Download Placebo

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 20th century, most
treatments were placebo
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.”

Lasagna, 1986 J All Clin Imm
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

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).
de la Fuente-Fernández, Lancet Neurol
2002
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
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
Horng & Miller, 2003
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
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’
http://www.wma.net/e/policy/b3.htm
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.

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
Kottow M. J Eval Clin Prac 2007
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 Meniere’s disease
(1983)
 Arthroscopic knee surgery for
osteoarthritis pain (2002)
 Fetal cell transplant for Parkinson’s
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
Ask the Experts
Arch Neurol 2005;62:1357-1360
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
What Do Patients Think?
Mov Dis Jan 2008
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?
90
% allowing study
80
70
60
50
unblinded
40
blinded
30
20
10
0
PD
Non-PD
Patient groups
PC
Compared to Scientist View
Opposite of patients
Is the risk to the subject justified by the potential
benefits to science and to society (%)?
Group
PD
Non-PD
PC
Yes
61.5
52
47.8
No
30.8
41.2
41.1
Maybe/Not Sure
1.9
2
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
Placebos in Clinical Practice?
J Gen Intern Med 2007;23(1):7–10
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

Thank You!
The Onion, "Wonder Drug" 10/23/04