1.
Placebo Effect in Clinical
Studies
Aleksandar Skuban, M.D.
September 14, 2012| Boston, MA

2.
disclaimer
The views and opinions expressed in the following
presentation are my own and do not represent the position
of my employer.
2All images used with permission: www.istockphoto.com or as noted

3.
One of the most successful physicians I have ever
known has assured me that he has used more bread
pills, drops of colored water, and powders of
hickory ashes, than all other medicines put together
Thomas Jefferson, 1807
3

4.
Overview
Role in Drug Development
Definition
Trends in Phase III clinical
trials
Mechanisms of Placebo
Response
Case Studies
Mitigation Strategies
Summary
4

5.
Role Of Placebo in Research
Biomedical Research1
Eliminate bias in an experimental setting
Demonstration of effectiveness of new
treatment
Superiority to Control Treatment (active or inactive)
Equivalent to known effective treatment
Equivalence alone does not prove effectiveness (few
exceptions)
Assay Sensitivity
The ability of a study to distinguish between active and
inactive treatment21 Including but not limited to pharmaceutical drug development
2 Temple 2000 5

6.
37% of Phase II-III Studies
1661
4509
Including Placebo control
All Phase II-III Trials
Number of Trials
Open, interventional, Phase 2, Phase 3, Adult
Population, Industry studies at www.clinicaltrials.gov
6

7.
22% of NIH Funded Studies
211
976
NIH studies with Placebo control
All ongoing NIH Studies
Number of Trials
Open, interventional, Adult Population, NIH sponsored studies at www.clinicaltrials.gov
as of
7

8.
Placebo Effect Matters
Placebo response is highly variable
across number of therapeutic
indications:
Multiple psychiatric and neurologic
indications, pain, hypertension,
angina pectoris, IBS, ulcerative
colitis, asthma, heart failure, arthritis,
allergy and others
Extensive literature since 1950s 8

9.
Development Timelines
4.6
5.3
5.4
5.8
6.4
6.5
6.5
6.8
8.1
0.5
0.8
1.2
2.4
1
1.3
1.2
0.7
1.9
AIDS
Anesthetic/Analgesic
Anit-infectives
GI
Immunologic
Cardiovascular
Endocrine
Cancer
Central Nervous System
Clinical Regulatory
9NMEs 2005-2009 (Kaitin 2011)

10.
Success Rates (1993-2004)
8.2
8.7
9.4
9.9
19.4
19.5
20.4
23.9
Central Nervous System
Cardiovascular
GI/metabolism
Respiratory
Cancer/Immunologic
Miscellaneous
Musculoskeletal
Systemic anti-infectives
Clinical Approval Success Rate (%)
10
Compounds that entered human clinical development from 1993 to 2004
DiMasi (2010)

11.
Understanding and controlling placebo
response is important to assess
difference between effective
treatments and placebo in well-
designed trials
Avoid costly development and
repeated clinical trials
11

12.
Trend of Placebo Effect in MDD
0
0.1
0.2
0.3
0.4
0.5
0.6
1980 1985 1990 1995 2000
Placebo SSRIs
12
Adapted from Walsh, et al JAMA, 2002 (simplified for illustrative purposes
only)
*1992: 9 trials to get 2 that showed a
difference between Paroxetine and placebo
(Hooper, 1998)

13.
Headline: Rising placebo response seen in
schizophrenia trials (Reuters Health 6/21/2012)
Background:
“A high and increasing placebo response and a
declining treatment effect are of great concern in
schizophrenia trials conducted in North America. In
this era of global clinical trials, close attention is
needed to the design and conduct of these trials.”1
13
1Exploratory Analyses of Efficacy Data From Schizophrenia Trials in Support of New Drug Applications
Submitted to the US Food and Drug Administration: Ni A. Khin, MD; Yeh-Fong Chen, PhD; Yang Yang,
PhD; Peiling Yang, PhD; and Thomas P. Laughren, MD J Clin Psychiatry 2012;73(6):856–864

14.
Recent Track Record in Phase III
Between 2007-2010
83 Phase III initial and major new indications
Combined success rate of phase III trials
and submissions ~ 50%
Lack of Efficacy in 66% of failed programs
33% of trials failed to show benefit over placebo
Nature Reviews Drug Discovery Vol. 10, February 2011 14

15.
Reason for Failure in Phase III
Nature Reviews Drug Discovery Vol. 10, February 2011
0 20 40 60 80 100
Undisclosed
Financial or Commercial
Safety (Risk/Benefit)
Lack of Efficacy
Reason for Failure (%) Vs Placebo Vs Add-on Vs Active
15

16.
Placebo
Substance or procedure objectively without
specific activity for the condition being
treated1
Placebo effect is the therapeutic effect
produced by placebo1
Denotes “positive/beneficial” effect
1Arthur K. Shapiro, M.D.
16

17.
History of Healing is History of
Placebo
The cure for the headache was kind
of a leaf, which required to
be accompanied by charm,
and if a person would repeat
the charm at the same time that
he used the cure, he would
made whole; but without the charm
the leaf would be of no avail
Socrates
17

18.
18
New Medical Dictionary (1785)
“A commonplace method of medicine”
Quincy’s Lexicon-Medicum (1811)
“An epithet given to any medicine adapted more
to please than to benefit the patient”

19.
Placebo In Clinical Research
1830s Homeopathic Studies in Russian
Army
treatment groups included homeopathic,
allopathic, placebo and no-treatment
1930s Angina Pectoris in cross-over
study
1938 first administered in a parallel
group: 19

20.
About Treatment Effect
•Conditions
fluctuate and
improve
irrespective of
treatment
•Validity
•Reliability
•Sensitivity
•Characteristics
•Magnitude
•Duration
•Outcomes
•Population
•Mechanism of
Action
Efficacy of
a Specific
Treatment
Non-specific
treatment
effects
(placebo
effect)
Natural history
and regression
to the mean
Measurement
20
Turner at al (JAMA 1994)- Placebo Effects on Pain

21.
Placebo≠No-Treatment
Placebo is provided as Intervention in:
Scientific Experiments
Clinical Treatment
Randomized Clinical Trials
Intervention + Context
No-Treatment Groups not
feasible in RCTs
21

22.
Components of Placebo Effect

23.
23
Who (Placebo Responder)
No specific subject type or traits
What (Placebo attributes)
“Effectiveness” of pills, procedures, surgery
Type and complexity of intervention
Origin of treatment, importance of size/shape/color
How (Administration)
“Two placebos are better than one”
Carryover-and cumulative effects, length of placebo
effect
Who, What, How, Where, When (Setting)
Who administers the treatment, doctor-patient
relationship
Physician and Staff attitude and behavior

24.
Open Placebo Administration
Open-label, randomized study in patients
with Irritable Bowel Syndrome (n=80)
Open-label placebo vs. no-treatment
Presented and explained in Informed
Consent
Placebo superior to no-treatment on global
improvement scores at D11 (p<0.001) and
D21(p=0.002)
24Kaptchuk 2010

25.
Mechanisms of Placebo Effect
Psychological
Expectancy
Classical
Pavlovian
Conditioning
Learning,
memory,
motivation,
somatic
focus
Neurobiological:
Placebo
analgesia
Endogenous
Opioid
Release
Non-opioid
mechanisms
Neurotransmitter
s
and
neuromodulators
25Modified after Enck 2008

26.
Mechanisms of Placebo Effect*
Pain Activation of endogenous opioids and dopamine (placebo)
Activation of cholecystokinin and deactivation of dopamine
(nocebo)
Parkinson’s
Disease
Activation of dopamine in the striatum
Depression Changes of electrical and metabolic activity in different brain
regions
Anxiety Changes in activity of the anterior cingulated and orbitofrontal
cortices
CV system Reduction of β-adrenergic activity of heart
Respiratory system Conditioning of opioid receptors in the respiratory centres
Endocrine system Conditioning of some hormones
Immune system Conditioning of some immune mediators
*Adapted after Finniss 2010
26

27.
Placebo vs. Placebo in IBS Study
Patients with IBS
3-weeks identical “sham”
acupuncture procedure
45 minutes
“Augmented” Initial
Conversation
5 minutes
“Limited” Initial
Conversation
Waiting List
27Kaptchuk 2008

28.
IBS Study Outcome
Treatment 3 Weeks
(acupuncture 2x per
week)
Outcomes: Symptom
relief and Quality of Life
Sustained after 3-week
acupuncture treatment
Patient-physician
relationship
62
44
28
Augmented Arm Limited Arm Waiting List
% of Patients with Adequate Pain
Relief
28Kaptchuk 2008

29.
What influences placebo
response?
29
621 volunteers treated for 1 week -“Positive
influence on mood and cognition”
7 different types of tablets (shape, color, origin,
price)
Questionnaire: mood, physical abilities, thinking
abilities, memory, attention
Significant improvement after therapy
(p<0.0001)
Dolinska, 1999

30.
Dimensions of placebo
response: Study Outcome
30
Origin: Polish manufactured (p<0.01)
Big white and small red produced better effect
than small white and large red tablet
(p<0.00001)
Best placebo for women German-produced
expensive pill (p<0.01)
Dolinska, 1999

31.
Factors Contributing to
Placebo Effect
Diagnostic Misclassification
Patient Selection and “symptomatic volunteers”
Patient and Clinician Expectations about the Trial
Non-Specific Therapeutic Effects
Natural Course of Illness-
“Regression to the Mean”
Inclusion/Exclusion Criteria
Sub-populations(type, severity, inflation of entry criteria)
Co-morbidities
Lack of Sensitivity to Change in Outcome Measures
Study Design Issues
Increased Complexity and Assessment Duration
High Attrition Rates
Modified after Fava 2003 and Walsh 2002
31

32.
What Can Be Done to Improve
Signal Detection?
Standardizing Diagnostic Procedures
Enrollment of Selected Populations
Criteria: broad vs. sub-populations, specific
characteristics
Investigator/Rater Training
Practice vs. research
Inter-rater Reliability
Minimizing Non-Specific Therapeutic Effects
Staff interaction with patients,
research-focus, setting expectations
Precision in Study Conduct (Data Generation) 32
Modified after Fava (2003), Walsh (2002)

33.
Study Design Strategies
Placebo lead-in phase (to identify placebo
responders)
Single or double blind, fixed or variable duration
Changing trial duration (extending vs. shortening)
Early vs. late placebo and treatment responses
Fewer number of sites, treatment arms
(simplification)
Challenging development timelines
Increasing Sensitivity of Outcome measures
Objective measures, minimizing rater bias
33

34.
Few Additional Points
Addressing Study Visit Issues
Fixed visit schedule, knowledge & expectation of
treatment end
“Major” vs. “minor” visits (communication, treatment
rituals)
Minimize decision bias (eligibility for randomization)
Simplification of Assessments
Major visits take several hours
Extra visits may contribute to placebo response
Global Differences in Placebo/Treatment
Effect
Emerging regional specificities
Changing clinical trial landscape 34

35.
Strategies for Neuropathic Pain
Studies1
Exclusion of patients with mild severity &
short episode
Reliability, validity, responsiveness of
outcome measure
Minimizing contact with investigative staff
Trial Duration, Treatment Groups
Dose designs (flexible vs. fixed-dose)
Run-in period considerations
35Dworkin 2005

36.
Novel
Study
Designs
36

37.
37
ACTIVE
ACTIVE
SPECIFIC NON-SPECIFIC
KNOWLEDGE
ACTIVE KNOWLEDGE
OUTCOME
OUTCOME
KNOWLEDGE
OUTCOME
ROUTINE MEDICAL
PRACTICE
TREATMENT WITH
PLACEBO
HIDDEN
TREATMENT
Adapted after Finnis 2010

38.
38
Patients with post-
operative pain needed >
50% higher dose of
medication in hidden
treatment setting than
subjects in the open-
treatment setting

39.
In Sum
Understand placebo response to
reliably evaluate effectiveness of
novel treatments in well-designed
trials
Avoid costly development and
repeated clinical trials
Renewed interest in placebo
research in the last 10-15 years
New hypotheses, experimental
models and biomarker support
Influencing medical practice,
ethics and trial designs
39

40.
40
Field trials are indispensible. They will
continue to be an ordeal. They lack glamour,
they strain our patience, and they protract the
moment of truth to excruciating limits.
Still, they are among the most challenging
tests of our skills. I have no doubts that when
the problem is well chosen, the study is
appropriately designed, and that when all the
populations concerned are made aware of
the route and the goal, the reward will be
commensurate with the effort.
If, in the major medical dilemmas, the
alternative is to pay the cost of perpetual
uncertainty, have we really any choice?
Donald S. Fredrickson, 1968
Director National Heart Institute
Thank you
Q&A