Friday, September 21, 2012

Trials in Alzheimer's Disease: The Long Road Ahead

Placebo Control is going purple today in support of Alzheimer’s Action Day.

A couple of clinical trial related thoughts on the ongoing struggle to find even one effective therapy (currently-approved drugs show some ability to slow the progression of AD, but not to effectively stop, much less reverse it):
  • The headlines so far this year have been dominated by the high-profile and incredibly expensive failures of bapineuzumab and solanezumab. However, these two are just the most recent of a long series of failures: a recent industry report tallies 101 investigational drugs that that have failed clinical trials or been suspended in development since 1998, against only 3 successes, an astonishing and painful 34:1 failure rate.

  • While we are big fans of the Alzhemier’s Association (just down the street from Placebo HQ here in Chicago) and the Alzheimer’s Foundation of America, it’s important to stress that the single most important contribution that patients and caregivers can make is to get involved in a clinical trial. That same report lists 93 new treatments currently being evaluated.  As of today, the US clinical trials registry lists 124 open trials for AD.  Many of these studies only require a few hundred participants, so each individual decision to enroll is important and immediately visible.

  • While all research is important, I want to single out the phenomenal work being done by ADNI, the Alzheimer’s Disease Neuroimaging Initiative. This is a public/private partnership that is
    collecting a vast amount of data – blood, cerebrospinal fluid, MRIs, and PET scans – on hundreds of AD patients and matched controls. Best of all, all of the data collected is published in a free, public database hosted by UCLA. Additional funding has recently led to the development of the ADNI-2 study, which will enroll 550 more participants.
Without a doubt, finding and testing effective medications for Alzheimer's Disease is going to take many more years of hard, frustrating work. It will be a path littered with many more failures and therapeutic dead-ends. Today's a good day to stop and recognize that fact, and strengthen our resolve to work together to end this disease.

Tuesday, September 18, 2012

Delivering the Placebic Payload

Two recent articles on placebo effects caught my attention. Although they come to the topic from very different angles, they both bear on the psychological mechanisms by which the placebo effect delivers its therapeutic payload, so it seems worthwhile to look at them together.
Placebo delivery: there's got to be a better way!

The first item is a write up of 2 small studies, Nonconscious activation of placebo and nocebo pain responses. (The article is behind a paywall at PNAS: if you can’t access it you can read this nice synopsis on Inkfish, or the press release issued by Beth Israel Deaconess (which includes bonus overhyping of the study’s impact by the authors).)

The studies’ premises were pretty straightforward: placebo effects are (at least in part) caused by conditioned responses. In addition, psychologists have demonstrated in a number of studies that many types of conditioned responses can be triggered subliminally.  Therefore, it might be possible, under certain circumstances, to elicit placebo/nocebo responses with nothing but subliminal stimuli.

And that, in effect, is what the studies demonstrate.  The first showed a placebo effect in patients who had been trained to associate various pain levels with pictures of specific faces. The second study elicited a (somewhat attenuated) placebo response even when those pictures were shown for a mere 12 milliseconds – below the threshold of conscious recognition. This gives us some preliminary evidence that placebo effects can be triggered through entirely subconscious mental processes.

Or does it? There seems to me to be some serious difficulties in making the leap from this highly-controlled lab experiment to the actual workings of placebos in clinical practice. First and foremost: to elicit subconscious effects, these experiments had to first provide quite a significant “pretreatment” of conscious, unambiguous conditioning to associate certain pain levels with specific images: 50 pain jolts in about 15 minutes.  Even then, the experimenters still felt the need to re-apply the explicit conditioning in 10% of the test cases, “to prevent extinction”.  This raises the obvious question: if even an intensive, explicit conditioning sequence can wear off that quickly, how are we to believe that a similar mechanism is acting in everyday clinical encounters, which are not so frequent and so explicit? The authors don’t seem to see an issue here, as they write:
Our results thereby translate the investigation of nonconscious effects to the clinical realm, by suggesting that health-related responses can be triggered by cues that are not consciously perceived, not only for pain … but also for other medical problems with demonstrated placebo effects, e.g., asthma, depression, and irritable bowel syndrome. Understanding the role of nonconscious processes in placebo/nocebo opens unique possibilities of enhancing clinical care by attending to the impact of nonconscious cues conveyed during the therapeutic encounter and improving therapeutic decisions.
So, the clinical relevance for these findings depends on how much you believe that precisely repeated blasts of pain faithfully replicate the effects of physician/patient interactions. I do not think I am being terribly skeptical when I say that I think clinical interactions are usually shorter and involve a lot more ambiguity – I am not even sure that this is a good model for placebo analgesia, and it certainly can’t be considered to have an lot of explanatory explanations for placebo effects in, eg, depression trials.

…Which brings me to the second article, a very different creature altogether.  It’s a blog post by Dike Drummond entitled Can digital medicine have a placebo effect? He actually comes very close to the study authors’ position in terms of ascribing placebo effects to subconscious processes:
The healing can occur without outside assistance — as the placebo effect in drug studies shows — or it can augment whatever medication or procedure you might also prescribe.  I believe it is the human qualities of attention and caring that trigger the placebo effect. These exist parallel to the provider’s ability to diagnose and select an appropriate medical treatment.
You can arrive at the correct diagnosis and treatment and not trigger a placebo effect. You can fail to make eye contact, write out a prescription, hand it to the patient and walk out the door.  Right answer — no placebo effect.  Your skills as a placebologist rely on the ability to create the expectation of healing in the patient. This is most definitely part of the art of medicine.
I will disagree a bit with Drummond on one point: if we could extinguish placebo effects merely by avoiding eye contact, or engaging in similar unsociable behavior, then we would see greatly reduced placebo effects in most clinical trials, since most sponsors do try to implement strategies to reduce those effects. In fact, there is some evidence that placebo effects are increasing in some trials. (Which, tangentially, makes me ask why pharmaceutical companies keep paying “expert consultants” to conduct training seminars on how to eliminate placebo effects … but that’s a rant for another day.)

Drummond ponders whether new technologies will be able to elicit placebo responses in patients, even in the complete absence of human-to-human interaction. I think the answer is “probably, somewhat”. We certainly have some evidence that physicians can increase placebo effects through explicit priming; it would seem logical that some of that work could be done by an iPad. Also, the part of the placebo effect that is patient-driven -- fed by their preexisting hopes and expectations – would seem to be transferrable to a non-personal interaction (after all, patients already derive placebic benefit from homeopathic and other ineffective over-the-counter cures with no physician, and minimal human, input).

The bottom line, I think, is this: we oversimplify the situation when we talk about “the” placebo effect. Placebo response in patients is a complex cluster of mechanisms, some or all of which are at play in each individual reaction. On the patient’s side, subconscious hope, conscious expectations, and learned associations are all in play, and may work with or against each other. The physician’s beliefs, transmitted through overt priming or subtle signals, can also work for or against the total placebo effect. There is even good evidence that placebo analgesia is produced through multiple distinct biochemical pathways, so proposing a single simple model to cover all placebo responses will be doomed to failure.

The consequence for clinical trialists? I do not think we need to start fretting over subliminal cues and secret subconscious signaling, but we do need to develop a more comprehensive method of measuring the impact of multiple environmental and patient factors in predicting response. The best way to accomplish this may be to implement prospective studies in parallel with existing treatment trials to get a clearer real-world picture of placebo response in action.

[Image: "Extraction of the Stone of Folly", Hieronymus Bosch, by way of Wikimedia Commons] Karin B. Jensen, Ted J. Kaptchuk, Irving Kirsch, Jacqueline Raicek, Kara M. Lindstrom, Chantal Berna, Randy L. Gollub, Martin Ingvar, & Jian Kong (2012). Nonconscious activation of placebo and nocebo pain responses PNAS DOI: 10.1073/pnas.1202056109

Friday, September 14, 2012

Clinical trials: recent reading recommendations

My recommended reading list -- highlights from the past week:

Absolute required reading for anyone who designs protocols or is engaged in recruiting patients into clinical trials: Susan Guber writes eloquently about her experiences as a participant in cancer clinical trials.
New York Times Well Blog: The Trials of Cancer Trials
Today's #FDAFridayPhoto features Harvey
Wiley, leader of the famed FDA "Poison Squad".

The popular press in India continues to be disingenuous and exploitative in its coverage of clinical trial deaths in that country. (My previous thoughts on that are here.) Kiran Mazumdar-Shaw, an industry leader, has put together an intelligent and articulate antidote.
The Economic Times: Need a rational view on clinical trials

Rahlen Gossen exhibits mastery of the understatement: “Though the Facebook Insights dashboard is a great place to start, it has a few significant disadvantages.” She also provides a good overview of the most common pitfalls you’ll encounter when you try to get good metrics out of your Facebook campaign. 

I have not had a chance to watch it yet, but I’m excited to see that has just posted a 7-part video editorial series by Yale’s Harlan Krumholz and Duke Stanford’s Bob Harrington on “a frank discussion on the controversies in the world of clinical trials”.