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The London School of Economics and Political Science Philosophical Issues in Evidence-Based Medicine: Evaluating the Epistemological Role of Double Blinding and Placebo Controls Jeremy Howick A thesis submitted to the Department of Philosophy, Logic, and Scientific Method of the London School of Economics for the degree of Doctor of Philosophy, London, March 2008 1 UMI Number: U615925 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U615925 Published by ProQuest LLC 2014. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 F Qrtlah Ltoraf y o< P - and Eoonomc Sc<©f' >- Declaration I certify that the thesis I have presented for examination for the PhD degree to the London School of Economics and Political Science is solely my own work other than where I have clearly indicated that it is the work of others (in which case the extent of any work carried out jointly by me and any other person is clearly identified in it). The copyright of this thesis is with the author. Quotation from it is permitted, provided that full acknowledgment is made. This thesis may not be reproduced without the prior written consent of the author. I warrant that this authorization does not, to the best of my belief, infringe the rights of any third party. 2 Abstract The Evidence-Based Medicine (EBM) movement endorses a hierarchy of evidence that places randomized controlled trials at the top. More specifically, double-blind, placebo- controlled trials are often considered to be the ‘best of the best’. This view leads to the paradox that treatments that seem to be most strongly supported by evidence, ranging from tracheotomies to rabies vaccines, have never been tested in randomized trials of any description and are hence supported by (allegedly) sub-optimal evidence. Moreover many of these treatments do not seem supportable by best evidence - how, for example do we keep the surgeons who perform tracheotomies ‘blind’? After a brief introduction (chapter 1), and review of the literature (chapter 2), I argue that criticisms of the EBM hierarchy can be launched from the simple basis that best evidence rules out the most plausible rival hypothesis (chapter 3). To examine the relative evidential weight of placebo controlled trials compared to ‘active’ controlled trials (in which the control treatment is an existing established treatment) requires a good deal of conceptual work. I defend a modified version of Griinbaum’s (1981/1986) definition of placebos (chapter 4), then provide constraints on what can count as a ‘legitimate’ placebo control (chapter 5). Next, I explain why double-blinding does not always rule out additional rival hypotheses. I then argue that the arguments for the superiority of placebo controls are flawed. The ‘assay sensitivity’ argument is limited in scope and based on a misconception about the nature of placebo controls (chapter 7), while the claim that only placebo controlled trials measure the absolute effect size relies on the questionable assumption that placebo and non-placebo effects add rather than interact (chapter 8). I conclude that the evidence hierarchy endorsed by EBM does not stand on solid foundations. 3 Acknowledgments This thesis is dedicated to Kor, Jack, and Raven. Many people helped me write this thesis. Many of the ideas for the thesis were developed during conversations with my primary supervisor, John Worrall. I credit John with most of the good ideas. John was also especially helpful in the final stages of writing up. My other supervisor, Nancy Cartwright, provided invaluable insights and advice at many key stages. She was also very helpful in San Diego where I spent a term studying under her at the UCSD. On a few occasions, Nancy stopped me from going insane and encouraged me to persevere. Roman Frigg, who also played a supervisory role in the early stages of my thesis, gave invaluable advice about the more technical aspects of my thesis. Discussions with several fellows at the Centre for the Philosophy of the Natural and Social Sciences, including Damien Fennell and Phillip Thonemann, were also helpful. Sharing ideas with Rupert Sheldrake was enlightening. Several research students were also involved in developing my ideas. These include Sheldon Steed, Lefteris Farmakis, Gary Jones, Foad Dizadji-Bahmani and Kizito Kiyimba. Writing the thesis also required support from family and friends. The unconditional love of my mother kept me on track. My father and younger sisters Samantha, Katie, and Teresa will be happy and proud that I’ve finished. Many long-time friends, including Mark, Sebastien, John, and Sam, where always there when I needed them. Frances was generous with her spare room. Mingy, Stephen, Carolyn and Dr. Bali all played a vital role. My examiners, Professor Donald Gillies and Professor Richard Ashcroft gave me extremely helpful comments; they were also very encouraging. Thanks to anyone I forgot to mention. 4 Table of Contents Chapter One. Overlooked Problems with the Received View that Placebo Controlled, Double-Blind, Randomized Trials Provide the ‘Best Evidence’ .......................................7 2. Chapter Two. The Double Blind, Placebo Controlled Trial to the Rescue: Attempts to Overcome Problems in Determining if a Treatment ‘Caused’ the Cure ..................... 12 3. Chapter Three. Evidence from a more fundamental viewpoint............................... 43 4. Chapter Four. Placebos as Treatments Without Characteristic Features .................58 5. Chapter Five. Placebo Controls: Problematic and Misleading ‘Baseline Measure of Effectiveness’........................................................................................................................ 88 6. Chapter Six. Double-Blinding: The Benefits and Risks of Being in the Dark 120 7. Chapter Seven. Ethics Versus Methodology: Active Controlled Trials and ‘Assay Sensitivity’...........................................................................................................................158 8. Chapter Eight. The Assumption of Additivity in Placebo controlled trials: Exploring the Myth that Placebo controlled trials Provide a Measure of Absolute Effect S ize.....................................................................................................................................193 9. Chapter Nine. The Conceptual Foundation of Methodological Problems 213 5 Table of Figures 1. Table 2.1: Hierarchy of study types ................................................................................20 2. Diagram 4.1: Illustration of therapeutic theory if/, used in clarifying the definition of ‘placebo’ (Griinbaum 1986, p. 22) ...................................................................................... 65 3. Diagram 4.2: Revised Illustration of Therapeutic theory , Used in Clarifying Definition of ‘Placebo’: Nonplacebo, Toxic, Placebo, and Nocebo Effects ...................72 4. Chart 5.1: Illegitimate Placebo Controls Deliver Mistaken Estimates of Effect Size 93 5. Table 5.1: Description of Exercise and ‘placebo’ Exercise Treatments in Dunn et al. 2005...................................................................................................................................... 104 6. Table 5.2: Efficacy Analysis after 12 Weeks of Treatment*. (Adapted from Dunn et a/.’s Table 3 2005) .............................................................................................................. 105 7. Chart 5.2: Acupuncture, ‘sham’ acupuncture, and conventional therapy ..................114 8. Figure 6.1: The amount of analgesic required to reduce pain by 50% for buprenorphine (A), tramadol (B), ketorolac (C), and metamizol (D). From (Amanzio et al. 2001, p. 209)...................................................................................................................130 9. Table 6.1: Mean gain in Total IQ after One Year by Experimental- and Control- Group Children in each of Six Grades.............................................................................. 132 10. Chart 6.1: Effect of Teacher Expectancy Measured as IQ Score Improvement......133 11. Table 6.2: Effect of Placebo in Trials with Binary or Continuous Outcomes (From Hrobjarsson and Gotzsche 2001, p. 1596) ........................................................................ 143 12. Table 6.3: Effect of Placebo on Specific Clinical Problems (From Hrobjartsson and Gotzsche, 2001, p. 1597)................................................................................................... 144 13. Table 7.1: Classification of Possible Decisions Based on Hypothesis Tests (Adapted from Blackwelder (Blackwelder 1982))...........................................................185 14. Figure 7.1: Null and Alternative Hypotheses for Equivalence, Noninferiority, and Superiority Trials (adapted from Hwang and Morikawa, pp. 1210-11)......................... 191 15. Chart 8.1: Smoking behaviour by instruction and drug group. The results are cumulative across the two weeks where assessments were made. Reproduced from