Equipoise and the ethics of clinical research

1
Equipoise and the ethics of clinical 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.

2
Placebo-controlled trials and the 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).

3
Two special cases

• patients refractory to standard treatment
• It 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)

4
Two 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)

5
Advantages of ACE Studies

• assumptions
• placebo, 25
• standard drug, 50
• new drug, 60
• sample size
• placebo study - 60 pts
• active study - 774 pts
• ACE study
• D10 - 150 pts
• D15 - 96 pts

6
Advantages 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?

7
Advantages 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

8
Advantages 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 sectorsThe 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)

9
Advantages 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

10
Conclusion

• 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.