Placebo: Ethics and

Alternatives
Samuel Frank, MD
Assistant Professor of Neurology
Boston University School of Medicine
Overview
Placebo vs. placebo effect
Justification for using placebos
Types of placebos
Ethical considerations in invasive
placebos
History of Placebos = History of Medicine
Medicine kills, nature heals
Paracelsus, 15th century
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
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.
Likely a mistranslation from I shall walk
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.
Types of Placebos
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
Examples: vitamins, inactive oil or agent to color
urine
Sham procedure
Why Placebos Are
Methodologically Necessary
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
Including iv vs. oral therapies vs. surgical
interventions
Blinding not possible if one arm does not receive
an intervention
Placebo Effect
= 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
de la Fuente-Fernndez, 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).
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.
Hill, BMJ 1963
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
The placebo control is methodologically
necessary to test the study hypothesis
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
Concern re: withholding treatment
Acceptable example: placebo in a trial of nausea
medication
Additional Justifications
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
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
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
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
Are Placebos Ethical?
How can subjects be randomized to treatments
that may be inferior?
Can delaying intervention be harmful?
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
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
Ignores distinction between clinical trials,
treatment in the context of clinical
medicine and the methodological
limitations of active-controlled trials.
Kottow M. J Eval Clin Prac 2007
Equipoise: Two Types
Medical alternatives are equivalent in
terms of effectiveness, cost, risks,
availability
Choosing one or the other has similar
consequences
Alternatives are highly controversial
When Placebos Harm
Also termed nocebo
Active placebos that have a higher chance
for 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
Use of Placebo in the Evaluation of
Novel Invasive Techniques
No Joke
How Surgical Techniques Have
Been 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
Examples of Abandoned Surgeries
Based on Sham Surgery Controls
Internal mammary artery ligation for
angina (1959)
Shunt surgery for Menieres disease
(1983)
Arthroscopic knee surgery for
osteoarthritis pain (2002)
Fetal cell transplant for Parkinsons
disease
NEJM 2001, Ann Neurol 2003
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 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)
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
Perspectives on Sham Surgery
PRO: Blinding & controls needed for rigorous
assessment of novel high risk interventions

CON: Sham surgery with its attendant risks is
never warranted given adverse
risk:benefit ratio
What is the Risk of Sham Surgery?
Table Adverse events using placebo (sham) surgery controls in Parkinson disease (PD)
surgical clinical trials
Sham Surgery Adverse Events
No serious adverse events from sham surgery
Although adverse events were reported, none were
directly attributable to sham surgery
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
Arch Neurol 2005;62:1357-1360
Ask the Experts
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 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)
Results
Results of Permissibility Question:
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.
Limitations:
U.S. based survey
Did not discuss investigator involvement in
trials
Mov Dis Jan 2008
What Do Patients Think?
Background: Identical to
Scientist Survey
Language appropriate for lay audience
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?
Gene transfer vs. best medical therapy + 2 burr holes
(blinded option)
Gene transfer vs. best medical therapy (open,
unblinded option)
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
Questions Posed
Personal participation in such trials
Permissibility of trials
Are risks to subjects justified by benefit to
society?
Which study would you choose
to participate in?
Which Study Would You Allow?
0
10
20
30
40
50
60
70
80
90
PD Non-PD PC
Patient groups
%

a
l
l
o
w
i
n
g

s
t
u
d
y
unblinded
blinded
Compared to Scientist View
Opposite of patients
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 2
PC 47.8 41.1 7.8

Risks of sham justified: 56% of all
respondents
Conclusions from Survey
Patients from all groups would rather participate
in trials involving unblinded surgery.
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:
Believe the risk is justified given the benefit
Would allow a blinded study
Would allow an unblinded study
J Gen Intern Med 2007;23(1):710
Placebos in Clinical Practice?
Placebos in Academic Practice
45% reported they had used a placebo in clinical
practice
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%)
Conclusions
Placebo was essentially standard medical care until the
last century
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
The debate regarding surgical placebos (sham surgery)
continues
Under the proper circumstances, most researchers and
potential study participants accept placebos, including
sham surgery
Thank you to our group
Scott Kim, MD, PhD
Karl Kieburtz, MD, MPH
Robert Holloway, MD, MPH
Renee Wilson
Carol Zimmerman, RN

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