1. Placebo: Ethics and Alternatives Samuel Frank, MD Assistant Professor of Neurology Boston University School of Medicine

2. Overview Placebo vs. placebo effect Placebo vs. placebo effect Justification for using placebos Justification for using placebos Types of placebos Types of placebos Ethical considerations in invasive placebos Ethical considerations in invasive placebos

3. History of Placebos = History of Medicine Medicine kills, nature heals Medicine kills, nature heals –Paracelsus, 15th century The art of medicine is to amuse the patient while nature cures the illness. The art of medicine is to amuse the patient while nature cures the illness. –Voltaire, 17th century Until the early 20 th century, most treatments were placebo Until the early 20 th century, most treatments were placebo

4. Lasagna, 1986 J All Clin Imm Placebo Used in early Christianity “Placebo Domino in regione vivorum” or “I shall be pleasing to the lord in the land of the living.” Used in early Christianity “Placebo Domino in regione vivorum” or “I shall be pleasing to the lord in the land of the living.” Likely a mistranslation from “I shall walk” Likely a mistranslation from “I shall walk” Definitions include an indifferent or inert substance in the form of a medication or substance Definitions include an indifferent or inert substance in the form of a medication or substance Some definitions include “given for the moral or suggestive effect.” Some definitions include “given for the moral or suggestive effect.”

5. Types of Placebos A substance in the form of a medicine as tablets or capsules A substance in the form of a medicine as tablets or capsules –Typically manufactured by company testing product –Can also encapsulate pills –Contain “inert” substances Active placebos contain an agent to induce effects, mimicking known side effects of the medication being tested Active placebos contain an agent to induce effects, mimicking known side effects of the medication being tested –Examples: vitamins, inactive oil or agent to color urine Sham procedure Sham procedure

6. Why Placebos Are Methodologically Necessary Demonstrates that physiological effects of intervention are responsible rather than: Demonstrates that physiological effects of intervention are responsible rather than: –Natural fluctuations in disease –Mode of administration –Psychosomatic effects from participant expectation Invasive procedures have larger placebo effect Invasive procedures have larger placebo effect –Including iv vs. oral therapies vs. surgical interventions Blinding not possible if one arm does not receive an intervention Blinding not possible if one arm does not receive an intervention

7. Placebo Effect = desirable physiological or psychological effects attributable to the use of “inert” medications = desirable physiological or psychological effects attributable to the use of “inert” medications Even when objective outcome measures are used, an effect can be measured due to exposure to placebos Even when objective outcome measures are used, an effect can be measured due to exposure to placebos

8. de la Fuente-Fernández, Lancet Neurol 2002 Placebo Effect in PD [11C]raclopride PET scans of a patient with Parkinson's disease. The lower radioactivity observed in the striatum after placebo (saline injection) reflects increased occupancy of striatal D2 receptors by dopamine (ie, placebo-induced dopamine release).

9. Heart of Debate about Using Placebos: The essential medical question at issue is how the new treatment compares with the old one, not whether the new treatment is better than nothing. The essential medical question at issue is how the new treatment compares with the old one, not whether the new treatment is better than nothing. –Hill, BMJ 1963

10. Horng & Miller, 2003 A Placebo-controlled Trial Can Be Ethically Justified If: There is a valuable, clinically relevant question to be answered by the research There is a valuable, clinically relevant question to be answered by the research The placebo control is methodologically necessary to test the study hypothesis The placebo control is methodologically necessary to test the study hypothesis The risk of the placebo control itself has been minimized The risk of the placebo control itself has been minimized –Debatable in more invasive controls The risk of a placebo control does not exceed a threshold of acceptable research risk The risk of a placebo control does not exceed a threshold of acceptable research risk –Concern re: withholding treatment –Acceptable example: placebo in a trial of nausea medication

11. Additional Justifications The risk of the placebo control is justified by valuable knowledge to be gained The risk of the placebo control is justified by valuable knowledge to be gained The misleading involved in the administration of a placebo control is adequately disclosed and authorized during the informed consent process The misleading involved in the administration of a placebo control is adequately disclosed and authorized during the informed consent process –Patients must be fully informed about the risks of entering a trial –If they still agree to participate, then there is no reason to prevent them from doing so. –Places burden patients –Reduces maternalistic medicine

12. http://www.wma.net/e/policy/b3.htm Declaration of Helsinki The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods Condemns the use of placebos except: Condemns the use of placebos except: –when ‘no proven prophylactic, diagnostic or therapeutic method exists’ or –for ‘placebo-controlled trials that entail only minor risks’ –An escape clause: placebo control is acceptable ‘when active control would not yield reliable results’

13. Are Placebos Ethical? How can subjects be randomized to treatments that may be inferior? How can subjects be randomized to treatments that may be inferior? Can delaying intervention be harmful? Can delaying intervention be harmful? Are researchers deluding themselves into thinking that there is equipoise and it matters? Are researchers deluding themselves into thinking that there is equipoise and it matters? –If there is no good basis for a choice between two or more options that may benefit a patient, there is a state of clinical equipoise –It is on this basis that clinical trials can be initiated and continued –Caution: positive trial publication bias alters equipoise

14. Equipoise Some argue that a subject's evaluation of the options is morally relevant and all that is needed is adequately informed, free, and unexploited consent Some argue that a subject's evaluation of the options is morally relevant and all that is needed is adequately informed, free, and unexploited consent Ignores distinction between clinical trials, treatment in the context of clinical medicine and the methodological limitations of active-controlled trials. Ignores distinction between clinical trials, treatment in the context of clinical medicine and the methodological limitations of active-controlled trials.

15. Kottow M. J Eval Clin Prac 2007 Equipoise: Two Types Medical alternatives are equivalent in terms of effectiveness, cost, risks, availability Medical alternatives are equivalent in terms of effectiveness, cost, risks, availability –Choosing one or the other has similar consequences Alternatives are highly controversial Alternatives are highly controversial

16. When Placebos Harm Also termed nocebo Also termed nocebo Active placebos that have a higher chance for harm alter the risk/benefit ratio Active placebos that have a higher chance for harm alter the risk/benefit ratio Examples: Examples: –Give a patient a liquid and tell them it is an emetic and often it will induce vomiting  The nocebo effect –Some use it with harm done to control group  No chance of benefit despite a procedure or intervention

17. Use of Placebo in the Evaluation of Novel Invasive Techniques

18. No Joke

19. How Surgical Techniques Have Been Evaluated Individuals Individuals Small open label studies Small open label studies Surgery vs. non-surgical control Surgery vs. non-surgical control –Optimal medical management –Or self as control (CAPSIT-PD) Surgery vs. surgical control Surgery vs. surgical control –Placebo intervention or delivery

20. Examples of Abandoned Surgeries Based on Sham Surgery Controls Internal mammary artery ligation for angina (1959) Internal mammary artery ligation for angina (1959) Shunt surgery for Meniere’s disease (1983) Shunt surgery for Meniere’s disease (1983) Arthroscopic knee surgery for osteoarthritis pain (2002) Arthroscopic knee surgery for osteoarthritis pain (2002) Fetal cell transplant for Parkinson’s disease Fetal cell transplant for Parkinson’s disease –NEJM 2001, Ann Neurol 2003

21. Objections to Invasive Placebos Risk of procedure (sham surgery) Risk of procedure (sham surgery) Active deception of participants Active deception of participants Can informed consent be truly obtained? Can informed consent be truly obtained? Examples: Examples: –Placebos that harm: sham surgery controls in clinical trials (London, 2002) –Sham neurosurgery in patients with Parkinson's disease: is it morally acceptable? (Dekkers, 2001) –The ethical problems with sham surgery in clinical research (Macklin, 1999) –I need a placebo like I need a hole in the head (Weijer, 2002)

22. A Placebo Dilemma: Sham Surgery in PD Research - Invasive experimental interventions -Cell transplant, gene transfer - Fetal cell studies ended after 2 placebo controlled trials demonstrated lack of efficacy in most groups and under-recognized adverse effects - Debate over need for placebo and blinding continues

23. Perspectives on Sham Surgery PRO: Blinding & controls needed for rigorous assessment of novel high risk interventions assessment of novel high risk interventions CON: Sham surgery with its attendant risks is never warranted given adverse never warranted given adverse risk:benefit ratio risk:benefit ratio

24. What is the Risk of Sham Surgery?

25. Table Adverse events using placebo (sham) surgery controls in Parkinson disease (PD) surgical clinical trials

26. Sham Surgery Adverse Events No serious adverse events from sham surgery No serious adverse events from sham surgery Although adverse events were reported, none were directly attributable to sham surgery Although adverse events were reported, none were directly attributable to sham surgery Higher incidence in intervention group: Higher incidence in intervention group: –Dyskinesia, dystonia, weight loss, GI symptoms, parasthesias, infection, hyponatremia –May be at higher risk for hemorrhage, seizure and infarction, if parenchyma disrupted

27. Arch Neurol 2005;62:1357-1360 Ask the Experts

28. Background Premise: Premise: –Rodent & primate studies and 8 subject Phase I trial of a gene transfer procedure completed  safe for 6 months  improved clinical features Question: What should be the design of the following Phase II 50 subject trial? Question: What should be the design of the following Phase II 50 subject trial? –Gene transfer vs. best medical therapy + 2 burr holes (blinded option) –Gene transfer vs. best medical therapy (open, unblinded option)

29. Results

30. Results of Permissibility Question:

31. Scientist Survey Conclusion It appears unlikely that the PD clinical research community will perceive future neurosurgical interventions for PD as truly efficacious unless a sham control condition (placebo) is used to test it. It appears unlikely that the PD clinical research community will perceive future neurosurgical interventions for PD as truly efficacious unless a sham control condition (placebo) is used to test it. Limitations: Limitations: –U.S. based survey –Did not discuss investigator involvement in trials

32. Mov Dis Jan 2008 What Do Patients Think?

33. Background: Identical to Scientist Survey Language appropriate for lay audience Language appropriate for lay audience Premise: Premise: –Rodent & primate studies and 8 subject Phase I trial of a gene transfer procedure completed  safe for 6 months  improved clinical features Question: What should be the design of the following Phase II 50 subject trial? Question: What should be the design of the following Phase II 50 subject trial? –Gene transfer vs. best medical therapy + 2 burr holes (blinded option) –Gene transfer vs. best medical therapy (open, unblinded option)

34. Three Groups of Participants PD patients PD patients – n=56, overall older, 60% men Other Neurology patients Other Neurology patients –n=113 Primary care Primary care –n=119, mostly women Overall 60% response rate Overall 60% response rate –No difference b/t groups

35. Questions Posed Personal participation in such trials Personal participation in such trials Permissibility of trials Permissibility of trials Are risks to subjects justified by benefit to society? Are risks to subjects justified by benefit to society?

36. Which study would you choose to participate in?

37. Which Study Would You Allow?

38. Compared to Scientist View Opposite of patients

39. Is the risk to the subject justified by the potential benefits to science and to society (%)? Risks of sham justified: 56% of all respondents

40. Conclusions from Survey Patients from all groups would rather participate in trials involving unblinded surgery. Patients from all groups would rather participate in trials involving unblinded surgery. PD patients skeptical about research participation PD patients skeptical about research participation –A higher proportion of PD patients would not participate in research involving any kind of surgery. Sham controls seem acceptable to many patients, as the majority, including those with PD: Sham controls seem acceptable to many patients, as the majority, including those with PD: –Believe the risk is justified given the benefit –Would allow a blinded study –Would allow an unblinded study

41. J Gen Intern Med 2007;23(1):7–10 Placebos in Clinical Practice?

42. Placebos in Academic Practice 45% reported they had used a placebo in clinical practice 45% reported they had used a placebo in clinical practice Reasons for use: Reasons for use: –to calm the patient (18%) –as supplemental treatment (18%) –“after ‘unjustified’ demand for medication” (15%) –“for nonspecific complaints” (13%) –“after all clinically indicated treatment possibilities were exhausted” (11%) –“to control pain” (6%) –“to get the patient to stop complaining” (6%) –“as a diagnostic tool” (4%)

43. Conclusions Placebo was essentially standard medical care until the last century Placebo was essentially standard medical care until the last century Placebo control groups in clinical trials can be appropriate and ethically acceptable Placebo control groups in clinical trials can be appropriate and ethically acceptable Using a placebo-control in clinical trials may be necessary to distinguish true effects of an intervention Using a placebo-control in clinical trials may be necessary to distinguish true effects of an intervention The debate regarding surgical placebos (sham surgery) continues The debate regarding surgical placebos (sham surgery) continues Under the proper circumstances, most researchers and potential study participants accept placebos, including sham surgery Under the proper circumstances, most researchers and potential study participants accept placebos, including sham surgery

44. Thank you to our group Scott Kim, MD, PhD Scott Kim, MD, PhD Karl Kieburtz, MD, MPH Karl Kieburtz, MD, MPH Robert Holloway, MD, MPH Robert Holloway, MD, MPH Renee Wilson Renee Wilson Carol Zimmerman, RN Carol Zimmerman, RN

45. The Onion, "Wonder Drug" 10/23/04 Thank You!