Placebos in medical research: how the Declaration of Helsinki has got it

exactly wrong.

Stephen Senn

(c) Stephen Senn 1

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.”

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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

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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?

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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?

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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.”

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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?

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Ethical dilemmas

Shocking young people Sweet old lady

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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

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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

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The Three Party System

Standard therapies

experimental

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A Rawlsian Bargainas 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

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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

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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

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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

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Placebo-controlled trials in AIDS

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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.

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Active

Placebo

Placebo

Placebos and ConsentPlacebo Run-ins

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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?

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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.

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Placebo Run-in

A period in which dummies give dummies in the hope that patients are as stupid as they are.

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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

Some Advice

As regards patients…

As regards the declaration of Helsinki

Don’t fool sufferers gladly

Don’t suffer fools gladly

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