Wednesday, May 15, 2013

Placebos: Banned in Helsinki?

One of the unintended consequences of my (admittedly, somewhat impulsive) decision to name this blog is that I get a fair bit of traffic from Google: people searching for placebo-related information.

Some recent searches have been about the proposed new revisions to the Declaration of Helsinki, and how the new draft version will prohibit or restrict the use of placebo controls in clinical trials. This was a bit puzzling, given that the publicly-released draft revisions [PDF] didn't appear to substantially change the DoH's placebo section.

Much of the confusion appears to be caused by a couple sources. First, the popular Pharmalot blog (whose approach to critical analysis I've noted before as being ... well ... occasionally unenthusiastic) covered it thus:
The draft, which was released earlier this week, is designed to update a version that was adopted in 2008 and many of the changes focus on the use of placebos. For instance, placebos are only permitted when no proven intervention exists; patients will not be subject to any risk or there must be ‘compelling and sound methodological reasons’ for using a placebo or less effective treatment.
This isn't a good summary of the changes, since the “for instance” items are for the most part slight re-wordings from the 2008 version, which itself didn't change much from the version adopted in 2000.

To see what I mean, take a look at the change-tracked version of the placebo section:
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention(s), except in the following circumstances: 
The use of placebo, or no treatment intervention is acceptable in studies where no current proven intervention exists; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, placebo or no treatment is necessary to determine the efficacy or safety of an intervention 
and the patients who receive any intervention less effective than the best proven one, placebo or no treatment will not be subject to any additional risks of serious or irreversible harm as a result of not receiving the best proven intervention 
Extreme care must be taken to avoid abuse of this option.
Really, there is only one significant change to this section: the strengthening of the existing reference to “best proven intervention” in the first sentence. It was already there, but has now been added to sentences 3 and 4. This is a reference to the use of active (non-placebo) comparators that are not the “best proven” intervention.

So, ironically, the biggest change to the placebo section is not about placebos at all.

This is a bit unfortunate, because to me it subtracts from the overall clarity of the section, since it's no longer exclusively about placebo despite still being titled “Use of Placebo”. The DoH has been consistently criticized during previous rounds of revision for becoming progressively less organized and coherently structured, and it certainly reads like a rambling list of semi-related thoughts – a classic “document by committee”. This lack of structure and clarity certainly hurt the DoH's effectiveness in shaping the world's approach to ethical clinical research.

Even worse, the revisions continue to leave unresolved the very real divisions that exist in ethical beliefs about placebo use in trials. The really dramatic revision to the placebo section happened over a decade ago, with the 2000 revision. Those changes, which introduced much of the strict wording in the current version, were extremely controversial, and resulted in the issuance of an extraordinary “Note of Clarification” that effectively softened the new and inflexible language. The 2008 version absorbed the wording from the Note of Clarification, and the resulting document is now vague enough that it is interpreted quite differently in different countries. (For more on the revision history and controversy, see this comprehensive review.)

The 2013 revision could have been an opportunity to try again to build a consensus around placebo use. At the very least, it could have acknowledged and clarified the division of beliefs on the topic. Instead, it sticks to its ambiguous phrasing which will continue to support multiple conflicting interpretations. This does not serve the ends of assuring the ethical conduct of clinical trials.

Ezekiel Emmanuel has been a long-time critic of the DoH's lack of clarity and structure. Earlier this month, he published a compact but forceful review of the ways in which the Declaration has become weakened by its long series of revisions:
Over the years problems with, and objections to, the document have accumulated. I propose that there are nine distinct problems with the current version of the Declaration of Helsinki: it has an incoherent structure; it confuses medical care and research; it addresses the wrong audience; it makes extraneous ethical provisions; it includes contradictions; it contains unnecessary repetitions; it uses multiple and poor phrasings; it includes excessive details; and it makes unjustified, unethical recommendations.
Importantly, Emmanuel also includes a proposed revision and restructuring of the DoH. In his version, much of the current wording around placebo use is retained, but it is absorbed into the larger concept of “Scientific Validity”, which adds important context to the decision about how to decide on a comparator arm in general.

Here is Emmanuel’s suggested revision:
Scientific Validity:  Research in biomedical and other sciences involving human participants must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and suitable laboratory, and as necessary, animal experimentation.  Research must be conducted in a manner that will produce reliable and valid data.  To produce meaningful and valid data new interventions should be tested against the best current proven intervention. Sometimes it will be appropriate to test new interventions against placebo, or no treatment, when there is no current proven intervention or, where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy and/or safety of an intervention and the patients who receive placebo, or no treatment, will not be subject to excessive risk or serious irreversible harm.  This option should not be abused.
Here, the scientific rationale for the use of placebo is placed in the greater context of selecting a control arm, which is itself subservient to the ethical imperative to only conduct studies that are scientifically valid. One can quibble with the wording (I still have issues with the use of “best proven” interventions, which I think is much too undefined here, as it is in the DoH, and glosses over some significant problems), but structurally this is a lot stronger, and provides firmer grounding for ethical decision making. Emanuel, E. (2013). Reconsidering the Declaration of Helsinki The Lancet, 381 (9877), 1532-1533 DOI: 10.1016/S0140-6736(13)60970-8

[Image: Extra-strength chill pill, modified by the author, based on an original image by Flikr user mirjoran.]


@oli_rayner said...

Do you think this amendment would make it more likely regulators who follow DoH (e.g. EMA) would want comparative studies (reflecting pertaining stand of care) rather than placebos. This is very important in Cystic Fibrosis particularly when it comes to new antibiotics. Most CF patients are on some combination of antibiotics as part of maintenance regimen so clinical trials using placebo are not very helpful and perhaps unethical.

Paul Ivsin said...


Good question. I don't think the revisions that are currently being suggested will have much of an impact in that regard. However, that already seems to be the case based on past interpretations of the DoH.

For CF, a recent example would seem to be Aeroquin (inhaled levofloxacin). There were two phase 3 trials conducted, and one was placebo-controlled while the other had an active comparator (tobi). Only the active-comparator trial had sites in Europe, and I suspect that its design was strongly influenced by European regulators.

I've seen this kind of split before, and I suspect it will remain the case for the foreseeable future -- especially in cases where it's perhaps still plausible that a patient can take a short break from treatment without serious risk (the placebo trial of Aeroquin lasted 56 days, and patient were discontinued if they experienced exacerbations).

One bedeviling thing about active-comparator trials is that certain things, like a high dropout rate, bias the study towards a positive outcome when the endpoint is "non-inferiority", as was the case in the Aeroquin trial. I haven't seen the data -- just the topline that was reported -- but that is always a serious concern, and is especially worth noting in this case, where the placebo-controlled trial actually failed to hit its primary endpoint.

(And ultimately, it is harder to call a placebo trial unethical if the placebo did as well as the investigational medication...)

Romilda Gareth said...