Placebo Control: What is it? Why do we use it? Is it ethical?

Placebo Control: What is it? Why do we use it? Is it ethical?
By:Tom Talbot, MD MPH
Vanderbilt School of Medicine

Placebo
* Placebo = “I shall please”
* Pharmocologically inert substances used to satisfy patients that something being done for them (“please the patient”)
* “Any therapeutic procedure (or that component of any therapeutic procedure) which is given deliberately to have an effect, or unknowingly has an effect on a patient, symptom, syndrome, or disease, but which is objectively without specific activity for the condition being treated. The therapeutic procedure may be given with or without the conscious knowledge that the procedure is a placebo, may be an active (non-inert) or inactive (inert) procedure, and includes, therefore, all medical procedures no matter how specific – oral and parenteral medications, topical preparations, inhalants, and mechanical, surgical, and psycho-therapeutic procedures. The placebo must be differentiated from the placebo effect which may or may not occur and which may be favorable or unfavorable. The placebo effect is defined as the changes produced by placebos. The placebo is also used to describe an adequate control in research.” -- Shapiro

Placebo: Why Use it?
* Need to control for therapeutic aspects of prescribing a medication or procedure not directly due to the medication or procedure itself
* i.e. . . . The Placebo Effect

Placebo: History
* First placebo-controlled trial:
o Sanocrysin vs. distilled water to treat TB
o 1931
The Story of Kebrozion
* Pt. with lymphosarcoma
* Patient given Kebrozion
* “The tumor masses had melted like snowballs on a hot stove, and in only a few days, they were half their original size!”
* 2 months later – Kebrozion outed
* Pt given a “new form” of Kebrozion
* Water injections
* Tumors resolved remission
* 2 months later: AMA – “This stuff’s worthless”
* Pt. returns in extremis and dies

Kebrozion, Pt 2
Issues
* Does use of placebo remove access to effective standard of care?
* Is a trial that does not use placebo arm scientifically rigorous?
* Does use of a placebo sacrifice ethics and an individual patient’s welfare?

Placebo-Control: PROS
* Need placebo control to insure validity
Placebo-Control: PROS
* Need placebo control to insure validity
* Argue that no drug should be approved for patient use if it is not clearly superior to placebo or no treatment
* Scientifically invalid research is itself unethical
* Harm and discomfort nonexistent or small in some cases

Placebo-Control: PROS
* Places patients at less risk of harm due to need for smaller numbers for placebo-controlled trials
o Greater power with smaller numbers than noninferiority trial
o Many more exposed to drug in non- placebo trial
* FDA:
o Placebo controls required for disorders of moderate severity and pain
o Beta-blocker not approved for angina (even though it was shown to be as efficacious as proven tx) due to lack of placebo comparison
* Unethical to withhold effective treatment
* Places demands of science ahead of right and well-being of patients
* Your study question has to change:
o Is the new drug better than proven effective therapy?

Placebo-Control: CONS
* Patients are owed medical care for ailments when they present to healthcare providers
* Not truly testing therapy against “no treatment” placebo effect
Rothman KJ et al NEJM 1994;331:394 Enserink M Science 2000;490:418-9
* Declaration of Helsinki:
o “Every patient -- including those of a control group, if any -- should be assured of the best proven diagnostic and therapeutic method.”
o 2000 Revision: Placebos may be used only when there are no other therapies available for comparison with a test procedure
* “Concedes to individual investigators and to IRBs the right to determine how much discomfort or temporary disability patients should endure for the purpose of research”
Clinician/Physician Clinical Researcher
Ethical?
* Subjects: Cancer patients
* Intervention: Odansetron vs. placebo
* Indication: Post-chemotherapy emesis and nausea
* ? Proven effective therapy for nausea
* Subjects: Men with hair loss
* Intervention: Compound X vs. placebo
* Indication: Prevent hair loss
* ? Lack of sequelae from placebo use
* Subjects: Pts. with depression
* Intervention: Compound X vs. placebo
* Indication: Reduction in depressive sx.
* ? Places placebo pts. at risk for severe sequelae of depression

Ethical Balance
* Valid research vs. Undue harm
Validity Minimize Risk
Ethical Balance Validity
Minimize Risk
* Valid research vs. Undue harm
Placebo-Control and Procedures/Surgery
“A Controlled Trial of Arthroscopic Surgery for Osteoarthritis of the Knee”
* Randomized, PLACEBO-controlled trial
* Endpoint: Pain in study knee
* Placebo:
o Did not receive general anesthesia
o Knee prepped, draped
o Three 1cm incisions made
o Knee manipulated as if arthroscopy performed
o No instruments entered the incisions
Placebo-Control and Procedures/Surgery
* Informed Consent:
o Explained study thoroughly
o Subjects had to write the following:
+ “On entering this study, I realize that I may receive only placebo surgery. I further realize that this means that I will not have surgery on my knee joint. This placebo surgery will not benefit my knee arthritis.”
o 44% declined
So . . . What do you think? Is this ethical?
Placebo-Control and Procedures/Surgery
* Placebo is not necessarily without risk
* Placebo surgery “violates an essential standard for research: the requirement to minimize the risk of harm to subjects.”
* Again – is there harm in performing an unvalidated procedure?
* Does the risk exceed that of other research procedures from which the subject does not receive benefit?
o Bronchoscopy in healthy adults
o Placement of P-A catheter in non-critically- ill subjects
o Muscle biopsy in healthy adults
* Must be informed
* Must be told that misleading tactics may be used
* Must not be misled about the chances of receiving the sham procedure
* Must be debriefed after study complete and unblinded
* Arthroscopy Study Results:
o No difference in pain scores
o The surgery itself had been causing undue risk (and cost – $3.25 billion/year)
o Without the placebo-controlled study, this would never had been discovered

Cultural Issues and Placebo-Control
* What about when conducting research in other countries?
* “Standard of care” is different due to:
o Access to meds
o Access to healthcare
o Basic infrastructure issues
o Cultural beliefs
* Prevention of fetal-maternal transmission of HIV
* Population: African women
* Intervention: Short course AZT vs. placebo
* Problem: AZT shown effective (longer course)
* Critics: Withheld effective, morbidity-reducing treatment
* Supporters: “Standard of care” in the country was no meds – no money or availability

Cultural Issues and Placebo-Control – Ethical?
* Generally felt that the cultural “standard of care” for studies in developing countries should be that of the investigator’s host country

THE USE OF PLACEBO
Placebo Acceptable If . . .
* Use of placebo does not impair health or cause “severe” discomfort
* Existing therapies only partly effective or have very serious side effects
* Low frequency of condition – would prevent enrollment for a larger trial
* Participants at risk of harm from nonresponse are excluded
* Placebo period is a limited to minimum required
* Careful monitoring is insured
* Explicit withdrawal criteria for AE
* Informed consent explicit as to why placebo should be used
* Improved survival or prevention of irreversible morbidity does not exist for any therapy
Questions

Placebo Control: What is it? Why do we use it? Is it ethical?.ppt