Placebo-controlled trials are they ethical?

Epub: Garattini et al. Placebo? no thanks, it might be bad for me! Eur J Clin Pharmacol. 2012 Sep 16.

OBJECTIVE: To assess the potential damage to MSers from the inappropriate use of placebo.

METHODS: Pivotal clinical trials of new drugs were evaluated for the treatment of MS following effective treatment with beta interferons and glatiramer acetate. The differences in the relapse rate between the experimental arms of the trials with interferons and glatiramer and the placebo groups were calculated.

RESULTS: In ten pivotal trials, 2,752 MSers were given placebo instead of the best proven* treatments. The annualized relapse rate was reported for 2,405 of these MSers. MSers receiving placebo suffered 630 more relapses than those treated with interferons or glatiramer.

* "I am sure the CCSVIers will have a comment (or 10) to make on the use of the word "proven". A word that appears to be absent from their general vocabulary."

CONCLUSIONS: The inappropriate use of placebo in clinical trials unduly harms MSers. The use of standard active comparators would preserve MSers' rights and better define the respective clinical value of new medicines.

"This is all well and good, but you need to tell the regulators. Both the FDA and EMA mandated placbo-controlled trials to show that DMTs work and neutralise any biases in clinical studies. In addition, how can you get information on safety without a comparator arm? I agree now that first-line oral therapies are emerging it may be harder to justify, but we need to be sure we don't jus assume this position. 

I acknowledge the ethical issues raised by this analysis and these issues have been the subject of MS-specific international guidelines, which concluded that PCTs were considered ethical provided that the patients gave informed consent after having received information of the possibility of treatment with available therapies. Since then specific policies in relation to informed consent have been implemented to address some of these issues. Firstly, statements in information sheets now specifically acknowledged the existence of licensed DMTs and that by participating in the study the subject could be denying themselves active treatment. Secondly, study participants are generally reconsented after each relapse and/or confirmed progression in trials. Thirdly, many trials now include rescue arms which allow study subjects treatment with a licensed-DMT if they have one or more exacerbations or their disease has progressed.

It is important to recognise that some MSers choose not to go onto injectable therapies (orals are not available as first-line therapies in most of the world); if we did all trials with an active comparator we would exclude these MSers from participating. People with needle phobia and those who have failed injectables because of side-effects tend to make up the majority of MSers volunteering for contemporary PCTs. Once oral DMTs are widely licensed, however, it will be very difficult to justify and recruit subjects for PCTs. I don’t agree with the stance that it unethical to do PCTs; it is paternalistic. Are MSers incapable of making an informed-decision about not taking-up the option of going on to a moderately effective licensed DMT and volunteering to participate in PCTs?

We have to realise that our current vantage point has only been made possible because we have effective DMTs and for that we have to thank all the MSers who volunteered to participate in clinical trials and take undefined risks. Thanks to them MSers who came after them have the privilege of being able to go onto effective DMTs and thanks to them we are having this debate!"

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