plan for a national network of pharmaceutical research centres of excellence, in conjunction with a national oversight body. The primary purpose is to produce policy-relevant information from post marketing studies that will help Health Canada and the provinces and territories make evidence-based decisions about drug policy that will improve the health of Canadians.

This Business Plan is intended to provide a business model along with related costs and benefits to address the first strategy above and that portion of the second strategy which relates to strengthening existing capabilities, through the development of a national network of centres of pharmaceutical research excellence.

1.4 Guiding Principles for the Plan

At the Working Conference on Strengthening the Evaluation of Real World Drug Safety and Effectiveness held in September 2005, two over-riding characteristics of a governance model for the proposed network and oversight body were identified Working Conference on Strengthening the Evaluation of Real World Drug Safety and Effectiveness: Summary.

• Build on what already exists and learn from existing models [e.g. CCOHTA (now CADTH or Canadian Agency for Drugs and Technologies in Health) and CPSI (Canadian Patient Safety Institute)].
• Structure a governance model that includes a national / central governing body with coordination and extensive involvement, commitment and collaboration by research centres, regulatory bodies, patients, health care providers, industry and governments.
• Stakeholders should include:
  • Regulators: federal, provincial
  • Drug plans / insurers - public and private
  • Manufacturers
  • Prescribers and their institutions
  • Pharmacists and their institutions
  • Health system governors and managers
  • Information management experts
  • Educators of providers and patients
  • Policy makers.
  • Patients and their families

These principles are fundamental to the plan presented herein.

1.5 Approach and Methodology

The Business Plan for a Drug Effectiveness and Safety Network was developed by a team of consultants from Donna Cona Inc. under the leadership of Health Canada and the guidance of the Project Authority Advisory Committee (PAAC).

The team included a senior business consultant with extensive experience in the development of business plans and business cases for Federal Government programs; and a senior consultant and researcher in the field of evidence-based medicine, clinical and economic evaluation of pharmaceuticals, drug review processes, and policy implications of pharmaceutical listings, among others. The PAAC represented a broad base of stakeholders from across Canada including researchers, patient representatives, and Federal and Provincial government representatives. The members of the PAAC were extremely supportive of the initiative and the project team throughout, providing both time and ideas. The PAAC members are listed in Appendix 1 Project Participants while Appendix 4: Approach and Methodology details the steps undertaken in the project.

1.6 Priority Projects

In parallel with the development of the business plan, the Project Authority along with the Canadian Institutes of Health Research undertook a project to identify a number of Priority Research Projects in the area of Real World Safety and Effectiveness. The intent of this initiative was to:

• Identify significant information gaps in real world safety and effectiveness of medicines and potential related research projects.
• Prioritize the projects and select four for further analysis including the development of a high level methodology and cost estimates for the completion of each project.
• Include those projects as possible first initiatives under the Research Network contemplated in this business plan.

This project was undertaken with input from a large number of participants across Canada. A workshop was held in Ottawa to review the suggested projects and select the final four. See Section 8.0: Priority Projects for further information.

2.0 Drug Safety and Effectiveness In Canada Today

2.1 Organizations Involved in Drug Assessments

2.1.1 Health Canada

Within Health Canada's Health Products and Food Branch (HPFB) there are three directorates that are directly involved in drug assessments: the Therapeutic Products Directorate (TPD), the Biologic and Genetic Therapies Directorate (BGTD) and the Marketed Health Products Directorate (MHPD). TPD and BGTD are primarily responsible for pre-market assessments while MHPD is responsible for post-marketing surveillance.

It should be noted that in both directorates there is active work on collaborating internationally for both pre and post marketing activities. For example, TPD is actively involved in the International Conference on Harmonisation (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use. ICH provides a forum for dialogue between regulatory authorities and the industry on harmonization issues. Its work focuses on the identification of areas for improvement and the recommendation of ways to achieve harmonization in the interpretation and application of technical guidelines and requirements for product review. The objective of ICH is to reduce or obviate differences in technical requirements in countries where new drugs / medicines are being developed with the eventual goal of eliminating the need for duplicate pre-clinical and clinical testing of product. Another example is ongoing work with the European Directorate for the Quality of Medicines (EDQM) Certificates of Suitability (CEP). For post-marketing surveillance, Health Canada struck an agreement with the Food and Drug Administration to allow access to a database containing over 350,000 adverse event reports. This database not only contains information from adverse events reported in the U.S. but also has information from European reports.

There was also a program called The Best Practices Contribution Program (BPCP). Managed by Health Canada, the BPCP built on the 2003 Accord commitment and ongoing efforts in this area by offering financial support to initiatives that:

• evaluate best practices related to optimal prescribing and utilization of drug therapy; and
• encourage the uptake of such best practices across jurisdictions.

In the past fiscal year, the BPCP focussed on the evaluation of initiatives aimed at fostering optimal drug therapy through the adoption of evidence into practice and the promotion of greater consumer/patient awareness. The program results were shared with the COMPUS program (see below under CADTH).

Five reports related to safety and effectiveness were commissioned by Health Canada as part of the Health Policy Research Program beginning in April 2002. Results are available at Real World Drug Safety and Effectiveness

2.1.1.1 Therapeutic Products Directorate (TPD) and Biologic and Genetic Therapies Directorate (BGTD)

Pharmaceutical manufacturers must submit substantive scientific evidence of a product's safety, efficacy, and quality. HPFB scientists review this evidence to determine whether the potential risks from the new pharmaceuticals are acceptable when balanced against the positive effects. HPFB has established a number of advisory committees to provide advice and, in some cases, to act as sounding boards.

2.1.1.2 Marketed Health Products Directorate (MHPD)

MHPD is responsible for the post-market surveillance activities of Health Canada's HPFB. It also coordinates the Canadian Adverse Drug Reaction Monitoring Program that collects and assesses reports of adverse reactions to drugs. MHPD will take appropriate action ranging from informing the public and health care community of new product safety information, to removing market authorization. Within the last year they have initiated the Medeffect website allowing anyone to report adverse drug events. The online reporting system is modelled after  MedWatch in the United States They also disseminate the Canadian Adverse Reaction Newsletter (CARN) to clinicians.

2.1.2 The Canadian Agency for Drugs and Technologies in Health (CADTH)

(Formerly known as CCOHTA - The Canadian Coordinating Office of Health Technology Assessment).

CADTH is an independent, not-for-profit agency funded by Canadian federal, provincial, and territorial governments to provide credible, impartial advice and evidence-based information about the effectiveness of drugs and other health technologies to Canadian health care decision makers. Any research conducted by or on behalf of CADTH is generally one of synthesis of existing information (with the exception of economic analyses/modeling). CADTH was established in 1990 to primarily conduct non-drug health technology assessments. By 1993, after a review of its programs, pharmaceutical reviews were added to the organization's mandate. Two other relevant drug programs were added in subsequent years: Common Drug Review (CDR) and the Canadian Optimal Medication Prescribing and Utilization Service (COMPUS).

2.1.2.1 Health Technology Assessment

The Health Technology Assessment (HTA) program conducts impartial, evidence-based reviews of the clinical effectiveness, cost effectiveness and broader impact of health technologies including drugs and health systems..

2.1.2.2 Common Drug Review (CDR)

In March 2002, the Common Drug Review (CDR) Directorate was established with the first submissions in September 2003. Its mandate was to reduce duplication of formulary submission reviews by provinces and provide equal access to high level evidence and expert advice, thereby contributing to the quality and sustainability of Canadian public drug plans. Reviews of each drug includes an evidence-based approach to clinical benefit/harm, a critical evaluation of the manufacturer's economic analysis ('cost-effectiveness') of the drug and an analysis of the impact of the product on each government plan's drug budget. (Note: Quebec conducts its own review).

2.1.2.3 Canadian Optimal Medication Prescribing & Utilization Service (COMPUS)

In 2004, the Canadian Optimal Medication Prescribing and Utilization Service (COMPUS) was launched. COMPUS, in partnership with the federal, provincial, and territorial health ministries, identifies and promotes optimal drug prescribing and use among health care providers and consumers. Its five stated roles are:

• Identify, evaluate, promote, and facilitate the implementation of best practices in drug prescribing and use;
• Consolidate information resources;
• Develop and support networks for best practices in drug prescribing and use;
• Encourage health care provider and consumer behaviours for improved drug related health outcomes; and
• Identify best practice information gaps.

2.1.3 The Patented Medicine Prices Review Board (PMPRB)

PMPRB is a federal independent quasi-judicial body established in 1987 under the Patent Act. PMPRB is responsible for ensuring that the prices that patentees charge wholesalers, hospitals, pharmacies and others for prescription and non-prescription patented drugs sold in Canada are not excessive. Currently it determines which price tests to apply, based on a clinical review of the drug in question, to establish the introductory maximum non-excessive price.

2.2 Current Evaluation Processes

2.2.1 Pre-marketing:

Pharmaceutical firms, wishing to bring a drug to the marketplace must submit evidence of safety and efficacy to Health Canada where it undergoes extensive evaluation. There are some major limitations. Sometimes the trials are limited to determining a drug's safety profile (common adverse events) and its efficacy (e.g. reducing blood pressure) but not its clinical effectiveness (e.g. reducing the incidence of strokes). Human trials are conducted in 3 phases. In phase I a new drug is tested in a small group of people (eg. 20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. In Phase II, the drug is given to a larger group of people (eg. 100-300) to determine its efficacy and further evaluate its safety. Finally, in Phase III, the treatment is generally given to a larger group of people (eg. 1,000 - 3,000) to confirm its efficacy and monitor side effects. Typically, in Phase III the drug is compared to placebo rather than active comparators although there are exceptions.

As outlined in Chapter 4 there are limitations to much of this information. Often times the information has internal validity (i.e. the study is valid for what is being evaluated) but does not necessarily have external validity (e.g. the population that the drug is being tested on may not reflect the general population of patients requiring the treatment). There are other issues as well such as lack of comparison with existing therapies, use of surrogate or intermediate outcomes (e.g. cholesterol reduction) rather than clinical outcomes (e.g. heart attacks), short time frames which impacts detection of some adverse events and/or clinically meaningful outcomes, and less than optimal number of patients evaluated in terms of determining both outcomes and adverse events when used in the "real world".

2.2.2 Post-marketing:

The primary means by which Health Canada surveys adverse drug reactions is through a voluntary reporting mechanism (by health care professionals and the general public). Any reports coming to the attention of the manufacturer must be forwarded to Health Canada. A database is maintained and analyzed to determine whether there are emerging adverse events occurring that have not been previously detected. The major problem with this activity is the voluntary nature of the activity. It is estimated that in countries where this type of activity takes place that only 1% to at most 10% of all adverse events are reported. Thus there is no ability to determine the frequency with which an adverse event is likely to occur. Furthermore, there is no linkage to any health database to determine if there are any particular populations at risk, impact on outcomes, impact on health resource utilization, etc.

2.2.3 Formulary Evaluations

Prior to the establishment of the Common Drug Review (CDR), each province conducted their own drug evaluations. However, with this new program a consistent, high level, unbiased evaluation is conducted with recommendations for listing or not listing. However, provinces are not obligated to follow these recommendations as there may be local issues that have an impact on listing decisions (e.g. financial). The CDR process utilizes an evidence-based approach focusing on clinical outcomes. The evaluations take place soon after Health Canada has approved the licensing of the product. Thus most of the information being evaluated is the same data that Health Canada has used in their evaluation although the focus of the review is somewhat different. Therefore most of the problems associated with the data listed above under pre-market review apply to this situation. There are instances that recommendations are made to restrict the product to specific populations and/or to conduct ongoing evaluations of the effectiveness of the product. Unfortunately some provinces do not have the necessary capacity to conduct these types of evaluations.

Recently the health insurance industry has started to conduct independent clinical and/or economic reviews. They often rely on the CDR evaluation although some conduct their own independent evaluations. Many of the insurance companies have now established formularies. However, they have no capacity to properly monitor or conduct follow-up studies. Rather only some basic utilization studies can be conducted with their databases.

2.3 Recent Trends

The following is a brief description of related organizations and / or programs.

2.3.1 Restricted / Conditional Listings

Many provincial jurisdictions now actively develop guidelines for reimbursement of drug products often based on CDR review of the evidence from clinical trials. Some provincial jurisdictions have had several years experience with this type of control especially in those jurisdictions with "real time" interaction between the dispensing pharmacy and provincial computers systems.

More recently some jurisdictions have explored the opportunity to develop agreements with pharmaceutical manufacturers on new products related to expected performance (risk sharing agreements). Based on the clinical and/or economic analyses, an agreement between the manufacturer and the provincial drug plan is initiated. Outcomes are then monitored by the province to determine whether the performance of the product meets expectations.

2.3.2 Progressive Licensing

Health Canada is exploring the potential of implementing Progressive Licensing for selected new products. (See: Blueprint for Renewal:This could potentially involve, for example, a conditional licence to market a product provided further information and/or active surveillance for a product is undertaken by the manufacturer. Failure to comply could result in the cancellation of the licence. However, while this program sounds sensible, the reality has proved quite different. The FDA in the USA has had this type of program in place for a number of years. Studies have determined that pharmaceutical firms often fail to comply, that is, the studies committed to are not completed. In fact, many were not even initiated. The FDA does not have the authority to take direct legal action against violators (Furberg, 2006).

2.4 Centres of Research in Canada Today

2.4.1 Types of Research/Activities

There are several ongoing activities in Canada pertinent to post-marketing surveillance of drugs. This is not intended to be an exhaustive list nor is the intent to rank their importance. However, some of the issues surrounding these activities is the lack of coordination of activities, the transparency of the process and what impact these activities might have.

2.4.1.1 National Prescription Drug Utilization Information System (NPDUIS)
  National Prescription Drug Utilization Information System (NPDUIS)

The Canadian Institute for Health Information has initiated a prescription claims level drug database capable of incorporating program data from publicly-funded drug plans. PMPRB utilizes this data in their analysis of prescription drug prices. Some recent projects utilizing this database include:

• Non-Insured Health Benefits Cost Drivers Study; Pharmaceutical Trends Overview Report (expenditures by therapeutic class; disaggregated expenditure growth into its component factors; costs per beneficiary; and costs of drugs per defined daily dose);
• Budget Impact Analysis Methodology (calculating the net financial impact of a provincial drug plan listing a new drug as a benefit - partnering with CADTH);
• Program Expenditure Forecasting Methodology (to develop best practices in forecasting drug program expenditure);
• Therapeutic Cost Index (an index that calculates the average increase in costs per defined daily dose (DDD) that reflects that patients do switch from one drug to another. These results will be calculated in aggregate for all drugs and by leading therapeutic classes using the data supplied to the PMPRB by the participating public drug plans).

2.4.1.2 IRIS-Quebec

IRIS-Quebec is a not-for-profit public corporation, owned by the four academic health centers and research-intensive universities in the province, that has created a secure, state-of-the-art health information infrastructure for clinical care and research. It is an ambitious project that links a variety of programs and databases ranging from MOXXI (Medical Office of the 21st century) to the provincial health database to inpatient and outpatient services of 22 hospitals.

2.4.1.3 Therapeutics Initiative (BC)
( Therapeutics Initiative)

The Therapeutics Initiative was established in 1994 by the Department of Pharmacology and Therapeutics in cooperation with the Department of Family Practice at the University of British Columbia to provide physicians and pharmacists with up to date, evidence based, practical information on rational drug therapy. The Initiative is an independent organization, which is at arms length from government, pharmaceutical industry and other vested interest groups. Among their objectives is to assess new and existing drug therapies by the standards of the best evidence of clinical effectiveness in the scientific literature. They are also mandated to design and implement a variety of educational strategies to deliver the evidence and recommendations to physicians and pharmacists. This includes the production of a bi-monthly drug newsletter (Therapeutics Letter). Finally, they act as an expert resource to Pharmacare, the BC drug benefit program.

2.4.1.4 Institute for Clinical Evaluative Sciences (ICES) - Ontario
( The Institute for Clinical Evaluative Sciences (ICES))

ICES was established in 1992 and provides unbiased, evidence-based knowledge and recommendations on both drug and non-drug issues. Their research encompasses the assessment of care delivery, patterns of service utilization, health technologies, drug therapies and treatment modalities. An important component of their work is the ability to link population-based health information on an individual patient bases allowing a more detailed evaluation of health utilization and outcomes.

2.4.1.5 Centre for the Evaluation of Medicines (CEM)
( Welcome to the Centre for Evaluation of Medicines)

The Centre for the Evaluation Medicines, located in Hamilton, Ontario was established in 1993 to provide expertise in clinical pharmacology and toxicology, economics, health policies, behavioural sciences, information technology, research design and biostatistics. They provide expertise in such areas as evaluation (e.g. clinical pharmacology studies, adverse drug reactions, technology assessment, etc), policy planning and interventions ranging from academic consultation for government and industry to the production and promulgation of evidence-based practice guidelines, and research methods development spanning from basic statistical research to pharmacist and patient research methods.

2.4.1.6 University of British Columbia Centre for Health Services and Policy Research
 ( The UBC Centre for Health Services and Policy Research)

The UBC Centre for Health Services and Policy Research conducts a diverse research program covering the gamut of health related issues including pharmaceutics and pharmaceutical policy. Expertise includes health economics, health services research and health policy analysis. It is the home to the BC Linked Health Database that provides a population-based data resource including pharmaceutical, hospital and physician contact data for applied health services and population health research.

2.4.1.7 University of Manitoba Centre for Health Policy
( Manitoba Centre for Health Policy)

The Centre conducts a wide variety of research that focuses on the best use of health care resources within the province of Manitoba. A large proportion of their work involves the conduct of six studies annually in partnership with the province of Manitoba usually involving the integrated health database within the province. The data base provides a population-based data resource including pharmaceutical, hospital, nursing home, home care and physician contact data - as well as mortality data.

2.4.1.8 Other Programs/Research

Many of the above programs are based in and/or partially funded by Canadian universities. There are also many individual research projects that focus on drugs, drug use, drug delivery and drug effectiveness. The Canadian Institutes of Health Research annually provides several million dollars of research money specifically focussed on drug research. There are other smaller health policy research units (e.g. Impart - Initiative for Medication Management Policy Analysis, Research Training at Dalhousie). However, their programs are generally small and focussed on a few projects at a time. They also usually do not have access to provincial databases on a routine basis.

There are a number of other initiatives as well as other integrated provincial health databases that include prescription drugs. One of the more outstanding and complete databases is in Saskatchewan where more than 95% of all prescription drugs are recorded regardless of who paid the prescription (provincial resources, health insurance, federal resources and/or the patient themselves). Some of the other integrated health databases mentioned previously (e.g. Ontario) only have drug information related to coverage by the provincial government. This probably covers less than one-third of all prescribed drugs within the province.

3.0 Issues with Drug information in Canada (RWS&E)

The programs and agencies identified in Section 2 all contribute to the knowledge base on the safety and effectiveness of drugs in Canada. Nevertheless, none of these programs or agencies is specifically responsible for routinely filling information gaps which Health Canada and/or the provinces identify. Hence, there are significant gaps in the information available to policy makers, health care practitioners and patients. Some of the issues being faced in Canada include:

• Large gaps in the evidence available on the safety and effectiveness of medicines used in the long term in a real world environment;
• The need for a Canadian organization with the mandate to proactively review the safety and effectiveness of medicines post market (the reactive process to address safety issues which emerge through adverse events tracking is limited).
• The need for capacity across the country to take on substantial post marketing surveillance research initiatives. That is, the need for significant investment in people, training programs and time;
• The lack of capacity to address urgent research requests in a timely manner to assess specific issues when they arise;
• The need for increased coherence re Key decision making, organization, dissemination; and
• The need for international "weather forecasting" regarding issues relevant to Canada that are emerging in other countries.

These issues are not unique to Canada. Most countries are struggling with the same problems.

This section provides more detail on the issues and gaps in evidence. These are addressed under five topic headings:

• The Approval Process
• Post Market Surveillance
• Research
• Capacity
• Data

3.1 Approval Process

3.1.1 General

Pre-market assessment is primarily focused on safety and efficacy (shows a treatment effect) of a product in comparison to placebo rather than an active comparator. Efficacy trials are undertaken to meet regulatory approval; their design maximises the potential for detecting efficacy in a population where toxicity is minimised. Effectiveness refers to whether the treatment transfers well to real-world populations and results in meaningful clinical effects.

Many of the characteristics of these Pre-market trials do not easily lend themselves to interpretation to the "real world" (what scientists refer to as "external validity".) Further, there is a limitation on adverse event monitoring in these trials. They will identify common adverse events but those infrequent but serious adverse events will usually not be identified as there are too few patients enrolled in the trials.

3.1.2 Health Canada

As stated above, the clinical trial data provided by manufacturers to Health Canada, although usually rigorous in their design, are of limited benefit in determining true effectiveness and the occurrence of infrequent but serious adverse drug events. These trials often are populated with patients who may not totally reflect the population for which the drug was intended. For example, one study found that 54% of their hospital outpatient psychiatric service had more severe depression than the patients enrolled in antidepressant trials (Zimmerman, 2002). Women, elderly patients, those patients with co-morbid conditions, and children are often underrepresented in these trials although many or all may be a major recipient of the drug as soon as it comes to market. Further, trials tend to be too short or have too small a population to properly determine clinical effectiveness and the true frequency of important adverse events. Finally, most new drugs entering the market have only been compared to placebo rather than existing products for the same indication(s).

3.1.3 Common Drug Review

As noted in Section 2.1.2.2, CDR critically evaluates the literature on a new drug entity to answer many of the questions of interest to policy makers; i.e. how effective is the drug and how does it compare to existing therapies. Unfortunately they are frequently hampered in answering that question as the information they review is usually the same as what Health Canada reviewed. Further CDR only critically reviews new drugs although they are planning on expanding to some existing therapies. One of the challenges for the CDR in evaluating existing drugs is that high level evidence of their safety and effectiveness is incomplete. They currently do not have access to information pertaining to the use of existing therapies contained in integrated provincial health databases.

3.1.4 Provincial Drug Plans

Most provincial plans initially rely on the analyses conducted by Health Canada and CDR to determine whether a drug should be listed and if there needs to be a restriction placed on the product (e.g. only selected physicians allowed to prescribe the product). There are some jurisdictions (e.g. BC) that have initiated programs where new products may be monitored to determine whether the real world use of the product actually translates into expected clinical and economic outcomes.

3.2 Post-Market Surveillance of Effectiveness and/or Safety

3.2.1 General

As stated in Section 2.0, there is no formal drug surveillance program, as envisaged by this business plan, in Canada after a drug is marketed. Researchers may pursue an evaluation of an individual product, to satisfy their own interests and / or for the purposes of publication. The majority of the available surveillance information is obtained through the voluntary reporting system for Adverse Events. However, this is not linked with health outcome data nor does it provide an idea of the frequency of the problem.

3.2.2 Health Canada

Health Canada relies on the voluntary reporting of adverse events by health care workers and patients. However, once a manufacturer is informed of such an event, reporting is mandatory. This system is estimated to detect less than 10% of all serious adverse events. Even if a signal event is identified there are large gaps in the information, which therefore reduces its usefulness. Health Canada currently has no access to provincial health databases nor does it have the research capacity to conduct the appropriate analyses to further refine the original findings. Providing an opportunity for Health Canada to participate in this program is an avenue for addressing some of these gaps on important drug issues.

3.2.3 Common Drug Review

CDR currently has no mechanism for requesting post marketing studies.

3.2.4 Provincial Drug Plans

Most provinces conduct some utilization reviews but they are usually limited in scope and rarely focus on clinical outcomes or adverse events. Occasionally, special projects are funded to look at specific drugs but they are also often limited in scope. Provinces are generally not involved in adverse drug event surveillance.

3.2.5 Researchers

There is a limited amount of funding from sources at arms-length from industry to conduct post-market surveillance. Research that is conducted is frequently not easily accessed by policy makers nor do most policy makers have access to researchers to properly conduct drug utilization and outcome studies. Further, competing interests reduces the opportunity for many researchers to pursue systematic surveillance of selected drugs.

3.3 Research

Currently there is only one research centre that focuses primarily on drug research (Centre for Evaluation of Medicines). There are provincial health policy organizations but their mandate typically includes drug issues as only one of many topic areas covered. There is no process to track all the research being done nationally, leading to potential duplication of research and lack of benefit from research conducted elsewhere. Collaboration between provinces is generally minimal although it has been demonstrated that a great deal of benefit may ensue from such interaction. For example, it would not only increase the sample base of individuals exposed to a particular drug, but it would also provide opportunities to determine the impact on subpopulations and to test the effectiveness of different health policies, given the variety of coverage options across the Provinces and Territories (Paterson, 2006).

3.4 Capacity

There are currently too few trained researchers to take on substantial additional research into the real world safety and effectiveness of medicines. There are also few programs that specifically train individuals to conduct this type of work. As stated previously, competing interests decreases the necessary time and resources (even if sufficient funds for research were made available.) One critical problem for research centres, is that it is difficult to attract researchers unless sustainable funding is available that is not linked to a time-limited project.

3.5 Data

There is substantial variability between provincial jurisdictions in the quality and quantity of information available. For example, in Ontario, there is almost complete information available on prescription use by the elderly and those on social services whose medicines are paid by provincially funded health programs. However, there is little or no information on the rest of the population. Some jurisdictions have almost complete drug information regardless of who has paid for the medication. Several provinces currently do not actively link drug use with any other component of the health care system reducing their ability to properly assess the usefulness of a drug product.

One of the limitations for most provinces is ready access to the provincial databases. Some organizations (e.g. ICES) have ready access to address questions that are posed. Others require special authorization that can take up to one year to obtain (Paterson, 2006). As stated previously, there is infrequent collaboration or accessibility across provincial jurisdictions. Although Canada only accounts for 2% of world drug sales it has some of the largest drug databases linked to other health information. There are international groups that sometimes use these linked databases for their research programs. For example, one of the US Centres for Education and Research in Therapeutics (CERTs) has an agreement with British Columbia to access their database as part of their program. A recent program (the National Prescription Drug Utilization Information System or NPDUIS), under the guidance of the Canadian Institute of Health Information, may help to address this issue.

4.0 International Experience

An international scan was conducted to determine if there were programs / organizations in place in other countries that assessed clinical effectiveness of drugs and had a systematic method of drug surveillance for adverse events. There were a number of sophisticated surveillance programs such as the Research on Adverse Drug Events and Reports (RADAR) program in the U.S. and the New Zealand Intensive Medicine Monitoring Program (see section 4.3), but there were no programs that actually monitored and undertook research into both safety and effectiveness issues with medicines in the real world. There were some national programs focussed on drug effectiveness but most tended to be 'one-off'; i.e. they were set up for one drug or drug class (e.g. Sweden's disease modifying biologics registry).

One program, the Centers for Education and Research on Therapeutics (CERTS) in the U.S. had a number of elements that fit the requirements of the proposed Canadian program. Therefore, the description of this program is provided in some detail. Some of these elements included: funding structure, some governance components, method used to select research centres, some project selection criteria, and research centre responsibilities. There were elements that did not fit the needs of this business case (e.g. research on medical devices).

4.1 Centers for Education and Research on Therapeutics (CERTS) - USA

 Centers for Education & Research on Therapeutics and
 The Centers for Education and Research on Therapeutics (CERTs) (PDF Version)

4.1.1 Mission:

To provide objective, scientific information on the safe and effective use of therapeutics. The CERTs vision is to be a trusted national resource for people and organizations seeking information about health care products. CERTs accomplishes this through research, education, dissemination and knowledge development.

4.1.2 Objective:

To improve the quality of health care while reducing the cost of health care through (I) an increase in the appropriate use of drugs, biological products or devices and (II) the prevention of adverse effects of drugs, biological products and devices and the consequences of such effects, such as unnecessary hospitalizations.

4.1.3 How Formed:

The Agency for Healthcare Research and Quality (AHRQ) was given responsibility for the development of the CERTs programs in coordination with the FDA. The U.S. Congress authorized a CERTs demonstration program. An initial RFA (request for application) was sent out and 4 centres were chosen. Within a year, the program became permanent and expanded to 7 centres again using the RFA process. Since then it again expanded further to 11 centres in 2005 and is now expanding to 12 centres. All funding is for a 5 year cycle but is dependent upon achieving the stated annual goals. After 5 years each centre must reapply.

In November 1998, AHRQ asked the community to nominate research topics. AHRQ then selected topics on the basis of several criteria ranging from high incidence to potential to improve decision making. Topics were selected which partially formed the basis of the RFA; i.e. a potential centre applied for a particular topic area and, if selected, would become the focus of the program.

4.1.4 Governance and Funding

CERTs Research Centre (RC) funding provides infrastructure support (a research team with adequate facilities, institutional support, and access to appropriate expertise needed to perform research, education, dissemination and translation of research into practice) such that an research centre can fulfill the CERTs objectives and support the strategic needs of AHRQ, FDA, and other Department of Health and Human Resources agencies with responsibilities for therapeutics.

Currently the funding is set at about $800,000/year/centre with an expected increase this year to $1,000,000/year/centre. Funding is for a 5 year period with a requirement to formally report their progress and future directions on an annual basis. Other funding for individual projects are sought from various public and private sources including the pharmaceutical industry.

There is a steering Committee for the program composed of a chairperson; the CERTs principal investigators; representatives from AHRQ, the FDA, and the National Institutes of Health (NIH); and three at-large members. One Center acts as the coordinator of the various centres with participation of other parties.

4.1.5 Research Focus:

Each center focuses on therapies in a particular patient population or therapeutic area. (e.g. disorders of the heart and blood vessels; drug use, safety & effectiveness in HMOs; musculoskeletal disorders; reducing drug interactions that result in harm to women; therapies for children; therapies for infection & antibiotic drug resistance; prescription drug use in a Medicaid population). Each centre must provide an initial implementation plan including a timeline for introducing interventions into the health care delivery process. Each year the centre has to provide a report of the progress they have made and what specific plans they have for the following year in order to continue to be funded.

4.2 Developing Evidence to Inform Decisions re Effectiveness (DeCIDE) - USA

  Agency for Healthcare Research and Quality

This is a network of research centers that AHRQ created in 2005 to generate new knowledge. This network, comprised of 13 centres, conducts accelerated practical studies about the outcomes, comparative clinical effectiveness, safety, and appropriateness of health care items and services. The network is comprised of research-based health organizations with access to electronic health information databases and the capacity to conduct rapid turnaround research.

As opposed to the CERTs program, the research centres do not conduct research on particular themes nor is it usually a collaborative program. In fact, for each project that needs to be done, all centres are invited to apply and one centre is chosen by the Department of Health and Human Services - i.e. each project is a 'one-off' study with tight timelines. The network is comprised of those centres that were initially determined to have the proper infrastructure (access to an integrated health database and sufficient, proven expertise).

The initial priorities of the program focused solely on conditions that are common and costly. All of the projects were identified internally by the Department of Health and Human Services according to their own priorities. It is anticipated that a broader input into project selection will be in place within 1 to 2 years.

4.3 Intensive Medicine Monitoring Program (IMMP) - New Zealand

The New Zealand Intensive Medicines Monitoring Programme (IMMP) was established in 1977 to enhance monitoring for previously unrecognized adverse drug reactions associated with selected new medicines. This involved establishing cohorts from prescription data and collection of event information - Prescription Event Monitoring (PEM). In the IMMP, PEM cohorts are established using information, supplied by pharmacies, from prescriptions for medicines that have been selected for monitoring. Events are identified subsequently from follow-up questionnaires to prescribing physicians and from other sources, including spontaneous reporting of events. High quality event reports are obtained from multiple sources including follow-up event returns from prescribers, reports received through the national spontaneous reporting program, prescription returns and from record linkage to other databases. Collaboration with other national centres and with the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring enables information on cases from their databases to be used in validation of IMMP signals.

The program has also made significant contributions in determining the incidence of certain adverse drug reactions and in carrying out in-depth epidemiological investigations relating to the safe use of medicines. New Zealand is a small country (approximately 4 million) and thus communication is relatively easy. This facilitates good rapport with prescribing doctors. However, mainly because of the small population, several years may be required to achieve a large cohort. Although this has drawbacks in terms of rapid results, it enables a longitudinal approach to prescription data analysis, including aspects of prescribing such as reasons for cessation of therapy and changes in prescribing practice.

4.4 Web-based Visual Data Mining Environment (WebVDME)- USA

In 2003, the FDA's Office of Drug Safety entered into a Cooperative Research and Development Agreement with Lincoln Technologies, Inc., MA to develop a Web-based Visual Data Mining Environment (WebVDME) for safety signal detection using data from the FDA's adverse event reporting system. The main goals were to create a user-friendly program for safety evaluators and epidemiologists to enhance efficiency of signal detection / evaluation; and to determine appropriate applications of the system. The tool is funded by both GlaxoSmithKline and FDA. The Medicines and Healthcare products Regulatory Agency (MHRA) of the UK has also signed a license with Lincoln Technologies, Inc. for the installation of Lincoln's WebVDME pharmacovigilance signal detection and signal management software at MHRA.

4.5 Research on Adverse Drug Events and Reports (RADAR) - USA

The RADAR project seeks to describe previously unrecognized, serious adverse drug events and identifies new patient populations at high risk. The project focuses on identification, evaluation and dissemination of information describing serious adverse drug events characterized as those resulting in death, severe organ failure, or precipitating major therapeutic interventions. The program is funded by grants from National Heart, Lung and Blood Institute, the National Cancer Institute, the American Cancer Society and the Department of Veterans Affairs.

The project, centered out of Chicago, is led by a hematologist / oncologist / health services researcher and consists of 25 core investigators located at VA and academic medical centres in 5 cities. An investigation is initiated when a clinical event that represents a possible occurrence of a serious adverse drug event is seen by a RADAR co-investigator or reported to a RADAR co-investigator by unaffiliated physicians. Several of their investigations have led either to "black box" warnings or withdrawal of the product from the market.

A key component of this proposed program is the ability to access integrated health databases. There are several health databases now used by either large health care organizations in the U.S. or by national health programs. The UK General Practice Research Database (GPRD) is an example of a system that has brought about linkages via electronic health records, and in doing so, increased the ability of researchers and policy makers. Another example, US Health Maintenance Organization (HMO) Kaiser Permanente, has large data sources collected via electronic health records since 1954. Both these systems are well developed with respect to measuring outcomes. Both have been used for individual projects by researchers or by organizations such as the National Institute for Clinical Excellence (NICE) when conducting drug reviews. However, both are recognized as having major limitations when compared with the potential of data derived from Canadian, population based resources. That is, a patient in a US HMO may well go outside the HMO for treatment of some conditions. These treatments would not be covered in the HMO database. Also, HMO databases typically cover the healthy working population, a population which may be very different from the broader population being prescribed a drug. Neither of these limitations affect the potential for assessing drug safety and effectiveness in Canada.

5.0 A Canadian Solution

5.1 Vision

Health Canada has a clear regulatory responsibility regarding the safety and efficacy of medicines and their use in Canada. This includes both pre-market approval and, following market authorization, post-market safety surveillance. However, as was noted, in Section 3.0: Issues with Drug Information in Canada (RWS&E) there are critical issues for Canada and Canadians regarding Real World Safety and Effectiveness of medicines, post-market.

The RWS&E Working Group of the NPS proposed a national initiative to address these issues. The initiative as proposed was comprised of two components - an Oversight Committee representing key stakeholders and a network of research centres of excellence.

The following were the fundamental concepts behind this vision:

1. The Oversight Committee would be responsible for setting priorities for research and providing mechanisms for input from affected stakeholders. The research priorities would fill information gaps for Health Canada and the provinces and territories to make evidence-based decisions about drug policy; and for health care providers and patients to make evidence-based decisions about the prescribing and use of medicines on a day-to-day basis.
2. The research would be undertaken by a strong, effective network of pharmaceutical research centres of excellence that function in a collaborative, coordinated manner, which is different from the current competitive funding models. The primary purpose of this network would be to produce evidence-based information from post market studies that will assist health care providers and patients to make informed decisions about prescribing and use of medicines on a day-to-day basis, and will help Health Canada and the provinces make fact based decisions about drug policy that will improve the health of Canadians..
3. Linking the above two principles, and respecting the regulatory role of Health Canada, there is a need for an effective feedback loop / mechanism between the oversight body and the network, as the network's investigations will likely identify emerging information needs or other signals that in turn could become future priorities.

This chapter outlines the vision for the program in greater detail.

5.2 Mission

The mission of the proposed program would be as follows:

To expand the body of evidence on the safety and effectiveness of medicines in a real world context, through a comprehensive, trusted national program that will provide timely and high quality information upon which policy makers, healthcare providers and patients may make reasoned decisions. To increase capacity, within Canada, to undertake quality research into the real world safety and effectiveness of medicines.

A national network of pharmaceutical research centres of excellence will develop trusted evidence to support pharmaceutical policy decisions and related treatment practices, under the guidance of a national oversight body, that will identify gaps in knowledge, evidence and information, and prioritize areas for research.

5.3 Program Objectives

The objectives of the program would be to:

• Identify gaps in information on the safety and effectiveness of medicines in a real world context.
• Research and make available evidence on the safety and effectiveness of medicines to health care practitioners, patients and policy makers.
• Provide a streamlined process such that critical issues can be addressed promptly.
• To develop research capacity throughout the country, including
  • Additional researchers, clinicians, analysts etc.
  • Enhanced training and mentoring programs to develop the needed skills.
  • Potential new research centres in the longer term (eg. a centre based in the Atlantic Provinces; a centre focused on the unique needs of the First Nations people).
• To develop new and enhance existing national and international partnerships to share information and research
• To improve the effectiveness of the national research effort through expanded collaboration

Privacy of individuals and the confidentiality of their information will be a considerable challenge for this program. "Network based" research will require agreements for data sharing across jurisdictions. This issue will have to be addressed for the program to succeed.

Knowledge Transfer, particularly as it relates to the effectiveness of the program in informing policy decisions and in changing treatment practice patterns, is a critical element of what this program will set out to achieve. However, it is a large and complex issue and will be addressed in detail outside the scope of this business plan.

5.4 Differentiators

As has been noted, considerable investment is already being made in Canada in research into the safety and effectiveness of medicines, post market. It is therefore reasonable to ask how this initiative would be different from the current work being done at McGill University, the University of British Columbia, the University of Manitoba, the Institute for Clinical Evaluative Sciences, McMaster University and other such institutions.

The key difference is in focus:

• This initiative will be focused on post market safety and effectiveness of medicines. All current programs address a far broader universe of research topics relating to healthcare. Research into the use and effect of medicines is simply one aspect of much larger programs. There is no specific priority given to research into the post market safety and effectiveness of medicines.
• The program is not just about answering ad hoc questions through research. Rather it is a formal program to co-ordinate and direct research to fill the most pressing gaps in evidence. The research will be prioritized and directed by a broad cross section of stakeholders interested in the results.
• The program will have a goal to build research capacity - to increase the number and the skills of researchers, including clinicians, clinical pharmacologists, database analysts, nurses, etc.
• The program will be organized to respond to urgent needs promptly, to get needed answers fast where feasible.
• The program will focus on collaboration between and among research centres - competition for resources and funds will be curtailed. This collaboration will have numerous benefits:
  • The strength and breadth of the evidence has the potential to be greater with participation of multiple jurisdictions and / or centres (more data / different populations)
  • The resources from multiple jurisdictions and / or centres will allow faster response and provide better access to data.
  • The opportunity to assess some health policies related to drugs: which ones work and which ones do not.

In addition to these differences, the program will be able to focus on research:

• Where more than one stakeholder requires the information - thereby avoiding potential duplication of research in different jurisdictions.
• Where there is only a small population affected by a drug issue and/or the local province or territory does not have the resources to do the research alone.

5.5 Structure Components

The two part structure to the program as envisioned by the RWS&E Working Group was reviewed and more details incorporated. These details address the operational issues of the program.

This expansion and the assignment of functions to the various organizational components of the program (refer to Sections 5.5.1 through 5.5.4) are provided for clarity and to create a basis upon which to determine costs. The detail is subject to modification when implemented.

The following figure identifies the major program components / members.

5.5.1 Stakeholders

The Stakeholders represent the parties in Canada which would have a vested interest in the success of the program. These include Health Canada; representatives of the Provincial and Territorial Ministries of Health; Patients; Health Care practitioners; the Common Drug Review program; Researchers; representatives of Drug Manufacturers and the Insurance Industry; and representatives of the International Stakeholders who might use the network and fund specific research.

It is the stakeholders who would suggest topics for research and who would seek the results of the projects undertaken. It has been suggested that an annual conference might be held to review the research results from the past period and to solicit ideas on priority areas of concern needing study.

5.5.2 Oversight Committee

Function
The Oversight body is a committee of representatives of the stakeholders. The Committee would:

• Set the strategic direction for the network.
• Establish priority research areas for the network in order to direct the overall program.
• Rank projects and select those which will be funded (NB: after some experience, it may be feasible to delegate some of this responsibility to the Scientific Director under the appropriate controls).
• Balance projects approved with research resources available.
• Provide Budget guidance and approve major expenditures.
• Review and approve the criteria for selecting research centres for funding within the network.
• Host an annual forum of the stakeholders to seek input on research priorities and to disseminate information on results from the research underway.
• Evaluate the performance and the progress of the program. And,
• Evaluate the performance of the Scientific Director.

Membership
Committee Membership should be limited to between 12 and 15 representatives of the stakeholders. While the ultimate membership needs to be decided by the program management, the following is based on input from the Key Informants and the Project Authority Advisory Committee:

• Representatives of Federal, Provincial and Territorial Drug Plan managers;
• Representatives of Health Canada's Regulators (Pre and Post market);
• Patient representatives;
• Health Care practitioners;
• Representatives of the Manufacturing and Insurance Industries;
• Researchers / Clinicians
• Representative(s) of international partners

The Scientific Director would attend meetings ex-officio. An international expert in post-market Pharmacosurvellance might be included.

Note that the Health Products and Food Branch has a regulatory mandate to follow-up and examine issues related to drug safety.

Selection of Members
At the outset of the program, the program implementation team would seek membership nominations from the noted stakeholders. Subsequently, the Committee would itself organize and manage the process to select members. In seeking nominations for non-government members, the selection team would consider approaching associations that represent the stakeholder group. It would be requested that individuals with a broad and unbiased perspective of the issues might be selected rather than individuals who have a vested interest in specific outcomes.

The selection of individuals to serve on the committee should be based on criteria such as the following. The individuals should:

• Understand the issues important to the identified stakeholder;
• Have knowledge of the issues with real world safety and effectiveness of medicines;
• Understand the importance of research and the need for knowledge transfer;
• Be able to function collaboratively in a committee;
• Avoid advocacy, but operate to the benefit of all Canadians; and
• Have a record of accomplishment, leadership and integrity recognizable by others.

Operational Issues
The term in office was suggested to be two to three years. The initial Committee members should be asked to sign on for terms of different lengths so that the committee would not turn over all at the same time. Members would have the option of a renewed term if offered by the Committee.

It is suggested that that the Oversight Committee meet quarterly face-to-face and by conference call as required.

5.5.3 Scientific Director and Secretariat

Function
The Scientific Director would act as the scientific administrator for the network and the program. The Director would also support the Oversight Committee by providing Secretariat services to the Committee.

The Scientific Director's functions would include but not necessarily be limited to:

• Research Network Management Functions
  • Implement the vision for the Network.
  • Manage the network:
    • Implement the selection and funding of research centres through a formal Request for Application process.
    • Review the annual plans of the funded centres.
    • Review and approve the budgets and accounting for the centres.
    • Evaluate the centres' contributions.
    • Oversee the process of inclusion to ensure there is collaboration among centres.
  • Manage the projects:
    • Assist the Oversight Committee in prioritizing research projects (gather input, organize, filter out requests that are incomplete or impractical, determine whether the project can be done within a reasonable time, determine whether the information and methodology is available to conduct the study (in conjunction with the research centres) present a draft list to the Committee.)
    • Assign research projects as prioritized by the Oversight Committee to the funded research centres.
    • Follow up projects to ensure they are managed to the approved schedule and budget.
    • Review project protocols and results to ensure appropriate quality.
    • Ensure that issues of privacy and confidentiality are addressed.
  • Other responsibilities:
    • Maintain a watching brief on pharmaceutical research across Canada to ensure that there is no duplication of research and to encourage collaboration.
    • With support from the Primary Funded Centres, monitor National and International research and signal events.
    • Financial Accountability.
    • Establishment and maintenance of a Clinical Advisory Committee.
    • Identify situations where Peer Review would be helpful and organize such a review.
    • Ensure proper dissemination of results.
• Secretariat Functions
  • Co-ordinate Committee Meetings;
  • Draft and maintain a strategic plan based on input from the Oversight Committee;
  • Evaluate program performance through the establishment and maintenance of indicators of the effectiveness of the network, including Knowledge Transfer;
  • Knowledge Transfer.
• Clinical Advisory Committee
  

  The Clinical Advisory Committee is a body of experts in the field of Pharmacosurveillance and drug focused research which will provide advice as and when requested to the Scientific Director and the Oversight Committee. The committee members will include recognized national and international experts from a variety of disciplines with extensive experience. Among other possible roles, the Committee will:

  • Provide input to the Scientific Director and Oversight Committee on international and national pharmaceutical research;
  • Advise on potential priorities for research;
  • Undertake Peer Reviews of research protocols and / or research results as required.

Scale of Operation
The functions of the Scientific Director are far too large to be handled by one individual. An "Office of the Scientific Director" would need to be established with appropriate resources.

5.5.4 The Network

There are numerous research centres and informal networks in place across Canada that are capable of undertaking post market research into the safety and effectiveness of medicines. For this program, the centres will be classed into to two groups:

• Primary Funded Research Centres, and
• Project Funded Research Centres.

Primary Funded Centres
The Primary Funded Centres will be selected through a Request For Application (RFA) process managed by the Scientific Director. There will be a discreet number of such centres selected at the outset (possibly 3 to 4), but the total number may be expanded as the program proves successful.

These centres will undertake direct responsibility for research, capacity building, and collaboration and be accountable for meeting agreed objectives in each area. Regarding the research findings, these centres will be responsible, in part with the Scientific Director, for Knowledge Transfer. (As noted in Section 5.3, Knowledge Transfer will be the subject of a separate Business Plan). These centres would also be accountable to the Scientific Director for managing and reporting on the funds provided with appropriate accounting techniques.

Following the RFA process, the selected centres would be provided core funding for 3 to 5 years, after which, they would have to re-apply for the contract and funding to continue. This core funding would be incremental to current funding received by the centre. It would not be used to replace other sources of funds. The funding would be used to manage the Pharmacosurveillance network research program in the centre and the projects assigned; to build the resource base of researchers and support personnel to undertake these assignments; to undertake and contribute to environmental scanning of pharmaceutical issues nationally and internationally; and to undertake a number of small research projects (such as observational database studies) directly. The majority of the funding for projects will be provided separately by the Oversight Committee based on the requirements of priority projects.

Theme Based Research Centres

Within the CERTS model in the USA, each research centre focuses on a specific theme - bone disease; diseases of women; cardiac research, etc.

The perspective is that within Canada, it may not be practical to have specific centres focus on a single theme at the outset.

For this reason, it is suggested that the Primary Funded Research Centres first be set up to do research projects appropriate to the resources available - that they generalize and collaborate with other centres to gain the data and skills required. After several years experience, this approach should be reviewed.

The criteria for selecting the centres for core funding would be based on such factors as:

• The experience of the proposed research team in the study of medicines post-market;
• The experience of the proposed team with one or more research methods (access to and analysis of observational data; development and operation of registries; randomized controlled trials; etc.);
• Existing capacity as well as plans for building capacity;
• The cost proposed and the relevant substantiation; and
• The reputation of the organization and proposed resources.

Project Funded Centres
The Project Funded Centres are those centres which do not seek or are not selected as a Primary Funded Research Centres. These centres may have specialized expertise and may be asked to undertake discrete projects by the Scientific Director or to participate in a larger project undertaken by another centre. These centres would be provided project funding as needed to fulfill the specific project requirements.

These centres would have the opportunity to apply for funding as a Primary Funded Research Centre under the RFA process at the outset of the program or at a later date if the program is expanded.

5.6 Operational Flow

The business flow of the network as relates to the prioritizing and performing research projects is shown in summary form in the diagram below.

The operational flow model is based on the concept that this is a stakeholder driven research program:

• Stakeholders generate ideas for research - they identify gaps in evidence from their unique perspectives. As they have the greatest stake in the success of the program, they are uniquely suited to participate in the Oversight Committee as full members.
• The Oversight Committee establishes criteria for ranking research and ensures that the most relevant research (relevant to the stakeholders) is carried out. (The ranking process is described in Section 5.7). The committee establishes targets for the development of research capacity and monitors the adequacy versus the demand. The committee takes overall responsibility for Knowledge Transfer and ensures that results are made available to the stakeholders promptly and in a manner suited for its dissemination and use.
• The Scientific Director is the agent of the Oversight Committee. The Director will:
  • Implement the vision for the network
  • Filter the project suggestions from the Stakeholders, ensuring that the projects are doable, and draft a list of research projects with a suggested priority for consideration by the Oversight Committee.
  • Set up and manage the flow of the projects to the centres and the flow of evidence back to the Stakeholders.
  • Have the option of directing the projects to Primary Funded Centres or, if more appropriate, to a Project Funded Centre. The latter is to allow the Director to take advantage of specialized data sources and skills as required.
  • Review research results and ensure timely dissemination - developing and investing in tools appropriate to the stakeholders needs (Knowledge Transfer).
  • Establish and monitor targets for capacity development within the Primary Funded Research Centres.
• The Network will:
  • Undertake the research, developing protocols, establishing data sources and partnerships with other centres, managing the process and delivering quality results.
  • Build a resource base of data and capable researchers (clinicians, analysts, nurses, etc.) to handle the demand for services.

5.7 Priority Setting Processes

As noted in earlier sections, there are significant gaps in the evidence on the safety and effectiveness of medicines in the real world context. In addition, new medicines and new uses for existing medicines are approved regularly, so the gaps are both widening and growing in number. The resources (both funding and skills) needed to fill the evidence gaps are so great that research will have to be focused on the areas of greatest need. Priorities will have to be established - the main responsibility of the Oversight Committee. But how should that be done?

There is no unique formula for a prioritization process with respect to research. There is no checklist or point weighted system that would magically rank projects after completing tables with questions related to the various projects. Indeed there is a great degree of subjectivity in the processes used by organizations faced with the same challenge today... The proposed project is "doable" or not; the cost is within reasonable limits or not. However, after passing the test of practicality, project submissions will have to be assessed by knowledgeable people based on a list of characteristics - each reviewer using his or her own judgement.

In the context of research into the real world safety and effectiveness of medicines - post market - the "do-ability" factor would be initially judged based on:

• The clarity of the research question;
• The availability of the appropriate data (whether inside or outside of Canada);
• The methodological approach (the research protocol);
• The cost and timeframe for response.

These factors are readily evident and the assessment could be done by the Scientific Director. The characteristics to be used for final assessment are a different matter.

At the workshop for Research Priorities for a Drug Safety and Awareness Network held in May 2006, Dr. Jan Hux of the Institute for Clinical Evaluative Sciences and Dr. Steve Morgan of UBC spoke to the need to establish characteristics for evaluating project proposals when setting priorities.

Dr. Hux proposed a series of characteristics for identifying possible projects to be considered by the workshop participants. She addressed Primary and Secondary Characteristics. The Primary Characteristics were:

• Safety: Relating to the health risk associated with the use of a drug or drug class;
• Effectiveness: Relating to the health benefits provided by the drug or drug class in the "real world";
• Cost: Relating to the cost effectiveness of the drug relative to other agents used for the same indication, and/or the cost implication of current utilization patterns;
• Multi-Jurisdiction: The question can be examined in multiple Canadian jurisdictions or by comparison between jurisdictions;
• Timely Results: The primary results will be available in a 1-3 year window.

The Secondary Characteristics were:

• Chronic Disease: The study would examine the pharmacologic management of a prevalent chronic disease (in other words the results could have wide impact);
• Vulnerable Population: The study would focus utilization, safety and outcomes in an identified vulnerable population (eg. the elderly);
• Product Novelty: The study would address a novel product on the market for less than five years.

Dr Hux anticipated that few projects would have all the above characteristics and that individual projects would not be selected on satisfying the greatest number of the characteristics. Rather, she suggested that considering these characteristics would be be helpful in identifying high priority projects.

Dr. Morgan's suggested a slightly different set of characteristics to consider:

• Product Novelty (how does this affect baseline evidence on efficacy; comparators or treatment alternatives; future use of or exposure to a class of medicines);
• Disease (acute, chronic; severity and prognosis; etc.)
• The population affected (small, large, particular ages, race, familial patterns, etc.)
• Safety (has a particular concern been identified? Can the risk be assessed?)
• Effectiveness (has an efficacy - effectiveness gap been identified? What is the degree of uncertainty? What factors are believed to influence/inhibit effectiveness?)
• Cost and Cost-effectiveness (has a specific cost issue been identified? Eg. System sustainability, burden to specific payers, cost-effectiveness compared to alternate treatment options; contextual - is there a broadening indication or off-label use?)
• Jurisdictions (have specific regional issues been raised or could the subject be studied in multiple regions?)
• Timely results (what is the time frame for results? Quick; 2 to 4 years; greater than 4 years)

Beyond the suggestions of Doctors Hux and Morgan, other characteristics suggested at the workshop included:

• The potential implications for related products / medicines; and
• The implication on patients if the research result were to lead to withdrawal or limitation on use of the product.

Dr Morgan noted that "characteristics" simply:

• Illustrate and legitimize a variety of priorities;
• Provide transparency for 'weighing tradeoffs';
• Clarify general themes of importance; and
• Assess feasibility.

In other words, there is no exact science to prioritization, but rather, the use of characteristics provides guidelines for a ranking or for assessing the rankings of projects deemed "doable"

The Oversight Committee, with its representation of stakeholders from all facets of the health care continuum, will have to establish its own criteria for assessing proposed research projects. Once established, the criteria will only provide guidance. The ultimate ranking will have to be done based on the experience and sensibilities of the committee members.

It should be noted that in the first few years of operation of the program, and until the prioritization process is fully established including all processes for identifying potential research topics, the priorities will have to be set based on the input of the Scientific Director and the research centres, and the knowledge of the Oversight Committee members.

Further information on the Priority Project Workshop may be found in Section 8.0: Priority Projects. The project selection criteria used for that workshop are fully defined in that section of the report.

5.8 Program Evaluation

The research network will, like all new programs and initiatives, be evaluated at some juncture to assess its contribution; to determine if it requires changes to be successful; and to assess whether it merits continued financial support. Key Informants overwhelmingly recommended that key success factors be established well in advance so that the stakeholders and members of the network clearly understand the expectations of the program.

There were numerous suggested measures for evaluating success:

• Expanded capacity
  • more researchers, better trained, with better access to improved data sources;
• Timely results
  • Projects having some urgency are started promptly;
  • Projects have a short turnaround time or have interim deliverables that inform stakeholders of progress and provide an indication of results;
• Quality results
  • Results are accepted for publication and, when required, satisfy a Peer Review;
• Useful results
  • Research results in better informed decisions - revised or new policies; changes in treatment patterns; etc
• Available results
  • Research results are promptly available through a variety of vehicles such as a program web-site; program newsletters; directed mailings to special interest groups.

The criteria for success and the basis for evaluation of the program will have to be established early on in the evolution of this initiative. For each criteria, specific measures need to be established and agreed.

5.9 Compelling Cases

Gaps in evidence and information relating to the real world experience with the safety and effectiveness of medicines can have a significant impact, both human and financial, on Canadians.

To illustrate the impact of this lack of evidence and information, as well as the benefits of a managed program of pharmacovigilance and post market surveillance, three "compelling cases" were identified, analysed and documented. These cases identify medicines which were proven safe and effective in Clinical Trials but which proved to have unexpected results in the real world. The human and financial impacts were analysed and documented, as were the potential benefits if the issue had been identified and researched sooner. More detailed accounts of these cases may be found in Appendix 2: Compelling Cases

Vioxx®

The first case, Vioxx®, demonstrates how a research network, as proposed, can assess the validity of benefits seen in Clinical Trials and identify significant negative side effects of the new medicine in a real world environment sooner than under current practice.

Vioxx® was approved by Health Canada in 1999 for the relief of acute adult pain. At that time, the existing alternatives were naproxen, ibuprofen, aspirin and other such nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical trials of Vioxx® seemed to indicate a reduction in gastrointestinal events - a problem with the existing therapies. Upon approval and listing, the use of the drug grew rapidly.

After a number of years on the market, it was determined that patients taking Vioxx® had an increased chance of suffering from serious cardiovascular events while gaining no significant reduction in gastrointestinal bleeds. After approximately four years, Vioxx® was voluntarily removed from the market.

Had a research network as described in this plan been available, this particular medicine would likely have been selected for Post Market surveillance due to the large number of potential users, the availability of a broad variety of alternative therapies and the price premium for this new drug. After an 18 month review, the cardiovascular risks associated with Vioxx® could have been identified and reported. With this information, the ultimate harm caused by the drug may have been reduced as one or more of the following could have been undertaken:

• more restrictions could be placed on the types of patients for which the drug was approved;
• further research re patient safety issues could have been required;
• changes could have been made to medication labels; and
• letters could have been sent by the manufacturer to physicians warning of the risks.

Gatifloxacin

The second case, gatifloxacin, demonstrates how the impact of adverse events that are not observed in clinical trials can be minimized by a research network as proposed.

Gatifloxacin was approved for marketing on February 21, 2001. It belongs to a class of antibiotics called fluoroquinolones - a popular choice for a variety of community-acquired infections even though there is insufficient evidence of their benefit relative to other available antimicrobials.

From 2001 to February 2003, Health Canada received 28 reports of abnormal glucose metabolism associated with gatifloxacin. The initial 28 cases reported to Health Canada were deemed serious and possibly life-threatening.

Had a research network as described in this plan been available, gatafloxacin would likely have been selected for Post Market Surveillance since several fluoroquinolones had been reported to cause serious adverse events - in some cases leading to the drug being withdrawn from the market.

Gatifloxacin was taken off the market in April 2006. Earlier analysis would have identified the extent and risk of its use and would have probably resulted in earlier warnings, restrictions or delisting of the product. In addition to avoiding significant morbidity and mortality, there would have been an economic benefit since other effective treatment options were available at up to one-half of the cost. Further, there would have been decreased hospitalizations and emergency room visits, saving, up to 3 million dollars annually in the Canadian health care system

Estrogen Therapy for Postmenopausal Women

The third case, Estrogen Therapy in Postmenopausal Women, demonstrates the importance of conducting the appropriate type of trial to determine whether the use of a drug can be definitively linked to suspected beneficial or harmful outcomes.

A number of studies using observational databases had demonstrated that estrogen therapy provided a range of benefits such as significantly lower rates of coronary heart disease. There were a variety of other related benefits and harms observed. The evidence indicated that estrogen therapy provided much greater benefit than risk at a very low cost, resulting in a number of clinicians advocating the use of estrogens routinely in post-menopausal women even when women were not seeking therapy.

In a series of Randomized Controlled Trials in the USA, strong evidence was observed that long term estrogen therapy will actually result in more harm than good, the opposite of what the observational studies seemed to indicate. The trials also noted that sub-populations of those treated are at differing risk of developing problems from estrogen therapy.

Had a research network as described in this plan been in place, estrogen therapy would likely have been selected for Post Market Surveillance due to the number of factors:

• The large population affected (post-menopausal women);
• The potentially important preventative strategy affecting leading causes of morbidity and mortality;
• The suggestive evidence of protective effect against several conditions (e.g. osteoporosis and coronary heart disease) but with potential offsetting adverse effects (e.g. breast cancer); and
• The lack of interest by the private sector for the topic (low cost drug and a high cost of the Randomized Controlled Trial).

6.0 Funding Concepts

How does one establish the cost of a research network for the safety and effectiveness of medicines as outlined in this Business Plan? The cost of operating an Oversight Committee and the office of the Scientific Director (including the Secretariat) can be established through estimating techniques relevant to the function of these business units. However, the cost of the network of centres is directly proportional to the number and scale of the projects approved as well as the targets for development of research capacity. The question then is "How much money will it take - how much should we budget for?"

There is no organization or network, either national or international, which exactly reflects the Canadian Vision, so comparisons have little value. In approaching the Key Informants and the members of the Project Authority Advisory Committee, most were unwilling to provide a budget number. Nevertheless, one suggestion was made. If we were to budget 0.1% of all the money spent on drugs in Canada in a year, we would have an annual budget framework of approximately $21 million. This level of funding was not considered unreasonable.

6.1 Funding Elements

There are four elements to this program which require funding:

• The Oversight Committee will require funding for a minimum of four meetings per annum. Funds would be required for travel; conference rooms; audio visual aids; etc. The funds may be managed by the Secretariat under the Scientific Director.
• The Scientific Directorwill require funds to establish the network (the RFA process); to operate the network (assigning projects to centres, reviewing results, knowledge transfer); to manage the finances (budgets and utilization); to peer review protocols and results when required; support the Oversight Committee for Strategic Planning, monitoring international and national events, etc.; legal services, information technology, et cetera.
• The Primary Funded Centres will require funds for capacity development including training and new research staff (program manager, clinicians, nurses, data analysts and database technologists among others); development of data sources; creation of local networks; equipment, floor space and supplies. Each centre will have unique needs to reach a position where it can contribute. The centres will outline their specific plans in response to an RFA. This funding is core funding and will ensure that the centre has the capacity to deliver on the capacity development and research objectives. The core funding will cover some relatively small studies, but projects will largely be funded from Project Funds.
• Project Funds are required to undertake the specific projects as approved by the Oversight Committee. As the cost of research projects can vary from $5000 to multi-millions, it would be inappropriate to allocate all project funds directly to the centres as part of their core funding. These funds would be allocated to the centres as projects are assigned. Over time, funding levels for specific types of projects (database projects, registries, and Randomized Controlled Trials) may emerge.

6.1.1 Program Fund Sources

The program will principally be funded by governments (federal, provincial and territorial) which have a major interest in the safety and effectiveness of drugs in the post marketing period. However, the manufacturing and insurance industries may wish to participate in project funding on a one-off basis where there is a particular interest. Such funding would have to established at 'arms length' to ensure that the research is not perceived to be biased in favour of the funding source.

Our contact with international organizations indicates great interest in this program from several perspectives. First, it is an opportunity to evaluate different health policies and its impact on outcomes and cost. Second, the integrated drug/health databases available in Canada are recognized as some of the largest and richest sources of data in the world. Although Canada accounts for only about 2% of the world's consumption of drugs, the ability to track the experience of all those who use (or don't use) specific drugs through hospital, physician, nursing home and home care records provides the opportunity to understand safety and effectiveness issues not available elsewhere. International research based organizations may well fund research in Canada and / or pay for access to the data.

6.1.2 Project Funding Baskets

Project Funds will ultimately be the largest component of the program cost. While the program is designed to meet the needs of a broad range of stakeholders, the primary funding agents, with responsibility for approval and listing of medicines, may have urgent needs for research targeting drugs for which certain adverse events have been observed. In such situations, the normal process used by the Oversight Committee for prioritizing and selecting projects will not be adequately responsive.

To address this issue, some or all of the project funding could be divided into baskets for specific purposes:

• Safety issues;
• Effectiveness issues;
• Other.

Each basket would be overseen by the Committee and managed by the Scientific Director on behalf of the stakeholders and funding agents.

Should this approach be pursued, the final decision on the number of baskets and purpose of the basket would be decided as part of the evolution of the program.

6.2 Funding Parameters

This section of the business plan is intended to provide a sense of the scale of the program cost. Detail program costs are provided in Section 7.0: Organizational Options.

1. Oversight and management costs
   This component consists of the costs of the Oversight Committee, the office of the Scientific Director and the Secretariat. These costs will in large part be dependent on the ultimate organization and governance option chosen and will be detailed in Section 7. Nevertheless, the total cost of this element will be less than 20% of the total cost of the program
2. Primary Funded Research Centres
   

   As each Primary Funded Centre will have different needs in order to grow to meet their commitments in achieving the program objectives, it was not practical to develop a single generic cost model to reflect the needs of all of the centres. Several models were developed with input from various research centres. Despite the differing needs, the estimates produced similar results with the average approximately $760,000 per annum.

Some Centre Costs

• Resources
  Senior Scientist, Analysts, Nurse, Statisticians, Programmers, Graduate Students
• Operating Needs
  Administrative support, space, furniture, equipment, supplies, overhead (eg. benefits) travel, etc.

These numbers were further compared to the cost of CERTS centres in the United States. While the overall CERTS program differs from the Canadian vision, the individual centre responsibilities are comparable. For that reason the CERTS experience was considered valuable as a comparator. The funding to individual centres has grown over the years since the inception of the program from approximately $640,000 per centre per year to the current level of $1,000,000 per centre per year. Funding however, includes extensive knowledge transfer functions including development of training programs for use by the decision makers impacted by the research findings.

The current vision is that the Canadian program should start with four centres funded for 3 to 5 years. The proposed cost would be $800,000 per centre per year, for a total annual cost of $3.2 million

1. Project Costs
   The project funding requirements are difficult to predict. Depending on the type of study to be undertaken, the costs can range from several thousand dollars for a straightforward analysis of data from Observational Databases to $1 million and up for a study requiring the establishment of a registry or a randomized controlled trial.
   
   The four Priority Projects selected in the workshop on May 2006 were estimated to cost $5,046,000 to $7,046,000. It was indicated that approximately $3 million would be required to undertake these projects in the first year.
   
   For planning purposes, it would appear appropriate to allow for project funding of $3 million in year 1, growing to a minimum of $15 million by Year 5. It should be noted that the $800,000/centre/year also accommodates some ability to conduct smaller projects.

6.3 Growth

The program funding requirements will grow over time. There are two principal reasons for this.

• First, there will be substantial lead time needed to establish the organization entities including the Oversight Committee, the Office of the Scientific Director and the Primary Funded Centres before significant project money will be required.
• Second, there is currently quite limited capacity in the existing research centres to take on substantial new research under this program. The funded centres will require time to set up their internal infrastructure and to commence the development of their own capacity to take on new studies.

The attached diagram summarizes the growth model. Funding will grow as the Office of the Scientific Director is fully staffed and as the Primary Funded Centres execute their plans for capacity development. It would take approximately three years to reach the targeted capacity for the anticipated workload. It should be noted that expansion of funding beyond Year 3 would be based on the number and scale of projects approved by the Oversight Committee and the funding available.

Year 1
In the first year after funding approval, the program focus will largely be directed to establishing the program. This would include such tasks as:

• Creation of the Oversight Committee and Office of the Scientific Director;
• Staffing key positions;
• Establishment of the Program Evaluation Criteria;
• Creation of the RFA for the selection of the Primary Funded Research Centres;
• Selection of the first centres, commencement of the centre plans for developing capacity;
• Assignment of the Priority Projects to the funded centres.

Year 2
In year 2, the focus would be:

• Completion of the organizational work and staffing commenced in year 1 (Office of the Scientific Director and the Primary Funded Centres);
• Continuation of the Priority Projects;
• Commencement, by the Oversight Committee, of the process to identify information gaps; document needed research projects; establish priorities and rank proposed studies;
• Some project requests will be directed to the Primary Research Centres.

Years 3 through 5
Year 3 would see a continued growth in the research being undertaken and performed:

• Elements of the Priority Projects would be completed;
• New prioritized research projects would be assigned to the Primary Funded Centres;
• Research capacity would continue to grow;
• The concept of themes for the centres would be considered

In the fourth and fifth years, funding would either stabilize at the Year 3 level or expand based on the priority projects approved and the funds available. In the fifth year, the program would be evaluated to assess performance and to give consideration to extending the program.

7.0 Organizational Options

7.1 Overview

The vision for the Oversight Body and Research network, as outlined in Section 5.0: A Canadian Solution, is a conceptual model. This section of the business plan addresses the organization structure, governance, accountability, costs and benefits needed to implement the conceptual model.

Only three components of the program (as outlined in Section 5.0) are being considered - the Oversight Committee; the Office of the Scientific Director and the Secretariat. The research centres are existing entities that will remain independent as outsourced centres of expertise.

7.2 Organization Options

A number of different organization models were prepared and discussed at length with the project manager and the Project Authority Advisory Committee. Two options were selected for further analysis.

A major consideration in selecting these two models was whether a net new organization was needed or desirable. The Committee was concerned with the apparent proliferation of organizations involved in the management and oversight of pharmaceuticals in Canada, and the apparent potential for overlap in function of this program with existing agencies having similar or related goals and objectives. For that reason, both organization model options show this program linked in some manner to an existing "host" agency.

The host could be one of many organizations such as the Canadian Institutes of Health Research (CIHR), or the Canadian Agency for Drugs and Technology in Health (CADTH) among others. A discussion of the potential hosts follows in Section 7.4: Options for the Host.

7.2.1 Option 1 - New Agency Co-Located with a Partner Agency

Model Description
Under this option, a new organization would be established to implement and manage the program. However, the organization would be linked to an existing host agency having compatible objectives and goals. The relationship would be one of sharing resources - the new program would not become part of the existing organization. The new organization would co-locate with the host to take advantage of professional synergies within the two teams and it would buy/share the cost of services such as Finance, Human Resources; Computer Services, Legal Counsel and other administrative functions.

The new organization would have a Board that would be drawn from senior representatives of the various stakeholder groups. The Board would function much as the Board of similar public agencies. The members would be strategic thinkers and would not necessarily be the same as the members of the Oversight Committee (where more clinical and detail knowledge of the drug programs would be required).

The Oversight Committee is a body that does not require formal infrastructure. No permanent staff will be part of the Committee since on-going support functions would be carried out by the Secretariat.

The Scientific Director would operate as the Chief Executive Officer of the organization. The Director's functions would be as described in Section 5.0. He/she would be accountable to the Oversight Committee for ensuring that only approved projects are funded. The Director would be accountable to the Board for the appropriate management of the funds, including those allocated to the centres, ensuring that appropriate financial controls are in place and executed. The structure of the Office of the Scientific Director would be determined by the selected manager.

The Secretariat would be a division of the Office of the Scientific Director. It would support the Committee and would report to the Scientific Director. The actual position of the Secretariat within the Office of the Scientific Director would be ultimately up to the Scientific Director.

The relationship between the Scientific Director and the CEO of the host organization would be one of equals. The Board and management of the host organization would have no control over the function of the new program. A contract would be signed between the two organizations whereby the program would purchase the necessary facilities and services.

Benefits
The benefits of this model are:

• Close collaboration between two programs and organizations with closely aligned objectives and goals.
• Synergy developed between the programs simply through the expedient of being co-located.
• The possibility that certain functions such as Knowledge Transfer could be combined so that there would be one public portal for related information.
• Lower costs for the new program since key infrastructure facilities and services such as the financial system, payroll, benefits programs, computer services, etc. would be provided by the host at a lower incremental cost than starting independently.
• Shorter start up time required for the new program since core facilities and services would be available almost immediately.

Negative Aspects
The negative aspects of this option are:

• No organization with related objectives and goals may be interested in providing the services on a fee for service basis.
• The divided governance may cause longer term differences in opinion where functions overlap, leading to a poor relationship and possible dissolution of the partnership.
• Few existing models.

Costs
The cost of the Board, Oversight Committee, Office of the Scientific Director and Secretariat are summarized in the following table. See Appendix 3: Costing Assumptions for detail on how the costs were generated.

No.	Item Description	Cost
One Time Costs
1	Leasehold improvements to the office space	$30,000
2	Furniture and Office Equipment	$75,000
3	Computer Equipment (Servers, desk top devices, laptops, projector, etc.)	$30,000
4	Computer Software (operating system, e-mail, database, web services, etc.)	$40,000
5	Phone System (switch, handsets, conference facility)	$5,000
6	Web site development	$75,000
7	Research Database Development	$55,000
Total One Time Costs		$310,000
Annual Operating Costs
Office of the Scientific Director
1	Salaries	$840,000
2	Benefits (13%)	109,200
3	Rent (1800 sq ft at $42 per sq ft including taxes and utilities)	$75,600
4	Telephone	$10,000
5	Supplies (Office and Computer)	$6000
6	Travel	$75,000
7	Professional fees (Miscellaneous services)	$25,000
8	Other	$15,000
9	Shared Services (finance, payroll, computer services, legal, etc.)	$50,000
10	Clinical Advisory Committee (fees and travel)	$40,000
Sub-Total Office of the Scientific Director		$1,245,800
Oversight Committee
1	Travel (4 trips, 15 people, Avg. $2000 cost)	$120,000
Board Costs
1	Travel (2 trips, 15 people, Avg. cost per person $2000)	$60,000
Total Annual Operating Costs		$1,425,800

Note that the annual operating costs reflect the costs when the organization is complete and functional. These costs will be less in the first year of operation. The costs for shared services are incremental to the host organization.

7.2.2 Option 2 - The Program Becomes Part of an Existing Agency

Model Description
This model is simply a logical extension of Option 1. Under this approach, the Office of the Scientific Director, including the Secretariat would become part of an existing organization.

The key difference in the organization structure would be that the Board of the existing agency would serve as the Board for the new program.

The roles and functions of the Oversight Committee and the Scientific Director would be as noted in Option 1. However, under this model, the Scientific Director would report to the CEO of the Host organization and a contract would not be required for the shared facilities and Services. The Secretariat function of the new program would remain part of the responsibility of the Office of the Scientific Director.

Benefits
The benefits of this option are:

• All of the benefits noted under option 1.
• A further reduction in the costs as certain facilities would not require modification or extension. (For example, there would be no need to create separate e-mail services, computer servers, web sites, instances of the financial system, etc. Administrative facilities such as reception, office supplies store, phone services, FAX and photocopying would not have to be duplicated.)

Negative Aspects
The negative aspects of this option are:

• As with Option 1, no agency may be willing to take on the added responsibility.
• The Board of the host may not be arms-length from the funding agencies and may not have the needed Stakeholder representation.
• The mission and objectives of the new program may be subsumed by those of the host.
• The chosen host may not be perceived to be effective or independent enough to the public or the stakeholders and this may reduce the effectiveness of the new program.
• Some key elements of governance and/or skill requirements may not exist within the existing organization.

Costs
The cost of the Oversight Committee, Office of the Scientific Director and Secretariat are summarized in the following table: See Appendix 3: Costing Assumptions for detail on how the costs were generated.

No.	Item Description	Cost
One - Time Capital
1	Leasehold improvements to the office space	$30,000
2	Furniture and Office Equipment	$50,000
3	Computer Equipment (Servers, desk top devices, laptops, projector, etc.)	$20,000
4	Computer Software (operating system, e-mail, database, web services, etc.)	$35,000
5	Phone System (switch, handsets, conference facility)	$5,000
6	Web site development	$75,000
7	Research Database Development	$55,000
Total One Time Costs		$270,000
Annual Operating Costs
Office of the Scientific Director
1	Salaries	$715,000
2	Benefits (13%)	$92,950
3	Rent (1200 sq ft at $42 per sq ft including taxes and utilities)	$50,400
4	Telephone	$5,000
5	Supplies (Office and Computer)	$6000
6	Travel	$55,000
7	Professional fees (Miscellaneous services)	$25,000
8	Other	$15,000
9	Shared Services (finance, payroll, computer services, legal, etc.)	$125,000
10	Clinical Advisory Committee	$40,000
Sub-Total Office of the Scientific Director		$1,128,950
Oversight Committee
1	Travel (4 trips, 15 people, Avg. $2000 cost)	$120,000
Total Annual Operating Costs		$1,248,950

7.3 Recommendation

There is no clear advantage to either organization option.

• While Option 1 implies a greater independence and possibly less interference with the operations of the Office of the Scientific Director and the Network than Option 2, there is no evidence that such interference would occur.
• The Board for Option 1 could be constituted to better represent the stakeholders and could reflect a greater "arms length" perspective to the stakeholders and public.
• There is a small cost advantage to Option 2 given the lack of a separate board for the new program and the potential for a greater sharing of common facilities such as reception, board rooms, etc.

Interestingly, when polling possible hosts, there were no strong objections to either option. One potential host noted that few organizations actually had experience selling services to another organization, so there could be some issues with that model. Nevertheless, that same organization indicated that they might prefer Option 1.

It would appear that given the lack of a clear advantage for either option, the final decision should be made by the management of the new program in consultation with the selected host.

7.4 Options for the Host

A number of organizations exist which have a mandate that overlaps with that of this program. These organizations include:

CIHR: The Canadian Institutes of Health Research
To excel, according to internationally accepted standards of scientific excellence, in the creation of new knowledge and its translation into improved health for Canadians, more effective health services and products and a strengthened Canadian health care system."

CADTH: The Canadian Agency for Drugs and Technologies in Health
CADTH is a national body that provides Canada's Federal, Provincial and Territorial health care decision makers with credible, impartial advice and evidence based information about the effectiveness and efficiencies of drugs and other health technologies.

CIHI: The Canadian Institute for Health Information
CIHI provides essential data and analysis on Canada's health system and the health of Canadians:

• Standardizing Quality Health Information
• Delivering Statistics and Information
• Health Research and Analysis

CHSRF: The Canadian Health Services Research Foundation
The CHSRF supports management of Canada's healthcare system by facilitating knowledge transfer and exchange - bridging the gap between research and healthcare management and policy.

These four organizations were approached and asked if they were interested in being considered as host for the new program. With the exception of the CHSRF, all were interested in learning more and in being considered as the host. The CHSRF indicated that its own mandate and direction precluded them from taking responsibility for a program that would involve primary research and the generation of new Information.

In order to differentiate the three remaining candidates, a number of criteria were established upon which an evaluation could be based. The following table summarizes the results:

No.	Criteria	CIHR	CADTH	CIHI
1	Experience with Real World Safety and Effectiveness issues with Pharmaceuticals.	3	3	2
2	Experienced with Primary Research on drugs - post market.	3	2	1
3	Access to data sources for research into drug utilization.	2	2	3
4	Has the knowledge and ability to assess the importance of the research results.	3	3	2
5	Has access to national and international experts in pharmaceutical research	3	3	2
6	Operates at Arms Length	2	1	2
7	Has a mandate that complements the Network.	3	3	2
8	Re Option 2 - Governance model (including board membership) should represent the stakeholders for the program - Funding agents, patients and health care providers	3	1	2
9	Has experience in capacity development	3	1	1
10	Interest in being host (*)	2	3	2
Rank		27	22	19

NB:
1. The analysis of each organization is somewhat subjective. For each criteria, each organization is assessed a score from 0 to 3 where "0" means no experience or no match to the criteria, and "3" means a perfect match to the criteria. The actual choice of a mark for a specific criteria is based on a perception of the relative strength of the three possible hosts with respect to that criteria.
2. Re "*" All three organizations expressed full support for and desire to be involved in the program. They also all expressed interest in being the host. One organization stood above the rest in its enthusiasm for the role.

Recommendation:

Any one of the three organizations would be a suitable host. Each has much to contribute to the program. However, the experience of the CIHR with its focus on research; its available clinical skills; its experience managing the funding of research, its experience in developing capacity, and its international and national reputation would make it the first choice.

8.0 Priority Projects

8.1 Background/Purpose

A workshop was held in May 2006 where key stakeholders had an opportunity to identify the top four research priorities for the proposed drug safety and effectiveness network. Prior to the workshop, input was garnered from over 100 stakeholders on potential research questions for the proposed network. The stakeholders included representatives from Health Canada, Canadian Expert Drug Advisory Committee, the provincial drug plans, researchers, clinicians, and industry and patient groups. These projects were identified as high priority by the participants and well within the capabilities of a coordinated effort of research centres.

The purpose of the workshop was to:

• Demonstrate the capacity of a research network;
• Select the current most important questions regarding real world safety and effectiveness;
• Stimulate collaboration across jurisdictions;
• Undertake projects that would generate prompt, initial deliverables as well as projects that might require an investment over years to determine long term outcomes; and
• Examine drug therapies in the context of chronic disease management, vulnerable populations and return on investment of public drug expenditure.

8.2 Priority Criteria

Listed below were the proposed criteria for choosing the four priority projects at the workshop for Research Priorities for a Drug Safety and Awareness Network held in May 2006. Of these, cost-effectiveness was considered the least important while timely results were considered the most important. Cost-effectiveness information was taken into consideration only after all other criteria had been addressed. Timely results were considered of greatest importance since the projects had to have a timeline within the proposed evaluation period of the program.

8.2.1 Product novelty

The study addresses a novel agent that has been on the market for less than five years. In this regard, questions to consider include how new is this class of drugs and how does this affect comparative and alternative treatments or safety and effectiveness at baseline. What is the future use of and exposure to the medicines?

8.2.2 Disease

The study examines the comprehensive pharmacologic management of a prevalent chronic disease. Considerations include the burden of illness, the spectrum of disease (i.e., acute, chronic, risk factor and even perhaps lifestyle), the severity of the prognosis, treatment modalities, the definition of indication and off-license uses.

8.2.3 Populations affected

The study examines utilization, safety and outcomes in an identified vulnerable population. There are two angles to this characteristic. The first pertains to small populations affected by a rare disease; and the second involves selecting something to which many people are exposed (e.g., Proton Pump Inhibitors or statins). Other considerations include race and age (e.g., increased burden, indication or outcomes) and familial patterns (e.g., uncover regional patterns).

8.2.4 Safety

The study examines health risks associated with the use of a drug or drug class. In this regard, the degree of risk is assessed as is the significance of the negative outcome (i.e., minor or major adverse event).

8.2.5 Effectiveness

The study examines the health benefits provided by the drug or drug class in the context of 'real world' use (as opposed to the context of the limited environment of the clinical trials in which the drug was first studied). Questions to consider include the following:

• Has an efficacy-effectiveness gap been identified as a concern? (e.g., is there reason to believe that a gap or a potential gap exists?)
• What is the degree of uncertainty? (e.g., what endpoints are not well established?)
• What factors are believed to influence/inhibit effectiveness? (e.g., is use/adherence a concern? Are specific sub-populations of interest? Are particular indications of interest?).
• Is there prescription 'creep'; i.e. is the drug being used for nonapproved indications?

8.2.6 Costs and Cost effectiveness

The study examines the cost-effectiveness of a drug relative to other agents used for the same indication. The cost implications of current utilization patterns can also be explored. Has a particular cost issue(s) been identified? Furthermore, is the issue a question of system sustainability? Is it a burden for particular payers? Or are there comparative or contextual cost-effectiveness issues (e.g., broadening indication or off-label use)?

8.2.7 Jurisdiction

The question can be examined in multiple Canadian jurisdictions or by comparison between jurisdictions. For example, have particular regional concerns been raised? Are there availability, access or affordability disparities by region? Similarly, can the study subject be studied in multiple jurisdictions leveraging Canada's varied coverage model (e.g., quasi-experimental design, regional capacity and receptor development on clinical effectiveness issues)?

8.2.8 Timely results

The primary results of the study will be available in a one to three year window (leveraging the low-hanging fruit concept). Participants were urged to consider if the issue is one of high priority today, or a medium (two to four years) or long-term investment (four or more years).

8.3 Projects Identified

Over 3 dozen potential projects were identified. Utilizing the priority criteria outlined above, 6 topics were identified by workshop participants. Four of these were developed into high level proposals (see Appendix). It should be noted that more detailed protocol development would be required including obtaining the buy in and support of relevant jurisdictions and stakeholders. The types of proposed studies ranged from evaluating multi-jurisdictional health databases to conducting randomized controlled trials.
The four major projects identified (most involving 2 or more separate studies), their rationale and potential impact are as follows:

8.3.1 Second Generation Antipsychotics (SGAs)

Second generation antipsychotics are approved for the treatment of schizophrenia and mania although they are increasingly used in patients with behavioural and psychological symptoms associated with dementia (BPSD), an unapproved indication. Although they have been available for over ten years, questions still persist involving both their safety and effectiveness in comparison to other older therapies. Adverse effects such as weight gain, elevated blood glucose and increased rates of diabetes have been reported in patients with schizophrenia. In patients with dementia, the drugs are associated with abnormal movements, somnolence and falls as well as conflicting reports of increased risk of stroke.

In schizophrenia the major questions are whether the marginal greater effectiveness of SGAs will be seen in actual clinical practice and whether the risks of diabetes and subsequent cardiovascular disease will have an impact on overall effectiveness. There is also the issue of whether the total costs (both in terms of clinical effectiveness and the ten-fold higher cost of these drugs in comparison with older agents) should impact utilization of these agents.

In the management of BPSD, it is not clear how individual agents within this class compare to one another and whether the choice of non-pharmacologic approaches has better/safer outcomes than pharmacologic interventions. Specifically, it needs to be determined what the risk of mortality associated with the use of SGAs in patients with dementia and the risk of specific morbidities (stroke or transient ischaemic attacks, hyperglycemia, etc).

The results of the proposed studies would

• quantify the risk of diabetes associated with the various SGAs and would therefore inform both clinical treatment decisions and the surveillance and management of cardiovascular risk factors that would need to be provided for safe application of these therapies.
• better define the risk profile associated with the use of SGAs in elderly patients with dementia.

• identify facilities which manage BPSD through non-pharmacologic approaches and describe those approaches.

8.3.2 Thiazolidinediones (TZDs)

Thiazolidinediones (TZDs) are a class of drugs used in the treatment of type 2 diabetes when diet and exercise have been unsuccessful. This class is commonly prescribed with the most recent data indicating over 1.2 million prescriptions at a cost of $170 million in one year. Approximately 1.8 million Canadians have type 2 diabetes, with rates highest among Aboriginal people. There is inadequate evidence regarding long-term effectiveness compared and in combination with other agents for the management of type 2 diabetes. Recently there have been some reports of cardiovascular and hepatic adverse reactions associated with this class of drugs.

The major questions that would be addressed in the proposed studies are: what are the relative rates of cardiovascular-related and all-cause hospitalization and mortality for diabetic patients treated with single TZD therapy, TZD therapies in combination with other classes of antidiabetic agents and in patients treated with antidiabetic agents other than TZDs. Since most of the studies in the literature only provide proof of efficacy using such markers as lipids, Haemoglobin A1C, etc. the studies would provide some evidence as to how well these types of simple measurements actually correlated with the relative rates of cardiovascular-related and all-cause hospitalization and mortality for diabetic patients.

The results of these studies would provide input into safety regulation pertaining to these drugs, help clarify their place in therapy, have an impact on drug coverage policies and perhaps alter treatment guidelines.

8.3.3 Cholinesterase Inhibitors (ChI)

Cholinesterase inhibitors are approved for use in the treatment of mild to moderate dementia. They are thought to slow the cognitive and functional decline associated with the disease. However, their effectiveness in terms of clinically important outcomes is controversial and there are a number of safety risks that have been poorly defined.

The two major questions that would be addressed are:

• What is the risk of mortality and of major adverse events associated with the use of cholinesterase inhibitors?
• What is the pattern of use of cholinesterase inhibitors in institutionalized patients with dementia? Is there evidence of prescription 'creep'?

If significant adverse events were identified, significant alteration in prescribing could occur given the equivocal data on effectiveness. If substantial prescription 'creep' were identified, a properly run clinical trial by the network could determine whether clinical effectiveness outweighed the emergence of adverse events and cost of therapy.

8.3.4 Biologic Response Modifiers (BRMs)

Biologic Response Modifiers (e.g. etanercept, infliximab, adalimumab and anakinra) are agents that interfere with the body's inflammatory response by altering immune system factors. Currently they are being used for the treatment of rheumatoid arthritis (RA), Crohn's Disease and other disabling conditions. In RA they may not only improve symptom control but also prevent deterioration over time. However, there is a lack of real-world data showing effectiveness and safety of these drugs. Clinical trials have been too short in duration to show what the long term impact of these agents might be on functional outcomes as well as long-term safety. The proposed study is meant to address these two issues.

The outcome of an independent randomized control trial would be known within 2 years. This would have an impact on eligibility criteria and standards of practice for rheumatoid arthritis patients.

9.0 Summary Costs and Next Steps

This section of the Business Plan for a National Oversight Body and Research Network to Improve Pharmacosurveillance in Canada:

• Summarizes the annual costs on an on-going basis;
• Identifies the major steps required to move the program forward; and
• Provides an estimate of costs for the first five years, as the program grows and reaches full operational capacity

9.1 Estimated Annual Costs - Full Program

Referring to Section 6.0: Funding Concepts and Section 7.0: Organizational Options, the following is estimated to be the annual operating cost of the program on an on-going basis. For planning purposes, the estimate is based on the selection of organization Option 1: New Agency Co-Located with a Partner Agency.

Estimated Annual Operating Costs

No.	Funding Element	Cost
1	Office of the Scientific Director	$1,245,800
2	Oversight Committee	$120,000
3	Board	$60,000
4	Primary Funded Research Centres (Assumes 4 Centres)	$3,200,000
5	Project Funding	$16,000,000
Total Annual Cost		$20,625,800

Note that:

• At the end of Year 5, the program should be assessed to determine whether it should continue and if so, whether there would be value in expanding the number of centres and amount of Project Funding.
• The Project Funding will vary based on the number and scale of the research initiatives undertaken. The $16 million is a starting point which can be evaluated at the end of year 5.
• There will be an additional $310,000 Capital costs in Year 1 for the Office of the Scientific Director.

9.2 Next Steps

Following the Project Authority Advisory Committee review and approval of the Business Plan, it will need to be circulated through the Real World Safety and Effectiveness Working Group and other interested bodies. After due consideration and with receipt of support, a budgetary submission could be made. The following steps are post budget approval:

Year 1
This is a formative year.

• Health Canada or a selected Stakeholder will establish a Project Office and commence the establishment of the Program.
• The host organization will be selected and the relationship negotiated.
• The Office of the Scientific Director will be established;
• The position of the Scientific Director filled along with other senior positions;
• The Oversight Committee will be established; and
• The Primary Funded Research Centres selected through a competitive process.

Year 2
In this year, the network building process will commence:

• The Office of the Scientific Director will be fully functional and the Health Canada Project Office will be closed;
• The Primary Funded Research Centres will begin to implement their plans for capacity development;
• The Priority Projects will be assigned to the centres as appropriate.
• The Priority Projects will get underway;
• The Oversight Committee will organize and hold its first Annual Conference to solicit research priority suggestions; and
• The first Project Priorities will be set and the projects assigned to the centres.

Years 3 through 5
In Year 3, the network will be fully operational and new projects will be assigned as others are completed. The program will continue through the fifth year. A key activity in the fifth year will be a program evaluation that will assess whether the program has achieved its goals and whether it should be expanded.

9.3 Estimated 5 Year Cost

The actual cost of the first five years of the program will be less than five times the annual cost shown in Section 9.1. The estimated cost per year for each of the five years is based on what can be accomplished, as shown in the plan.

The approximate cost breakdown is shown in the following table:

No.	Funding Element	Year 1	Year 2	Year 3	Years 4 &5 (Per Year)	Total 5 Years
1	Project Office	$150,000				$150,000
2	Office of the Scientific Director (1)	$966,400	$1,245,800	$1,245,800	$1,245,800	$5,949,600
3	Oversight Committee	$40,000	$120,000	$120,000	$120,000	$520,000
4	Board (Option 1 only)		60,000	$60,000	$60,000	$240,000
5	Primary Funded Research Centres (2)	$500,000	$2,400,000	$3,200,000	$3,200,000	12,500,000
6	Project Funds Four Priority Projects (3,4) Committee Selected Priority Projects (5)	$500,000	$3,500,000 $3,500,000	$3,000,000 $9,000,000	$16,000,000	$7,000,000 $44,500,000
Total 5 Year Cost (6)		$2,156,400	$10,825,800	$16,625,800	$20,625,800	$70,859,600

Notes to the cost table:

1. Costs for the Office of the Scientific Director are based on Organization Option 1.
2. The costs shown for the Primary Funded Centres assumes 4 such centres will be funded. It may later be determined that additional centres are required (eg a First Nations Centre.)
3. The Four Priority Projects could be started before the final selection of the Primary Funded Centres. This would allow needed research to begin without delay and would result in these costs being incurred sooner than represented.
4. The Oversight Committee may wish to review the proposed Priority Projects to determine if other higher priorities for research have arisen since this selection.
5. The maximum annual investment in Committee Selected Priority Projects is shown as $16,000,000. This may prove inadequate over time as the Network proves its worth
6. Costs are in constant dollars with no allowance for inflation.

Appendix 1: Project Participants

Project Authority Advisory Committee

Paul Armstrong

Professor of Medicine, University of Alberta

David Clapin

Branch Science Advisor, Health Canada

Andreas Laupacis

Currently: Director, Li Ka Shing Knowledge Institute, St. Michael's Hospital (At the time of the development of the business plan: CEO, Institute for Clinical Evaluative Sciences)

Bill Leslie*

Manager, Quality Use of Medicines, Health Canada

Denis Morrice

Best Medicines Coalition

Susan Paetkau

Director, Drug Programs Branch, Ministry of Health and Long Term Care, Ontario

Noralou Roos

Professor, Faculty of Medicine, University of Manitoba

Robyn Tamblyn

Professor, Faculty of Medicine, McGill University

Stephanie Young

School of Pharmacy, Memorial University

* Committee Chair

Key Informants

Marc Berthiaume

Director, Marketed Pharmaceuticals and Medical Devices Bureau, Health Canada

Pierre Charest

Director General, Biologics and Genetic Therapies Directorate, Health Canada

Scott Doidge

Manager, Pharmacy Group, Non-Insured Health Benefits Directorate, Health Canada

David Juurlink

Scientist, Institute for Clinical Evaluative Sciences (ICES) Researcher, Sunnybrook Health Sciences

Irene Klatt

Assistant Vice President, Canadian Life & Health Insurance Association Inc.

Kathy Kovacs-Burns

Chair, Best Medicines Coalition Director of Research, Nursing Faculty, University of Alberta

Rav Kumar

Vice President, Pharmaceutical R&D, GlaxoSmithKline

Isra Levy

Director of the Office for Public Health, Chief Medical Officer, Canadian Medical Association

Susan Pierce

Pharmacy Consultant, Non-Insured Health Benefits Directorate, Health Canada

Fred Rumpel

Senior Manager, Pharmaceutical Policy and Programs Branch, Alberta Health and Wellness

Ingrid Sketris

College of Pharmacy, Dalhousie University

Suzanne Solven

Executive Director, BC Pharmacare

Ruth Wilson

Department of Family Medicine, Queen's University

Stephanie Young

School of Pharmacy, Memorial University

Other Participants

Colleen Flood

Scientific Director, Health Services and Policy Research, CIHR

Mark Bisby

Vice President Research, CIHR (Now retired)

Morris Baer

Past Scientific Director, Health Services and Policy Research, CIHR

Scott R. Smith,

Director, Pharmaceutical Outcomes Research Center for Outcomes & Evidence Agency for Healthcare Research and Quality

Colleen Metge

Associate Professor, Faculty of Pharmacy ,University of Manitoba

Judith M. Kramer

Principal Investigator, Duke CERTs Research Center

Bruce Seeman

AHRQ

Appendix 2: Compelling Cases

Case I: Vioxx

Issue:

Vioxx® (rofecoxib) was approved by Health Canada in 1999 for the relief of the signs and symptoms of osteoarthritis (OA) in adults as well as acute adult pain relief and the treatment of menstrual pain. In 2002 there were over 3.4 million prescriptions for Vioxx® in Canada. Clinical trial data provided by Merck demonstrated Vioxx® to be superior to naproxen, a commonly used nonsteroidal anti-inflammatory drug (NSAID) for the outcome measure: upper gastrointestinal events. Merck then applied to each province for listing on their "formulary" (making the drug eligible for provincial reimbursement). Vioxx® was listed in most provinces (though not in British Columbia). Ontario listed Vioxx® in its formulary in April 2000 but granted only a Limited Use listing. This was meant to restrict Vioxx® use to: 1) patients with osteoarthritis who had failed on, or could not tolerate several non-selective NSAIDs (such as ibuprofen or naproxen), and 2) those with a history of gastrointestinal hemorrhage or ulcers. Within the first year, following a high- powered marketing campaign to patients and physicians, over 15,000 elderly Ontario residents had been prescribed Vioxx®. The VIGOR trial, which was published in 2000, compared naproxen with rofecoxib in patients with osteoporosis, showed increased incidence of cardiovascular events, specifically myocardial infarction in the Vioxx® group, but Merck explained this potentially damaging data for Vioxx® by suggesting the comparator drug, naproxen, acted like aspirin in reducing cardiovascular events. No trials clarifying cardiovascular harms were required by Health Canada.

How important are these outcomes?

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen are commonly used and relatively safe drugs. They are used for both acute pain as well as for chronic pain states such as osteoarthritis and rheumatoid arthritis. The rate of serious lower GI clinical events, defined as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, obstruction, ulceration, or diverticulitis is approximately 1% in those taking NSAIDs for one year (such as patients with rheumatoid arthritis). All NSAIDs have the propensity to cause this problem. Thus if an NSAID is reported to significantly decrease this problem it would have a significant benefit for this population. The most effective intervention, at the time, was thought to be the use of a group of drugs called proton pump inhibitors prescribed with an NSAID to reduce the risk of a gastrointestinal bleed.

In terms of some NSAIDs such as aspirin, significant decreases in cardiovascular events such as myocardial infarction have been demonstrated. However, the data are less clear with other NSAIDs. Thus it would be important to determine whether the use of Vioxx would have a net benefit in the population treated.

These issues are not only important insofar as clinical outcomes are concerned but they also had an economic impact. The cost of Vioxx®/day ranged from 2 to 9 times greater than other available anti-inflammatory drugs (with the exception of the other new NSAID, Celebrex®).

Why was it important to further study this drug?

There was a great deal of controversy at the time of the release of Vioxx® as to whether there was a real risk of increased cardiovascular events or whether it would have no impact. Even if Vioxx® was found to have no impact there were concerns that some of the potential benefits that ASA would provide re: decreasing risk of cardiac events would be lost with the use of Vioxx®. Further, there were concerns whether a true decrease in significant gastrointestinal bleeds would be seen with the use of Vioxx® once it was available on the market. Finally, since some jurisdictions attempted to restrict the use of the drug to 'at risk' patients (e.g. those with a history of gastrointestinal bleeding from NSAIDs) it was important to determine whether Vioxx® was being used properly in these jurisdictions and whether physicians were adhering to the restrictions and whether the use of the drug would result in a decrease in the incidence of gastrointestinal bleeds.

What if the Network of Centres for Pharmaceutical Research had existed?
What Might Have Happened?

Due to the potential benefits and harms with the use of Vioxx® and since there was a concern it may be overused, Vioxx use would likely have met the criteria for post-marketing surveillance. Manitoba, Ontario, Nova Scotia all have centres working with provincial drug and hospital data which could have started monitoring drug use and adverse outcomes, shortly after the first Vioxx® prescription was written. BC, where the drug was not listed could have acted as a control to see if the patients in the province where Vioxx® was not listed had a different rate of serious adverse events in comparison to patients in the provinces funding the drug. Several provinces have experienced researchers and detailed electronic medical record data that could be searched for adverse drug reactions. One or more of the provincial drug plans might also have asked a Centre to track whether Vioxx® use was in fact confined to the limited use populations for which reimbursement had been approved.

What would the Research Network have found and what were the major findings from utilization studies?:

Vioxx® users were at considerable risk of developing new heart problems or of aggravating old ones. In a study examining new users of Vioxx®, it was estimated that for every 14 patients treated with Vioxx® who had not required medications for heart problems the prior year, one patient would be prescribed antihypertensives or drugs for congestive heart failure, and for every 400 patients prescribed Vioxx®, one patient would be hospitalized for heart failure.

Meanwhile, over the period when Vioxx® use was expanding rapidly, there were no fewer hospital admissions among the Ontario elderly for upper gastrointestinal hemorrhage. In fact, admissions for GI hemorrhage increased. Overall, the number of prescriptions for any NSAID more than doubled in Ontario, translating into at least 90,000 new users annually, with the use of Vioxx and another new COX-2 inhibitor, Celebrex, driving this finding. Associated drug costs escalated from $28 million annually between 1997 and 2000 to greater than $75 million in the subsequent three-year period.

What might have happened with the results?

The Research Centre could have briefed government bodies and industry at regular intervals. Within 60 days of submitting a final report, they would have reported their findings publicly, ensuring that patients, physicians, pharmacists and the media were well-informed.

With a system of post-marketing surveillance in place, Health Canada could have approved the drug for a limited period (perhaps 2-3 years ³) subject to obtaining real world safety and effectiveness data, at the 18 month review, the cardiovascular risks associated with Vioxx® would have been identified and reported. One or more of the following outcomes could have occurred:

• the time period for conditional approval be extended;
• more restrictions be placed on the types of patients for which the drug was approved;
• further research re patient safety issues was required- e.g. an independent real world randomized trial ⁴. Currently Health Canada has no authority to require these types of studies. However, an established program as proposed in this business plan might have proceeded with a study at the request of Health Canada.
• medication label changes and /or letters be sent out by Merck to physicians warning of these risks.
• Merck sales representatives issue doctors explicit warnings about the risks associated with Vioxx®

If a provincial drug plan received a report after 6 or 12 months of provincial formulary approval, showing there was significant prescribing for uses inconsistent with the funding rules (in Ontario's case if it had been found that osteoarthritis patients who had not previously tried the recommended alternative drugs and who had no prior GI disease were being prescribed Vioxx® in large numbers), the province might have:

• registered a complaint with the company and if necessary the Pharmaceutical Advertising Advisory Board (which has jurisdiction over journal and other print advertising ⁵) that Vioxx® promotion was resulting in non-approved use and/or
• reviewed the conditions of the Limited Use listing and provided feedback to physicians that if prescribing did not conform to the funding rules, further restrictions would be applied, and/or considered taking Vioxx® off the provincial formulary and/or
• insisted that Vioxx® only be available within a large randomized trial that would address benefits, harms and costs in real-world patients. For this to occur, the provinces need to develop funding mechanisms in conjunction with industry that would allow the research network to develop, coordinate and analyze the data from these large RCTs at arms length from industry and/or
• reviewed its risk-sharing agreement with the manufacturer and sought compensation for greater-than-predicted costs of the drug, plus, perhaps, the costs associated with unanticipated increases in physician and hospital use.

References

Mamdani M. Are rates of gastrointestinal bleeding higher following the introduction of COX-2 inhibitors. Expert Opin Drug Saf. 2005; 4(3): 591-8

Mamdani M, Juurlink DN, Kopp A et al. Gastrointestinal bleeding after the introduction of COX 2 inhibitors: ecological study. BMJ. 2004; 328(7453): 1415-6

Bombardier C, Laine L, Reicin A et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000; 343(21): 1520-8.

Case II: The Case for Gatifloxacin (Tequin®)

Issue

Gatifloxacin (Tequin®) belongs to a class of broad-spectrum antibiotics called fluoroquinolones. Gatifloxacin was first approved for marketing on February 21st, 2001. As a class they have become one of the most popular choices for a variety of community-acquired infections even though experts have indicated there is insufficient evidence of their benefit relative to other available antimicrobials. However, a number of serious adverse events related to the class as well as to individual drugs within that class have been reported.

Spontaneous reports of hypoglycaemia / hyperglycemia began to be received by Health Canada following the market introduction of gatifloxacin, resulting in an update of the product monograph in December 2002. Several other countries also received individual case reports of these adverse events. Health Canada received 28 reports of abnormal glucose metabolism associated with gatifloxacin (44% of total reports received for the drug) from Feb. 21, 2001 to Feb. 28, 2003: 19 were of hypoglycemia, 7 were of hyperglycemia and 2 were of both hypoglycemia and hyperglycemia. This information was published by Health Canada in the Canadian Adverse Reaction Newsletter, July 2003. By December 2005 the drug monograph was changed to reflect the increasing concern about these adverse events and cautioned its use in diabetics. In the U.S. labelling changes and warnings of these types of adverse events were published in February, 2006. In May 2006, the Canadian monograph was further changed to indicate the drug was contraindicated in diabetics. As well, a Canadian study, published by ICES in 2006, using provincial database information, determined the frequency of adverse events was much higher than anticipated. By the end of April, 2006 the manufacturer decided to discontinue commercialization of the drug in all countries in which they market it, for commercial reasons. The last shipment to wholesalers was in June, 2006.

How important are some of these outcomes?

The initial 28 cases reported to Health Canada were deemed serious and possibly life-threatening. Nineteen of the patients were admitted to hospital or had a prolonged hospital stay because of the reaction. Death, possibly related to the use of gatifloxacin, occurred in two elderly patients who had developed hyperglycemia despite not having any prior history of diabetes prior to the occurrence of hyperglycemia.

Why was it important to further study this drug?

It was highly unusual that a drug could cause both hyper- and hypoglycemia. Further, it was not known how frequently this event occurred, how long before symptoms would appear or what populations would be most at risk. It appeared that diabetics as well as elderly patients receiving the drug were at the greatest risk. It was not known whether these adverse events occurred more frequently with this drug than others in its class or whether the frequency was higher than other antibiotics. Episodes of hyper- or hypoglycemia could result in significant morbidity and even death.

To settle some of these questions an analysis was conducted by ICES of the Ontario provincial database linking drug use with hospital and emergency room use.

What were the major findings of the ICES study?

The study evaluated the prescription records of Ontario residents 65 years of age or older. Over a two-year time period:

• 788 patients received hospital care for hypoglycemia within 30 days of receiving gatifloxacin. Over 90% were diabetics who had received gatifloxacin while 50% had received the drug within 6 days. Almost one-half were admitted to hospital for a median length of stay of 7 days with 8.1% dying before discharge. When compared to a macrolide antibiotic (commonly used for similar types of infections) it was found that the risk of developing hypoglycemia was 4 times greater with gatifloxacin.
• There was a further 470 cases of hyperglycemia-related hospital visits within 30 days of beginning gatifloxacin. More than one-third of these patients had not been receiving any treatment related to diabetes within the previous 6 months. Of these cases presenting to hospital emergency rooms, almost one-half were admitted to hospital (median length of stay 9 days) with more than 16% dying before discharge. The incidence of hyperglycemia was 17 times higher than any other antibiotic.

A total of 16,697 courses of gatifloxacin treatment were associated with 178 hospital visits (1.1%) for dysglycemia within 30 days. A further analysis determined that the risk of either gatifloxacin-associated hypoglycemia or hyperglycemia was no different between patients receiving treatment for diabetes and those not receiving such treatment. The risk of both hypoglycemia and hyperglycemia are probably underestimated as milder cases or in some cases (particularly hypoglycemia) may have resulted in death outside the hospital setting.

Would the network have identified gatifloxacin as a drug for postmarketing surveillance earlier than the report published in 2006?

• Several fluoroquinolones have been reported to cause serious adverse events over the last 15 years. These include hemolytic anemia accompanied by renal dysfunction (temafloxacin), cardiac arrhythmias (e.g. grepafloxacin), severe skin reactions (e.g. sparfloxacin) and hepatitis (e.g. trovafloxacin). In some cases this has lead to the drug being withdrawn from the market (e.g. grepafloxacin). Since some of these adverse events appear to be class related while others are specific to the individual drug, post-marketing surveillance would have been an important tool to determine if any of these adverse events were associated with gatifloxacin.
• Almost immediately after gatifloxacin was released on the market (February, 2001), Health Canada began to receive reports of hypoglycemia and hyperglycemia even in patients without a history of diabetes. Health Canada issued a formal notification in 2003 identifying a possible association between the use of gatifloxacin and hyper- or hypoglycemia. However, there was no information as to whether there were certain predisposing risks for developing this problem, the frequency with which these problems occur nor the extent of the severity of these adverse events. These unanswered questions would have been a strong signal to proceed with a formal post-marketing surveillance study.
• Fluoroquinolones are a common choice for treating outpatient infections. Since the approved indications for gatifloxacin were broader than the other available 'respiratory' fluoroquinolones the potential was for this drug to be used extensively in the community.

Why would involvement of a formal post-marketing surveillance been important?

Earlier analysis, similar to the ICES study, would have identified the extent and risk of the problem and would have probably resulted in earlier warnings, restrictions or delisting of the product from provincial formularies. This would not have affected the choice of antibiotic for clinicians as gatifloxacin offers relatively few therapeutic advantages over alternative antibiotics. Aside from avoiding significant morbidity and mortality, substantial savings would have accrued as many of the other choices for treatment are up to one-half of the cost of a course of gatifloxacin. Since the extent of the problems associated with gatifloxacin would have been known one to two years prior to the seminal study by ICES, other costs would have been reduced due to decreased hospitalizations and use of emergency departments. Using a conservative estimate of $700/day for inpatient care costs, up to 3 million dollars would have been saved annually in the Canadian health care system.

With a formal program in place additional information may have been able to be obtained. For example the ICES study results would have been enhanced by comparing a jurisdiction which did not cover the costs of gatifloxacin (BC) with a province that did (Ontario).

References for Gatifloxacin Case

Advisory Warning from HC - Dec 19/2005

Canadian Adverse Reaction Newsletter 13(3), July 2003

Gatifloxacin (Park-Wyllie LY, Juurlink DN, Kopp A et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. NEJM 2006; 354:1352-61

Gurwitz JH. Serious adverse drug effects - seeing the trees through the forest. NEJM 354: 1413-15

Case III: Estrogen Therapy for Postmenopausal Women

Issue

Hormone replacement therapy (HRT) provides women with, or replaces, hormones that their ovaries stop making. HRT is most often prescribed to help with the symptoms of menopause. Orally active estrogen replacement therapy (Premarin®) was first marketed in Canada in 1941 and, with intensive marketing, became the number one dispensed drug by the mid-1970's. By the early 1980's several oral estrogen preparations were in common use. However, by the mid-1970's it became evident that unopposed estrogen administration (exogenous estrogen without progesterone) had adverse effects on the endometrium resulting in invasive as well as non-invasive endometrial cancer. A number of well-designed observational studies, including ones where post-menopausal women's health was monitored for years, had demonstrated that estrogen therapy with or without progesterone provided a range of benefits beyond the 'normal' indication for the treatment of menopausal (e.g. flushing) and postmenopausal (e.g. vaginal drying) symptoms. The strongest evidence appeared to be significantly lower rates of coronary heart disease in women who take post-menopausal estrogen than in women not receiving this therapy. This association was particularly strong for secondary prevention in women with coronary heart disease, with hormone users having 35% to 80% fewer recurrent events than nonusers. Other effects (both beneficial and harmful) ascribed to estrogen therapy in this population were:

• Reduced incidence of colorectal cancer and a lowered risk of death from the disease: 20% reduction in the incidence of colorectal cancers among women who had ever taken hormones and a 34% reduction among women who were taking them at the time of the study, as compared with women who had never taken hormones. (Note: There are no other known preventative measures.)
• Increased risk of gallbladder disease by as much as twofold to fourfold.
• Conflicting results on the impact of estrogen therapy on strokes (results varied between the studies from increased risk to decreased risk).
• Increase in bone mineral density thereby decreasing the risk of fractures (hip, wrist, ankle) secondary to osteoporosis. This effect was still seen in some analyses years after discontinuing therapy.
• Small risk of increased breast cancer.

The evidence appeared to indicate that estrogen therapy provided much greater benefit than risk, resulting in a number of clinicians advocating using estrogens routinely in post-menopausal women even when women were not seeking therapy for post-menopausal symptoms. In fact, conducting a randomized controlled trial in this population was felt by some to be unethical as by the very nature of the study some would receive the 'beneficial' treatment while others would be denied. This simple preventative strategy was thought to provide significant clinical benefit (reduced cardiovascular events such as heart attacks and lowered fractures) at a very low cost (less than $30/month).

The difficulty with any observational study, no matter how well done is controlling certain basic variables. Women with healthy behaviours, such as those who follow a low-fat diet and exercise regularly, may selectively use postmenopausal hormones. These differences in behaviour are usually not measured in these types of studies.

How Important are some of these outcomes?

• Osteoporosis: One out of every six women will have a hip fracture during her lifetime. Osteoporotic fractures contribute to increased disability and lessen the quality of life in older women. Hip fractures are more common that combined risk of breast, uterine and cervical cancer. Fractures occur more frequently in women than men (3 to 4 times more) in those over 50 years of age.
• Heart Disease in Women: It is the second leading cause of death in postmenopausal women (23% of all deaths in 2002).
• Colorectal Cancer: It is the 3rd leading cause of cancer deaths in women (approximately 8,400 deaths annually.

How was it handled?

An initial study [the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial sponsored by the National Heart, Lung, and Blood Institute, USA as part of the Women's Health Initiative (WHI) trial] was conducted comparing estrogen with or with progestin with placebo. One of the primary findings was that estrogen appeared to lower "bad" cholesterol (LDL) and increase good cholesterol (HDL). This provided further evidence of possible beneficial cardiac effect. However, data was still missing on actual clinical outcomes.

Two further studies followed those initial results. The first was sponsored by one of the manufacturers of estrogen replacement therapy (Wyeth - HERS trial or Heart and Estrogen/progestin Replacement Study) while the other study was sponsored by the National Heart, Lung, and Blood Institute, USA (WHI - Women's Health Initiative trial). The HERS trial focused on the subpopulation most likely to get benefit from estrogens according to the observational studies: women requiring secondary prevention with established coronary heart disease.

What were the major findings?

1. HERS trial: After an average of 4.1 years, no reduction in overall rate of coronary heart disease events in postmenopausal women with established coronary disease was found. Women on hormone therapy had almost a threefold increase in risk for thromboembolic events including deep vein thrombosis and pulmonary embolus. This translated into one extra case of a venous thromboembolic event for every 256 women treated. A small increased risk for biliary tract surgery was seen in women on estrogens. There was no increased risk of stroke events.
2. WHI trial: After an average of 5.2 years the following was found (numbers are risk then number of extra cases/10,000 women treated):

1. Estrogen plus progestin (used in those women with intact uterus):
   • Breast cancer: 26% increased risk: 8 more cases/10,000 women treated
   • Stroke: 41% increased risk: 8 more cases/10,000 women treated
   • Heart attack: 29% increased risk: 7 more cases/10,000 women treated.
   • Blood clots: Doubled rates: 18 more cases/10,000 women treated.
   • Colorectal cancer: 37% less risk: 6 less cases/10,000 women treated
   • Fractures: 37% fewer hip fractures: 5 less cases/10,000 women treated.
   • No effect: deaths, total cancer cases.
2. Estrogen Alone (used in those women without a uterus)
   • Stroke: 39% increased risk: 12 more cases/10,000 women treated
   • Blood clots: 47% increased risk: 6 more cases/10,000 women treated
   • Coronary heart disease: no significant effect
   • Colorectal/total cancer: no significant effect
   • Deaths: no significant effect
   • Breast cancer: uncertain effect
   • Fractures: 39% fewer hip fractures: 6 less cases/10,000 women treated.

Why are these findings important?

• It demonstrates that strong signals of harm or benefit sometimes requires a formal randomized controlled trial conducted over several years to determine whether harm or benefit from an intervention can be demonstrated.
• It provides strong evidence that long term estrogen therapy will actually result in more harm than good, the opposite of what the observational studies seemed to indicate.
• Subpopulations are at differing risk of developing problems.
• Proper policy translation of these findings will result in the avoidance of unnecessary costs both in terms of drug and other health care costs (e.g. hospitalizations).
• Many of these types of trials require funding from public sources. The secondary prevention trial was funded by one of the manufacturers because the population chosen was thought to be able to demonstrate the highest chance of benefit based on the observational studies; i.e. there was a potentially significant financial gain for the company if positive results could be demonstrated. To answer questions of harm or benefit in a larger potential population required the funding from government agencies.
• The WHI trial resulted in an immediate 32% decrease in prevalence of use of estrogen replacement therapy among elderly women as well as a significant decrease in new cases (incidence of new use) compared to similar time periods.

What would have triggered the network to pick up this topic?

The following factors may have triggered the network to pick up this topic and determine that a randomized control trial was required. As stated above, the only evidence of major benefit was from observational studies and some clinical trial data demonstrating significant beneficial effects on cholesterol.

• Large population affected (post-menopausal women).
• Potentially important preventative strategy affecting leading causes of morbidity and mortality.
• Suggestive evidence of protective effect against several conditions (e.g. osteoporosis and coronary heart disease) but with potential offsetting adverse effects (e.g. breast cancer).
• Lack of interest by the private sector for the topic. Once the HERS study results were made public it would be unlikely any private interests would have studied this issue in the broader population.

References for Estrogen Case Study

Davis SR, Dinatale , Rivera-Woll L, Davison S. Postmenopausal hormone therapy: from monkey glands to transdermal patches. J Endocrinology 2005; 185: 207-22

Grady D. Management of menopausal symptoms. NEJM. 2006; 355:2338-47.

Hsia J, Langer RD, Manson JE et al. Conjugated equine estrogens and coronary heart disease: the Women's Health Initiative. Arch Intern Med. 2006; 166(3): 357-65

Simon JA, Hunninghake DB, Agarwal SK et al. Effect of Estrogen plus progestin on risk for biliary tract surgery in postmenopausal women with coronary artery disease. Ann Intern Med. 2001; 135: 493-501

Simon JA, Hsia JH, Cauley JA et al. Postmenopausal hormone therapy and risk of stroke. The Heart and estrogen-progestin replacement study (HERS). Circulation. 2001; 103: 638-42

Chlebowski RT, Wactawski-Wende J, Ritenbaugh C et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N Engl J Med 2004; 350: 991-1004.

Grady D, Wenger NK, Herrington D et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. The heart and estrogen/progestin replacement study. Ann Intern Med. 2000; 132: 689-96.

Manson JE. Hsia J, Johonson KC et al. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003; 349(6): 523-34

Austin PC, Mamdani M, Tu K, Jaakkimainen L. Prescriptions for estrogen replacement therapy in Ontario before and after publication of the Women's Health Initiative Study. JAMA 2003; 289(24): 3241-2.

Also see:  Postmenopausal Hormone Therapy

Appendix 3: Scientific Director Office Salary Costing Assumptions

Resources:
Total personnel: 12 people
Total Salaries: $840,000

Resources
Total personnel: 9 people
Total Salaries: $715,00

Appendix 4: Approach and Methodology

Project Steps

The business plan was developed between May 2006 and February 2007 and involved the phases described below.

1. Project Kick Off

In the Project Kick Off Phase, the project plan was reviewed and finalized. The PAAC was established with confirmed membership and defined roles and responsibilities. The PAAC identified a number of Key Informants from across Canada who would be interviewed as part of the information gathering phases of the project. They also provided initial input into roles of the Research Centres.

2. Environmental Scan

A literature review was undertaken to identify relevant background and supporting material for the Business Plan. Subsequently, there was a review of international initiatives and Canadian pharmaceutical research & policy centres. Among other organizations, the team consulted with Duke University, Center for Disease Control and Prevention, Department of Health and Human Resources (USA), University of Chicago, University of Manitoba, Jesse Browne VA Medical Center, Dalhousie University, Agency for Healthcare Research and Quality and Centre for Health Services and Policy Research.

The purpose of the scan was to identify the current Canadian programs and capabilities regarding the assessment of the real world safety and effectiveness of medicines and to identify gaps in information and capabilities. It was also to identify how other countries were addressing the same issues.

3. Compelling Cases

Three significant real world safety and effectiveness issues were selected for review. The purpose of the analysis was to determine whether and how gaps in existing research in Canada may have contributed to negative health results, and to demonstrate the possible benefits and impact if a managed, national research network had been in place.

4. Draft Conceptual Model

Based on the literature search, contact with similar organizations, and input from the Advisory Committee, a number of concept models for the structure and operation of the Network and Oversight Body were documented. The models were reviewed and one was approved by the PAAC for use in the planned Key Informant Interviews to elicit comment.

5. Key Informant Interviews

Key Informants representing a broad spectrum of interested stakeholders in real world safety and effectiveness of medicines were identified and interviewed about this initiative. These individuals gave freely of their time and their thoughts. Their input was invaluable. The Key Informants are identified in Appendix 1 Project Participants.

An interview outline was developed around the concept model and sent to the Key Informants. The interview outline was in the form of a series of questions designed to solicit the Informants detail input, ideas and opinions. The questions were open ended and focused on the issues addressed in the Statement of Work from the RFP. Each interview was documented and notes returned to the informant in order to correct any errors.

6. Revised Conceptual Model

Based on the feedback from Key Informants, the conceptual model for the Oversight Body and Research Network was expanded and refined. The model identified key components of the program and the operational flow of information. A variety of organizational models were identified to address governance and accountability. Two options were selected for review. Possible hosts for the new program were interviewed to assess their interest in the program and the "fit" of this program within their current mandate. Relative costs and benefits of the models were developed.

7. Draft Report

A draft report based on all the input received was developed for review and comment by the Project Authority and the PAAC. The draft included a chapter documenting a high level road map to the future.

8. Final Report

Upon approval of the draft, a final report including the Executive Summary and all appendices was documented for circulation,.

Notes

Appendices