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.]

The Case against Randomized Trials is, Fittingly, Anecdotal

I have a lot of respect for Eric Topol, and am a huge fan of his ongoing work to bring new mobile technology to benefit patients.

The Trial of the Future

However, I am simply baffled by this short video he recently posted on his Medscape blog. In it, he argues against the continued use of randomized controlled trials (RCTs) to provide evidence for or against new drugs.

His argument for this is two anecdotes: one negative, one positive. The negative anecdote is about the recently approved drug for melanoma, Zelboraf:

Well, that's great if one can do [RCTs], but often we're talking about needing thousands, if not tens of thousands, of patients for these types of clinical trials. And things are changing so fast with respect to medicine and, for example, genomically guided interventions that it's going to become increasingly difficult to justify these very large clinical trials. 

For example, there was a drug trial for melanoma and the mutation of BRAF, which is the gene that is found in about 60% of people with malignant melanoma. When that trial was done, there was a placebo control, and there was a big ethical charge asking whether it is justifiable to have a body count. This was a matched drug for the biology underpinning metastatic melanoma, which is essentially a fatal condition within 1 year, and researchers were giving some individuals a placebo.

First and foremost, this is simply factually incorrect on a couple extremely important points.

1. Zelboraf was not approved based on any placebo-controlled trials. The phase 1 and phase 2 trials were both single-arm, open label studies. The only phase 3 trial run before FDA approval used dacarbazine in the comparator arm. In fact, of the 34 trials currently listed for Zelboraf on ClinicalTrials.gov, only one has a placebo control: it’s an adjuvant trial for patients whose melanoma has been completely resected, where no treatment may very well be the best option.
2. The Zelboraf trials are not an example of “needing thousands, if not tens of thousands, of patients” for approval. The phase 3 trial enrolled 675 patients. Even adding the phase 1 and 2 trials doesn’t get us to 1000 patients.

Correcting these details take a lot away from the power of this single drug to be a good example of why we should stop using “the sanctimonious [sic] randomized, placebo-controlled clinical trial”.

The second anecdote is about a novel Alzheimer’s Disease candidate:

A remarkable example of a trial of the future was announced in May. For this trial, the National Institutes of Health is working with [Banner Alzheimer's Institute] in Arizona, the University of Antioquia in Colombia, and Genentech to have a specific mutation studied in a large extended family living in the country of Colombia in South America. There is a family of 8000 individuals who have the so-called Paisa mutation, a presenilin gene mutation, which results in every member of this family developing dementia in their 40s. 

Researchers will be testing a drug that binds amyloid, a monoclonal antibody, in just 300 family members. They're not following these patients out to the point of where they get dementia. Instead, they are using surrogate markers to see whether or not the process of developing Alzheimer's can be blocked using this drug. This is an exciting way in which we can study treatments that can potentially prevent Alzheimer's in a very well-demarcated, very restricted population with a genetic defect, and then branch out to a much broader population of people who are at risk for Alzheimer's. These are the types of trials of the future. 

There are some additional disturbing factual errors here – the extended family numbers about 5,000, not 8,000. And estimates of the prevalence of the mutation within that family appear to vary from about one-third to one-half, so it’s simply wrong to state that “every member of this family” will develop dementia.

However, those errors are relatively minor, and are completely overshadowed by the massive irony that this is a randomized, placebo-controlled trial. Only 100 of the 300 trial participants will receive the active study drug, crenezumab. The other 200 will be on placebo.

And so, the “trial of the future” held up as a way to get us out of using randomized, placebo-controlled trials is actually a randomized, placebo-controlled trial itself. I hope you can understand why I’m completely baffled that Topol thinks this is evidence of anything.

Finally, I have to ask: how is this the trial of the future, anyway? It is a short-term study on a highly-selected patient population with a specific genetic profile, measuring surrogate markers to provide proof of concept for later, larger studies. Is it just me, or does that sound exactly like the early lovastatin trials of the mid-1980’s, which tested cholesterol reduction in a small population of patients with severe heterozygous familial hypercholesterolemia? Back to the Future, indeed.


[Image: time-travelling supercar courtesy of Flickr user JoshBerglund19.]