CLINICAL TRIALS, CANCER, AND THE EMERGENCE OF HUMAN SUBJECT RESEARCH ETHICS IN CANADA, 1921-1980 A Thesis Submitted to the College of Graduate and Postdoctoral Studies In Partial Fulfillment of the Requirements For the Degree of Doctor of Philosophy In the Department of History University of Saskatchewan Saskatoon by FEDIR V. RAZUMENKO Copyright Fedir V. Razumenko, September 2018. All rights reserved. PERMISSION TO USE In presenting this dissertation in partial fulfillment of the requirements for a PhD degree from the University of Saskatchewan, I agree that the Libraries of this University may make it freely available for inspection. I further agree that permission for copying of this dissertation in any manner, in whole or in part, for scholarly purposes may be granted by the professors who co- supervised my dissertation work or, in their absence, by the Head of the Department or the Dean of the College in which my dissertation work was done. It is understood that any copying or publication or use of this dissertation or parts thereof for financial gain shall not be allowed without my written permission. It is also understood that due recognition shall be given to me and to the University of Saskatchewan in any scholarly use which may be made of any material in my dissertation. Requests for permission to copy or to make other uses of materials in this dissertation in whole or part should be addressed to: Head of the Department of History University of Saskatchewan 711 Arts Building, 9 Campus Drive Saskatoon, Saskatchewan S7N 5A5 Canada OR Dean College of Graduate and Postdoctoral Studies University of Saskatchewan 116 Thorvaldson Building, 110 Science Place Saskatoon, Saskatchewan S7N 5C9 Canada i ABSTRACT Clinical cancer trials in the 21st century take place only with the ethics review committee’s approval and the written informed consent of human subjects. How and why professionals reached these standards of a modern regulatory framework for clinical research by the late 1970s is the subject matter of this dissertation. An historical examination of burgeoning cancer care and clinical trial programs in Canada offers insight into socio-cultural factors that enabled the transformation of experimental treatment into clinical research. This dissertation is a history of the creation, coordination, and contestation of new practices in Canadian clinical settings wherein surgical, radio- and chemo-therapeutic procedures were devised, evaluated, and eventually regulated. Using historical epistemology and the constructivist methodology of science studies, this dissertation demonstrates that medical research ethics emerged through clinical investigation rather than philosophical speculation. Since ethically questionable clinical trials usually provoked professional disapproval, public outcry, and official condemnation from the judiciary, clinicians continually modified their research protocols based on empirical evidence and ethical imperatives. Over the decades, new protocols induced changes in the ethical acceptability of human subject research (HSR) and in its regulation. This process culminated with randomized controlled clinical trials (RCTs) in the 1950-1960s, when their ethical rationalization became more problematic. As this dissertation shows, clinical investigators first raised these concerns in the late 1950s, which later resonated among medical professionals, patients, judges, philosophers and others, all of whom contributed to reshaping the ethics of HSR. Renegotiation and reinterpretation of the meaning of ethical HSR occurred through a series of critical junctures: institution-building, technological innovation, inter-professional struggle, exploitation of cancer patients, litigation, and challenges to the culture of clinical experimentation. This dissertation concludes that both scientific and cultural factors interacted to produce a parallel development of clinical cancer investigation and its ethics, which became embodied in the RCT protocol. Facilitating both the conduct of RCTs and their ethical regulation, protocols generated a feedback loop between the RCT content and the codification of HSR ethics. Ultimately, RCT protocols made possible an increasing professionalization in oncology and an enhanced administrative oversight of clinical research. ii ACKNOWLEDGEMENTS Ideas form in a collective, and this dissertation would have been impossible without the cooperation of many people. My gratitude goes first to Erika Dyck and Larry Stewart whose timely advice and encouragement helped me shape this dissertation. Their perceptive co- supervision fostered a dialectical ingenuity in me, which substantially contributed to equilibrating this interdisciplinary project. I am further indebted to my dissertation committee members, Geoff Cunfer, Mirela David, and Roger Pierson, for their constructive comments and questions. This dissertation also benefited greatly from the expertise of the external examiner, Carsten Timmermann, who provided insightful and detailed suggestions for improvement. Financial assistance from the University of Saskatchewan, the Government of Saskatchewan, and Canada Research Chair funds of Erika Dyck made much of this research possible. To archivists, who enabled me to do historical research efficiently, I owe a considerable debt of gratitude. I wish to express a special thanks to Bonnie Dahl and Nadine Charabin at the PAS, Ani Orchanian-Cheff at the UHNA, Jim Franks at the UAA, Christopher Hives and Erwin Wodarczak at the UBCL, Jordan Bass at the UMFMA, Cheryl Avery and Tim Hutchinson at the USL, Harold Averill at the UTA, and Anne Daniel at the WUA, whose courtesy and assistance in tracking down my requests made a difference. Additionally, several people evinced a strong interest in this historical study – Jacalyn Duffin, Stuart Houston, Charles Hayter, Joseph Pater, Tony Miller – and this dissertation profited from their wisdom. I am extremely thankful to Norman Zepp and Judith Varga, since this dissertation would have taken longer to complete without the welcome distraction of their companionship. Most significant of all in the completion of this project was a tremendous support of my family. Words cannot express the profound gratitude I feel towards my parents, Vera and Viktor, who sustained me with their love and faith throughout this process. Misha, I could not have conceived this project without your immensely helpful participation, nor could I thank you enough for setting the outstanding example of a doctoral-level work that inspired mine. iii DEDICATION To my family, Misha, Vera and Viktor. iv CONTENTS Permission to Use i Abstract ii Acknowledgements iii Dedication iv Table of Contents v List of Abbreviations vii List of Figures ix List of Tables x Introduction: Ethics on Trial 1 Chapter I The Rise of Cancer Challenges Therapeutic and Organizational Standards 29 1.1. Through Invisible to Noticeable: Radiation and Cooperation 33 1.2. Radiotherapy and Anti-Cancer Initiatives 45 1.3. Conclusion 58 Chapter II Shifting Sands of Organizing, Problematizing, and Rationalizing Cancer 60 Research in Post-War Canada 2.1. The NCIC: Origins and Objectives 64 2.2. Betatron and Experimental Treatment 74 2.3. Isotopes 85 2.4. Cobalt-60 90 2.5. Conclusion 105 Chapter III The Hard Way to Randomized Clinical Trials in Canada 108 3.1. The Untouchables of Medical Practice Reaffirm their Status 111 3.2. Professionalization of Radiotherapy and Diversification of Surgery 122 3.3. Chemotherapy Finds a Haven in the Stronghold of Radiotherapists 134 3.4. Strange Bedfellows 142 3.5. Conclusion 149 Chapter IV Evolving Standards of Clinical Investigation and its Regulation 152 v 4.1. Randomized and Not Randomized Clinical Trials 163 4.2. Clinical Trials and Human Subject Research Ethics 179 4.3. Institutions and Regulation of Human Experimentation 199 4.4. Conclusion 209 Chapter V The Construction of Meaning: Ethics in Clinical Cancer Research 211 5.1. Two Uncommon Tumors and One Common Sense 218 5.2. Development of the NCIC Cooperative Program 236 5.3. Investigators’ Consensus, Institutional Regulations, Patient Consent 252 5.4. Conclusion 265 Conclusions 268 Bibliography 273 vi List of Abbreviations AECB Atomic Energy Control Board (Canada) AECL Atomic Energy of Canada Limited ACS American College of Surgeons ASCC American Society for the Control of Cancer (US) BCCI British Columbia Cancer Institute BCG Bacillus Calmette-Guérin CAC Clinical Advisory Committee of the NCIC CCI W.W. Cross Cancer Institute CCNSC Cancer Chemotherapy National Service Center (US) CCS Canadian Cancer Society CDBS Canada Dominion Bureau of Statistics CMA Canadian Medical Association CSCC Canadian Society for the Control of Cancer DCH Dominion Council of Health DHEW Department of Health, Education, and Welfare (US) DNHW Department of National Health and Welfare (Canada) DRB Defense Research Board FDD Food and Drug Directorate (Canada) FDA Food and Drug Administration (US) ICRF Imperial Cancer Research Fund (UK) MCTRF Manitoba Cancer Treatment and Research Foundation MOPP Nitrogen Mustard, Oncovin, Procarbazine, Prednisone MRC Medical Research Council NCI National Cancer Institute (US) NCIC National Cancer Institute of Canada NIH National Institutes of Health (US) NRC National Research Council (Canada) vii NSCC National Study Committee on Cancer (Canada) OCI Ontario Cancer Institute OCTRF Ontario Cancer Treatment and Research Foundation OIR Ontario Institute of Radiotherapy PHS Public Health Service (United States) PMH Princess Margaret