frank placebo
TRANSCRIPT
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Placebo: Ethics and
AlternativesSamuel Frank, MD
Assistant Professor of NeurologyBoston University School of Medicine
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Overview
Placebo vs. placebo effect
Justification for using placebos
Types of placebos Ethical considerations in invasive
placebos
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History of Placebos = History of Medicine
Medicine kills, nature heals
Paracelsus, 15th century
The art of medicine is to amuse thepatient while nature cures the illness.
Voltaire, 17th century
Until the early 20thcentury, mosttreatments were placebo
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Lasagna, 1986 J All Clin Imm
Placebo
Used in early Christianity Placebo Dominoin regione vivorum or I shall be pleasingto the lord in the land of the living.
Likely a mistranslation from I shall walk
Definitions include an indifferent or inertsubstance in the form of a medication orsubstance
Some definitions include given for themoral or suggestive effect.
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Types of Placebos
A substance in the form of a medicine as tabletsor capsules Typically manufactured by company testing product Can also encapsulate pills
Contain inert substancesActive placebos contain an agent to induce
effects, mimicking known side effects of themedication being tested
Examples: vitamins, inactive oil or agent to colorurine
Sham procedure
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Why Placebos AreMethodologically Necessary
Demonstrates that physiological effects ofintervention are responsible rather than: Natural fluctuations in disease
Mode of administration Psychosomatic effects from participant expectation
Invasive procedures have larger placebo effect Including iv vs. oral therapies vs. surgical
interventions
Blinding not possible if one arm does not receivean intervention
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Placebo Effect
= desirable physiological or psychologicaleffects attributable to the use of inertmedications
Even when objective outcome measuresare used, an effect can be measured dueto exposure to placebos
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de la Fuente-Fernndez, Lancet Neurol2002
Placebo Effect in PD
[11C]raclopride PET scans of a patient with Parkinson's disease. Thelower radioactivity observed in the striatum after placebo (saline
injection) reflects increased occupancy of striatal D2 receptors by
dopamine (ie, placebo-induced dopamine release).
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Heart of Debate about UsingPlacebos:
The essential medical question at issue ishow the new treatment compares with theold one, not whether the new treatment is
better than nothing. Hill, BMJ 1963
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Horng & Miller, 2003
A Placebo-controlled Trial CanBe Ethically Justified If:
There is a valuable, clinically relevant questionto be answered by the research
The placebo control is methodologicallynecessary to test the study hypothesis
The risk of the placebo control itself has beenminimized Debatable in more invasive controls
The risk of a placebo control does not exceed a
threshold of acceptable research risk Concern re: withholding treatmentAcceptable example: placebo in a trial of nausea
medication
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Are Placebos Ethical?
How can subjects be randomized to treatmentsthat may be inferior?
Can delaying intervention be harmful?
Are researchers deluding themselves intothinking 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 astate of clinical equipoise
It is on this basis that clinical trials can be initiatedand continued
Caution: positive trial publication bias alters equipoise
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Equipoise
Some argue that a subject's evaluation ofthe options is morally relevant and all thatis needed is adequately informed, free,
and unexploited consent
Ignores distinction between clinical trials,treatment in the context of clinical
medicine and the methodologicallimitations of active-controlled trials.
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Kottow M. J Eval Clin Prac 2007
Equipoise: Two Types
Medical alternatives are equivalent interms of effectiveness, cost, risks,availability
Choosing one or the other has similarconsequences
Alternatives are highly controversial
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When Placebos Harm
Also termed nocebo
Active placebos that have a higher chancefor harm alter the risk/benefit ratio
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
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Use of Placebo in the Evaluation ofNovel Invasive Techniques
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No Joke
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How Surgical Techniques HaveBeen Evaluated
Individuals
Small open label studies
Surgery vs. non-surgical control Optimal medical management Or self as control (CAPSIT-PD)
Surgery vs. surgical control Placebo intervention or delivery
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Examples of Abandoned SurgeriesBased on Sham Surgery Controls
Internal mammary artery ligation forangina (1959)
Shunt surgery for Menieres disease(1983)
Arthroscopic knee surgery forosteoarthritis pain (2002)
Fetal cell transplant for Parkinsonsdisease
NEJM 2001, Ann Neurol 2003
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Objections to Invasive Placebos
Risk of procedure (sham surgery)Active deception of participants Can informed consent be truly obtained?
Examples: Placebos that harm: sham surgery controls in clinicaltrials (London, 2002)
Sham neurosurgery in patients with Parkinson'sdisease: is it morally acceptable? (Dekkers, 2001)
The ethical problems with sham surgery in clinicalresearch (Macklin, 1999) I need a placebo like I need a hole in the head
(Weijer, 2002)
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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 blindingcontinues
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Perspectives on Sham Surgery
PRO: Blinding & controls needed for rigorous
assessment of novel high risk interventions
CON: Sham surgery with its attendant risks isnever warranted given adverserisk:benefit ratio
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Table Adverse events using placebo (sham) surgery controls in Parkinson disease (PD)surgical clinical trials
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Arch Neurol 2005;62:1357-1360
Ask the Experts
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Background
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 thefollowing 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)
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Results
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Results of Permissibility Question:
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Scientist Survey Conclusion
It appears unlikely that the PD clinicalresearch community will perceive futureneurosurgical interventions for PD as truly
efficacious unless a sham control condition(placebo) is used to test it.
Limitations: U.S. based survey
Did not discuss investigator involvement intrials
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Background: Identical toScientist Survey
Language appropriate for lay audience Premise:
Rodent & primate studies and 8 subject Phase I trialof a gene transfer procedure completed
safe for 6 months improved clinical features
Question: What should be the design of thefollowing 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)
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Three Groups of Participants
PD patients
n=56, overall older, 60% men
Other Neurology patients
n=113
Primary care
n=119, mostly women
Overall 60% response rate
No difference b/t groups
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Questions Posed
Personal participation in such trials
Permissibility of trials
Are risks to subjects justified by benefit tosociety?
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Which Study Would You Allow?
0
10
20
30
40
50
60
70
80
90
PD Non-PD PC
Patient groups
%a
llowings
tudy
unblinded
blinded
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Compared to Scientist View
Opposite of patients
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Is the risk to the subject justified by the potential
benefits to science and to society (%)?
Group Yes No Maybe/Not Sure
PD 61.5 30.8 1.9
Non-PD 52 41.2 2PC 47.8 41.1 7.8
Risks of sham justified: 56% of allrespondents
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Conclusions from Survey
Patients from all groups would rather participatein trials involving unblinded surgery.
PD patients skeptical about researchparticipationA higher proportion of PD patients would not
participate in research involving any kind of surgery.
Sham controls seem acceptable to manypatients, as the majority, including those withPD: Believe the risk is justified given the benefit
Would allow a blinded study
Would allow an unblinded study
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J Gen Intern Med 2007;23(1):710
Placebos in Clinical Practice?
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Placebos in Academic Practice
45% reported they had used a placebo in clinicalpractice
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%)
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Thank you to our group
Scott Kim, MD, PhD
Karl Kieburtz, MD, MPH
Robert Holloway, MD, MPH Renee Wilson
Carol Zimmerman, RN
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Thank You!