Clinical Trials Regulatory Review: Stakeholder Consultation Workshop: Discussion Summary Report

Ottawa, Ontario
March 26, 2007
Prepared by INTERSOL

Contact: Clinical Trials Regulatory Review

Table of Contents

• I. Background
• II. Introduction
• III. Setting the Context
  • Key Themes
    1. Scope of the Regulations
    2. Flexibility of the Regulations
    3. Roles and Responsibilities
    4. Participant questions and answers
• IV. Feedback on Key Themes
  • Discussion #1 - Scope and Flexibility of the Regulations
    1. Scope of the Regulations
    2. Flexibility of the Regulations
  • Discussion #2 - Roles and Responsibilities
    • Health Canada
  • Summary of Group Observations/Recommendations
• V. Closing Remarks and Next Steps
• Appendix A - Reference documents
• Appendix B - Invited Participant List
• Appendix C - Participant's Evaluation Summary
• Appendix D - Glossary
• Appendix E - Responses to participants questions

I. Background

Building on progress made under the Health Products and Food Branch's Strategic Plan 2004-2007, Health Canada has begun a renewal of its regulatory system-the Blueprint for Renewal initiative^{Footnote 1} - which aims to modernize the regulatory system for health products and food. By addressing key challenges and opportunities affecting Canada's regulatory environment, Health Canada can better serve Canadians now and into the future.

Health Canada has made significant gains in the efficiency and responsiveness of its health product review system. For example, the Department has eliminated its new drug submission review backlog in pharmaceuticals and biologics, and is now meeting internationally-comparable drug submission review targets. Equally, Health Canada clinical trial reviews have consistently met regulatory performance review targets (i.e. 30-days), and have also consistently met the administrative 7-day review target reserved for certain types of trials (i.e. bioequivalence trials).

Health Canada has also implemented new measures to strengthen the safety of the regulatory system and has made significant progress in increasing the transparency and openness of its regulatory activities. This recent progress marks a great achievement for the Branch and presents a new opportunity to talk about the future.

With the introduction of the 2001 regulatory framework for clinical trials, Health Canada committed to a comprehensive review of the framework and engaged in a summer 2006 e-consultation to seek the views from stakeholders on the impact and effectiveness of the framework. Building on the results from the e-consultation, the March 26, 2007 workshop provided an opportunity for stakeholders to continue the dialogue and to provide their input on ways to improve the clinical trial regulatory framework for the future.

This report presents an overview of the key observations and recommendations stemming from the workshop discussions. The discussion document, presentation deck and report of results are available on the Health Canada website^{Footnote 2}.

II. Introduction

Mr. Neil Yeates^{Footnote 3} opened the meeting with a welcome to all participants^{Footnote 4}, reflecting on recent regulatory renewal history and accomplishments. In his remarks, he introduced the purpose and importance of this workshop in the overall process and spoke of the following:

A number of important amendments to the clinical trials regulations came into force in 2001 to modernize the regulatory regime. The key objectives were to strengthen safety of patients involved in human clinical trial research in Canada and to offer an internationally competitive regime to support investments in clinical research and development in Canada.

Health Canada had committed to review the 2001 regulatory framework within five years of implementation. In summer 2006, the review of the regulatory framework was supported by an e-consultation, to which some of the participants in this workshop provided their views.

The purpose of the workshop was to further explore some of the key issues, and identify suggestions to help improve the framework for the future. Mr. Yeates acknowledged the diverse group of experts representing broad stakeholder perspectives whose input will be very valuable to Health Canada, and thanked the group for participating in this important exercise.

The review of the clinical trials regulatory framework is linked to the broader review of the Branch's policies, program and resources - the Blueprint for Renewal initiative. Other key initiatives from the Blueprint related to the clinical trials review include: the development of a Canadian approach to the registration and disclosure of clinical trials; work towards establishing a progressive licensing framework for pharmaceuticals and biologics; and a review of the Special Access Programme. Separate consultations on these initiatives have taken place or are expected to take place in the near future.

III. Setting the Context

Dr. Stephen Lucas^{Footnote 5}, provided an overview presentation^{Footnote 6} to establish the context for the workshop and to provide a foundation for the group by presenting the key themes and issues for discussion during the workshop: the scope of the regulations, the flexibility of the regulations and roles and responsibilities.^{Footnote 7}

Key Themes

1. Scope of the Regulations

For the purposes of this workshop, the scope of the regulations was determined to be which trials require authorization by the regulator through a clinical trial application (CTA) and the level of detail required for submission and review.

Current regulations address the sale or importation of a drug for the purposes of a clinical trial (CT) involving human subjects. The focus of clinical trial applications 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 (e.g. Phase IV).

Changes brought by the 2001 regulations expanded the scope of clinical trial review to include:

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

Exploring the issues

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:

1. Applying a risk based approach to clinical trial submission and review requirements: Some respondents to the summer 2006 e-consultation questioned the appropriateness of CTA requirements involving trials of perceived low-risk (e.g., drugs outside their approved indication however used widely in clinical practice for that indication; where the drug is used due to its properties; bioavailability/bioequivalence trials where the safety profile is well-known.) A number of other regulators have adopted guidance with clear criteria based on the type of clinical investigation (e.g., exploratory versus clinical trial), submission requirements (e.g. CTA amendment, notification), and product (e.g., preventive, diagnostic, therapeutic).
2. Phase IV and post-market trends: Many respondents to the summer 2006 e-consultation supported an expansion of the regulatory framework to include all trials, including: phase O - very early phase I/exploratory trials (e.g. screening, microdose); and phase IV trials.
3. Alternate access mechanisms: Respondents to the summer 2006 e-consultation supported 'compassionate use' trials to bridge the gap between the Special Access Programme (SAP) and clinical trials. Trials are the preferred mechanism to access drugs during their development phase. Other regulators (e.g. US FDA) have mechanisms to provide access to unapproved drugs. Requests through the SAP often go beyond the original intent and design of the program.

2. Flexibility of the Regulations

The flexibility of the regulations refers to their interpretation, predictability and transparency. Flexibility can also be considered in the context of the regulatory framework's ability to adapt to changes in the clinical trials environment, such as with advancements in science and globalization. While maintaining flexibility, the regulator must maintain adequate levels of human protection to address safety, efficacy and ethical concerns.

Exploring the issues

1. Interpretation: 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. Clarification may be required in certain provisions such as labeling and amendments. Harmonization was desired for other provisions such as records retention.
2. Adaptability: Flexibility in the current regulatory framework may/may not be enough to accommodate:
   • advances in science and technology (e.g. nanotechnology), which challenge the current boundaries of the clinical trials regulatory framework (e.g., pharmacogenomics, biomarkers);
   • innovative approaches in clinical trial design, which present alternative study methods to the traditional empirical study, often resulting in challenges to current data and submission requirements, potentially affecting the manner and efficiency in which trial review is performed (i.e., adaptive design, long-term studies)
   • the impacts of globalization where the conduct of trials, particularly multi-country, multi-centre trials, may require assurances of harmonization to international standards and best practices if Canada is to remain competitive and to promote investment in clinical trials.

3. Roles and Responsibilities

The shared responsibility to ensure the safe and ethical conduct of clinical trials was noted, as was the various actions and strategies developed by stakeholders to strengthen the quality of clinical trials and the protection of human research participants. Since 2001, there have been changes in the roles and approaches to the administration of clinical trials, challenging the current application / interpretation of regulatory requirements. The e-consultation identified that the 2001 requirements posed challenges to certain stakeholder groups (i.e. academia) and that there may be opportunities to streamline and increase efficiencies of processes. The roles and responsibilities of all parties require re-examination to increase transparency and improve accountability.

Particular examples stemming from the e-consultation include: the support of 71% of respondents for an accreditation system for Research Ethics Boards (REBs) to address issues with the oversight and ethic review system; the benefit and/or requirement to expand the regulations to include other health professionals (i.e. who is a Qualified Investigator/Private Investigator); requiring guidelines for the use of Data Safety Monitoring Board (DSMB) and Contract Research Organizations (CROs) in the conduct and monitoring of trials.

Stakeholders in the e-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. Other regulators have introduced measures to provide additional support to the stakeholder community as a means to increase the quality of data, increase compliance and to support innovation (e.g. Office of Small and Medium-sized Enterprise in Europe). The summer 2006 electronic consultation supported the need for additional services to be offered by Health Canada (e.g., early engagement with the regulator).

Exploring the issues

Clarity is required so that each entity may understand their role and accountability in order to undertake their work effectively and accordingly within the health care system. 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.

Some stakeholders feel that there are delays due to process (e.g. REB). Streamlining and efficiency measures could be introduced to ease the burden of regulatory and process requirements, throughout the system.

This review needs to identify and prioritize successes and gaps in order to increase efficiencies and harmonization in decision-making. In addition, Health Canada will need to ensure sufficient authorities and capacities are in place to support effective compliance and enforcement activities.

4. Participant questions and answers

Participants were provided the opportunity to request clarification on the workshop approach and content. These question and answer sessions included specific clarifications on sections of the regulations and their requirements, clarifications related to Health Canada's operational capacity to meet regulatory review obligations, and details on clinical trial activity in Canada. Health Canada committed to provide additional responses to three specific questions, which are outlined in Annex E of this report.

IV. Feedback on Key Themes

Dr. Lucas reviewed the three topic areas for group discussion: Scope of the regulations, Flexibility of the Regulations and Roles and Responsibilities. Participants used workbooks to help guide and record their discussions. Each discussion session (two) was followed by a plenary session, providing each group the opportunity to share a summary of their discussions and participants the opportunity to share comments and questions for clarification.

The following is a summary of responses captured from the table report books, as well as from the comments, questions and answers provided by participants during the plenary discussions.

Discussion #1 - Scope and Flexibility of the Regulations

1. Scope of the Regulations

Participants provided their comments on trial phases that are currently regulated as well as the advantages and disadvantages of regulating other types of trials. Generally, the regulation of the current Phases I, II and III are fine and comparable to other regulators' requirements. There was varying support to expanding the regulatory framework to include trials that are not currently regulated (e.g., phase IV and phase 0).  It was noted that the regulator must be cautious not to over-regulate research at the expense of investment in clinical trials in Canada. Below are some considerations related to expanding the scope of regulated trials:

1. Approaches to Oversight of Various Trial Types
   • 7-day: Health Canada should clarify between those trials that should have an administrative 7-day review period and consider those that could have a longer regulatory default review period (e.g., 14-day; 30-day). There was a recommendation to consider regulating a longer default period instead of the 7-day administrative target for certain classes of trials (e.g. some first in man, Phase I trials using a patient population versus healthy human participants);
   • Low-risk: Health Canada should consider a notification system instead of a full clinical trial application for studies such as bioequivalence, single dose and PK/Pd where the drug is well known. 'Low-risk' trial will need to be well defined in guidance, specifically to indicate when research is not considered a clinical trial;
   • Phase O: These trials could also be considered for regulation to support harmonization with other major regulatory jurisdictions (e.g. pilot studies), to increase patient safety and oversight, and to collect information on a new drug. Phase 0 trials need to be clearly defined;
   • Phase IV: Some participants stated the advantages for Phase IV regulation to increase patient safety through the collection of information (e.g. new side-effect discoveries, drug/drug interactions, monitoring of safety signals) and to increase transparency. Others proposed the focus for phase IV should be on regulating drugs that further commercial development and not those that are investigator-driven (e.g., individual research). Comments received on the disadvantages to regulating Phase IV included the potential cost and stifling of research, particularly for academic and investigator-led studies. A notification system was proposed for Phase IV, requiring clear definitions and guidelines which include requirements for REB review, enforcement of good clinical practices (GCP), etc.
   • There needs to be clear, consistent and widely-shared definitions and guidance on the various types of clinical trials and the associated requirements. Health Canada should apply different scrutiny to review protocols for different drugs and families of drugs. Consideration could be given to include gender, age and ethnicity for all trials so appropriate analysis can be done;
   • Health Canada needs to carefully assess the costs vs. benefits of what is regulated and what is not regulated (e.g., impacts/burden on investigator-driven research). In addition, there is a need to understand the resource implications for the regulator and prioritize which areas would need to be expanded (if any).
2. Access by Patients
   • Health Canada could use the regulatory framework to promote clinical research for specific populations (e.g., rare diseases, small-population therapies) and should review circumstances related to the special needs for compassionate use.
   • Compassionate protocols' and orphan drugs require either guidance or a regulatory strategy to support these populations' needs. Advantages include data collection and oversight, however, any Health Canada considerations should not delay the availability of the product to the patient.
   • Health Canada should look at clinical research within context of the broader health care system (e.g., market availability, formulary listing, etc.).

2. Flexibility of the Regulations

Participants provided comments on the flexibility of the regulations in terms of their interpretation and their adaptability to changes in the clinical trials environment (e.g. trial design, globalization, advances in science and technology).

1. Interpretation regarding the provisions in the regulations
   • Labelling:  Labelling requirements should be harmonized with other regulators, such as the use of a nomenclature system. Consistency and clarification for inner-outer labels (e.g., bilingual requirements and feasibility due to size of the container) and the expiry date is required. The rationale for labelling requirements should be incorporated into guidance documents.
   • Record Retention: Requirements need to be harmonized with global practice in terms of the length of retention, The rationale for the 25 years records retention requirement in the regulations is not clear. Clarity is required in regards to accountability for record keeping including: who owns the data, who is required to store what information (i.e. site versus sponsor) and what are acceptable types of storage (e.g. electronic). Clear guidance is required.
   • Clinical Trial Applications Amendments (CTA-A): There is great variation in the nature of Clinical Trial Application amendments (CTA-A) with a potential to streamline the requirements and process. Health Canada should look at simplifying the requirements related to various types of CTA amendments according to the risk of the amendment (low-risk change could adopt a notification system versus full CTA-A). A Health Canada review may be required for CTA amendments but it may not be necessary to have a full REB review for all amendments. There needs to be greater clarity on CTA-A requirements as well as the differences with the Notification process.
   • Good Clinical Practices (GCP): There needs to be greater clarity, consistency and harmonization on the interpretation of the GCP requirements, which could be accomplished through activities such as the development of guidance documents, best practices, standard operating procedures, posting 'Frequently Asked Questions' to the website and by clarifying how the International Conference on Harmonization (ICH) GCP guidance applies in Canada. Health Canada needs to improve the Inspectorate's capacity and consistency. The number of GCP audits should increase and inspections should be based by study as opposed to trial site.
2. Flexibility of the Framework regarding changes in the CT Environment
   • Comments indicated that the current regulatory framework appears to be flexible enough to accommodate the changing regulatory environment. However, Canada needs to be a player at the international level to keep abreast of best practices, scientific/regulatory advances, and to be in a position to leverage regulatory resources at the international level, etc. For emerging science areas (e.g., nanotechnology, pharmacogenomics), stakeholder engagement and development of guidance and communication tools will be key.
   • Safety, efficacy and quality requirements will need to be more clear for trials using 'seamless' or adaptive design approaches. Requirements should be in guidance and be consistent locally and internationally.
3. International harmonization
   • There was consensus that Canada needs to play more at the international level in the areas of clinical trials if we are to maintain and attract investment. Canada is a 'small' country and to handle science and technology changes, there needs to be sharing of expertise and the promotion of worksharing opportunities, such as joint reviews with other regulatory agencies.
   • While retaining independent decision-making, Canada needs to harmonize where it makes sense (e.g., records retention, circumstances when a CTA is required in Canada but not an IND in the US). There is potential for harmonization in the area of registration and disclosure of clinical trials (e.g., World Health Organization registration policy) and to adopt a centralized approach to REB reporting.

Discussion #2 - Roles and Responsibilities

Participants identified the issues and provided comments with respect to the roles and responsibilities of the various players involved in clinical trials. Below is a summary of participants recommendations to address these issues, as well as areas where Health Canada could support those carrying out clinical trial activities.

Health Canada

Greater consistency in interpretation of the regulations and communications are essential within Health Canada (e.g., decision making, cases where double reporting of Adverse Drug Reactions (ADR) occurs when marketed drugs are also being used in clinical trials (CTs). There is also a need for greater transparency, predictability, clarity of regulatory requirements. Standard operating procedures (SOPs) and clearer definitions in regulation and guidance are required for roles and responsibilities in the clinical trials environment (i.e. what can be delegated and to whom) and to define terminologies (i.e. Phase IV, Phase 0).

Greater synchronization is required between Health Canada and other players (such as REBs) to support the communication of REB decisions, the collection and sharing of ADR information and compliance/enforcement activities. Health Canada needs to be a source of guidance and information. Safety reporting needs to be non-duplicative and meaningful, and requires proper analysis within the context of the use of the drug (particularly for marketed drugs). Suggestions for implementation include: creating a help line, providing educational materials, holding workshops and information sessions, using electronic systems (e.g., registries, web site FAQ and posting results), create standards for reporting, and increasing monitoring functions.

There needs to be consistent engagement along the entire product life cycle including: early engagement between the regulator and the sponsor; better continuity within Health Canada to ensure review staff are involved on a product from the pre-CTA meetings to the review of the new drug submissions; and the development of guidance documents (e.g., combination products). A life-cycle engagement approach could strengthen Health Canada's role as a regulator for providing trusted and unbiased information.

Compliance and Enforcement

Compliance and enforcement activities in some areas could be improved (e.g., GCP, Good Laboratory Practices). Individual inspector reports should be available and accessible to the public. Better dialogue with stakeholders and additional education and training for the Inspectorate staff is required. Health Canada needs to better understand the burden of regulations on stakeholder and could play a role to assist in areas such as safety reporting for independent investigators.

Other players

Greater harmonization of REBs is required as is the need to streamline the REB review processes to improve coordination and consistency in decision-making. Some identified issues related to the capacity of REBs in terms of knowledge and ability to track and analyse adverse event issues due to the volume of trials under their review. Suggestions to improve the REB process include the establishment of: a national REB for multi-centre trials (with linkages to local REBs); a national accreditation system for REBs (mixed views); a quality and control oversight system for REBs. Health Canada could consider regulating REBs and/or requiring a conflict of interest disclosure (as well as for investigators and others involved in clinical trials).

There needs to be a better definition of roles and responsibilities of CROs and DSMBs. Suggestions varied between regulating these entities to developing accreditation systems, charters, guidance and guidelines for their use in clinical trials. Responsibilities and legal accountability will need to be clarified for submission and compliance to the regulations for multi-country situations. Harmonization or adoption of other regulator's guidelines could be used as a starting point to develop the Canadian context (i.e. FDA DSMB guidelines).

Clarification is required in guidance on what is meant by and who can be a Qualified Investigator (QI) and a Principal Investigator (PI) in trials (e.g., pharmacists, nurses, geneticists). Some participants said that Health Canada needs to involve Provinces and Territories (PTs) in this discussion.

Other areas

There were various issues related to informed consent forms (e.g., responding to patient needs versus administrative requirements). In addition, participants noted that there was also a lack of clear therapeutic guidelines for clinical research in Canada.

Summary of Group Observations/Recommendations

Below is a summary of the key observations and recommendations provided by participants during the course of the plenary and workgroup discussions:

1. Health Canada's role as the regulator should be transparent. There was some confusion about Health Canada's ability, capacity and authority (e.g., to audit a process). Health Canada requires an increase in resources and expertise to carry out its functions. There is a perceived loss of continuity between trial phases resulting in duplication on the part of Health Canada, in turn, causing duplication on the part of industry. Participants want consistency and predictability in terms of the process and interpretation of the regulations.
2. Better guidance documentation is needed. Health Canada is expected to provide better clarity of the process, requirements, roles and responsibilities. There needs to be clear, consistent and widely-shared definitions and guidance on the requirements for various types of clinical trials. Other recommendations include the creation of 'frequently asked questions', the inclusion of a glossary of terms at the back of all documents and to have these regularly published and posted to the Health Canada website. Stakeholder engagement will be key, as will the development of guidance and communication tools.
3. Health Canada should pursue harmonization with other jurisdictions (domestic and international) wherever possible. Harmonization applies across jurisdictions within Canada as well as internationally, where Health Canada could leverage the work done by other regulators and could ensure Canada is consistent with best practices. Recommendations include: adopting guidance developed by other regulators (e.g., record retention requirements) and participating in global discussions on standards and harmonization efforts.
4. The roles and responsibilities of other players involved in clinical trials need to be clarified. Some participants indicated that some players need to be regulated, defining their roles in addition to defining the process (e.g., REBs, CROs, DSMBs and the QI/PI). There was a varying degree of agreement that there should be an accreditation process for REBs in Canada. Participants identified that many of these issues are provincial in nature, and therefore, the provinces and territories need to be involved in this discussion.
5. A better safety reporting system is required. The safety reporting process of today is not helpful, is paper-extensive and comes from a number of different places. It was recommended that Health Canada could act as the 'clearinghouse' so that all could better understand the safety issues.

V. Closing Remarks and Next Steps

Dr. Lucas closed the meeting by highlighting the key messages heard throughout the day and thanked participants for their valued input to the process. The feedback received from the participant evaluation questionnaires (Appendix C) indicated that: the workshop was very positively received; participants were appreciative of being consulted early in the process; participants were very impressed with the quick consolidation of the discussions contained in the closing presentation^{Footnote 8}; and were in general agreement that the key issues had been identified as a result of this process.

Next steps

The results from this workshop will help inform the development of short, medium and long term measures to strengthen the regulatory framework for clinical trials which could include:

• regulatory amendments;
• development of policy tools (e.g., guidance, standards); and/or
• administrative measures (e.g., operational improvements, outreach activities).

The public will have the opportunity to provide their input through additional consultations that will be undertaken by the Branch, as necessary, as Health Canada moves forward on the initiative, including:

• through the Canada Gazette process, if regulatory amendments are being considered
• consultations on the progressive licensing framework for pharmaceuticals and biologics.

Participants were encouraged to visit the "Blueprint" web site^{Footnote 9} for updates and consultations on this project and other related initiatives.

Appendix A - Reference documents

1. Blueprint for Renewal: Transforming Canada's Approach to Regulating Health Products and Food (October 2006)
2. Presentation - Context of the Review, Drivers of Change and Path Forward (Clinical Trials Regulatory Review - Stakeholder Workshop March 26, 2007 Presentation Slides Handout)
3. Discussion Document -- 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)
4. Division 5 - Drugs for Clinical Trials Involving Human Subjects; Interpretation
5. Food and Drug Regulations - Amendment (Schedule No. 1024) Clinical Trial Framework; Notification of passage of Schedule dated June 22, 2001
6. Clinical Trials Regulatory Framework Review - Results of 2006 E-Consultation

Appendix B - Participant List

The following is the complete list of participants for the workshop. There were a total of 48 participants.

Appendix C - Participant's Evaluation Summary

In general, the participants' workshop evaluation responses (n=33) were very favourable and noted areas which could be improved for future sessions. Below is a summary of the actual evaluation responses submitted by participants, grouped by common theme.

1. What did you like about the workshop?

• Opportunity for Discussion
  'The ability to have an open discussion with stakeholders from mixed backgrounds, in small size groups, to share information on a broad range of issues produced interesting conversations. It provided an opportunity to hear different perspectives and viewpoints which stimulated more considered opinions.'
• Learning Opportunity
  'It was also a learning opportunity; providing an opportunity for industry participants to provide their perspective and to contribute to the improvement in the regulations. The session was informative, interactive and we need to do more of this with the key stakeholders. It was an opportunity to provide feedback on the Health Canada process related to clinical trials in Canada and associated processes.'
• The Approach
  'The documents pre-circulated to participants were good. The size of the group was good. The structure of the meeting with a focus on discussion rather than presentations was appropriate. The seating plan produced well balanced tables with multiple backgrounds to discuss issues & viewpoints. The round table topic discussion as small groups allowed interactive discussions and the amount of time for this activity was appropriate. Good discussion was generated through the question/discussion paper format, but did not restrict the conversation to those issues. It was beneficial to work in small breakout groups before discussing "key" issues in greater depth. Rapid integration of feedback and presentation of results/opinions was an efficient way to hear the other tables' viewpoint. Conclusions given at the end of the meeting as well as "path forward" provided a great wrap-up.'
• General Comments
  'The presentations by Stephen Lucas were excellent. Participants felt they were consulted early in the process, not after everything has been decided. The meeting hit on all the relevant topics for regulatory reform. Participants are looking forward to Health Canada's commitment to follow through with changes.'

2. What suggestions for improvements would you make?

• Participants Preparation for the Meeting
  'It would be helpful to provide more advance notice for meetings like this and provide the pre-read documents at least a week in advance with the instructions that it is a requirement to read the information before coming to the workshop. Significant time was lost since some participants had not read the document. It would also be helpful to provide the discussion questions in advance so they can be discussed before the workshop.'
• Participant Selection
  'It would be helpful if there was greater lead time for choosing participants, distributing pre-reading materials, and rationale for choice and # of stakeholders. The organizer should assure the knowledge base of participants so that quality discussions can occur.'
• Time Allocation
  'It would have been beneficial to allow more time on the agenda to discuss participant's concerns and topics brought up. One suggestion was to take less time for HPFB overview and positioning and give extra time to workshop activities. One person thought that the plenary reports took too long. The wrap-up session was a good overview, but everyone was tired by then! '
• Discussion Questions
  'Some participants said the questions to focus the discussions were not as clear as they could have been, therefore some were not answered. Some topics in the pre-read materials were not covered in the discussions. It would have been helpful to provide some examples of what is working or not, to help guide the discussions. The plenary should be a little more structured -- wrap-ups were often repetitive and hard to follow.'
• Follow-up Request
  'One participant would like more operational information on the Branch's spending and activities. Another thought there should be stronger commitment for future change so participants feel their time was well spent. One observed that Health Canada participants were at times defensive rather than just listening to the feedback.'
• Some Participant Viewpoints were not captured
  'Several participants commented that their concerns and suggestions were not reflected in their group's table report and they were also concerned that their verbal comments may not have been captured either. It was suggested by a couple of participants that participants should be encouraged to provide written examples where possible to illustrate their position to ensure all concerns and suggestions of participants are reflected in the report. Another suggestion was to have impartial record keeper of discussion and moderator for each table to limit bias in the results presented.'

Appendix D - Glossary

ADR

Adverse Drug Reaction

CDR

Common Drug Review

CT

Clinical Trial

CTA

Clinical Trial Application

CTA-A

Clinical Trial Application Amendment

CRO

Contract Research Organization

DSMB

Data Safety Monitoring Board

FAQ

Frequently Asked Question

GCP

Good Clinical Practice

GLP

Good Laboratory Practice

GMP

Good Manufacturing Practice

HPFB

Health Products and Food Branch

ICH

International Conference on Harmonization (of Technical Requirements for the Registration of Pharmaceuticals for Human use)

IRB

Institutional Review Board

PI

Principal Investigator

PD

Pharmacodynamic

PK

Pharmacokinetic

PT

Provinces and Territories

Q/A

Quality assessment

QI

Qualified Investigator

R&D

Research and Development

REB

Research Ethics Board

SAP

Special Access Programme

SME

Small and Medium-sized Enterprise

SMO

Site Management Organization

SOP

Standard Operating Procedures

US FDA

US Food and Drug Association

WHO

World Health Organization

Appendix E - Responses to participants questions

Health Canada committed to provide follow-up information related to participants questions on the following specific topic areas: environmental assessment; clinical trial R&D comparisons between Canada and other countries; Health Canada's capacity planning related to HPFB clinical trials activities.

1. Environmental Assessment

Q1. ' Within the short period of review, it is my understanding that Health Canada has some responsibility for ensuring a safety component of environmental protection. During review, what kind of information is provided or required for e.g. the excretion of different kinds of drugs, the impact on the environment, the disposal of drugs and the area of genetics? How can these be considered within the process?'

A1. The obligations in terms of information requirements for environmental assessment of new substances are presently prescribed in the New Substance Notification Regulations (NSNR) under the Canadian Environmental Protection Act, 1999. The NSNR apply to both manufacturers and importers of new substances. A notification and assessment is required for any new substance within new drug submissions.

The Canadian Environmental Protection Act, 1999 (CEPA) requires that all new substances for use in Canada be evaluated for their potential risks to the Canadian environment and human health. New substances contained in products regulated under the Food and Drugs Act (FD&A) are currently regulated under the New Substance Notification Regulations (NSNR)^{Footnote 10}. However, the NSNR were mainly developed for industrial substances. As such, there is a need to develop Environmental Assessment Regulations with specific information requirements to more appropriately determine the risks to the environment and human health of substances in FD&A regulated products.  Until these regulations are promulgated, the NSNR will apply.

Health Canada's Environmental Impact Initiative (EII) was established within the Health Products and Food Branch (HPFB) in 2001. EII has been working with the Healthy Environments and Consumer Safety Branch (HECSB) of Health Canada, HPFB Directorates and the New Substances Division of Environment Canada to develop appropriate Environmental Assessment Regulations that will meet the requirements of CEPA.  The development of these regulations will cover all new substances contained in products regulated under the F&DA including:

• pharmaceuticals/ radiopharmaceuticals
• biologics/ generic therapies
• veterinary drugs
• natural health products
• medical devices
• cosmetics
• food additives and novel foods

Along with the previous mentioned working partners, EII also collaborates with other colleagues, in Canada and internationally, to build the scientific evidence base regarding the environmental and health impacts of substances in products regulated under the F&DA, and to identify best practices to help manage them.

To date, the EII has developed an Issues Paper (2003) and Options Paper (2005), the latter which explores options to pursue in the development of these regulations with regard to legislative authorities and regulatory frameworks. In 2006, the EII has established an Environmental Assessment Working Group (EAWG) to provide broad, strategic advice on policy, technical, operational and regulatory issues to assist in the development of the regulations. On March 29-30, 2006, Health Canada and Environment Canada hosted public consultations on the Development of Environmental Assessment Regulations in Ottawa, Ontario. Stakeholders discussed issues related to the development of the regulations and path forward^{Footnote 11}.

For more information on the Environmental Impact Initiative (EII).

2.Clinical R&D comparisons between Canada and other countries

Q2. ' The initial objective of the 2001 amendments were both very good and in looking at the period between 2001 and 2005, the increase of research investments was close to 20 percent. Do we have comparative data with respect to the increase of clinical research in Canada versus other G8 or G20 countries?'

A2. Where Canada ranks in the world is a mix of economic and social considerations. It is difficult to confirm global clinical trial activity trends due to the use of multiple reporting and data standards, the existence of multiple trial registries, the growing nature of multi-country clinical trials, among a few issues. Below are a few observations provided by various sited reports that have profiled clinical trial and research and development trends in Canada and the world.

A. Overview - Canada and the world

A recent report published by KPMG^{Footnote 12} indicates that Canada continues to be a choice for trials by multinational pharmaceutical companies for the following reasons:

• A proven track record in leadership for basic biomedical research, strengthened by funding provided through CIHR and other federal and provincial agencies;
• Numerous leading clinical centres, internationally renown, with the capacity to lead large-scale multi-country trials;
• International recognition for excellence in clinical researchers, nationally integrated research centres and networks (e.g. cancer, stroke, HIV trials, arthritis) where smaller centres are linked through a common health system structure;
• Strong information management system (tele-health advancements such as the Canada Health Infoway, provincial population-based patient care databases);
• Reputation for meeting recruitment targets and can offer a diverse, multi-ethnic population with broad genetic heterogeneity and sub-populations to support research in a variety of unique populations - Canada ranked in the top 3 compared to other G8 countries with respect to the number of patients enrolled in Phase II/III trials in 2003-2004 in 8 therapeutic categories;
• High standards of reliability in clinical data, the conduct and reporting of clinical research and the generation of highly reliable results. A common standard of care permits for easier integration of data across many sites;
• Experienced CRO with competitive and effective nation-wide trial activities;
• Work towards efficiencies by creating centralized ethics review (e.g. Ontario Cancer Research Ethics Board);
• A generous R&D tax treatment, such as through the Scientific Research and Experimental Development Tax Incentive Program (SR&ED): permanent program, tax credits are refundable. After-tax costs for R&D expenditure almost half compared to the US, depending on the province.

B. Domestic performance

During the course of the CT review, the following information was collected on the domestic clinical trial activity from sources including Health Canada, Patented Medicines Review Board annual performance reports, Canadian Institutes for Health Research data, Industry Canada's Prices Innovation and Clinical Trials reports.

Phase type and number: 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. With the changes to the regulatory framework in 2001, there has been a substantial increase in Phase I 7-day bioequivalence trials in Canada.

Research and development is growing globally by 12.6% per year, and is projected to continue this pattern to 2008. Clinical trials compose 40% of global R&D activity.

In Canada, R&D growth has been 8.6%. Phase III trials continue to require the most expenditures in terms of R&D investment (31%). Phase II is maintaining its activity level at 10% of R&D investment.

A recent research activity identifies that SME in biotechnology are expected to grow at an annual rate of 28% in Canada. Canada is well positioned in the field of biotechnology as it accounts for approximately 10% of the world's biotech related revenues, ranking second behind the US in the number of biotechnology firms^{Footnote 13}. Further projections identify that Canadian companies will increase their drug development activities by 90%, where 80% of the biopharmaceutical companies are expected to have their products in Phase I trials:

• There are currently over 500 biopharmaceutical products in the pipeline^{Footnote 14};
• The estimated pipeline activity for therapeutics identifies products in the following sectors: cancer (35%), infectious disease (15%), neurological (13%), cardiovascular (9%), other (28%)^{Footnote 15}
• There are over 500 biotech companies in Canada, with over 53% in the health sector - Canada is a leader in the world for biotechnology.

C. International Context

A recent document outlines clinical trial activity in terms of a comparative study to Canadian-based versus US based clinical trial selection.^{Footnote 16} R&D spending was at 33$B US worldwide in 2001, growing at an estimated rate of 15% per year^{Footnote 17}. The report identified the following:

• 40% of R&D expenditure is towards clinical trials, due to the increased complexity of new drug development and increased pressures due to regulatory requirements;
• 1.3$B USD is spent on clinical trial recruitment: 1$B US on patient recruitment, 300$M US on physicians;
• Cost savings to clinical trials are directly associated through introduction of reliable and efficient study processes, advanced data gathering techniques, and economic metrics;
• There has been a 20% increase in clinical trial activity worldwide, where 60% of these are performed outside of Canada and US, primarily in the UK. Canada is ranked 3rd behind EU and US as for location predominance. There is an increase of clinical trials activity in India and China;
• A 15% growth per year in R&D expenditures in the biopharmaceutical industry is expected to be the trend^{Footnote 18};

3. Operational planning related to HPFB clinical trials activities

Q3.' The background information provided information that the Directorate has more funds to allocate to review activities. Given the exponential number of trials, how will Health Canada continue to meet its obligations in review and inspection?'

A3. Health Canada has been able to meet the review targets by hiring additional full-time employee resources (since 2001) and by introducing streamlined operational practices. Health Canada continues to examine the resource requirements for the future to ensure performance to its obligations.

Budget 2005 committed $170 million in incremental resources to implement a series of targeted measures to enhance the safety and effectiveness of drugs and other therapeutic products, including strengthened Health Canada capacity to review and monitor clinical trials, and increased inspections of clinical trial sites.

To date, Budget 2005 budget allocation has supported clinical trial oversight responsibilities by:

• Staffing for BGTD CTA review functions and to support pre-CTA meetings, resulting in an overall improvement to the quality of review and timeliness of decisions. Future plans include hiring technical staff to support laboratory and management systems as well as expertise in Bayesian statistics to support CTA protocol review and the development of new modeling methods to improve the generation of safety signals and action plans;
• Staffing to support an increase in clinical trial inspections and post-market ADR review;
• Staffing to support the monitoring capacity and safety assessment of marketed health products, including improvements to risk mitigation strategies and communications activities;
• Staffing of the Office of Pediatrics Initiative and plans to hire more to support integration of pediatric issues to pre-market approval and post-market surveillance and evaluation;
• Staffing for TPD CTA and ADR review functions, medical devices and policy development positions, resulting in an increased review capacity and improved collaboration in review and monitoring functions across Directorates.

Future plan continue to staff for assessment and monitoring functions to engage in:

• more frequent and efficient pre-application engagement meetings with sponsors;
• more effective risk communications and support for REB (e.g., accreditation project, standards development), clinical trial investigators and sponsors;
• linkages with foreign regulators;
• CTA ADR review and assessment improvements and efficiencies;
• Increased inspection activities.