1. The Shame of Sham Study Designs Paul A Sobotka, MD
Sham trial designs, a panacea or crutch?

2. Conflict of Interest Rox Medical, Inc. Chief Science Officer
Cibiem, Inc Chief Medical Officer
Rainbow Medical, Inc. Consultant
Abbott Ventures Consultant
Boston Scientific, Inc. Consultant
Ablative Solutions, Inc. Consultant

3. Sham Design- Deliberate Patient Deception to Illuminate Placebo Effect
Patient-subject is kept in ignorance, and the clinician, who can distinguish active from inactive treatment, may be required to engage in active deception
Purpose is to illuminate potential participation of a placebo effect in the outcome of interest

4. Ethical Basis of Sham Trial
Sham interventions do not violate the rights of patient-subjects IF they have been adequately informed that they will receive either a real or a sham intervention
efforts will be made to make the sham procedure indistinguishable from the real treatment under investigation.
Prior authorization makes the difference between legitimate and unethical deception.
Professional integrity for investigators conducting sham-procedure trials is preserved ONLY by recognition that they are operating primarily as scientists, not as clinicians (not as benevolent advocates)

5. What Justifies the Potential Harm of a Sham Surgical Procedure
Participants receiving the sham intervention will have no prospect of benefit while being exposed to its risks.
Creation of a sham trial requires anticipation that there exists a Placebo effect sufficient to justify the inherent harm associated with the sham procedure.
Benevolent patient subjects?????
Placebo effect is often seen for subjective endpoints- e.g. perception of dyspnea, pain, quality of life.
Placebo effect is not generally appreciated for objective measures, particularly objective measures for which the patient is blinded.

6. Ethical Hazy Space
In the absence of well known evidence of a placebo effect for the endpoint of interest, demanding a sham surgical procedure, with inherent patient risks, violates most physician codes of conduct.
Thus, consideration of a sham procedure requires documentation that the placebo effect is significant and modifies the endpoint of interest.

7. Sham Trial Designs An umbrella for sloppy trial execution
I submit to you:
Sham trial designs often have insufficient documentation that the targeted placebo effect is exists or cannot otherwise be mitigated.
Sham trial designs function principally to mask sloppy trial execution.

8. Sham Study Design
Sham study design is justified when a known placebo effect obfuscates the endpoint of interest
Sham study design is NOT justified when its is used to mask trail mal conduct: Sham trial design entrains
Placebo effect
Migration to mean
Hawthorne effect
Freddy Kruger effect

9. Migration To Mean Selection bias introduced by entry criteria
If the entry criteria has a large natural standard deviation
Then the trial design can establish an exceptional base measure that is not representative of “average” and will differ on the next measure
Example: entry criteria of sBP > 160, (oBP has a sd of ~15 mmHg ,entirely possible that this “baseline” from a population with a true average sBP of ~ 153.
Both treatment and control groups will exhibit migration to mean, not a sham effect, but a reflection of poor trial execution

10. Hawthorne Effect vs Sham Effect
One ought do no wrong when others are looking
individuals improve an aspect of their behavior in response to their awareness of being observed
Dr. House, “Patients lie, they always lie”
The Hawthorne effect impacts treatment and control groups, increases SD and reduces trial power

11. Pygmalion and Golem Effect
The Pygmalion effect, in which greater the expectation placed upon people, the better they perform
Named after the Greek myth of Pygmalion, a sculptor who fell in love with a statue he had carved.
The Golem effect, in which low expectations lead to a decrease in performance
Named after the clay sculpture given life by Rabbi Loew of Prague in Jewish mythology.

12. The Freddy Kruger Effect: Scaring patients into changing behaviors
“Reduction in blood pressure may decrease risk of …heart attack, stroke, heart failure”
“We cannot guarantee…. This is going to work
We trust that you will not change your diet, exercise or medications through this study that reduces your risk of dying due to elevated blood pressure
Are you kidding?

13. Sham Trial Design
Sham trials are NOT justified to mask poor trial execution
Migration to Mean
Hawthorne effect
Freddy Kruger effect
Sham trial designs are justified when there is a known placebo effect that is not addressed through trial design
Sham trial design confounds placebo effect with sloppy trial execution

14. Time and Thoughtful Analysis Needed…..
"Dewey Defeats Truman" was a famously incorrect banner headline in the Chicago Tribune on November 3, 1948, the day after incumbent US President Harry S. Truman won an upset victory over Thomas Edmund Dewey in the 1948 Presidential Election.
“The reports of my death are greatly exaggerated.” Mark Twain, New York Journal. June 1897: The correction was occasioned by newspaper accounts of Twain’s being ill or dead. At the time, Twain’s cousin James Ross Clemens was seriously ill in London, and appears that some reports confused him with Clemens.

15. The Golem of Clinical Trials Blind advocacy of sham trials
The monster of fate silent horror film by Wegener and Galeen.