Dr. Walter Ling, one of the world’s most respected addiction treatment researchers, has completed the first long-term placebo-controlled trial of PROMETA. This alleged miracle cure for methamphetamine addiction proved completely ineffective. I have a short commentary in the journal Addiction (pdf here) describing the rise and fall of this heavily-promoted treatment protocol.
60 Minutes did some investigative reporting on PROMETA a few years back, noting that the treatment protocol was never FDA-approved and that a suspicious number of its advocates were discovered to have a financial stake in the product. The whole story is worth watching as a cautionary tale.
As someone who has worked with addicted patients, I am struck by the moment when journalist Scott Pelley asks the creator of PROMETA (a former junk bond salesman named Terren Peizer) about the need for evidence before an addiction treatment is marketed. Peizer responds as follows:
If you had a son. If you had a son or a daughter, and maybe you do. If he’s strung out on meth. And he’s going to kill himself. Would you, if you had the opportunity. And I said to you, will you treat your son with Prometa?…Would you take that option for your son?”
The answer to this question is yes for many people, but this undermines rather than supports Peizer’s contention that it’s wrong to wait for evidence. Rather, it is *because* people are so desperate for a cure to addiction that we have a responsibility to rigorously research putative cures before they are marketed to the public. Otherwise, vulnerable, frightened people may spend thousands of dollars on ineffective treatments instead of pursuing other options that have a greater chance of restoring them to health.
Are these Hythiam clowns still around? Oh sorry I see they’re now Catasys. Anyone with eyes could see that they were selling smoke in 2005 (and an easily replicated high nutrition regimen.)
Amen, amen.
And the evidence better come from a placebo-controlled double-blinded trial. Yes, I know that we are condemning some fraction of the participants to fighting their addiction with a sugar pill (or calcium carbonate or whatever the currently au fait inactive binder is. Yes, I have some ethical qualms about it. But we can break the code once it becomes apparent that there is a difference among the treatment groups, and we can get all the participants onto whatever works (if anything).
Insofar as anything is currently known to work better than placebo, you can run a double blind with the best current treatment as the control arm.
But what interests me more about this is the cognitive bias (and we’ve pretty much all got it) that says there’s something ethically suspect about giving some of the people in trials an inactive or insufficiently-active treatment. That’s only true if we know that the test drug works; if the test drug doesn’t work, then the people who get it aren’t receiving any advantage, and the control group isn’t at any disadvantage. In fact, in lots of cases where a test drug has adverse effects without improving the condition under study, the control group is better off. But somehow we all want patients to get the “real” medicine, whether it works or not.
(And this has of course led to horrible results when clinicians do things like breaking the blinding to make sure that their most deserving patients get the study drug…)
Technically, it is allocation concealment that is broken when clinicians subvert the randomization to make sure their favored patients receive the study drug; this creates selection bias in the trial, and happens before the study treatments are administered. Blinding is compromised when the effects of the interventions are assessed; this happens later in the trial and creates information bias.
Many times, blinding cannot be done; allocation concealment can almost always be done. Breakdowns in each lead to different kinds of bias, and most methods of judging the quality of clinical trials score them separately.
Sorry. In the cases I read of the clinicians apparently had access (albeit by nonstandard means) to the list of which code numbers for medications corresponding to the study drug and which didn’t. You’re right, with careful controls it’s possible to maintain allocation concealment. Blinding is much harder, unless of course the active treatment isn’t particularly.
Of course, you should never use a placebo arm when there is an effective treatment. But this (methamphetamine addiction) doesn’t appear to have an effective treatment.
The cognitive bias about placebos being less-than-fully-ethical is a result of our understanding that drugs and treatments don’t get to Phase III trials without substantial evidence of its safety and probable efficacy. We want patients on the active arm because our prior beliefs suggest that the treatment probably works.
Desperation almost certainly corrupts critical thinking and dispassionate evaluation and thus springs, I guess, your call for reinforced commitment to rigorous research. But the obvious tension amongst the above statements is that desperation implies severe delay discounting and rigorous research implies a long-term wait. So unless the desperation itself is managed, people will still end up spending thousands of dollars on unproven treatments. One of the suggestions made in a book/essay by a former FDA official that I like is to separate safety and efficacy and issue a restricted approval if the intervention shows evidence for a reasonable degree of safety and preliminary evidence of efficacy. Not sure how that would work in practice or the number of false positives that would slip through, but it could contain the fallout brought about by the long wait of a rigorous evaluation. Simply doubling down on the current regime without addressing the desperation of the patients & caregivers just maintains the status quo.
One of the things that make me lean towards a policy mix of enforcement and treatment is that, AFAIK, there is no effective treatment for severe heroin, meth or crack addiction. Australia did a major trial of opiate dependency treatments in the 90s, and methadone was the only one that “worked”. But how to tell families that?