Summary Report: Clinical Trials Ontario Working Groups · Clinical Trials Ontario Working Groups April, 2013 . Clinical Trials Ontario | Summary report on ... REB Qualification Manual

Summary Report: Clinical Trials Ontario Working Groups April, 2013

Clinical Trials Ontario | Summary report on Working Groups | April 2013 1

Contents

Background ............................................................................................................................................................. 2

Clinical Trials Ontario ..................................................................................................................................... 2

Call for Nominations for the Working Groups ....................................................................................... 2

Working Group Members .............................................................................................................................. 3

Working Group Meetings ............................................................................................................................... 5

Key Recommendations ....................................................................................................................................... 6

Summary of Deliverables ................................................................................................................................... 8

Working Group on REB Streamlining ....................................................................................................... 8

Working Group on IT Harmonization & Performance Metrics ....................................................... 9

Working Group on Legal & Liability Issues ......................................................................................... 13

Appendix 1: Potential Roles for Clinical Trials Ontario in the Delegated Board of Review Streamlining Model ........................................................................................................................................... 16

Appendix 2: Potential Selection Criteria for Board of Record .......................................................... 18

Appendix 3: Delegated Board of Record Model ..................................................................................... 19

Appendix 4: Draft Participation Agreement ............................................................................................ 20

Appendix 5: Draft Board of Record Study Agreement ......................................................................... 34

2 Clinical Trials Ontario | Working Group on Legal and Liability Issues | April 2013

Background

Clinical Trials Ontario

Clinical Trials Ontario (CTO) is an independent not-for-profit organization that was established

through the Ministry of Research and Innovation as part of Ontario’s Life Sciences

Commercialization Strategy. Its mandate is to provide the life sciences industry with a streamlined

approach to conducting multi-centre clinical trials in Ontario while ensuring the highest ethical

standards for patient safety.

Competitiveness in the field of industry-sponsored clinical research is largely contingent on speed,

quality, and cost. While historically a strong competitor with respect to clinical trial investment,

Ontario is experiencing a 12% annual loss in global clinical trial activity and has been facing

escalating competition from generous tax and subsidy regimes in developed nations to rapidly

increasing clinical trial capacity and quality in low-cost emerging economies. As Ontario is widely

recognized as a jurisdiction that generates high quality data, the greatest gains in competitiveness

can be achieved by making structural changes to improve speed and efficiency, while sustaining

quality, at the same or reduced costs.

From 2009-2011, a stakeholder-led working group, convened by the Ontario Ministry of Research

and Innovation, assessed the multi-factorial issues and barriers to maintaining and increasing

Ontario’s share of global clinical trials and recommended the formation of Clinical Trials Ontario in

2011. Clinical Trials Ontario will build on Ontario’s recognized strengths while providing province-

wide solutions to identified structural problems.

CTO is led and supported by the provincial community of stakeholders involved in clinical trials in

Ontario including the Council of Academic Hospitals of Ontario, Ontario Council on University

Research, Council of Ontario Faculties of Medicine, BIOTECanada, Canada’s Medical Technologies

Companies through MEDEC and Canada’s Research-Based Pharmaceutical Companies through

Rx&D.

Call for Nominations for the Working Groups

In August 2012, immediately following the July inaugural meeting, CTO issued a public call for

nominations for participants to provide experienced advice to CTO on key aspects of CTO’s core

projects. CTO established three expert Working Groups from a broad cross-section of stakeholders:

1. Working Group on REB Review Streamlining

2. Working Group on Information Technology Harmonization and Performance Metrics

3. Working Group on Legal & Liability Issues

The members of these Working Groups were announced in September 2012.


Working Group Members

Working Group on Research Ethics Board Streamlining

Frank Naus (Chair)

Director, Research Administration, Office of Integrated Research Services, Hamilton Health

Sciences Corporation

Michael Borrie

Medical Director, Aging Brain and Memory Clinic and Geriatric Clinical Trials Group

Jack Corman

President, IRB Services

Padraig Darby

Research Ethics Board Chair, Centre for Addiction and Mental Health

Paul Macpherson

Director, Grants, Contracts and Ethics Review Services, UHN

Janet Manzo

Executive Director, Ontario Cancer Research Ethics Board

Nicole McLean

Manager, North American Clinical Operations - Clinical Trial Site Services, Eli Lilly Canada Inc.

Keitha McMurray

Director, Clinical Studies Resource Centre and Research Ethics Office, Sunnybrook Health

Sciences Centre

Suzette Salama

Research Ethics Board Chair, Hamilton Health Sciences Corporation

Ron Heslegrave/ Susan Marlin (ex-officio)

Interim Executive Director / Executive Director, Clinical Trials Ontario

Working Group on Information Technology Harmonization and Performance Metrics

Femida Gwadry-Sridhar (Chair) Director of Health Informatics, Lawson Health Research Institute

Wendy Fiander

Director Programme Management, Oncology, Hoffmann-La Roche Limited

Trinh Luong

Director, Health Technology Assessment & Federal Policy, Novartis Pharmaceuticals Canada Inc.


Jack Holland Oncology REB Review Panel Chair, University Health Network

Simon Wong Senior Business Analyst, Ontario Cancer Research Ethics Board

Michael Hendley Manager, Business Systems Integration, Ottawa Hospital Research Institute

Adam Cole Vice President Information Technology, Canadian Clinical Trial Network

Joe Downey

Urology Research Administration, Financial and Regulatory Administrator, Queen’s University



Working Group on Legal and Liability Issues

Cheryl Litchfield (Chair)

Manager, Grants and Contracts, Lawson Health Research Institute

Delilah Ofosu-Barko

Research Consultant, Research Office & Research Ethics Board, Trillium Health Partners

Doug Meneilley

Senior Contracts Officer, Ottawa Hospital Research Institute

Jennifer Horton

Legal Counsel, The Hospital for Sick Children

Kelly Clark

Clinical Research Manager – Vaccines, Merck

Kelly Morris

Manager, Research Ethics St. Joseph’s Care Group & Thunder Bay Regional Health Sciences

Centre

Beena Cracknell

Director of Finance and Contracts, Population Health Research Institute

Tricia Houston

Associate Director Clinical Development Clinical Development, Regulatory and Medical Affairs,

Novo Nordisk Canada Inc.




Working Group Meetings

Working Group In-Person Meetings Teleconferences

Research Ethics Board Streamlining

September 27, 2012

October 22, 2012

November 14, 2012

October 12, 2012

October 31, 2012

December 13, 2012

Information Technology Harmonization and Performance Metrics

September 24, 2012

October 17, 2012

December 18, 2012

October 11, 2012

October 24, 2012

November 16, 2012

December 3, 2012

January 9, 2013

Legal and Liability Issues

September 17, 2012

October 15, 2012

November 26, 2012

September 28, 2012

October 25, 2012

October 30, 2012

December 19, 2012

The Working Groups were supported by Manal Siddiqui (Project Manager) and Erin Menzies (Research Analyst), Clinical Trials Ontario; and by lawyers from Dykeman Dewhirst O’Brien LLP. CTO also recognizes and appreciates the contributions of the following guests who shared their expertise in the areas of IT platforms, and insurance and indemnification considerations for a streamlined ethics review system.

• Ronald Fehst, President, Ronald Fehst Research Consultants

• Telmo Coelho, Account Manager, HUB International

• Sean Duggan, VP & Partner, HUB International

• Marie Lofthouse, Senior VP, Healthcare & Life Sciences Industry Practice, Marsh Canada

• Suzanne Liberman, Managing Director, Healthcare & Life Sciences Industry Practice,

Marsh Canada

• Neil McRuer, VP, Simmlands Insurance Services


Key Recommendations The Working Group on Research Ethics Board (REB) Streamlining recommends that:

1. There be a “qualification” process for REBs;

2. The Toronto Academic Health Science Network (TAHSN) REB Qualification Manual (2012)

be used as a starting point for an Ontario REB qualification process with select

modifications from the greater Ontario stakeholder community as needed;

3. CTO use the TAHSN Qualification Process, with select modifications.

4. CTO manages the qualification process, initially using a third party vendor engaged by CTO;

5. CTO use criteria to qualify Boards of Record. It was concluded that it is too early to

recommend who should decide which REB will act as a Board of Record in any particular

case; and

6. A pilot project consists of a proof of concept study that retrospectively walks a clinical trial

study that has already been reviewed, through the new mechanisms.

The Working Group on Information Technology Harmonization and Performance Metrics

recommends:

1. The development of a secure, inter-operable, user-friendly, cloud-based service to house

information and to receive/deliver, analyze, and aggregate data for all of the identified

stakeholders;

2. The identification of metrics and time-points which automatically allows CTO to track

timeliness of the clinical trials progress to identify areas of efficiency;

3. The aggregation of Principal Investigator (PI) areas of expertise so Sponsors/Industry can

easily identify collaborators;

4. The intention to aggregate REB areas of expertise in a database which outlines which board

has expertise to handle particular clinical trials to assist in Board selection for delegation

purposes;

5. The development of a patient portal providing education on and access to information on

clinical trials taking place in Ontario;

6. CTO consider the benefits and disadvantages of all potential systems, open source or

proprietary, though thoughtful consideration of ideal functionality;

7. CTO engage with and learn from other jurisdictions that have experienced undertaking this

type of harmonization project;

8. CTO determine the functionalities of all Ontario systems and identify requirements for

interoperability;


9. CTO implement a clear communication strategy to address various stakeholders. CTO

should engage stakeholders and constantly solicit and respond to their feedback, including

communicating benefits of a centralized system:

a. Economic impact of declining clinical trials revenues;

b. Purpose/need/solution and potential risks associated with involvement in CTO

system;

c. Continuity plan for turnover is necessary for systems maintenance over time ;

10. CTO hold a province-wide meeting of appropriate stakeholders, including government, to

examine the impact of institutional overhead and other direct or indirect costs on:

a. success/failure rates of potential clinical trial activity;

b. the time to finalize the clinical contract;

11. CTO establish a costing model that defines the ultimate goals of proposed reforms,

infrastructure support necessary to achieve those goals and projected return on investment

on population health, academic prestige and the provincial economy.

The Working Group on Legal and Liability Issues recommends that:

1. To implement the Delegated Board of Record model for industry-sponsored multi-site

clinical trials in Ontario, CTO:

a. contract with participating institutions in Ontario;

b. develop a template inter-institutional Delegated Board of Record Agreement and

administratively support execution of this agreement for institutions participating

in each clinical trial.

2. CTO develop an agreement with industry sponsors with consideration given to

confidentiality, the reporting of aggregated metrics, and the parties’ roles relative to the

Delegated Board of Record model.

3. Excepting participating investigators, each party to an inter-institutional Delegated Board of

Record Agreement with responsibilities under the Delegated Board of Record model should

provide limited indemnification to the other party(ies) for their negligence or willful

misconduct in carrying out their responsibilities.

Further to these recommendations, The Working Group on Legal and Liability Issues also

drafted two agreements that are attached as appendices to this summary report.


Summary of Deliverables

Working Group on REB Streamlining The REB Streamlining Working group was established to provide expert advice to help guide the development and implementation of:

1. Ontario standards to support the delegated Board of Record review model (harmonized

with national and international standards as appropriate);

2. A framework for streamlining research ethics review to support a delegated Board of

Record review model; and

3. An appropriate framework to support the implementation of the delegated Board of Record

review model for Ontario.

The outcomes from this Working Group included:

1. Recommendations for an Ontario REB qualification process;

2. Recommendations for an appropriate framework for implementation of the delegated

Board of Record Review model and recommendations on conducting a pilot study.

In order to establish a new framework for multi-centre clinical trials in Ontario, with a focus on creating a delegated Board of Record model, it is imperative that stakeholders trust that the Board of Record is appropriately qualified, and that the tenets of patient safety will be met. The REB qualification process is the means by which a delegating institution (through its Board of Directors, which is ultimately accountable) will achieve sufficient trust in the system to choose to participate in the CTO initiative. A standard qualification process is a matter of due diligence; it serves to assure delegating institutions that minimum standards will be met as a condition for the local REB role being relinquished to the delegated Board of Record. The Working Group concluded that in order to recommend a qualification process for Ontario REBs, the process must comply with international regulatory requirements and ethical standards; set minimum standards for all participating REBs to encourage trust among institutions, partners and participants so that delegation to a Board of Record can occur with confidence; create consistency to help REBs move forward to common processes and policies and move toward developing standard operating procedures for REBs; have efficient processes while maintaining highest ethical standards; and, not be complex or overly bureaucratic . The Working Group discussed the options for how to describe the process. Many potential terms were discussed, but the middle ground of “qualification” was favoured in part because it is a standard currently being adopted by a significant number of teaching hospitals through TAHSN, and therefore will already have been given an Ontario lens. The Working Group identified existing initiatives, standards and processes1 to evaluate REBs. Upon review of these, the Working Group decided to recommend using the TAHSN REB Qualification

1 Canadian General Standards Board (CGSB), Toronto Academic Health Science Network (TAHSN) Research Ethics Board

Qualification Manual, Association for the Accreditation of Human Research Protection Programs Inc. (AAHRPP), Canadian Institutes of Health Research (CIHR) streamlining of REBs, National Institutes of Health (NIH) REB self-evaluation tool


Manual (2012) and adapt it for use by a provincial group. It was felt that the Manual provides an initial framework and process and that the checklist format is user-friendly and comprehensive. Special consideration will be given to incorporating International Conference on Harmonization Good Clinical Practices, Office of Human Research Protections, and other guidance documents. The Working Group discussed the potential impact a qualification process could have on local REBs. For example, the Working Group raised questions about whether REBs have sufficient resources and whether funding will be available to REBs so they can participate in a qualification process. It was acknowledged that many REBs struggle with their workloads already. The Working Group recognized the potential conflict if CTO assumes the roles of both qualifying and delegating an REB as a Board of Record. One solution was to have CTO sub-contract the process of qualifying REBs to an independent third party vendor (the qualification criteria will have been established by CTO based on Working Group recommendations). The potential role of CTO going forward was given considerable attention in the deliberations of the REB Streamlining Working Group. The “Potential Roles for Clinical Trials Ontario” document is attached as Appendix 1 to this report. Similarly, the Working Group recommends that CTO use criteria to qualify Boards of Record, but concluded that it was too early to recommend who should decide which REB will act as a Board of Record in any particular case. In starting to develop a model for the selection of a Delegated Board of Record, the Working Group recommends that CTO consider several criteria, detailed in Appendix 2. The Working Group recommended that once an REB has been identified as a Board of Record, that REB must continue to act as the Board of Record unless they must withdraw (which would be discouraged). There must be a contingency plan developed to address the rare circumstances where a Board of Record would have to withdraw in the middle of a study. Finally, the Working Group recommended that there be a pilot project to consist of a proof of concept study that retrospectively walks a clinical trial study that has already been reviewed through the new mechanisms. The Working Group made no recommendations about IT aspects of a pilot, but noted that the IT platform must be simple and accessible to all.

Working Group on IT Harmonization & Performance Metrics

The IT Harmonization & Performance Metrics Working Group was established to provide expert advice to develop recommendations to address the need for a technical solution to assist in the streamlining of the research ethics review process in Ontario. The outcomes from this Working Group included:

1. Definition of stakeholder objectives and requirements, establish associated workflows and

identify desired functionality for the technological solution.

2. Provisional performance metrics to assess the impact of Clinical Trials Ontario activities

and propose the most effective manner to collect and analyze these metrics.


3. Recommendations for implementing the preferred technological solution in support of the

Delegated Review Model, including a communications strategy and an assessment of

barriers and possible solutions.

The Working Group held discussions which included examination of the three most commonly used commercial systems: Click Commerce/Huron, Infonetica, and ROMEO. Additionally, the Working Group discussed the required functionality of the proposed system, and determined that a cloud-based model would best meet the needs of a system which would gather and share data to locations across the province. The discussion outlined the proposed system requirements and suggestions for the operability of a technological solution to streamlining the Research Ethics Board process. The Working Group on IT Harmonization and Performance Metrics recognized the existence of two very different and occasionally divergent varieties of metrics. They are 1) metrics which measure global industry investment and Ontario’s current standing, and 2) metrics which will track and measure the success of Clinical Trials Ontario as an initiative. The Working Group also recognized the importance of defining the responsibilities of principal investigators, institutions and sponsors in recording and reporting data which will assist CTO in gathering meaningful metrics over time. There is the expectation that all parties will endeavor to respond to inquiries as quickly as possible, that all parties will adhere to ICH-GCP and furthermore, all parties (study manager, business manager etc.) will have or will acquire any and all appropriate training to ensure they can adhere to any qualification standard established by CTO and their stakeholders. In establishing clear responsibilities, the Working Group also believes that there is a substantial role for CTO to act as a facilitator to train and educate PIs, sponsors, and REBs on best practices to truly establish Ontario as the highest quality and most efficient jurisdiction to conduct clinical trials globally. The Working Group was able to identify four categories of metrics:

Timeliness Data-Driven Operations-Driven Financial

To assess the success of the REB streamlining process & to identify/track efficiencies driven by the implementation of this process.

These metrics are defined as those tracking the amount of time taken between steps of the research ethics process.

To assess the quality of the information gathered from the system/to measure increased quality.

These are defined as those which track the quality of the review process and conduct of a clinical trial.

To assess success of the harmonized IT solution.

These are defined as those which help assess the impact of operational activity.

Metrics which assess a) financial impacts including costs, and b) investments.

By identifying the major types of data required to evaluate any streamlining IT solution, the Working Group was able to identify and bucket some provisional metrics (see figure above). Many of these metrics are industry-level, and indicate the success of sites to adhere to agreed-upon terms.


Industry representatives indicated that the most important metrics for their purposes are process and investment focused. Through this process, the Working Group developed a preliminary Metrics Dictionary with the intention to clarify and define specific metrics with precision. The CDISC Clinical Research Glossary2 was identified as a potential tool to clarify metrics. The lack of specificity and the known variability of metrics on an institutional basis were identified as a potential roadblock, and this Metrics Dictionary initiative was a proactive step towards unified metrics. Many proposed performance metrics focus on internal measures of the efficiency of a centralized ethics review process encompassed by a functioning Clinical Trials Ontario structure. In this context they appear appropriate for the task. However, financial imperatives outside the current scope of CTO have potential to undermine the basic intent of centralized review. These include the following:

• Variation in institutional assignment of research overhead/direct and indirect clinical trial

costs;

• Limitation in CTO infrastructure support in relation to the potential return on investment;

• Absence of a defined mechanism for reviewing Ontario and Canada’s performance in a

global context, both immediate and long term.

The Working Group developed two recommendations to address the need for financially-based metrics, which are detailed below: 1. Operational Overhead/Direct and Indirect Costs

A province-wide meeting of appropriate stakeholders, including government, should be established to examine the impact of institutional overhead and other direct or indirect costs on: success/failure rates of potential clinical trial activity; the time to finalize the clinical contract; other appropriate measures. It is envisaged that a process similar to that adopted by CAHO in harmonizing the language and understanding of the clinical contract could be followed. 2. Return on Investment/Global Perspectives

Canada’s estimated share of the “clinical trials market” of $50 billion annually is approximately 4%, or $2 billion per year. Furthermore Ontario’s population size and academic strengths contribute significantly to the total. For this reason, it would seem essential that economic measures be put in place that would allow for immediate and short term evaluation of the impact of all changes directed at improving Ontario’s clinical trial performance, including that of Clinical Trials Ontario. Given the potential return on investment of re-establishing a leading role for Ontario in clinical trials, from health, academic and economic perspectives, a costing model should be established immediately that should define the ultimate goals of proposed reforms, the infrastructure support necessary to achieve those goals and the projected return on investment on population health, academic prestige and the provincial economy.

2 http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/article/articleDetail.jsp?id=751876


The Working Group identified other recommendations for next steps which will help facilitate the selection and implementation of an IT solution for REB harmonization:

1. CTO should consider benefits and disadvantages of open source vs. proprietary systems,

with attention to functionality. Open source systems offer the opportunity to expand

functionality, which is not as common with proprietary systems. However, for open source

systems, a major risk is long-term maintenance (e.g. in-house staff to support system could

leave).

2. CTO should consider the benefits and disadvantages of a system agnostic solution. It may

be more attractive to managers of commercial systems in use in Ontario to connect to an

open source solution vs. CTO choosing a solution which implements a competing

proprietary system.

3. CTO should make efforts to identify and understand functionality of existing systems

worldwide.

4. CTO should identify and understand other jurisdictional successes and failures.

5. CTO should conduct outreach to determine functionalities of all Ontario systems and

identify what would need to be done to get all on same level of functionality and

interoperability.

6. CTO should draft appropriate questions to ask each institution and should identify the local

custodian of data (IT or VP Research) who is the ultimate decision maker for sharing data.

7. CTO should assess stakeholder willingness to participate in the CTO (centralized) model

and should ask the following questions:

a. What is your willingness to provide CTO access to your data in a centralized system?

b. What format would you support for import/export?

c. Do we move towards an RFP? What would that RFP look like?

8. Involve community in the development of the system so they do not feel that sharing their

information is “sharing with a 3rd party” but instead feel a sense of ownership.

9. Clearly communicate the benefits to the stakeholder and explain why Ontario is engaged in

the activity of streamlining REB reviews including the financial impact of reduction in the

number of trials. Indicate the impact on institutions and the province (employment,

reduced budgets, reduced projects) if this endeavor fails.

It was noted that whatever IT solution is ultimately implemented, there exists a commercial opportunity for CTO to recoup some of their initial development investment through forming partnerships with other national or international bodies. The Working Group gave careful consideration to the types of communication which would be best utilized as a tool for gaining support and buy-in from stakeholders for a harmonized IT solution. The recommendations, below, detail first steps for establishing a stakeholder sense of ownership, and puts building relationships and partnerships as a critical step in CTO’s communications success:

1. CTO should clearly communicate who they are, their mandate and vision to all potential

stakeholders.

2. CTO should engage stakeholders and constantly solicit and respond to their feedback.


3. Communicate benefits of centralized system:

a. Economic impact of declining clinical trials revenues

b. Purpose/need/solution and risk CTO provides on investment

c. Continuity plan for turnover is necessary for systems maintenance over time

4. Clarify dissemination plans such as email, print, face-to-face plans, outreach, partnerships,

and leveraging supportive relationships.

Finally, gaining a firm commitment from government and/or other funders over a longer period of time was seen as critical for the implementation of any technological solution. One of CTO’s goals is to diversify revenue streams to build alternate (non-government) funding partnerships. This will be critical to gain stakeholder buy-in over time.

Working Group on Legal & Liability Issues The Legal and Liability Issues Working Group was established to provide expert advice to develop recommendations on the most appropriate mechanism and legal implications arising out of agreements between CTO and participating institutions, including an evaluation of insurance and liability implications. The Working Group discussed the rationale for a proposed Delegated Board of Record model to address stakeholder concerns with the timeliness and duplication of multiple REB reviews for each multi-site clinical trial. Limitations of various models were discussed it was concluded that the Delegated Board of Record model for research ethics review may be cost effective and is likely to improve efficiency and turnaround times. The Working Group identified and addressed several liability issues for both CTO and for institutions. These included:

For Clinical Trials Ontario

CTO will have liability exposure to industry sponsors and member institutions to the extent of its stated responsibilities for the administration of the Delegated Board of Record model. This exposure will arise predominantly from: (i) CTO’s responsibility to identify (and through its oversight, monitoring and audit process,

confirm) those qualified Research Ethics Boards which are eligible to act as Delegated Boards of Record, and

(ii) CTO’s responsibility to select a Delegated Board of Record for each clinical trial.

CTO may seek a limited form of indemnification from each member institution, indemnifying CTO for losses and liabilities to the extent arising from negligent acts or omissions, or the willful misconduct, of the institution’s Delegated Board of Record, and for the institution’s oversight of its Delegated Board of Record and the institution’s conduct of the clinical trial.


For Institutions

“Host” Institutions: The “host” institution whose research ethics board acts as the Delegated Board of Record will have increased liability exposure given its research ethics board’s expanded role and responsibility to other member institutions, in providing delegated research ethics review and oversight for a clinical trial. As the hosting institution is also a participating institution, it already assumes liability for ethics review and oversight for the clinical trial in which it and its investigator are participating. Non-“Host” Institutions: Non-“host” institutions participating in a clinical trial (whose REBs are not acting as the Delegated Board of Record) will rely upon: (i) CTO to properly identify, qualify and select an eligible Delegated Board of Record, and

(ii) the Delegated Board of Record to ensure the ethics review and oversight of the clinical trial

is performed in accordance with required standards. To implement the Delegated Board of Record model for industry-sponsored multi-site clinical trials in Ontario, it is recommended that CTO: (a) contract with Ontario institutions, and (b) develop a template inter-institutional Delegated Board of Record Agreement and administratively support execution of this agreement for institutions participating in each clinical trial. (a) CTO – Institutions

CTO will also require a contract with each institution wishing to participate in CTO initiatives beginning with the Delegated Board of Record model (see Appendix 3). The Working Group discussed the appropriate contracting parties and there was consensus that these would be CTO and the institution. The REBs of the institutions are not legal entities and so would not be formal parties to the agreements, but their Board chairs may play a role internally to influence their institution’s senior leadership’s decision on participation. (b) “Host” Institution – Non-“Host” Institution & Investigator

A Delegated Board of Record Agreement will be required between the Delegated Board of Record host institution, participating institution, and participating institution investigator. The Working Group has drafted a non-negotiable template agreement modeled after the Ontario Cancer Research Ethics Board (OCREB) Board of Record Agreement (see Appendix 4). Almost all academic hospitals in Ontario with research programs in oncology participate in OCREB reviewed clinical trials and are therefore familiar with the OCREB contracts, roles, and responsibilities. From the Working Group’s perspective, using the OCREB model is a potential selling point to institutions that have used this model for a number of years.


(c) CTO – Industry CTO will require an agreement with each industry sponsor wishing to participate in CTO initiatives including the Delegated Board of Record model. This agreement is outside the scope of the Working Group’s Terms of Reference. The Working Group also consulted a sampling of institution insurers to assess feasibility of possible limited indemnifications associated with CTO and the Delegated Board of Record model. The Working Group recommended that, excepting participating investigators, each party to an inter-institutional Delegated Board of Record Agreement with responsibilities under the Delegated Board of Record model should provide limited indemnification to the other party(ies) for their negligence or willful misconduct in carrying out their responsibilities.


Appendix 1: Potential Roles for Clinical Trials Ontario

in the Delegated Board of Review Streamlining Model

Role 1: REB Qualification

• Take responsibility for “qualifying” REBs as a voluntary opt-in process for Ontario REBs.

• In partnership with others, establish qualification standards for REBs.

• Require participating REBs to conduct internal self-assessments.

• Issue or facilitate “report cards” with green/yellow/red.

• Facilitate external audits (or as a long-term goal, conduct external audits).

Notes about this role:

• Opportunity for CTO to qualify REBs as long as each individual institution remains the

ultimate decision-maker and a representative from each institution signs off on each study.

• Concern that this role could conflict with other proposed roles for CTO (such as funneling or

determining which REB will act as Board of Record) therefore, potential conflicts of interest

must be managed.

• If CTO fulfills this role, there will need to be a timeframe within which “qualification” lasts

such as 2-3 years.

Role 2: REB Quality Management, Education and Information

• Disseminate information to participating REBs.

• Partner with other agencies to develop Standard Operating Procedures for REBs. Facilitate

educational opportunities for REBs, researchers and research staff on a broad range of

issues (such as technology, ethical issues and GCP).

• As a long-term goal, perform site monitoring.

• Facilitate implementation tools or a manual for Ontario REBs.


• Some of the large research institutions have their own QA. An opt-in approach might work.

• The scope of these activities may be limited based on CTO’s available resources.

Role 3: Board of Record Delegation

• Establish the criteria for how to decide which REB will act as an REB of Record – meaning

establish the pathway of how to select an REB as Board of Record.

• Manage CTO-Institutional agreements and study-specific Board of Record agreements.


• Provide communications tools like toolkits and template briefing packages to hospitals and

other partners containing draft board resolutions etc. encouraging uptake of the Board of

Record model.


• Agreement is needed on what criteria would be used to determine who should be the REB

Board of Record.

• Selection must be non-biased.

Role 4: Data Gathering & Analysis

• Act as a repository of all qualified REBs of Record.

• Conduct REB asset mapping.

• Host a centralized platform to

o Gather and then anonymize clinical trial performance metrics (recruitment data,

timeliness) /ownership of online portal); and

o Track investments.

• Act as a main hub for study information (institutional templates such as informed consent

language for individual institutions e.g. faith-based institutions vs. community hospitals;

local standards of care and practice; local policy content information).


• Will CTO “support” Boards of Record? Will offering supports to Boards of Record be a

separate role in addition to providing data and data analysis?

• CTO will be able to show its value through the data it collects – although not all data should

be available publicly without being anonymized.

Role 5: Communications and Stakeholder Relationship Management

• Identify key CTO stakeholders.

• Determine how stakeholder engagement will happen.

• Build trust between stakeholder groups.

• Liaise with sponsors on behalf of all participating Ontario REBs.


• What CTO is building will actually help large community hospitals perform industry-calibre

research.

• Concern that small institutions may be worried about losing infrastructure for clinical trials

when they will still have ongoing PI-initiated and student-led studies.

o PI-initiated studies still need the REB to approve studies conducted at one site.


Appendix 2: Potential Selection Criteria for Board of

Record

• All participating REBs must be located in Ontario

• All participating REBs must volunteer to be considered to be a Delegated Board of Record

• Which sites with REBs are participating?

• Is the study an investigator-led clinical trial or a sponsored clinical trial?

• Are academic sites involved only? Are private sites involved only?

• Has the sponsor chosen a site it would like to act as Board of Record?

• Are academic institutional resources required to run the study?

• Which REB is available?

• Which REB is ready first?

• Which REB has the earliest next meeting date?

• What is the nature of the protocol? (should this be categorized by disease or topic?)

• Which REBs have expertise to review the protocol?

• Do the investigators have a preference of which site acts as a Board of Record?

• Do the other sites have a choice in the Board of Record? (to accept or reject another site as

acting as the Board of Record?)

• Has a site refused or declined appointment as Board of Record?

• Which site is next on the rotation?

• Is there an REB that wants to act as Board of Record?

• Has a sponsor refused or objected to the site acting as the Board of Record (because of past

poor performance)?


Appendix 3: Delegated Board of Record Model


Appendix 4: Draft Participation Agreement THIS AGREEMENT is made as of the Effective Date.

BETWEEN :

CLINICAL TRIALS ONTARIO (“CTO”)

CLINICAL TRIALS ONTARIO [ADDRESS] (herein the “CTO” )

–and –

[FULL LEGAL NAME] [ADDRESS] (herein “PARTICIPATING ORGANIZATION” OR “PO” )

Each a “Party” and together, the “Parties”

RECITALS:

A. CTO is an independent not-for-profit organization established through the Ministry of Economic Development and Innovation to support efforts to maximize research investment in Ontario, with a goal of creating a single point of entry initially for industry sponsored multi-centre trials through a delegated research ethics review (“Delegated Board of Record”) model within the Province of Ontario.

B. The PO wishes to participate in the Delegated Board of Record model.

D. The purpose of this Agreement is to set out CTO’s and the PO’s respective rights and obligations in connection with the Delegated Board of Record model.

THEREFORE, the parties agree as follows:

ARTICLE 1 DEFINITIONS AND PRINCIPLES OF INTERPRETATION

1.1 Definitions

In this Agreement, the following words and terms have the following meanings:

(a) “Agreement” means this agreement including all schedules, exhibits, and all amendments or restatements as permitted, and references to “Article ”, “ Section”, “Schedule” or “Exhibit ” means the specified Article, Section, Schedule or Exhibit of or to this Agreement;


(b) “Clinical Trial” means a clinical trial which as a result of this Agreement and arising out of an agreement between a clinical trial sponsor and CTO, will have research ethics review coordinated through the Delegated Board of Record model;

(c) “Confidential Information ” means as defined in s. 5.1 below;

(d) “Effective Date” means the date of final execution of this Agreement, as set out on the execution pages hereto;

(e) “End of Study” means until all accountabilities of Host Institution REB are met (i.e., database lock and/or study closure at all participating sites for which the REB is responsible, and document retention obligations) [Note to draft: group may wish to consider more fully what “End of Study” constitutes]

(f) “FIPPA” means the Freedom of Information and Protection of Privacy Act (Ontario) and any amendments thereto;

(g) “Force Majeure Event” has the meaning set out in Section •

(h) “Host Institution ” means a PO whose research ethics board has been qualified by CTO (or its agent) to assume the role of a Delegated Board of Record for the purpose of assuming the research ethics review, approval and oversight of a specific study.

(i) “ Intellectual Property Rights” means all rights in and to any and all intellectual and industrial property of any kind, including works protected by the law of copyright or in which copyright may subsist such as documentation, software, data and information, whether in printed, electronic, magnetic, optical or other material or tangible form, compilations of information and databases (whether or not any of same are protected by copyright); designs; trade-marks and trade names; patents, inventions, processes and discoveries; industrial designs; trade secrets; know-how; Confidential Information or other information of a confidential nature and any other works that are subject to intellectual and industrial property protection under the laws of Canada, any foreign country, or any political subdivision thereof;

(j) “Institution” means, as applicable, a PO that has agreed to participate in the Delegated Board of Record model;

(k) “Laws and Regulations” means all statutes, regulations, codes, ordinances, decrees, rules, municipal by-laws, judicial or arbitrable or administrative or ministerial or departmental or regulatory judgments, orders, decisions, rulings or awards enacted or promulgated by any regulatory body pursuant to any statutory authority or requirement and, in all cases, applicable, binding and enforceable in Canada, all as amended from time to time, and “Law or Regulation” has a corresponding meaning;


(l) “Non-Host Institution” means a PO that has agreed to delegate the review function of its research ethics board to a Host Institution’s research ethics board for a particular study

(m) “Parties” means CTO and PO and “Party” means any one of them;

(n) “Personal Health Information” has the same meaning as defined in PHIPA;

(o) “Personal Information” means any information about an identifiable individual, including Personal Health Information, that is required to be protected pursuant to PHIPA, PIPEDA or other Laws and Regulations pertaining to the protection of personal information;

(p) “PHIPA ” means the Personal Health Information Protection Act, 2004 (Ontario) and any amendments thereto;

(q) “PIPEDA” means the Personal Information Protection and Electronic Documents Act (Canada) and any amendments thereto;

(r) "Term" has the meaning given to it in Section •;

1.2 Interpretation

This Agreement shall be interpreted in accordance with the following, unless the context otherwise specifies or requires:

(a) Words importing the singular number include the plural and vice versa; words importing the masculine gender include the feminine and vice versa; and words importing persons include individuals, corporations, partnerships, joint ventures, associations, trusts, pension funds, unions, governmental agencies, officials, boards, tribunals, ministries, commission or departments; corporations, partnerships, trusts and unincorporated organizations.

(b) The headings used in this Agreement are inserted for reference purposes only and are not to be considered or taken into account in construing the terms or provisions hereof or to be deemed in any way to clarify, modify or explain the effect of any such terms or provisions.

(c) Any references in this Agreement to any law, agreement, rule, regulation, order or act of any government, governmental body or other regulatory body shall be construed to reference it as amended or re-enacted from time to time or to reference any successor to it.

(d) The contra proferentum rule (which requires that any ambiguity in an agreement shall be interpreted against the Party drafting the agreement) shall not apply to the interpretation of this Agreement.


(e) In this Agreement, “in writing” or “written” shall mean and include printing, typewriting or any electronic means of communication capable of being permanently reproduced in alphanumeric characters at the point of reception.

1.5 Schedules

The following are Schedules to this Agreement: Schedule A Qualification requirements - Delegated Board of Record Schedule B Selection criteria for choosing a Delegated Board of Record Schedule C Fee structure Schedule D Delegated Board of Record Agreement template Schedule E CTO Forms

1.6 Conflicts

In the event of any conflict or inconsistency between the terms of this Agreement and any Schedule, the terms of this Agreement prevail.

ARTICLE 2 TERM & TERMINATION

2.1 Term & Termination

(a) The term of this Agreement shall commence on the Effective Date and shall be for a three (3) year term with annual renewals thereafter as confirmed in writing by the parties, subject to earlier termination in accordance with the provisions hereof.

(b) PO shall provide written notice to CTO of its election to terminate the agreement not later than ninety (90) days prior to the end of the term.

(c) Despite clause 2.1(b) above, a PO that is a Host Institution may not terminate this agreement prior to the end of its research ethics board’s delegated Board of Record accountabilities as assigned through this Agreement.

ARTICLE 3 RESPONSIBILITIES OF PARTIES

3.1 CTO Responsibilities

CTO shall have the following responsibilities:


(a) administering Board of Record agreements with organizations that agree to act as Host and/or Non-Host Institutions;

(b) facilitating registration of participating organizations that wish to self-assess their potential to become a Delegated Board of Record based on established qualifications (Schedule “•”);

(c) appointing the Delegated Board of Record for each Clinical Trial based on established selection criteria (Schedule “•”);

(d) maintaining in a manner available to PO a current list of Delegated Boards of Record;

(e) maintaining repository of local institution requirements pertaining to research ethics, particularly informed consent document language;

(f) monitoring the work of Delegated Board of Records and auditing compliance with the established qualifications at CTO’s discretion and no less than every two years;

(g) setting template and standards for protocol submissions for Delegated Boards of Record;

(h) establishing standard review criteria for use by Delegated Boards of Record;

(i) facilitating e-tools for communications and coordination, including of serious adverse event (“SAE”) reporting; and

(j) handling of research ethics board review fees, including disbursement of research ethics board fees to Host Institution’s research ethics board.

3.2 PO Responsibilities

PO shall have the following responsibilities:

(a) providing one point of contact (the “PO Contact”) at the PO who will timely manage the implementation and operation of the delegated Board of Record model for the PO, including execution of Delegated Board of Record Agreement in the form provided in Schedule “•”;

(b) confirming with CTO within seven (7) days of selection, PO acceptance of role as Host Institution for a particular study;

(c) committing to decline the invitation to act as Host Institution only in rare and

legitimate situations including but not limited to lack of Research Ethics Board expertise in an area pertinent to the particular study;


(d) as Host Institution, fulfilling the obligations identified in the Delegated Board of Record Agreement, providing timely review using the e-tools provided by CTO for communication and reporting; [Note to draft: may be dependent on outcome of the work done by the Working Group on REB Streamlining]

(e) as Non-Host Institution, assuming administrative duties including requiring

principal investigator signoff on study protocols; and (f) fulfilling and complying with its other obligations in this Agreement.

ARTICLE 4 REPRESENTATIONS AND WARRANTIES

4.1 Representations and Warranties

Each party represents and warrants to the other party that it:

(a) has full power and authority to enter into this Agreement and to observe, perform, and comply with the terms and conditions of this Agreement;

(b) shall operate in compliance with all Laws and Regulations related to any aspect of this Agreement;

(c) it holds all permits, licenses, consents, Intellectual Property Rights, and authorities necessary to perform its obligations under this Agreement;

ARTICLE 5 INTELLECTUAL PROPERTY RIGHTS

5.1 Reservation of Rights

Except as expressly provided in this Agreement, no Party shall acquire any right, title or interest in or to any Intellectual Property Rights of another Party or of its licensors or subcontractors. For greater clarity, no right, title or interest in or to CTO’s e-tools that support the Delegated Board of Record model are hereby granted save a non-exclusive, royalty free license during the term of this Agreement to use the e-tools solely in support of fulfilling obligations under this Agreement.


ARTICLE 6 ACCESS TO INFORMATION/CONFIDENTIALITY

6.1 Confidential Information

(a) From time to time a party (“Disclosing Party”) may provide to the other party (“Receiving Party”) information (“Confidential Information”) in accordance with its obligation pursuant to this Agreement. The Receiving Party agrees that it will not at any time, directly or indirectly, disclose the Confidential Information of the Disclosing Party to any person, other than to the Receiving Party’s directors, officers, employees, and professional advisors, in each case strictly on a need-to-know basis and in order for the Receiving Party to exercise its rights or perform its obligations hereunder, except as otherwise specifically authorized by the Disclosing Party.

(b) The requirement of confidentiality shall survive for a period of ten (10) years.

(c) Upon termination of the Agreement, the Receiving Party may retain one secure archival copy of the Confidential Information and otherwise shall return it, or upon written authorization of the Disclosing Party, securely destroy it and provide notice of its secure destruction.

(b) For greater certainty, nothing in this Agreement imposes liability upon a Receiving Party for making disclosures of a Disclosing Party’s Confidential Information where such information:

(i) at the time of or after its disclosure is in or becomes part of the public domain, other than as a result of a breach by the undersigned of its obligations hereunder; or

(ii) can be demonstrated to have been disclosed to the Receiving Party by a third party that was not bound by a confidentiality agreement or otherwise prohibited from transmitting such information by a contractual, legal or fiduciary obligation;

(iii) was independently developed by Receiving Party without benefit of the Confidential Information as demonstrated by written records; or

(iii) is required to be disclosed by any applicable Laws or Regulations.


ARTICLE 7 INSURANCE & INDEMNITY

7.1 Insurance Coverage Requirements

Each party shall maintain for the period during which the Agreement is in effect, at its own cost and expense:

(a) Commercial General Liability Insurance (including any excess liability coverage) on an occurrence basis for third party bodily injury, personal injury and property damage, to an inclusive limit of not less than $5,000,000 per occurrence. The policy shall name the Parties to this Agreement as additional insureds but only with respect to this Agreement and shall include the following:

(i) contractual liability coverage;

(ii) cross-liability clause; and

(iii) a thirty (30) day written notice of cancellation, termination or material change;

[Note to draft: we will have to arrange for insurers to review this and the indemnification language; and necessity, if any for E&O]

7.2 Indemnities

(a) CTO agrees to indemnify, and undertakes to defend and hold harmless, PO, its officers, directors, investigators, employees and agents (collectively, the “PO Indemnitees”), from and against all losses resulting from:

(i) the death of or bodily injury to any third party or to any employee of the PO (or other person for whom the PO is responsible in law) to the extent caused by the negligence or wilful misconduct of CTO or any subcontractor of CTO in performance of its obligations under this Agreement;

(ii) the loss of or damage to the real or tangible personal property (whether owned or leased) of any third party or any of the PO Indemnitees, to the extent caused by the negligence or wilful misconduct of CTO or any subcontractor of CTO in the performance of its obligations hereunder;

(iii) any action, claim or demand arising as a result of CTO’s failure to perform its obligations under this Agreement.

(b) PO agrees to indemnify, and undertakes to defend and hold harmless, CTO, its officers, directors, employees and agents (collectively, the “CTO Indemnitees”), from and against all losses resulting from:


(i) the death of or bodily injury to any third party or to any employee of CTO (or other person for whom CTO is responsible in law) to the extent caused by the negligence or wilful misconduct of PO or any subcontractor of PO in performance of its obligations under this Agreement;

(ii) the loss of or damage to the real or tangible personal property (whether owned or leased) of any third party or any of the CTO Indemnitees, to the extent caused by the negligence or wilful misconduct of PO or any subcontractor of PO in the performance of its obligations hereunder; or

(iii) any action, claim or demand arising as a result of PO’s failure to perform its obligations under this Agreement.

ARTICLE 8 DISPUTE RESOLUTION

8.1 Dispute Resolution Process

(a) Prior to the initiation of formal dispute resolution procedures, the parties shall first attempt to resolve any dispute, controversy or claim (including any failure by the parties to reach agreement where expressly provided for in this Agreement) arising under or in connection with this Agreement (a “Dispute”) informally, with senior representatives of each party to meet as often and as promptly as the parties deem necessary to discuss the Dispute and negotiate in good faith in an effort to resolve the Dispute.

(b) If the relevant representatives are unable to resolve the Dispute within fifteen (15) days after the referral of the Dispute to them, the Dispute will be referred to “•” (the “Committee”). The Committee shall use reasonable efforts to resolve such Dispute, including, without limitation, negotiating a modification or amendment to this Agreement. The Committee shall meet as often and as promptly as the parties reasonably deem necessary to discuss the Dispute and negotiate in good faith in an effort to resolve the Dispute. [Note to draft: determine whether such a Committee shall be established]

(c) During the course of such discussions, all reasonable requests made by one Party to another for non-privileged information, reasonably related to the Dispute, will be honoured in order that each of the Parties may be fully apprised of the other’s position. The specific format for such discussions will be decided by mutual agreement of the Parties, but may include the preparation of agreed-upon statements of fact or written statements of position.

(d) If the Dispute has not been resolved by the Parties within thirty (30) days (or such longer period to which the Parties may agree) after the referral of such Dispute


thereto, any Party may upon written notice to the other Party elect to submit the Dispute to arbitration in accordance with the Arbitration Act. [Note to draft: consider fleshing this out, e.g. method of selecting arbitrator(s)]

8.2 Confidentiality

The proceedings of all negotiations, mediations and arbitrations as part of the Dispute resolution process shall at all times be privately conducted. The Parties agree that all information, materials, statements, conduct, communications, negotiations, mediations, arbitrations, offers of settlement, documents, decisions, and awards of either Party, in whatever form and however disclosed or obtained in connection with that portion of the Dispute resolution process which precedes the commencement of formal legal proceedings in a court or other tribunal: (i) shall at all times be Confidential Information; (ii) shall not be offered into evidence, disclosed or used for any purpose other than the Dispute resolution process under this agreement; and (iii) will not constitute an admission or waiver of rights.

ARTICLE 9 GENERAL

9.1 Further Assurances

The Parties shall sign such further and other documents, cause such meetings to be held, cause such resolutions to be passed, exercise their vote and influence and do and perform (and cause to be done and performed) such further and other acts or things as may be necessary or desirable in order to give full effect to this Agreement and every part of it.

9.2 Publicity

All notices to third parties and other publicity concerning the transactions contemplated by this Agreement will be mutually planned and coordinated between the Parties.

9.3 Notices

(a) All notices under this Agreement shall be in writing and shall be delivered by personal delivery/courier, fax, email or registered mail:

(i) to CTO at:

[ADDRESS]

[FAX]

Attention: [NAME, TITLE]


(ii) to the PO at:

[ADDRESS]

[FAX]


The notice shall be deemed to have been delivered on the day of personal delivery, on the day received by fax (as evidenced by a transmission confirmation) or by e-mail, or on the fifth day following mailing.

9.4 Applicable Law

This Agreement and all other documents provided for in this Agreement and the rights and obligations of the parties thereto shall be governed by and construed and enforced in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein and the parties hereto attorn to the jurisdiction of the courts of the Province of Ontario.

9.5 Severability

Each of the provisions contained in this Agreement are distinct and severable. Any declaration by a court of competent jurisdiction of the invalidity or unenforceability of any provision or part of a provision will not affect the validity or enforceability of any other provision of this Agreement.

9.6 Waiver

No delay or omission by a Party to exercise any right or power it has under this Agreement shall impair or be construed as a waiver of such right or power. A waiver by any Party of any breach or covenant shall not be construed to be a waiver of any succeeding breach or any other covenant. All waivers must be in writing and signed by the Party waiving its rights.

9.7 Counterparts

This Agreement may be executed in any number of counterparts, each of which shall be deemed an original and all of which, taken together, shall constitute one and the same instrument. Delivery by facsimile or email of any executed counterpart of this Agreement shall be equally as effective as delivery of a manually executed counterpart thereof.

9.8 Entire Agreement

This Agreement, including the Schedules hereto, constitutes the entire agreement between the Parties with respect to the subject matter hereof and cancels and supersedes any prior understandings and agreements between the Parties. There are no


representations, warranties, forms, conditions, undertakings or collateral agreements, express, implied or statutory between the Parties other than as expressly set forth in this Agreement. Except as otherwise explicitly set out herein, this Agreement may only be amended by a written document signed by the Parties.

9.9 Relationship of Parties

In connection with this Agreement, each Party is an independent contractor. This Agreement does not and shall not be deemed to create a joint venture, partnership, fiduciary or agency relationship between the Parties for any purpose. With respect to its own personnel, each Party is independently responsible for all obligations incumbent upon an employer.

9.10 Assignment

This Agreement will be binding upon and inure to the benefit of the Parties and their respective successors and permitted assigns. No Party shall assign this Agreement or any part hereof or any benefit or interest herein without the prior approval of the other Party.

9.11 Force Majeure

No Party shall be liable for any delays in the performance of any of its obligations hereunder due to causes beyond its reasonable control (“Force Majeure Event”), including, but not limited to, fire, strike, war, riots, acts of terrorism and/or of a public enemy, acts of any civil or military authority, acts of God, floods, unusually severe weather, epidemics, pandemics or quarantine restrictions, public utility failure or service fluctuation, judicial action and acts and failures to act by governmental authorities.

9.12 Survival

Notwithstanding the expiration or earlier termination of this Agreement for any reason, the following Articles and sections of this Agreement shall survive any such termination or expiration: 5.1, 6, 8, 9.4 •

THE REMAINDER OF THIS PAGE IS INTENTIONALLY LEFT BL ANK


IN WITNESS WHEREOF the Parties have executed this Agreement as of the last signature below.

CLINICAL TRIALS ONTARIO By: __________________________

[NAME, TITLE]

Date: ______________________ By: ________________________

[NAME, TITLE]

Date: ______________________

[PARTICIPATING ORGANIZATION] By: ________________________

[NAME, TITLE]

Date: ______________________ By: ________________________

[NAME, TITLE]

Date: ______________________


SCHEDULE A QUALIFICATION REQUIREMENTS - DELEGATED BOARD OF RECORD SCHEDULE B SELECTION CRITERIA FOR CHOOSING A DELEGATED BOARD OF RECORD SCHEDULE C FEE STRUCTURE SCHEDULE D DELEGATED BOARD OF RECORD AGREEMENT TEMPLATE SCHEDULE E CTO FORMS


Appendix 5: Draft Board of Record Study Agreement

CTO Study ID Number: Agreement Among:

__________________________ (“Participating Institution”):

Address for direction of legal notices under this agreement:

Address:

Attention:

And

__________________________ (“Host Institution”)


Address: Attention:

And

Participating Institution Principal Investigator Name (“Participating Institution PI”):

Name: Address:

Phone: Fax: Email:

Study Title (the “Study”):


Preamble Host Institution has registered with Clinical Trials Ontario (“CTO”) to have Host Institution REB act as a delegated Board of Record responsible to provide ethics review of multi-centre trials upon request. Host Institution REB has been selected by CTO to act as the delegated Board of Record for the Study. This inter-institutional agreement sets out the terms and conditions for Participating Institution’s delegation of research ethics review, approval and oversight to Host Institution REB for the Study.

CTO is an independent not-for-profit organization with a provincial mandate to provide the life sciences industry with a streamlined approach to conducting multi-centre clinical trials in Ontario while ensuring the highest ethical standards for patient safety. CTO has entered into separate agreements with participating institutions to participate in a delegated Board of Record model.

The parties hereby agree as follows: 1. Board of Record 1.1 The Participating Institution retains Host Institution, and Host Institution agrees to Host

Institution REB acting, as the Research Ethics Board of Record (“Board of Record”) for the Participating Institution in respect of the Study.

1.2 Participating Institution and Host Institution agrees that Host Institution REB may approve,

reject, propose modifications to, put on hold or terminate the Study at its sole discretion (“Board of Record Determinations”).

1.3 In agreeing that its REB shall act as delegated Board of Record, Host Institution agrees that

Host Institution REB shall act:

(i) in accordance with its responsibilities set out in the attached Schedule A, including but not limited to Host Institution’s Participation Agreement with CTO; and

(ii) in compliance with all applicable laws, regulations and guidelines, including but not

limited to the Second Edition of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2); the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline E6; the Canadian Food and Drugs Act and its applicable regulations, in particular Part C, Division 5; the Canadian General Standards Board’s “Research Ethics Oversight of Biomedical Clinical Trials” and Ontario’s Personal Health Information Protection Act, 2004 (“PHIPA”) and its applicable regulations (“Applicable Laws”).


1.4 Host Institution acknowledges that the documents and information that Host Institution REB receives from the Participating Institution are subject to strict confidentiality obligations pursuant to agreements between or among Participating Institution, Participating Institution PI, and the Study sponsor (“Sponsor Agreements”). Therefore Host Institution and those for whom it is responsible at law shall maintain in confidence all documents and information received from the Participating Institution and/or Participating Institution PI and shall not disclose them to third parties without prior written permission of the sponsor and/or Participating Institution and Participating Institution PI as applicable. In the event that Host Institution (a) reasonably believes that information or documents obtained from the Participating Institution and/or Participating Institution PI must be disclosed in the interest of protecting the safety of Study participants, or (b) Host Institution is required by law, regulation or court order to disclose information or documents obtained from the Participating Institution, then Host Institution shall before making any such disclosure notify the Participating Institution and Participating Institution PI so that Host Institution, Participating Institution and Participating Institution PI may collectively determine how disclosure may be made without breach of Sponsor Agreements. The obligations contained in this paragraph shall survive completion or earlier termination of this Agreement. [Note to draft: further consideration will be given to safeguarding PHI in accordance with PHIPA]

1.5 In the event of an on-site assessment by Host Institution REB, Participating Institution and

Participating Institution PI may be required in accordance with Schedule A to provide direct access to Study participants’ records of personal health information (as that term is defined under PHIPA) that are in the direct or indirect control of the Participating Institution and/or Participating Institution PI (“Participants’ Records”). Should that occur, Host Institution REB will hold the Participants’ Records in confidence, use them solely for the purpose of carrying out its duties under this Agreement, and will not copy or remove said records or transfer any information contained in them to anyone other than employees and agents of Host Institution REB with a need to know, without the prior written consent of Participating Institution or in accordance with Applicable Laws.

1.6 Host Institution represents and warrants that Host Institution REB operates and is

constituted in accordance with all Applicable Laws and that it is registered with Health Canada and as an IRB with the U.S. Office for Human Research Protections, as applicable and meets or exceeds the CTO qualification standards.

2. Obligations of the Participating Institution and Participating Institution PI The Participating Institution and Participating Institution PI agree to comply with all Board of Record Determinations with respect to the Study, and each with respect to its/his/her own role to conduct the Study in accordance with all Applicable Laws and in accordance with its/his/her responsibilities set out in the attached Schedule A.


3. Relationship of the Parties

Host Institution, the Participating Institution and the Participating Institution PI are and at all times shall remain independent of each other and are not and shall not represent themselves to be the principal, agent, joint venturer, partner or employee of the other(s). No representations shall be made or actions taken by a party which could establish or imply any apparent relationship of agency, joint venture, partnership or employment with another, and other than expressly provided under this Agreement, no party shall be bound in any manner whatsoever by any agreements, warranties or representations of another party. 4. Assignment Neither this Agreement nor any of the rights or obligations of any party may be assigned without prior written consent of the other parties to this Agreement. 5. Term and Termination 5.1 This Agreement remains in place for the duration of the Study (including with respect to

document retention) unless terminated in accordance with this Article 5. 5.2 Providing that alternate REB oversight of the Study is in place in accordance with the

parties’ obligations and this Agreement and the Participation Agreement with CTO, termination may occur only in the following circumstances:

(i) Where the Participation Agreement between CTO and either or both of the

Participating Institution or Host Institution is terminated; (ii) Upon mutual agreement in writing by the parties

6. Statement of Responsibility

6.1 Except as otherwise provided in this Agreement,

(i) Each party assumes its/his/her own liability for any damages, losses or costs arising out of suits or claims on account of injuries (including death) to persons participating in the Study or damage to property to the extent that such injuries or damage arise out of its/his/her activities in the course of the Study or the performance of this Agreement, or out of the activities of those for whom in law it/he/she is responsible; and

(ii) No party or its/his/her trustees, directors, officers, employees, and agents (the “first

party’’) shall be liable to any other party (the “second party’’) for any damages, losses or costs arising out of suits or claims brought by the second party or made against the second party except to the extent caused by negligence or willful misconduct on the part of the first party.


(iii) For greater clarity, Host Institution REB obligations under this Agreement include research ethics review, initial and ongoing approvals of the Study at Participating Institution, and any liabilities related to such review, approval and oversight.

6.2 Each institutional party shall maintain appropriate insurance sufficient to cover its liabilities

that may arise under this Agreement; and, in the case of the Participating Institution PI, he/she shall maintain membership in the Canadian Medical Protective Association (CMPA) that includes coverage for his/her respective clinical research activities under the Study protocol. Upon request, each party shall provide to the others a certificate of insurance or other proof of insurance or of CMPA membership, as appropriate.

7. Dispute Resolution In the event that a dispute arises related to this Agreement, the parties will initially and in good faith discuss the matter through their contacts named at the beginning of the Agreement and seek a resolution. If no resolution has been reached within fifteen (15) days from the commencement of discussions, the parties shall be free to pursue any other remedies available to them. In the event that any party receives notice of a legal proceeding by a third party against it that is related to the Study, it shall immediately notify the other parties in writing through its contacts named at the beginning of the Agreement. While a dispute is being settled, the Host Institution REB is required to continue with its role as delegated Board of Record. 8. Governing Law This Agreement shall be governed by, and construed and interpreted in accordance with, the laws in force in the Province of Ontario and shall be treated in all respects as an Ontario contract. 9. Severability

If any provision of this Agreement is determined to be invalid or unenforceable in whole or in part, such invalidity or unenforceability shall attach to such provision and the remainder of the Agreement shall continue in full force and effect; and the parties shall in good faith negotiate a substitute for any provision declared unenforceable, which shall most nearly approximate the intent of the parties in entering into this Agreement. 10. Signatures By signing, the signatories agree that a signed photocopy or electronic version (e.g., *.pdf or fascimile) of this Agreement is as valid as an original. This Agreement may be signed in counterparts, each of which is to be considered an original, and taken together as one and the same document. A copy of this Agreement executed in counterpart shall be provided by each party to the other parties.


Participating Institution

Name: Title:

Signature:

Date:

Authorized Signing Officer (“I have authority to bind the Participating Institution”)

Host Institution

Name: Title:

Signature: Date:

Authorized Signing Officer (“I have authority to bind Host Institution”)

Participating Institution Principal Investigator: Witness:

Name: Name:

Signature: Signature:

Date: Date: All counterparts of this fully executed Agreement should be kept on file at Host Institution, Participating Institution, and in the Participating Institution PI’s essential Study documents file.


SCHEDULE A

Division of Responsibilities among Host Institution, the Participating Institution and Participating Institution PI

I. The responsibilities of HOST INSTITUTION are to:

1. Abide by the terms and conditions of its Participation Agreement with CTO with respect to the delegated board of record model for ethics review of multi-Participating Institution clinical trials.

2. Maintain its registration with Health Canada and as an IRB with the U.S. Office for Human Research Protections, and with CTO.

3. Mandate its REB to review and consider the application materials submitted by the Participating Institution PI, correspond with the Participating Institution PI regarding any issues or recommended changes to the Study, and make a decision about approval of the Study at the Participating Institution.

4. Mandate its REB to be familiar with the CTO list of Participating Institution-specific informed consent language/preferences.

5. Mandate its REB to conduct the ethics review of the Study and correspond with the Participating Institution PI regarding any issues or recommended changes to the Participating Institution PI’s materials.

6. Mandate its REB to ensure an ongoing monitoring plan is in place with respect to the Study, which includes an annual review of the approved Study or more frequently at the discretion of Host Institution REB, a review of all site-specific serious adverse events (“SAEs”) in accordance with the Study protocol and review of and decision regarding approval of any protocol amendments/modifications to the Study submitted to HOST INSTITUTION REB by the Participating Institution PI, as applicable. [Note to draft: CTO decision required on whether other materials to be submitted by the sponsor, e.g., CIOMs/PSUR reports. All investigators will have to maintain the reports with their study file and the Delegated Board will have to maintain as well.]

7. Maintain Participating Institution REB Materials as well as the Host Institution review letter(s), investigator response letter(s), Host Institution REB determination letters, local SAE reports received from all Participating Institutions using Host Institution REB. [Note to draft: decision required on who maintains CIOMs/PSUR reports]

8. Maintain written Host Institution REB policies and procedures, and make such documents accessible to designated Participating Institution and Participating Institution PI staff members.

9. Mandate its REB to adhere to the requirements of the Participating Institution’s Federal Wide Assurance and CTO qualification standards.

10. Mandate its REB to immediately notify the Participating Institution and Participating Institution PI in writing if the Study is placed on hold or terminated by Host Institution REB.


11. In the event that the Study closes at Host Institution prior to closure at the other Participating Institutions, continue in its role as Host Institution REB.

12. Mandate its REB to notify in writing, and cooperate with, the Participating Institution and the Participating Institution PI concerning any significant Study-related communication received by Host Institution REB that has not been received by the Participating Institution or Participating Institution PI, including, but not limited to Study participant complaints, protocol deviations and privacy breaches.

II. The responsibilities of the Participating Institution:

1. Participating Institution shall inform Host Institution of the appropriate Participating Institution representative to be copied on key correspondence (including but not limited to notification of approvals) from Host Institution in addition to the Participating Institution PI.

2. Participating Institution shall maintain a Federal Wide Assurance (FWA) and designate Host Institution as an REB responsible to the Participating Institution under the Participating Institution’s FWA.

3. Participating Institution shall administratively assess and approve the Study based on feasibility and resource assessments of the Participating Institution and Participating Institution PI and provide confirmation to Host Institution REB of its final approval of the Study budget and contract with the Study sponsor. For greater certainty, although HOST INSTITUTION may approve the ethical aspects of the Study, the final decision to conduct the Study at the Participating Institution rests with the Participating Institution. [Note to draft: discussion by the Working Group on Legal and Liability Issues as to whether it should be standardized in this agreement that REB reviews budget; industry raised concerns about confidentiality; some felt this was supported by TCPS 2, others felt it was discretionary.]†

III. The responsibilities of the Participating Institution PI:

1. Participating Institution PI shall submit materials to HOST INSTITUTION REB in accordance with HOST INSTITUTION REB’s policies, procedures and requirements. This includes any amendments or modifications to the Study (including but not limited to protocol amendments, revised consent forms and external SAEs/safety reports), and any new information (including but not limited to data safety monitoring board reports) that may adversely affect the safety of the participants or significantly affect the conduct of the Study.[Note to draft: may be updated if CTO SOPs are also developed]

2. Participating Institution PI shall conduct the Study at the Participating Institution in accordance with the Study protocol, Participating Institution policies, procedures and requirements, and all Applicable Laws.

3. Participating Institution PI shall be appropriately qualified to conduct the Study at all times and Participating Institution and Participating Institution PI shall immediately advise Participating Institution and Host Institution REB should it/he/she become aware


of any information that would indicate that the qualifications of the Participating Institution PI may no longer be appropriate to the Study.

4. Participating Institution PI shall promptly report to Host Institution REB all local SAEs in respect of the Study (as defined by the Study protocol and by Host Institution REB) and any new information (including but not limited to protocol deviations) that may adversely affect the safety of the participants or significantly affect the conduct of the Study.

5. In addition to reporting in accordance with Participating Institution policies (e.g., to the Privacy Officer), Participating Institution PI shall promptly report to Host InstitutionREB all privacy breaches in respect of the Study, and any corrective action taken.

6. Participating Institution PI shall notify Host Institution REB immediately in writing:

a) if the Study has been placed on hold or terminated at the Participating Institution;

b) of any significant Study-related communication including, but not limited to participant complaints, protocol deviations and privacy breaches.

†

TCPS 2 states:

Clinical Trial Budgets

Budgets for clinical trials are usually calculated based on per capita costs – that is, the sponsor pays the

researcher a fixed sum for each participant, based on the duration and complexity of the trial and the tests

and procedures it requires.

Article 11.11 REBs shall ensure that clinical trial budgets are reviewed to ensure that conflicts of interest are

identified and minimized, or otherwise managed.

Application REBs may delegate the review of clinical trial budgets to an appropriate institutional body. The

body should ensure financial conflicts of interest are reported to the REB. When no such institutional body

exists, the REBs shall review clinical trial budgets for financial conflicts of interest.As a general guide,

payments for clinical trial procedures should be no greater than the usual amounts charged by health care

providers for the provision of comparable services. Researchers should disclose all kinds and amounts of

payment to the REB (see Article 7.4).

A particular concern in the context of clinical trials is the use of inappropriate incentives by the sponsor to

encourage researchers to recruit participants quickly and without regard to their suitability for the trial.

Differential incentives paid for different levels of recruitment, such as higher per-participant payments for

those recruited above a set target, may also encourage inappropriate recruitment practices and should be

prohibited. The REB can assist the researcher in identifying these and other types of financial conflicts and

managing them appropriately (see Article 7.4).

It is recommended that the issue of budget review and appropriateness should be left to the Participating

Institution who advises the Host Institution REB that it has done so. Local institutions are more likely to be aware

of possible Conflict of Interest issues as well.

Report: Working

Group on Research

Ethics Board

Streamlining April, 2013

Clinical Trials Ontario | Working Group on Research Ethics Board Streamlining | April 2013 1

Contents

Background ............................................................................................................................................................. 2


Call for Nominations for the Working Group ......................................................................................... 2

REB Streamlining Working Group ............................................................................................................. 2


Ontario REB qualification process.................................................................................................................. 4

Framework for Implementation of the Delegated Board of Record Review Model.................... 6

Recommendations for a Pilot Study .............................................................................................................. 7

Appendix: Potential Roles for Clinical Trials Ontario in the Delegated Board of Review

Streamlining Model .............................................................................................................................................. 8

2 Clinical Trials Ontario | Working Group on Research Ethics Board Streamlining | April 2013

Background







Call for Nominations for the Working Group

In August 2012, CTO issued a public call for nominations for participants to provide experienced

advice to CTO on key aspects of CTO’s core projects. CTO established three expert Working Groups

from a broad cross-section of stakeholders:





REB Streamlining Working Group

Purpose: To provide expert advice to help guide the implementation of the following aspects of

CTO’s activities:

1. Develop Ontario standards to support the delegated Board of Record review model

(harmonized with national and international standards as appropriate);

2. Define a framework for streamlining research ethics review to support a delegated Board of

Record review model; and

3. Develop an appropriate framework to support the implementation of the delegated Board of

Record review model for Ontario.

Goals and Responsibilities

1. Evaluate the current parallel initiatives related to REB standards and put forward options and

recommendations for implementation of a province-wide mechanism for Ontario REB

qualification;

2. Develop an appropriate framework to support the delegated Board of Record review process,

including the criteria that will be used for the selection of a delegated Board of Record; and

3. Develop recommendations for the pilot study roll-out of the new streamlined REB review

system.


Deliverables and Deadlines

1. Recommend an Ontario REB qualification process (due by November 2, 2012);

2. Develop an appropriate framework for implementation of the delegated Board of Record

Review model (due by November 20, 2012); and

3. Recommend how to roll out the pilot study (due by December 14, 2012).


Frank Naus (Chair)

Director, Research Administration, Office of Integrated Research Services, Hamilton Health Sciences

Corporation

Michael Borrie

Medical Director, Aging Brain and Memory Clinic and Geriatric Clinical Trials Group

Jack Corman

President, IRB Services

Padraig Darby

Research Ethics Board Chair, Centre for Addiction and Mental Health

Paul Macpherson

Director, Grants, Contracts and Ethics Review Services, UHN

Janet Manzo

Executive Director, Ontario Cancer Research Ethics Board

Nicole McLean

Manager, North American Clinical Operations - Clinical Trial Site Services, Eli Lilly Canada Inc.

Keitha McMurray

Director, Clinical Studies Resource Centre and Research Ethics Office, Sunnybrook Health Sciences

Centre

Suzette Salama

Research Ethics Board Chair, Hamilton Health Sciences Corporation



The Working Groups were supported by Manal Siddiqui (Project Manager) and Erin Menzies

(Research Analyst), Clinical Trials Ontario; and by lawyers from Dykeman Dewhirst O’Brien LLP.


Ontario REB Qualification Process

In order to establish a new framework for multi-centre clinical trials in Ontario, with a focus on

creating a delegated Board of Record model, it is imperative that stakeholders trust that the Board

of Record is appropriately qualified, and that the tenets of patient safety will be met. The need for a

more efficient review process has been cited as a key concern (see CTO Inaugural Strategic Plan

2012-2017). Issues of the Board of Record’s and delegating institution’s liability are also important

(and are being addressed primarily by the Working Group on Legal and Liability Issues). Industry

representatives have clearly identified that if a new model is to be adopted, it must create cost

efficiencies and improve “cycle times” with respect to the end to end ethics review process (while

acknowledging that ethics review is merely one component in the timeline, and some local delays

are the result of legal review of clinical trial agreements and other administrative hurdles).

In short, the REB qualification process is the means by which a delegating institution (through its

Board of Directors, which is ultimately accountable) will achieve sufficient trust in the system to

choose to participate in the CTO initiative. A standard qualification process is a matter of due

diligence; it serves to assure delegating institutions that minimum standards will be met as a

condition for the local REB role being relinquished to the delegated Board of Record.

The Working Group concluded that in order to recommend a qualification process for Ontario REBs,

the process must:

• Comply with international regulatory requirements and ethical standards;

• Set minimum standards for all participating REBs to encourage trust among institutions,

partners and participants so that delegation to a Board of Record can occur with

confidence;

• Create consistency to help REBs move forward to common processes and policies (and

potentially to move toward developing standard operating procedures for REBs);

• Have efficient processes while maintaining highest ethical standards; and

• Not be complex or overly bureaucratic.

The Working Group also discussed the options for how to describe the process. The following terms

were discussed:

• “Accreditation” was considered to be overly far-reaching and would need to be

circumscribed;

• “Certification” was felt to create a generally unachievable standard;

• “Credentialing” was considered and favoured by some, while others found it to be over-

reaching;

• “Qualification” curried favour as a potential middle ground;


• “Registration” was likened to the pre-qualification done by vendors in a procurement

process where they self-evaluate and state their compliance; but the model appeared to lack

the rigour that the Working Group wished to see in place.

The middle ground of “qualification” was discussed at length, and was favoured in part because it is

a standard currently being adopted by a significant number of teaching hospitals through the

Toronto Academic Health Science Network (TAHSN), and therefore will already have been given an

Ontario lens. Adaptations may be made to that model, and an opt-in approach utilized.

After reviewing the options, the Working Group recommends a “qualification”

process for REBs.

The Working Group identified existing initiatives, standards and processes to evaluate REBs,

including:

• Canadian General Standards Board (CGSB);

• Toronto Academic Health Science Network (TAHSN) Research Ethics Board Qualification

Manual, which was developed in 2012. TAHSN is comprised of the University of Toronto

and its nine fully-affiliated academic hospitals. The Manual is intended to be a living

document. It includes a preliminary assessment to be completed by the REB itself and an

audit by an external group

• Association for the Accreditation of Human Research Protection Programs Inc. (AAHRPP);

• Canadian Institutes of Health Research (CIHR) streamlining of REBs; and

• National Institutes of Health (NIH) REB self-evaluation tool.

Upon review of these, the Working Group decided to use the TAHSN Manual and adapt it for use by

a provincial group. While some concerns were raised that the Manual does not exhaustively identify

all of the initiatives, standards and processes noted above (which the Working Group suggested will

require CTO to exercise enhanced vigilance going forward), the Working Group felt that the TAHSN

Manual is a broadly written document that could be adapted. It was felt that the Manual provides an

initial framework and process and that the checklist format is user-friendly and comprehensive. It

was noted that the nine TAHSN hospitals would be reticent to adopt a different CTO process since

they have invested time in their own qualification process but that they would be willing to make

modifications to their own process to comply with CTO requirements.

The Working Group recommends using the TAHSN REB Qualification Manual

(2012) as a starting point for an Ontario REB qualification process. The

Working Group concluded that it makes sense to start here with modifications

from the greater Ontario stakeholder community as needed.

The Working Group discussed the potential impact a qualification process could have on local REBs.

For example, the Working Group raised questions about whether REBs have sufficient resources


and whether funding will be available to REBs so they can participate in a qualification process. It

was acknowledged that many REBs struggle with their workloads already.

The Working Group discussed the role of CTO in the qualification process, such as:

• Taking responsibility for “qualifying” REBs

• Establishing standards for REBs, requiring internal self-assessments, and conducting

external audits of REBs

• Training REBs

The Working Group used the TAHSN Manual as a starting point as the process for REB

qualifications, with consideration of adapting it for province-wide implementation. Special

consideration will be given to incorporating International Conference on Harmonization Good

Clinical Practices, Office of Human Research Protections, and other guidance documents.

The Working Group recommends the TAHSN Qualification Process, with select

modifications.

The Working Group recognized the potential conflict if CTO assumes the roles of both qualifying

and delegating an REB as a Board of Record. One solution was to have CTO sub-contract the process

of qualifying REBs to an independent third party vendor (the qualification criteria will have been

established by CTO based on Working Group recommendations).

CTO manages the qualification process, initially using third party vendor

engaged by CTO.

Framework for Implementation of the Delegated

Board of Record Review Model

Creation of an implementation framework for the Board of Record review model is critical to its

success, and dovetails with the work of the other two Working Groups, which will address both

technical infrastructure to support a Board of Record model as well as any arising liabilities and

insurance issues, respectively.

The administrative structure to support a Board of Record model was reviewed in depth, with the

option of an enhanced role for CTO. The potential role of CTO going forward was also given

considerable attention in the deliberations of Working Group 1. The “Potential Roles for Clinical

Trials Ontario” document is attached as an Appendix to this report.

The Working Group recommends that CTO use criteria to qualify Boards of

Record.


The Working Group concluded that it was too early to recommend who should decide which REB

will act as a Board of Record in any particular case. In starting to develop a model for the selection

of a Delegated Board of Record, the Working Group recommends that CTO consider the following

criteria:

• All participating REBs must be located in Ontario

• All participating REBs must volunteer to be considered to be a Delegated Board of Record

• Which sites with REBs are participating?

• Is the study an investigator-led clinical trial or a sponsored clinical trial?

• Are academic sites involved only? Are private sites involved only?

• Has the sponsor chosen a site it would like to act as Board of Record?

• Are academic institutional resources required to run the study?

• Which REB is available?

• Which REB is ready first?

• Which REB has the earliest next meeting date?

• What is the nature of the protocol? (should this be categorized by disease or topic?)

• Which REBs have expertise to review the protocol?

• Do the investigators have a preference of which site acts as a Board of Record?

• Do the other sites have a choice in the Board of Record? (to accept or reject another site as

acting as the Board of Record?)

• Has a site refused or declined appointment as Board of Record?

• Which site is next on the rotation?

• Is there an REB that wants to act as Board of Record?

• Has a sponsor refused or objected to the site acting as the Board of Record (because of past

poor performance)?

The Working Group suggested that once an REB has been identified as a Board of Record, that REB

must continue to act as the Board of Record unless they must withdraw (which would be

discouraged). There must be a contingency plan developed to address the rare circumstances

where a Board of Record would have to withdraw in the middle of a study.

Recommendations for a Pilot Study

The Working Group put forward the suggestion that there should be a pilot project to consist of a

proof of concept study that retrospectively walks a clinical trial study that has already been

reviewed through the new mechanisms.

The Working Group made no recommendations about IT aspects of a pilot, but noted that the IT

platform must be simple and accessible to all.


Appendix: Potential Roles for Clinical Trials Ontario

in the Delegated Board of Review Streamlining Model

Role 1: REB Qualification

• Take responsibility for “qualifying” REBs as a voluntary opt-in process for Ontario REBs.

• In partnership with others, establish qualification standards for REBs.

• Require participating REBs to conduct internal self-assessments.

• Issue or facilitate “report cards” with green/yellow/red.

• Facilitate external audits (or as a long-term goal, conduct external audits).


• Opportunity for CTO to qualify REBs as long as each individual institution remains the

ultimate decision-maker and a representative from each institution signs off on each study.

• Concern that this role could conflict with other proposed roles for CTO (such as funneling or

determining which REB will act as Board of Record) therefore, potential conflicts of interest

must be managed.

• If CTO fulfills this role, there will need to be a timeframe within which “qualification” lasts

such as 2-3 years.

Role 2: REB Quality Management, Education and Information

• Disseminate information to participating REBs.

• Partner with other agencies to develop Standard Operating Procedures for REBs. Facilitate

educational opportunities for REBs, researchers and research staff on a broad range of

issues (such as technology, ethical issues and GCP).

• As a long-term goal, perform site monitoring.

• Facilitate implementation tools or a manual for Ontario REBs.


• Some of the large research institutions have their own QA. An opt-in approach might work.

• The scope of these activities may be limited based on CTO’s available resources.

Role 3: Board of Record Delegation

• Establish the criteria for how to decide which REB will act as an REB of Record – meaning

establish the pathway of how to select an REB as Board of Record.

• Manage CTO-Institutional agreements and study-specific Board of Record agreements.


• Provide communications tools like toolkits and template briefing packages to hospitals and

other partners containing draft board resolutions etc. encouraging uptake of the Board of

Record model.


• Agreement is needed on what criteria would be used to determine who should be the REB

Board of Record.

• Selection must be non-biased.

Role 4: Data Gathering & Analysis

• Act as a repository of all qualified REBs of Record.

• Conduct REB asset mapping.

• Host a centralized platform to

o Gather and then anonymize clinical trial performance metrics (recruitment data,

timeliness) /ownership of online portal); and

o Track investments.

• Act as a main hub for study information (institutional templates such as informed consent

language for individual institutions e.g. faith-based institutions vs. community hospitals;

local standards of care and practice; local policy content information).


• Will CTO “support” Boards of Record? Will offering supports to Boards of Record be a

separate role in addition to providing data and data analysis?

• CTO will be able to show its value through the data it collects – although not all data should

be available publicly without being anonymized.

Role 5: Communications and Stakeholder Relationship Management

• Identify key CTO stakeholders.

• Determine how stakeholder engagement will happen.

• Build trust between stakeholder groups.

• Liaise with sponsors on behalf of all participating Ontario REBs.


• What CTO is building will actually help large community hospitals perform industry-calibre

research.

• Concern that small institutions may be worried about losing infrastructure for clinical trials

when they will still have ongoing PI-initiated and student-led studies.

o PI-initiated studies still need the REB to approve studies conducted at one site.

Report: Working Group on Information Technology Harmonization and Performance Metrics April, 2013

Clinical Trials Ontario | Working Group on IT Harmonization and Performance Metrics | April 2013 1

Contents

Background ..................................................................................................................................... 2

Clinical Trials Ontario .................................................................................................................. 2

Call for Nominations for the Working Group .............................................................................. 2

IT Harmonization and Performance Metrics Working Group ..................................................... 2

Working Group Members ........................................................................................................... 3

Consideration of Currently Used Commercial Systems .................................................................. 4

Justification of a Cloud-Based System ............................................................................................ 5

Definition of System Requirements for a Technological Solution .................................................. 6

Performance Metrics ...................................................................................................................... 7

Identifying Provisional Performance Metrics to Assess the Impact of CTO Activities ................... 8

Timeliness Metrics....................................................................................................................... 9

Data-Driven Metrics .................................................................................................................. 10

Operations-Driven Metrics ........................................................................................................ 11

Financial Imperatives and CTO Performance Measures ........................................................... 12

Collecting and Analyzing Metrics .................................................................................................. 13

Technical Implementation ............................................................................................................ 13

Communications Strategy ............................................................................................................. 14

Appendix 1: Dataflow Illustration ................................................................................................. 15

Appendix 2: Dataflow Matrix ........................................................................................................ 16

Appendix 3: Metrics Champion Consortium Sample Matrix .............................................................. 17

Appendix 4: Metrics Dictionary .................................................................................................... 18

2 Clinical Trials Ontario | Working Group on IT Harmonization and Performance Metrics | April 2013

Background












2. Working Group on Information Technology (IT) Harmonization and Performance Metrics



IT Harmonization and Performance Metrics Working Group


CTO’s activities:

1. Evaluate the current online and administrative application systems utilized by REBs;

2. Develop recommendations for a technological solution for online administrative and

application systems in support of the Delegated Board of Record Review Model; and

3. Develop appropriate performance metrics and targets to demonstrate the impact of Clinical

Trials Ontario’s streamlining activities.

4. Develop a multi-faceted communications strategy to constituents outside of the Working Group

to engage leadership at different institutions.


1. Provide recommendations and/or options for a technological solution to support institutional

requirements for REB communications with investigators, sponsors and REBs;

2. Develop recommendations for the implementation of a technological solution and provide

input into the development of an RFP, if deemed necessary;

3. Suggest key performance metrics to demonstrate the impact of the Delegated Board of Record

Review Model;


4. Provide advice on performance targets that need to be achieved to ensure that the streamlining

initiatives are effective; and

5. Create a communication strategy to engage different levels of leadership.


1. Define stakeholder objectives and requirements, establish associated workflows and identify

desired functionality for the technological solution (November 2, 2012)

2. Provide provisional performance metrics to assess the impact of Clinical Trials Ontario

activities and propose the most effective manner to collect and analyze these metrics.

(December 2, 2012)

3. Recommendations for implementing the preferred technological solution in support of the

Delegated Review Model, including a communications strategy and an assessment of barriers

and possible solutions. (January 14, 2013)


Femida Gwadry-Sridhar (Chair) Director of Health Informatics, Lawson Health Research Institute Wendy Fiander Director Programme Management, Oncology, Hoffmann-La Roche Limited Trinh Luong

Director, Health Technology Assessment & Federal Policy, Novartis Pharmaceuticals Canada Inc.

Jack Holland Oncology REB Review Panel Chair, University Health Network Simon Wong Senior Business Analyst, Ontario Cancer Research Ethics Board Michael Hendley Manager, Business Systems Integration, Ottawa Hospital Research Institute Adam Cole Vice President Information Technology, Canadian Clinical Trial Network Joe Downey

Urology Research Administration, Financial and Regulatory Administrator, Queen’s University




(Research Analyst), Clinical Trials Ontario.


Consideration of Currently Used Commercial

Systems In preparation for the work completed by the IT Working Group, a survey was circulated to 55 institutions (26 responses were received) across Ontario to determine the type of platform currently being used to maintain and access REB data. Most institutions have IT platforms with limited functionality and use systems like Excel or Access, though several institutions have invested heavily in proprietary and commercial systems. After thoughtful consideration, the Working Group came to believe that there would not be institutional buy-in for an IT solution which requires assimilation to a common platform. Instead, the vision of this technological solution is a cloud-based, interoperable portal which ensures privacy and security requisites are met, working in tandem with existing software in use by individual institutions. The Working Group requested presentations to provide more information on the three major commercial REB document management systems currently in use, which took place at the 24 September meeting. The group thoughtfully determined the interoperability requirements of any technological solution to be proposed by CTO. The commercial systems are outlined below:

Infonetica Ronald Fehst, a research consultant with IRB services presented a summary introduction to Infonetica, the system used by most REBs in the United Kingdom. It is a user-friendly system which does not require extensive training and which has proven secure. Different versions of this program exist due to regulatory and legislated requirements of different jurisdictions, and Infonetica can be further customized to adapt to site or study-specific requirements based on workflow. The costs associated with Infonetica were unclear at the time of presentation, but programming charges were identified as being considerable. Hosting fee would be dependent upon the amount of data stored.

Click Commerce/Huron

Simon Wong, OCREB Business Analyst presented a summary introduction to Click Commerce/Huron. This system is used for processing documents from pre-admission to approval and can store PI profile and PI CVs. Click Commerce/Huron is highly customizable and allows for data to be stored in the cloud or on a local server. The system is easily configured and can be programmed locally and raw data can be imported/exported to Access and Excel. Despite all the benefits listed, it was noted that this program requires significant REB Chair time commitment. The costs associated with Click Commerce/Huron are a monthly licensing fee and any software upgrade charges.

ROMEO

Femida Gwadry-Sridhar, Director of Health Informatics at the Lawson Research Institute presented a summary introduction to ROMEO. This system was perceived negatively during implementation by users at Lawson as it is not designed around process or workflow.


The program is costly as institutions must purchase modules that are Ethics-specific or Researcher-specific. The Working Group agreed that it is frequently the case that new systems are met with initial disappointment, likely due to user unfamiliarity with the application.

Justification of a Cloud-Based System The Working Group recognizes the limits of their ability to conduct assessments of the broad variety of potential software solutions, and in their ability to assess the feasibility of acquiring/developing an interoperable cloud-based solution. While some concerns were raised that there has not been exhaustive analysis of all options noted above, which the Working Group suggests CTO exercise enhanced vigilance going forward, it was felt that a cloud-based solution would provide the potential features required for interoperability. This document is developed and presented as informed advice, but should not be the only directive for progress. There will be the need for CTO to examine the financial and political implications as well as the feasibility of implementation of such an initiative. Before coming to the conclusion that a custom cloud-based solution would work to support the streamlining and harmonization of Ontario’s Clinical Trials REB process, the Working Group first discussed the possibility of utilizing existing platforms/software. Early on in these discussions, the Working Group concluded that a new independent and isolated system (off the shelf, in-house or custom) in itself would not provide the preferred solution. Instead, the Working Group felt the best technological solution would be a one that would first and foremost serve the needs of CTO based on Working Group recommendations but would also provide interoperability with current systems in use across the province. The concept of a cloud-based system could provide an elastic, scalable and inherently redundant solution that would dynamically interact with current in-house and commercial systems at fixed points through the yet to be defined workflows. Canadian Health Infoway has identified the definition outlined by The National Institute for Standards and Technology (NIST) in the United States as the authoritative definition for cloud computing:

Cloud computing is a model for enabling ubiquitous, convenient, on-demand network access to a

shared pool of configurable computing resources (e.g., networks, servers, storage, applications, and

services) that can be rapidly provisioned and released with minimal management effort or service

provider interaction.

There are three service models for the cloud as defined by NIST, which have been clarified below with an explanation of how they could be utilized by CTO:

1. Software as a service – CTO provides software for sites to use in case they do not have their

own systems to run board meetings/ manage applications, etc. or CTO uses software

provided by third party running off of third party infrastructure. [SaaS]

2. Platform as a service – CTO outsources development environment and operating system.

[PaaS]

3. Infrastructure as a service - CTO uses another organization’s virtual hardware or CTO

provides virtual hardware to clients. [IaaS]


The Working Group on IT Harmonization and Performance Metrics recommends a Cloud-Based solution for several reasons. Firstly, a cloud-based solution through virtualization could remove hardware component failure as a possibility allowing for dynamic distribution of computing based on load as well as hardware availability. Secondly, a truly elastic and scalable solution could automatically scale up and down as load increases on the server(s) without the need to monitor and constantly deploy new physical servers. Thirdly, a true cloud-based solution would distribute content dynamically across differently physical locations therefore decreasing user access times (latency) as well providing protection against catastrophic server/data centre failures. This solution could be customized or developed for interoperability with existing systems, reducing the need for additional training and education for site-staff. This solution could also be developed with the different roles and information needs of different stakeholders (see Appendix 1 – Dataflow Matrix) and would be reflective of the relationships between stakeholders (see Appendix 2 – Workflow Illustration) and the information requirements of each type of user.

Definition of System Requirements for a

Technological Solution The Working Group identified stakeholder groups who would influence the system requirements of this “clinical trials cloud”. Stakeholders were organized under broad headings: Researchers, Community-based organizations, Sponsors/Industry, REBs, Government organizations/regulators, Patients, and Clinical Trials Ontario. Each of these groups has different requirements and goals for this system and as such it has been important to detail individual requirements to determine the necessary platform requirements. The Working Group also identified the difference between document management and data management. Each stakeholder has different document management needs which will assist them in streamlining their part of the REB process. There is also the need for back-end data management that will facilitate the collection of performance metrics which help identify efficiencies and increases in clinical trials investments in Ontario over time.

The IT Harmonization and Performance Metrics Working Group recommends

the development of a secure, inter-operable, user-friendly, cloud-based service

to house information and to receive/deliver, analyze, and aggregate data for all

of the identified stakeholders.

The “clinical trials cloud” should:

• Use cloud-based services to house information, receive and transmit data, as well as integrating elements like finance, contracts and other data.

• Be an interoperable cloud-based solution which works with existing REB repositories to gather, aggregate and distribute data and metrics to streamline the REB process.

• Provide a user-friendly interface with simple controls.

• Use smart forms (electronic forms which expand and contract based on user needs).


• Provide the opportunity for institutional customization which provides adaptability depending upon the needs of each study/institution.

• Provide a secure and user-friendly platform that will not tie users to one interface or software solution.

• Ensure compliance with privacy legislation and provide secure data/document encryption to protect patients, stakeholders, and systems

• Provide the functionality of downloading and uploading information to and from individual stakeholders as required.

• Include a robust database which tracks and manages all applications and provide a communication tool which allows relevant parties to address inefficiencies and allows stakeholders to track review (e.g. application, amendment, renewal) clinical trial progress in real time.

• Provide a scalable infrastructure with secure backups and network redundancy.

• Automatically allow CTO to track time metrics for the application processes from submission to approval to identify areas of efficiency. These metrics are gathered from event-driven actions (e.g. application submission).

• Identify and aggregate PI areas of expertise so Sponsors/Industry can easily identify collaborators.

• Aggregate REB areas of expertise in a database which outlines which board has expertise to handle particular clinical trials to assist in Board selection for delegation purposes.

• Take into account and identify key performance metrics that describe efficient REB of Record approval processes, oversight of clinical trials and performance metrics that identify Ontario as a preferred location to conduct clinical trials.

The IT Harmonization and Performance Metrics Working Group recommends:

• The identification of metrics and time-points which automatically allows

CTO to track timeliness of the clinical trials progress to identify areas of

efficiency;

• The intention to aggregate Principal Investigator (PI) areas of expertise so

Sponsors/Industry can easily identify collaborators;

• The intention to aggregate REB areas of expertise in a database which

outlines which board has expertise to handle particular clinical trials to

assist in Board selection for delegation purposes; and

• The development of a patient portal providing education on and access to

information on clinical trials taking place in Ontario.

Performance Metrics The Working Group on IT Harmonization and Performance Metrics recognizes the existence of two very different and occasionally divergent varieties of metrics. They are 1) metrics which measure global industry investment and Ontario’s current standing, and 2) metrics which will track and


measure the success of Clinical Trials Ontario as an initiative. Both types of metrics are indicated in this report. The Working Group also recognizes the importance of defining the responsibilities of principal investigators, institutions and sponsors in recording and reporting data which will assist CTO in gathering meaningful metrics over time. There is the expectation that all parties will endeavor to respond to inquiries as quickly as possible, that all parties will adhere to ICH-GCP and furthermore, all parties (study manager, business manager etc.) will have or will acquire any and all appropriate training to ensure they can adhere to any qualification standard established by CTO and their stakeholders. In establishing clear responsibilities, the Working Group also believes that there is a substantial role for CTO to act as a facilitator to train and educate PIs, sponsors, and REBs on best practices to truly establish Ontario as the highest quality and most efficient jurisdiction to conduct clinical trials globally as a facilitator of knowledge, the Working Group recommends:

• Setting clear expectations for performance of CTO members.

• Provide education on how to use IT infrastructure and web-based tools.

• Provide education and outreach on value of services offered by CTO.

• Provide and facilitate training to assist members to reach performance expectations (e.g.

establish communities of practice, online forums, or use a ticketing system such as

zendesk.com).

• Thoughtfully utilize professional communications tools and frequently participate in

outreach activities with stakeholders.

• Develop and deploy an integrated support system (FAQ, ticketing, email support, etc.)

• Develop and deploy seminars (face-to-face training sessions, webinars, etc.) to support

training goals.

• Brand this facilitation service as “research-administration-as-a-service”.

The Working Group believes that it is critical to empower CTO partners through education (e.g. SOPs) to establish and maintain the highest standards in clinical research.

Identifying Provisional Performance Metrics to

Assess the Impact of CTO Activities

The Working Group framed their discussion of provisional performance metrics in the context of moving forward from the recommended cloud-based technological solution. The initial recommendations envision a harmonized, cloud-based IT platform that would allow for the tracking of very specific data metrics and which would allow for the reporting of these metrics to stakeholders including institutions and industry, as relevant. To begin this process, the Working Group were provided sample metrics (Appendix 3) gathered from a variety of sources, such as the Metrics Champion Consortium (MCC), developing metrics to drive efficiencies and identify bottlenecks in the clinical trial ecosystem. Through the work completed by organizations like the MCC, the Working Group was able to identify three categories of metrics. Each category of metric is included to gather a different sort of data:


• To assess the success of the REB streamlining process and to identify/track efficiencies

driven by the implementation of this process (timeliness);

• To assess the quality of the information gathered from the system (increased quality/data-

driven); and

• To assess success of the harmonized IT solution (operations quality/operations-driven).

By identifying the three major types of data required to thoughtfully analyze and evaluate any streamlining and/or IT solution, the Working Group was able to identify and bucket some provisional metrics, which are detailed in Figure 1, below.

Figure 1: Provisional Performance Metrics to Assess CTO Activities

Timeliness Data-Driven Operations-Driven

Time from submission to review

SAE reports Stakeholder satisfaction score

Date distributed to reviewers to date reviewed

Budget accuracy Buy-in (number of institutions who join from total number of potential participants)

Date revisions requested from PI to date revisions received from PI

Patient retention

Time from provincial approval of study to submission of each centre application

% planned vs. actual screen failure rate

Contract negotiation from start to finish

Change in local site burden

Protocol approval to first site activated

Recruitment to target

Time to process protocol amendments

Number of sites with 0 or 1 patient

Time to process protocol deviations

Overall cost per patient

Time to CDA execution

Site capacity

Time to First Patient In (FPI)

Time to database lock

Time to site closeout

Timeliness Metrics

The Working Group defined timeliness metrics as those tracking the amount of time taken between steps of the research ethics process. The working group worked to build upon the timeliness metrics identified in Figure 1 and established a general process for a research ethics review, complete with timeliness. This process workflow is identified in Figure 2.


Figure 2: Review Process Workflow and Time Metrics 1 through 13

These metrics track the time point-to-point throughout the application to site activation process and should help CTO to develop a benchmark of current standards, and should help to identify bottleneck areas and areas of efficiencies. In discussions it became clear that sites do not track these time points in the same manner, for example some sites end their internal tracking process once the protocol has been approved, while others will track the first patient enrolled. To address this lack of clarity, each of the above-identified time points have been clearly defined (Appendix 4) as the first step in the development of a Metrics Dictionary. This Metrics Dictionary is intended to become a resource that will assist in standardizing the information gathered from site-to-site.

Data-Driven Metrics

Data-driven metrics are those which track the quality of the review process and conduct of a clinical trial. Many of these metrics are industry-level, and indicate the success of sites to adhere to agreed-upon terms. Industry representatives indicated that the most important metrics for their purposes are process and investment focused. For example:

• How much is it costing to conduct trials in Ontario?

• What do you get for this cost?

• How much is the cost changing over time?

• What does industry get for this ‘extra’ money that they don’t get elsewhere globally?

• How do overhead rates contribute to the cost of conducting trials in Ontario?

As outlined in Figure 1 above, many of these metrics are related to the ability of individual sites to meet the expectations set forth in the clinical trials agreement, such as meeting their patient recruitment target (screen failure rates), patient retention rates, budget accuracy and etc. These metrics help to assess the quality of services being provided to industry by local sites, and also


allows local sites to identify where they may be falling short or succeeding. These metrics would assist Industry in identifying sites who work efficiently and are successful at meeting recruitment targets and staying within planned budgets. These metrics are provided with some suggestions for best practices in Figure 3, below: Figure 3: Industry-Priority Metrics

Operations-Driven Metrics

Operations-driven metrics are those which help to assess the impact of operational activity. For example, some provisional metrics in this category can include more qualitative measures, such as user satisfaction of the harmonized IT solution or quantitative measures such as number of institutions buying-in to the model after certain periods of time.

Performance

Metrics

Explanation Relevance Suggestions of best practices Who?

Site/Sponsor/BoR

Priority

Time to Site

Activation

Time from documents

received at site to

activation (including

initiation visit)

Same as above Outline milestones of expected

dates, share with site study

team. Book initiation visit at

beginning so goal date is

transparent and have more

time to secure a date

maximizing attendance.

Site and Sponsor Y

Recruitment

to target

Planned vs. Actual

Recruitment

Shows reliability of

commitments supporting

efficiencies and

maintaining the cost per

patient overall. Improves

predictability and

supports reinvesting in

the site for future

studies.

Collaboratively building a

recruitment curve (site and

sponsor), with transparent

understanding of rationale.

Site and Sponsor Y

Overall cost

per patient.

To discuss

with group on

how to

capture this

and retain

financial

confidentiality

Includes patient cost

(as per schedule of

assessments) + overall

site costs (start up,

pharmacy, radiology,

annual fees, etc.)

divided by overall

number of patients

enrolled

Remain competitive

globally to ensure

maximum number of

trials come to Canada,

with a high number of

sites.

Education of how overall cost

per patient is calculated.

Understanding of impact of

increasing costs at all levels at

institutions.

Sponsor Y

Site capacity Ratio of newly recruited

subjects to number of

newly opened site in

Ontario

To measure how

productive sites in one

jurisdiction (e.g. Ontario)

compared to another

Higher site capacity is

preferred to reduce costs for

sponsor and sites

site Y


Financial Imperatives and CTO Performance Measures

The performance metrics under consideration have focused essentially on internal measures of the efficiency of a centralized ethics review process encompassed by a functioning Clinical Trials Ontario structure. In this context they appear appropriate for the task. However, financial imperatives outside the current scope of CTO have potential to undermine the basic intent of centralized review. These include the following:

• Variation in institutional assignment of research overhead/direct and indirect clinical trial

costs

• Limitation in CTO infrastructure support in relation to the potential return on investment

• Absence of a defined mechanism for reviewing Ontario and Canada’s performance in a

global context, both immediate and long term

Without a clearly defined strategy to address these issues, it is entirely possible that the implementation of a successful CTO-driven harmonization model may be inadequate to deal with Canada’s 12-16% annual loss in clinical trial activity. Ironically, Canada’s declining competitiveness in the global clinical trials arena has been the major impetus for the establishment of the system that is evolving into Clinical Trial Ontario. The working group developed two recommendations to address the need for financially-based metrics, which are detailed below:

Operational Overhead/Direct and Indirect Costs

A province-wide meeting of appropriate stakeholders, including government, should be established to examine the impact of institutional overhead and other direct or indirect costs on success/failure rates of potential clinical trial activity, the time to finalize the clinical contract, and other appropriate measures. It is envisaged that a process similar to that adopted by CAHO in harmonizing the language and understanding of the clinical contract could be followed.

Return on Investment/Global Perspectives Canada’s estimated share of the “clinical trials market” of $50 billion annually is approximately 4%, or $2 billion per year. Furthermore Ontario’s population size and academic strengths contribute significantly to the total. For this reason, it would seem essential that economic measures be put in place that would allow for immediate and short term evaluation of the impact of all changes directed at improving Ontario’s clinical trial performance, including that of Clinical Trials Ontario. Given the potential return on investment of reestablishing a leading role for Ontario in clinical trials, from health, academic and economic perspectives, a costing model should be established immediately that should define the ultimate goals of proposed reforms, the infrastructure support necessary to achieve those goals and the projected return on investment on population health, academic prestige and the provincial economy.


Collecting and Analyzing Metrics The Working Group on IT Harmonization and Performance Metrics sees the collection and analysis (reporting) of metrics as a critical function of the IT Solution. The solution proposed in that document is a system that is robust and scalable, and which will allow for the automatic collection of the metrics as outlined in this document, and for the reporting and analysis of these metrics to stakeholders. To facilitate that metrics gathered will be reported identically by different institutions and Boards of Record, the Working Group recommends the development of a detailed Metrics Dictionary, which narrowly defines each metric to be tracked. This will ensure that the information gathered will be consistent across the province, which will allow CTO to analyze and make projections with confidence.

Technical Implementation

1. CTO should consider benefits and disadvantages of open source vs. proprietary systems,

with attention to functionality. Open source systems offer the opportunity to expand

functionality, which is not as common with proprietary systems. However, for open source

systems, a major risk is long-term maintenance (e.g. in-house staff to support system could

leave).

2. CTO should consider the benefits and disadvantages of a system agnostic solution. It may

be more attractive to managers of commercial systems in use in Ontario to connect to an

open source solution vs. CTO choosing a solution which implements a competing

proprietary system.

3. CTO should make efforts to identify and understand functionality of existing systems

worldwide.

4. CTO should identify and understand other jurisdictional successes and failures.

5. CTO should conduct outreach to determine functionalities of all Ontario systems and

identify what would need to be done to get all on same level of functionality and

interoperability.

6. CTO should draft appropriate questions to ask each institution and should identify the local

custodian of data (IT or VP Research) who is the ultimate decision maker for sharing data.

7. CTO should assess stakeholder willingness to participate in the CTO (centralized) model

and should ask the following questions:

a. What is your willingness to provide CTO access to your data in a centralized system?

b. What format would you support for import/export?

8. Do we move towards an RFP? What would that RFP look like?

9. CTO should involve community in the development of the system so they do not feel that

sharing their information is “sharing with a 3rd party” but instead feel a sense of ownership.

10. CTO should clearly communicate the benefits to the stakeholder. Explain why Ontario is

engaged in the activity of streamlining REB reviews including the financial impact of


reduction in the number of trials. Indicate the impact on institutions and the province

(employment, reduced budgets, reduced projects) if this endeavor fails.

It was noted that whatever IT solution is ultimately selected, there exists a commercial opportunity for CTO to recoup some of their initial development investment through forming partnerships with other national or international bodies. An evaluation of this point is out of scope for the Working Group, but it may be valuable for future business planning.

Communications Strategy The Working Group gave careful consideration to the types of communication which would be best utilized as a tool for gaining support and buy-in from stakeholders for a harmonized IT solution. The recommendations, below, detail first steps for establishing a stakeholder sense of ownership, and puts building relationships and partnerships as a critical step in CTO’s communications success.

1. CTO should clearly communicate who they are, their mandate and vision to all potential

stakeholders.

2. CTO should engage stakeholders and constantly solicit and respond to their feedback.

3. Communicate benefits of centralized system:

4. Economic impact of declining clinical trials revenues

5. Purpose/need/solution and risk CTO provides on investment

6. Risks: Continuity plan for turnover is necessary for systems maintenance over time

7. Clarify dissemination plans such as email, print, face-to-face plans, outreach, partnerships,

and leveraging supportive relationships.

8. Gain a firm commitment from government and/or other funders over a longer period of

time. One of the CTO mandates is to diversity revenue streams to build alternate (non-

government) funding partnerships. This will be critical to get stakeholder buy-in in the

future.


Appendix 1: Dataflow Illustration

Appendix 2: Dataflow Matrix


Appendix 3: Metrics Champion Consortium

Sample Matrix


Appendix 4: Metrics Dictionary

Clinical Trials Ontario Receives Application – The date a completed submission (application

form, protocol attached, PI identified, lead institution identified, etc.) is received by the CTO IT

Solution.

Clinical Trials Ontario Accepts Application – The date a completed submission has been

reviewed and accepted for distribution to a CTO-qualified Board of Record.

Clinical Trials Ontario Delegates Board of Record – The date CTO identifies and delegatesi a

Board of Record for a protocol review.

Initiate Sponsor Site Selectionii– The date the sponsor selects their first clinical site.

Application Received by Board of Record – The date the delegated BoR acknowledges receipt of

the completed submission from CTOiii.

Application Accepted by Board of Record – The date the delegated BoR confirms they have

accepted the completed submission for review.

Date of Review – The date where the delegated Board discusses/considers, FOR THE FIRST TIME

the completed submission for ethics approval.

Issue of First Response/Outcome Letter – The date the delegated BoR issues their first response

document. This first response may coincide with final BoR ethics approval or may require

applicant response.

Applicant Response – The date the applicant’s response is received by the BoR. Please note this is

not the date the applicant response is reviewed by the BoR.

Final Board of Record Ethics Approval – The date where the delegated BoR considers and

provides ethics approval for the completed submission. This date may coincide with the Issue of

First Response/Outcome Letter or may be a date following the Applicant Response.

Approval of Additional Sites – This date occurs when ALL additional sites have been identified

and issued ethics approval. The latest date of approval is recorded as the end point for this metric.

Study Site Activation – The date the first site is permitted to begin recruiting and enrolling

patients into the study.

First Patient In – The date the first patient at the first site successfully passes screening and is

enrolled as a subject in the study.

Study Initiation – The date the first patient at the first site receives the first intervention as a result

of their involvement in the clinical trial.


Time to CDA Execution - Time from confidentiality agreement sent to signed & received.

Time to First Patient In - Time from documents to site to first patient enrolled.

Time to database lock - Time from first patient in to final data cleansing after last patient in =

database lock

Time to site closeout - Time from site activation to closeout

Recruitment to target - Planned vs. Actual Recruitment

Overall Cost Per Patient - Includes patient cost (as per schedule of assessments) + overall site

costs (start up, pharmacy, radiology, annual fees, etc.) divided by overall number of patients

enrolled

Site Capacity - ratio of newly recruited subjects to number of newly opened site in Ontario

i The process for delegating a board of record is to be determined, and is part of the mandate of the Working Group on Research Ethics Board Streamlining. ii Initiate Sponsor Site Selection is a special case, in that it begins early in the process and acts as a parallel activity alongside many other time points. iii This would be an automated, time-stamped receipt date similar to an email read receipt.

Report: Working

Group on Legal and

Liability Issues April, 2013

Clinical Trials Ontario | Working Group on Legal and Liability Issues | April 2013 1

Contents

Background ............................................................................................................................................................. 2


Call for Nominations for the Working Group ......................................................................................... 2

Legal and Liability Issues Working Group .............................................................................................. 2


Delegated Board of Record Review Model .................................................................................................. 4

Role of Clinical Trials Ontario .......................................................................................................................... 4

Liability Issues........................................................................................................................................................ 6

Insurance and Indemnification ........................................................................................................................ 7

Legal Framework .................................................................................................................................................. 8

Appendix 1: Delegated Board of Record Model ..................................................................................... 10

Appendix 2: Draft Participation Agreement ............................................................................................ 11

Appendix 3: Draft Board of Record Study Agreement ......................................................................... 25


Background















Legal and Liability Issues Working Group


CTO’s activities:

1. Establish the most suitable mechanism for an Institutional Agreement between Clinical Trials

Ontario and participating institutions to support the Delegated Board of Record Review model

in complement to the work being undertaken by the Clinical Trials Ontario Working Group on

REB Streamlining;

2. Develop draft Institutional Agreements that best support the Delegated Board of Record Review

Model at the institutional level; and

3. Provide advice on how to implement such agreements.


1. Evaluate existing inter-institutional agreements;

2. Determine the most appropriate inter-institutional agreement approach;

3. Provide recommendations on the legal implications of institutional agreements through Clinical

Trials Ontario to support the Delegated Board of Record Review Model;

4. Define the roles and responsibilities of Clinical Trials Ontario and those participating with

regard to legal and liability issues;


5. Provide a draft of a proposed Institutional Agreement between Clinical Trials Ontario and

participating Institutions;

6. Provide recommendations on additional documents necessary to support such an agreement;

7. Evaluate enhanced institutional liability issues and implications for the insurer(s) associated

with the implementation of the Delegated Board of Record Review Model; and


1. Recommendations on the most appropriate mechanism and legal implications arising out of

agreements between Clinical Trials Ontario and participating Institutions, including an

evaluation of Insurance and Liability Implications. (October 30, 2012)

2. Draft Institutional Agreement to support the Delegated Board of Record Review model.

(December 7, 2012)


Cheryl Litchfield (Chair)

Manager, Grants and Contracts, Lawson Health Research Institute

Delilah Ofosu-Barko

Research Consultant, Research Office & Research Ethics Board, Trillium Health Partners

Doug Meneilley

Senior Contracts Officer, Ottawa Hospital Research Institute

Jennifer Horton

Legal Counsel, The Hospital for Sick Children

Kelly Clark

Clinical Research Manager – Vaccines, Merck

Kelly Morris

Manager, Research Ethics St. Joseph’s Care Group & Thunder Bay Regional Health Sciences Centre

Beena Cracknell

Director of Finance and Contracts, Population Health Research Institute

Tricia Houston

Associate Director Clinical Development Clinical Development, Regulatory and Medical Affairs,

Novo Nordisk Canada Inc.




(Research Analyst), Clinical Trials Ontario; and by lawyers from Dykeman Dewhirst O’Brien LLP.


Delegated Board of Record Review Model

The Working Group discussed the rationale for a proposed Delegated Board of Record review

model (see Appendix 1) to address stakeholder concerns with the timeliness and duplication of

multiple Research Ethics Board (REB) reviews for each multi-site clinical trial.1 Limitations of

various models were discussed and the Working Group concluded that the Delegated Board of

Record model for research ethics review may be cost effective and is likely to improve efficiency

and turnaround times. This is consistent with the recommendation of the Stakeholder Committee

as presented in the CTO Inaugural Strategic Plan (2012-2017).2 The initial focus for CTO is on

implementing the Delegated Board of Record model for multi-site industry-sponsored clinical trials

in Ontario. The subsequent expansion of the initiative to include investigator-initiated clinical

trials, whether industry supported or otherwise, is intended.

Role of Clinical Trials Ontario

In the context of legal and liability issues, the Working Group discussed the role of CTO in

implementing the Delegated Board of Record model, with regard to:

Industry Sponsors

Implementation of the Delegated Board of Record model must improve efficiency and speed of

research ethics review (“cycle time”) while maintaining quality of reviews. From industry’s

perspective this is of paramount importance as CTO considers practical matters associated with the

implementation such as template agreements, e-tools for communication and e-approvals. Costs

borne by industry sponsors for research ethics review and oversight under a Delegated Board of

Record model should not exceed those under the current system of multiple institutional reviews

(and fees), nor should the cycle time take longer.

For a given clinical trial, it is expected that industry sponsors would approach CTO with a list of

initial Ontario principal investigators, who have confirmed interest and access to the protocol

specific patient population and these investigators’ sites (institutions and private sector). Based on

the principal investigators’ institutional affiliations, CTO would then select the institution whose

Research Ethics Board will act as the Delegated Board of Record for institutions on this particular

clinical trial.

Qualification of Delegated Board of Record

While this was an area of discussion for the Working Group, it was considered a focal point for the

Working Group on Research Ethics Board Streamlining whose recommendations would be

incorporated in the roles and responsibilities delineated within the legal framework for CTO.

1 The term “trial” as used here is intended to encompass clinical trials as well as other research studies. 2 Available on-line at: http://www.ctontario.ca/wp-content/uploads/2012/07/CTO-Strategic-Plan-June-2012.pdf (last accessed October

28, 2012).


Qualification Process

CTO would need to adopt a system for qualifying REBs so that they are eligible to act as a potential

Delegated Board of Record. The details of this qualification system are expected to be modeled on

the Toronto Academic Health Sciences Network (TAHSN) Qualification Manual. The qualification

standards must be compliant with all existing requirements including the Tri-Council Policy

Statement (TCPS2), ICH-GCP, Health Canada regulations, United States Office of Human Research

Protections’ Federal Wide Assurance, and when implemented, the Canadian General Standards

Board requirements for research ethics oversight of biomedical clinical trials.

Registration of Eligible Boards

CTO should administer the qualification program which will involve registration of REBs eligible to

act as a Delegated Board of Record. Registration is likely to involve self-assessment and submission

of documentation to CTO.

Audits

CTO should be responsible to ensure eligible Delegated Boards of Record are meeting the required

qualifications. This may be done directly by CTO or CTO may contract with a third party to conduct

audits of REBs on its behalf. Consideration must be given to frequency of mandatory audits, and the

potential for audits at CTO’s discretion to address arising concerns.

Selection of Delegated Board of Record

The Working Group will respond to the guidance provided by the Working Group on Research

Ethics Board Streamlining when incorporating CTO’s role in selection of a Delegated Board of

Record into the legal framework of CTO.

� Principles

It was discussed that the selection of the Delegated Board of Record from amongst those

REBs eligible to serve in this capacity should follow principles of transparency and

equitable distribution. Consistent application of a set of selection criteria to be used by CTO,

and the listing of clinical trials currently under the responsibility of each Delegated Board of

Record, will support these principles.

� Criteria

The selection criteria to be used are likely to include: institutional affiliation of the lead

multi-site principal investigator (when applicable), metrics of the eligible Research Ethics

Boards (e.g. turnaround times), composition of the REB (e.g. pediatrics trial requiring a

Board with appropriate expertise), number of trials for which a Board is already acting as

Delegated Board of Record, how recently a Board has been selected to serve as a Delegated

Board of Record.


� Other Considerations

The Working Group discussed the possibility that an eligible REB could decline CTO’s

selection of that Board as Delegated Board of Record, but only under certain limited

circumstances; for example, the appropriate expertise was lacking to review a specific

clinical trial or was experiencing resource/capacity issues such that it could not meet

turnaround or oversight and monitoring requirements.

The Working Group also discussed the possibility that an investigator at the institution

hosting the Delegated Board of Record ceased to be involved in the clinical trial. The

Working Group on REB Streamlining may provide direction on this matter. The transfer of

Delegated Board of Record responsibilities to another eligible Board may be necessary,

however it is possible that the original Delegated Board of Record may have to continue to

serve, since there may be insufficient financial and/or administrative resources to transfer

responsibility, and possible delays if a successor Delegated Board of Record’s review

required revisions of the trial protocol or consent forms.

Local Requirements - Informed Consent Language

CTO could maintain a repository of any particular local institutional requirements for that site’s

research participant letter of information (informed consent document) for example, local policy or

specific subject injury or faith-based institution language requirements (such local requirements

must have industry sponsor approval). This would assist the Delegated Board of Record to

streamline the research ethics review process.

E-tools

With guidance from the Working Group on Information Technology Harmonization and

Performance Metrics, CTO could directly, or through engagement of a third party, develop and

maintain e-tools to support communication, administration, and metrics reporting for the

Delegated Board of Record model. Efficiency will depend on the functionality of the e-tools.

Liability Issues

For Clinical Trials Ontario

CTO will have liability exposure to industry sponsors and member institutions to the extent of its

stated responsibilities for the administration of the Delegated Board of Record model. This

exposure will arise predominantly from:

(i) CTO’s responsibility to identify (and through its oversight, monitoring and audit process,

confirm) those qualified Research Ethics Boards which are eligible to act as Delegated

Boards of Record, and

(ii) CTO’s responsibility to select a Delegated Board of Record for each clinical trial.


CTO may seek a limited form of indemnification from each member institution, indemnifying CTO

for losses and liabilities to the extent arising from negligent acts or omissions, or the willful

misconduct, of the institution’s Delegated Board of Record, and for the institution’s oversight of its

Delegated Board of Record and the institution’s conduct of the clinical trial.

For Institutions

“Host” Institutions:

The “host” institution whose research ethics board acts as the Delegated Board of Record will have

increased liability exposure given its research ethics board’s expanded role and responsibility to

other member institutions, in providing delegated research ethics review and oversight for a

clinical trial. As the hosting institution is also a participating institution, it already assumes liability

for ethics review and oversight for the clinical trial in which it and its investigator are participating.

Non-“Host” Institutions:

Non-“host” institutions participating in a clinical trial (whose REBs are not acting as the Delegated

Board of Record) will rely upon:

(i) CTO to properly identify, qualify and select an eligible Delegated Board of Record, and

(ii) the Delegated Board of Record to ensure the ethics review and oversight of the clinical trial

is performed in accordance with required standards.

Insurance and Indemnification

The Working Group consulted a sampling of institution insurers to assess feasibility of possible

limited indemnifications associated with CTO and the Delegated Board of Record model.

Healthcare Insurance Reciprocal of Canada (HIROC)

The Delegated Board of Record model would be feasible within the scope of the HIROC insured’s

coverage. It may require the institution hosting the Delegated Board of Record to provide a limited

indemnification to participating institutions (and possibly to CTO) for claims arising from negligent

acts or omissions, or misconduct, of the Delegated Board of Record in the ethics review and

oversight of a clinical trial. From the representative’s perspective, this limited indemnification is

possible within the scope of the existing HIROC coverage – everyone is responsible for their

respective negligence. The representative did agree that “[c] larity is needed on the parties’

responsibilities and indemnities, if any, when one party delegates to a Board of Record [the REB of

the other party]. This Delegated Board of Record will be responsible for review, approval, and

monitoring of protocols, which it does on behalf of other institutions. Typically, a research ethics

board is indemnified by its own institution; but indemnification of a Delegated Board of Record by

the institution delegating the review would be in place to cover the narrow circumstance where the

delegating institution may be found partially responsible for the loss.”3

3 Email exchange with M.J. Dykeman, October 9, 2012.


HUB International/Marsh Canada/Simmlands Insurance Services

Insurance policies sometimes react differently than black letter law; contracts and indemnifications

must dovetail with language of the insured’s policy. A representative indicated that the Board of

Record is responsible for the protocol and other requirements, and assumes responsibility for the

Informed Consent Form and standards as these move over from the “non-host institution”. It was

generally agreed that there will be enhanced liability for the host institution in providing a Board of

Record to conduct reviews. It was unclear if the increase in risk exposure of the host institution

proportionate to the number of sites for which it acts as Board of Record. Insurers could not

confirm the extent to which a host institution would be exposed simply by virtue of assuming the

Board of Record role.

One insurer explained briefly how insurance companies insure themselves (i.e., obtain reinsurance)

to help cover the risks that they assume. There was also a discussion of the merits of being added as

additional insured. The comfort zones of groups such as Aviva/HIROC may be exceeded in the

research context. Their example was, if in the course of one of the players provides bad data or bad

process, that party could suffer financial loss for that omission (for example, extra dollars would be

required to recreate a clinical trial). Agreements rest on the intent of the coverage, i.e., what was it

intended to cover as to what the exposure would be; versus breadth of policy language. The focus

should be on how to reduce risk contractually; a non-host institution will always want to be on as

an additional insured of the host institution and clarified language of “defend and hold harmless”.

Legal Framework

To implement the Delegated Board of Record model for industry-sponsored

multi-site clinical trials in Ontario, it is recommended that CTO: (a) contract

with Ontario institutions, and (b) develop a template inter-institutional

Delegated Board of Record Agreement and administratively support execution

of this agreement for institutions participating in each clinical trial.

CTO – Institutions

CTO will also require a contract with each institution wishing to participate in CTO initiatives

beginning with the Delegated Board of Record model (see Appendix 2). The Working Group

discussed the appropriate contracting parties and there was consensus that these would be CTO

and the institution. The REBs of the institutions are not legal entities and so would not be formal

parties to the agreements, but their Board chairs may play a role internally to influence their

institution’s senior leadership’s decision on participation.

“Host” Institution – Non-“Host” Institution & Investigator

A Delegated Board of Record Agreement will be required between the Delegated Board of Record

host institution, participating institution, and participating institution investigator. The Working

Group has drafted a non-negotiable template agreement modeled after the Ontario Cancer Research

Ethics Board (OCREB) Board of Record Agreement (see Appendix 3). Almost all academic hospitals

in Ontario with research programs in oncology participate in OCREB reviewed clinical trials and are

therefore familiar with the OCREB contracts, roles, and responsibilities. From the Working Group’s


perspective, using the OCREB model is a potential selling point to institutions that have used this

model for a number of years.

The Working Group recommends that, excepting participating investigators,

each party to an inter-institutional Delegated Board of Record Agreement with

responsibilities under the Delegated Board of Record model should provide

limited indemnification to the other party(ies) for their negligence or willful

misconduct in carrying out their responsibilities.

CTO – Industry

CTO will require an agreement with each industry sponsor wishing to participate in CTO initiatives

including the Delegated Board of Record model. This agreement is outside the scope of the

Working Group’s Terms of Reference.

The Working Group recommends that CTO develop an agreement with industry

sponsors with consideration given to confidentiality, the reporting of

aggregated metrics, and the parties’ roles relative to the Delegated Board of

Record model.


Appendix 1: Delegated Board of Record Model


Appendix 2: Draft Participation Agreement

THIS AGREEMENT is made as of the Effective Date.

BETWEEN :

CLINICAL TRIALS ONTARIO (“CTO”)

CLINICAL TRIALS ONTARIO [ADDRESS] (herein the “CTO” )

–and –

[FULL LEGAL NAME] [ADDRESS] (herein “PARTICIPATING ORGANIZATION” OR “PO” )

Each a “Party” and together, the “Parties”

RECITALS:

A. CTO is an independent not-for-profit organization established through the Ministry of Economic Development and Innovation to support efforts to maximize research investment in Ontario, with a goal of creating a single point of entry initially for industry sponsored multi-centre trials through a delegated research ethics review (“Delegated Board of Record”) model within the Province of Ontario.

B. The PO wishes to participate in the Delegated Board of Record model.

D. The purpose of this Agreement is to set out CTO’s and the PO’s respective rights and obligations in connection with the Delegated Board of Record model.

THEREFORE, the parties agree as follows:

ARTICLE 1 DEFINITIONS AND PRINCIPLES OF INTERPRETATION

1.1 Definitions

In this Agreement, the following words and terms have the following meanings:

(a) “Agreement” means this agreement including all schedules, exhibits, and all amendments or restatements as permitted, and references to “Article ”, “ Section”, “Schedule” or “Exhibit ” means the specified Article, Section, Schedule or Exhibit of or to this Agreement;


(b) “Clinical Trial” means a clinical trial which as a result of this Agreement and arising out of an agreement between a clinical trial sponsor and CTO, will have research ethics review coordinated through the Delegated Board of Record model;

(c) “Confidential Information ” means as defined in s. 5.1 below;

(d) “Effective Date” means the date of final execution of this Agreement, as set out on the execution pages hereto;

(e) “End of Study” means until all accountabilities of Host Institution REB are met (i.e., database lock and/or study closure at all participating sites for which the REB is responsible, and document retention obligations) [Note to draft: group may wish to consider more fully what “End of Study” constitutes]

(f) “FIPPA” means the Freedom of Information and Protection of Privacy Act (Ontario) and any amendments thereto;

(g) “Force Majeure Event” has the meaning set out in Section •

(h) “Host Institution ” means a PO whose research ethics board has been qualified by CTO (or its agent) to assume the role of a Delegated Board of Record for the purpose of assuming the research ethics review, approval and oversight of a specific study.

(i) “ Intellectual Property Rights” means all rights in and to any and all intellectual and industrial property of any kind, including works protected by the law of copyright or in which copyright may subsist such as documentation, software, data and information, whether in printed, electronic, magnetic, optical or other material or tangible form, compilations of information and databases (whether or not any of same are protected by copyright); designs; trade-marks and trade names; patents, inventions, processes and discoveries; industrial designs; trade secrets; know-how; Confidential Information or other information of a confidential nature and any other works that are subject to intellectual and industrial property protection under the laws of Canada, any foreign country, or any political subdivision thereof;

(j) “Institution” means, as applicable, a PO that has agreed to participate in the Delegated Board of Record model;

(k) “Laws and Regulations” means all statutes, regulations, codes, ordinances, decrees, rules, municipal by-laws, judicial or arbitrable or administrative or ministerial or departmental or regulatory judgments, orders, decisions, rulings or awards enacted or promulgated by any regulatory body pursuant to any statutory authority or requirement and, in all cases, applicable, binding and enforceable in Canada, all as amended from time to time, and “Law or Regulation” has a corresponding meaning;


(l) “Non-Host Institution” means a PO that has agreed to delegate the review function of its research ethics board to a Host Institution’s research ethics board for a particular study

(m) “Parties” means CTO and PO and “Party” means any one of them;

(n) “Personal Health Information” has the same meaning as defined in PHIPA;

(o) “Personal Information” means any information about an identifiable individual, including Personal Health Information, that is required to be protected pursuant to PHIPA, PIPEDA or other Laws and Regulations pertaining to the protection of personal information;

(p) “PHIPA ” means the Personal Health Information Protection Act, 2004 (Ontario) and any amendments thereto;

(q) “PIPEDA” means the Personal Information Protection and Electronic Documents Act (Canada) and any amendments thereto;

(r) "Term" has the meaning given to it in Section •;

1.2 Interpretation

This Agreement shall be interpreted in accordance with the following, unless the context otherwise specifies or requires:

(a) Words importing the singular number include the plural and vice versa; words importing the masculine gender include the feminine and vice versa; and words importing persons include individuals, corporations, partnerships, joint ventures, associations, trusts, pension funds, unions, governmental agencies, officials, boards, tribunals, ministries, commission or departments; corporations, partnerships, trusts and unincorporated organizations.

(b) The headings used in this Agreement are inserted for reference purposes only and are not to be considered or taken into account in construing the terms or provisions hereof or to be deemed in any way to clarify, modify or explain the effect of any such terms or provisions.

(c) Any references in this Agreement to any law, agreement, rule, regulation, order or act of any government, governmental body or other regulatory body shall be construed to reference it as amended or re-enacted from time to time or to reference any successor to it.

(d) The contra proferentum rule (which requires that any ambiguity in an agreement shall be interpreted against the Party drafting the agreement) shall not apply to the interpretation of this Agreement.


(e) In this Agreement, “in writing” or “written” shall mean and include printing, typewriting or any electronic means of communication capable of being permanently reproduced in alphanumeric characters at the point of reception.

1.5 Schedules

The following are Schedules to this Agreement: Schedule A Qualification requirements - Delegated Board of Record Schedule B Selection criteria for choosing a Delegated Board of Record Schedule C Fee structure Schedule D Delegated Board of Record Agreement template Schedule E CTO Forms

1.6 Conflicts

In the event of any conflict or inconsistency between the terms of this Agreement and any Schedule, the terms of this Agreement prevail.

ARTICLE 2 TERM & TERMINATION

2.1 Term & Termination

(a) The term of this Agreement shall commence on the Effective Date and shall be for a three (3) year term with annual renewals thereafter as confirmed in writing by the parties, subject to earlier termination in accordance with the provisions hereof.

(b) PO shall provide written notice to CTO of its election to terminate the agreement not later than ninety (90) days prior to the end of the term.

(c) Despite clause 2.1(b) above, a PO that is a Host Institution may not terminate this agreement prior to the end of its research ethics board’s delegated Board of Record accountabilities as assigned through this Agreement.

ARTICLE 3 RESPONSIBILITIES OF PARTIES

3.1 CTO Responsibilities

CTO shall have the following responsibilities:


(a) administering Board of Record agreements with organizations that agree to act as Host and/or Non-Host Institutions;

(b) facilitating registration of participating organizations that wish to self-assess their potential to become a Delegated Board of Record based on established qualifications (Schedule “•”);

(c) appointing the Delegated Board of Record for each Clinical Trial based on established selection criteria (Schedule “•”);

(d) maintaining in a manner available to PO a current list of Delegated Boards of Record;

(e) maintaining repository of local institution requirements pertaining to research ethics, particularly informed consent document language;

(f) monitoring the work of Delegated Board of Records and auditing compliance with the established qualifications at CTO’s discretion and no less than every two years;

(g) setting template and standards for protocol submissions for Delegated Boards of Record;

(h) establishing standard review criteria for use by Delegated Boards of Record;

(i) facilitating e-tools for communications and coordination, including of serious adverse event (“SAE”) reporting; and

(j) handling of research ethics board review fees, including disbursement of research ethics board fees to Host Institution’s research ethics board.

3.2 PO Responsibilities

PO shall have the following responsibilities:

(a) providing one point of contact (the “PO Contact”) at the PO who will timely manage the implementation and operation of the delegated Board of Record model for the PO, including execution of Delegated Board of Record Agreement in the form provided in Schedule “•”;

(b) confirming with CTO within seven (7) days of selection, PO acceptance of role as Host Institution for a particular study;

(c) committing to decline the invitation to act as Host Institution only in rare and

legitimate situations including but not limited to lack of Research Ethics Board expertise in an area pertinent to the particular study;


(d) as Host Institution, fulfilling the obligations identified in the Delegated Board of Record Agreement, providing timely review using the e-tools provided by CTO for communication and reporting; [Note to draft: may be dependent on outcome of the work done by the Working Group on REB Streamlining]

(e) as Non-Host Institution, assuming administrative duties including requiring

principal investigator signoff on study protocols; and (f) fulfilling and complying with its other obligations in this Agreement.

ARTICLE 4 REPRESENTATIONS AND WARRANTIES

4.1 Representations and Warranties

Each party represents and warrants to the other party that it:

(a) has full power and authority to enter into this Agreement and to observe, perform, and comply with the terms and conditions of this Agreement;

(b) shall operate in compliance with all Laws and Regulations related to any aspect of this Agreement;

(c) it holds all permits, licenses, consents, Intellectual Property Rights, and authorities necessary to perform its obligations under this Agreement;

ARTICLE 5 INTELLECTUAL PROPERTY RIGHTS

5.1 Reservation of Rights

Except as expressly provided in this Agreement, no Party shall acquire any right, title or interest in or to any Intellectual Property Rights of another Party or of its licensors or subcontractors. For greater clarity, no right, title or interest in or to CTO’s e-tools that support the Delegated Board of Record model are hereby granted save a non-exclusive, royalty free license during the term of this Agreement to use the e-tools solely in support of fulfilling obligations under this Agreement.


ARTICLE 6 ACCESS TO INFORMATION/CONFIDENTIALITY

6.1 Confidential Information

(a) From time to time a party (“Disclosing Party”) may provide to the other party (“Receiving Party”) information (“Confidential Information”) in accordance with its obligation pursuant to this Agreement. The Receiving Party agrees that it will not at any time, directly or indirectly, disclose the Confidential Information of the Disclosing Party to any person, other than to the Receiving Party’s directors, officers, employees, and professional advisors, in each case strictly on a need-to-know basis and in order for the Receiving Party to exercise its rights or perform its obligations hereunder, except as otherwise specifically authorized by the Disclosing Party.

(b) The requirement of confidentiality shall survive for a period of ten (10) years.

(c) Upon termination of the Agreement, the Receiving Party may retain one secure archival copy of the Confidential Information and otherwise shall return it, or upon written authorization of the Disclosing Party, securely destroy it and provide notice of its secure destruction.

(b) For greater certainty, nothing in this Agreement imposes liability upon a Receiving Party for making disclosures of a Disclosing Party’s Confidential Information where such information:

(i) at the time of or after its disclosure is in or becomes part of the public domain, other than as a result of a breach by the undersigned of its obligations hereunder; or

(ii) can be demonstrated to have been disclosed to the Receiving Party by a third party that was not bound by a confidentiality agreement or otherwise prohibited from transmitting such information by a contractual, legal or fiduciary obligation;

(iii) was independently developed by Receiving Party without benefit of the Confidential Information as demonstrated by written records; or

(iii) is required to be disclosed by any applicable Laws or Regulations.


ARTICLE 7 INSURANCE & INDEMNITY

7.1 Insurance Coverage Requirements

Each party shall maintain for the period during which the Agreement is in effect, at its own cost and expense:

(a) Commercial General Liability Insurance (including any excess liability coverage) on an occurrence basis for third party bodily injury, personal injury and property damage, to an inclusive limit of not less than $5,000,000 per occurrence. The policy shall name the Parties to this Agreement as additional insureds but only with respect to this Agreement and shall include the following:

(i) contractual liability coverage;

(ii) cross-liability clause; and

(iii) a thirty (30) day written notice of cancellation, termination or material change;

[Note to draft: we will have to arrange for insurers to review this and the indemnification language; and necessity, if any for E&O]

7.2 Indemnities

(a) CTO agrees to indemnify, and undertakes to defend and hold harmless, PO, its officers, directors, investigators, employees and agents (collectively, the “PO Indemnitees”), from and against all losses resulting from:

(i) the death of or bodily injury to any third party or to any employee of the PO (or other person for whom the PO is responsible in law) to the extent caused by the negligence or wilful misconduct of CTO or any subcontractor of CTO in performance of its obligations under this Agreement;

(ii) the loss of or damage to the real or tangible personal property (whether owned or leased) of any third party or any of the PO Indemnitees, to the extent caused by the negligence or wilful misconduct of CTO or any subcontractor of CTO in the performance of its obligations hereunder;

(iii) any action, claim or demand arising as a result of CTO’s failure to perform its obligations under this Agreement.

(b) PO agrees to indemnify, and undertakes to defend and hold harmless, CTO, its officers, directors, employees and agents (collectively, the “CTO Indemnitees”), from and against all losses resulting from:


(i) the death of or bodily injury to any third party or to any employee of CTO (or other person for whom CTO is responsible in law) to the extent caused by the negligence or wilful misconduct of PO or any subcontractor of PO in performance of its obligations under this Agreement;

(ii) the loss of or damage to the real or tangible personal property (whether owned or leased) of any third party or any of the CTO Indemnitees, to the extent caused by the negligence or wilful misconduct of PO or any subcontractor of PO in the performance of its obligations hereunder; or

(iii) any action, claim or demand arising as a result of PO’s failure to perform its obligations under this Agreement.

ARTICLE 8 DISPUTE RESOLUTION

8.1 Dispute Resolution Process

(a) Prior to the initiation of formal dispute resolution procedures, the parties shall first attempt to resolve any dispute, controversy or claim (including any failure by the parties to reach agreement where expressly provided for in this Agreement) arising under or in connection with this Agreement (a “Dispute”) informally, with senior representatives of each party to meet as often and as promptly as the parties deem necessary to discuss the Dispute and negotiate in good faith in an effort to resolve the Dispute.

(b) If the relevant representatives are unable to resolve the Dispute within fifteen (15) days after the referral of the Dispute to them, the Dispute will be referred to “•” (the “Committee”). The Committee shall use reasonable efforts to resolve such Dispute, including, without limitation, negotiating a modification or amendment to this Agreement. The Committee shall meet as often and as promptly as the parties reasonably deem necessary to discuss the Dispute and negotiate in good faith in an effort to resolve the Dispute. [Note to draft: determine whether such a Committee shall be established]

(c) During the course of such discussions, all reasonable requests made by one Party to another for non-privileged information, reasonably related to the Dispute, will be honoured in order that each of the Parties may be fully apprised of the other’s position. The specific format for such discussions will be decided by mutual agreement of the Parties, but may include the preparation of agreed-upon statements of fact or written statements of position.

(d) If the Dispute has not been resolved by the Parties within thirty (30) days (or such longer period to which the Parties may agree) after the referral of such Dispute


thereto, any Party may upon written notice to the other Party elect to submit the Dispute to arbitration in accordance with the Arbitration Act. [Note to draft: consider fleshing this out, e.g. method of selecting arbitrator(s)]

8.2 Confidentiality

The proceedings of all negotiations, mediations and arbitrations as part of the Dispute resolution process shall at all times be privately conducted. The Parties agree that all information, materials, statements, conduct, communications, negotiations, mediations, arbitrations, offers of settlement, documents, decisions, and awards of either Party, in whatever form and however disclosed or obtained in connection with that portion of the Dispute resolution process which precedes the commencement of formal legal proceedings in a court or other tribunal: (i) shall at all times be Confidential Information; (ii) shall not be offered into evidence, disclosed or used for any purpose other than the Dispute resolution process under this agreement; and (iii) will not constitute an admission or waiver of rights.

ARTICLE 9 GENERAL

9.1 Further Assurances

The Parties shall sign such further and other documents, cause such meetings to be held, cause such resolutions to be passed, exercise their vote and influence and do and perform (and cause to be done and performed) such further and other acts or things as may be necessary or desirable in order to give full effect to this Agreement and every part of it.

9.2 Publicity

All notices to third parties and other publicity concerning the transactions contemplated by this Agreement will be mutually planned and coordinated between the Parties.

9.3 Notices

(a) All notices under this Agreement shall be in writing and shall be delivered by personal delivery/courier, fax, email or registered mail:

(i) to CTO at:

[ADDRESS]

[FAX]



(ii) to the PO at:

[ADDRESS]

[FAX]


The notice shall be deemed to have been delivered on the day of personal delivery, on the day received by fax (as evidenced by a transmission confirmation) or by e-mail, or on the fifth day following mailing.

9.4 Applicable Law

This Agreement and all other documents provided for in this Agreement and the rights and obligations of the parties thereto shall be governed by and construed and enforced in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein and the parties hereto attorn to the jurisdiction of the courts of the Province of Ontario.

9.5 Severability

Each of the provisions contained in this Agreement are distinct and severable. Any declaration by a court of competent jurisdiction of the invalidity or unenforceability of any provision or part of a provision will not affect the validity or enforceability of any other provision of this Agreement.

9.6 Waiver

No delay or omission by a Party to exercise any right or power it has under this Agreement shall impair or be construed as a waiver of such right or power. A waiver by any Party of any breach or covenant shall not be construed to be a waiver of any succeeding breach or any other covenant. All waivers must be in writing and signed by the Party waiving its rights.

9.7 Counterparts

This Agreement may be executed in any number of counterparts, each of which shall be deemed an original and all of which, taken together, shall constitute one and the same instrument. Delivery by facsimile or email of any executed counterpart of this Agreement shall be equally as effective as delivery of a manually executed counterpart thereof.

9.8 Entire Agreement

This Agreement, including the Schedules hereto, constitutes the entire agreement between the Parties with respect to the subject matter hereof and cancels and supersedes any prior understandings and agreements between the Parties. There are no


representations, warranties, forms, conditions, undertakings or collateral agreements, express, implied or statutory between the Parties other than as expressly set forth in this Agreement. Except as otherwise explicitly set out herein, this Agreement may only be amended by a written document signed by the Parties.

9.9 Relationship of Parties

In connection with this Agreement, each Party is an independent contractor. This Agreement does not and shall not be deemed to create a joint venture, partnership, fiduciary or agency relationship between the Parties for any purpose. With respect to its own personnel, each Party is independently responsible for all obligations incumbent upon an employer.

9.10 Assignment

This Agreement will be binding upon and inure to the benefit of the Parties and their respective successors and permitted assigns. No Party shall assign this Agreement or any part hereof or any benefit or interest herein without the prior approval of the other Party.

9.11 Force Majeure

No Party shall be liable for any delays in the performance of any of its obligations hereunder due to causes beyond its reasonable control (“Force Majeure Event”), including, but not limited to, fire, strike, war, riots, acts of terrorism and/or of a public enemy, acts of any civil or military authority, acts of God, floods, unusually severe weather, epidemics, pandemics or quarantine restrictions, public utility failure or service fluctuation, judicial action and acts and failures to act by governmental authorities.

9.12 Survival

Notwithstanding the expiration or earlier termination of this Agreement for any reason, the following Articles and sections of this Agreement shall survive any such termination or expiration: 5.1, 6, 8, 9.4 •

THE REMAINDER OF THIS PAGE IS INTENTIONALLY LEFT BL ANK


IN WITNESS WHEREOF the Parties have executed this Agreement as of the last signature below.

CLINICAL TRIALS ONTARIO By: __________________________

[NAME, TITLE]

Date: ______________________ By: ________________________

[NAME, TITLE]

Date: ______________________

[PARTICIPATING ORGANIZATION] By: ________________________

[NAME, TITLE]

Date: ______________________ By: ________________________

[NAME, TITLE]

Date: ______________________


SCHEDULE A QUALIFICATION REQUIREMENTS - DELEGATED BOARD OF RECORD SCHEDULE B SELECTION CRITERIA FOR CHOOSING A DELEGATED BOARD OF RECORD SCHEDULE C FEE STRUCTURE SCHEDULE D DELEGATED BOARD OF RECORD AGREEMENT TEMPLATE SCHEDULE E CTO FORMS


Appendix 3: Draft Board of Record Study Agreement

CTO Study ID Number: Agreement Among:

__________________________ (“Participating Institution”):


Address:

Attention:

And

__________________________ (“Host Institution”)


Address: Attention:

And

Participating Institution Principal Investigator Name (“Participating Institution PI”):

Name: Address:

Phone: Fax: Email:

Study Title (the “Study”):


Preamble Host Institution has registered with Clinical Trials Ontario (“CTO”) to have Host Institution REB act as a delegated Board of Record responsible to provide ethics review of multi-centre trials upon request. Host Institution REB has been selected by CTO to act as the delegated Board of Record for the Study. This inter-institutional agreement sets out the terms and conditions for Participating Institution’s delegation of research ethics review, approval and oversight to Host Institution REB for the Study.

CTO is an independent not-for-profit organization with a provincial mandate to provide the life sciences industry with a streamlined approach to conducting multi-centre clinical trials in Ontario while ensuring the highest ethical standards for patient safety. CTO has entered into separate agreements with participating institutions to participate in a delegated Board of Record model.

The parties hereby agree as follows: 1. Board of Record 1.1 The Participating Institution retains Host Institution, and Host Institution agrees to Host

Institution REB acting, as the Research Ethics Board of Record (“Board of Record”) for the Participating Institution in respect of the Study.

1.2 Participating Institution and Host Institution agrees that Host Institution REB may approve,

reject, propose modifications to, put on hold or terminate the Study at its sole discretion (“Board of Record Determinations”).

1.3 In agreeing that its REB shall act as delegated Board of Record, Host Institution agrees that

Host Institution REB shall act:

(i) in accordance with its responsibilities set out in the attached Schedule A, including but not limited to Host Institution’s Participation Agreement with CTO; and

(ii) in compliance with all applicable laws, regulations and guidelines, including but not

limited to the Second Edition of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2); the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline E6; the Canadian Food and Drugs Act and its applicable regulations, in particular Part C, Division 5; the Canadian General Standards Board’s “Research Ethics Oversight of Biomedical Clinical Trials” and Ontario’s Personal Health Information Protection Act, 2004 (“PHIPA”) and its applicable regulations (“Applicable Laws”).


1.4 Host Institution acknowledges that the documents and information that Host Institution REB receives from the Participating Institution are subject to strict confidentiality obligations pursuant to agreements between or among Participating Institution, Participating Institution PI, and the Study sponsor (“Sponsor Agreements”). Therefore Host Institution and those for whom it is responsible at law shall maintain in confidence all documents and information received from the Participating Institution and/or Participating Institution PI and shall not disclose them to third parties without prior written permission of the sponsor and/or Participating Institution and Participating Institution PI as applicable. In the event that Host Institution (a) reasonably believes that information or documents obtained from the Participating Institution and/or Participating Institution PI must be disclosed in the interest of protecting the safety of Study participants, or (b) Host Institution is required by law, regulation or court order to disclose information or documents obtained from the Participating Institution, then Host Institution shall before making any such disclosure notify the Participating Institution and Participating Institution PI so that Host Institution, Participating Institution and Participating Institution PI may collectively determine how disclosure may be made without breach of Sponsor Agreements. The obligations contained in this paragraph shall survive completion or earlier termination of this Agreement. [Note to draft: further consideration will be given to safeguarding PHI in accordance with PHIPA]

1.5 In the event of an on-site assessment by Host Institution REB, Participating Institution and

Participating Institution PI may be required in accordance with Schedule A to provide direct access to Study participants’ records of personal health information (as that term is defined under PHIPA) that are in the direct or indirect control of the Participating Institution and/or Participating Institution PI (“Participants’ Records”). Should that occur, Host Institution REB will hold the Participants’ Records in confidence, use them solely for the purpose of carrying out its duties under this Agreement, and will not copy or remove said records or transfer any information contained in them to anyone other than employees and agents of Host Institution REB with a need to know, without the prior written consent of Participating Institution or in accordance with Applicable Laws.

1.6 Host Institution represents and warrants that Host Institution REB operates and is

constituted in accordance with all Applicable Laws and that it is registered with Health Canada and as an IRB with the U.S. Office for Human Research Protections, as applicable and meets or exceeds the CTO qualification standards.

2. Obligations of the Participating Institution and Participating Institution PI The Participating Institution and Participating Institution PI agree to comply with all Board of Record Determinations with respect to the Study, and each with respect to its/his/her own role to conduct the Study in accordance with all Applicable Laws and in accordance with its/his/her responsibilities set out in the attached Schedule A.


3. Relationship of the Parties

Host Institution, the Participating Institution and the Participating Institution PI are and at all times shall remain independent of each other and are not and shall not represent themselves to be the principal, agent, joint venturer, partner or employee of the other(s). No representations shall be made or actions taken by a party which could establish or imply any apparent relationship of agency, joint venture, partnership or employment with another, and other than expressly provided under this Agreement, no party shall be bound in any manner whatsoever by any agreements, warranties or representations of another party. 4. Assignment Neither this Agreement nor any of the rights or obligations of any party may be assigned without prior written consent of the other parties to this Agreement. 5. Term and Termination 5.1 This Agreement remains in place for the duration of the Study (including with respect to

document retention) unless terminated in accordance with this Article 5. 5.2 Providing that alternate REB oversight of the Study is in place in accordance with the

parties’ obligations and this Agreement and the Participation Agreement with CTO, termination may occur only in the following circumstances:

(i) Where the Participation Agreement between CTO and either or both of the

Participating Institution or Host Institution is terminated; (ii) Upon mutual agreement in writing by the parties

6. Statement of Responsibility

6.1 Except as otherwise provided in this Agreement,

(i) Each party assumes its/his/her own liability for any damages, losses or costs arising out of suits or claims on account of injuries (including death) to persons participating in the Study or damage to property to the extent that such injuries or damage arise out of its/his/her activities in the course of the Study or the performance of this Agreement, or out of the activities of those for whom in law it/he/she is responsible; and

(ii) No party or its/his/her trustees, directors, officers, employees, and agents (the “first

party’’) shall be liable to any other party (the “second party’’) for any damages, losses or costs arising out of suits or claims brought by the second party or made against the second party except to the extent caused by negligence or willful misconduct on the part of the first party.


(iii) For greater clarity, Host Institution REB obligations under this Agreement include research ethics review, initial and ongoing approvals of the Study at Participating Institution, and any liabilities related to such review, approval and oversight.

6.2 Each institutional party shall maintain appropriate insurance sufficient to cover its liabilities

that may arise under this Agreement; and, in the case of the Participating Institution PI, he/she shall maintain membership in the Canadian Medical Protective Association (CMPA) that includes coverage for his/her respective clinical research activities under the Study protocol. Upon request, each party shall provide to the others a certificate of insurance or other proof of insurance or of CMPA membership, as appropriate.

7. Dispute Resolution In the event that a dispute arises related to this Agreement, the parties will initially and in good faith discuss the matter through their contacts named at the beginning of the Agreement and seek a resolution. If no resolution has been reached within fifteen (15) days from the commencement of discussions, the parties shall be free to pursue any other remedies available to them. In the event that any party receives notice of a legal proceeding by a third party against it that is related to the Study, it shall immediately notify the other parties in writing through its contacts named at the beginning of the Agreement. While a dispute is being settled, the Host Institution REB is required to continue with its role as delegated Board of Record. 8. Governing Law This Agreement shall be governed by, and construed and interpreted in accordance with, the laws in force in the Province of Ontario and shall be treated in all respects as an Ontario contract. 9. Severability

If any provision of this Agreement is determined to be invalid or unenforceable in whole or in part, such invalidity or unenforceability shall attach to such provision and the remainder of the Agreement shall continue in full force and effect; and the parties shall in good faith negotiate a substitute for any provision declared unenforceable, which shall most nearly approximate the intent of the parties in entering into this Agreement. 10. Signatures By signing, the signatories agree that a signed photocopy or electronic version (e.g., *.pdf or fascimile) of this Agreement is as valid as an original. This Agreement may be signed in counterparts, each of which is to be considered an original, and taken together as one and the same document. A copy of this Agreement executed in counterpart shall be provided by each party to the other parties.


Participating Institution

Name: Title:

Signature:

Date:

Authorized Signing Officer (“I have authority to bind the Participating Institution”)

Host Institution

Name: Title:

Signature: Date:

Authorized Signing Officer (“I have authority to bind Host Institution”)

Participating Institution Principal Investigator: Witness:

Name: Name:

Signature: Signature:

Date: Date: All counterparts of this fully executed Agreement should be kept on file at Host Institution, Participating Institution, and in the Participating Institution PI’s essential Study documents file.


SCHEDULE A

Division of Responsibilities among Host Institution, the Participating Institution and Participating Institution PI

I. The responsibilities of HOST INSTITUTION are to:

1. Abide by the terms and conditions of its Participation Agreement with CTO with respect to the delegated board of record model for ethics review of multi-Participating Institution clinical trials.

2. Maintain its registration with Health Canada and as an IRB with the U.S. Office for Human Research Protections, and with CTO.

3. Mandate its REB to review and consider the application materials submitted by the Participating Institution PI, correspond with the Participating Institution PI regarding any issues or recommended changes to the Study, and make a decision about approval of the Study at the Participating Institution.

4. Mandate its REB to be familiar with the CTO list of Participating Institution-specific informed consent language/preferences.

5. Mandate its REB to conduct the ethics review of the Study and correspond with the Participating Institution PI regarding any issues or recommended changes to the Participating Institution PI’s materials.

6. Mandate its REB to ensure an ongoing monitoring plan is in place with respect to the Study, which includes an annual review of the approved Study or more frequently at the discretion of Host Institution REB, a review of all site-specific serious adverse events (“SAEs”) in accordance with the Study protocol and review of and decision regarding approval of any protocol amendments/modifications to the Study submitted to HOST INSTITUTION REB by the Participating Institution PI, as applicable. [Note to draft: CTO decision required on whether other materials to be submitted by the sponsor, e.g., CIOMs/PSUR reports. All investigators will have to maintain the reports with their study file and the Delegated Board will have to maintain as well.]

7. Maintain Participating Institution REB Materials as well as the Host Institution review letter(s), investigator response letter(s), Host Institution REB determination letters, local SAE reports received from all Participating Institutions using Host Institution REB. [Note to draft: decision required on who maintains CIOMs/PSUR reports]

8. Maintain written Host Institution REB policies and procedures, and make such documents accessible to designated Participating Institution and Participating Institution PI staff members.

9. Mandate its REB to adhere to the requirements of the Participating Institution’s Federal Wide Assurance and CTO qualification standards.

10. Mandate its REB to immediately notify the Participating Institution and Participating Institution PI in writing if the Study is placed on hold or terminated by Host Institution REB.


11. In the event that the Study closes at Host Institution prior to closure at the other Participating Institutions, continue in its role as Host Institution REB.

12. Mandate its REB to notify in writing, and cooperate with, the Participating Institution and the Participating Institution PI concerning any significant Study-related communication received by Host Institution REB that has not been received by the Participating Institution or Participating Institution PI, including, but not limited to Study participant complaints, protocol deviations and privacy breaches.

II. The responsibilities of the Participating Institution:

1. Participating Institution shall inform Host Institution of the appropriate Participating Institution representative to be copied on key correspondence (including but not limited to notification of approvals) from Host Institution in addition to the Participating Institution PI.

2. Participating Institution shall maintain a Federal Wide Assurance (FWA) and designate Host Institution as an REB responsible to the Participating Institution under the Participating Institution’s FWA.

3. Participating Institution shall administratively assess and approve the Study based on feasibility and resource assessments of the Participating Institution and Participating Institution PI and provide confirmation to Host Institution REB of its final approval of the Study budget and contract with the Study sponsor. For greater certainty, although HOST INSTITUTION may approve the ethical aspects of the Study, the final decision to conduct the Study at the Participating Institution rests with the Participating Institution. [Note to draft: discussion by the Working Group as to whether it should be standardized in this agreement that REB reviews budget; industry raised concerns about confidentiality; some felt this was supported by TCPS 2, others felt it was discretionary.]†

III. The responsibilities of the Participating Institution PI:

1. Participating Institution PI shall submit materials to HOST INSTITUTION REB in accordance with HOST INSTITUTION REB’s policies, procedures and requirements. This includes any amendments or modifications to the Study (including but not limited to protocol amendments, revised consent forms and external SAEs/safety reports), and any new information (including but not limited to data safety monitoring board reports) that may adversely affect the safety of the participants or significantly affect the conduct of the Study.[Note to draft: may be updated if CTO SOPs are also developed]

2. Participating Institution PI shall conduct the Study at the Participating Institution in accordance with the Study protocol, Participating Institution policies, procedures and requirements, and all Applicable Laws.

3. Participating Institution PI shall be appropriately qualified to conduct the Study at all times and Participating Institution and Participating Institution PI shall immediately advise Participating Institution and Host Institution REB should it/he/she become aware


of any information that would indicate that the qualifications of the Participating Institution PI may no longer be appropriate to the Study.

4. Participating Institution PI shall promptly report to Host Institution REB all local SAEs in respect of the Study (as defined by the Study protocol and by Host Institution REB) and any new information (including but not limited to protocol deviations) that may adversely affect the safety of the participants or significantly affect the conduct of the Study.

5. In addition to reporting in accordance with Participating Institution policies (e.g., to the Privacy Officer), Participating Institution PI shall promptly report to Host Institution REB all privacy breaches in respect of the Study, and any corrective action taken.

6. Participating Institution PI shall notify Host Institution REB immediately in writing:

a) if the Study has been placed on hold or terminated at the Participating Institution;

b) of any significant Study-related communication including, but not limited to participant complaints, protocol deviations and privacy breaches.

†

TCPS 2 states:

Clinical Trial Budgets

Budgets for clinical trials are usually calculated based on per capita costs – that is, the sponsor pays the

researcher a fixed sum for each participant, based on the duration and complexity of the trial and the tests

and procedures it requires.

Article 11.11 REBs shall ensure that clinical trial budgets are reviewed to ensure that conflicts of interest are

identified and minimized, or otherwise managed.

Application REBs may delegate the review of clinical trial budgets to an appropriate institutional body. The

body should ensure financial conflicts of interest are reported to the REB. When no such institutional body

exists, the REBs shall review clinical trial budgets for financial conflicts of interest.As a general guide,

payments for clinical trial procedures should be no greater than the usual amounts charged by health care

providers for the provision of comparable services. Researchers should disclose all kinds and amounts of

payment to the REB (see Article 7.4).

A particular concern in the context of clinical trials is the use of inappropriate incentives by the sponsor to

encourage researchers to recruit participants quickly and without regard to their suitability for the trial.

Differential incentives paid for different levels of recruitment, such as higher per-participant payments for

those recruited above a set target, may also encourage inappropriate recruitment practices and should be

prohibited. The REB can assist the researcher in identifying these and other types of financial conflicts and

managing them appropriately (see Article 7.4).

It is recommended that the issue of budget review and appropriateness should be left to the Participating

Institution who advises the Host Institution REB that it has done so. Local institutions are more likely to be aware

of possible Conflict of Interest issues as well.