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Blinding: History and Current Issues

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Blinded clinical trials only became standardized into their current form in the 1980s. The history before this very recent phenomenon has become almost invisible, even though it was challenged right from the start by the AIDS crisis. The challenge to the RCT as the principle image of clinical research continues with the Ebola crisis and Right to Try legislation.

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Blinding: History and Current Issues

  1. 1. Clinical Trial Blinding: History and Analysis of an Imperfect Research Method, with new 21st Century Challenges SoCRA RTP, 01 June 2015 Mary K.D. D’Rozario MSCR, MBA, CCRP, RAC, CCRA President, CRP Social Media by Clinical Research Performance, Inc. mary.drozario@crplink.com www.crplink.com @marydrozario marydrozario marykddrozario
  2. 2. Blinding: Do we know it when we see it? Results: “Physician respondents identified 10, 17 and 15 unique interpretations of single, double, and triple blinding, respectively, and textbooks provided 5, 9 and 7 different definitions of each.” PJ Devereaux, BJ Manns, WA Ghali et al. Physician interpretations and textbook definitions of blinding terminology in randomized controlled trials. Journal of the American Medical Association. 2001;285(15):2000-2003
  3. 3. Blinding: Do we know it when we see it? • Some suggest “masking” rather than blinding. [1] • Some suggest blinding be specifically explained in the study report. [1] KF Schulz, I Chalmers, DG Altman. The landscape and lexicon of blinding in randomized trials. Annals of Internal Medicine. 2002;136:254-9
  4. 4. Blinding: Why do we do it? • scientific legitimacy • persuasion • competition for resources • flight to quality • subject retention TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433
  5. 5. Blinding: How well are we doing? • Of 200 randomly chosen studies from 2001, 19% stated they were “double blind” but had not blinded either patients, health care providers, or data collectors. [1] M Haahr, A Hróbjartsson. Who is blinded in randomized clinical trials? A study of 200 trials and a survey of authors. Clin Trials. 2006;3:360-5
  6. 6. Blinding: How well are we doing? Literature Review 1 (2004) 2 (2000) 3 (2004) Type of study evaluated: Placebo-controlled Antidepressant Nicotine Replacement Therapy Number of studies: 97 91 73 Number of studies that evaluated the blind: 7 8 17 Number which noted the blind compromised: 5 4 12 1. “Turning a blind eye: the success of blinding reported in a random sample of randomized, placebo controlled trials,” British Journal of Medicine, doi:10.1135/bmj.37952.631667.EE published 2004 2. “Critical approach to antidepressant trials: Blindness protection is necessary, feasible and measurable,” The British Journal of Psychiatry, 2000:177:47:51 3. “The blind spot in the nicotine replacement therapy literature: Assessment of the double-blind in clinical trials,” Addictive Behavior, 2004:29:673-684
  7. 7. History of Blinding: How we got here. • Blinding Discovered and Re-discovered at several times and places. • Contributing issues include:  competing concepts of scientific truth and medical treatment  social barriers between different groups of scientists and physicians  language barriers TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433 Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician. Baltimore: The Johns Hopkins University Press. 1997 Hacking I. Telepathy: Originals of Randomization in Experimental Design. Isis. Sept 1988, A Special Issue on Artifact and Experiment (79);3:427-51
  8. 8. Galen: Canon of Medicine –Galen (129 – c. 200) –Canon compiled by Ibn Sīnā (Avicenna) in Arabic, completed 1025 –Considered authoritative on some subjects into the early 20th century
  9. 9. James Lind’s Treatise of the Scurvy, 1753 • Detailed study of the available literature. • Detailed study of actual patients. • Empirical study of treatments.
  10. 10. Mesmerism • 1784 • Commission appointed by King Louis XVI • Headed by Benjamin Franklin TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433
  11. 11. Nuremberg Salt Test • 1835 • Test of homeopathy Stolberg M. Inventing the randomized double-blind trial: the Nuremberg salt test of 1835. J R Soc Med. 2006;99:642-643
  12. 12. Test of “Smallest Discernible Difference in Sensation” • 1884 • Charles Sanders Peirce (founder of the philosophy known as American pragmatism) • student Joseph Jastrow TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433
  13. 13. Subcutaneous Injection of Animal Testicles • 1889, announced to the Société de Biologie, Paris, by Charles E. Brown- Séquard • Tested by M.G. Variot at the Hôtel Dieu • Controlled for “suggestion” TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433
  14. 14. Diphtheria Trial (randomized, not blinded) • 1897 • Designed by Johannes Fibiger, age 28 (Dutch) • Systematic randomization to either standard treatment or standard treatment plus serum
  15. 15. Anglo-American Tests of Psychotropics • 1910 through 1920 • W.H.R. Rivers at Cambridge • H.L. Hollingsworth at Columbia University • Torald Sollmann at the AMA Council of Pharm. and Chem. • David Macht at Johns Hopkins University • Control for “interest and excitement” TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433 Cambridge University. © Andrew Dunn, 2004, Creative Commons Licensing
  16. 16. Blinded Test of Diphtheria Serum • 1914 • Adolf Bingel • First major blinded trial of a pharmaceutical product • 937 randomized subjects • Double-blind • Control for “suggestion” TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433 Braunschweig, Germany, circa 1900. Library of Congress.
  17. 17. 1920’s English Speaking • Michigan Tuberculosis Trial (1926-1931) [1]  Single blind  Control for instability of disease state • Cardiac Department of London Hospital Angina Study, 1930 [1]  Control for variations of symptoms • Claude Bernard’s paper “An Introduction to the Study of Experimental Medicine” translated and published in New York, 1927 [2]  Used the term “comparative method” and described blinding 1. TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433 2. Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician. Baltimore: The Johns Hopkins University Press. 1997
  18. 18. Paul Martini, Methodenlehre der therapeutischen Untersuchung • 1932 • “exclude suggestive or other irrelevant factors in the unwissentliche Versuchsanordnung” • Literally, “unwitting test” or “test without knowing” TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433 Stoll S, Raspe H. Paul Martini and the development of clinical epidemiology in Germany. The Paul Martini Foundation. [poster]
  19. 19. R.A. Fischer, The Design of Experiments • 1935 • Botanist • Inventor of the field of experimental design  Made experiment “scientific” • Considered randomization important • Blinding less important and easy to do
  20. 20. Harry Gold: The Invention of “Pharmacology” and the Gold Standard of Blinding for Research • 1937, conducted first blinded study • No previous exposure to blinding methods • Got the word “blinding” from a cigarette advertisement • First person assigned a professorial position in “pharmacology,” at Cornell University TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433 Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician. Baltimore: The Johns Hopkins University Press. 1997 Gold H. Clinical pharmacology: historical note. Journal of Clinical Pharmacology and Journal of New Drugs. 1967(7):309-11
  21. 21. Streptomycin Clinical Trial • 1948 • Austin Bradford Hill • “deliberately left out the words ‘randomization’ and ‘random sampling numbers’ at the time because… I might have scared them [collaborating physicians] off.” TJ Kaptchuk, "Intentional Ignorance: A History of Blind Assessment and Placebo Controls in Medicine", Bulletin of the History of Medicine. 1998;72.3:389-433
  22. 22. Acceptance of Randomized Controlled Clinical Trials Grows • 1976, JAMA Special Article: Randomized Clinical Trials: Perspectives on Some Recent Issues  “Ethical considerations suggest that randomized trials are more suitable than uncontrolled experimentation in protecting the interests of patients. Randomized clinical trials remain the most reliable method for evaluating the efficacy of therapies.”
  23. 23. ICH Definition (ICH launched 1990) “Blinding is an important means of reducing or minimizing the risk of biased study outcomes. A trial where the treatment assignment is not known by the study participant because of the use of placebo or other methods of masking the intervention, is referred to as a single blind study. When the investigator and sponsor staff who are involved in the treatment or clinical evaluation of the subjects and analysis of data are also unaware of the treatment assignments, the study is double blind.”
  24. 24. Declaration of Helsinki, October 2013 Amendment, Section 33: Use of Placebo The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances: Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option.
  25. 25. Some other thinking on blinding: • Kolahi J. Abrishami M. Multiple-blind: Towards a new blinding protocol for future generations of clinical trials. Med Hypotheses. 73(2009):843-5  Suggest expanding blinding, including requiring blinded creation of dual study reports and blinding evaluation of study reports. (Some of these techniques were implemented by Gold, but did not catch on for general use. [1]) • Bang H et al. Assessment of blinding in clinical trials. Controlled Clinical Trials 2004;(25):143-56  Provides a method for arriving at a blinding index. • JR Rees, TJ Wade, DA Levy, JM Colford Jr., JF Hilton. Changes in beliefs identify unblinding in randomized controlled trials: a method to meet CONSORT guidelines. Contemporary Clinical Trials. 2005;26:25-37  Suggest adding patient preference arms to studies. • -D’Rozario MKD, Unblinded monitoring programs: design and education. SoCRA Source. February 2011: 70-75  Discusses the need for unblinded monitoring and how to implement an unblinded monitoring program. 1. Shapero AK, Shapero E. The powerful placebo: From Ancient Priest to Modern Physician. Baltimore: The Johns Hopkins University Press. 1997
  26. 26. HIV Activism • 1984  FDA credited (some were unofficial “look the other way”) with first allowing compassionate use. • 1987  AIDS Quilt first displayed on the National Mall  Drugs typically took 10 years to be approved.  AZT was the first fast-track (law itself not established until 1997) drug, approved in 25 months.  Lengthened life by about a year.  First Study: • 12 centers. All with different standard-of- care protocols. • Had been designed as a 6 month blinded study. • Mean participation of 120 days when study was unblinded. • Claims that they study was never blinded because of obvious adverse events, product testing by subjects, product pooling, etc. *Highlighted information from a variety of sources, not necessarily covered in this book.
  27. 27. HIV Activism • 1989: Compound Q  Open-label patient-led study of an herbal product.  Closed after patient deaths.  Made famous in the movie Dallas Buyers Club. *Highlighted information from a variety of sources, not necessarily covered in this book.
  28. 28. Ebola • 11 AUG 2014: Advisory Panel meets, creates publication “Ethical considerations for use of unregistered interventions for Ebola virus disease”  Determine that it is ethical to offer unproven therapies • Consent required  Therapies should be distributed fairly  Communities should be involved in distribution decisions  Moral requirement to collect data from such interventions
  29. 29. Ebola • 20-21 OCT 2014: WHO Ethics Working Group meets, creates publication “Ethical issues related to study design for trials on therapeutics for Ebola virus disease  “monitored emergency use of unregistered and experimental interventions (MEURI)” instead of “compassionate use”  Trials should not take away from the care received by other patients  Real time data collection and sharing  Provides a worksheet to compare a randomized controlled trial against other options.
  30. 30. Right to Try • Current Law in 19 states  Arizona Arkansas Colorado Indiana Louisiana Maine Michigan Minnessota Mississipi Missouri Montana Nevada North Dakota Oklahoma South Dakota Tennessee Utah Virginia Wyoming  Link to all current and draft legislation: http://www.raps.org/regulatory- focus/news/right-to-try
  31. 31. Right to Try Example: Arkansas  Terminally ill  No current treatment  No clinical trial within 100 miles of home  Manufacturer can charge for the product • Insurance may, but not required, to pay for product • Insurance must pay for all other treatment • Debt related to product cannot be collected from family
  32. 32. Right to Try Example: DRAFT North Carolina  Terminally ill  No current treatment  Detailed informed consent requirements  Manufacturer protected from liability  Prescribing doctor protected from sanctions  Manufacturer can charge for the product • Insurance may, but not required, to pay for product • Insurance must pay for all other treatment • Debt related to product cannot be collected from family

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