Placebo Effect In Clinical Studies


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Placebo effect in clinical research is a fascinating and widely researched phenomenon in biomedical research and medicine in general. Presentation is an overview of origins and impact of placebo effect in development of new medicines.

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Placebo Effect In Clinical Studies

  1. 1. Placebo Effect in Clinical Studies Aleksandar Skuban, M.D. September 14, 2012| Boston, MA
  2. 2. disclaimer The views and opinions expressed in the following presentation are my own and do not represent the position of my employer. 2All images used with permission: or as noted
  3. 3. One of the most successful physicians I have ever known has assured me that he has used more bread pills, drops of colored water, and powders of hickory ashes, than all other medicines put together Thomas Jefferson, 1807 3
  4. 4. Overview Role in Drug Development Definition Trends in Phase III clinical trials Mechanisms of Placebo Response Case Studies Mitigation Strategies Summary 4
  5. 5. Role Of Placebo in Research Biomedical Research1 Eliminate bias in an experimental setting Demonstration of effectiveness of new treatment Superiority to Control Treatment (active or inactive) Equivalent to known effective treatment Equivalence alone does not prove effectiveness (few exceptions) Assay Sensitivity The ability of a study to distinguish between active and inactive treatment21 Including but not limited to pharmaceutical drug development 2 Temple 2000 5
  6. 6. 37% of Phase II-III Studies 1661 4509 Including Placebo control All Phase II-III Trials Number of Trials Open, interventional, Phase 2, Phase 3, Adult Population, Industry studies at 6
  7. 7. 22% of NIH Funded Studies 211 976 NIH studies with Placebo control All ongoing NIH Studies Number of Trials Open, interventional, Adult Population, NIH sponsored studies at as of 7
  8. 8. Placebo Effect Matters Placebo response is highly variable across number of therapeutic indications: Multiple psychiatric and neurologic indications, pain, hypertension, angina pectoris, IBS, ulcerative colitis, asthma, heart failure, arthritis, allergy and others Extensive literature since 1950s 8
  9. 9. Development Timelines 4.6 5.3 5.4 5.8 6.4 6.5 6.5 6.8 8.1 0.5 0.8 1.2 2.4 1 1.3 1.2 0.7 1.9 AIDS Anesthetic/Analgesic Anit-infectives GI Immunologic Cardiovascular Endocrine Cancer Central Nervous System Clinical Regulatory 9NMEs 2005-2009 (Kaitin 2011)
  10. 10. Success Rates (1993-2004) 8.2 8.7 9.4 9.9 19.4 19.5 20.4 23.9 Central Nervous System Cardiovascular GI/metabolism Respiratory Cancer/Immunologic Miscellaneous Musculoskeletal Systemic anti-infectives Clinical Approval Success Rate (%) 10 Compounds that entered human clinical development from 1993 to 2004 DiMasi (2010)
  11. 11. Understanding and controlling placebo response is important to assess difference between effective treatments and placebo in well- designed trials Avoid costly development and repeated clinical trials 11
  12. 12. Trend of Placebo Effect in MDD 0 0.1 0.2 0.3 0.4 0.5 0.6 1980 1985 1990 1995 2000 Placebo SSRIs 12 Adapted from Walsh, et al JAMA, 2002 (simplified for illustrative purposes only) *1992: 9 trials to get 2 that showed a difference between Paroxetine and placebo (Hooper, 1998)
  13. 13. Headline: Rising placebo response seen in schizophrenia trials (Reuters Health 6/21/2012) Background: “A high and increasing placebo response and a declining treatment effect are of great concern in schizophrenia trials conducted in North America. In this era of global clinical trials, close attention is needed to the design and conduct of these trials.”1 13 1Exploratory Analyses of Efficacy Data From Schizophrenia Trials in Support of New Drug Applications Submitted to the US Food and Drug Administration: Ni A. Khin, MD; Yeh-Fong Chen, PhD; Yang Yang, PhD; Peiling Yang, PhD; and Thomas P. Laughren, MD J Clin Psychiatry 2012;73(6):856–864
  14. 14. Recent Track Record in Phase III Between 2007-2010 83 Phase III initial and major new indications Combined success rate of phase III trials and submissions ~ 50% Lack of Efficacy in 66% of failed programs 33% of trials failed to show benefit over placebo Nature Reviews Drug Discovery Vol. 10, February 2011 14
  15. 15. Reason for Failure in Phase III Nature Reviews Drug Discovery Vol. 10, February 2011 0 20 40 60 80 100 Undisclosed Financial or Commercial Safety (Risk/Benefit) Lack of Efficacy Reason for Failure (%) Vs Placebo Vs Add-on Vs Active 15
  16. 16. Placebo Substance or procedure objectively without specific activity for the condition being treated1 Placebo effect is the therapeutic effect produced by placebo1 Denotes “positive/beneficial” effect 1Arthur K. Shapiro, M.D. 16
  17. 17. History of Healing is History of Placebo The cure for the headache was kind of a leaf, which required to be accompanied by charm, and if a person would repeat the charm at the same time that he used the cure, he would made whole; but without the charm the leaf would be of no avail Socrates 17
  18. 18. 18 New Medical Dictionary (1785) “A commonplace method of medicine” Quincy’s Lexicon-Medicum (1811) “An epithet given to any medicine adapted more to please than to benefit the patient”
  19. 19. Placebo In Clinical Research 1830s Homeopathic Studies in Russian Army treatment groups included homeopathic, allopathic, placebo and no-treatment 1930s Angina Pectoris in cross-over study 1938 first administered in a parallel group: 19
  20. 20. About Treatment Effect •Conditions fluctuate and improve irrespective of treatment •Validity •Reliability •Sensitivity •Characteristics •Magnitude •Duration •Outcomes •Population •Mechanism of Action Efficacy of a Specific Treatment Non-specific treatment effects (placebo effect) Natural history and regression to the mean Measurement 20 Turner at al (JAMA 1994)- Placebo Effects on Pain
  21. 21. Placebo≠No-Treatment Placebo is provided as Intervention in: Scientific Experiments Clinical Treatment Randomized Clinical Trials Intervention + Context No-Treatment Groups not feasible in RCTs 21
  22. 22. Components of Placebo Effect
  23. 23. 23 Who (Placebo Responder) No specific subject type or traits What (Placebo attributes) “Effectiveness” of pills, procedures, surgery Type and complexity of intervention Origin of treatment, importance of size/shape/color How (Administration) “Two placebos are better than one” Carryover-and cumulative effects, length of placebo effect Who, What, How, Where, When (Setting) Who administers the treatment, doctor-patient relationship Physician and Staff attitude and behavior
  24. 24. Open Placebo Administration Open-label, randomized study in patients with Irritable Bowel Syndrome (n=80) Open-label placebo vs. no-treatment Presented and explained in Informed Consent Placebo superior to no-treatment on global improvement scores at D11 (p<0.001) and D21(p=0.002) 24Kaptchuk 2010
  25. 25. Mechanisms of Placebo Effect Psychological Expectancy Classical Pavlovian Conditioning Learning, memory, motivation, somatic focus Neurobiological: Placebo analgesia Endogenous Opioid Release Non-opioid mechanisms Neurotransmitter s and neuromodulators 25Modified after Enck 2008
  26. 26. Mechanisms of Placebo Effect* Pain Activation of endogenous opioids and dopamine (placebo) Activation of cholecystokinin and deactivation of dopamine (nocebo) Parkinson’s Disease Activation of dopamine in the striatum Depression Changes of electrical and metabolic activity in different brain regions Anxiety Changes in activity of the anterior cingulated and orbitofrontal cortices CV system Reduction of β-adrenergic activity of heart Respiratory system Conditioning of opioid receptors in the respiratory centres Endocrine system Conditioning of some hormones Immune system Conditioning of some immune mediators *Adapted after Finniss 2010 26
  27. 27. Placebo vs. Placebo in IBS Study Patients with IBS 3-weeks identical “sham” acupuncture procedure 45 minutes “Augmented” Initial Conversation 5 minutes “Limited” Initial Conversation Waiting List 27Kaptchuk 2008
  28. 28. IBS Study Outcome Treatment 3 Weeks (acupuncture 2x per week) Outcomes: Symptom relief and Quality of Life Sustained after 3-week acupuncture treatment Patient-physician relationship 62 44 28 Augmented Arm Limited Arm Waiting List % of Patients with Adequate Pain Relief 28Kaptchuk 2008
  29. 29. What influences placebo response? 29 621 volunteers treated for 1 week -“Positive influence on mood and cognition” 7 different types of tablets (shape, color, origin, price) Questionnaire: mood, physical abilities, thinking abilities, memory, attention Significant improvement after therapy (p<0.0001) Dolinska, 1999
  30. 30. Dimensions of placebo response: Study Outcome 30 Origin: Polish manufactured (p<0.01) Big white and small red produced better effect than small white and large red tablet (p<0.00001) Best placebo for women German-produced expensive pill (p<0.01) Dolinska, 1999
  31. 31. Factors Contributing to Placebo Effect Diagnostic Misclassification Patient Selection and “symptomatic volunteers” Patient and Clinician Expectations about the Trial Non-Specific Therapeutic Effects Natural Course of Illness- “Regression to the Mean” Inclusion/Exclusion Criteria Sub-populations(type, severity, inflation of entry criteria) Co-morbidities Lack of Sensitivity to Change in Outcome Measures Study Design Issues Increased Complexity and Assessment Duration High Attrition Rates Modified after Fava 2003 and Walsh 2002 31
  32. 32. What Can Be Done to Improve Signal Detection? Standardizing Diagnostic Procedures Enrollment of Selected Populations Criteria: broad vs. sub-populations, specific characteristics Investigator/Rater Training Practice vs. research Inter-rater Reliability Minimizing Non-Specific Therapeutic Effects Staff interaction with patients, research-focus, setting expectations Precision in Study Conduct (Data Generation) 32 Modified after Fava (2003), Walsh (2002)
  33. 33. Study Design Strategies Placebo lead-in phase (to identify placebo responders) Single or double blind, fixed or variable duration Changing trial duration (extending vs. shortening) Early vs. late placebo and treatment responses Fewer number of sites, treatment arms (simplification) Challenging development timelines Increasing Sensitivity of Outcome measures Objective measures, minimizing rater bias 33
  34. 34. Few Additional Points Addressing Study Visit Issues Fixed visit schedule, knowledge & expectation of treatment end “Major” vs. “minor” visits (communication, treatment rituals) Minimize decision bias (eligibility for randomization) Simplification of Assessments Major visits take several hours Extra visits may contribute to placebo response Global Differences in Placebo/Treatment Effect Emerging regional specificities Changing clinical trial landscape 34
  35. 35. Strategies for Neuropathic Pain Studies1 Exclusion of patients with mild severity & short episode Reliability, validity, responsiveness of outcome measure Minimizing contact with investigative staff Trial Duration, Treatment Groups Dose designs (flexible vs. fixed-dose) Run-in period considerations 35Dworkin 2005
  36. 36. Novel Study Designs 36
  38. 38. 38 Patients with post- operative pain needed > 50% higher dose of medication in hidden treatment setting than subjects in the open- treatment setting
  39. 39. In Sum Understand placebo response to reliably evaluate effectiveness of novel treatments in well-designed trials Avoid costly development and repeated clinical trials Renewed interest in placebo research in the last 10-15 years New hypotheses, experimental models and biomarker support Influencing medical practice, ethics and trial designs 39
  40. 40. 40 Field trials are indispensible. They will continue to be an ordeal. They lack glamour, they strain our patience, and they protract the moment of truth to excruciating limits. Still, they are among the most challenging tests of our skills. I have no doubts that when the problem is well chosen, the study is appropriately designed, and that when all the populations concerned are made aware of the route and the goal, the reward will be commensurate with the effort. If, in the major medical dilemmas, the alternative is to pay the cost of perpetual uncertainty, have we really any choice? Donald S. Fredrickson, 1968 Director National Heart Institute Thank you Q&A