Placebo Effect in Clinical Studies

Aleksandar Skuban, M.D.

September 14, 2012| Boston, MA

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

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

Overview Role in Drug DevelopmentDefinition Trends in Phase III clinical trialsMechanisms of Placebo ResponseCase Studies Mitigation StrategiesSummary

4

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 treatmentEquivalence alone does not prove effectiveness (few exceptions)

Assay SensitivityThe ability of a study to distinguish between active and inactive treatment2

1 Including but not limited to pharmaceutical drug development2 Temple 2000

5

37% of Phase II-III Studies

Including Placebo control

All Phase II-III Trials

1661

4509

Number of Trials

Open, interventional, Phase 2, Phase 3, Adult Population, Industry studies at www.clinicaltrials.gov as of 17 Aug 2012

6

22% of NIH Funded Studies

NIH studies with Placebo control

All ongoing NIH Studies

211

976

Number of Trials

Open, interventional, Adult Population, NIH sponsored studies at www.clinicaltrials.gov as of 17 August 2012

7

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 1950s8

Development Timelines

AIDS

Anesthetic/Analgesic

Anit-infectives

GI

Immunologic

Cardiovascular

Endocrine

Cancer

Central Nervous System

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

Clinical Regulatory

9NMEs 2005-2009 (Kaitin 2011)

Success Rates (1993-2004)

Central Nervous System

Cardiovascular

GI/metabolism

Respiratory

Cancer/Immunologic

Miscellaneous

Musculoskeletal

Systemic anti-infectives

8.2

8.7

9.4

9.9

19.4

19.5

20.4

23.9

Clinical Approval Success Rate (%)

10Compounds that entered human clinical development from 1993 to 2004DiMasi (2010)

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

Trend of Placebo Effect in MDD

1980 1985 1990 1995 20000

0.1

0.2

0.3

0.4

0.5

0.6

Placebo SSRIs

12Adapted 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)

*

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

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

Reason for Failure in Phase III

Nature Reviews Drug Discovery Vol. 10, February 2011

Undisclosed

Financial or Commercial

Safety (Risk/Benefit)

Lack of Efficacy

0 10 20 30 40 50 60 70 80 90 100Reason for Failure (%) Vs Placebo Vs Add-on Vs Active

15

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

History of Healing is History of Placebo

The cure for the headache was kind of a leaf, which required tobe 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

Socrates17

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”

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 study1938 first administered in a parallel group:

Substantial improvement in placebo group lead to negative study in cold vaccine trial

19

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 Treatmen

t

Non-specific treatment

effects (placebo effect)

Natural history and

regression to the mean

Measurement

20Turner at al (JAMA 1994)- Placebo Effects on Pain

Placebo≠No-Treatment

Placebo is provided as Intervention in:

Scientific ExperimentsClinical Treatment Randomized Clinical Trials

Intervention + ContextNo-Treatment Groups notfeasible in RCTs

21

Components of Placebo Effect

23

Who (Placebo Responder)No specific subject type or traits

What (Placebo attributes)“Effectiveness” of pills, procedures, surgeryType and complexity of interventionOrigin 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 relationshipPhysician and Staff attitude and behaviorInformed Consent

Open Placebo Administration

Open-label, randomized study in patients with Irritable Bowel Syndrome (n=80)

Open-label placebo vs. no-treatmentPresented and explained in Informed ConsentPlacebo superior to no-treatment on global improvement scores at D11 (p<0.001) and D21(p=0.002) 24Kaptchuk 2010

Mechanisms of Placebo Effect

Psychological

Expectancy

Classical Pavlovian

Conditioning

Learning, memory,

motivation, somatic

focus

Neurobiological:

Placebo analgesia

Endogenous Opioid Release

Non-opioid mechanism

s

Neurotransmitters and

neuromodulators

25Modified after Enck 2008

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 IBS3-weeks identical

“sham” acupuncture procedure

45 minutes“Augmented”

Initial Conversation

5 minutes“Limited” Initial Conversation

Waiting List

Kaptchuk 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

Augmented Arm

Limited Arm Waiting List

62

44

28

% of Patients with Adequate Pain Relief

Kaptchuk 2008

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

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

Factors Contributing to Placebo EffectDiagnostic Misclassification

Patient Selection and “symptomatic volunteers”

Patient and Clinician Expectations about the TrialNon-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 MeasuresStudy Design Issues

Increased Complexity and Assessment Duration

High Attrition Rates

Modified after Fava 2003 and Walsh 200231

What Can Be Done to Improve Signal

Detection?Standardizing Diagnostic ProceduresEnrollment of Selected Populations

Criteria: broad vs. sub-populations, specific characteristics

Investigator/Rater TrainingPractice vs. researchInter-rater Reliability

Minimizing Non-Specific Therapeutic EffectsStaff interaction with patients, research-focus, setting expectations

Precision in Study Conduct (Data Generation) 32

Modified after Fava (2003), Walsh (2002)

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

Few Additional PointsAddressing 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 AssessmentsMajor visits take several hours Extra visits may contribute to placebo response

Global Differences in Placebo/Treatment Effect

Emerging regional specificities Changing clinical trial landscape (more experienced global sites)Recurrent patient participation in clinical studies

34

Strategies for Neuropathic Pain Studies1

Exclusion of patients with mild severity & short episode Reliability, validity, responsiveness of outcome measureMinimizing contact with investigative staffTrial Duration, Treatment GroupsDose designs (flexible vs. fixed-dose)Run-in period considerations

35Dworkin 2005

Novel Study

Designs36

37

ACTIVE

ACTIVE

SPECIFIC NON-SPECIFIC

KNOWLEDGE

ACTIVE KNOWLEDGE

OUTCOME

OUTCOME

KNOWLEDGE

OUTCOME

ROUTINE MEDICALPRACTICE

TREATMENT WITH PLACEBO

HIDDEN TREATMENT

Adapted after Finnis 2010

38

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

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

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, 1968Director National Heart Institute

Thank youQ&A