Traditional and innovative experimental and clinical trial designs and their advantages and pitfalls

Handbook of Experimental Pharmacology

Volumn 225, Issue , 2014, Pages 237-272

  Weimer, Katja ^a   Enck, Paul ^a  

^a UNIVERSITY HOSPITAL TÜBINGEN   (Germany)

Author keywords

Control group; Experimental designs; Placebo effect; Trial designs

Indexed keywords

ARTICLE; ASSAY; BALANCED CROSSOVER DESIGN; BALANCED PLACEBO DESIGN; CLINICAL TRIAL (TOPIC); COMPARATIVE EFFECTIVENESS; CONTROL GROUP; DELAYED RESPONSE PARADIGM; EXPERIMENTAL DESIGN; FREE CHOICE PARADIGM; HABITUATION; HUMAN; INTERVENTION STUDY; LABORATORY; MEDICAL INFORMATION; MEDICAL RESEARCH; MODEL; NOCEBO EFFECT; OPEN HIDDEN PARADIGM; PATIENT CODING; PERSONALIZED MEDICINE; PLACEBO EFFECT; RANDOMIZATION; REGISTER; REINFORCEMENT; RESEARCH ETHICS; SENSITIVITY ANALYSIS; SENSITIZATION; SIGNAL NOISE RATIO; SOCIAL LEARNING; STUDY DESIGN; METHODOLOGY;

CLINICAL TRIALS AS TOPIC; HUMANS; NOCEBO EFFECT; PLACEBO EFFECT; RANDOM ALLOCATION; RESEARCH DESIGN;

EID: 84921796057     PISSN: 01712004     EISSN: 18650325     Source Type: Book Series    
DOI: 10.1007/978-3-662-44519-8_14     Document Type: Article

References (108)

1. Amanzio M, Pollo A, Maggi G et al (2001) Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain 90: 205-215.
2. Aslaksen PM, Flaten MA (2008) The roles of physiological and subjective stress in the effectiveness of a placebo on experimentally induced pain. Psychosom Med 70: 811-818.
3. Aslaksen PM, Myrbakk IN, Høifødt RS et al (2007) The effect of experimenter gender on autonomic and subjective responses to pain stimuli. Pain 129: 260-268.
4. Baer L, Ivanova A (2013) When should the sequential parallel comparison design be used in clinical trials? Clin Invest 3: 823-833.
5. Benedetti F, Maggi G, Lopiano L et al (2003) Open versus hidden medical treatments: the patient's knowledge about a therapy affects the therapy outcome. Prevention Treatment 6(1). http://psycnet. apa. org/journals/pre/6/1/1a. html. Accessed 28 Jan 2014.
6. Benedetti F, Carlino E, Pollo A (2011) Hidden administration of drugs. Clin Pharmacol Ther 90: 651-661.
7. Bingel U, Wanigasekera V, Wiech K et al (2011) The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med 3: 70ra14.
8. Boehmer J, Yong P (2009) How well does blinding work in randomized controlled trials?: a counterpoint. Clin Pharmacol Ther 85: 463-465.
9. Boutron I, Estellat C, Guittet L et al (2006) Methods of blinding in reports of randomized controlled trials assessing pharmacologic treatments: a systematic review. PLoS Med 3: e425.
10. Boutron I, Guittet L, Estellat C et al (2007) Reporting methods of blinding in randomized trials assessing nonpharmacological treatments. PLoS Med 4: e61.
11. Bridge JA, Birmaher B, Iyengar S et al (2009) Placebo response in randomized controlled trials of antidepressants for pediatric major depressive disorder. Am J Psychiatry 166: 42-49.
12. Colloca L, Benedetti F (2006) How prior experience shapes placebo analgesia. Pain 124: 126-133.
13. Colloca L, Benedetti F (2009) Placebo analgesia induced by social observational learning. Pain 144: 28-34.
14. Colloca L, Lopiano L, Lanotte M et al (2004) Overt versus covert treatment for pain, anxiety, and Parkinson's disease. Lancet Neurol 3: 679-684.
15. D'Agostino RB (2009) The delayed-start study design. N Engl J Med 361: 1304-1306.
16. De Allegri M, Pokhrel S, Becher H et al (2008) Step-wedge cluster-randomised community-based trials: an application to the study of the impact of community health insurance. Health Res Policy Syst 6: 10.
17. de la Fuente-Fernández R (2012) The powerful pre-treatment effect: placebo responses in restless legs syndrome trials. Eur J Neurol 19: 1305-1310.
18. Desai JR, Bowen EA, Danielson MM, Allam RR et al (2013) Creation and implementation of a historical controls database from randomized clinical trials. J Am Med Inform Assoc 20: e162-e168.
19. Diener HC, Dowson AJ, Ferrari M et al (1999) Unbalanced randomization influences placebo response: scientific versus ethical issues around the use of placebo in migraine trials. Cephalalgia 19: 699-700.
20. Dunn AG, Mandl KD, Coiera E et al (2013) The effects of industry sponsorship on comparator selection in trial registrations for neuropsychiatric conditions in children. PLoS ONE 8: e84951.
21. Edward SJ, Stevens AJ, Braunholtz DA et al (2005) The ethics of placebo-controlled trials: a comparison of inert and active placebo controls. World J Surg 29: 610-614.
22. Ehni HJ, Wiesing U (2008) International ethical regulations on placebo-use in clinical trials: a comparative analysis. Bioethics 22: 64-74.
23. Elsenbruch S, Kotsis V, Benson S et al (2012) Neural mechanisms mediating the effects of expectation in visceral placebo analgesia: an fMRI study in healthy placebo responders and nonresponders. Pain 153: 382-390.
24. Enck P, Vinson B, Malfertheiner P et al (2009) Placebo effects in functional dyspepsia-reanalysis of trial data. Neurogastroenterol Motil 21: 370-377.
25. Enck P, Klosterhalfen S, Zipfel S (2011a) Novel study designs to investigate the placebo response. BMC Med Res Methodol 11: 90.
26. Enck P, Klosterhalfen S, Weimer K et al (2011b) The placebo response in clinical trials: more questions than answers. Philos Trans R Soc Lond B Biol Sci 366: 1889-1895.
27. Enck P, Grundy D, Klosterhalfen S (2012a) A novel placebo-controlled clinical study design without ethical concerns-the free choice paradigm. Med Hypotheses 79: 880-882.
28. Enck P, Horing B, Weimer K et al (2012b) Placebo responses and placebo effects in functional bowel disorders. Eur J Gastroenterol Hepatol 24: 1-8.
29. Enck P, Bingel U, Schedlowski M et al (2013) The placebo response in medicine: minimize, maximize or personalize? Nat Rev Drug Discov 12: 191-204.
30. Estellat C, Ravaud P (2012) Lack of head-to-head trials and fair control arms: randomized controlled trials of biologic treatment for rheumatoid arthritis. Arch Intern Med 172: 237-244.
31. Evans KR, Sills T, Wunderlich GR et al (2004) Worsening of depressive symptoms prior to randomization in clinical trials: a possible screen for placebo responders? J Psychiatr Res 38: 437-444.
32. Fava M, Evins AE, Dorer DJ et al (2003) The problem of the placebo response in clinical trials for psychiatric disorders: culprits, possible remedies, and a novel study design approach. Psychother Psychosom 72: 115-127.
33. Fiorillo CD, Tobler PN, Schultz W (2003) Discrete coding of reward probability and uncertainty by dopamine neurons. Science 299: 1898-1902.
34. Gracely RH, Dubner R, Wolskee PJ et al (1983) Placebo and naloxone can alter post-surgical pain by separate mechanisms. Nature 306: 264-265.
35. Grelotti DJ, Kaptchuk TJ (2011) Placebo by proxy. BMJ 343: d4345.
36. Hegerl U, Mergl R (2010) The clinical significance of antidepressant treatment effects cannot be derived from placebo-verum response differences. J Psychopharmacol 24: 445-448.
37. Horing B (2013) Placebo effects and their prediction across multiple experimentally induced symptoms: motion sickness, cutaneous heat and cold pain, and rectal distension. Ph. D. thesis, University of Tübingen Medical School, Tübingen.
38. Horing B, Weimer K, Muth ER et al (2014) Prediction of placebo responses: a systematic review of the literature. Front Psychol (in press).
39. Hróbjartsson A, Gøtzsche PC (2001) Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med 344: 1594-1602.
40. Hróbjartsson A, Gøtzsche PC (2004) Is the placebo powerless? Update of a systematic review with 52 new randomized trials comparing placebo with no treatment. J Intern Med 256: 91-100.
41. Hróbjartsson A, Forfang E, Haahr MT et al (2007) Blinded trials taken to the test: an analysis of randomized clinical trials that report tests for the success of blinding. Int J Epidemiol 36: 654-663.
42. Hunter T, Siess F, Colloca L (2013) Socially induced placebo analgesia: a comparison of a pre-recorded versus live face-to-face observation. Eur J Pain 18: 914-922. doi: 10. 1002/j. 1532-2149. 2013. 00436. x.
43. Iovieno N, Papakostas GI (2012) Does the presence of an open-label antidepressant treatment period influence study outcome in clinical trials examining augmentation/combination strategies in treatment partial responders/nonresponders with major depressive disorder? J Clin Psychiatry 73: 676-683.
44. Ivanova A, Tamura RN (2011) A two-way enriched clinical trial design: combining advantages of placebo lead-in and randomized withdrawal. Stat Methods Med Res. doi: 10. 1177/0962280211431023.
45. Ivanova A, Qaqish B, Schoenfeld DA (2011) Optimality, sample size, and power calculations for the sequential parallel comparison design. Stat Med 30: 2793-2803.
46. Kaptchuk TJ, Kelley JM, Deykin A et al (2008) Do "placebo responders" exist? Contemp Clin Trials 29: 587-595.
47. Kelemen WL, Kaighobadi F (2007) Expectancy and pharmacology influence the subjective effects of nicotine in a balanced-placebo design. Exp Clin Psychopharmacol 15: 93-101.
48. Kessner S, Wiech K, Forkmann K et al (2013) The effect of treatment history on therapeutic outcome: an experimental approach. JAMA 173: 1468-1469.
49. King M, Nazareth I, Lampe F et al (2005) Conceptual framework and systematic review of the effects of participants' and professionals' preferences in randomised controlled trials. Health Technol Assess 9: 1-186, iii-iv.
50. Kirsch I (2000) Are drug and placebo effects in depression additive? Biol Psychiatry 47: 733-735.
51. Kirsch I (2005) Placebo psychotherapy: synonym or oxymoron? J Clin Psycholb 61: 791-803.
52. Kirsch I, Deacon BJ, Huedo-Medina TB et al (2008) Initial severity and antidepressant benefits: a meta-analysis of data submitted to the food and drug administration. PLoS Med 5: e45.
53. Krogsbøll LT, Hróbjartsson A, Gøtzsche PC (2009) Spontaneous improvement in randomised clinical trials: meta-analysis of three-armed trials comparing no treatment, placebo and active intervention. BMC Med Res Methodol 9: 1.
54. Kunz M, Rainville P, Lautenbacher S (2011) Operant conditioning of facial displays of pain. Psychosom Med 73: 422-431.
55. Lauer MS, D'Agostino RB Sr (2013) The randomized registry trial-the next disruptive technology in clinical research? N Engl J Med 369: 1579-1581.
56. Lee S, Walker JR, Jakul L, Sexton K (2004) Does elimination of placebo responders in a placebo run-in increase the treatment effect in randomized clinical trials? A meta-analytic evaluation. Depress Anxiety 19: 10-19.
57. Leon AC (2012) Challenges in designing comparative-effectiveness trials for antidepressants. Clin Pharmacol Ther 91: 165-167.
58. Levine JD, Gordon NC, Fields HL (1978) The mechanism of placebo analgesia. Lancet 2: 654-657.
59. Lewis DW, Winner P, Wasiewski W (2005) The placebo responder rate in children and adolescents. Headache 45: 232-239.
60. Lidstone SC, Schulzer M, Dinelle K et al (2010) Effects of expectation on placebo-induced dopamine release in Parkinson disease. Arch Gen Psychiatry 67: 857-865.
61. Lindström D, Sundberg-Petersson I, Adami J et al (2010) Disappointment and drop-out rate after being allocated to control group in a smoking cessation trial. Contemp Clin Trials 31: 22-26.
62. Lund K, Vase L, Petersen GL et al (2014) Randomised controlled trials may underestimate drug effects: balanced placebo trial design. PLoS ONE 9: e84104.
63. Machado LA, Kamper SJ, Herbert RD et al (2008) Imperfect placebos are common in low back pain trials: a systematic review of the literature. Eur Spine J 17: 889-904.
64. Mallinckrodt CH, Zhang L, Prucka WR et al (2010) Signal detection and placebo response in schizophrenia: parallels with depression. Psychopharmacol Bull 43: 53-72.
65. Mangione-Smith R, McGlynn EA, Elliott MN et al (1999) The relationship between perceived parental expectations and pediatrician antimicrobial prescribing behavior. Pediatrics 103: 711-718.
66. Martin AL, Katz J (2010) Inclusion of authorized deception in the informed consent process does not affect the magnitude of the placebo effect for experimentally induced pain. Pain 149: 208-215.
67. Marušić A, Ferenčić SF (2013) Adoption of the double dummy trial design to reduce observer bias in testing treatments. J R Soc Med 106: 196-198.
68. McRae AD, Weijer C, Binik A et al (2011) When is informed consent required in cluster randomized trials in health research? Trials 12: 202.
69. Metrik J, Rohsenow DJ, Monti PM et al (2009) Effectiveness of a marijuana expectancy manipulation: piloting the balanced-placebo design for marijuana. Exp Clin Psychopharmacol 17: 217-225.
70. Miller FG, Wendler D, Swartzman LC (2005) Deception in research on the placebo effect. PLoS Med 2: e262.
71. Moncrieff J, Wessely S, Hardy R (2004) Active placebos versus antidepressants for depression. Cochrane Database Syst Rev: CD003012.
72. Ney PG, Collins C, Spensor C (1986) Double blind: double talk or are there ways to do better research? Med Hypotheses 21: 119-126.
73. Papakostas GI, Fava M (2009) Does the probability of receiving placebo influence clinical trial outcome? A meta-regression of double-blind, randomized clinical trials in MDD. Eur Neuropsychopharmacol 19: 34-40.
74. Petrovic P, Kalso E, Petersson KM et al (2002) Placebo and opioid analgesia: imaging a shared neuronal network. Science 295: 1737-1740.
75. Pollo A, Torre E, Lopiano L et al (2002) Expectation modulates the response to subthalamic nucleus stimulation in Parkinsonian patients. Neuroreport 13: 1383-1386.
76. Prady SL, Burch J, Crouch S et al (2013) Insufficient evidence to determine the impact of patient preferences on clinical outcomes in acupuncture trials: a systematic review. J Clin Epidemiol 66: 308-318.
77. Quilici S, Chancellor J, Löthgren M et al (2009) Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol 9: 6.
78. Rao S, Lembo AJ, Shiff SJ et al (2012) A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 107: 1714-1724.
79. Relton C, Torgerson D, O'Cathain A et al (2010) Rethinking pragmatic randomised controlled trials: introducing the "cohort multiple randomised controlled trial" design. BMJ 340: c1066.
80. Rief W, Glombiewski JA (2012) The hidden effects of blinded, placebo-controlled randomized trials: an experimental investigation. Pain 153: 2473-2477.
81. Rief W, Nestoriuc Y, Weiss S et al (2009) Metaanalysis of the placebo response in antidepressant trials. J Affect Disord 18: 1-8.
82. Rief W, Bingel U, Schedlowski M et al (2011) Mechanisms involved in placebo and nocebo responses and implications for drug trials. Clin Pharmacol Ther 90: 722-726.
83. Rosenberger WF, Lachin JM (1993) The use of response-adaptive designs in clinical trials. Contemp Clin Trials 14: 471-484.
84. Rutherford BR, Sneed JR, Rosse SP (2009) Does study design influence outcome? Psychother Psychosom 78: 172-181.
85. Rutherford BR, Sneed JR, Tandler JM et al (2011) Deconstructing pediatric depression trials: an analysis of the effects of expectancy and therapeutic contact. J Am Acad Child Adolesc Psychiatry 50: 782-795.
86. Saarto T, Wiffen PJ (2007) Antidepressants for neuropathic pain. Cochrane Database Syst Rev: CD005454.
87. Schmid J, Theysohn N, Gaß F et al (2013) Neural mechanisms mediating positive and negative treatment expectations in visceral pain: a functional magnetic resonance imaging study on placebo and nocebo effects in healthy volunteers. Pain 154: 2372-2380.
88. Scott DJ, Stohler CS, Egnatuk CM et al (2007) Individual differences in reward responding explain placebo-induced expectations and effects. Neuron 55: 325-336.
89. Shah E, Triantafyllou K, Hana AA et al (2013) Adverse events appear to unblind clinical trials in irritable bowel syndrome. Neurogastroenterol Motil 26: 482-488. doi: 10. 1111/nmo. 12289.
90. Sinyor M, Levitt AJ, Cheung AH et al (2010) Does inclusion of a placebo arm influence response to active antidepressant treatment in randomized controlled trials? Results from pooled and meta-analyses. J Clin Psychiatry 71: 270-279.
91. Stone DA, Kerr CE, Jacobson E et al (2005) Patient expectations in placebo-controlled randomized clinical trials. J Eval Clin Pract 11: 77-84.
92. Suchman AL, Ader R (1992) Classic conditioning and placebo effects in crossover studies. Clin Pharmacol Ther 52: 372-377.
93. Swider K, Babel P (2013) The effect of the sex of a model on nocebo hyperalgesia induced by social observational learning. Pain 154: 1312-1317.
94. Vase L, Riley JL, Price DD (2002) A comparison of placebo effects in clinical analgesic trials versus studies of placebo analgesia. Pain 99: 443-452.
95. Vögtle E, Barke A, Kröner-Herwig B (2013) Nocebo hyperalgesia induced by social observational learning. Pain 154: 1427-1433.
96. Volkow ND, Wang GJ, Ma Y et al (2003) Expectation enhances the regional brain metabolic and the reinforcing effects of stimulants in cocaine abusers. J Neurosci 23: 11461-11468.
97. Vray M, Girault D, Hoog-Labouret N et al (2004) Methodology for small clinical trials. Therapie 59: 273-286.
98. Weijer C, Grimshaw JM, Eccles MP et al (2012) The Ottawa statement on the ethical design and conduct of cluster randomized trials. PLoS Med 9: e1001346.
99. Weimer K, Enck P, Klosterhalfen S (2010) Gender effects in placebo responses. Z Med Psychol 19: 146-153.
100. Weimer K, Gulewitsch M, Schlarb AA et al (2013a) Placebo effects in children: a review. Pediatr Res 74: 96-102.
101. Weimer K, Horing B, Stürmer J et al (2013b) Nicotine expectancy differentially affects reaction time in healthy non-smokers and smokers depending on gender. Exp Clin Psychopharmacol 21: 181-187.
102. Weimer K, Horing B, Walentin S et al (2013c) Nicotine stimulus expectancy but not nicotine affects cognitive performance in healthy smokers and non-smokers. Psychosom Med 75: A115.
103. Whalley B, Hyland ME (2013) Placebo by proxy: the effect of parents' beliefs on therapy for children's temper tantrums. J Behav Med 36: 341-346.
104. Whalley B, Hyland ME, Kirsch I (2008) Consistency of the placebo effect. J Psychosom Res 64: 537-541.
105. Woods SW, Gueorguieva RV, Baker CB et al (2005) Control group bias in randomized atypical antipsychotic medication trials for schizophrenia. Arch Gen Psychiatry 62: 961-970.
106. World Medical Association (2013) World medical association declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310: 2191-2194.
107. Zelen M (1979) A new design for randomized clinical trials. N Engl J Med 300: 1242-1245.
108. Zhang L, Rosenberger WF (2006) Response-adaptive randomization for clinical trials with continuous outcomes. Biometrics 62: 562-569.