frank placebo

8/11/2019 Frank Placebo

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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!

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