Placebo: Ethics and Placebo: Ethics and AlternativesAlternatives

Samuel Frank, MDSamuel Frank, MD

Assistant Professor of NeurologyAssistant Professor of Neurology

Boston University School of Boston University School of MedicineMedicine

OverviewOverview

Placebo vs. placebo effectPlacebo vs. placebo effect Justification for using Justification for using

placebosplacebos Types of placebosTypes of placebos Ethical considerations in Ethical considerations in

invasive placebosinvasive placebos

History of Placebos = History of History of Placebos = History of MedicineMedicine

Medicine kills, nature healsMedicine kills, nature heals– Paracelsus, 15th centuryParacelsus, 15th century

The art of medicine is to amuse the The art of medicine is to amuse the patient while nature cures the illness.patient while nature cures the illness.– Voltaire, 17th centuryVoltaire, 17th century

Until the early 20Until the early 20thth century, most century, most treatments were placebotreatments were placebo

Lasagna, 1986 J All Clin ImmLasagna, 1986 J All Clin Imm

PlaceboPlacebo

Used in early Christianity “Placebo Domino Used in early Christianity “Placebo Domino in regione vivorum” or “I shall be pleasing in regione vivorum” or “I shall be pleasing to the lord in the land of the living.”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 Definitions include an indifferent or inert

substance in the form of a medication or substance in the form of a medication or substancesubstance

Some definitions include “given for the Some definitions include “given for the moral or suggestive effect.”moral or suggestive effect.”

Types of PlacebosTypes of Placebos A substance in the form of a medicine as A substance in the form of a medicine as

tablets or capsulestablets or capsules– Typically manufactured by company testing Typically manufactured by company testing

productproduct– Can also encapsulate pillsCan also encapsulate pills– Contain “inert” substancesContain “inert” substances

Active placebos contain an agent to induce Active placebos contain an agent to induce effects, mimicking known side effects of effects, mimicking known side effects of the medication being testedthe medication being tested– Examples: vitamins, inactive oil or agent to Examples: vitamins, inactive oil or agent to

color urinecolor urine Sham procedureSham procedure

Why Placebos Are Why Placebos Are Methodologically NecessaryMethodologically Necessary

Demonstrates that physiological effects of Demonstrates that physiological effects of intervention are responsible rather than:intervention are responsible rather than:– Natural fluctuations in diseaseNatural fluctuations in disease– Mode of administrationMode of administration– Psychosomatic effects from participant Psychosomatic effects from participant

expectationexpectation Invasive procedures have larger placebo Invasive procedures have larger placebo

effecteffect– Including iv vs. oral therapies vs. surgical Including iv vs. oral therapies vs. surgical

interventionsinterventions Blinding not possible if one arm does not Blinding not possible if one arm does not

receive an interventionreceive an intervention

Placebo EffectPlacebo Effect

= desirable physiological or = desirable physiological or psychological effects attributable to psychological effects attributable to the use of “inert” medicationsthe use of “inert” medications

Even when objective outcome Even when objective outcome measures are used, an effect can be measures are used, an effect can be measured due to exposure to measured due to exposure to placebosplacebos

de la Fuente-Fernández, Lancet de la Fuente-Fernández, Lancet Neurol 2002Neurol 2002

Placebo Effect in PDPlacebo 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).

Heart of Debate about Using Heart of Debate about Using Placebos:Placebos:

The essential medical question at The essential medical question at issue is how the new treatment issue is how the new treatment compares with the old one, not compares with the old one, not whether the new treatment is better whether the new treatment is better than nothing.than nothing.– Hill, BMJ 1963 Hill, BMJ 1963

Horng & Miller, 2003Horng & Miller, 2003

A Placebo-controlled Trial A Placebo-controlled Trial Can Be Ethically Justified If:Can Be Ethically Justified If:

There is a valuable, clinically relevant There is a valuable, clinically relevant question to be answered by the researchquestion to be answered by the research

The placebo control is methodologically The placebo control is methodologically necessary to test the study hypothesisnecessary to test the study hypothesis

The risk of the placebo control itself has The risk of the placebo control itself has been minimizedbeen minimized– Debatable in more invasive controlsDebatable in more invasive controls

The risk of a placebo control does not The risk of a placebo control does not exceed a threshold of acceptable research exceed a threshold of acceptable research riskrisk– Concern re: withholding treatmentConcern re: withholding treatment– Acceptable example: placebo in a trial of nausea Acceptable example: placebo in a trial of nausea

medicationmedication

Additional JustificationsAdditional Justifications The risk of the placebo control is justified by The risk of the placebo control is justified by

valuable knowledge to be gainedvaluable knowledge to be gained The misleading involved in the administration of a The misleading involved in the administration of a

placebo control is adequately disclosed and placebo control is adequately disclosed and authorized during the informed consent processauthorized during the informed consent process– Patients must be fully informed about the risks of Patients must be fully informed about the risks of

entering a trialentering a trial– If they still agree to participate, then there is no reason If they still agree to participate, then there is no reason

to prevent them from doing so.to prevent them from doing so.– Places burden patientsPlaces burden patients– Reduces maternalistic medicineReduces maternalistic medicine

http://www.wma.net/e/policy/http://www.wma.net/e/policy/b3.htm b3.htm

Declaration of HelsinkiDeclaration of Helsinki The benefits, risks, burdens and effectiveness The benefits, risks, burdens and effectiveness

of a new method should be tested against of a new method should be tested against those of the best current prophylactic, those of the best current prophylactic, diagnostic, and therapeutic methods diagnostic, and therapeutic methods

Condemns the use of placebos except:Condemns the use of placebos except:– when ‘no proven prophylactic, diagnostic or when ‘no proven prophylactic, diagnostic or

therapeutic method exists’ or therapeutic method exists’ or – for ‘placebo-controlled trials that entail only minor for ‘placebo-controlled trials that entail only minor

risks’risks’– An escape clause: placebo control is acceptable An escape clause: placebo control is acceptable

‘when active control would not yield reliable ‘when active control would not yield reliable results’ results’

Are Placebos Ethical?Are Placebos Ethical? How can subjects be randomized to treatments How can subjects be randomized to treatments

that may be inferior?that may be inferior? Can delaying intervention be harmful?Can delaying intervention be harmful? Are researchers deluding themselves into Are researchers deluding themselves into

thinking that there is equipoise and it matters?thinking that there is equipoise and it matters?– If there is no good basis for a choice between two or If there is no good basis for a choice between two or

more options that may benefit a patient, there is a more options that may benefit a patient, there is a state of clinical equipoisestate of clinical equipoise

– It is on this basis that clinical trials can be initiated It is on this basis that clinical trials can be initiated and continuedand continued

– Caution: positive trial publication bias alters Caution: positive trial publication bias alters equipoise equipoise

EquipoiseEquipoise

Some argue that a subject's evaluation Some argue that a subject's evaluation of the options is morally relevant and of the options is morally relevant and all that is needed is adequately all that is needed is adequately informed, free, and unexploited consent informed, free, and unexploited consent

Ignores distinction between clinical Ignores distinction between clinical trials, treatment in the context of trials, treatment in the context of clinical medicine and the clinical medicine and the methodological limitations of active-methodological limitations of active-controlled trials.controlled trials.

Kottow M. J Eval Clin Prac 2007Kottow M. J Eval Clin Prac 2007

Equipoise: Two TypesEquipoise: Two Types

Medical alternatives are equivalent in Medical alternatives are equivalent in terms of effectiveness, cost, risks, terms of effectiveness, cost, risks, availabilityavailability– Choosing one or the other has similar Choosing one or the other has similar

consequences consequences Alternatives are highly controversialAlternatives are highly controversial

When Placebos HarmWhen Placebos Harm

Also termed noceboAlso termed nocebo Active placebos that have a higher chance Active placebos that have a higher chance

for harm alter the risk/benefit ratiofor harm alter the risk/benefit ratio Examples:Examples:

– Give a patient a liquid and tell them it is an Give a patient a liquid and tell them it is an emetic and often it will induce vomitingemetic and often it will induce vomiting The nocebo effectThe nocebo effect

– Some use it with harm done to control groupSome use it with harm done to control group No chance of benefit despite a procedure or No chance of benefit despite a procedure or

interventionintervention

Use of Placebo in the Use of Placebo in the Evaluation of Novel Invasive Evaluation of Novel Invasive

TechniquesTechniques

No JokeNo Joke

How Surgical Techniques Have How Surgical Techniques Have Been EvaluatedBeen Evaluated

IndividualsIndividuals Small open label studiesSmall open label studies Surgery vs. non-surgical control Surgery vs. non-surgical control

– Optimal medical managementOptimal medical management– Or self as control (CAPSIT-PD)Or self as control (CAPSIT-PD)

Surgery vs. surgical controlSurgery vs. surgical control– Placebo intervention or deliveryPlacebo intervention or delivery

Examples of Abandoned Examples of Abandoned Surgeries Based on Sham Surgeries Based on Sham

Surgery ControlsSurgery Controls Internal mammary artery ligation for Internal mammary artery ligation for

angina (angina (19591959)) Shunt surgery for Meniere’s disease Shunt surgery for Meniere’s disease

(1983)(1983) Arthroscopic knee surgery for Arthroscopic knee surgery for

osteoarthritis pain (osteoarthritis pain (20022002)) Fetal cell transplant for Parkinson’s Fetal cell transplant for Parkinson’s

diseasedisease– NEJM 2001, Ann Neurol 2003NEJM 2001, Ann Neurol 2003

Objections to Invasive Objections to Invasive PlacebosPlacebos

Risk of procedure (sham surgery)Risk of procedure (sham surgery) Active deception of participantsActive deception of participants Can informed consent be truly obtained?Can informed consent be truly obtained? Examples:Examples:

– Placebos that harm: sham surgery controls in Placebos that harm: sham surgery controls in clinical trials (London, 2002)clinical trials (London, 2002)

– Sham neurosurgery in patients with Sham neurosurgery in patients with Parkinson's disease: is it morally acceptable? Parkinson's disease: is it morally acceptable? (Dekkers, 2001)(Dekkers, 2001)

– The ethical problems with sham surgery in The ethical problems with sham surgery in clinical research (Macklin, 1999)clinical research (Macklin, 1999)

– I need a placebo like I need a hole in the head I need a placebo like I need a hole in the head (Weijer, 2002)(Weijer, 2002)

A Placebo Dilemma:A Placebo Dilemma:Sham Surgery in PD ResearchSham Surgery in PD Research

- Invasive experimental interventionsInvasive experimental interventions- Cell transplant, gene transferCell transplant, gene transfer

- Fetal cell studies ended after 2 placebo Fetal cell studies ended after 2 placebo controlled trials demonstrated lack of efficacy controlled trials demonstrated lack of efficacy in most groups and under-recognized adverse in most groups and under-recognized adverse effectseffects

- Debate over need for placebo and blinding Debate over need for placebo and blinding continuescontinues

Perspectives on Sham SurgeryPerspectives on Sham Surgery

PRO:PRO: Blinding & controls needed for rigorous Blinding & controls needed for rigorous assessment of novel high risk interventionsassessment of novel high risk interventions

CON: Sham surgery with its attendant risks isCON: Sham surgery with its attendant risks is never warranted given adversenever warranted given adverse risk:benefit ratiorisk:benefit ratio

What is the Risk of Sham What is the Risk of Sham Surgery?Surgery?

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

Sham Surgery Adverse Sham Surgery Adverse EventsEvents

No serious adverse events from sham surgeryNo serious adverse events from sham surgery Although adverse events were reported, none Although adverse events were reported, none

were directly attributable to sham surgerywere directly attributable to sham surgery Higher incidence in intervention group:Higher incidence in intervention group:

– Dyskinesia, dystonia, weight loss, GI symptoms, Dyskinesia, dystonia, weight loss, GI symptoms, parasthesias, infection, hyponatremiaparasthesias, infection, hyponatremia

– May be at higher risk for hemorrhage, seizure and May be at higher risk for hemorrhage, seizure and infarction, if parenchyma disrupted infarction, if parenchyma disrupted

Arch Neurol 2005;62:1357-1360

Ask the ExpertsAsk the Experts

BackgroundBackground

Premise:Premise:– Rodent & primate studies and 8 subject Phase I Rodent & primate studies and 8 subject Phase I

trial of a gene transfer procedure completedtrial of a gene transfer procedure completed safe for 6 monthssafe for 6 months improved clinical featuresimproved clinical features

Question: What should be the design of Question: What should be the design of the following Phase II 50 subject trial?the following Phase II 50 subject trial?– Gene transfer vs. best medical therapy + 2 Gene transfer vs. best medical therapy + 2

burr holes (blinded option)burr holes (blinded option)– Gene transfer vs. best medical therapy (open, Gene transfer vs. best medical therapy (open,

unblinded option)unblinded option)

ResultsResults

Results of Permissibility Results of Permissibility Question:Question:

Scientist Survey ConclusionScientist Survey Conclusion

It appears unlikely that the PD It appears unlikely that the PD clinical research community will clinical research community will perceive future neurosurgical perceive future neurosurgical interventions for PD as truly interventions for PD as truly efficacious unless a sham control efficacious unless a sham control condition (placebo) is used to test itcondition (placebo) is used to test it..

Limitations:Limitations:– U.S. based surveyU.S. based survey– Did not discuss investigator involvement Did not discuss investigator involvement

in trialsin trials

Mov Dis Jan 2008Mov Dis Jan 2008

What Do Patients Think?What Do Patients Think?

Background: Identical to Background: Identical to Scientist SurveyScientist Survey

Language appropriate for lay audienceLanguage appropriate for lay audience Premise:Premise:

– Rodent & primate studies and 8 subject Phase I Rodent & primate studies and 8 subject Phase I trial of a gene transfer procedure completedtrial of a gene transfer procedure completed safe for 6 monthssafe for 6 months improved clinical featuresimproved clinical features

Question: What should be the design of Question: What should be the design of the following Phase II 50 subject trial?the following Phase II 50 subject trial?– Gene transfer vs. best medical therapy + 2 Gene transfer vs. best medical therapy + 2

burr holes (blinded option)burr holes (blinded option)– Gene transfer vs. best medical therapy (open, Gene transfer vs. best medical therapy (open,

unblinded option)unblinded option)

Three Groups of ParticipantsThree Groups of Participants

PD patientsPD patients– n=56, overall older, 60% menn=56, overall older, 60% men

Other Neurology patientsOther Neurology patients– n=113n=113

Primary care Primary care – n=119, mostly womenn=119, mostly women

Overall 60% response rateOverall 60% response rate– No difference b/t groupsNo difference b/t groups

Questions PosedQuestions Posed

Personal participation in such trialsPersonal participation in such trials Permissibility of trialsPermissibility of trials Are risks to subjects justified by Are risks to subjects justified by

benefit to society?benefit to society?

Which study would you Which study would you choose to participate in?choose to participate in?

Which Study Would You Which Study Would You Allow?Allow?

0

10

20

30

40

50

60

70

80

90

PD Non-PD PC

Patient groups

% a

llo

win

g s

tud

y

unblinded

blinded

Compared to Scientist ViewCompared to Scientist View

Opposite of patients

Is the risk to the subject justified by the potential Is the risk to the subject justified by the potential benefits to science and to society (%)?benefits to science and to society (%)?

Group Yes No Maybe/Not Sure PD 61.5 30.8 1.9 Non-PD 52 41.2 2 PC 47.8 41.1 7.8

Risks of sham justified: 56% of all respondents

Conclusions from SurveyConclusions from Survey Patients from all groups would rather Patients from all groups would rather

participate in trials involving unblinded surgery.participate in trials involving unblinded surgery. PD patients skeptical about research PD patients skeptical about research

participationparticipation– A higher proportion of PD patients would not A higher proportion of PD patients would not

participate in research involving any kind of surgery.participate in research involving any kind of surgery. Sham controls seem acceptable to many Sham controls seem acceptable to many

patients, as the majority, including those with patients, as the majority, including those with PD:PD:– Believe the risk is justified given the benefitBelieve the risk is justified given the benefit– Would allow a blinded studyWould allow a blinded study– Would allow an unblinded studyWould allow an unblinded study

J Gen Intern Med 2007;23(1):7–10J Gen Intern Med 2007;23(1):7–10

Placebos in Clinical Placebos in Clinical Practice?Practice?

Placebos in Academic Placebos in Academic PracticePractice

45% reported they had used a placebo in 45% reported they had used a placebo in clinical practiceclinical practice

Reasons for use:Reasons for use:– to calm the patient (18%)to calm the patient (18%)– as supplemental treatment (18%)as supplemental treatment (18%)– ““after ‘unjustified’ demand for medication” after ‘unjustified’ demand for medication”

(15%)(15%)– ““for nonspecific complaints” (13%)for nonspecific complaints” (13%)– ““after all clinically indicated treatment after all clinically indicated treatment

possibilities were exhausted” (11%)possibilities were exhausted” (11%)– ““to control pain” (6%)to control pain” (6%)– ““to get the patient to stop complaining” (6%)to get the patient to stop complaining” (6%)– ““as a diagnostic tool” (4%)as a diagnostic tool” (4%)

ConclusionsConclusions Placebo was essentially standard medical care Placebo was essentially standard medical care

until the last centuryuntil the last century Placebo control groups in clinical trials can be Placebo control groups in clinical trials can be

appropriate and ethically acceptableappropriate and ethically acceptable Using a placebo-control in clinical trials may be Using a placebo-control in clinical trials may be

necessary to distinguish true effects of an necessary to distinguish true effects of an interventionintervention

The debate regarding surgical placebos (sham The debate regarding surgical placebos (sham surgery) continuessurgery) continues

Under the proper circumstances, most Under the proper circumstances, most researchers and potential study participants researchers and potential study participants accept placebos, including sham surgeryaccept placebos, including sham surgery

Thank you to our groupThank you to our group

Scott Kim, MD, PhDScott Kim, MD, PhD Karl Kieburtz, MD, MPHKarl Kieburtz, MD, MPH Robert Holloway, MD, MPHRobert Holloway, MD, MPH Renee WilsonRenee Wilson Carol Zimmerman, RNCarol Zimmerman, RN

The Onion, "Wonder Drug" The Onion, "Wonder Drug" 10/23/0410/23/04

Thank You!Thank You!