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Jeremy Howick discusses whether it is ethical for clinicians to recommend that their patients sign up for a trial, even if there is an established therapy.

“The good physician treats the disease; the great physician treats the patient who has the disease.”
- William Osler

The revised Declaration of Helsinki allows for placebo-control trials to be used even when there is an established therapy, provided there are adequate ‘methodological’ advantages. This means, for example, that a depressed patient might be enrolled in a trial of a new antidepressant compared with placebo, in spite of the fact that there are known pharmacological and non-pharmacological treatments for depression. But is it ethical for clinicians to recommend that their patients sign up for a trial even if there is an established therapy? This seems to violate the clinician’s ethical duty to help patients whenever possible (beneficence).

The supposed methodological advantages of placebo controls even when there is an established therapy were put forth in a series of papers by Robert Temple and Susan Ellenberg of the United States Food and Drug Administration. I found their arguments difficult to accept. For simplicity I will refer to placebo-controlled trials as ‘PCTs’ and trials that use established effective (active) therapies as controls as ‘ACTs’.

Temple and Ellenberg’s first argument is that PCTs but not ACTs possess ‘assay sensitivity’, which is the ability of a trial to distinguish between effective and ineffective treatments. They use the example of selective serotonin reuptake inhibitors (SSRIs) to illustrate. They begin by asserting that they know SSRIs to be effective, yet SSRIs sometimes do and sometimes do not demonstrate superiority to placebos in clinical trials. So if we were to compare a new SSRI with an ‘active’ control (say another SSRI), and the new SSRI was as good as the established one, we could not infer that the new SSRI was effective, because in that trial the established SSRI control might not have been superior to placebo.

There are two problems with this argument. First, it does not apply to superiority ACT trials, where we seek to learn whether the new treatment is superior to the control. If a new SSRI were more effective than an established SSRI then we could infer that the new SSRI was effective even if the established SSRI were no better than placebo in that trial (provided, of course, that the established therapy were no worse than placebo).

Temple and Ellenberg could reply that ACTs should not be superiority trials because all we need to do is show that the new treatment is as good as (equivalent or non-inferior to) the old one. Demonstrating rough equivalence is sometimes justified on the grounds that a new treatment might be no more effective, but have fewer side effects, is more cost-effective, less invasive, or can be used in patients who are resistant to the established therapy. These justifications are sometimes warranted, but are often not. While we might like to have a few options in the case of resistance or side effects, we don’t need dozens of options. In the case of antidepressants there are dozens of options such as tricyclic agents, monoamine oxidase inhibitors (MAOIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NASSAs), norepinephrine (noradrenaline) reuptake inhibitors (NRIS), and norepinephrine-dopamine reuptake inhibitors. Furthermore, there are additional treatment options for depression that are non-pharmaceutical. Moreover, if the justification for a new equivalent treatment is that it has fewer side effects, then we can test for a superior side effect profile.

The second, and more serious, problem seems to be that Temple and Ellenberg confuse a property of trials with a property of treatments. They claim that assay sensitivity is the inability of a trial to detect whether a treatment is superior to placebo. However, an alternative explanation for failure to demonstrate superiority to placebo is that the treatment in the trial is not more effective than placebos. Indeed, some evidence suggests that SSRI antidepressants are not (much) better than placebos for mild to moderate depression.

The next alleged advantage of PCTs is that only the former provide a measure of ‘absolute effect size’. If a treatment is better than a placebo, then we supposedly know the absolute incremental benefit of the treatment, whereas comparing a new treatment to an established one does not provide this information. This would be true if placebo effects were constant, which they are not. Different placebos have different effects and even the same placebos have variable effects. For example, in studies comparing cimetidine for treatment of ulcers to placebo the effects of the placebo in the same trials ranged from 10% to 90% of the drug effect. Moreover what patients really want to know isn’t how a new drug compares to placebo but how it compares with other options. To summarize, Temple and Ellenberg’s attempt to provide ‘sound methodological reasons’ for conducting PCTs even when there are established therapies, are problematic at best and. At worst they fail to provide an ethical justification for placebo-controlled trials when effective therapies are available.

What is arguably worse is the lack of evidence that Temple and Ellenberg considered patient views when developing their arguments. It is easy to see how testing another ‘me too’ drug in a placebo-controlled trial serves commercial interests. However, we suspect that most patients would not agree to sign up for a placebo-controlled trial if they knew there was an established therapy. It is arguably

It’s time to revise the Declaration of Helsinki so that it reflects common sense and patient views.