The document criticizes the Declaration of Helsinki's stance on placebo-controlled trials. It argues that when a proven intervention exists, placebo-controlled trials are often the only ethical way to research new treatments. The author believes equipoise is a flawed concept, as a doctor cannot truly be uncertain between two options. Additionally, denying patients access to experimental treatments by not enrolling them in trials is unethical. The document advocates for a Rawlsian perspective, where individuals behind a "veil of ignorance" would choose to live in a society that allows clinical trials with placebos when added to proven therapies.

1. Placebos in medical research:
how the Declaration of Helsinki has got it
exactly wrong.
Stephen Senn
(c) Stephen Senn 1

2. The Declaration of Helsinki is Exactly Wrong
“The use of placebo, or no treatment, is acceptable in studies where
no current proven intervention exists”
World Medical Association Declaration of Helsinki, Seoul revision October
2008, paragraph 32
This should read
“Where a current proven intervention exists placebo controlled trials will
often be the only ethically acceptable approach.”
(c) Stephen Senn 2

3. The Equipoise Nonsense
• You can’t randomise patients unless you have
equipoise.
• Even if you have equipoise it won’t last long
• Therefore, you must finish as soon as you start
(c) Stephen Senn 3

4. The Problem of Saintly Idiots
• Is it only belief which matters in ethics?
• Or does it have to be well founded?
• Are you justified in (only) tickling your
patients’ feet to treat cancer if you believe it is
effective?
(c) Stephen Senn 4

5. To Return to Equipoise
• Drugs in development are not freely available
– Only under ‘IND’ etc
• Patient’s only chance of getting drug may be
to enter trial
• What then is the relevance of equipoise?
(c) Stephen Senn 5

6. The Consequence of Equipoise
“I cannot enter patients into this trial
because I believe that the new treatment is
superior and I am not in equipoise…
...therefore I insist on giving all my patients
the standard treatment that I believe to be
inferior.”
(c) Stephen Senn 6

7. A Rawlsian View
• Based on John Rawls’s Theory of Justice
• Try your hand at this one.
– The spending priorities of Great Britain Ltd
• Currently spend millions on frivolous holidays for the
young in Ibiza
• We have lots of deserving elderly on the waiting lists
for hip replacement etc.
• Shouldn’t we tax the young and single to pay for these
operations?
(c) Stephen Senn 7

8. Ethical dilemmas
Shocking young people Sweet old lady
(c) Stephen Senn 8

9. Consider Yourself in the “Original
Position”
• You are about to start your life
• But you don’t know who you will be
• Do you want society to be
– For “ants” only
• No holidays
• High taxes when young to pay for eventual old age
– Or for “grasshoppers”
• Let’s have fun while we are young
(c) Stephen Senn 9

10. The Original Position and Medical
Research
• You are in the original position and have a
choice between
– Society A
• No clinical trials
• You get whatever Doctor thinks is best
– Society B
• Cures are on a restricted list until proved efficacious in
clinical trials
(c) Stephen Senn 10

11. The Three Party System
Standard
therapies
experimental
(c) Stephen Senn 11

12. A Rawlsian Bargain
as per A Theory of Justice ,1971
(John Rawls 1921-2002)
• As a patient you are entitled to what we as a society (which
includes you before you were ill) decide is reasonable
• This includes proven treatment
• It excludes experimental treatment
• There is no requirement then for equipoise between the two
arms of a trial
• We just have to believe that a patient is not worse off by
being in the trial
• The only way you can have a chance of experimental
treatment is by entering a trial
(c) Stephen Senn 12

13. The Ethical Alternative
• Trials are performed because the experimental arm is
believed better by the trialist
• The experimental treatment is only available in the
trial
• The trialist must believe that no patient is worse off
by entering the trial
• Experimentation continues until
– either the trialist no longer believes new is better
– or the trialist convinces Society that it is better
(c) Stephen Senn 13

14. The Way Trials Should be run
• We establish what the basic entitlement is
• We then consider modifying this as follows
– M= Maintenance (the typical control)
– A= Augmentation (as in “add-on” trials)
– E= (partial) Elimination (as in withdrawal trials)
– S=Substitution =E+A
• In serious diseases with proven remedies we have “add- on”
placebo controlled trials = (A v M)
• For such diseases active control studies A v S is usually
unethical
(c) Stephen Senn 14

15. The Misunderstood Placebo
• Typical piece of nonsense is that giving
placebo implies withholding effective care
• A placebo is specific to an experimental
treatments
• The issue as to what treatment is given in
addition is logically independent
(c) Stephen Senn 15

16. Placebo-controlled trials in AIDS
(c) Stephen Senn 16

17. Consent or Deception?
…. PATIENTS AND METHODS: After a 4-week placebo run-in period, 1058 men
with BPH-LUTS were randomly allocated to receive once daily treatment with
placebo or tadalafil (2.5, 5, 10, or 20 mg) for 12 weeks.
Roehrborn, CG, Kaminetsky, JC, Auerbach, SM, Montelongo, RM, Elion-Mboussa, A,
Viktrup, L. Changes in peak urinary flow and voiding efficiency in men with signs and
symptoms of benign prostatic hyperplasia during once daily tadalafil treatment, BJU Int
2010; 105: 502-507.
(c) Stephen Senn 17

18. Active
Placebo
Placebo
Placebos and Consent
Placebo Run-ins
(c) Stephen Senn 18

19. Placebo Run-Ins
• a) Lie to the patient and tell her she is receiving an active
treatment when he isn’t
......or.....
• b) tell her “take this useless pill twice daily for the next four
weeks”
.....or......
• c) somehow fudge the issue, so that you don’t actually lie, but
avoid having to tell the whole truth in the hope that she won’t
guess it?
(c) Stephen Senn 19

20. The Argument from the Stupidity of Others
Not only is strategy c) unethical but it relies on the assumption:
Patients are too stupid to guess what physicians, statisticians and nurses regard as good
practice.
If you do this, I hope you exclude physicians, statisticians and nurses from your trials.
(c) Stephen Senn 20

21. Placebo Run-in
A period in which dummies give dummies
in the hope that patients are as stupid as
they are.
(c) Stephen Senn 21

22. In Summary
• Where an effective treatment exists it will
often be the case that placebo is the only
acceptable treatment
– As an add-on
• We must look at experiments in terms of what
the patient’s entitlements and expectations
both within and outside the trial are
• Consent is central
• Placebo run-ins must be abandoned

23. Some Advice
As regards patients…
As regards the declaration of Helsinki
Don’t fool sufferers gladly
Don’t suffer fools gladly
(c) Stephen Senn 23