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Pressures at the front lines : investigative sites and contract research organizations in Canadian clinical… Preto, Christina Louise 2014

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PRESSURES AT THE FRONT LINES: INVESTIGATIVE SITES AND CONTRACT RESEARCH ORGANIZATIONS IN CANADIAN CLINICAL TRIALS  by Christina Louise Preto   A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Interdisciplinary Studies)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)   January 2014  ? Christina Louise Preto, 2014 ii  Abstract Commercialization of medical research, and clinical trials in particular, has been the subject of scrutiny by policy makers and academics. However, little attention has focused on a more recent but now dominant actor: the contract research organization (CRO).  Over the past twenty-five years, CROs have assumed much of academia?s role in the conduct and control of clinical trials, and are now the de facto face of industry sponsors for those working at investigative sites. This dissertation examines sites, their relationship with CROs, and the extent to which Canadians are protected by Canada?s clinical trials oversight framework.   This dissertation includes both empirical and normative components. First, and based on an extensive review of industry and academic literature, I describe the lay of the land of clinical trials in Canada and set the regulatory and economic context. Second, a qualitative interview study explores the relatively unexamined interface between site and CRO to identify key areas of concern from the perspective of those working at the frontlines of Canadian clinical trials.  This is based on 24 semi-structured interviews.  Participants were recruited so as to provide a range of perspectives relevant to the practice realities at the frontlines and the challenges that arise in relation to site-CRO interactions. It includes participants working at sites, CROs, pharmaceutical companies and in consultancy roles with clients across these categories.  Third, a critical legal and ethical analysis of the regulatory and policy frameworks governing clinical trials in Canada is undertaken to determine areas of weakness in light of the issues identified in the qualitative study.  A number of shortcomings with Canada?s approach to clinical trial oversight in relation to both investigator and industry-initiated trials are identified.  Key among these is an overreliance on sponsors for trial oversight, which raises different concerns in industry and investigator-initiated trials.  These and other critical issues are explored and recommendations to address such concerns are made.  This study supports the growing call for an evidence based approach to protecting human subjects in research and is particularly timely given the intense efforts currently underway to attract more industry funded clinical trials to Canada.  iii  Preface This dissertation is an original intellectual product of the author, Christina Preto. The fieldwork reported in Chapters 4-6 was approved by the University of British Columbia?s Behavioural Research Ethics Board and is covered by UBC Ethics Certificate number H10-00289.   iv  Table of Contents  Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iii Table of Contents ......................................................................................................................... iv List of Tables ..................................................................................................................................x List of Figures ............................................................................................................................... xi List of Abbreviations .................................................................................................................. xii Glossary ........................................................................................................................................xv Acknowledgements .................................................................................................................. xviii Dedication .....................................................................................................................................xx Chapter 1: Introduction ................................................................................................................1 Chapter 2: Clinical Trials In Canada: A Brief Overview ..........................................................9 2.1 The Pharmaceutical Industry: Down, But Certainly Not Out ............................................ 9 2.2 Clinical Trials: A Brief Overview .................................................................................... 12 2.3 Clinical Trials In Canada: Feeling The Pinch .................................................................. 16 2.4 Keeping Canada On The Map: Initiatives To Attract Clinical Trials .............................. 20 2.5 Structure Of The Clinical Trials Industry ........................................................................ 24 2.6 Outsourcing In The Pharmaceutical Industry .................................................................. 26 2.6.1 Outsourcing In The Pharmaceutical Industry: Drivers ............................................. 27 2.6.2 Outsourcing In The Pharmaceutical Industry: The Cast ........................................... 31 2.6.2.1 Investigative Sites .............................................................................................. 32 2.6.2.2 Site Personnel..................................................................................................... 35 2.6.2.2.1 Qualified/Principal Investigator (QI/PI) ..................................................... 35 2.6.2.2.2 Clinical Research Coordinator (Coordinator or CRC)................................ 36 2.6.2.3 Site Management Organizations (SMOs) .......................................................... 37 2.6.2.4 Contract Research Organizations (CROs) ......................................................... 38 2.6.2.5 CRO Personnel................................................................................................... 39 2.6.2.5.1 Clinical Research Associate (CRA or Monitor) ......................................... 40 2.6.2.5.2 Project Manager .......................................................................................... 41 v  2.6.2.6 Academic Research Organizations .................................................................... 42 2.6.2.7 Private Ethics Review Boards ............................................................................ 44 2.7 Effectiveness Of Outsourcing Relationships ................................................................... 47 2.8 Conclusion ....................................................................................................................... 48 Chapter 3: Methodology..............................................................................................................50 3.1 Goal Of This Research ..................................................................................................... 50 3.2 Rationale: Why Clinical Trials? Why Sites And CROs? Why Now? ............................. 50 3.3 Research Study: Design And Methodology ..................................................................... 55 3.4 Qualitative Interview Study ............................................................................................. 55 3.4.1 Sampling And Recruitment ...................................................................................... 57 3.4.2 Data Collection ......................................................................................................... 63 3.4.3 Data Analysis ............................................................................................................ 64 3.5 Critical Legal And Policy Analysis ................................................................................. 67 3.6 Situating The Researcher ................................................................................................. 69 Chapter 4: Examining Investigative Sites And Their Internal Challenges: Investigator Training ........................................................................................................................................73 4.1 Context ............................................................................................................................. 74 4.2 A Cause For Concern: Investigator Training ................................................................... 77 4.3 Knowledge Gaps .............................................................................................................. 77 4.4 Training Opportunities ..................................................................................................... 80 4.4.1 Medical School ......................................................................................................... 81 4.4.2 Sponsor & CRO Initiatives ....................................................................................... 82 4.4.3 Professional Organizations And Other For-Profit Offerings .................................... 83 4.5 A Matter Of Priorities ...................................................................................................... 86 4.6 Discussion ........................................................................................................................ 87 Chapter 5: Examining Investigative Sites And Their Internal Challenges: Investigator Involvement, Staff Training And Institutional Support ..........................................................97 5.1 Context ............................................................................................................................. 98 5.2 Investigator Involvement ................................................................................................. 99 5.2.1 Early Engagement Of The Research Team ............................................................. 100 vi  5.2.1.1 Workload.......................................................................................................... 100 5.2.1.2 Fit And Design Issues ...................................................................................... 102 5.2.2 Providing Ongoing Oversight ................................................................................. 105 5.3 Staff Training ................................................................................................................. 108 5.4 Institutional Support....................................................................................................... 113 5.5 Discussion ...................................................................................................................... 116 Chapter 6: Challenges Reported By Sites Working With CROs ..........................................121 6.1 Context ........................................................................................................................... 121 6.2 Do CROs Exert More Pressure On Sites Than Sponsors? ............................................. 123 6.3 Specific Challenges Described By Site-Based Participants ........................................... 130 6.3.1 Ethical Challenges: Privacy And Data Security ..................................................... 130 6.3.1.1 Recruitment ...................................................................................................... 131 6.3.1.2 Data Monitoring Practices ............................................................................... 133 6.3.1.3 GCP Violations: A Matter Of Interpretation ................................................... 134 6.3.2 CRO As Middleman ............................................................................................... 136 6.3.2.1 Frustrated Communication And Increased Workload ..................................... 136 6.3.2.2 Disrupted Relationship..................................................................................... 140 6.3.3 ?Ticky Box? Police Approach ................................................................................. 144 6.3.4 Training And Staff Issues ....................................................................................... 145 6.3.4.1 General Competency Levels ............................................................................ 145 6.3.4.2 Staff Turnover .................................................................................................. 149 6.3.5 Organizational Elements ......................................................................................... 150 6.3.6 CROs vs. AROs ...................................................................................................... 152 6.3.7 Advantages For Sites Working With CROs ........................................................... 153 6.4 Discussion ...................................................................................................................... 154 Chapter 7: Legal And Policy Landscape For Clinical Trials In Canada .............................158 7.1 Clinical Trials In Canada: Contextualizing Our Approach ............................................ 158 7.2 Clinical Trial Oversight: Role Of The Regulator, The REB, And The Sponsor ........... 164 7.2.1 Initial Assessment & Review .................................................................................. 165 7.2.2 Ongoing Review: Regulator (Health Canada) ........................................................ 166 vii  7.2.3 Ongoing Review: REB ........................................................................................... 167 7.2.4 Shortcomings With Regulatory And REB Oversight ............................................. 168 7.2.5 Role Of The Sponsor .............................................................................................. 171 7.2.6 Sponsor Oversight: Areas Of Concern ................................................................... 172 7.2.7 The Final Assessment: New Drug Submissions ..................................................... 176 7.3 What Are The Applicable Rules And To Whom Do They Apply? ............................... 179 7.3.1 Food And Drugs Act And Division 5 Regulations ................................................. 180 7.3.2 ICH-GCP Guidelines .............................................................................................. 183 7.3.2.1 Research Ethics Board ..................................................................................... 184 7.3.2.2 Investigator ...................................................................................................... 184 7.3.2.3 Sponsor ............................................................................................................ 186 7.3.2.4 CRO ................................................................................................................. 187 7.3.2.5 Monitor ............................................................................................................ 187 7.3.3 TCPS2 ..................................................................................................................... 188 7.3.4 Codes Of Conduct ................................................................................................... 189 7.4 Clinical Trial Governance: How Does Canada Compare? ............................................ 191 7.4.1 Concerns With Opacity ........................................................................................... 192 7.4.2 A Flexible Approach But At What Cost? ............................................................... 195 7.4.3 Another Comparison: Investigator Training ........................................................... 196 7.5 CRO: Diffused Accountability ...................................................................................... 199 7.6 Moving Forward: Suggestions For Greater Accountability ........................................... 201 7.6.1 Establishing Clear Jurisdiction Of Health Canada Over Key Parties ..................... 201 7.6.2 Increase Training And Independence Of REBs & Clarify Scope .......................... 202 7.6.3 Clearly Articulate Roles And Limitations Of Regulator, REB And Sponsor ........ 203 7.6.3.1 Clarify Role Of Health Canada In Initial Review ............................................ 203 7.6.3.2 Clarify Role Of Health Canada In Ongoing Reviews ...................................... 204 7.6.4 Additional Suggestions ........................................................................................... 205 7.7 Summary ........................................................................................................................ 206 Chapter 8: Contractual Agreements & Other Sources Of Legal Obligation .......................208 8.1 Contractual Obligations ................................................................................................. 208 viii  8.1.1 Sponsor-CRO .......................................................................................................... 209 8.1.2 Sponsor/CRO-Site .................................................................................................. 211 8.1.3 Sponsor/CRO-Other ................................................................................................ 212 8.1.4 Sites ......................................................................................................................... 212 8.2 Potential Sources Of Liability ........................................................................................ 213 8.2.1 Breach Of Statute .................................................................................................... 214 8.2.2 Breach Of Contract ................................................................................................. 214 8.2.3 Tort (Negligence) .................................................................................................... 215 8.2.3.1 CRO/Sponsor ................................................................................................... 216 8.2.3.2 Subject Injury ................................................................................................... 217 8.2.3.3 Sponsor Liability: A Closer Look .................................................................... 219 8.2.4 Fiduciary Duties ...................................................................................................... 222 8.2.4.1 Tying Down An Elusive Concept .................................................................... 222 8.2.4.2 Researcher As Fiduciary .................................................................................. 223 8.2.4.3 REB As Fiduciary ............................................................................................ 224 8.2.4.4 Sponsor As Fiduciary ....................................................................................... 225 8.2.4.5 Implications Of Fiduciary Obligations And Relationships .............................. 225 8.2.5 Criminal Law .......................................................................................................... 226 8.2.6 Charter .................................................................................................................... 226 8.3 Clinical Trial Litigation: An Evolving Field ................................................................. 227 Chapter 9: Conclusion ...............................................................................................................229 9.1 Narrative A: If clinical trials could be extricated from profound commercialized interests of pharmaceutical sponsors, there would be a return to a golden age of high quality, objective and unbiased research. ............................................................................................................ 229 9.1.1 Should GCP Apply To Investigator-Initiated Trials? ............................................. 233 9.2 Narrative B: Health Canada is the body that keeps sites, CROs and sponsors in line and makes sure their obligations are met so that the interests of Canadians and Human Subjects are protected. ................................................................................................................................. 238 9.3 Narrative C: The drugs being developed, tested and approved for the Canadian market typically result in therapeutic benefit for Canadians. ............................................................. 243 ix  9.4 Encouraging Findings Emerging From This Study ....................................................... 248 9.5 Closing Comments ......................................................................................................... 250 9.6 Contributions And Recommendations Emerging From This Research ......................... 251 9.6.1 Recommendations Narrative A (Golden Age Of Investigator-Initiated Trials) ..... 251 9.6.2 Recommendations Narrative B (Health Canada?s Key Role In Oversight) ........... 252 9.6.3 Recommendations Narrative C (New Drugs Yield Therapeutic Benefit) .............. 252 9.6.4 Additional Recommendations (Legal & Policy Framework (Chapter 7)) .............. 253 9.7 Limitations Of The Research ......................................................................................... 253 9.8 Areas For Future Research ............................................................................................. 255 Bibliography ...............................................................................................................................258 Appendices ..................................................................................................................................280 Appendix A : Interview Protocols (Site; CRO; Sponsor; Consultant) ................................... 280 A.1 Investigative Site Interview Schedule ....................................................................... 280 A.2 CRO Interview Schedule .......................................................................................... 284 A.3 Sponsor Interview Schedule...................................................................................... 287 A.4 Consultant Interview Schedule ................................................................................. 292 Appendix B : Initial Codes in NVIVO after 8 interviews coded (all categories) ................... 295 Appendix C : List of 34 themes as distributed on Venn Diagram .......................................... 297 Appendix D : Summary of Main Issues Discussed by Participants in Chapter 6 ................... 298  x  List of Tables Table 3.1: Distribution of Participants, based on role at time of interview (Total: 24) ........ 61 Table 3.2: Distribution of full range of experience of participants .......................................... 62 Table D.1: Summary Table for Chapter 6................................................................................................ 298  xi  List of Figures Figure 2.1: Phases of Clinical Trials ............................................................................................. 14 Figure 2.2: Cost of Drug Discovery and Development ................................................................ 15 Figure 2.3: Economic Impact of Rx&D Companies ..................................................................... 17 Figure 2.4: Global Distribution of Clinical Trials ........................................................................ 19 Figure 2.5: Key Relationships in a Clinical Trial Involving a CRO ............................................. 32 Figure 8.1: Key Contractual Relationships in Outsourced Clinical Trials ................................. 209 Figure B.1: NVIVO Codes Part 1_Screenshot ........................................................................... 295 Figure B.2: NVIVO Codes Part 2_Screenshot ........................................................................... 296   xii  List of Abbreviations ACRO: Association of Clinical Research Organizations ACRP: Association of Clinical Research Professionals AHC/AMC: Academic Health Centres/Medical Centres (used interchangeably) ARO: Academic Research Organization BCCRIN: British Columbia Clinical Research Infrastructure Network BCEHI: British Columbia Ethics Harmonization Initiative CFR: Code of Federal Regulations (U.S.) CHS: Centring the Human Subject (Research Study) CIHR: Canadian Institutes of Health Research CITI: Collaborative Institutional Training Initiative CMA: Canadian Medical Association CME: Continuing Medical Education CNA: Canadian Nurses Association CNE: Continuing Nursing Education CPI: Certified Principal Investigator CRA: Clinical Research Associate (or Monitor) CRC: Clinical Research Coordinator (or Coordinator) CRF: Case Report Form CRO: Contract or Clinical Research Organization (used interchangeably) CTA: Clinical Trial Application (equivalent to the U.S. IND application) CTSU: Clinical Trial Support Unit CTU: Clinical Trial Unit CV: Compliance Verification EDC: Electronic Data Capture EPL: Effective Patent Life EU: European Union FDA: Food and Drugs Act (Canada) FDA: Food and Drug Administration (U.S.) FSP: Functional Service Provider xiii  GCP: Good Clinical Practices GMP: Good Manufacturing Practices HC: Health Canada HPFBI: Health Products & Food Branch Inspectorate  ICH: International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use  ICH-GCP: Guidelines for Good Clinical Practice established by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use   IEC: Independent Ethics Committee IND: Investigational New Drug Application (U.S.) IOM: Institute of Medicine (U.S.) IRB: Institutional Review Board LRCC: Law Reform Commission of Canada MSFHR: Michael Smith Foundation for Health Research  N2: Networks of Networks  NACTRC: Northern Alberta Clinical Trials & Research Centre  NCCA: National Commission for Certifying Agencies  NCIC-CTG: National Cancer Institute of Canada-Clinical Trial Group NDS: New Drug Submission NOL: No Objection Letter NRC: National Research Council  NSERC: Natural Sciences and Engineering Research Council OCREB: Ontario Cancer Research Ethics Board  PI/QI: Principal Investigator/Qualified Investigator (used interchangeably) PM: Project Manager PREB: Private Research Ethics Board R&D: Research and Development REB: Research Ethics Board Rx&D: Canada?s Research-Based Pharmaceutical Companies  SAE: Serious Adverse Event xiv  SMO: Site Management Organization SoCRA: Society of Clinical Research Associates SOP: Standard Operating Procedures SSHRC: Social Sciences and Humanities Research Council SUADR: Serious Unexpected Adverse Drug Reaction TCPS2: Tri-Council Policy Statement 2 TIMI: Thrombolysis In Myocardial Infarction (ARO affiliated with Harvard University) TPD: Therapeutic Products Directorate WMA: World Medical Association  xv  Glossary The definitions included below are based largely on the ICH-GCP Guidelines and Health Canada?s Guidance Document For Clinical Trial Sponsors: Clinical Trial Applications.   Adverse Drug Reaction: Any noxious and unintended response to a drug that is caused by the administration of any dose of the drug.  Adverse Event: Any adverse occurrence in the health of a clinical trial subject who is administered a drug, that may or may not be caused by the administration of the drug, and includes an adverse drug reaction.  Case Report Form (CRF): A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.  Clinical Research Associate (or Monitor): An employee of, or contractor to, either the Sponsor or CRO who is responsible for monitoring the conduct of the trial.  The Monitor essentially becomes the representative of the Sponsor to the Site.  In particular, the purpose of the Monitor is to ensure (a) the rights and well-being of human subjects are protected; (b) the reported trial data are accurate, complete, and verifiable from source documents; and (c) the conduct of the trial is in compliance with the currently approved protocol and amendment(s), with GCP, and with the applicable regulatory requirement(s).  Clinical Research Coordinator (or Coordinator): The person at the site responsible for most of the day to day conduct of the clinical trial activities.  They are at once the primary contact at the site for participants and also for the monitor.  Among the many tasks that now generally fall within a coordinator?s job description are patient recruitment, screening, enrolling, document management (including regulatory documents) and even budget and contract negotiations in some instances.   Clinical Trial: An investigation in respect of a drug for use in humans that involves human subjects and that is intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events in respect of the drug, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.  Contract Research Organization (CRO): A CRO can be described as an organization that is contracted by a sponsor to manage various steps in the drug development process, including conduct of preclinical studies, clinical study design and execution, data management, analysis, medical writing, and regulatory submission.  For the purpose of this dissertation, the focus is on the use of CROs in relation to clinical trials. The terms Clinical Research Organization and Contract Research Organization are referred to interchangeably throughout this document  Good Clinical Practices: Generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons. xvi   Industry-Initiated Clinical Trial: A clinical trial that is funded, designed and controlled by a pharmaceutical or biotechnology company.  Investigator-Initiated Clinical Trial: A clinical trial that is initiated and conducted by an individual investigator (or research institution).  For such trials, the investigator (or institution) is considered to be the sponsor of the trial and must fulfill all the regulatory obligations of the sponsor as outlined in the Division 5 Regulations under the Food and Drugs Act, and the GCP Guidelines. See also: Sponsor-Investigator.   Investigative Site (Site): An investigative site is a company or clinic that conducts studies, often though not exclusively, through contracts with pharmaceutical companies or other funders or CROs.  These can be located in a wide range of settings, from large academic health centers and teaching hospitals, to community research institutions to smaller community health clinics and physician practices.  Monitoring: The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).  Protocol: A document that describes the objectives, design, methodology, statistical considerations and organization of a clinical trial.  Principal Investigator/Qualified Investigator (PI/QI): The investigator in charge at any given site is referred to in the ICH- GCP Guidelines as the Principal Investigator, and this term is widely used in the literature.  Health Canada, under the Division 5 Regulations, terms this position the Qualified Investigator.   I use the terms PI and QI interchangeably throughout this dissertation.  Research Ethics Board: A body that is not affiliated with the sponsor, and the principal mandate of which is to approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being.   Serious Adverse Drug Reaction: An adverse drug reaction that requires in-patient hospitalization or prolongation of existing hospitalization, that causes congenital malformation, that results in persistent or significant disability or incapacity, that is life threatening or that results in death.  Serious Unexpected Adverse Drug Reaction: A serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out in the investigator's brochure or on the label of the drug.  Sponsor: An individual, corporate body, institution or organization that conducts a clinical trial as per Division 5. The sponsor must comply with its obligations as set out in the Division 5 xvii  Regulations under the Food and Drugs Act and the ICH-GCP Guidelines in adhering to good clinical practices for the proper use of the drugs, drug labelling requirements, record keeping, submission of information, reporting of ADRs, and trial discontinuation reporting requirements.  Sponsor-Investigator: An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.   Standard Operating Procedures (SOPs): Detailed, written instructions to achieve uniformity of the performance of a specific function.  xviii  Acknowledgements This dissertation would not have been possible without the efforts and energies of many people.  I want to start by thanking the participants in my study who gave so generously of their time and shared their experiences and insights with me, and whose passion for their work brought this study to life.  My supervisor, Dr. Michael McDonald, and committee members, Dr. Susan Cox and Professor Timothy Caulfield, have guided me through this process and generously offered me the immense benefit of their expertise and insights as I moved forward.  My experience as a co-investigator with the CIHR funded Canadian Network for the Governance of Ethical Health Research Involving Humans: Evidence, Accountability and Practice, was invaluable.  Through the Network, I had incredible opportunities to learn from, and collaborate with, many of the leading scholars in research ethics in Canada.  Dr. Pierre Deschamps and Dr. Ray Saginur in particular provided suggestions and insights during the research phase of this dissertation.  In addition, I had the privilege of being part of the CIHR Ethics of Health Research and Policy Training Program, which also provided invaluable opportunities to work with key figures in bioethics in Canada and introduced me to an inspiring group of peers.  My colleagues at the Centre for Applied Ethics at UBC were also instrumental in shaping my doctoral training and providing rich food for thought.  I am particularly grateful for the opportunities I had to work with Dr. Mike Burgess and Dr. Anita Ho.  My colleagues and friends Dr. Holly Longstaff and Dr. Alice Virani have been important sources of inspiration and encouragement throughout this process. I also want to thank Dr. Rana Ahmad, Dr. Heather Walmsley and Veronica McCaffrey for our many conversations over the years, and Heather for her extremely helpful comments on an early chapter of the dissertation.  I am extremely grateful to CIHR for the Doctoral Research Award that helped support this research.  This dissertation unfolded over a number of years, and throughout that time my family and friends were critical sources of encouragement and support. My mom provided support in many ways, but in particular she made it possible for me to find the hours in the day to get this done by tirelessly caring for a rambunctious toddler.  My dad provided no end of encouragement and offered extensive critical feedback on the complete draft.  Thank you so much to Jodi, Mike, Han and Becky for providing comments and feedback on very short notice!  I am also indebted to Shannon who took on the herculean task of proof reading-thank you!!  I also want to thank xix  Louise for being a wonderful aunty for Zach and giving me a few extra weekend hours to write.  Thank you also to so many of my friends who were always there for a chat, walk or a glass of wine!  Finally, my husband Jonathan has been on the frontlines as this project has evolved and has been at once an important sounding board and an amazing source of support.  Together he, Alynn, Cass, Bailey and Zach made sure the long periods of writing and reflection were interspersed with laughter and dancing.   xx  Dedication I dedicate this dissertation to my parents.  Without all of your love, support (in so many ways!) and encouragement I would not have been able to do this.  I also dedicate this to my son Zachary who has been (mostly) patient as I have pursued this goal, and who is a source of endless wonder and amazement.  . 1  Chapter 1: Introduction  The drug development industry involves high stakes for a wide range of parties.  Pharmaceutical companies spend billions of dollars developing and testing drugs in clinical trials and stand to make or lose billions on those investments.  Host countries like Canada and many others around the world actively seek out clinical trials because they are major economic and scientific drivers. The range of companies and service providers who have evolved to meet industry?s needs now constitute a multi billion dollar industry with the dominant service provider (the contract research organization (?CRO?)), alone having a projected market share of $37.4 billion in 2013.1  Academic health centers and research institutions, despite having lost much of their share of clinical trial activity to the private sector, continue to rely in large part on industry sponsored research for their survival and to help fund a wide range of important basic research initiatives. Physician investigators, both in academia and private practice, are motivated by a number of factors to participate in clinical trials as they strive to improve the care and treatment options available for their patients and in their field. And of course, the patient populations living with and dying from a wide range of conditions and diseases are hoping that those billions of dollars in drug development translate into some therapeutic benefits or cures that positively affect their quality of life and/or prognosis. As illustrated above, a number of complex and profound interests converge in the drug development process. As will be described further in Chapter 2, this convergence takes place within a broader context and one that is dominated by the commercialization of science (and more specifically for present purposes, of medical research and clinical trials). McDonald & Preto (2011), observe that,                                                   1Association of Clinical Research Organizations (ACRO) website (Market Share).  Available at: http://www.acrohealth.org/cro-market1.html. Accessed September 7, 2013. ACRO explains on its site that it is extremely difficult to get an accurate sense of the market share for CROs, since ?the definition of "CRO" and the scope of services included in market size may differ from source to source.?  Interestingly, accuracy of terminology is a challenge throughout this industry.  For example, variations in job descriptions and titles for research coordinators have been discussed in the literature.  Grady & Edgerly (2009) note that research coordinators may be called research coordinators, study coordinators, clinical trial nurses-among other labels. Roberts et al.,(2006) suggest that improving clarity of job descriptions could be an important step in formalizing the position and having it better understood.  2  [v]arious factors (e.g. slow commercialization of research by public research institutions, lack of government support for research, and an increasingly powerful private sector) support a shift away from science as a ?public calling which research findings should be shared and made publicly accessible? (Lemmens, 2004, 644) to a field dominated by a heavy commercial focus on patents and other intellectual property protections.  Many governments have encouraged this as part of a deliberate shift towards a growing, competitive knowledge-based economy. (327)  The extensive literature relating to the dangers associated with commercialization of science addresses a variety of concerns (Downie, Baird & Thompson, 2002; Krimsky, 2003; Labonte & Torgerson, 2005; Lemmens, 2004). Key among these are the negative effects on exchange of information and sharing of ideas resulting from a focus on protecting and capitalizing on intellectual property, as well as conflicts of interest that erode the objectivity and disinterestedness of those designing and conducting the research and reporting the research findings (McDonald & Preto, 2011).  It is important to highlight the difference in funding of clinical research as between public and industry sources.  Whereas the Canadian Institutes of Health Research (CIHR)2 invested a total of $129 million for all clinical research in 2010-2011, industry3 invested $465 million in phase I-III clinical trials.4  Given the difference in numbers, it is not at all surprising that approximately 80% of all clinical trials are funded by industry (Lexchin, 2012).  Moreover, and as will be discussed further in Chapter 2, since the mid 1990s there has been a dramatic shift of clinical trials out of public or academically affiliated sites and into private community based physician practices, clinics and research units. In fact, 70% of all clinical trials in Canada are now being done in the community and only 30% done in academically affiliated sites (Ogilvie, 2012).  The rise of the CRO has been an integral part of this shift, with such organizations assuming many of the responsibilities previously filled by academic institutions and investigators (Mirowski & Van Horne, 2005; Shuchman, 2007).  The                                                  2 CIHR is the dominant public funder of health research in Canada (Ogilvie, 2012; Vanderwel, 2012). See also: Canadian Institutes of Health Research (CIHR) Moving Forward: CIHR Performance Across the Spectrum: From Research Investments to Knowledge Translation, 2011. Available at: http://www.cihr-irsc.gc.ca/e/44585.html  3 These numbers refer specifically to the investments reported by companies to the Patented Medicines Prices Review Board (PMPRB). 4 As will be explained further in Chapter 7, these numbers are low because they do not reflect expenditures that do not qualify for tax credits. Such exemptions include, among other things, grants to universities and hospitals for investigator-initiated trials (Vanderwel, 2012).   3  implications of this shift are described throughout this dissertation; however, and as will be discussed in Chapters 2, 6 and 7, key consequences include a much more limited role for academic investigators in industry sponsored trials (Angell, 2008; Lemmens & Bouchard, 2007; Lenzer, 2008; Mirowski & Van Horne, 2005) and reduced public oversight, as the majority of clinical trials are now subject to review by private-for profit instead of public research ethics boards (Koski et al, 2005; Lemmens & Freedman, 2000; Lexchin, 2008; Shuchman, 2007). In this high-powered, high stakes, and ever-evolving context, Canadians need to know that their health and well-being, both as potential research subjects and as future consumers of the products being developed, are protected for two important reasons.  First, this is quite simply something Canadians rightly expect and something that Health Canada as the relevant regulatory body holds itself out as doing.5 This expectation is part of a trust-based obligation that the state has to protect the interests of its citizens.  As Miller & Weijer (2006a) put it, the state relies on volunteers ?to advance the public interest in science?, and ?as a result?the state is morally obliged to exercise its powers to protect their interests.?  Second, and perhaps more practically, when Canadians lose trust that their interests are being protected, the very fabric that supports research and makes medical advances possible is threatened (Cohen, 2001; McDonald et al., 2008; Yarborough & Sharpe, 2002).  But how is one to assess the extent to which the interests of Canadians are being protected? Certainly, this can be ascertained in part by analyzing the legal and ethical frameworks that govern drug development in this country; however, such an investigation would only provide a limited perspective revealing at best what is supposed to happen and what protections are supposed to be in place.  To obtain a more realistic picture, it is necessary to look not only at the normative aspects?that is, what should happen?but also at the descriptive elements to determine what is in fact happening.  This is because contextual and practice realities shape how the regulations, rules and standards are interpreted and implemented both at the frontlines and at all levels of the research endeavor.                                                    5 As indicated on their website, ?Health Canada is the federal regulator responsible for authorizing the importation and sale of drugs for the purpose of clinical trials?One of the objectives of Health Canada's review is to ascertain that subjects participating in the trial will not be exposed to undue risks.? http://www.hc-sc.gc.ca/dhp-mps/prodpharma/databasdonclin/index-eng.php. Accessed September 7, 2013.  4  This dissertation takes a number of steps in this direction.  My goal in conducting this study is three fold: (1) to explore the ethical and legal issues that arise at the interface between the investigative site (both academic and community based) and CRO in commercialized clinical trials; (2) to situate these issues against the framework governing clinical trials in Canada to determine whether and where there are gaps or weaknesses; and (3) to suggest improvements in the governance framework.  I could have focused my study in a number of different ways; for example, by exploring the interactions between the regulator and industry sponsors, or between the sponsors and the organizations to whom they now regularly outsource some or all components of clinical trials and their management?namely, CROs.  However, I instead focus on the frontlines and specifically on the interface between CROs and investigative sites.  This is done for a number of reasons. In part, I find the frontline focus compelling.  The challenges and issues reported by those at the frontlines have an immediate impact on clinical trials and are therefore a good starting point to assess how well the governing frameworks reflect and address the realities of clinical trial research.  This frontline approach also makes it possible to compare how the presence of the CRO?an entity that has dramatically changed academia?s role in clinical trials and yet one that has received relatively little academic attention?affects what challenges are reported by the site.  Finally, there is also an element of convenience and accessibility.  As will be discussed further in the methods section, I am an outsider to the clinical world and to clinical trials.  However, through my work with a separate CIHR-funded study entitled Centring the Human Subject in Health Research: Understanding the Meaning and Experiences of Research Participation6, I had the opportunity to meet with and present to different sites and professional organizations for those working at the frontlines of clinical trials.  This basic level of familiarity with sites and site staff, combined with anticipated obstacles in terms of accessibility and secrecy with those more upstream (e.g., and in ascending order: CROs, sponsors, regulators), also informs the frontline focus of this study.  One additional point to highlight is that while I refer to ?sites?, the perspective I focus on almost exclusively within this category is that of the research staff?be they research coordinators, site managers or other research staff?but not the investigators.  The reasons for                                                  6See, for example, McDonald et al. (2008) for a description of this research study.  5  this are described in Chapter 3, but very briefly the key reasons have to do with the importance of the coordinator?s role in CRO-site interactions, very limited accessibility to physician investigators, and the fact that I did not want to risk compromising the openness and frankness of the coordinators participating in my study.  Particularly on these last two related points, it became clear to me that if I wanted to interview physicians an important point of access would be through the coordinator.  While I did initially consider this approach, I ultimately chose not to pursue it.  This was because, as the data collection process unfolded, I realized that coordinators were being quite frank with me about some of the challenges they experience within their own site.  Instead of jeopardizing this frankness with a request to speak to their investigator, I focus solely on the staff perspective, and on the coordinator?s perspective in particular.  In addition to the intended focus on the CRO-Site interface, a second compelling area emerges from the data that led me to broaden my scope and inquire more deeply into issues and concerns raised by my site-based participants.  These are not issues between sites and third party CROs, but within the investigative sites themselves.  Most of the participating site staff work with their respective investigator(s) across both commercialized and investigator-initiated clinical trials?with CROs typically being involved with the former, but not the latter.  In my interviews, I ask participants specifically about their experiences working with CROs?what works well, and what doesn?t?for example.  But I also ask more generally what challenges they encounter in their day to day clinical trial activities, and (in later interviews) what (if any) ethical issues they encounter.  In response, and also through generally unprompted comparisons between commercialized and investigator-initiated clinical trials, a number of interesting issues emerge.  My participants highlight that the internal dynamics of a site have important implications not only for the staff working there, but also (& as corroborated by participants in other categories) for the site?s external relationships (e.g., with the CRO).  Moreover, and as I will argue later in this dissertation, some of these findings suggest some important weaknesses in Canada?s research oversight system?particularly in relation to investigator-initiated trials.  As such, I have decided that these site-based issues deserve detailed exploration in their own right.  While there is industry and some medical literature discussing the CRO-Site interface, such articles tend to focus primarily on the logistical challenges, obstacles and proposed solutions to maximizing efficiency and speed of trial conduct, without considering the broader 6  implications (Getz, 2005; Getz, 2007a; Lamberti et al., 2011; Pierre, 2013; Smed & Getz, 2013). There is also relatively little academic literature (empirical or otherwise) exploring or discussing the broader legal and ethical implications that can follow from CRO-site interactions (Fisher, 2009; Mirowski & Van Horn, 2005), although there is a growing literature looking at this interface in the context of clinical trials in emerging markets (i.e. in less developed and developing countries), (Adobor, 2012; Petryna, 2009; Schipper et al., 2011).  My study contributes to this limited literature and does so with a Canadian focus?something that has been lacking to date.   In contrast, there is a richer literature exploring the kinds of internal site issues that I describe in Chapters 4 and 5 of this study. That being said, my findings are interesting in part because they again provide a Canadian perspective (something that has been largely missing in this context), and in part because they emerge so strongly despite not being part of the original focus of the study.  Related to this last point, and as noted above, my data also suggest a relationship between the internal functioning of a site and the effectiveness of its relationship with CROs.  By way of brief overview, then, this dissertation is an outsider?s exploration of a portion of the complex domain of clinical trials in Canada.  Chapter 2 reviews industry and limited academic literature about the pharmaceutical industry in order to provide a ?lay of the land? within which to situate clinical trials in Canada.  Because the pharmaceutical industry is truly a global one and one dominated by the U.S., this chapter describes this broader international context as well.  Chapter 3 describes the research question and rationale, as well as the methods and processes adopted in this study.  These include a qualitative interview-based study across multiple categories of participants, and a critical legal and ethical analysis situating the findings within the specifics of the Canadian regulatory and policy frameworks governing clinical trials.  The dissertation then reports on the findings of this study.  First, the challenges and pressures that research staff encounter within their own site as they compete for and conduct clinical trials in this high pressure environment are explored.  These findings are divided into two chapters, with the first chapter (Chapter 4) examining in detail issues related to gaps in investigator training and the second (Chapter 5) exploring challenges associated with lack of investigator involvement, gaps in staff training and insufficient institutional support. In Chapter 6, the 7  dissertation shifts its focus to the CRO-site interface and the challenges encountered therein.  Ultimately, the findings detailed in this chapter suggest that while the CRO may have a critical role to play in making clinical trials possible and profitable for sponsors in today?s global economic and regulatory climates, they also at the very least exacerbate existing (and may even create new), ethical tensions and concerns in their interactions with sites.  These concerns must be addressed in order to ensure the safety and integrity of clinical trials in Canada.  It should be noted that while the primary vantage point across all three data chapters is the investigative site7, this is supplemented and enriched by insights from CROs, sponsors and industry consultants where participants in these categories commented on the issues in question.  This site-centered but multi-faceted approach not only serves as a sort of verification through triangulation of the key issues, but also results in much more nuanced and detailed insights and findings. Shifting somewhat away from the strictly data driven chapters, Chapter 7 provides a detailed examination of the law and policy landscape that shapes how clinical trials in Canada are conducted and informs how those involved in clincial trials understand and define their roles and responsibilities, and then in turn how those responsibilities are enforced.  In addition, potential gaps or weaknesses in the legal and policy frameworks that pertain to the key issues raised by participants in earlier chapters are highlighted.  Specific questions pertaining to liability and legal exposure are briefly discussed in Chapter 8.  The concluding discussion (Chapter 9) revisits the key findings in the report, but does so by situating them against three commonly held ideas or narratives that the findings challenge. Specifically, these are that: ? If clinical drug trials could be extricated from the profoundly commercial interests of the pharmaceutical industry there would be a return to a golden age of high quality, publicly funded objective, unbiased research; ? The regulator (namely, Health Canada), is the key authority that ensures sites (and CROs) are meeting the established legal requirements and ethical standards, thereby protecting human subject and public interests;                                                  7 The reasons for this choice are described in detail in Chapter 3.  8  ? Clinical trials bring medical benefits both in their own right and in terms of the drugs they ultimately support to market. Drawing on my findings and analysis in the preceding chapters, I challenge these narratives and offer a more nuanced, realistic picture of clinical trials in Canada. This concluding chapter also discusses the ways in which this research contributes to the existing literature, highlights some possible practical applications for its findings, acknowledges and describes its weaknesses and limitations and suggests possible areas for further inquiry. Finally, although some of the issues discussed by my participants in both commercialized and investigator-initiated trials have been described to varying degrees in the industry and/or academic (nursing, medical, bioethics, health law) literature, there has been very little academic empirical research exploring these issues in a specifically Canadian context.  This study addresses this gap and then builds on the data to identify weaknesses in Canada?s regulatory and policy frameworks that could have important implications at the frontlines, especially in light of concentrated efforts currently underway to attract more industry-funded clinical trials to Canada.    9  Chapter 2: Clinical Trials In Canada: A Brief Overview   The clinical trials industry is at once vast, complex and global in scope. While this dissertation focuses on a very narrow sliver?namely investigative sites and their interactions with CROs in Canada?it is important to situate this narrow sliver within the broader context. The purpose of this chapter is to provide that context, based on a review of (mostly) industry and (some) academic literature about the pharmaceutical industry. More specifically, this chapter describes key pressures facing the pharmaceutical industry and briefly explains how these pressures have affected clinical trials in Canada. It then looks at the evolution of pharmaceutical outsourcing into a multi-billion dollar industry, introduces the key actors in this regard and then situates these actors within the Canadian context.  Together, these elements provide the big picture or lay-of-the-land within which the findings of the qualitative interview study (Chapters 4-6) and critical legal and policy analysis (Chapters 7 and 8), must be situated in order to be properly understood.8  2.1 The Pharmaceutical Industry: Down, But Certainly Not Out There are a number of challenges facing the pharmaceutical industry today. So-called blockbuster drugs are few and far between, numbers of potential products in later stages of development are dropping9, patents on many of the critical money-making drugs have or are about to expire10, regulatory requirements are numerous and complex, and costs associated with drug development are increasing in leaps and bounds. As one recent industry report states, ?the average cost of bringing a new product successfully to market has increased by 21 percent from                                                  8 It is worth highlighting that in relation to this ?lay of the land? chapter, my literature searches yielded more in the way of industry and grey literature than academic sources and I have relied heavily on these throughout this chapter in particular.  9  The Big Pharma Recession Report (2012). Available at www.pharma-iq.com/downloadContent.cfm?ID=648. This report observes that between 2010-2011, the number of late-stage compounds in development dropped from 23 on average per company to 18 per company. Accessed September 12, 2013.  10 This patent cliff started in 2011, with Pfizer?s Lipitor going off patent.  As has been noted elsewhere, ?[f]aced with more than 110 drugs losing patent exclusivity in the U.S., including 14 "blockbusters", the world's leading pharmaceutical companies face considerable risk to their revenue streams in next three years.? See R&D Spending, Approvals Down in 2011. Available at: http://www.dddmag.com/news/2011/06/r-d-spending-approvals-down-2011 10  $830 million in 2010 to $1.048 billion in 2011.? 11  Other estimates put the cost at closer to 1.9 billion in 2012 (Carroll, 2012).12 Given that clinical development is the most costly part of the drug development process (Roy, 2012; PhRMA, 2013), it is informative to look at the increased expenditures in this domain to get a sense of the pressures facing industry and the costs they are trying to control in order to remain competitive and profitable. For example, of the $48.6 billion USD PhRMA13 member companies invested in research and development in 2011, 57% (~$28 billion) was spent on phase I-III clinical trials, of which 35.8% (almost $17.4 billion) was on phase III clinical trials (PhRMA 2013). Other figures highlight the substantial increase in per patient clinical trial costs that have plagued the industry in recent years, with some figures putting the increase in per patient costs for phase III trials between 2008-2011 as high as 87% (Santos-Serrao, 2012).14 The key factors cited as major contributors to this increase include higher enrollment costs for patients, increasing vendor fees, recruitment of clinical trial sites as well as increasing costs in technology.  Increased staffing for clinical trials was also a major contributing cost, with all phases of trials at minimum doubling in their staffing levels in this time period, and phase I and II increasing by 108 and 106% respectively.15                                                    11 The Big Pharma Recession Report (2012). Available at www.pharma-iq.com/downloadContent.cfm?ID=648. 12 It is important to note that these numbers are not uncontested.  Critics (Collier, 2009; Light & Warburton, 2005) highlight that there is a profound lack of transparency around how such numbers are reached and point to a number of other concerns. For example, the inclusion of lost opportunity costs (instead of limiting it to actual out of pocket costs), lack of identification of government funding and failure to deduct amounts saved in tax breaks are identified as serious flaws. 13 PhRMA, the Pharmaceutical Research and Manufacturers of America, is the organization that represents the country?s leading biopharmaceutical researchers and biotechnology companies. See more at: http://www.phrma.org/about#sthash.4FRfVGJ0.dpuf  14 This article cites data from a 2011 report entitled ?Clinical Operations: Benchmarking Per-Patient Trial Costs, Staffing and Adaptive Design Cutting Edge Research? by Cutting Edge Information consultants.  Unfortunately, as with much industry based data detailing the economic and business trends in the industry, access was prohibitively expensive (a copy of the report would have cost nearly $8000).  As such, the figures cited herein are taken from summaries of the report provided by other sources. 15 As noted by Silverman (2011), an increase in clinical research associates was a major factor in this regard as ?[i]n 2008, the average Phase II trial employed 3.6 clinical research associates, but that rose 9 in 2011. The average ratio of CRAs per site was 10 in Phase IIIb and 6.3 in Phase 11  Despite these and other challenges, however, the pharmaceutical industry is still going strong.  Global sales were projected at $880 billion USD16 in 2011 and research and development spending reached $68 billion USD17 which, while a three year low within the industry, is second only to computing/electronics and far ahead of the third place automotive industry.18  In terms of international investments, global members of Canada?s Research Based Pharmaceutical Companies (Rx&D) alone invest $110 billion annually to support their research related activities in countries around the world, including $1 billion in Canada.19 As has been the case for nearly 3.5 decades then, the pharmaceutical industry continues to be a very powerful and influential force.  Countries around the world, including Canada, are working hard to make themselves more attractive to the industry in order to compete for ever shrinking?though clearly still substantial?research dollars, the bulk of which are associated with clinical trials.20  The above is a reminder that the pharmaceutical industry is at once an international high stakes, high pressure environment that is currently facing unprecedented challenges, and yet?relative to other global industries?one that continues to yield almost unparalleled influence on a global level. The remainder of this chapter is comprised of a series of sections that provide the important background information to support the analysis and discussion chapters. The first section briefly situates the discussion in the Canadian context and provides some illustration of how the economic challenges facing the pharmaceutical industry globally are being felt and                                                                                                                                                              IIIa.? Available at: http://www.pharmalot.com/2011/07/clinical-trial-costs-for-each-patient-rose-rapidly/  16 IMAP (2011). Pharmaceuticals & Biotech Industry Global Report. Available at: http://www.imap.com/imap/media/resources/IMAP_PharmaReport_8_272B8752E0FB3.pdf, accessed September 13, 2013. 17 See R&D Spending, Approvals Down in 2011. Available at: http://www.dddmag.com/news/2011/06/r-d-spending-approvals-down-2011, accessed September 13, 2013 18Making Ideas Work: The 2012 Global Innovation 1000 Study. Available at: http://www.booz.com/media/file/BoozCo_The-2012-Global-Innovation-1000-Results-Summary.pdf, accessed November 30, 2012 19 As described by Mr. Russell Williams, president of Rx&D, June 12, 2012. http://www.canadapharma.org/editorletters.asp?a=view&id=3. 20 Ibid. See also for example the report by Rx&D, CIHR & ACAHO, ?An Action Plan to Help Attract More Clinical Trials to Canada: To Your Health & Prosperity? (March 2012). Available at: http://www.acaho.org/?policy_2012. Accessed September 13, 2013.  12  addressed in this country.  This is followed by a description of why and how outsourcing has evolved in the drug development arena and an introduction to the key actors in this domain.  2.2 Clinical Trials: A Brief Overview Clinical trials are a critical phase of the drug development process, and they come in many shapes and sizes. As noted previously around 80% of clinical trials in Canada are industry funded. Most industry-funded trials are also designed and conducted by industry sponsors or the CROs to whom they delegate such responsibilities.  Such so called industry-initiated trials are often conducted to gather information about the safety and efficacy of new drugs in order to meet regulatory requirements necessary to have their products admitted to market in a given country or to be able to market the drug to a new population or for a new indication.  However, clinical trials are also undertaken for a number of other reasons, including for example, to test newly approved drugs against standard treatment, or simply to learn more about drugs on the market within the terms for which they are approved.  In contrast to the clinical trials supporting a new drug?s initial market approval, these other kinds of clinical trials may be funded and conducted by parties other than the pharmaceutical company who developed the drug in question.21  For example, such clinical trials may be funded by groups who have a special interest in a specific disease or condition, or by a public funding agency.  Such funders might then issue a grant to a physician investigator (or collective of physician investigators) to design and ultimately conduct the trials.  In such cases (called ?investigator-initiated? or ?grant-funded? trials), the physician investigator is called the ?sponsor-investigator? and is responsible for both their investigator based duties, but also for sponsor based duties. The responsibilities associated with these various roles and the implications thereof, are discussed further in Chapter 7. The point here is simply to explain that there is a wide range of clinical trials, and that whereas some are funded and controlled by industry, others are funded, designed and conducted by a range of other kinds of stakeholders.22                                                  21 Although, and as is discussed elsewhere in this dissertation, such trials may also be funded in whole or in part by industry.  22 The Canadian Cancer Research Alliance (CCRA) provides a more concrete illustration of the ratio of investigator to industry-initiated trials. In its 2011 report (State of Cancer Clinical Trials 13  Although there are some nuances, and regardless of who is funding or conducting the trial, clinical trials generally fall into one of four categories.  Very briefly, and as described by Health Canada, the categories may be defined as follows: Phase I trials  Initial safety studies on a new drug, including first administration of the drugs into humans, usually conducted in healthy volunteers. Phase II trials  Clinical trials to evaluate the efficacy of the drug in patients with medical conditions to be treated, diagnosed or prevented and to determine the side effects and risks associated with the drug. Phase III trials  Controlled or uncontrolled trials conducted after preliminary evidence suggesting efficacy of the drug has been demonstrated. Phase IV trials  All studies performed after the drug has been authorized by the regulator for the market, and related to the authorized indication.23  The above description suggests a sharp demarcation between the various phases; however, in actual practice there is a great deal more overlap.  The figure below (Figure 2.1)24 illustrates that clinical trials tend to extend along a continuum and evolve over time.   The dark spots indicate the main objectives of a given kind of study and what phase these goals are concentrated in, but the clear spots illustrate that such goals can cross phases.  For example, while phase III studies                                                                                                                                                              in Canada) it finds that as clinical trials are getting more complex and more expensive, industry funded trials are supplanting academic trials.  Participating sites reported that between 50-75% of studies they conducted are industry-initiated, with the remainder being initiated by investigators or academic collaborative groups such as the NCIC-Clinical Trial Group22.  Moreover, the report also finds that the ratio of industry funded to non-industry funded trials has shifted dramatically over the 10 previous years.  As noted in the report, ?for the three sites with historical data, this pattern has been completely reversed; just a decade ago, more than half of all trials were academic cooperative group studies? (p.2). Report available at: http://www.micyrn.ca/PDF/ReportontheStateofCancerClinicalTrialsInCanada.pdf. Last accessed September 19, 2013.  23 Health Canada Guidance Document: Clinical Trials.  http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/clini/cta_background-eng.php.  Accessed June 29, 2013.   For more information, see also Friedman et al. (2010).  24 Copyright International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).  This figure is copied directly from the ICH-E8 guideline, General Considerations for Clinical Trials, p.5.   14  are the main point in which therapeutic aspects of the drug are being confirmed, this process evolves out of the therapeutic exploratory stage (phase II) and continues through to phase IV.  Figure 2.1: Phases of Clinical Trials Recalling the dramatic figures outlined above in relation to the cost of studies, it is also worth highlighting that not all compounds or products that start the clinical testing process will proceed through all stages.  In fact, the attrition rate from pre-clinical phases to market is quite astounding.  As described by Rx&D (the industry association representing research based pharmaceutical and biotechnology companies in Canada), for every 250 compounds that go through preclinical testing, 5 will enter the clinical testing phase.  From those 5, only 1 will ultimately be approved.  Figure 2.2 helps illustrate the attrition process, as well as the time and number of subjects typically involved in each phase.25                                                         25 Used with permission from Canada?s Research Based Pharmaceutical Companies (Rx&D).  Available at: http://www.canadapharma.org/en/our-industry/industry-facts/saving-lives---transforming-care/info-graphics  15  Figure 2.2: Cost of Drug Discovery and Development  For all phase I-III clinical trials, the sponsor must submit a clinical trial application to Health Canada (this is not a requirement for phase IV studies).  While the legal and ethical frameworks for the oversight of clinical trials will be described in great detail in Chapter 7, it is helpful here to just very briefly introduce the key documents. Health Canada?s authority to regulate clinical trials and approve new drugs in Canada is established in the Food and Drugs Act (?the Act?), and further described in its Division 5 Regulations (Drugs for Clinical Trials Involving Human Subjects, hereinafter ?the Regulations?)26.  In addition, Health Canada has adopted the ICH-Good Clinical Practice (GCP) Guidelines as a guidance document.27 The guidelines constitute an international standard for the ethical and scientific conduct of clinical trials, providing principles and practices related to the protection of clinical trial subjects rooted in the Declaration of Helsinki28, as well as standards to ensure the integrity and reliability of                                                  26 Food and Drugs Act, R.S.C. 1985, c. F-27; Division 5 Regulations C.R.C., c. 870 27 These are the Guidelines for Good Clinical Practice established by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH-GCP), E6 (R1), June 10, 1996. 28 It is important to note that while the ICH-GCP Guidelines may be rooted in the Declaration of Helsinki, the extent to which they are ethical documents is limited (Goodyear et al, 2009; 16  clinical trial data. Whereas the Division 5 Regulations outline sponsor responsibilities, the GCP Guidelines describe the roles and responsibilities of other key parties including the CRO, the Monitor, the PI and the REB.  The Regulations and GCP Guidelines apply to all clinical trials in Canada, regardless of whether they are industry or investigator-initiated.  Finally, the standards established for the ethical conduct of research by the Tri-Council Policy Statement 2 (TCPS2)29 apply to all clinical trials funded in whole or in part by one of the three federal funders (CIHR, SSHRC, NSERC), or which studies take place in whole or in part at institutions receiving such funding.  The principles and standards of the entire document apply to clinical trials; however, Chapter 11 also addresses considerations specifically relevant to clinical trials. While not an exhaustive list30, taken together these legislative documents and guidelines constitute the mainframe of the legal framework governing clinical trials in Canada.  2.3 Clinical Trials In Canada: Feeling The Pinch Although clinical trials are perhaps most often thought of in a health context, and while some have profound implications for the health and wellbeing of Canadians31, they are also extremely important economically.  For example, and as illustrated by Figure 2.332, the activities of Canada?s Research Based Pharmaceutical Companies alone contribute over $3 billion to the                                                                                                                                                              Kimmelman et al, 2011). Moreover, whereas the ICH Guidelines are the product of a small group of voting members, the Declaration of Helsinki is developed by a much larger and more representative group.  These issues are discussed further in chapters 7 and 9.  29 Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada, Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, December 2010.  30 For example, other relevant aspects include privacy legislation and consent legislation (among others) that address the research context within a broader focus.  31Not all clinical trials are created equal. As will be discussed further in Chapter 9, critics point out that some trials (both phase IV and earlier) are much more about furthering a sponsor?s economic interests than they are about bringing new or improved health benefits. For example, one recent report suggests that 77 out of the 109 newly patented drugs in Canada in 2011 offered ?little or no therapeutic benefit? over current therapies. (PMPRB, 2011; Gagnon, 2012) 32 Figure copyrighted to Canada?s Research-Based Pharmaceutical Companies (Rx&D).  Used with permission (granted September 3, 2013).  17  Canadian economy each year, from research and development spending to direct employment and contributing to the creation of additional jobs across the country.33  Figure 2.3: Economic Impact of Rx&D Companies  However, Canada has been impacted by the hard times hitting the pharmaceutical industry, with industry investments in Canada decreasing since 2008. Whereas total investment                                                  33 According to a 2013 report by KPMG (SECOR-KPMG analysis of simulations by Statistics Canada based on internal data provided by Rx&D) Rx& D and its members contributes $1.08 billion to Research and Development in Canada, which translates into contributions of more than $3 billion to the Canadian economy ? $2 billion directly and $1 billion indirectly.  The report finds, for example, that the research based pharmaceutical industry supports 46,000 full time jobs across Canada. KPMG (2013). Summary of 2012 R&D Spending and Investments by Rx&D Members Available at: http://www.canadapharma.org/CMFiles/Media%20Centre/News%20Releases%20and%20Statements/20130514_KPMG_Summary_2012_Spending_Investments_EN.PDF. Accessed September 13, 2013.  18  by patentees in 2007 was $1.32 billion, this same group invested $991.7 million in 2011, a decrease of 15.8% over 2010.   Of this $991.7 million, $525.1 million went to applied research, of which 75.2% was allotted to clinical trials.34    While clearly an important economic driver in the Canadian economy, Canada?s share of the overall pharmaceutical research and development market is quite small.  By way of illustration, the map below (Figure 2.4) shows the global distribution of all clinical trials listed in the clinicaltrials.gov database.35  As can be seen, Canada hosts only a small fraction (11322 of 151261-or about 7%) of such trials.  The U.S. holds the largest share (71147, or approximately 47%).  According to these figures, in terms of countries Canada actually places second behind the U.S., with Germany following in third place with about 6.9%. Within Canada, the bulk of the clinical trial activity is in Ontario (7099) and Quebec (4183) with only 2950 taking place in British Columbia.  This echoes findings from the 2011 annual report of the Patented Medicines Prices Review Board (PMPRB) which indicates that Ontario and Quebec account for 86% of total pharmaceutical R&D expenditure, with the western provinces accounting for just 12.6 % of total R&D expenditure.36                                                            34 PMPRB Annual Report (2011). Available at:  http://www.pmprb-cepmb.gc.ca/english/view.asp?x=1625&mid=1552. Last accessed September 19, 2013.  35 Clinicaltrials.gov. Available: http://clinicaltrials.gov/ct2/search/map?map=NA%3ACA 36 PMPRB Annual Report (2011): http://www.pmprbcepmb.gc.ca/english/view.asp?x=1625&mid=1552. Last accessed September 12, 2013.   19  Figure 2.4: Global Distribution of Clinical Trials    Given the significant implications and potential benefits for both the health and prosperity of the country, it is no wonder that there has been a great deal of interest and attention paid to reports that Canada?s share of clinical trials is in fact dropping (Saryeddine et al., 201137) and that the competition for industry dollars is getting more fierce as industry sponsors reap the benefits of hosting their trials in developing countries with their dense, often treatment na?ve populations, lower costs, and in many cases lighter regulatory requirements (Saryeddine et al., 2011; Schipper et al., 2011). The President of Rx&D noted in June 2012, that  international competition for research dollars is fierce and it has become more and more difficult for Canadian CEOs to win global investments for Canada? Without question, we must attract more international investment ? a larger share of the $110 billion being invested by our global companies annually.38                                                   37 This is the background document (Canadian Clinical Trial Summit: Starting the Conversation) from the Clinical Trial Summit hosted by Canada?s Research Based Pharmaceutical Companies (Rx&D), Canadian Institutes of Health Research (CIHR) and the Association of Canadian Academic Healthcare Organizations (ACAHO) on September 15, 2011 in Ottawa.  A number of examples of initiatives that were underway at the time of the summit are listed by province.  The report is available at: http://www.acaho.org/?policy_2011. Last accessed September 12, 2013. 38 Comments made by Mr. Russell Williams, president of Rx&D, June 12, 2012. http://www.canadapharma.org/editorletters.asp?a=view&id=3.  20   Canada?s concern about regaining and growing its share of the clinical trial market was also clear at the clinical trial summit held in Ottawa in September 15, 2011.  As reported by Vanderwel (2012), Health Canada data on the decline in the number of clinical trials in Canada were presented by Rx&D, CIHR and ACAHO.  These three orgs believed that while patients are available in Canada to be enrolled in trials, the cost/performance, operational environment and recruitment reliability are seen as areas in which Canada has ?lost our edge??.A call was made to improve the research infrastructure to maintain Canada?s attractiveness for fast, efficient and reliable research. (p.17) Fewer industry dollars for pharmaceutical research and development affects not only research and clinical trials directly funded by industry, but also has a huge impact on grant funded or investigator-initiated trials since these too are partially supported by industry through fees charged by research institutions as well as through financial and in kind contributions, university chair endowments, charitable donations, grants or sponsorships (Vanderwel, 2012).  As such, it is not surprising that this sense of urgency to regain and grow the contract (i.e., industry sponsored) clinical trial industry in Canada is being felt and broadcasted not just by industry organizations, but also by federal and provincial regulators, federal and provincial research funders, academic institutions, private or community research units and sites, and others.39   2.4 Keeping Canada On The Map: Initiatives To Attract Clinical Trials A wide variety of national and provincial initiatives and networks are being undertaken to try to make Canada a more inviting place in which to conduct trials?these include (among others) efforts to harmonize the ethics review process, to improve infrastructure and streamline regulatory requirements and develop and share tools, training opportunities and best practices to enhance Canada?s research capacity (Rx&D et al., 2012a; Saryeddine et al., 2011). Health Canada for example has made changes to the regulatory framework under the Food and Drugs Act and Division 5 Regulations.  These changes are discussed in Chapter 7, but include (among                                                                                                                                                               39 As discussed further in chapter 9, it is important to note that the vast majority of drugs tested in clinical trials will not offer much in terms of improved therapeutic benefit. As such, the main value of these trials is to the pharmaceutical companies, in terms of being able to get their new drugs onto the market.  21  other things) faster review times and penalties for the regulator for failure to meet those review times.40   Other national level initiatives include the Network of Networks (N2), which creates networks and connections between existing disease networks, universities, institutions, sponsors and other stakeholders specifically to enhance Canada?s research capability and capacity.41 CIHR?s Strategy for Patient-Oriented Research (SPOR) is another national level effort to build capacity and also to: (a) establish an integrated, leading edge, pan-Canadian clinical research infrastructure along the full continuum of patient-oriented research; and  (b) to strengthen organizational, regulatory and financial support for clinical studies in Canada and enhance patient and clinician engagement in these studies.42   While not directly geared at attracting industry clinical trials, making Canada more competitive and attractive to industry partners to support the commercialization of research is certainly among its explicitly stated goals.43 There are also a wide variety of provincial initiatives underway across the country to entice industry sponsors.  In British Columbia, for example, the BC Clinical Research Infrastructure Network (BCCRIN) is a major collaboration between provincial health authorities, research institutions, universities, industry associations and funding agencies to help increase B.C.?s competitiveness in the global clinical trials market.44 As explicitly stated on their website, BCCRIN was formed in direct response to the decreasing numbers of industry sponsored clinical trials coming to Canada and declining levels of government support for clinical research in                                                  40 The penalties for failure to meet the review times were implemented in 2004 and are outlined in the User Fees Act (S.C. 2004, c. 6).  These and other changes and associated concerns are discussed in Chapter 7.   41 For more information on N2, please see: http://n2canada.ca/ (last accessed September 12, 2013).  42 Please see CIHR?s description of this important national level initiative at: http://www.cihr-irsc.gc.ca/e/44000.html  43 As is discussed in more detail in chapter 7, the ever increasing commercialization of research has a number of important implications at a global level, not the least of which is a lack of attention to, and prioritization of, global health inequality and much needed health policy and systems research. See for example, Pratt & Loff (2012) and McDonald & Preto (2011).  44 As described on the BC CRIN website, available at: http://www.bccrin.ca/what-were-about/.  22  B.C.45 While still relatively new (launched in 2010), a broad range of important initiatives are well underway and include, among others, capacity building and training efforts, patient recruitment efforts (including research participant survey to identify relevant factors influencing decisions regarding research participation), contract and tool development, and business development.   Another important initiative in this province is the BC Ethics Harmonization Initiative (BCEHI), funded and facilitated by the Michael Smith Foundation for Health Research (MSFHR)46. The initiative involves BC?s six provincial health authorities and four major research universities (University of British Columbia, Simon Fraser University, University of Victoria, University of Northern British Columbia). Also running since 2010, the goal is to improve BC?s attractiveness as a location for multi-site, multi-region health research (including clinical trials) by streamlining ethics review processes and reducing duplication.  Lack of REB standardization, accreditation and transparency?problems that have been discussed in detail elsewhere and which suffer from a profound lack of national level leadership in Canada?are among the hurdles this initiative needs to overcome (Glass, 2006; Hebert & Saginur, 2009; McDonald, 2000; McDonald et al., 2011).  An important, though preliminary, milestone in this effort was achieved in May 2013 when an agreement was reached granting the 14 review boards under the jurisdiction of the various BCEHI collaborators authority to work together to develop processes by which to streamline ethics review between participating institutions.47 Whether and how this agreement leads to the hoped for results remains to be seen.  Perhaps one of the most comprehensive and multifaceted provincial initiatives is Clinical Trials Ontario, which aims ?to make Ontario a preferred location for global clinical trials, while maintaining the highest ethical standards.? As indicated on their website, this is an integral part of Ontario?s Life Sciences Commercialization Strategy and has been allocated a 3-year commitment from the Ministry of Economic Development and Innovation with an annual budget of $1.5 million. Key partners providing input and additional support are drawn from the                                                  45 BC CRIN Website: http://www.bccrin.ca/who-we-are/ Last accessed September 1, 2013.  46See the BCEHI website at: http://www.msfhr.org/our-work/activities/bc-ethics-harmonization-initiative. Last Accessed September 12, 2013.   47 Ibid. 23  provincial community of stakeholders involved in clinical trials in Ontario from the public and private sectors.48 The main goals of this initiative, which launched in 2012, are threefold: to reduce time and cost of conducting trials in Ontario by harmonizing the ethics review and other administrative processes; grow strategic partnerships with and between investigators, industry and government to attract clinical trial investment to Ontario; and to engage patients and the public to recognize the benefits of clinical trials for their own health and that of their families and society and to improve recruitment through education.49 The above is just a sample of some of the many initiatives currently underway to help promote Canada to industry as an attractive place to conduct clinical trials.  A relatively brief review of the literature did not yield many academic critiques of these various efforts-either individually or collectively.  However, Vanderwel (2012) in her report to Health Canada entitled International and Canadian Activities Related to the Ethical Review of Clinical Trials does provide an overview of national and provincial efforts in this regard and offers a few observations in relation thereto. Many of her comments address the important issues and concerns raised by others (Anderson et al., 2011; McDonald, 2000; McDonald 2001) that ethics review, oversight and accreditation efforts still tend to be too narrowly limited to the research ethics board instead of adopting a broader, system wide approach.  More specifically related to the efforts to attract clinical trials to Canada, she observed an important disconnect; that is, that while most efforts currently underway target the streamlining and harmonization of activities and structures for research taking place within academic or public institutions?the vast majority (65-75%) of clinical trials are taking place in private or community based settings. One aspect of this is that, as Vanderwel notes (and as echoed by some of my participants) community based sites have strengths and successes that public sites could perhaps learn from. However, this also raises the question as to whether private, community based sites as a group are being overlooked in                                                  48 The website (http://www.ctontario.ca/) lists the following partners: 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. 49 In addition to the examples described in the text above, another important effort includes the Ontario Cancer Research Ethics Board that functions as a single REB in that province to facilitate scientific and ethical review of multi-centre oncology trials.  24  other kinds of ways too-in terms of oversight, for example. Some of the challenges and weaknesses of the Canadian approach to clinical trial oversight are discussed in Chapter 7.   As suggested earlier, however, it is not just Canada?s share of the market pie that is shrinking?the pie itself is getting smaller (Vanderwel, 2012).  In order to stay competitive in these circumstances, the pharmaceutical industry has undergone some profound changes in the last 3 decades.  These changes include, among others, transitioning away from working closely with academic institutions for the design and conduct of clinical trials to a heavy reliance on a variety of private sector service providers, including contract research organizations (CROs).  This transition is described in more detail below.  2.5 Structure Of The Clinical Trials Industry  Prior to the 1980s, ?industry grants to academic institutions to fund studies by faculty members gave investigators total responsibility? (Angell, 2008), including control over study design, data collection, analysis, and reporting of results.  Since the 1980s, a number of factors have come together to create a very different reality, and have lead to a dramatic increase in the overall level of industry control and influence over the drug discovery and development processes (Angell, 2008; Krimsky, 2003; Lemmens & Bouchard, 2007; Lenzer, 2008; Mirowski & Van Horne, 2005).  A key factor in this shift has been an increased reliance on industry funding and a blurring of boundaries between the public and private sectors in the scientific enterprise. As has been discussed in the extensive literature on the commercialization of science, this process began in earnest in the economy of the 1980s when many countries including the U.S., the UK and Canada instituted major budget cuts for public services, including universities (Brown, 2002).  In addition to cutting funding support, various governments also introduced incentives to bring industry and academia into closer contact.  For example, in the American context, the passage of the Bayh-Dole Act in 1980 is widely recognized as a primary cause of the commercialization of medical research in the U.S. (Lemmens, 2004; 2004a).  By allowing universities and researchers to obtain patents on the results of their publicly funded research, this legislation encouraged academics to enter into relationships with industry to help them develop commercial applications for their discoveries (Krimsky, 2003; Lemmens, 2004, 2004a).  Around this same time period, the pharmaceutical industry was experiencing significant growth with the development of blockbuster drugs for a wide range of diseases and disorders. With profits in the 25  billions, the pharmaceutical industry?s sphere of influence and incentive to exercise such influence, increased dramatically (Lemmens, 2004a).   Although the industry sphere of influence was growing in leaps and bounds through the 1980s and early 1990s, the bulk of industry dollars for clinical research were still going to academic health centers (AHCs) (CenterWatch, 2008; Gelijns & Thier, 2002; Mirowski & Van Horne, 2005; Rettig, 2000). This started to shift significantly in the mid-late 1990s.   Some statistics indicate that academia?s share of industry sponsored clinical research went from 80% in 1988 to 40% in 1998.  Other statistics suggest that the AHCs share of the industry clinical trials market fell from 71% in 1991 to 23% in 2006 (CenterWatch, 2008; Mirowski & Van Horne, 2005).  As one industry analyst notes, Up until the early 1990s, academic medical centers (AMCs) were the primary and predominant home of industry sponsored clinical trials.  As these programs became larger and more complex and costly, industry sponsors grew tired of the inherent inefficiencies in working with academia, including protracted contractual and budget negotiations, bureaucratic and slow moving institutional review boards (IRBs), and higher relative costs associated with poorer performance.? (Getz, 2007a)  As will be described below, a range of for profit auxiliary service providers?dominated by the contract research organization (CRO)?picked up the slack created by industry?s dissatisfaction with their academic partners.  Hence, ?in a trend that has received surprisingly little attention, contract research organizations have gradually taken over much of academia?s traditional role in drug development over the past decade? (Shuchman, 2007).   The shift away from academia has taken place in at least two different ways.  First, and as illustrated above, there has been an exodus of clinical trials being conducted in academic sites in favor of private community based sites.  Approximately 80% of all clinical drug trials in Canada are funded by industry (Lexchin, 2012) and roughly 2/3 or almost 70% of clinical trials in Canada now take place in the community at privately owned and operated facilities, as opposed to academic sites or hospital settings (Ogilvie, 2012).50  However, not all clinical trials can be                                                  50This is the report by the Standing Senate Committee on Social Affairs, Science and Technology (2012). Canada?s Clinical Trial Infrastructure: A Prescription for Improved Access to New Medicines.  This report can be downloaded at: www.senate-senat.ca/social.asp. Last accessed September 12, 2013.  26  conducted in the community51 and yet even for those clinical trials that take place in the academic setting, there has been a shift in the locus of control. Whereas academic investigators used to have significant control over the trials with which they were involved, they are now much more likely to simply be collecting data and, as others have described, ?at the extreme?have become little more than hired hands, supplying patients and collecting data according to the company protocol.? (Angell, 2008) Control over the design, management, trial conduct, results reporting and other key aspects, has been transferred from academics to CROs.  Hence, even those industry-initiated52 trials that still take place in academia are largely out of the hands of the investigators. 2.6 Outsourcing In The Pharmaceutical Industry It is worth noting that industry sponsors might have decided to (more or less) abandon academia in favor of a more in-house approach wherein the individual pharmaceutical companies would assume responsibility for (e.g.,) design and conduct of clinical trials required to test and develop their products.  However, as the pharmaceutical industry was looking for more attractive alternatives to their relationship with academia, there was also a larger trend in the broader business community towards outsourcing, which has seen the large, diversified ?mega-corp? being replaced by  an organizational form in which a nucleus of ?core? activities is performed permanently in-house by full time employees, the rest being supplied through contract with other organizations or individuals. Its hallmark is a relatively narrow focus?concentrating on activities in which it believes it has a distinct advantage, or that are essential to its competitive survival. (Domberger, 1998, p.18)   In very general terms, the goal of outsourcing is to support the ?enhancement of the financial performance? (Nichol, 2006, p.409) of the outsourcing company.  Outsourcing is today                                                  51 For example, some clinical trials target diseases or conditions which are commonly treated in an academic and/or large tertiary care setting.  52As described previously, academic investigators tend to conduct a combination of industry-initiated trials (i.e., trials that are funded, designed, controlled by industry) and investigator-initiated trials, wherein the investigator designs and controls all aspects of the study.  Such studies are funded by a variety of sources-government, not for profit organizations, and are also frequently funded in whole or in part by the pharmaceutical industry.  27  considered by pharmaceutical companies to be ?strategically critical to their long-term viability? (Getz, 2012).  2.6.1 Outsourcing In The Pharmaceutical Industry: Drivers There is no question that the Contract Research Organization (CRO) industry has grown up fast. Revenues of about $50 million in the late 1970s have advanced to about $10 billion [in 2004] alone?the size of the outsourcing market to CROs is continuing to rise. By any measure we are a healthy, growing industry that has a significant role in the drug development process. (Gillings, 2004, p.6)   Nine years later, this statement is just as accurate.  While figures vary quite widely in terms of assessing the size of the global CRO market (Getz et al., 2012), some estimates put the worldwide CRO market at $37.4 billion in 2013.53 Other assessments looking specifically at the U.S. pharmaceutical contract services market valued it at $39.5 billion USD, with 16% ($6.5 billion) of that attributed to clinical research services (Getz et al., 2012). In terms of numbers, 3244 individual contract research organizations were identified as functioning in the U.S. across the entire range of services related to the pharmaceutical industry, with a sub total of 643 being active in clinical research (Getz et al., 2012).  As others have noted, ?there is no doubt that pharmaceutical R&D outsourcing is big business? (Scott, 2008). Despite the prominence of the CRO, it has been noted by Mirowski & Van Horne (2005), that apart from some scattered comments in industry literature and some aggregate industry data, it is extremely difficult to get information about the history of their development and evolution.  One source puts the origins of the first commercial contract services provider in this industry around 1975 (Nichol, 2006). Another source claims that generally speaking, the CRO did not exist before 1980, and observes that,  of the four largest pharmaceutical CROs, Quintiles Transnational was incorporated in 1982, and Parexel International was founded in 1983.  Covance was formed in 1987?CROs differ profoundly from earlier for-profit toxicology, bioassay and pharmaceutical testing firms, which they have tended to drive out of business.?  (Mirowski & Van Horne, 2005, p.538 (fn 5))                                                   53 Association of Clinical Research Organizations (CRO Market), available at: http://www.acrohealth.org/cro-market1.html. Accessed September 12, 2013. 28  What history is available suggests that CROs have arisen at least in part in response to increasingly stringent regulatory requirements around the drug development process that date back to the Thalidomide controversy and resulting legislative amendments.  In the U.S., these were the 1962 Kefauver-Harris Amendments under the Federal Food Drug and Cosmetic Act (1938), through which the FDA exercised their jurisdiction and set the standards and format of drug testing from the pre-clinical stage through to final human clinical trials (Lemmens & Bouchard, 2007; Mirowski & Van Horne, 2005).  Under the new regulations, drug companies had to demonstrate both the safety and efficacy of a drug before marketing it, and the standards set out ultimately shaped accepted international standards (Nichol, 2006).  CROs emerged, at least in part, as a result of the increased regulatory stringency and regulatory requirements that demanded more and higher quality data to support new drug applications (Thomis & Desai, 2006). Another driver of the outsourcing trend is simply the need for speed in the drug development process.  The development of a new drug is a lengthy (6-10 years)54, expensive process with estimates of the associated cost ranging from $200 million to $1.9 billion.55  Moreover, the cost of every day of delay in getting a drug approved has been quoted at $1.3 million (Brody, 2007).  Reducing the time that it takes to get a drug through the various development stages is a key factor in reducing overall costs, and allowing maximum realization of profits.  The patent protection system is a critical factor in this regard.  While a detailed exploration of the patent considerations in the drug development process exceeds the scope of this dissertation, it is important to recognize that the time of market exclusivity from the time a drug is admitted to market (known as the effective patent life (EPL)) is central to a company?s ability to recover costs and make a profit on the substantial R&D investments that go into drug                                                  54 PhRMA (2013) Industry Profile, available at: http://phrma.org/sites/default/files/pdf/PhRMA%20Profile%202013.pdf .  See also CenterWatch, State of Clinical Trials Industry (2008).  55 http://www.fiercebiotech.com/story/economists-cite-soaring-costs-behind-average-19b-price-tag-drug-rd/2012-12-03?utm_medium=nl&utm_source=internal.  It is difficult to get reliable numbers in terms of costs in this industry.  For a good discussion on this point, see Collier (2009).  29  innovation.  Given that the life of the patent is generally 20 years56, and that the drug development process from the time the patent is filed can take more than 10 years, in effect the EPL is generally about 10 years in the Canadian context (Grootendorst, 2007).  To address this shortfall, some jurisdictions such as the United States, the European Community and Japan, have implemented ?patent term restoration? legislation.57  As has been noted elsewhere, the very purpose of the CRO in clinical trials is to speed up the process (Wadman, 2006) and they are apparently effective in this regard. According to one independent analyst, ?clinical trials conducted by CROs are completed an average of 30 percent more quickly than those conducted in-house.  This results in an average time savings of some four or five months, translating to $120 million to $150 million in increased revenue potential.?58  However, while a key factor encouraging outsourcing is certainly the potential for increased speed, and while in some ways, this consideration underlies most of the other factors, there are other considerations.  For example, outsourcing also can be an effective way of easily increasing or decreasing capacity while maintaining constant levels of personnel and overhead in-house.  This can be particularly important in smaller companies that are moving into new areas of specialty or biotechnology firms who find themselves at the point of needing to conduct clinical research (Getz et al., 2012; O?Donnell, 2007).  Instead of developing the skill sets and infrastructure necessary to do this, they can instead choose to contract this out to others specializing in these areas (Getz et al., 2012; Rettig, 2000).  Globalization also supports the move towards outsourcing to international CROs that are more familiar with the regulations and                                                  56 Pursuant to the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), patent life for any product is 20 years from the date that a patent application is filed in all World Trade Organization member countries.  57 As explained by Grabowski (2006), in the U.S. the Drug Price Competition and Patent Term Restoration Act (Public Law 98-417, otherwise known as the Hatch-Waxman Act) was passed in 1984.  This essentially makes it possible to seek patent extensions for up to 5 years over the normal 20 year patent lifespan; however, the total patent life for the product in question cannot exceed 14 years from the product?s approval date.  58 This information is from the Association for Clinical Research Organizations (ACRO) website at http://www.acrohealth.org/industry-ataglance.php. The quote is attributed to KMR Group, Inc., a management consulting firm specializing in resource management, benchmarking, process analysis and decision making for the pharmaceutical industry.  As explained on the ACRO site, the ?quoted profits are based on market expectation that an average product generates $1 million in revenues per day: PAREXEL?s Pharmaceutical R&D Statistical Sourcebook 2004/2005.? 30  requirements of emerging markets (Schipper et al., 2011; Thiers et al., 2008).   Having an understanding of the locale within which a trial is situated can be critical for ensuring it runs as smoothly and efficiently as possible.  Moreover, the international CROs can often address regulatory and other requirements in multiple jurisdictions effectively and efficiently (Getz, 2007b; Rainville, 2002; Rettig, 2000; Schipper et al., 2011).  In addition, sponsors are increasingly looking to run early phase clinical trials (Phase I/IIa) in special populations in order to make quicker go/no go decisions thereby saving significant time and resources by avoiding going too far down an ultimately unsuccessful path.59  As such, it is beneficial to sponsors to be able to draw on CROs that have access or databanks of special patient populations and particular expertise in a range of relevant therapeutic areas in all phases of clinical trials (Rettig, 2000).  Not unreasonably, some commentators have also opined that in the 1980s and 1990s there was ?a growing hostility of the FDA towards free-market pharmaceutical manufacturers...[and that] the use of contract researchers seem[ed] to enhance FDA?s perception of the objectivity of a trial? (Olmstead, 1992).  However, this claim that outsourcing was in part an effort to insulate pharmaceutical companies from the conduct of the clinical trial process, and thereby mitigate, or appear to mitigate, conflicts of interest, is not unchallenged.  Azoulay (2003), for example, rightly indicates that CROs do not shift the locus of responsibility for trial integrity away from the sponsor.  Azoulay (2003) also points to the fact that pharmaceutical sponsors do not seem to appeal to the mitigation of conflicts of interest as a rationale for their decision to outsource, and the fact that FDA medical examiners reviewing trial data are often unaware of whether a study they are reviewing has been outsourced. For these reasons, Azoulay (2003) concludes that mitigating real and apparent conflicts of interest was not a driving force for outsourcing in the pharmaceutical context, but that this move was much more about work-force cohesion and bottom-line considerations. Finally, outsourcing to CROs also allows the sponsoring companies to maintain greater control over clinical trial data.  Unlike academic investigators, CROs are not interested in publishing and therefore do not make any demands on their clients to release data in a timely fashion or at all (Mirowski & Van Horne, 2005).                                                   59 This is alluded to in the marketing materials for Quintiles International that I received at a conference in 2009.  31  2.6.2 Outsourcing In The Pharmaceutical Industry: The Cast For all the reasons discussed above, the contract research industry has become a key resource for pharmaceutical companies in their efforts to trim costs, speed up drug development and maximize available profits.  A wide range of ?auxiliary agents? have emerged ?to mitigate pharmaceutical companies? losses from R&D development? (Fisher, 2009, p.8). These include among others investigational sites, site management organizations (SMOs), contract research organizations, academic research organizations and private research ethics boards.60 While the dominant player, and often responsible for engaging, coordinating and monitoring the activities of the others, CROs are only one part of this larger industry. Although sponsors typically rely heavily on CROs (Getz, 2012), CROs are not involved in all clinical trials and sponsors may only delegate some subset of their responsibilities.  It is impossible to capture the nuances in these relationships without a specific example; however, figure 2.5 illustrates in general terms the relationships and lines of communication in an industry-sponsored clinical trial wherein the CRO has been delegated all of the sponsor?s clinical trial responsibilities.   As explained by Mello & Joffe (2003), the study protocol is typically part of the clinical trial agreement (denoted by purple line below), which delineates the scope of work for the investigative sites. The list of entities in the bracket on the right represent a selection of other outsourced service providers that may also be contracted by either the sponsor or CRO.                                                     60 Fisher (2009) provides a helpful discussion of the various ?auxiliary agents? and their relative place on the contract research organizational hierarchy, and I have drawn on her work here.  In addition to the parties discussed above, she also mentions more peripheral service providers such as study brokers, clinical advertising agencies, and central patient recruitment companies.  Of these more secondary service providers, the patient recruitment organizations are most relevant to our discussion and could be considered a niche service CRO. One example of such an organization is HCG (Health Care Communications Group), who specifically state they ?[have] one specialty?professional clinical trials recruitment services. We help pharmaceutical companies involved in drug development build their subject recruitment plans upon a foundation that will enroll and retain patients in Phase II - IV research studies.? http://www.hcg.com/default.asp While there are such niche service providers, patient recruitment is a service that is also a staple offering of the full service CROs.  32  Figure 2.5: Key Relationships in a Clinical Trial Involving a CRO  2.6.2.1 Investigative Sites Fisher (2009) describes a contract research industry hierarchy in which the investigative site is placed at the base as ?the most basic level organization?(p.9).  Investigative sites are companies or clinics that conduct studies through contracts with pharmaceutical companies or CROs.  These can be located in a wide range of settings, from large academic health centers and 33  teaching hospitals, to community research institutions to smaller community health clinics and physician practices (Fisher, 2009). In each domain, sites may be more or less sophisticated or structured, be more or less well integrated with the clinical practices that are often run out of the same space and provide access to at least some of the study subject population, and have access to more or less external research support.   In many instances, the (largely U.S. based) literature tends to describe a dichotomy between academic and community based sites; however, in the context of the Canadian publicly funded health care system, it is perhaps clearer to describe sites as falling inside or outside the public system.61  For example, according to the 2011 Clinical Trials and Preclinical Infrastructure Asset Map published by Genome B.C.,62 there are at least 59 clinical trials units (CTUs), centres and study sites across 5 of the 6 health authorities in B.C. (the 6th health authority, Northern Health does not yet conduct clinical trials).  The asset map identifies a range of levels of infrastructure within the sites it lists. 63  For example, some sites are identified as clinical trial units or centres, which the report defines as ?a cohesive entity with dedicated study nurses and data managers. It acts as an independent management unit even if it has no dedicated space.? In addition to investigators and staff, such units also offer ?quality control/assurance procedures, of which Standard Operating Procedures (SOPs) and Good Clinical Practice (GCP) regulations and guidelines provide an integral part? and a variety of administrative support                                                  61 As noted in the glossary at the start of this dissertation, for the purposes of this document I use academic and public interchangeably; likewise, sites not falling into the public/academic category are identified interchangeably as ?private?, ?community?, ?independent? or ?non-academic?.  62 As will be described in the next chapter and Chapter 9, while B.C. is a distant third to Ontario and Quebec in terms of clinical trial activity, this research study looks at the Canadian clinical trials industry through a B.C. lens.  For example, many of my participants in the qualitative interview study were located in B.C., and my first hand exposure to the industry has really been limited to this province.  That being said, I have attended industry conferences in other parts of the country and a number of my participants brought a more trans Canadian perspective to their interviews as a result of having had experience working in other provinces.  63 As noted by Genome B.C., ?the CTUs, centres, and study sites included here are probably not all-inclusive. The listings contain only those facilities that the authors were able to discover through extensive searches and discussions with hospital and health authority personnel.? In fact, they also specify that this number (59) does not include individual physicians conducting clinical trials out of some of the smaller regional hospitals?even though they list some of these investigators in an appendix to their report.    34  including contract services, budget negotiations, accounting, REB submissions, and regulatory requirements among others. 64   Other sites, while not qualifying as units or centres, still ?employ study nurses or coordinators? and many can access additional support from the appropriate Clinical Trials Support Unit (?CTSU?), though access and available services vary across health authorities.65  CTSUs in turn offer a range of services, which generally include assistance with study design, methodology and protocol development, budget planning, REB submissions, regulatory documentation and training in clinical trials procedures and Good Clinical Practices, among others.66 In addition, the report notes that some of the province?s smaller hospitals also have individual investigators who perform clinical trials, but does not indicate whether they have research staff or support available to them.67 Hence, within the context of public sites?across universities, large academic hospitals, smaller community hospitals, and other medical units within the various health authorities?there are numerous investigative sites of varying degrees of structural complexity and infrastructure.  In addition to the sites working within the public system, the Genome B.C. asset map reports that there are also at least 25 independent organizations that provide a range of clinical trial support services, including at least 8 for-profit independent investigative sites working outside the public system, 5 of which are disease-specific (cancer, urology, endocrinology, gastrointestinal, and cardiology).68  Extrapolating from the U.S. literature (Fisher, 2009; IOM, 2012) and the data from the present study, the variation in terms of site infrastructure                                                  64Genome B.C. Asset Map, p. 7. 65 For example, a review of the report suggests that investigators who are in Interior Health do not have access to a formal Clinical Trial Support Unit.  66 For a full list of the services provided, please see: Clinical Trials and Preclinical Infrastructure - Asset Map, available at: http://www.genomebc.ca/profile/publications/asset-maps/  67 It seems reasonable to assume, however, that while some of these investigators would have some level of support or research staff, others likely do not.  Again, depending on where they are located, these investigators would also have varying levels of access to services provided by Clinical Trial Support Units. 68 The 17 other for-profit organizations offer clinical trial support across a variety of services, including among others: a few CROs, one for profit REB and a range of analytic and preclinical service providers.  As previously noted, there are undoubtedly many other investigators participating in clinical trials out of their private offices and/or small regional hospitals who have not been counted.  35  and sophistication in terms of research readiness and support also varies significantly within the private context.   Much as the less sophisticated sites within the public domain can sometimes seek support or assistance from the Clinical Trial Support Units, sites working within the private sector may have the option of working with a Site Management Organization (described later in this section), to gain access to additional support including training, staffing and regulatory assistance among other services.  An important distinction between the public and private sites is in relation to research ethics review.  Whereas clinical trials taking place at investigative sites that are part of the public system must be approved by the appropriate institutional research ethics board (there are 23 in B.C.) private investigative sites may use private research ethics boards.  The use of centralized or private research ethics review is a significantly faster and more streamlined process than the institutional review board reviews and provides the industry sponsor or CRO much greater control and predictability in terms of timeline for approval.  As such, whether or not a site is free to use a private REB can often be an important consideration for industry sponsors or CROs in the site recruitment process.69 Concerns and challenges associated with both commercial and institutional research ethics boards are discussed later in this chapter (2.9.11), as well as in Chapter 7.  2.6.2.2 Site Personnel The investigative site is the key point of interaction between human subjects and the study.  It is the place where the study procedures occur and data is collected and reported. The key personnel at investigative sites include a single Qualified or Principal Investigator (PI) for the site, who by Canadian law must be a physician for all clinical drug trials70, and a study coordinator (or Clinical Research Coordinator (CRC)).  2.6.2.2.1 Qualified/Principal Investigator (QI/PI) The PI is the individual responsible for the conduct of the clinical trial at the investigative site.  He or she is also responsible for ensuring that the data that is ultimately reported back to the                                                  69 It is important to clarify that where an independent site needs to access hospital services as part of the clinical trial (for example, for surgical services or imaging services) then the research will have to be approved by the institutional REB.   70 This is the case, except where the drug in question is to be used for dental purposes only, when the PI can be a dentist. (Division 5 Regulations, pursuant to the Food and Drugs Act) 36  study sponsor is accurate (Nesbitt, 2006).  Although the PI has a range of responsibilities, these are not described in Canadian regulations71, which focus solely on the sponsor; instead, one has to look to the ICH-GCP Guidelines. 72 Pursuant to the guidelines, the investigator must (among other things) be thoroughly familiar with the specifics of the trial, conduct the trial according to Good Clinical Practices and ?other regulatory requirements?, and ensure that all individuals assisting with the trial are qualified to complete the tasks delegated to them.  Investigators are also responsible for reporting serious adverse events (SAEs) to the sponsor, for timely communication with the REB, and for complying with the protocol-among a myriad of other duties. In addition, legislated responsibilities may accrue to Canadian PIs who are participating as a Canadian site in a trial under an Investigational New Drug (IND) application to the U.S. Food and Drug Administration.73  Further legal responsibilities can also be delegated to the PI under the terms of the contract signed with the sponsor or CRO.  These examples simply serve to illustrate some of the range of potential sources of obligation for the PI.  The discussion of the legal framework within which those responsibilities accrue will be addressed later in Chapter 7.  2.6.2.2.2 Clinical Research Coordinator (Coordinator or CRC) While the study coordinator?s (or CRC?s) position can vary tremendously depending on how many other research staff are on site, a key and constant element of the role is that the coordinator is the ?person with whom subjects interact the most, and the one most able to identify their needs and employ necessary procedural safeguards? (Davis et al., 2002, p. 418). Originally conceived as a clinical manager for research subjects with a relatively limited range of duties (Speicher et al., 2012), the many tasks that now generally fall within a coordinator?s job description include ?recruiting patient subjects, screening and enrolling patient-subjects into particular studies, managing the regulatory documents like IRB submissions and FDA forms, and overseeing the financial end of contract negotiation and fee collection? (Fisher, 2009, p.67). In                                                  71 The relevant regulations would be the Division 5 Regulations under the Food and Drugs Act.  R.S.C. 1985, c.F-27; Division 5 Regulations, C.R.C., c.870 72 TCPS 2 also described investigator responsibilities that are relevant in the context of clinical trials that fall within its jurisdiction.   73 U.S. Department of Health and Human Services (Food and Drug Administration) (2008): Information Sheet Guidance for Sponsors, Clinical Investigators and IRBs.  Frequently Asked Questions-Statement of Investigator (Form FDA 1572) Draft Guidance Document 37  addition, coordinators are often responsible for performing study related procedures that don?t require a physician.  In essence, and  different from any other position in the clinical trials industry, coordinators are very much the face of pharmaceutical drug development.   It is primarily through coordinators that patients interact with the clinical trials industry and come to trust that they are being cared for.  Coordinators understand that the quality of their interactions with patients and the rapport they build with them affects how well they are able to recruit, enroll and retain those patients in studies. (Fisher, 2009, p. 68)  Coordinators also are often the ones that transcribe source documentation such as medical records, clinic and lab notes etc, into case report forms (CRF) supplied by the study sponsor (Nesbitt, 2006). In terms of the relationship between sites and the CRO or the sponsor, coordinators again hold a very key position in that they are often the ones that interact with the clinical research associate (CRA or monitor), appointed by the CRO or the sponsor to monitor the various clinical trial sites.  Just as the coordinator becomes the face of the research for the human subject, he or she also becomes the personality with which the sponsor or contracting CRO interacts and therefore has significant influence in the relationship between the site and the CRO/sponsor (Nesbitt, 2006; Speicher et al., 2012).  This in turn can have significant implications for the site?s ability to attract future research.   2.6.2.3 Site Management Organizations (SMOs) SMOs are private organizations that essentially provide a range of services to individual primary care physicians conducting clinical trials.  They create networks of trained, supported community based (primary care) physicians that sponsors and CROs can access to conduct clinical trials.  This is of value for sponsors because it streamlines site recruitment and often improves overall quality of community sites.  The Trial Management Group (TMG) is an example of a Canadian SMO.  As advertised on their website, TMG ?is Canada?s leading clinical investigator network with the largest number of high-performing primary care investigators across the country. Our experienced investigators are trained in Good Clinical Practice (GCP) and have successfully completed hundreds of Phase II-IV trials across multiple therapeutic areas.?74 I do not discuss SMOs in much detail here because my research tends to focus more on                                                  74TMG website is available at: http://www.tmginvestigators.com/ 38  academic sites.  It is my understanding that because such sites tend to have access to their own internal infrastructure (CTSUs, for example) they do not typically work with SMOs.  2.6.2.4 Contract Research Organizations (CROs) As alluded to earlier, the dominant auxiliary organization in the pharmaceutical outsourcing business is the CRO. These organizations in turn are certainly not a homogenous group and range widely in size, services provided, and expertise.  In fact, CROs have  expanded into nearly every stage of the discovery, developing and marketing of new pharmaceuticals? Their activities range from initial screening of molecules for biocompatibility, in vitro screening, pharmacokinetic modeling, chemical synthesis and analysis, all phases of clinical testing, dosage formulation and pharmacy services, to all aspects of the regulatory process. (Mirowski & Van Horn, 2005, p.507)  Three levels of CRO have emerged: the small niche CRO, the mid-size CRO, and finally, the full service, multinational CRO (Nichol, 2006; Getz, 2007b).  However, as has been observed by others, ?small and mid-size contract research organizations have largely been left behind while major CROs-the only organizations with sufficient scale to and diverse talent? are dominating (Getz, 2012).  This trend is echoed by the Association of Clinical Research Organizations (ACRO), which observed that ?the industry is evolving toward a full-service model, where CROs offer services from the earliest stages of development through clinical trials and post-approval research.? Full service CROs offer a full range of services related to clinical trials (phase I-IV), including: trial design, project and site selection and management, investigator and subject recruitment, monitoring, data management, biostatistics and bioanalysis, medical affairs, medical writing, regulatory affairs and submissions.  It is becoming increasingly common for full service CROs to handle post-marketing concerns now as well, including phase IV trial design and management, post marketing surveillance, data management issues and others (Getz, 2012; Thomis & Desai, 2006).  In addition to this full range of services spanning both the discovery and development stages, another key feature in the increasingly globalized context of the pharmaceutical industry is the ability of these organizations to effectively recruit subjects, physicians and run trials across multiple jurisdictions (Adobor, 2012; Schipper et al., 2011).  Finally, in considering the role of the CRO in the drug development process, it is important to distinguish between their role in early clinical trial development (i.e., phase I-IIa 39  clinical trials) and later stage clinical trials (phase II-III).75  Phase I trials involve relatively small numbers of human subjects and generally take place at one site.  While traditionally sponsors conducted phase I trials in their own in-house facilities, it has become more common now to outsource these to full service CROs with their own in-house phase I facilities; alternatively, CROs will contract with a single site or unit to conduct the trial.76 In contrast, later stage trials (phase II-III and post marketing or phase IV trials) generally involve multiple sites (and therefore multiple PIs) and hundreds or thousands of human subjects, often on an out patient basis.  In addition, such trials can also involve multiple sponsors, CROs, and other auxiliary service providers.  A key role of the CRO in these trials is to coordinate all of the various service providers and sites, and provide additional trial related services as contracted for by the sponsor.  As alluded to earlier, in all trial phases, sponsors can choose to contract out the running of the entire trial or only certain select services. Where sponsors outsource only select services, these often include patient recruitment, monitoring, data management and medical writing, however new services are also being constantly introduced in response to sponsors demands for faster trials and globalization (Getz, 2012; Nesbit, 2006). 2.6.2.5 CRO Personnel Among the many different positions within a CRO, clinical research associates (also referred to as monitors) and project managers play particularly important roles in the interactions with sponsors and with other auxiliary service providers.  While an exhaustive look at the changing and evolving roles of each of these positions exceeds the scope of this study77, it is important to gain at least an initial appreciation of these roles to understand how the way in which outsourcing in clinical development unfurls.                                                     75 The phases of clinical trials are described near the beginning of this chapter.  76 This was a key point that was raised by a phase I recruiter/marketer for a large CRO in a personal communication in 2009.  This individual provided me with extensive materials describing the Phase I capacities of his company, including three separate Phase I units in different countries for a total of 275 beds, extensive expertise and emergency simulation units for educational purposes.  77 Fisher (2009) does provide a detailed discussion on each of these roles.  40  2.6.2.5.1 Clinical Research Associate (CRA or Monitor) As noted in an earlier section, the clinical coordinator is generally the person at the investigative site who interacts with and reports to the CRA or monitor, who in turn is (at least in theory) the representative of the sponsoring pharmaceutical company, but who may be employed by the sponsoror by the CRO, or be an independent contractor hired by either sponsor or CRO for a specific study  (Doyle, 2008; Fisher, 2009; Getz, 2007c; Nesbitt, 2006).   Pursuant to the ICH-GCP Guidelines78, the purpose of the Monitor is to verify that: ? The rights and well-being of human subjects are protected. ? The reported trial data are accurate, complete and verifiable from source documents. ? The conduct of the trial is in compliance with the currently approved protocol/amendments, with GCP, and with the applicable regulatory requirements.    Moreover, the guidelines state that monitors should be appointed by the sponsor, be the main line of communication between the sponsor and the investigator, be appropriately trained, and have the scientific and/or clinical knowledge needed to monitor the trial adequately.  While there may be significant diversity in any additional roles a monitor is assigned, the basic process of monitoring a clinical trial involves selecting an appropriate site, monitoring the conduct of the trial at that site, and closing the site. Each of these stages requires the monitor to attend in person.  Given that a monitor has a wide range of responsibilities across multiple trials for multiple sponsors in multiple jurisdictions, it is not surprising that burnout and high turnover rates are common problems (Doyle, 2008; Fisher, 2009; Miseta, 2013).79                                                     78 As noted by a subgroup of the Interagency Panel on Research Ethics (PRE) working on procedural issues looking at the harmonization of the TCPS and GCP Guidelines, ?the assumption on the part of Health Canada inspectors and trial sponsors is that the ICH-GCP guides the conduct of clinical trials in Canada. In addition, it should be noted that the acceptability of Canadian research data in submissions to foreign regulators, such as the U.S. Food and Drug Administration, is based on compliance with ICH-GCP.? Harmonisation of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS) and ICH-Good Clinical Practice: Conflict or Clarification? Submitted by Subgroup on Procedural Issues for the TCPS (ProGroup): A Working Committee of the Interagency Advisory Panel on Research Ethics (PRE). 79 In addition to intense workload, heavy travel requirements and inconsistent training, another challenge for monitors involves lines of communication.  While the CRA is supposed to be the sponsor?s representative at the site, project managers and other administrators at the sponsor 41  Interestingly, despite the significance of this role it seems that there is little consistency in the training received by monitors. For example,  some pharmaceutical companies and CROs have formal classroom style training whereas others assign new employees to work with more experienced monitors to learn the system and skills?Other monitors pay out of pocket for training courses offered by the Drug Information Association or the Society of Clinical Research Associates (SoCRA) as a way of obtaining formal credentials and increasing their marketability towards the top CROs or pharmaceutical companies. (Fisher, 2009, p. 106)  This lack of consistency in education and training for monitors is no doubt exacerbated by the fact that ?even the Association of Clinical Research Professionals (ACRP), the leading CRA certifier, is still trying to define what the minimum education and training requirements for study monitors ought to be? (Getz, 2007c). 2.6.2.5.2 Project Manager  Another important role within the clinical development outsourcing relational web is the project manager. Like the CRA, this is a position that is evolving as the clinical trials context continues to change and become increasingly complex. The role of project manager is becoming one of strategic oversight and leadership, whose key purpose is ?to oversee the entire clinical trial process, often including complex relationships with many stakeholders, including multiple sponsors, CROs, Academic Research Organizations etc? (Burgess, 2008).  Sponsors are reportedly shifting away from having large management teams reviewing the work of the CROs, and instead adopting a more removed oversight role.  This shift places greater responsibility on the project manager as the key liaison with the sponsor?s key decision makers on a day to day basis.  In essence, their role on a given trial is to keep track of the various sites for which their organization is responsible (drawing on the information provided by the monitors, for example), making adjustments as needed to stay on track with timelines, and motivating the team members to accomplish project goals on time and to a high quality. They are then responsible for reporting quickly and effectively to the sponsor and ensuring that their client?s needs and expectations are being effectively met (Burgess, 2008).                                                                                                                                                              and/or CRO often contact the site directly, thereby leaving the monitor out of the communication and undercutting the authority and respect the monitor can command at the site. (Fisher, 2009)  42  As a very basic summary of the communication lines involved between sites, CROs, and sponsors then: the coordinator is responsible for managing all trial related activities at the site, under the supervision and ultimate responsibility of the PI.  The coordinator interacts with the monitor, who comes to review site activities from site selection to conducting the trial, to site wrap up and closure at the end of the trial. The monitor in turn reports to the CRO?s project manager (or to the sponsor?s project manager where no CRO is involved). The project manager serves as the key contact between the sponsor and the CRO. 2.6.2.6 Academic Research Organizations It is interesting to note that, ?whereas the mid 1990s saw a flurry of academic institutions establish clinical trial offices to better handle industry relationships, the late 1990s through mid-2000s saw a reversal of that trend? (Getz, 2007a, p.35).  In recent years industry observers have again suggested increasing collaborations between CROs and academic medical centres (AMCs) (Getz, 2007a; Henderson, 2009), though it is not clear how best to structure such relationships (Goldenberg et al., 2011). There are benefits to both academia and industry in increasing their collaborations.  For academia, dollars are clearly relevant, but so to is the benefit of being involved with cutting edge innovation (Henderson, 2009).  For industry, collaborations with academia are appealing because they offer access to specialized expertise in certain areas, and increased patient access for certain more complex conditions and diseases (Henderson, 2009).  Moreover, given growing public skepticism around industry integrity, academia also provides a certain reputational value to industry sponsors; however, as others have warned, ?although academic research organizations offer the imprimatur of university based research, like commercial organizations they are beholden to their industry sponsors? (Lenzer, 2008, p.604). In their efforts to make themselves more marketable as potential collaborators in industry sponsored drug trials some academic centers have been banding together to form networks that provide sponsors and CROs access to multiple trial sites that use a single contract, ethics board and budget. The Duke Clinical Research Institute, for example, is the largest academic research organization in the world.  As noted on its website, it is ?a comprehensive academic research organization (ARO) and the only one of its kind that can offer all the services of a commercial contract research organization (CRO) with the academic credibility and expertise of an academic 43  research institute.?80  Another American example is the TIMI (Thrombolysis In Myocardial Infarction) Study Group which is affiliated with Brigham and Women?s Hospital and Harvard Medical School and conducts and coordinates clinical trials in patients with cardiovascular disease or risk factors for cardiovascular disease.  As described on its webpage, its services include ?leadership in terms of study design, protocol development, statistical analysis planning, on-going trial supervision, trial closeout, and finally manuscript development.?81   In Canada, the Canadian VIGOUR Centre is located at the University of Alberta and is the Canadian arm of the international VIGOUR (Virtual Coordinating Centre for Global Collaborative Cardiovascular Research) Group, an international ARO specializing in clinical trials (phase II-IV) in cardiovascular disease. They offer a wide range of services, including: trial design, development, phase III and IV clinical trial management, and trial monitoring among many others.82  Another example, the Northern Alberta Clinical Trials and Research Center (NACTRC), is a joint venture between Alberta Health Services, and the University of Alberta.  Partnered with 13 hospitals and 6 primary care centers in Alberta, they offer ?access to a network of over 250 qualified researcher and clinicians in all health disciplines?83.  NACTRC creates a ?one-stop shopping? option and boasts being the least expensive location to conduct clinical trials in North America in 2004.  However, both the above examples still rely on the University of Alberta?s clinical research ethics board for their reviews. This is because in Canada, unlike in the U.S. where institutions may delegate ethics review of commercially sponsored research to private REBs84, research collaborations between industry and academy must still be reviewed by the                                                  80 https://www.dcri.org/our-services. Last accessed September 13, 2013.  81http://www.timi.org/?page_id=782.  Another example is the BRANY (Biomedical Research Alliance of New York) network, which promises ?to provide a comprehensive solution from start to finish by providing independent IRB and IBC (institutional biosafety committee), educational, consulting, site identification and administrative services to sponsors and investigative sites around ? the world? BRANY is able to offer its partners a turnkey solution for expedited site identification and study startup, including a single contract, IRB and budget? (www.brany.com/about). Last accessed September 13, 2013.  82 http://www.vigour.ualberta.ca/Services.aspx.  Last accessed September 13, 2013.  83 See website at: http://www.clinicaltrials.ualberta.ca/ Last accessed September 13, 2013.  84 As Koski et al. (2005) explain, commercial ethics review boards in the states have been reviewing an increasing amount of both industry and federally funded research since the 44  institutional REB85.  As such, they are still subject to the problems and delays that have been a key and continuing source of frustration for industry in their collaborations with academia.  While this will be discussed in further detail in Chapter 6, it is worth noting here that the academic or institutional sites that participated in this study almost invariably expressed a strong preference for working with AROs over private CROs.  Among the key reasons cited for this preference were better service and support levels and increased confidence in the ARO abilities and expertise.  2.6.2.7 Private Ethics Review Boards In addition to investigative sites, site management organizations, contract research organizations and AROs, private or non-institutional ethics review boards have also emerged to support the commercialized drug development industry. Some of the drivers frequently cited for the rise of the CRO in the 1990s have been mentioned earlier in this chapter.86 However, another important factor that continues to encourage pharmaceutical companies not only to outsource but to choose commercial entities over more traditional academic ones is the perpetual problem of slow and ineffective research ethics review in the university and hospital setting (Gelijns & Thier 2002; Lexchin, 2008; Rettig, 2000).   Under the Canadian and American regulatory frameworks, all federally funded research involving human subjects, as well as all research (regardless of funding source), being used to support an application for approval of new drugs must be approved by a duly constituted research ethics board (REB)87, whose primary mandate is to ensure protection of the ?rights,                                                                                                                                                              Department of Health and Human Services gave permission to do so in 1995.  However, it is interesting to note that the authors underscore that even where a commercial REB reviews the protocol, local ethics review boards at the specific cites still conduct full reviews.  They observe that this redundancy ?could be reduced through more effective use of cooperative models? (p. 3). 85 Interestingly, in the TCPS2 there is a far more extensive discussion around multi center review and explicit references made to external specialized boards.  As such, there seems to be an increased openness (over TCPS) to the possibility of having research based at an AHC reviewed by a commercial REB, although this is not explicitly stated. 86 As noted above, these factors included: an increasingly complex regulatory framework, FDA?s apparent increasing concern with conflicts of interest, and heightened market pressure to downsize expensive internal labour forces. 87 As discussed by Lemmens & Freedman (2000).  In the Canadian context, for example, pursuant to the Division 5 Regulations under the Canadian Food and Drugs Act, sponsors must 45  safety and well-being? of human subjects.88 As noted earlier, in the Canadian context, all research that is funded by, or occurs within the jurisdiction of an institution receiving funds from, one of the three main federal funding agencies must be reviewed by a local research ethics board. Where the REB is not satisfied that the research protocol meets appropriate ethical standards as set out in the relevant guidance documents89, they can request amendments be made or, if such steps do not resolve their concerns, they can reject the protocol.  However, as has been noted elsewhere, ?despite general agreement on the aims and guiding principles for research involving human subjects, there is no overarching structure for the governance of research in Canada and, consequently, no process for ensuring that those aims and guiding principles are attained and implemented? (Glass, 2006, p.38).90  Others have described the law in Canada as applying ?almost inadvertently to the enterprise of biomedical research? (McDonald, 2000, p.93).  Given the high demand for ethics review, the fact that institutional research ethics boards (i.e., those housed in universities and hospitals) are chronically under-supported and over taxed in their endeavors, and the patchwork approach to governance in this area (McDonald 2000)91, it is not surprising that there is an ever increasing variety of research ethics boards (both in terms of structure and kind) emerging and functioning within the human subjects? research arena (Lemmens & Freedman, 2000).92                                                                                                                                                               file a clinical trial application prior to undertaking any clinical trial supporting the development of a drug.  As part of this clinical trial application, the sponsor must include the name and contact information of each research ethics board that approved the protocol at each clinical trial site.  Regulatory requirements are discussed in Chapter 7.  88Division 5 Regulations (C.05.001) pursuant to the Food and Drugs Act. 89 For example, in Canada these would be the GCP Guidelines which have been adopted by Health Canada as applying to the conduct of clinical trials in Canada, as well as those standards established in the Tri-Council Policy Statement (TCPS2).  90 See also Miller (2006) for a good discussion of these concerns. 91 See also, Anderson et al., 2011; Glass & Lemmens 2002; McDonald 2001; McDonald et al., 2011)  92 For example, in addition to the most traditional set up, wherein a research ethics board is affiliated with an academic institution or publicly funded hospital, there are also provincial research ethics boards, REBs attached to administrative licensing bodies, free standing private for profit REBs, and REBs that are situated within or closely affiliated with particular pharmaceutical companies or contract research organizations.  For the purposes of this paper, the focus will be on commercial REBs as compared with traditional institutionally based REBs. 46  While an extensive discussion of the types of boards and their associated strengths and weaknesses exceeds the scope of this paper, it is highly relevant to draw a comparison between commercial research ethics boards and university or hospital-based boards. Commercial boards can be free standing private for profit boards, or they can be situated within or closely affiliated with particular pharmaceutical companies or contract research organizations.  An important concern with commercial boards is that their ability to provide an objective and effective review is compromised by their reliance upon their industry clients (Lemmens & Freedman, 2000; Lemmens, 2004). In other words, the survival of such boards is dependent upon keeping their clients (generally, pharmaceutical sponsors or CROs working for the sponsors), happy. While this might arguably be mitigated somewhat in the case of a board with a diverse clientele, it seems heightened for boards which have a close and virtually exclusive relationship with any particular CRO or sponsor.  In such circumstances, the fact that the board is technically independent of the CRO seems almost irrelevant in effect.   As Lemmens and Freedman noted, ?the difference between commercial and academic IRBs lies primarily in the context in which they operate and, to some extent, in the goals of the medical research that these IRBs are reviewing.? (2000, p. 550)  Traditional research ethics boards are generally located in a university or hospital and are set up to review the research that takes place in those (largely) publicly funded institutions or by physicians affiliated with those institutions.  Members of these REBs receive little or no compensation or protected time in recognition of what can often be fairly heavy time commitments.93 Finally, evidence suggests that the levels of training and ongoing education for board members varies tremendously across boards and in many cases is little to none (Glass, 2006; Lexchin, 2008; McDonald, 2000; McDonald et al., 2011).   In contrast, commercial boards mostly review studies on behalf of commercial entities such as CROs or pharmaceutical companies.  They are able to target their clientele and ensure they have appropriate expertise represented on their board or boards. Moreover, unlike academic or institutional REBs, these boards are not staffed by volunteers but by individuals for whom it is a significant part of their formal and acknowledged workload. As such, some of the key benefits                                                  93 For example, research I conducted for my Masters degree suggests people can spend up to 15 hours of prep time plus a four hour meeting on a monthly, and sometimes twice monthly, basis. 47  of working with commercial boards (and which are highlighted in their marketing efforts), include speed of review, the quality and variety of services offered, and the ability to review multi-site projects (Koski et al., 2005; Lemmens & Freedman, 2000).  The lack of consistency and national accreditation standards, combined with patchwork governance and regulation, creates a number of problems.  For example, with no real prohibition against so-called ?forum shopping?94, sponsors can take their protocol to sites where they can expect the most favourable and speedy reviews.  Moreover, while the criticism is often raised that commercial boards suffer from an inherent conflict of interest that compromises their ability to provide a meaningful review because their continued business depends upon meeting the expectations of their industry customers for fast approval times (Lemmens & Freedman, 2000; Lemmens, 2004; Lexchin, 2008), it is not at all clear that university and hospital boards are not subject to similar pressures.  These public institutions are coming to rely more and more heavily on industry dollars and, as such, they too (and their boards) are in a position of being potentially vulnerable to industry demands (Lemmens & Freedman, 2000; Shuchman, 2007).  The lack of consistency and clear standards in REB oversight arguably exacerbates this vulnerability. In addition to the above actors, there are also a number of other auxiliary service providers that support the pharmaceutical industry. These include, among a myriad of others, laboratories, electronic data capture (EDC) companies, and patient recruitment services.  Typically these other actors are referred to as vendors, although whether and how they are distinguished from niche CROs is not always clear.95 2.7 Effectiveness Of Outsourcing Relationships Domberger (1998) highlights that ?successful contractual relationships are not simple spot transactions. Contracting appears to yield greatest benefits when it combines market discipline with longer-term, cooperative relationships? (p.50). However, the progression away                                                  94 While there is no prohibition or real controls on forum shopping, under the Food and Drugs Act, the sponsor must provide as part of their clinical trial application submissions to Health Canada an account of any refusals to approve the protocol in question by an REB (as well as any refusals by any regulatory authorities outside Canada).  95 In many instances, these services will also be part of what is offered by full service CROs.  For example, many larger CROs have developed their own EDC systems.  As described in the industry literature (Babre, 2011; Borfitz, 2009), and as will be seen in Chapter 6, such systems vary tremendously and can dramatically affect site satisfaction levels.  48  from strictly transactional interactions towards increasingly close and cooperative relationships (for example, preferred partnerships, strategic partnerships and ultimately strategic alliances) requires levels of trust, candor and transparency that have apparently been lacking in the pharmaceutical context (Azoulay, 2003; Azoulay et al., 2010; Getz, 2012; Scott, 2008; Thomis & Desai, 2006).  Sponsor size is one relevant consideration in this context, as the trend is for smaller and mid-size pharma and biotechnology companies to primarily use transactional outsourcing, whereas the larger firms have been trying (though frequently ineffectively) to establish integrated relationships with CROs (Azoulay et al., 2010; Getz, 2012).   While a detailed discussion of the outsourcing relationships and tensions exceeds the scope of this dissertation, one aspect of the dynamic is important as it has a direct influence on the relationships between sites and CROs, which is one of the main foci of this study.   The point to highlight is that as the pharmaceutical sponsors have been looking to contain costs, they have been asking their CROs (and sites) to do more with less.  As others have put it,  regardless of the types of relationships that sponsors and CROs form, contract services profitability is being challenged. Sponsors want more flexible and fluid drug development operations at lower relative cost?and are requiring CROs to provide more favorable preferential pricing for both project-based tasks and portfolio based services?Integrated relationship customization is also deeply squeezing large CRO profitability?.Every sponsor wants to establish relationships that uniquely suit their culture, their operating style and practices, their systems and their management models?Customization cannot be scaled. It demands more infrastructure and management and eats into the CROs ability to operate efficiently. (Getz, 2012)  CROs, in turn, must look for other ways to improve their profitability and, as will be seen later in this dissertation, this has real implications for their interactions with investigative sites.  It might mean, for example, that CROs cut back on their on-site monitoring, or hire fewer and less experienced staff who will work for less, or develop fewer tools to assist sites with the running of trials, or take on more projects and so be spread too thinly to provide much in terms of monitoring or support for the trial site, among other issues.  In any event, and not surprisingly, belt tightening at the top levels has implications that reach all the way down to the frontlines. These tensions will be described in further detail in Chapter 6 of this dissertation. 2.8 Conclusion The purpose of this chapter has been to describe some of the key pressures and influences that have shaped the pharmaceutical industry in recent decades?both globally and then within 49  Canada. It has also introduced the key actors and relationships that form the backbone of clinical trial outsourcing. This provides the relevant context for the findings of the current study, which is described in detail in the following chapter (Chapter 3).  50  Chapter 3: Methodology  The previous chapter provides a detailed lay-of-the-land or overview of the clinical trials industry in Canada, including some of the historical context, a description of the key parties involved and a discussion of current trends or challenges.  Against this backdrop, the present chapter will (1) describe the goals of the current study, (2) provide a rationale for why I chose to focus the study as I did by briefly outlining some of the broader contextual considerations, and (3) detail the methodological processes and steps I took to complete this research.  Finally, I will situate myself within the research by briefly describing my background. I will also explain how having some of my key assumptions challenged by the data ultimately helped shape this study.  3.1 Goal Of This Research This dissertation examines investigative sites and their relationship with CROs to offer insight into (a) the challenges that arise at this interface and (b) the extent to which Canadians are protected by Canada?s clinical trials oversight framework. This study is comprised of two main components which, while distinct methodologically, build on and inform each other.  The first is a qualitative interview study examining the relationship between investigative sites and CROs, predominantly?though certainly not exclusively?from the site?s perspective.96 The second is a critical legal and ethical analysis of the Canadian legal and policy frameworks for clinical trials, including a review of the obligations, responsibilities, and liabilities under those frameworks, as well as an assessment of their blind spots or weaknesses.  This critical assessment is informed by and sensitive to the issues identified in the findings of the interview study, and as such moves beyond a normative account to provide some insight on the extent to which the legal and policy frameworks are attune to current research realities at the Canadian frontlines.  3.2 Rationale: Why Clinical Trials? Why Sites And CROs? Why Now? Why Clinical Trials? From both bioethics and popular perspectives, clinical trials are among the most visible and controversial forms of health research. The increasingly competitive, high-stakes clinical trials industry has been the backdrop for a myriad of unethical and even illegal behaviors by                                                  96 The reasons for, and implications of this decision are described later in this chapter.  51  various parties in this field?from the pharmaceutical sponsors funding the trials, to the CROs running the trials and the investigators interacting with the subjects and collecting the data.97 This fact, combined with the major contributions such trials have made to medicine and human health and their continued promise in this regard, make this an intriguing and strategic area for study. Why Sites and CROs? While some aspects of the complex clinical trials industry have been well examined, others have not.  The increased commercialization of academic research generally, and medical research and clinical trials in particular, continues to be widely discussed and described in the wake of a number of high profile cases.98  Such cases have sparked intense debate and initiatives both nationally and internationally that have crossed the domains of law, policy, science and ethics.  For example, those working in the field of research ethics have written extensively about the concerns associated with commercialization of research and clinical trials, including conflicts of interest of researchers, research institutions and private research ethics boards, among others (Angell, 2008; Ferris & Naylor, 2006; Krimsky, 2003; Krimsky, 2006; Lemmens & Freedman, 2000; Lemmens 2004; Lenzer, 2008).  Central to these discussions are questions around how to manage and rein in the powerful interests that at once drive innovation and drug development, but also threaten to compromise the testing and development of safe, affordable and effective medications.  Legislative99 and policy100 initiatives promoting transparency and providing                                                  97 The range of such behaviors include everything from biased study designs and underreporting of negative results (Krimsky, 2003; Lemmens, 2004), total disregard for inclusion/exclusion criteria and lack of meaningful consent processes (Wilson, 2010), to bribery and other forms of blatant misconduct particularly in developing or emerging markets (McMahon et al., 2013).  98 Such cases include, for example, those involving Nancy Olivieri, Jesse Gelsinger, and David Healy. For more information on each of these cases, please see Thompson, Baird & Downie, 2001; Lemmens and Waring, 2006; Schaffer, 2004 respectively.  99 A very recent example-and one that is being negatively received by some industry associations-is the U.S. Final Rule under the Physician Payments Sunshine Act, which came into force August 1, 2013.  The legislation requires the reporting of payments made to physicians by pharmaceutical sponsors and their designates (including, for example, CROs). For some discussion on what this means for industry, please see: Sullivan, T. (2013) Physician Payment Sunshine Act: Opportunities and Challenges for Global Implementation http://www.policymed.com/2013/05/physician-payment-sunshine-act-opportunities-and-challenges-for-global-implementation.html. Accessed September 16, 2013.   52  guidance on the identification and management of conflicts of interest at the individual and institutional levels have been widely implemented, albeit with varying levels of success and impact (Ferris & Naylor, 2006; Shnier et al., 2013; Weinfurt et al., 2006). However, and somewhat surprisingly, another aspect of the commercialization of medical research, namely the dramatic shift of clinical trials out of academia into private sector CROs, has received relatively little academic attention (Fisher, 2009; Mirowski & Van Horne, 2005; Shuchman, 2007).  While there is rich, though often inaccessible,101 industry data and literature examining both this move and the relationship between sites, CROs and sponsors (Lamberti et al., 2011), the focus is invariably how to improve functionality, efficiency, and productivity in clinical trials and rarely looks at the broader implications.  Trial integrity, subject safety and other research ethics considerations are typically addressed only as they pertain to bottom line considerations.  For example, industry surveys indicate that communication problems and delays, poorly trained monitors, high staff turnover, site payment issues and protocol design are common sources of frustration reported by sites in relation to CROs?and to a lesser extent, sponsors (Harper, 1997; Korieth & Anderson, 2011; Lamberti et al., 2011; Pierre, 2013).  Such challenges can negatively impact recruitment, lead to slower trials and poorer data quality?all of which of course have important cost and profit implications.  However, these issues also clearly have                                                                                                                                                              100 See for example, AAMC Task Force on Financial Conflicts of Interest in Clinical Research. Protecting subjects, preserving trust, promoting progress I: policy and guidelines for the oversight of individual financial interests in human subjects research. Available at: https://www.aamc.org/download/75302/data, last accessed September 16, 2013; AAMC Task Force on Financial Conflicts of Interest in Clinical Research. Protecting subjects, preserving trust, promoting progress II: principles and recommendations for oversight of an institution's financial interests in human subjects research. Available at: http://ccnmtl.columbia.edu/projects/rcr/rcr_conflicts/misc/Ref/AAMC_2002CoIReport.pdf. Last accessed September 16, 2013. 101 A major obstacle to such literature and research is cost.  While brief synopses of some reports may be made public in some instances-mostly by way of a hook to entice potential buyers- the details often come with a hefty price tag.  For example, a 2012 CRO quality benchmarking report published by Insight Pharma Reports is available for $6800.   More affordable are survey results published by CentreWatch, a company that collects and provides global clinical trials information.  For example, CentreWatch publishes the results of an annual survey wherein sites rate their preferred CROs. These results are available to those with a subscription to their monthly publication ($400/year) or one can purchase the relevant issue for $60.  53  important ethical implications and it is not surprising that many of these issues are also key concerns in the more limited academic literature in this area, including the present study.  As alluded to above, while still relatively limited, academic scrutiny of CROs and their broader implications for the ethical conduct of clinical trials has been building in recent years.  Much of this focus has been in the context of emerging102 clinical trial markets (Petryna, 2009; Schipper et al., 2011), but there has also been important work done in the more traditional or established markets (Fisher, 2009)103,104.  Given the focus of this dissertation, the literature relating to the established markets is most relevant although many of the same problems arise in both contexts. Chapter 2 of this dissertation outlined some of the key drivers of outsourcing of clinical trials to CROs, but the basic idea is faster, cheaper trials.   It is to be expected, then, that many of the issues associated with CROs have been described as arising from ?trade offs between costs, speed and quality of clinical trials? (Schipper et al., 2011) and that these issues arise in both the emerging and traditional markets.   For example, issues associated with poorly trained and overworked CRO staff (including monitors), high staff turnover, poor communication with sites (slow response rates to site queries; duplication of requests; lack of clearly established lines of communication) and generally increased workload for investigative sites related to these and other challenges are prominent in the research and literature arising out of both contexts (Fisher, 2009; Petryna, 2009; Schipper et al., 2011).    What is perhaps more surprising are the similarities across emerging and established markets in relation to fracturing of accountability and lack of regulatory oversight of clinical trials.  This is described as a major area of concern in relation to outsourced clinical trials conducted offshore (e.g., taking place in emerging markets), (Adobor, 2012; Petryna, 2009; Schipper et al., 2011), and one that has potentially profound ethical and safety implications, especially given a wide range of factors that tend to increase the vulnerability of the populations                                                  102 Key emerging markets in this context are Latin America, India, China, Eastern Europe and Russia (Schipper et al., 2011). 103 Traditional or established markets tend to be largely defined as Western Europe and North America (Schipper et al., 2011). 104 While not directly on point, it is also worth mentioning that another source of academic scrutiny of the CRO has been the work of Pierre Azoulay (2003; et al., 2010), that provides in depth analysis of why the sponsor-CRO outsourcing relationship has remained relatively difficult as compared to outsourcing in other industries.  54  in question.  Because offshoring is?at least in part?done as another way of decreasing the cost of clinical trials, the receiving countries tend to be low-middle income countries with less developed infrastructure and regulatory oversight whose populations tend to be less educated and less well-off financially as compared to more established clinical trial markets (U.S., Canada  & Western Europe for example) (Adobor, 2010; Schipper et al., 2011). 105  However, while the challenges may be particularly acute in these regions, lack of regulatory oversight of clinical trials and uncertain accountabilities are not challenges isolated to emerging markets.  Recent literature suggests that (1) even in the most well established of markets (i.e., the United States) there is an overreliance by regulators on sponsors to ensure the ethics, safety and quality of clinical trials-and (2) that sponsors have not been doing enough in this regard (Getz, 2010; Halloran, 2012).  The findings of the present study confirm views expressed by other scholars (Flood and Dyke, 2012; Herder, 2012) that these concerns are also valid in the Canadian context and that a number of factors (including, for example, a lack of express regulatory jurisdiction over parties other than the sponsor) may further exacerbate the problems.  Why Now? In addition to the relatively unexplored implications of CROs as a dominant force in industry-initiated clinical trials (beyond those considered by industry) and the apparently limited oversight and accountability of CROs under Canada?s clinical trial governance structures, there is a third factor that suggests this as a timely and important area of study. As described in Chapter 2, Canada is currently losing ground in terms of its share of industry dollars for clinical trials.  There is significant pressure within Canada to protect and grow our role in the clinical trial business?i.e., to access more of the increasingly rare industry CT dollars. This push to at once stop the slide and promote growth of the industry in Canada is explicitly stated by a range of institutions?including federal and provincial regulators, public research sponsors, research institutions and hospitals, private sector research organizations (e.g., CROs and other auxiliary service providers), as well as individual medical and research professionals and their professional organizations.   The combination of these three factors raised a number of questions                                                  105 While cost is probably the key factor, offshoring is also described as having other important advantages for pharmaceutical sponsors and CROs, including a way of accessing treatment na?ve populations.   55  for me.  One in particular (drawing on my background in law and research ethics), was the extent to which our current research oversight framework was attuned to the current pressures and realities of clinical drug trials and?to the extent it is or is not?how well does the current framework protect the interests of the human subjects and public as future consumers of drugs from these trials?  Such considerations seemed particularly pertinent and important given the major focus from all levels on attracting additional clinical trials to Canada on the one hand, and the recognized lack of regulatory oversight of clinical trials on the other.   3.3 Research Study: Design And Methodology In order to understand how well Canada?s framework for clinical trial oversight addresses current research realities, I decided to conduct a two-part study.  The first part consists of a qualitative interview study with a focus on the interface between CRO and site.  This was done to start uncovering, from the perspective of those people working at the frontlines of clinical trials in Canada, what the pressures and challenges were that arose between the CRO and the site and how these compared to trials where there was no CRO (that is, where the site interacted directly with the sponsor).  The second part is a critical ethical and legal analysis of the laws and policies relating to clinical trials in Canada.  A key rationale for this two-part approach that combines empirical and normative elements is the idea that an examination of the rules and guidelines can only provide insight into how things are supposed to unfold.  Ultimately, it is only by going to the front lines and speaking with those directly involved that we can determine whether and to what extent what is supposed to happen is actually what is happening, and how the inevitable complexities of real life change and affect how the rules and regulations are implemented.  Each of these components will now be described in turn. 3.4 Qualitative Interview Study This research includes a qualitative, interview based study approved by the University of British Columbia?s Behavioural Research Ethics Board. A qualitative methodology is appropriate where there is little known about the topic area, and where the researcher seeks to describe what is going on.  Morse and Richards (2002) list a number of instances in which qualitative methods may be the best or only way of proceeding, including forays into areas about which little is known.  As they note, ?if you don?t know what you are likely to find, your project requires methods that will allow you to learn what the question is from the data? (p.28).  These 56