Placebo Control trials

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?

Placebo:

Placebo Placebo = “I shall please” Pharmocologically inert substances used to satisfy patients that something being done for them (“please the patient”)

Placebo:

Placebo “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?:

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:

Placebo: History First placebo-controlled trial: Sanocrysin vs. distilled water to treat TB 1931

The Story of Kebrozion:

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

Kebrozion, Pt 2:

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:

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:

Placebo-Control: PROS Need placebo control to insure validity = PLACEBO = A B >

Placebo-Control: PROS:

Placebo-Control: PROS Need placebo control to insure validity = PLACEBO = A B =

Placebo-Control: PROS:

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

Placebo-Control: PROS:

Places patients at less risk of harm due to need for smaller numbers for placebo-controlled trials Greater power with smaller numbers than noninferiority trial Many more exposed to drug in non- placebo trial Placebo-Control: PROS

Placebo-Control: PROS:

FDA: Placebo controls required for disorders of moderate severity and pain Beta-blocker not approved for angina (even though it was shown to be as efficacious as proven tx) due to lack of placebo comparison Placebo-Control: PROS

Placebo-Control: CONS:

Unethical to withhold effective treatment Places demands of science ahead of right and well-being of patients Your study question has to change: Is the new drug better than proven effective therapy? Placebo-Control: CONS

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 Placebo-Control: CONS

Placebo-Control: CONS:

Rothman KJ et al NEJM 1994;331:394 Enserink M Science 2000;490:418-9 Declaration of Helsinki: “ Every patient -- including those of a control group, if any -- should be assured of the best proven diagnostic and therapeutic method.” 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” Placebo-Control: CONS

Slide 17:

Clinician/Physician Clinical Researcher

Ethical?:

Ethical? Subjects: Cancer patients Intervention: Odansetron vs. placebo Indication: Post-chemotherapy emesis and nausea ? Proven effective therapy for nausea

Ethical?:

Ethical? Subjects: Men with hair loss Intervention: Compound X vs. placebo Indication: Prevent hair loss ? Lack of sequelae from placebo use

Ethical?:

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?

Ethical Balance:

Ethical Balance Valid research vs. Undue harm Validity Minimize Risk ?

Ethical Balance:

Ethical Balance Validity Minimize Risk ? Valid research vs. Undue harm

Placebo-Control and Procedures/Surgery:

Moseley JB et al NEJM 2002;347:81 Placebo-Control and Procedures/Surgery “A Controlled Trial of Arthroscopic Surgery for Osteoarthritis of the Knee” Tx for osteoarthritis  lavage and debridement 650,000 procedures/yr App. $5,000/each

Placebo-Control and Procedures/Surgery:

Moseley JB et al NEJM 2002;347:81 Placebo-Control and Procedures/Surgery Randomized, PLACEBO-controlled trial Endpoint: Pain in study knee Placebo: Did not receive general anesthesia Knee prepped, draped Three 1cm incisions made Knee manipulated as if arthroscopy performed No instruments entered the incisions

Placebo-Control and Procedures/Surgery:

Moseley JB et al NEJM 2002;347:81 Placebo-Control and Procedures/Surgery Informed Consent: Explained study thoroughly 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 .” 44% declined

So . . . What do you think? Is this ethical?:

So . . . What do you think? Is this ethical?

Placebo-Control and Procedures/Surgery:

Placebo-Control and Procedures/Surgery Placebo is not necessarily without risk Risk inherent in the procedure May be small (saline injection) or not-so- small (abdominal incision) Involves active misleading of subjects

Placebo-Control and Procedures/Surgery:

Placebo-Control and Procedures/Surgery 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?

Placebo-Control and Procedures/Surgery:

Placebo-Control and Procedures/Surgery Does the risk exceed that of other research procedures from which the subject does not receive benefit? Bronchoscopy in healthy adults Placement of P-A catheter in non-critically- ill subjects Muscle biopsy in healthy adults

Placebo-Control and Procedures/Surgery:

Placebo-Control and Procedures/Surgery 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

Placebo-Control and Procedures/Surgery:

Moseley JB et al NEJM 2002;347:81 Placebo-Control and Procedures/Surgery Arthroscopy Study Results: No difference in pain scores The surgery itself had been causing undue risk (and cost – $3.25 billion/year) Without the placebo-controlled study, this would never had been discovered

Cultural Issues and Placebo-Control:

Cultural Issues and Placebo-Control What about when conducting research in other countries? “Standard of care” is different due to: Access to meds Access to healthcare Basic infrastructure issues Cultural beliefs

Cultural Issues and Placebo-Control – Ethical?:

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?

Cultural Issues and Placebo-Control:

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

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THE USE OF PLACEBO THE USE OF PLACEBO

Placebo Acceptable If . . .:

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 Acceptable If . . .:

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 Placebo Acceptable If . . .