For a good while now I have been occasionally posting on a regular theme from Dr. Roy Poses's Health Care Renewal Blog, for instance:
http://brodyhooked.blogspot.com/2011/07/kid-gloves-on-corporate-crime-different.html
--that we cannot expect drug/device industry wrongdoing to cease so long as the corporation merely has to pay a fine for legal transgressions; they merely budget the looked-for fine as a cost of doing business and go merrily on their way. Only if individual execs are held accountable under criminal law can we expect behavior to improve.
Well, at least one French judge seems to have gotten the message (not sure if non-subscribers can access but here goes anyway):
http://www.theheart.org/article/1283233.do
Basic bottom line-- a drug (benfluorex) was approved for use in Europe but not the U.S. that seems to be a cousin of the fen-phen combo that I discussed in HOOKED, marketed as a weight loss drug and then shown to cause deadly adverse reactions including heart valve damage and pulmonary fibrosis. The head of Servier, France's second-largest drug company, has been charged with involuntary manslaughter, aggravated deception, and fraud for marketing the drug despite known risks. The CEO has had to post $5.5M bail (which, if French CEO compensation is anything like the U.S., he probably was carrying around as loose change).
My own comment is that the French more or less have the right idea, but I'm an old softie. I would have been happy with just the aggravated deception (whatever that is) and fraud charges. I would not have seen the need to add manslaughter.
Thursday, September 22, 2011
Monday, September 12, 2011
From GoozNews: Doing the Right Thing on New Devices?
Apologies if you cannot access this post by Merrill Goozner; I am not sure if you need to be a subscriber to reach his blog:
http://gooznews.com/?p=3156
"Gooz," author of the excellent book, The $800 Million Pill, offers a comment on the recent NIH study showing that stents for arteries in the brain do not prevent strokes and indeed worsen the stroke risk. The good news was that Medicare-Medicaid had held off paying for these stents even with an earlier, smaller study funded by the stent company (Stryker) that was much more promising. (The definitive study, that was stopped early due to the poor outcomes, was funded by NIH.) This was billed as a success story for evidence-based medicine. Medicare-Medicaid insisted that any patient who wanted such a stent had to be enrolled in a proper clinical trial so that the evidence could be collected.
Gooz says-- not so fast. Why wasn't Stryker required to do the large-scale study right from the get-go? He even suggests that the US taxpayers ought to get a refund for the NIH study.
Gooz may be counseling perfection on some matters, but I concur with his general point that the FDA requirements for approving new devices need to be tightened up generally, as we have addressed in previous posts such as:
http://brodyhooked.blogspot.com/2011/08/more-on-iom-report-on-fda-scrutiny-of.html
http://gooznews.com/?p=3156
"Gooz," author of the excellent book, The $800 Million Pill, offers a comment on the recent NIH study showing that stents for arteries in the brain do not prevent strokes and indeed worsen the stroke risk. The good news was that Medicare-Medicaid had held off paying for these stents even with an earlier, smaller study funded by the stent company (Stryker) that was much more promising. (The definitive study, that was stopped early due to the poor outcomes, was funded by NIH.) This was billed as a success story for evidence-based medicine. Medicare-Medicaid insisted that any patient who wanted such a stent had to be enrolled in a proper clinical trial so that the evidence could be collected.
Gooz says-- not so fast. Why wasn't Stryker required to do the large-scale study right from the get-go? He even suggests that the US taxpayers ought to get a refund for the NIH study.
Gooz may be counseling perfection on some matters, but I concur with his general point that the FDA requirements for approving new devices need to be tightened up generally, as we have addressed in previous posts such as:
http://brodyhooked.blogspot.com/2011/08/more-on-iom-report-on-fda-scrutiny-of.html
Thursday, September 8, 2011
Colorado Institutions Riding Herd on Doctors
I said in my last post to expect that local news media (at least the handful that still have an investigative reporter on staff) would be eagerly mining the ProPublica Dollars for Docs database to see what till their local physicians had their hands in. When I wrote that post I had not yet scrolled my e-mail down to my Kaiser Family Foundation Daily Health Policy Report. On that site I found just such a story by Michael Booth of the Denver Post:
http://www.denverpost.com/search/ci_18848973
What's most intriguing here to my mind is the reports of how two institutions, the U. Colorado School of Medicine and National Jewish Health, have taken on the task of prohibiting many practices that constitute conflicts of interest and demanding oversight of other relationships between their physicians and pharmaceutical companies. The U. was especially embarrassed by how many of their docs were listed on the first ProPublica database when it came out last year and so vowed to take action.
The upshot is that suppose you read on the database that Dr. House at one of these centers took $100,000 from Eli Lilly. You are not sure just what to make of that. But the institution can now tell you that it looked over the contract and that Dr. House is doing legitimate research with that money, not putting it in his own pocket, and not shilling for Lilly.
This seems to be another example to demonstrate that while mere disclosure of conflicts of interest cannot make everything ethically pristine-- a song I've been singing since this blog started--disclosure can lead to other steps that constitute a true ethical advance.
http://www.denverpost.com/search/ci_18848973
What's most intriguing here to my mind is the reports of how two institutions, the U. Colorado School of Medicine and National Jewish Health, have taken on the task of prohibiting many practices that constitute conflicts of interest and demanding oversight of other relationships between their physicians and pharmaceutical companies. The U. was especially embarrassed by how many of their docs were listed on the first ProPublica database when it came out last year and so vowed to take action.
The upshot is that suppose you read on the database that Dr. House at one of these centers took $100,000 from Eli Lilly. You are not sure just what to make of that. But the institution can now tell you that it looked over the contract and that Dr. House is doing legitimate research with that money, not putting it in his own pocket, and not shilling for Lilly.
This seems to be another example to demonstrate that while mere disclosure of conflicts of interest cannot make everything ethically pristine-- a song I've been singing since this blog started--disclosure can lead to other steps that constitute a true ethical advance.
ProPublica's Updated Sunshine Database
The good folks at ProPublica:
http://www.propublica.org/article/piercing-the-veil-more-drug-companies-reveal-payments-to-doctors
--announce that they have updated their "Dollars for Docs" database:
http://projects.propublica.org/docdollars/
They note that they are offering a sneak preview of 2013 when the Federal sunshine provisions in the health reform law take effect, and disclosures that are now semi-voluntary become required. (I say "semi" because some of the companies now disclosing are doing so under orders from court settlements.) The total database accounts for $760M betweeen 2009 and 2011. Given Gagnon and Lexchin's estimate several years ago that the US pharmaceutical industry spends a total of $57B annually on marketing, and given that at least some of the money on the database is in the form of research grants which at least officially is not marketing, we still have to ask how much of the total picture we are seeing.
To my mind the big news from ProPublica's initial analysis of their data is the possibility that sunshine is having an impact. There is some evidence of cutting back on the amount companies pay to speakers, in particular. The companies pitch this as a purely business decision, but it has several twists:
http://www.propublica.org/article/piercing-the-veil-more-drug-companies-reveal-payments-to-doctors
--announce that they have updated their "Dollars for Docs" database:
http://projects.propublica.org/docdollars/
They note that they are offering a sneak preview of 2013 when the Federal sunshine provisions in the health reform law take effect, and disclosures that are now semi-voluntary become required. (I say "semi" because some of the companies now disclosing are doing so under orders from court settlements.) The total database accounts for $760M betweeen 2009 and 2011. Given Gagnon and Lexchin's estimate several years ago that the US pharmaceutical industry spends a total of $57B annually on marketing, and given that at least some of the money on the database is in the form of research grants which at least officially is not marketing, we still have to ask how much of the total picture we are seeing.
To my mind the big news from ProPublica's initial analysis of their data is the possibility that sunshine is having an impact. There is some evidence of cutting back on the amount companies pay to speakers, in particular. The companies pitch this as a purely business decision, but it has several twists:
- A mini-scandal erupted when the media noted that a number of drug company speakers were in trouble with their state licensing boards. This has led some companies both to pare back and also to be more selective about paid speakers. (They also mention it's smarter from a business point of view to pay fewer speakers to give more talks each; saves on training.) But that scandal was indirectly due to the sunshine of Dollars for Docs, as that provided the database for enterprising journalists to compare to the lists of in-trouble docs.
- Some universities with policies prohibiting their faculty from being paid speakers had not been enforcing those policies, but Dollars for Docs makes them look pretty silly and has emboldened more of them to search the database for names of their own faculty. Apparently anticipating this scrutiny, some of those docs have chosen to withdraw from speakers' bureaus.
Indirect evidence that the Dollars for Docs is having an impact is the fact that PhRMA seemed to feel it necessary to come out with a preeptive-strike news release just before the update was announced, in which they defended their payments to physicians.
Expect to see more stories from the database as journalists around the country now start peering into their local doctors' names and tracking down what they are up to.
Wednesday, September 7, 2011
None Dare Call It Corruption
Warning: Strident, intemperate post follows (at least at the end).
Exhibit A is a great summary from our friend Dr. Roy Poses at Health Care Renewal of the case of the contaminated heparin:
http://hcrenewal.blogspot.com/2011/08/jama-article-begs-key-questions-about.html
Bottom line: As most people have by now forgotten, 21 Americans died in 2007 due to contaminated heparin sold by Baxter Laboratories and made from ingredients manufactured in China. Dr. Poses shows that even recently written reports and news summaries dodge the tough questions of corporate responsibility. If a madman had slipped poison into bottles of an over-the-counter medicine and 21 people died, there would be a huge hue and cry and demands that heads roll. As Dr. Poses lays out in detail, various people made some important corporate decisions, all in the name of saving money, that predictably resulted in an unsafe drug being inflicted upon US patients. If you buy a Rolex at a certain discounted price, we all assume, with justification, that you ought to know that it's been stolen. Similarly, if Dr. Poses's summary is factual, anyone buying the heparin or the raw ingredients at the discounted prices being charged ought to have known that the chemicals came from unsupervised and unregulated workshops where purity and safety could not be assured. Not to have carefully tested and monitored the chemicals thus obtained, even assuming it was OK to get the chemicals from those sources at all, was another deliberate corporate decision. Yet no one, apparently, is accountable.
Exhibit B is an investigative reporting piece published by the AP today:
http://www.google.com/hostednews/ap/article/ALeqM5g5Jh7VmaKckgs3H035JJcYuzQttw?docId=d1b5a7b87097484b9b140838f50a88e7
Ricardo Alonso-Zaldivar, who's written many good pieces on the pharmaceutical industry, here reports on a recent study of campaign contributions to the twelve members of the Congressional "supercommittee" charged with coming up with a deficit reduction plan. Not surprisingly, deep-pockets health care interests, including Pharma and doctors, are near the top of the list. Not surprisingly, the offices of the involved congresspeople deny that any of these saintly individuals is ever swayed by mere campaign cash. Not surprisingly, if you believe that line, you have to believe that smart people who manage to make large bundles of money are completing wasting millions of dollars of it by giving campaign donations that produce no results for them at all.
As we have commented on previously:
http://brodyhooked.blogspot.com/2011/09/does-drug-industry-trust-super.html
--the smart Washington money is currently betting that these health-care special interests want the supercommittee plan to fail, based on their assumption that the across-the-board cuts that would automatically be triggered by that failure would be easier for them to live with than targeted and really smart Medicare and Medicaid cost reductions that were aimed at those things that don't help patients. (Given that doctors, hospitals, and drug and device companies all make billions off tests and treatments that fail to provide health benefits according to the best scientific evidence.) Is it possible that all the supercommittee members who take such major campaign contributions from these special interests are not going to be influenced by this preference of their corporate handlers?
The above was all reasonably temperate. Here comes the intemperate part. If all this was happening in Afghanistan or India, and corporations were getting away with murder and the media was keeping quiet about it just because it was corporate and not individual behavior, and politicians were being bought (or even appeared to be bought) by big money, the word we would use for it is "corruption." So my question is--why are people so reluctant to use this word when this happens right in front of us in the USA? Why don't we admit flat out that we have a corrupt corporate system, and that with the Citizens United Supreme Court decision opening the door wide to unrestricted corporate campaign contributions, we have let the corruption flow unhindered from the corporate world into government; and that the media, owned by large corporate interests, has little desire to shine much light at least on the corporate side of the equation?
Exhibit A is a great summary from our friend Dr. Roy Poses at Health Care Renewal of the case of the contaminated heparin:
http://hcrenewal.blogspot.com/2011/08/jama-article-begs-key-questions-about.html
Bottom line: As most people have by now forgotten, 21 Americans died in 2007 due to contaminated heparin sold by Baxter Laboratories and made from ingredients manufactured in China. Dr. Poses shows that even recently written reports and news summaries dodge the tough questions of corporate responsibility. If a madman had slipped poison into bottles of an over-the-counter medicine and 21 people died, there would be a huge hue and cry and demands that heads roll. As Dr. Poses lays out in detail, various people made some important corporate decisions, all in the name of saving money, that predictably resulted in an unsafe drug being inflicted upon US patients. If you buy a Rolex at a certain discounted price, we all assume, with justification, that you ought to know that it's been stolen. Similarly, if Dr. Poses's summary is factual, anyone buying the heparin or the raw ingredients at the discounted prices being charged ought to have known that the chemicals came from unsupervised and unregulated workshops where purity and safety could not be assured. Not to have carefully tested and monitored the chemicals thus obtained, even assuming it was OK to get the chemicals from those sources at all, was another deliberate corporate decision. Yet no one, apparently, is accountable.
Exhibit B is an investigative reporting piece published by the AP today:
http://www.google.com/hostednews/ap/article/ALeqM5g5Jh7VmaKckgs3H035JJcYuzQttw?docId=d1b5a7b87097484b9b140838f50a88e7
Ricardo Alonso-Zaldivar, who's written many good pieces on the pharmaceutical industry, here reports on a recent study of campaign contributions to the twelve members of the Congressional "supercommittee" charged with coming up with a deficit reduction plan. Not surprisingly, deep-pockets health care interests, including Pharma and doctors, are near the top of the list. Not surprisingly, the offices of the involved congresspeople deny that any of these saintly individuals is ever swayed by mere campaign cash. Not surprisingly, if you believe that line, you have to believe that smart people who manage to make large bundles of money are completing wasting millions of dollars of it by giving campaign donations that produce no results for them at all.
As we have commented on previously:
http://brodyhooked.blogspot.com/2011/09/does-drug-industry-trust-super.html
--the smart Washington money is currently betting that these health-care special interests want the supercommittee plan to fail, based on their assumption that the across-the-board cuts that would automatically be triggered by that failure would be easier for them to live with than targeted and really smart Medicare and Medicaid cost reductions that were aimed at those things that don't help patients. (Given that doctors, hospitals, and drug and device companies all make billions off tests and treatments that fail to provide health benefits according to the best scientific evidence.) Is it possible that all the supercommittee members who take such major campaign contributions from these special interests are not going to be influenced by this preference of their corporate handlers?
The above was all reasonably temperate. Here comes the intemperate part. If all this was happening in Afghanistan or India, and corporations were getting away with murder and the media was keeping quiet about it just because it was corporate and not individual behavior, and politicians were being bought (or even appeared to be bought) by big money, the word we would use for it is "corruption." So my question is--why are people so reluctant to use this word when this happens right in front of us in the USA? Why don't we admit flat out that we have a corrupt corporate system, and that with the Citizens United Supreme Court decision opening the door wide to unrestricted corporate campaign contributions, we have let the corruption flow unhindered from the corporate world into government; and that the media, owned by large corporate interests, has little desire to shine much light at least on the corporate side of the equation?
Saturday, September 3, 2011
Journal Conflicts: Drilling Down Farther
When I was writing HOOKED, one of the most frustrating subtopics that I encountered was the financial aspect of medical journal publication. I found it nearly impossible to gather data about the degree to which most journals were entangled with the drug industry. Andreas Lundh and his colleagues at the Nordic Cochrane Center were able to do a better job than I at uncovering some key data but still came up partly empty-handed:
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000354
In this somewhat older article (hat tip to Primary Care Medical Abstracts and Drs. Bukata and Hoffman for pointing it out) the authors tried to gather data on how many studies in six of the top medical journals in English are industry-sponsored, what impact these articles have on the impact factor of the journal; and how much money the journals make from industry ads and from sales of reprints to drug companies. The impact factor is key; journals are in cutthroat competition over this measure of how widely cited their articles are in the rest of the medical literature. Impact factor plays a role in determining where important studies are submitted, how many libraries subscribe to the journal, and how easily the journal can attract advertising.
When Lundh and colleagues went looking for the financial data, they adopted the excellent initial strategy of asking. Of the six journals they were studying, BMJ and Lancet replied, while JAMA, Archives of Internal Medicine, New England Journal, and Annals of Internal Medicine refused to supply any data. When the authors then obtained tax reports and tried to calculate some of the relevant numbers, and sent their calculations to the publishing organizations for confirmation, American College of Physicians (publishers of Annals) responded but the others again refused to divulge any financial information.
Bottom line: most medical journals keep their financial numbers very close to the vest--even journals that have editorial policies that encourage full disclosure of financial conflicts among other parties.
So with what they could get their hands on, Lundh and colleagues noted that the percentage of clinical trials supported solely by industry varied from a low of 3% in BMJ to 32% in New England Journal. Industry-funded trials were more widely cited than other studies (a phenomenon noted in a number of previous surveys; being sure to write more articles that cite a successful study, and then placing those articles in turn in higher-impact journals, is standard industry marketing practice). Therefore as one would expect, publishing more industry-sponsored studies has an effect on the journal's impact factor. Had those studies not been published the impact factor would have dropped only by 1% at BMJ, the low end of the scale, but by 15% for NEJM. In other words, journals have a significant financial interest in publishing industry-sponsored studies on the grounds of impact factor alone even before we get to ad and reprint sales.
For the only two journals for which they could raise the data, Lundh et al. found that journal reprints made up only 3% of revenue for BMJ but all of 41% for Lancet. Tax returns indicate that the AMA, publisher of JAMA and Archives, derives 12% of revenue from reprint sales and a whopping 53% from ads.
The authors end with the following sensible recommendation: "We suggest that journals abide by the same standards related to conflicts of interest, which they rightly require from their authors, and that the sources and the amount of income are disclosed to improve transparency."
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000354
In this somewhat older article (hat tip to Primary Care Medical Abstracts and Drs. Bukata and Hoffman for pointing it out) the authors tried to gather data on how many studies in six of the top medical journals in English are industry-sponsored, what impact these articles have on the impact factor of the journal; and how much money the journals make from industry ads and from sales of reprints to drug companies. The impact factor is key; journals are in cutthroat competition over this measure of how widely cited their articles are in the rest of the medical literature. Impact factor plays a role in determining where important studies are submitted, how many libraries subscribe to the journal, and how easily the journal can attract advertising.
When Lundh and colleagues went looking for the financial data, they adopted the excellent initial strategy of asking. Of the six journals they were studying, BMJ and Lancet replied, while JAMA, Archives of Internal Medicine, New England Journal, and Annals of Internal Medicine refused to supply any data. When the authors then obtained tax reports and tried to calculate some of the relevant numbers, and sent their calculations to the publishing organizations for confirmation, American College of Physicians (publishers of Annals) responded but the others again refused to divulge any financial information.
Bottom line: most medical journals keep their financial numbers very close to the vest--even journals that have editorial policies that encourage full disclosure of financial conflicts among other parties.
So with what they could get their hands on, Lundh and colleagues noted that the percentage of clinical trials supported solely by industry varied from a low of 3% in BMJ to 32% in New England Journal. Industry-funded trials were more widely cited than other studies (a phenomenon noted in a number of previous surveys; being sure to write more articles that cite a successful study, and then placing those articles in turn in higher-impact journals, is standard industry marketing practice). Therefore as one would expect, publishing more industry-sponsored studies has an effect on the journal's impact factor. Had those studies not been published the impact factor would have dropped only by 1% at BMJ, the low end of the scale, but by 15% for NEJM. In other words, journals have a significant financial interest in publishing industry-sponsored studies on the grounds of impact factor alone even before we get to ad and reprint sales.
For the only two journals for which they could raise the data, Lundh et al. found that journal reprints made up only 3% of revenue for BMJ but all of 41% for Lancet. Tax returns indicate that the AMA, publisher of JAMA and Archives, derives 12% of revenue from reprint sales and a whopping 53% from ads.
The authors end with the following sensible recommendation: "We suggest that journals abide by the same standards related to conflicts of interest, which they rightly require from their authors, and that the sources and the amount of income are disclosed to improve transparency."
Placebo Effect and Adherence: A Challenge to Pharma?
As all four of the regular readers of this blog are aware, I am an avid listener to Rick Bukata's and Jerry Hoffman's monthly audio recordings, Primary Care Medical Abstracts (free advertising for them: www.ccme.org). So here I am all innocently driving my car and listening to the CD for their August 2011 issue, when I am shocked to hear the CD shouting out my name. Jerry is asking that I respond to a query about one of the papers he and Rick had been discussing, in my capacity as someone who has a long-standing interest in the placebo effect.
So here is my answer to Jerry. You'll naturally wonder why it's here on this blog which is about ethics and Pharma and not about placebo effect. In the end I'll suggest an important connection.
The paper that started all this is a thoughtful editorial by Wilson (subscription required) about the placebo effect and adherence. There have now been a good number of studies that show that when you do a double-blind trial with a placebo arm, there is quite often (indeed rather consistently) a significant improvement of outcomes among those who take their placebos faithfully, compared to those who are relatively non-adherent to taking their placebos. Wilson does a neat analysis of what we know, and what we don't yet know, about this adherence phenomenon, and suggests linkages to what we are learning about placebo effects and why this phenomenon might be viewed (at least as a working hypothesis) as a variant of placebo effect.
Jerry then raises the question: what's the message here for clinicians? Should we give patients pep talks to try to both encourage and energize them about the treatments we're prescribing (whether drug or nondrug) to try to enhance their expectations of a good outcome, which has been shown to be positively associated with a placebo response? Should this pep talk include advice to be sure to take their pills (or other treatments) faithfully? Or might it be the case that the adherence research shows that what really matters is what's already inside the patient's head, not what we say--that those in the trials that were more adherent were simply that sort of person, and being that sort of person is what matters in terms of triggering a placebo effect--and our pep talk is worthless?
OK, Jerry, here's my answer, followed by my hunch.
My answer, as Wilson's nice review suggests, is: we don't know. No one has yet done the sort of fine-grained study of the more-adherent research subjects, analogous to some of the latest generation of placebo-effect research done in the last decade with brain imaging etc. So the underlying psychological and neurochemical factors that might explain the adherence-placebo effect link are unknown.
Now my hunch. The placebo effect is almost certainly multifactorial. Indeed, Fabrizio Benedetti of Turin titled his excellent 2009 book Placebo Effects (rather than Placebo Effect) to make the argument that continued research will almost certainly reveal multiple underlying mechanisms that may operate in different diseases and different organ systems.
The best available evidence that we have suggests two very general psychological mechanisms for most placebo effects--expectancy and conditioning. Expectancy is basically forward looking--your body is likely to heal itself when you think it will get better in the future. Conditioning is backward--your body is more likely to heal itself when you associate the circumstances you're in now with circumstances in which your body experienced healing previously.
The adherence effect probably partakes of both. Subjects who take their medicines regularly probably anticipate a good outcome with greater confidence. These same people probably got better in the past when they religiously took their pills, and so conditioning can contribute to their getting better this time by reactivating the same neural pathways.
Now what happens if a physician acts enthusiastic and encouraging about the nature of the treatment? This is likely to increase both expectancy and conditioning effects--expectancy for obvious reasons, conditioning because the patient probably associates an emotionally supportive environment with past healing (going as far back as when Mommy kissed your boo-boo and it got better afterwards). So I cannot see how the encouraging physician could detract in any way from the patient's inner tendency to experience an adherence-placebo reaction, and I can see several ways that the former might enhance the latter. So: bring on the pep-talk.
I have recently become interested in the connection between placebo response and medicine viewed as ritual/performance/theater. We scientific types are used to dismissing ritual as meaningless superstition, but the current placebo research indicates the neuroanatomical and neurochemical reasons why ritual can be efficacious in changing bodily function as well as in altering our cognitive and emotional views of the world. Much of medicine, when we think about it, is ritual and/or performance. (Science writer Nicholas Wade once wrote something like, "All medicine is a form of theater.") Rituals include taking one's pills once or several times a day and can readily trigger both expectancy and conditioning responses. Smart physicians who prescribe exercise and other lifestyle changes try whever possible to suggest rituals to patients to increase adherence, in some cases going so far as to write the instructions on a prescription pad, which when in practice I always found especially powerful. All of these measures seem well calculated to increase placebo effects, as well as to make patients healthier by way of the drug or the exercise or whatever.
I promised in the end to bring this back around to Pharma, so here goes. I suggest that you read Wilson's article and look especially at the effect sizes reported for the adherence-placebo effect. Just for example: Mortality difference between adherent and nonadherent placebo group subjects in the Coronary Drug Project (1980): 15% vs. 25%. More recently, adherence effect in mortality in heart failure, based on the SOLV-TT and SOLV-PT trials: hazard ratio 0.52 (Avins 2010). And remember, according to the body of data Wilson reviews, these are not one-time flukes. And remember too we are talking here about people keeling over dead, not some meaningless surrogate endpoint.
Why is this of importance? The drug companies would kill to come up with a new drug that had efficacy numbers this good. So you could spin this in a pro- or anti-industry fashion. On the side of the industry, have a pity--look what they have to overcome to show that a new drug is better than placebo, when the placebo effect alone can be this powerful. But on the other side of the coin, when mere encouragement and positive thinking can have this much beneficial effect on patient outcomes, why in heaven's name would we want to give drugs that have dangerous side effects and that cost an arm and a leg, unless the drugs had been clearly shown to be really superior to cheap and safe encouragement?
Wilson IB. Adherence, placebo effects, amd mortality [editorial]. Journal of General Internal Medicine 25:1270-1272, December 2010.
Avins AL, Pressman A, Ackerson L, et al. Placebo adherence and its association with morbidity and mortality in the studies of left ventricular dysfunction. Journal of General Internal Medicine 25: 1275-1281, December 2010.
So here is my answer to Jerry. You'll naturally wonder why it's here on this blog which is about ethics and Pharma and not about placebo effect. In the end I'll suggest an important connection.
The paper that started all this is a thoughtful editorial by Wilson (subscription required) about the placebo effect and adherence. There have now been a good number of studies that show that when you do a double-blind trial with a placebo arm, there is quite often (indeed rather consistently) a significant improvement of outcomes among those who take their placebos faithfully, compared to those who are relatively non-adherent to taking their placebos. Wilson does a neat analysis of what we know, and what we don't yet know, about this adherence phenomenon, and suggests linkages to what we are learning about placebo effects and why this phenomenon might be viewed (at least as a working hypothesis) as a variant of placebo effect.
Jerry then raises the question: what's the message here for clinicians? Should we give patients pep talks to try to both encourage and energize them about the treatments we're prescribing (whether drug or nondrug) to try to enhance their expectations of a good outcome, which has been shown to be positively associated with a placebo response? Should this pep talk include advice to be sure to take their pills (or other treatments) faithfully? Or might it be the case that the adherence research shows that what really matters is what's already inside the patient's head, not what we say--that those in the trials that were more adherent were simply that sort of person, and being that sort of person is what matters in terms of triggering a placebo effect--and our pep talk is worthless?
OK, Jerry, here's my answer, followed by my hunch.
My answer, as Wilson's nice review suggests, is: we don't know. No one has yet done the sort of fine-grained study of the more-adherent research subjects, analogous to some of the latest generation of placebo-effect research done in the last decade with brain imaging etc. So the underlying psychological and neurochemical factors that might explain the adherence-placebo effect link are unknown.
Now my hunch. The placebo effect is almost certainly multifactorial. Indeed, Fabrizio Benedetti of Turin titled his excellent 2009 book Placebo Effects (rather than Placebo Effect) to make the argument that continued research will almost certainly reveal multiple underlying mechanisms that may operate in different diseases and different organ systems.
The best available evidence that we have suggests two very general psychological mechanisms for most placebo effects--expectancy and conditioning. Expectancy is basically forward looking--your body is likely to heal itself when you think it will get better in the future. Conditioning is backward--your body is more likely to heal itself when you associate the circumstances you're in now with circumstances in which your body experienced healing previously.
The adherence effect probably partakes of both. Subjects who take their medicines regularly probably anticipate a good outcome with greater confidence. These same people probably got better in the past when they religiously took their pills, and so conditioning can contribute to their getting better this time by reactivating the same neural pathways.
Now what happens if a physician acts enthusiastic and encouraging about the nature of the treatment? This is likely to increase both expectancy and conditioning effects--expectancy for obvious reasons, conditioning because the patient probably associates an emotionally supportive environment with past healing (going as far back as when Mommy kissed your boo-boo and it got better afterwards). So I cannot see how the encouraging physician could detract in any way from the patient's inner tendency to experience an adherence-placebo reaction, and I can see several ways that the former might enhance the latter. So: bring on the pep-talk.
I have recently become interested in the connection between placebo response and medicine viewed as ritual/performance/theater. We scientific types are used to dismissing ritual as meaningless superstition, but the current placebo research indicates the neuroanatomical and neurochemical reasons why ritual can be efficacious in changing bodily function as well as in altering our cognitive and emotional views of the world. Much of medicine, when we think about it, is ritual and/or performance. (Science writer Nicholas Wade once wrote something like, "All medicine is a form of theater.") Rituals include taking one's pills once or several times a day and can readily trigger both expectancy and conditioning responses. Smart physicians who prescribe exercise and other lifestyle changes try whever possible to suggest rituals to patients to increase adherence, in some cases going so far as to write the instructions on a prescription pad, which when in practice I always found especially powerful. All of these measures seem well calculated to increase placebo effects, as well as to make patients healthier by way of the drug or the exercise or whatever.
I promised in the end to bring this back around to Pharma, so here goes. I suggest that you read Wilson's article and look especially at the effect sizes reported for the adherence-placebo effect. Just for example: Mortality difference between adherent and nonadherent placebo group subjects in the Coronary Drug Project (1980): 15% vs. 25%. More recently, adherence effect in mortality in heart failure, based on the SOLV-TT and SOLV-PT trials: hazard ratio 0.52 (Avins 2010). And remember, according to the body of data Wilson reviews, these are not one-time flukes. And remember too we are talking here about people keeling over dead, not some meaningless surrogate endpoint.
Why is this of importance? The drug companies would kill to come up with a new drug that had efficacy numbers this good. So you could spin this in a pro- or anti-industry fashion. On the side of the industry, have a pity--look what they have to overcome to show that a new drug is better than placebo, when the placebo effect alone can be this powerful. But on the other side of the coin, when mere encouragement and positive thinking can have this much beneficial effect on patient outcomes, why in heaven's name would we want to give drugs that have dangerous side effects and that cost an arm and a leg, unless the drugs had been clearly shown to be really superior to cheap and safe encouragement?
Wilson IB. Adherence, placebo effects, amd mortality [editorial]. Journal of General Internal Medicine 25:1270-1272, December 2010.
Avins AL, Pressman A, Ackerson L, et al. Placebo adherence and its association with morbidity and mortality in the studies of left ventricular dysfunction. Journal of General Internal Medicine 25: 1275-1281, December 2010.
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