Equipoise and the ethics of Equipoise and the ethics of clinical researchclinical research

When is it ethical to initiate a randomized-controlled trial? Freedman, NEJM, 1987.

“There exists (or in the case of novel therapy, there may soon exist) an honest, professional disagreement among expert clinicians about the preferred treatment. A clinical trial is instituted with the aim of resolving this dispute.”

Placebo-controlled trials and Placebo-controlled trials and the logic of clinical purposethe logic of clinical purpose

When may the control be a placebo? Freedman, IRB, 1990.– no standard therapy– standard therapy no better than placebo– standard treatment is placebo– doubt regarding the net therapeutic advantage

of standard therapy– standard treatment is unavailable (cost, supply).

Two special casesTwo special cases

patients refractory to standard treatment– [I]t is more important to know ‘whether the

treatment is better than nothing’ and will therefore offer an alternative for patients who do not have a response to the conventional treatment or cannot tolerate its adverse effects.” (Solomon, letter, NEJM, 1995)

Two special casesTwo special cases

add-on treatments to standard therapy– “Patients are randomly assigned to receive a

new drug or placebo, which is added to the existing treatment. Thus, patients in both the placebo and active treatment groups receive all medications that would normally be prescribed.” (Gilbert, letter, NEJM, 1995)

Advantages of ACE StudiesAdvantages of ACE Studies

0.1

1

10

0.0

0

0.0

5

0.1

0

0.1

5

0.2

0

0.2

5

ACES/PLACEBO

ACES/ACTIVE

assumptions placebo, 25% standard drug, 50% new drug, 60%

sample size– placebo study - 60 pts

– active study - 774 pts

– ACE study D=10% - 150 pts D=15% - 96 pts

Advantages of ACE studyAdvantages of ACE study

scientific and clinical advantages more clinically relevant than placebo-

controlled trial A placebo-controlled trial asks: “Is this

treatment better than nothing?” ACE study asks: “Is this treatment as good

as what we are using now?”

Advantages of ACE studyAdvantages of ACE study

scientific and clinical advantages possibility of using multiple hypotheses

– toxicity a new treatment is of interest if it is roughly equally

efficacious and has less side effects

– negative symptoms a new treatment is of interest if it is roughly equally

efficacious and and is better at treating negative symptoms

Advantages of ACE studyAdvantages of ACE study

regulatory advantages a new drug may be superior to placebo but

substantially inferior to standard treatment Cost to society:

– “Many new drugs are expensive, and in some countries drug budgets are growing faster than other health care sectors…The key questions are: how much better are the new drugs than the old ones, how much more does it cost to obtain the additional benefits, and does the extra cost represent value for the money. (Henry and Hill, BMJ, 1995)

Advantages of ACE studyAdvantages of ACE study

ethical and legal advantages patients are not knowingly given inferior

treatment possible liability:

– doctors owe a duty of care to their patients– an investigators chief concern ought to be the

health and well being of his patient– providing a placebo may be negligent

ConclusionConclusion

Placebo-controlled trials: Are they ethical? Are they necessary?

placebo controls may be acceptable in carefully defined circumstances (add-on treatment, treatment-resistant patients…)

ACE study is to be preferred: scientific, clinical, regulatory, ethical and legal advantages.