Review of the 2001 Clinical Trials Regulatory Framework: Part C, Division 5 of the Food and Drug Regulations (Drugs for Clinical Trials Involving Human Subjects)

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Table of Contents

Foreword

The review of the 2001 clinical trials regulatory framework is being undertaken as part of the Health Products and Food Branch's (HPFB) 'Blueprint for Renewal' initiative, which aims to modernize the regulatory system for health products and food.

An electronic consultation on the review of the clinical trials regulatory framework was held over the summer of 2006 to seek initial feedback from stakeholders on the impact and effectiveness of the regulatory amendments that were introduced in 2001, as well as on approaches to further strengthen the framework for the future. Results from this electronic consultation are available on the Blueprint web site.

Building on the results from the electronic consultation, HPFB has developed this discussion paper to help guide the next phase of stakeholder involvement on this initiative, which consists of a stakeholder workshop on March 26, 2007 in Ottawa. Through this second consultation phase, the Branch will be seeking specific input from stakeholders on ways to improve Canada's regulatory framework for clinical trials. A report from the stakeholder workshop will be posted on the Blueprint web site in May 2007.

Results from the electronic consultation and the workshop will help inform the development of short, medium and long-term measures to strengthen the regulatory framework. Additional consultations will be undertaken by the Branch as necessary as we move forward on this initiative, including through the Canada Gazette process if regulatory amendments are being considered.

This document and the corresponding consultations are specific to products captured under Division 5 of the Food and Drugs Regulations (i.e. pharmaceutical, biological and radiopharmaceutical drugs) and for the purpose of this document, these products will be referred to as 'drugs.' This document and the corresponding consultations do not apply to products such as natural health products and medical devices, which are regulated under separate regulations.

Introduction

On September 1, 2001, the regulatory amendments to Part C, Division 5 of the Food and Drugs Regulations (Drugs for Clinical Trials Involving Human Subjects) came into force, with two overarching objectives: to strengthen protections for human research participants; and to attract and sustain investment in research and development in Canada. In the Regulatory Impact Analysis Statement (RIAS) that accompanied the 2001 regulatory amendments, Health Canada's Health Products and Food Branch (HPFB) committed to assessing the impact of the new regulations within three to five years.

A review of the clinical trials regulatory framework was undertaken in 2006. An electronic consultation was held in the summer of 2006 to seek feedback from stakeholders on the 2001 framework. A number of thematic areas were covered as part of the electronic consultation, including: the impact, scope and flexibility of the regulations, as well as the changing roles and responsibilities of the various players within the clinical trials environment in Canada. A report summarizing the results from the electronic consultation is available on the Branch's Blueprint for Renewal website.

This discussion document further articulates some of the key considerations related to the further improvement of the regulatory framework for clinical trials. The analysis in this document is supplemented by the views and suggestions received as part of the electronic consultation.

The document is divided into three sections:

  • Section I provides an overview of the clinical trials regulatory framework including: limitations of the pre-2001 framework; objectives and components of the 2001 regulatory framework; implementation and impacts of the new regulations; and general views of stakeholders on the effectiveness of the framework.
  • Section II explores the various 'drivers of change' which will impact the clinical trials environment, many of which are currently challenging the boundaries of the clinical trials regulatory framework. Issues such as emerging science and technology, product development and globalization are discussed.
  • Section III focuses on three key thematic areas and outlines specific questions to support discussions with stakeholders. The three thematic areas are: scope of the regulations; flexibility of the regulations; and roles and responsibilities.

The results of the review will help inform the development by HPFB of measures to improve the clinical trials regulatory framework in the short, medium and long term.

This review has been undertaken as part of the Branch's 'Blueprint for Renewal' initiative, which aims to modernize the regulatory system for health products and food.

HPFB released the discussion document Blueprint for Renewal: Transforming Canada's Approach to Regulating Health Products and Food in October 2006, which articulates the vision and objectives for the renewal of our regulatory system. Consultations on the Blueprint were held from October to December 2006. The results of these consultations are available on the Blueprint web site at the address mentioned above.

There are a number of objectives under the Blueprint which underpin the review of the clinical trials regulatory framework, including:

  • enabling timely access to safe, effective and high quality health products;
  • improving regulatory efficiency and predictability;
  • enhancing accountability, openness and transparency;
  • developing strategies to ensure regulatory interventions are proportional to risk;
  • strengthening safety oversight through the adoption of life cycle approaches to the regulation of pharmaceuticals and biologics;
  • strengthening post-market surveillance and risk communication; and
  • increasing international collaboration, harmonization and worksharing.

As well, there are a number of other Blueprint initiatives currently underway that are linked to the review of the clinical trials regulatory framework, including:

  • the development of a Canadian approach to the registration and disclosure of clinical trial information;
  • the review of the Special Access Programme;
  • the development of a new Progressive Licensing Framework for pharmaceuticals and biologics.

Section I - The Current Clinical Trials Regulatory Framework

A. Limitations of the pre-2001 clinical trials regulatory framework

The regulatory requirements respecting drugs used for the purposes of clinical trials were originally developed in the early 1960s under the Food and Drugs Act. Over time, the Act and related regulations did not keep pace with the changing environment of clinical trials and drug development in Canada, creating gaps in a number of areas. For example, the regulator lacked the authority to investigate and suspend unauthorized trials, to detect instances of sponsors not following an approved trial protocol, or to identify non-reporting of serious and unexpected adverse events. As another example, the evolving requirements related to record keeping and ethics reviews were not explicitly stated in the regulations.

B. Establishment of a new regulatory framework in 2001

Regulatory amendments to Part C, Division 5 of the Food and Drugs Regulations came into force on September 1, 2001. Their objectives were to further improve the health and safety of human subjects within the context of clinical trials and to sustain and attract investment in research and development. The new regulatory framework incorporated the following features:

  • New authorization requirements for phase I, II and III clinical trials involving new drugs and drugs where the proposed use would be outside the parameters of the authorized conditions of use (e.g., new indications, dosage regimen, target patient populations).
  • Clear and transparent requirements for application amendments, notification, labelling, record keeping and the reporting of serious unexpected adverse drug reactions.
  • An inspection program to assess compliance with the Food and Drugs Act and its associated regulations and adherence to good clinical practices (GCP); promote standardization by harmonizing with GCP standards developed by the International Conference on Harmonization (ICH).
  • Strengthened oversight of clinical trials by requiring that all clinical trials for drugs undergo review and approval by a research ethics board (REB) prior to commencement.
  • A 30-day default period for Health Canada to review applications to sell or import a drug for the purpose of a clinical trial (reduced from the previous 60-day default time); and
  • Clear Ministerial authority to refuse an application, suspend or cancel the sale of drugs for use in clinical trials in Canada where regulatory requirements are not satisfied.

An administrative target of seven days for the review of bioequivalence trials and some Phase I trials in healthy adult volunteers was introduced to stimulate clinical research and development in Canada, but was not included in the text of the regulations.

The regulations were structured to place priority on patient safety by further clarifying the roles and responsibilities of stakeholders involved in the clinical trials environment. In particular, the responsibility of sponsors to ensure the safety of trial subjects was more clearly defined, while recognizing the roles of others in the process, including REBs and qualified investigators.

C. Implementation of the 2001 clinical trials regulations

The 2001 clinical trials regulatory framework brought Canada in line with other regulators through: the introduction of competitive default review periods; the establishment of an inspection program; awareness and information strategies; increased harmonization with international standards; and strengthening oversight functions.

This section provides an overview of how the key components of the new regulatory framework were implemented by the various players involved in clinical trials in Canada.

Inspection strategy

The inspection strategy was implemented in 2002 in order to verify and assess compliance to the regulatory requirements, adherence to the generally accepted principles of good clinical practices, and the validity of the data generated. The program involves inspecting clinical trial sites and investigating complaints. Inspection activities cover sponsors, contract research organizations (CROs), research ethics boards (REBs) and qualified investigator sites. These activities involve the verification of source documents (e.g., medical records, drug storage conditions) as a means to improve compliance and to further protect the safety of human research subjects.

To raise awareness of the regulatory requirements and to improve compliance, the HPFB Inspectorate:

  • publishes annual reports of clinical trial inspections, including a summary listing of deviations from regulatory requirements;
  • develops guidance documents to address particular gaps in interpretation (e.g., records retention); and
  • targets inspections of up to 2% of Canadian clinical trial sites per yearFootnote 1 based on a risk management approach to site selection. Up to 60 GCP inspections have been conducted in Canada each year, plus an additional 15 to 20 compliance verification investigations arising from complaints.

Awareness strategies

HPFB undertook several outreach activities to raise awareness and educate stakeholders on the new regulatory requirements. These included the development of guidance documents (e.g., chemistry and manufacturing review, record keeping), templates, annual reports and other communications materials, such as the clinical trials application guidelines. Access to information was also facilitated through communications by e-mail as well as the increased availability of on-line information. In addition, Health Canada representatives made numerous presentations and participated in several public forum events and grand rounds with researchers and research coordinators affiliated with regional health centres and research groups. These events enabled the stakeholder community to ask questions and to seek clarification on the new requirements. In 2006, the Branch also launched the clinical trials e-manual to help facilitate the filling of successful applicationsFootnote 2, which has been well received by stakeholders.

Harmonization

The Branch has actively been engaged in international harmonization forums, such as the International Conference on Harmonization (ICH), to develop common standards for the conduct, evaluation and monitoring of clinical trials, as well as for other aspects of drug development and registration (e.g., guidance for data safety reports). In some cases, Health Canada has adopted ICH documents, with Canadian addenda where necessary, in order to respond to unique domestic issues and to clarify operational requirements. For example, Health Canada:

  • adopted the ICH E11 guidance (Clinical Investigation of Medicinal Products in the Pediatric Population) in 2003, along with an addendum that clarified the timing and conduct of pediatric trials;
  • updated the templates for the chemistry and manufacturing aspects of drugs for clinical trials to ensure consistency with ICH guidelines; and
  • adopted the ICH E6 good clinical practices guidelines.

Human research protections

The new framework and inspection system have reinforced and validated activities already underway by sponsors, researchers, and other stakeholders aimed at promoting research excellence through greater awareness and application of good clinical practice principles, and increasing oversight through monitoring and REB review. Stakeholders have played various roles in enhancing the quality of research conducted in Canada and strengthening protection of human research participants, through collaborative efforts with research partners, participation in learning activities and initiatives to address regulatory issues. Examples include:

  • The National Council on Ethics in Human Research (NCEHR) continues to provide national leadership in promoting high ethical standards for research involving humans through voluntary institutional site visits, learning events, a listserve and support to the Forum of Canadian and US (FOCUS) REBs and institutional review boards (IRBs).
  • The Canadian Association of Research Ethics Boards (CAREB) was established in 2002 to improve networking among REBs to pursue harmonization of REB procedures and administration, and to be the voice of domestic REBs on policy issues such as privacy and trial registration.
  • The Canadian Institutes of Health Research (CIHR) have increased funding to support clinical research, adopted policies on trial registration, ethics review and inspection results notification, and actively participates in global action on the registration and disclosure of clinical trials.
  • The Panel on Research Ethics (PRE) continues its stewardship and evolution of the Tri-Council Policy Statement (TCPS), developed by granting councils in 1998.
  • Increased development of in-house monitoring and compliance programs by industry and stakeholders.

Review performance, trends in clinical trial applications and research and development

The introduction of the 30-day default review and the development of templates, guidances and on-line information facilitated rapid and efficient processes for the preparation, review and approval of clinical trial applications (CTAs).

In the period from September 1, 2001 to the end of fiscal year 2002 (i.e., March 31, 2002), the number of CTAs for pharmaceuticals increased 40%, and the number of CTAs for biologics increased by 70%. From 2002 to 2006, CTAs have increased on average by 6.2% annually for pharmaceuticals and by 9.6% for biologics.

Despite this increase of CTAs, as well as the increasing volume of amendments that were submitted for review, HPFB consistently met its 7-day and 30-day review targets since their introduction in 2001.

Table 1 shows the distribution of CTAs received by category since 2001. For pharmaceuticals, most of the increase from 2002 to 2006 resulted from the 37% increase in the number of Phase I bioequivalence trials subject to the 7-day administrative review target. There was a modest increase in the number of Phase I and Phase II pharmaceutical CTAs subject to the 30-day default, but the number of incoming Phase III pharmaceutical CTAs was virtually unchanged. The bulk of the increase in the number of biologic CTAs originated from the 30% increase in the number of Phase II trials.

Table 1a. CTA activity for pharmaceuticals reported for the period 2001-2006
Period (year) 2006 2005 2004 2003 2002 2001Footnote 1
Footnote 1

Regulatory amendments came into force September 1, 2001.

Return to footnote 1 referrer

N/A Not available

Phase Pharmaceuticals
Joint review 1 6 N/A N/A N/A 445
PH1 Bioequivalence - 7 day 908 1006 944 749 630 138
PH1 Healthy Human - 7 day 94 81 85 49 45 9
PH1 Healthy Human - 30 day 4 2 4 4 7 8
PH1 Other - 30 day 55 58 59 53 32 0
PH2 - 30 day 247 226 259 247 211 55
PH3 - 30 day 329 303 324 334 327 96
Phase ½- 30 day 7 10 12 6 6 6
Phase 2⁄3 - 30 day 8 10 9 4 13 3
Phase unassigned - 30 day 39 38 34 38 16 11
Totals 1686 1740 1730 1484 1287 771
Table 1b. CTA activity for biologics reported for the period 2001-2006
Period (year) 2006 2005 2004 2003 2002 2001Footnote 1
Phase Biologics
Footnote 1

Regulatory amendments came into force September 1, 2001.

Return to footnote 1 referrer

PH1 Healthy Human - 30 day 1 7 3 3 4 0
PH1 Other - 30 day 29 11 24 34 25 4
PH2 - 30 day 81 72 69 55 61 16
PH3 - 30 day 138 105 120 87 71 28
Phase ½ - 30 day 4 3 5 2 5 0
Phase 2⁄3 - 30 day 1 0 1 3 6 1
Phase unassigned - 30 day 18 41 36 27 8 5
Totals 272 239 258 211 180 54

While trends in specific characteristics of incoming CTAs are not routinely tracked, a review of bioequivalence CTAs was conducted covering the period of June to December 2004, which revealed that 40% of trials were conducted to satisfy US requirements and 25% to support foreign market applications.Footnote 3

Clinical trial research and development trends

A number of factors influence clinical trial investment decisions by stakeholders. A favourable tax structure (e.g., tax credits for research and development expenditures), access to skilled clinical researchers, the presence of well-funded academic health institutions, a competitive cost structure (e.g., labour, laboratory costs), regulatory requirements, and patent incentives are among the economic considerations that can affect investment in clinical research and development. Figures of clinical trial investment are often difficult to dis-aggregate as they are typically reported with other types of expenditure, making it difficult to quantify/qualify trends for industry. This difficulty applies equally to institution and investigator-initiated trials.

Table 2. Clinical research and development expenditures from 2001 to 2005
Type of research 2005 ($M) 2004 ($M) 2003 ($M) 2002 ($M) 2001 ($M) Overall % increase (2001-05)
Footnote 1

"Other qualifying" research expenditures are also eligible for the federal Investment Tax Credit. This includes costs associated with drug regulation submissions.

Return to footnote 1 referrer

Source: Annual reports, Patented Medicines Prices Review Board.

Applied - Phase I 70 54.3 54.4 40.1 23.2 202%
Applied - Phase II 109.8 109.5 103.2 104.8 96.2 14%
Applied - Phase III 387.3 338.1 330.9 297.9 326.4 19%
Applied - subtotal 567.1 501.9 488.5 442.8 445.6 27%
Other qualifyingFootnote 1 230.1 244.2 332.6 304.3 242.6 -5%
Basic research 215.1 221.7 180.3 198.6 163.1 32%
Total 1012.3 967.6 1001.4 945.7 851.5 19%

Data reported to the Patented Medicines Prices Review Board by innovative drug companies reveal an increase of 19% in nominal clinical research and development expenditures in the period between 2001 and 2005 (see table 2). There was a significant increase in expenditures related to Phase I trials, while more modest increases can be observed for Phase II and Phase III trials.

D. Stakeholder views on the overall effectiveness and impact of the 2001 regulatory amendments

The questionnaire of the summer 2006 electronic consultation on the review of the regulatory framework included a number of questions on stakeholders' views of the overall effectiveness and impact of the 2001 regulatory amendments.

Table 3 summarizes the views of the 73 respondents to the electronic consultation on the extent to which the various objectives of the new regulations were met. The majority of respondents (75%) felt that overall, the 2001 regulatory framework met its objectives. In particular, stakeholders indicated strong support that the following objectives have been met: improving safety mechanisms for clinical trials subjects (77%); shortening review times (73%); ensuring a flexible framework containing sufficient safeguards to ensure the review of clinical trial applications is not unduly delayed (70%); and improving monitoring and follow-up by the regulator (63%).

Table 3. Measure of agreement: 2001 regulatory changes met the RIAS objectives
Regulatory Impact Assessment Statement (RIAS) objectives met partially met partially unmet not met don't know
Footnote 1

Figures represent percentages.

Return to footnote 1 referrer

To shorten the time required for clinical trial application review, without endangering the health and safety of Canadians; 42Footnote 1 18 13 10 18
To improve safety mechanisms for clinical trial subjects, such as compliance with generally accepted principles of good clinical practice; 29 35 8 11 17
To improve monitoring and follow-up of the conduct of clinical trials (by the regulator) 19 44 11 15 10
To ensure that Canada has a clinical trial framework which is flexible, but contains sufficient safeguards to ensure the review of clinical trial applications is not unduly delayed; 21 41 13 14 10
To introduce additional operational efficiencies; 11 28 18 11 31
To remove obstacles to additional research and development in Canada, where they do not endanger the health and safety of Canadians; 10 39 13 24 14
To ensure that Canadians have improved access to innovative therapies and advice from Canadian physicians with research expertise in these new therapies. 9 29 19 28 16

Responses also indicated some differences of opinion among stakeholder groups. In particular, academic and institutional groups were more likely to report that the new regulatory framework added barriers to research and development in Canada due, in part, to the cost related to meeting new regulatory requirements.

Table 4 summarizes the views of the 73 respondents on the impact the implementation of the regulatory amendments had on their activities.

The majority of respondents expressed a positive response on the impact of regulatory amendments, administrative processes and outreach activities introduced by Health Canada to support the 2001 framework. The following activities received particularly high positive responses: the 30-day default review period, the review of applications and protocols by a research ethics board (REB), and the availability of guidance documents and of annual reports of clinical trial inspections. However, results demonstrated that certain regulatory changes appear to be more problematic to stakeholders, including requirements for record keeping, labelling and CTA amendments.

Table 4. Measure of impact of regulatory amendments, administrative processes and outreach activities on stakeholders' clinical trials activities
Regulatory amendments: administrative processes and outreach activities positive impact negative impact no impact don't know
30-day default review period for clinical trial applications 66Footnote 1 9 10 15
Footnote 1

Figures represent percentages.

Return to footnote 1 referrer

New authorization requirements for Phase I, II and III clinical trials 41 19 19 21
Requirements for amendments 33 22 25 20
Requirements for notification 30 15 36 19
Requirements for labelling 26 23 32 19
Requirements for record keeping 30 46 12 12
Requirements for adverse drug reactions reporting 43 7 40 10
Inspection program 44 23 15 19
Review of applications / protocols by a REB prior to commencement of conduct of a trial 57 4 35 4
7-day default administrative target for bioequivalence trials 34 9 21 36
Print and electronic guidance documents and articles 57 6 26 12
Presentations at conferences and symposia and grand rounds 49 4 27 20
Annual reports of clinical trial inspections 53 11 21 14

The majority of participants agreed that the objectives of the 2001 regulatory framework are still relevant to meet future needs. However, many noted that additional flexibility is required in certain areas to ensure the regulatory framework can address emerging trends in the clinical trials environment, such as: adaptative clinical trial designs; pharmacogenomics; and addressing the needs of specific populations.

Respondents also provided specific suggestions to improve the regulatory framework for clinical trials and its operational impact, which are further discussed in Section III of this document. Some of these suggestions include:

  • Developing more relevant and timely guidances;
  • Providing more assistance to stakeholders;
  • Increasing harmonization with global partners and regulators;
  • Expanding and increasing the flexibility of the current regulatory framework related to the needs and expectations of small populations, genomics, scientific breakthroughs, and the multi-national nature of clinical trials and drug development;
  • Expanding outreach activities by providing education to researchers on the regulatory process and drug development;
  • Strengthening the capacity of the regulator in areas of review and inspection;
  • Ensuring consistency and predictability of the interpretation of the regulations;
  • Introducing data management efficiencies.

Stakeholder feedback received to-date suggest that overall, the implementation of the 2001 regulatory framework has had a positive impact on the clinical trials environment in Canada. The framework still generally meets the intended objectives, but specific issues regarding its implementation and its flexibility to adapt to a rapidly changing clinical trial environment were raised. These issues will be the focus of the next two sections.

Section II - Drivers of Change

Regulations are only one of many factors affecting clinical trial activity, and regardless of how unambiguous or exhaustive they may appear on implementation, no set of regulations can anticipate every eventuality. Advances in science and technology, trends in clinical trial design, product development challenges and globalization will shape the future clinical trial environment. These trends are explored below.

Emerging scientific and technological trends

Emerging science and technology has allowed new clinical scenarios. Research in areas such as pharmacogenomics, gene therapy, tissue engineering, and nanotechnology is in the early stages. Clinical trials in these fields are either occurring or can be expected to occur in the near future. In Canada, the biotechnology sector is growing rapidly, representing approximately 31% of investment and activity, and is expected to be a significant sector of growth in both domestic and global drug development markets. Scientific advances are challenging the evidence thresholds that are required for submission and review, and requiring regulators to reconsider standards for risk-benefit assessments (e.g., biomarkers, surrogate endpoints).

As an example, the use of pharmacogenomics may be able to increase the safety of products by improved targeting of patient populations to whom the drug product will be administered, and therefore decrease the numbers of adverse reactions. This targeting has been considered as a step to 'personalize' therapies and also increase the efficacy of therapeutic products, thereby improving their risk-benefit profile.

The Health Products and Food Branch (HPFB) has recently released a guidance document for sponsors intending to submit pharmacogenomics information to Health Canada, clarifying that clinical trials involving pharmacogenomics testing are subject to the requirements for the filing of a clinical trials application.

The review of clinical trials involving breakthrough technologies raises several issues, including: the need to ensure scientific capacity and platforms to assess risk and benefit; the ethical implications of human participation in clinical trials (e.g., drugs for rare diseases, drugs for emergency use, privacy protection and assent and informed consent with children); and process implications (e.g., 'compassionate' trials'). Scientific and technology breakthroughs test the current boundaries of the regulatory framework.

Trends in clinical trial design

Regulators around the world are evaluating new models of clinical trial design in efforts to improve drug safety and the efficiency of product development and submission reviews. As an example, the US Food and Drug Administration's Critical Path Initiative and Opportunities List aims to streamline clinical trials using alternatives from the traditional 'empirical' models, such as: learning trials, disease-specific, mini-dosing and indication-specific trials. The European Medicines Agency (EMEA) has also released new guidelines for trial design for small populationsFootnote 5, indicating that less conventional methodologies are acceptable to maximize the efficiency and statistical power of a trial involving a small population, but recognizing that these may be at the cost of increased complexity and bias.

Long-term studies to monitor safety and efficacy of medication for the treatment of chronic conditions are another trend that has become more common in the wake of post-market safety concerns regarding COX-II inhibitors and other products.

There has also been an increase in combination and co-development products involving drugs and medical devices. Recent advances in the development and authorization of diagnostics brings new challenges to policy makers, regulators and health system administrators. Challenges include application requirements and assessment, quality assurance, and authorization, to name a few.

To take advantage of advances in science and developments in trial designs, Health Canada can help enable innovation to increase access to new therapies, but must also mitigate potential risks to human research participants. Patients demand access to information and treatments that will meet their health needs (i.e., increased access to new therapies through alternate clinical trial designs), but require assurances that the system will address potential ethical and risk concerns. The research community and industry require guidance and clarity on the regulatory framework within which they operate and make drug development decisions.

Product development challenges

Drug development is an increasingly costly undertaking, with estimates of between $800M and $1.7B to market a new drug when the costs of researching unsuccessful candidates are factored in. According to the US FDA, a drug entering phase I trials in 2000 was less likely to reach the market than one entering phase I trials in 1985 (14% vs. 8%).

Challenges to drug development, in addition to cost and access to funding sources and patient populations, also include capacity issues such as experience with regulatory processes. Contract research organizations (CROs) are often hired for their efficiencies and expertise in this area, but the emerging biotech Small Medium Entreprise (SME) market may require more support.

Many regulators are devising strategies to modernize their regulatory frameworks to optimize research collaborations, improve predictability, production, process efficiencies and innovations in drug development. Strategies include a variety of engagement activities to provide assistance early on and during the drug development life-cycle, to improve information sharing, and by bringing clarity of interpretation through development of specific guidance and regulations.

Regulators around the world are also adopting various strategies to address these challenges. The nature of services provided includes development of guidances and sponsor engagement. For example, the EMEA has established an Office of Small and Medium Entreprise (SME) which provides advice to drug developers at the early stages of product development.

Trends in product licensing and life-cycle approaches

Systems of conditional or probationary licensing have been established internationally to accelerate access to drugs for serious and life-threatening diseases on the basis of early evidence of safety and efficacy (e.g., accelerated approval regulations in the US, conditional marketing authorization process in the EU). These systems are incorporating requirements for solid pharmacovigilance strategies for products when introduced to broader markets. Health Canada is actively exploring the development of a progressive licensing framework for pharmaceuticals and biologics to address the life-cycle management and review of drugs, which will incorporate similar concepts to the life-cycle approaches being adopted by other regulators.

Research on specific populations

Internationally, governments and institutions have taken a variety of policy, regulatory and legislative measures to stimulate investment in research and conduct of trials on specific sub-populations, such as womenFootnote 6, ethnic minorities and children (e.g., extension of patent protectionFootnote 7 for paediatric trials, EMEA child medicines guidance, and EU paediatric clinical trials registry). Research on vulnerable populations such as children raises challenges for the oversight of ethics (e.g., informed consent and assent practices). However, the need for a broader evidence base to informed use of drugs in these populations makes such research imperative. In fact, many drugs are not desgined or formulated specifically for children, resulting in challenges to develop precise information on the label to guide use in children.

Clinical trials in special populations are needed to better serve the interests of these populations because medications may have different pharmacokinetics and pharmacodynamics in different populations. Trials that look at appropriate therapies for conditions and diseases where there are gender differences in disease patterns, such as cardiovascular disease, are also encouraged.

Research in public health emergency situations

The conduct and oversight of clinical trials in response to infectious disease outbreaks (e.g., SARS) poses unique challenges for regulators. Regulatory systems need to be sufficiently flexible, yet robust, to enable research to be conducted during public health emergencies. Similarly, novel approaches may need to be pursued, including pre-approval of trial protocols by regulators and REBs, to facilitate implementation when an emergency situation arises.

Vaccine development for new infectious diseases (e.g., West Nile Virus, avian influenza pandemic) is raising particular concerns related to: intellectual property (IP) rights and protections; research and development capacity; regulatory capacity and effectiveness; and the preferred use of clinical trials for safety and efficacy determinations.

Health Canada is currently developing a regulatory amendment to permit the block release of non-marketed drugs for health emergency or bio-defence situations, which is expected to be published in Canada Gazette I in June 2007.

Openness and transparency

Over the last few years, there has been increased international focus on developing and implementing approaches to the registration of clinical trials and the disclosure of clinical trials results to respond to calls for greater openness and transparency in this area. The World Health Organization (WHO) has recently published its registration policyFootnote 8. Other entities have adopted policies, such as the International Committee of Medical Journal Editors and the Canadian Institutes for Health Research, which include requirements to register clinical trials in order to be considered for publishing and grant funding. International and domestic needs and priorities will inform the development of approaches related to: data sets required for submissions and registries; access to information; standards and reporting formats; and privacy and commercial confidentiality. Health Canada recently completed a series of public consultationsFootnote 9 on the registration and disclosure of clinical trials to identify options to improve public access to information. Health Canada will work with the results of these consultations to develop options for a Canadian approach to registration and disclosure.

Globalization

Globalization will impact the drug industry in Canada, both in terms of investment in research and development, and the conduct of clinical trials. Canada currently has a 2% global market share of clinical trial activity and is recognized for having competitive science capacity, expertise and regulatory requirements and incentives. However, global trends indicate an increase in investments in clinical trials overseas (e.g., India and China) due, in part, to reduced costs, efficiencies in recruitment practices, recognized scientific capacity and expertise, and legislative and regulatory frameworks that promote investment. There is also an increase in the number of multi-centred and multi-country clinical trials, raising concerns as to access to information (adverse event reporting, results), regulatory equivalency and interpretations, ethical practices and timeliness of the various approvals (including Health Canada, REBs, etc.).

Section III - Key Thematic Areas and Questions for Discussion

This section outlines some of the key issues that are being explored by HPFB as part of the review of the clinical trials regulatory framework and proposes a number of specific questions for discussion with stakeholders. This will help guide the dialogue with stakeholders and the identification of options and recommendations to strengthen the framework and ensure that it is responsive to future needs. The issues and questions for discussion are organized in what follows under three thematic areas: the scope of the regulatory framework; the flexibility of the regulations; and roles and responsibilities.

A. Scope of the regulatory framework

The scope of the regulations determines which trials require authorization by the regulator through a clinical trial application, and the level of detail required for submission and review.

The clinical trials regulations address the sale or importation of a drug for the purposes of a clinical trial involving human subjects. A clinical trial is further defined as "an investigation in respect of a drug that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug". In the regulations, 'drug' is further defined as 'a drug for human use that is to be tested in a clinical trial'. The current focus of clinical trial application and review requirements relates to drug development (i.e., new drugs or new indications for approved drugs) for phase I to phase III trials. Marketed drugs are excluded from the requirement for authorization if the trial is being conducted within the drug's approved indication.

Changes brought by the 2001 regulations expanded the scope of clinical trial review from clinical trials conducted by a manufacturer to support drug development and market authorization to include:

  • "practice of medicine" trials by investigators and research consortia investigating new or innovative uses of marketed drugs; and
  • many trials in which marketed drugs were used "off-label" within accepted standards of medical practice, or as research tools.

The findings and observations from the regulatory review to-date have identified the following issues related to the scope of trials subject to the regulations:

  • applying a risk-based approach to clinical trial submission and review requirements;
  • phase IV trials and post-market trends; and
  • alternate access mechanisms.

Applying a risk-based approach to clinical trial submission and review requirements

The regulations were drafted to acknowledge the reality that clinical trials are diverse in scope, and requirements in certain trial contexts may not be relevant in others. For example, a risk-benefit analysis for a drug used to treat a life-threatening disease is very different from an analysis for a drug used to treat a minor, non life-threatening condition. The regulator may exercise flexibility if a protocol is deemed to be moderate or low risk. It is important to recognize, however, that risk-benefit assessments occur in a rapidly evolving health care system, requiring regulators to have substantive knowledge of changing standards of care and medical practice, and to apply judgement, reasonableness and proportionality in approach.

A number of respondents in the summer 2006 electronic consultation have questioned the appropriateness of the current scope of trials requiring a clinical trial application (CTA). Some debate the value-added and opportunity cost of reviewing CTAs in instances of perceived low-risk. For example:

  • Trials involving drugs outside their approved indication but where the drug is widely used in clinical practice for this indication.
  • Health Canada routinely receives clinical trial applications or enquiries regarding research trials in which the drug is being used because of its properties. However, these are not considered clinical trials under the current definition.
  • Bioavailability/bioequivalence trials for generics, where the safety profile of the product is well-known.

Other regulators have outlined exemptions and have established guidance documents advising sponsors not to submit certain trials for regulatory review and to permit more limited data (e.g., pre-clinical evidence) than would normally be required. For example, the US Food and Drug Administration's 2004 Guidance for Investigational New Drug Submission Requirements for Studies of Marketed Drugs for the Treatment of Cancer states that trials involving marketed products outside their approved indication are permitted 'to the extent that such changes are supported by the scientific literature and generally known clinical experience'.

In other instances, where drugs are used in trials for their properties as opposed to discover or verify the properties of the drug (i.e., off-label use of a drug to alter heart rate in examination of cardiovascular responses to certain exercises), submission requirements are under review. Also, very early phase I trials/exploratory trials (e.g. screening and microdose studies), which generally have no therapeutic intent, may not be subject to the same requirements as other studies, as long as sufficient, scientific evidence is provided and the protocol is such that the safety of the participants is not compromised. Often, these and other exceptions integrate conditions as part of the exemption requirements (e.g., compliance to good clinical practices, ethics review, relaxed chemistry and manufacturing requirements).

Health Canada's electronic consultation raised the need for clarity with respect to clinical trial submission requirements. Sponsors and others involved in clinical research expect regulatory requirements to be clear, predictable and consistent with other standards to which they must adhere. Any exemptions would require clear articulation of submission and review requirements associated to the type of clinical investigation (e.g., exploratory versus clinical trial); submission (e.g., CTA, amendment, notification); and product (e.g., preventive, diagnostic, therapeutic).

Phase IV trials and post-market trends

Some respondents in the summer 2006 electronic consultation expressed a desire to expand the current framework to require submission for all research involving humans, including observational studies and phase IV trials.

Currently, a clinical trial application is not required for phase IV trials involving marketed products which focus on the approved indication. However, they need to comply with some of the regulatory requirements for clinical trials. While Health Canada has regulatory responsibility for the approval of new drugs, it does not have authority over the practice of medicine. Traditionally, trials conducted with marketed drugs within their approved indication have been categorized as phase IV studies. They include safety or efficacy studies comparing two products as they would be used in medical practice, as well as studies evaluating the outcomes of medical practice where the drug is only one component. There can also be a blurring of divisions between 'pre and post marketing' phases, where marketed products are used 'off-label' in the practice of medicine.

Currently, Health Canada does not have the regulatory authority to require that post-market studies once a product has been approved. Requirements to conduct post-marketing studies are currently being considered as part of HPFB's progressive licensing framework initiative.

Alternate access mechanisms

Drugs that have not received marketing authorization by Health Canada may be accessed through the Special Access Programme (SAP) or through an authorized clinical trial. Each of these mechanisms have different objectives.

The purpose of the SAP is to provide limited access to drugs and medical devices that cannot otherwise be sold or distributed in Canada. Authorization for access is provided to health care practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, unavailable or offer limited options.

Products released through the SAP are not subject to a detailed regulatory review, as is the case with new drug submissions and clinical trial applications. This supports the intent of the Programme to allow for decisions to be made quickly within the context of a medical emergency.

Results from the 2006 electronic consultation indicate support for 'compassionate use' trials to bridge the gap between the Special Access Programme (SAP) and clinical trials, particularly in cases where exclusion and inclusion criteria in clinical trial protocols may impede patient access to investigational drugs or treatments. Other regulators, such as the US FDA, have adopted alternate mechanisms to provide access to unapproved drugs. The SAP has occasionally been interpreted by stakeholders as a means of 'compassionate' access to unapproved drugs, although the program currently has no defined authority in this regard. Consequently, there have been some requests through the SAP that go beyond the original intent and design of the program. A review of the SAP is currently underway to establish a modernized framework that would encourage the appropriate use of the SAP, and provide an ethical foundation for permitting compassionate access to new therapies outside of clinical research.

A majority of respondents in the electronic consultation were of the view that clinical trials should be the preferred mechanism to access drugs during their development phase.

Questions for discussion - scope of the regulatory framework

  1. Are there certain types of trials that should not be regulated or regulated differently under Canada's Food and Drug Regulations (e.g., Phase IV, bioequivalency trials for generics, notification process for low-risk trials)? If so, under what circumstances, conditions and/or exclusion criteria?
  2. Does the current framework adequately meet the various access needs of the Canadian population or should it be expanded (e.g., to include compassionate use trials)?

B. Flexibility of the regulations

The flexibility of the regulations refer to their interpretation by Health Canada and regulated parties, as well as their predictability and transparency. Flexibility can also be considered in the context of the framework's ability to adapt to changes in the clinical trials environment.

Health Canada, through its framework and supporting guidances, endeavours to allow for appropriate and sufficient flexibility to meet the needs of current and emerging products and protocol designs, while maintaining adequate levels of human protection and addressing safety, efficacy and ethical concerns. In addition, clarity in predictability, interpretation and application of the regulatory requirements is essential.

Trends in clinical trial design, pharmacogenomics, and product development challenges (see Section II) raise questions about whether the current regulatory frameworks may need to be revised to take into consideration the impacts of emerging science and technology.

(i) Interpretation issues

Respondents to the summer 2006 electronic consultation indicated a need for consistent interpretation of the regulations, particularly concerning the following provisions: labelling, records retention, amendments, and good clinical practices.

Labelling

The labelling requirements for drugs used in clinical trials are based on the expectation that a trial will be conducted with a new drug. The requirements outline the responsibility of the sponsor to ensure the drug bears a label in both official languages, including, but not limited to, the following: the name, number or identifying mark of the drug; the expiration date of the drug; the recommended storage conditions for the drug; the lot number; the name and address of the sponsor; the protocol code or identification. Trial drugs may have several labels (shipping box, vials, dispensed patient container, etc.), and many trials are conducted with marketed drugs, often taken "off the shelf." There have been interpretation issues related to the use of expiry date, whether the re-test date or the expiry date is to be identified, and whether labels should be affixed on package inserts only.

Records retention

The 2001 regulatory amendments included records retention requirements mandating the sponsor to retain documents related to the conduct of the clinical trial, including all versions of the investigator's brochure and adverse events from inside or outside Canada, for a period of 25 years. Several issues related to these requirements were identified during the electronic consultation. Concerns were raised related to the accountability for document retention (e.g., where records must be kept, who is to keep the records) and the confidentiality of documents and information (e.g., who has access to the records, transfer of patient medical records to the sponsor or between entities over time). The suitability of the record keeping requirements in a risk-based approach has also been questioned. For example, should the record keeping requirements for bioequivalence studies be the same for those for stem cell research and vaccines. Some have also noted that Canada's records retention period (25 years) is longer than what is required by many other leading regulators.

Amendments

The requirements for CTA amendments appear to be burdensome to some stakeholder groups. These respondents have identified the need to clarify the regulatory requirements, to streamline processes and to review the amount of information that is required. In particular, comments indicated that Health Canada should consider limiting full amendment submissions to filing only substantive changes and to further define 'minor' and 'major' changes.

Good clinical practices

In 1997, Health Canada adopted the International Conference on Harmonization's "Good Clinical Practices - E6 guidance" as a standard for clinical trials in Canada. This guidance is intended to provide a unified standard to facilitate mutual acceptance of clinical data by regulatory authorities and should be followed when generating data to be submitted to regulatory authorities. Accordingly, ICH E6 includes rigorous standards for the administrative conduct of clinical trials, including extensive monitoring and quality control.

Canada's current regulatory framework defines good clinical practices as "generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons, and the good clinical practices referred to in Section C.05.010" (which outlines the sponsor's responsibilities). The consistency in interpretation and application of good clinical practices was raised by some as an issue in the summer 2006 consultation.

(ii) The clinical trials environment

Traditional drug development has proceeded from phase I to phase III studies, where typically, marketing is authorized after phase III. Phase IV therapeutic use studies may be conducted after marketing, or the manufacturer may choose to repeat phase II and III as they seek new indications. Traditional drug development has always required flexibility in approach because of the different requirements at different stages of development. For example, the sponsor/investigator may have tight control over the conditions and treatment of subjects in a phase I trial, but the phase III trial subjects must be representative of the disease population and may have other co-morbidities and conditions.

Advances in technology, changes in statistical and theoretical principles applied in clinical trial protocols, and societal concerns of safety and effectiveness of marketed drugs are changing the process of drug development. The stages of drug development are often blurred and rendered more complex, challenging the boundaries of regulatory frameworks. For example, academic/investigator driven studies may not fit within the traditional framework, particularly when evaluating 'off-label' use in clinical practice. Concerns regarding the safety and effectiveness of marketed products lead to the need for post-market studies as part of a life-cycle approach to the regulation of drug products (e.g., Health Canada's proposed progressive licensing framework for pharmaceuticals and biologics). There are also increasing demands to collect and disseminate more information on drug safety and safety in special populations (e.g., paediatrics, geriatrics).

Further, the development of biomarkers and new scanning methods for disease progression are setting new targets for innovative medicines. Improvements to protocol design and consequent decision making will increase as the understanding of the science behind the process develops. Challenges for the regulator include setting standards and criteria for acceptance, removing barriers for innovation and facilitating movement of drug products through the drug development process.

Trends in clinical trial design (e.g., adaptive, long-term studies) raises scientific, ethical, design and statistical challenges not typically encountered in trials examining disease types with larger affected populations. These alternative study methods to the traditional 'empirical' clinical trial study often allow for smaller patient population size, unblinding, use of new technology and science (e.g., biomarker use for intermediate endpoint testing) and perhaps shorter trial length in which to gather evidence. These 'new' design models challenge current data and submission requirements, and can equally be expected to affect the manner and efficiency in which trial review is performed. Regulators need to assess the demands of these variable designs on the interpretation of the regulations and the capacity of reviewers to effectively perform their duties.

Other regulators are moving away from a decentralized approach to manage regulatory review in cases where products do not follow the traditional drug development plan. For example, the US has established an Office of Combination Products. Regulators have also developed guidance and policies to clarify regulatory requirements for these design circumstances.

Globalization

One of the goals of the 2001 regulatory amendments was to bring Canada's regulatory framework in line with international standards and best practices in terms of scope, compliance to good clinical practices, and oversight (e.g., inspections, ethics committee review). In some areas, Canada leads other major regulators, including in its 30-day default review period and administrative 7-day review target for bioequivalence trials.

Results from the summer 2006 electronic consultation indicated that some Canadian requirements (e.g., Canadian addenda to ICH guidelines, chemistry and manufacturing requirements) are more stringent than in other countries, often leading to increased barriers to Canadian participation in clinical trials on the global stage. For example, attracting science expertise to Canada to participate in clinical research and or attracting foreign investment in clinical research in Canada was noted to be influenced by the administrative burdens related to regulatory requirements.

The effects of globalization may have had an impact on the clinical trials environment in terms of investment in research and development and the conduct of clinical trials on the global stage. Some trends that have surfaced include an increase in multi-centre and multi-country trials with large sample sizes in order to establish safety and efficacy endpoints. Sponsors conducting trials involving rare diseases are required to cross borders in search of eligible research participants. Equally, there are expectations on the part of regulators in some countries that clinical trial research be conducted on a domestic population (or a representative and proportionate sampling thereof) as part of a new drug submission.

Questions for discussion - flexibility of the regulations

  1. What should Health Canada address in regulation and/or with other policy instruments to ensure that the requirements are clear and transparent?
  2. Is the current regulatory framework flexible enough to accommodate advances in science and technology and/or for innovative approaches in conducting clinical trials (e.g., adaptive trial designs, nanotechnology)? What changes (if any) to the current regulatory framework would be required?
  3. Are the current regulations sufficiently harmonized with international standards and best practices? If not, where would further harmonization of regulatory requirements be desirable?
  4. What measures could be taken to further strengthen the health and safety of research subjects?
  5. Are there barriers to further R&D investment? Would addressing these barriers have a significant impact on R&D investment in Canada?

C. Roles and responsibilities

Many drivers of change are impacting on the traditional roles and responsibilities along the drug development cycle, from pre-clinical research through to market access and even to post-market monitoring and surveillance. Equally, the influences of science and technology breakthroughs, the changing nature of drug development and the increased participation of various players in the clinical trials environment raise concern as to the relevance and sufficiency of the roles and responsibilities currently outlined in the regulatory framework.

Ensuring the safe and ethical conduct of clinical trials is a shared responsibility for sponsors, researchers, research ethics boards, contract research organizations, research funders, health care institutions, and Health Canada. Many of these players have taken action and developed strategies to strengthen the quality of clinical trials and the protection of human research participants. The roles and responsibilities of all parties requires re-examination to increase transparency and improve accountability. The following explores challenges posed by the changing roles of "players", models of oversight systems, the role of others supporting clinical research in Canada and the role of the regulator.

(i) Changing roles of players in the conduct and oversight of clinical trials

The scope of the regulations was expanded under the 2001 clinical trials framework to include clinical trials for all drugs used outside their marketed indication. The "sponsor" of the trial was no longer just the manufacturer, but also included '...individuals, corporate body, institution or organization that conducts a clinical trial'. Since 2001, there have been changes in the roles and approaches to the administration of clinical trials, which may pose challenges to the current application and interpretation of regulatory requirements:

  • The "players" who must now comply with the regulations expanded from manufacturers to include academics, research institutes, health care institutions, health professionals and independent researchers. One issue identified in the summer 2006 electronic consultation was that the new regulatory requirements are seen as a barrier to academic and independent research because of the increased regulatory burden.
  • Under the 2001 regulations, all of the regulatory responsibility is with the sponsor. However, the sponsor is only one player in a clinical trial process which also includes contract research organizations (CROs), research ethics boards (REBs) and investigators, to name a few. The summer 2006 consultation identified that the responsibilities of the sponsor may be blurred in cases where the CRO conducts or monitors the clinical trial on behalf of the sponsor.
  • There has been an expanded role of other players not currently captured under the regulatory framework, such as Data Safety Monitoring Boards (DSMBs), who are routinely engaged to monitor safety and efficacy results during the conduct of a trial.
  • Under the current framework, the sponsor of a research agency-funded trial (e.g., by the Canadian Institutes for Health Research) or an investigator-initiated trial is regarded as the institution in which the trial is conducted, not the investigator.

The changing roles of these various players have challenged the lines of accountability in the conduct and oversight of trials in Canada. The stakeholders are requesting clarity so that each may understand their role and accountability in order to undertake their work effectively and accordingly within the system.

(ii) Oversight systems

A review of oversight systems is important to ensure that human protection systems are efficient, capable and redress is timely. Exploring ways to improve the system of human research protection in Canada begins by examining the roles and capacities of various players and to consider strategies to support the regulations, such as: establishing a national ethics review approach for higher risk trials (e.g., gene therapy); expanding the use of Data Safety Monitoring Boards (or equivalent) to support research on proof of clinical trial results and review of adverse event reports; and introducing measures which could extend the reach of the regulations beyond the trial sponsor. However, the role of federal regulatory oversight must also be mindful of the provincial/territorial jurisdictions related to the practice of medicine.

The functioning of REBs plays a central role to ensuring human research protections within the oversight system of clinical trials in Canada. Not only are REBs mandated to ensure the protection of patient rights, safety and well-being, but they are also required to perform monitoring and review functions outside of the trial protocol such as: compensation, informed consent forms and process; and reviewing local and institutional considerations that may affect the conduct of a trial. Although the role is identified in regulation and guidance (e.g., good clinical practices, Tri-Council Policy Statement), there is often limited information provided on how REBs are expected to fulfil their mandate (e.g., how to act on adverse events reports).

Concerns have been raised that the scope of responsibility that is required by REB may extend beyond their current capacity. There are other organizations active in the clinical trials environment which could potentially assist in relieving some stresses on REBs such as Data Safety Monitoring Boards (DSMB), who are external monitoring bodies composed of experts in their field, but not connected to the study. The primary role of DSMBs is to protect the safety of trial participants through the analysis of interim outcome data and adverse events. Although they can make recommendations to discontinue trials, there are no provisions in regulation requiring the functioning nor oversight of these monitoring bodies, although they are used widely in practice.

The use of contract research organizations (CROs) has increased since the inception of the 2001 regulations, and similar entities (e.g., site management organizations) are being engaged frequently by industry and academia to conduct clinical trials on behalf of sponsors. There is also an increase in independent clinical trial activities, an area where the regulator and human research protections systems, including REBs, currently have limited oversight capacity. As indicated previously, the current framework identifies accountabilities in the conduct of clinical trials through the sponsor, which may or may no longer be sufficient, given the changing roles and administrative approaches.

Concerns have also been raised as to the current oversight of REBs, particularly in situations where REBs function within public health institutions or operate privately. The complications due to the role of REBs also extend to the trends observed in the conduct of clinical trials, which are increasingly multi-centre and multi-site in nature. The requirements for review submissions by multiple REBs have been expressed as a burden by certain stakeholders in the research community, as well as dealing with the results of the REB review process (e.g., cases where one REB approves while another does not).

The results of the summer 2006 electronic consultation indicated delays due to REB process, and that efficiency measures could be introduced to ease the burden. Respondents supported an accreditation system for REBs and the development of national standards as a step in the right direction to addressing some of these issues identified above.

(iii) Role of others supporting clinical research in Canada

Research funders

There are several other stakeholders supporting clinical trials and research in Canada, including government agencies (e.g., CIHR), provincial governments, charitable organizations (e.g., Heart and Stroke Foundation), independent foundations, foreign governments (US National Institute of Health), universities, and individual researchers.

These different organizations, who provide funding for human research, often have their own review processes in order to ensure scientific rigour of protocols and protection for research subjects. For example, many research funding agencies, such as CIHR, also require extensive ethics review prior to approving a grant. With the coming into force of the 2001 regulatory framework, all research must be approved by a REB. Results from the summer 2006 electronic consultation identified the need for efficiencies and streamlining of practices throughout the system.

Qualified investigator / Principal investigator

Under the current framework, a qualified investigator (QI) must be a licenced medical practitioner (MD) or dentist. However, the principal investigator of many investigator initiated trials may not be an MD or dentist, thus cannot be the QI even though activities in the trial fall within the normal realm of practice. With the growing complexity of trials that are being conducted in Canada, and the approach to allow involvement of licensed professionals in the conduct of trials pertaining to the risk profile of the trial, the exclusion of certain professions (e.g., pharmacists, hospital pharmacists, nurses) from participation in the clinical trials environment is being questioned. The results of the summer 2006 consultation indicated support to expand professions listed under the QI and principal investigator (PI) definitions, such as nurse practitioners and pharmacists.

(iv) Role of the regulator

The 2001 regulatory framework and inspection system have reinforced and validated activities already under way by sponsors, researchers, and other federal government departments aimed at promoting research excellence through greater awareness and application of good clinical practice principles, and increased oversight through monitoring and REB review.

The role of the regulator is, in part, to exercise due diligence by: reviewing incoming trial applications, amendments and adverse events reports; inspecting trials sites and investigating allegations of regulatory non-compliance; and to ensure the protection of research subjects. While it is recognized that oversight of clinical trials expands beyond the regulator (e.g., to REBs, DSMB, etc.), the summer 2006 consultation identified that Health Canada should play a primary role in patient safety, the development of national standards, compliance and enforcement activities, compassionate access and international harmonization.

Compliance and enforcement

In 2001, a new inspection program was designed and subsequently implemented. Health Canada established an inspection strategy in order to verify regulatory compliance, to ensure that generally accepted principles of good clinical practices are met, and to validate data quality. The Strategy sets out two types of compliance activities: inspections (an official review of documents, facilities, records and other resources related to the trial) and compliance verifications/investigations (a specific response to known or suspected non-compliance). Inspections of clinical trial sites and complaint-driven investigations encompass research sponsors, contract research organizations, REBs and qualified investigators, to allow for the verification of source documents, including medical records and drug storage conditions.

Results from the summer 2006 consultation identified that the Inspection program has realized its objectives although some improvements could be brought to the program. A review of compliance and enforcement issues is timely in that successes and gaps can be identified and prioritized to move towards increased harmonization in decision-making, efficiencies, and ensuring sufficient authorities and capacity are in place for effective compliance and enforcement.

Support to stakeholders - the role of the regulator for the future

There has been significant movement by other regulators to offer particular services to support various sub-communities involved in clinical trials, and to improve the streamlining and regulatory compliance of stakeholders involved in clinical trials. For example, the US Food and Drug Administration engages in early discussions with sponsors to support drug development plans and interpretation of regulatory requirements along the drug development life cycle.

There has been a significant growth in the number of Small and Medium-sized Enterprises (SMEs) involved in drug development in Canada, particularly in the area of biotechnology. Trends identify that SMEs and the biotechnology industry are an emerging research and development investment market that may require earlier regulatory guidance and advice in order to achieve their potential.

It is generally viewed that limited experience with the regulatory process may impact the quality of clinical trial applications. Some regulators such as the European Medicines Agency (EMEA) are establishing advisory services beyond guidance documents, policies and outreach activities to include special offices to serve the needs of certain types of stakeholder, providing protocol, scientific and/or drug development advice. Regulators have introduced such measures to provide additional support to the stakeholder community as a means to increase the quality of data, increase compliance and to support innovation.

Some respondents to the summer 2006 electronic consultation supported the need for additional services to be offered by Health Canada, such as the adoption of joint review committees and pre-CTA meetings to discuss requirements, share information and receive input on products along the drug development life cycle.

Questions for discussion - roles and responsibilities

  1. Is the current oversight system sufficiently clear as to the roles and responsibilities of the various players involved in clinical trials? If not, how could they be clarified?
  2. Are there discrepancies that need to be addressed or efficiencies that can be gained between the oversight processes of 'research funders' and those of Health Canada as a regulatory authority?
  3. Should Health Canada allow those engaged in certain aspects of health professional practice to function as a QI or PI for clinical trials? Under what conditions and criteria?
  4. What kind of support could Health Canada provide to other sponsors or research performers in carrying out their clinical trial activities (e.g., guidances, pre-CTA meetings, advice for industry/researchers, etc.)?

Section IV - Next Steps

Results from the consultation activities on the review of the clinical trials regulatory framework will help inform the development of short, medium and longer term measures to strengthen the regulatory framework for the future. Additional consultations will be undertaken by the Branch as necessary as we move forward on this initiative, including through the Canada Gazette process if regulatory amendments are being considered, as well as consultations on the progressive licensing framework for pharmaceuticals and biologics.

The Health Products and Food Branch will continue to provide progress reports on this initiative through its Blueprint for Renewal web site.

Annex A - Acronyms

ADR
Adverse Drug Reaction
CAREB
Canadian Association of Research Ethics Boards
CIHR
Canadian Institutes of Health Research
CT
Clinical Trial
CTA
Clinical Trial Application
CTA-A
Clinical Trial Application amendment
CRO
Contract research organizations
DSMB
Data Safety Monitoring Boards
EMEA
European Medicines Agency
EU
European Union
FDA
Food and Drugs Act
FDR
Food and Drug Regulations
FOCUS
Forum of Canadian and US REBs/IRBs
GCP
Good Clinical Practice
HPFB
Health Products and Food Branch's
IRB
Institutional review board
ICH
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
NCEHR
National Council on Ethics in Human Research
PRE
Panel on Research Ethics
PMPRB
Patented Medicines Prices Review Board
RIAS
Regulatory Impact Analysis Statement
R&D
Research and Development
REB
Research Ethics Boards
SAP
Special Access Programme
TCPS
Tri-Council Policy Statement
WHO
World Health Organization
UK
United Kingdom
US
United States
US FDA
US Food and Drug Administration

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