One of my most faithful pen-pals (if such a term can be applied to people who send me e-mails) shipped over this link:
http://dissidentvoice.org/2012/10/bad-pharma-bad-journalism/
Briefly, this blog post recounts the history of an exchange between Dr. Ben Goldacre, a British physician/journalist and author of a new book called Bad Pharma, and a dissident economist, Harry Shutt. Goldacre's book appears based on what I've heard so far to be same ol', same ol' for readers of this blog--he nails the drug industry and its medical hangers-on for their addiction to profits over science and health. Shutt's criticism was that all Goldacre calls for is improved regulation of the industry. How, he asked, can you assume that's any sort of adequate measure, when you've just compiled this huge body of evidence that the industry snaps its fingers at all the regulation previously put in place? Goldacre first sent a wimpy reply back, then ceased to respond at all as Shutt pressed him further.
This exchange points out a basic feature of my book HOOKED as well as of this blog. I'm guilty as Goldacre is charged. I have clung to the position that I accept that we live in a capitalist society and that the drug industry is going to continue to be run as a for-profit endeavor. I have called for a lot of changes in how the industry, medicine, and government all do business, but have not called for nationalization of the industry or making it a public utility.
I may be accused of similar wimpiness in my recent book, The Golden Calf (see http://brodyhooked.blogspot.com/2011/11/shameless-commerce-division-new-book.html). I there attack economism, the belief in an unregulated free market as the solution to all human social problems. But to the extent that I offer a vision for an improved future, it's largely a return to the capitalism of the 1950s where the power of government and organized labor helped balance out the excesses of big business, and not the overthrow of capitalism.
I cannot honestly report that I have a deep philosophical commitment to capitalism, though I am persuaded by authors such as economist-philosopher Amartya Sen that basic respect for human rights and human liberty has to include respect for rights to participate in fair markets. My overall goal has been strategic rather than philosophical. I am trying to get the attention of readers, most especially my fellow physicians and health professionals. If the position from which I started is anti-capitalist, I could expect that hardly any of them would read beyond the first sentence. If I stay under the capitalist big tent and specifically detail the problems with medicine and Pharma, maybe at least a few more of them will pay attention.
Is that a coherent and responsible position to take? The beauty of a blog is that y'all get to decide.
Thursday, October 25, 2012
Wednesday, October 24, 2012
Yet More from the Belly of the Beast: Pfizer's Campaign to Market Neurontin Off-Label
Thanks as so often to Dr. Roy Poses over at Health Care Renewal--
http://hcrenewal.blogspot.com/2012/10/when-clinical-trials-are-meant-for.html
--we are alerted to the recent publication by S. Swaroop Vedula and colleagues:
http://www.trialsjournal.com/content/13/1/136
These authors were part of the team that testified in lawsuits brought against Pfizer related to the drug Neurontin (gabapentin). As a result they had access to a trove of internal e-mails and documents. Here they report their analysis of these documents, from two separate legal actions in 2004 and 2008, providing a longitudinal account of how the company approached publication of clinical trial data on gabapentin for off-label uses. (The drug was approved by the FDA for two relatively narrow indications, epilepsy and post-herpetic neuralgia;and the company wanted to extend sales by showing that it worked also for migraine, bipolar disorders, neuropathic pain, and nociceptive pain.)
First the authors documented: "For each of the four off-label indications we included in our study, a document titled ‘marketing assessment,’ designed to examine the financial impact of seeking FDA approval for a new indication versus other methods of increasing sales for the indication, preceded clinical trials sponsored by Pfizer ..." That is, before the company or independent academic scientists had a go at designing and conducting a clinical trial, the marketing people already had their innings and decided on the overall strategy. In this instance, the key decision was not to try to gather data that would allow an aplication to the FDA to expand the approved indications for Neurontin, but to find data that would support off-label prescribing for that usage. And that key decision was made not based on the scientific results of clinical trials, but before the clinical trials were even begun. A critical difference is that if the company had approached the FDA, they would have been legally required to hand over all study results, both favoring the drug and not; while by going the off-label route, they could cherry-pick what they published, as we'll come to. (Reminder: a company cannot legally market a drug for off-label use directly, but its physician "key opinion leaders" are free to recommend off-label use so long as it seems to be at arm's length from the company. Today, drug reps can also hand out trial report reprints that support off-label use, hence the need to publish trials that are favorable.)
The other main reason, besides more control over publication, was that the patent on Neurontin was about the expire and it made no business sense for the company to expand its use just as the drug was about to go generic. In one instance, the decision as to publication of negative results seems to have been driven by the form's "evergreening" strategy, which was to roll out the "new" drug pregabalin as a me-too drug to replace gabapentin as their expensive, heavily-marketed brand-name drug. As pregabalin was about to be launched, the company may have wanted negative trials published about Neurontin, so as to lay the groundwork for later being able to claim that pregabalin was really head and shoulders better than its predecessor.
The next major finding from the authors was, "According to the internal company documents, 'affiliate-driven manuscripts' were written for Pfizer ... by [Medical Action Communications, a medical communication company] and sent to the authors for approval. Each article was coordinated by a manuscript team, consisting of representatives from the medical and marketing divisions of the company." This suggests that ghostwriting--having paid writers spin the research papers the way the company wanted them, and only then letting the scientific "authors" see the drafts of the papers--was simply standard operating procedure within the company. The entire process showed that Pfizer, and especially its marketing division, kept everyone involved in the publication of a paper on a short leash.
Finally, the authors demonstrated that the journals in which papers were published, and the timing of publication, were also chosen for maximum marketing impact--for instance, with positive results published in high-impact journals and published quickly, and with negative results showing up in low-circulation journals years later.
As the authors summarize: "In this study we also observed that publication occurred in journals with higher or lower circulations related to statistical significance of findings; delay in publishing statistically non-significant findings; tailoring of publication content to reflect key marketing messages; adding spin to scientific publications such that conclusions favoring gabapentin were emphasized and conclusions that did not favor gabapentin were explained away; and indicators of ghost authorship. Each form of bias, and spin, on its own, could be seen as a relatively minor issue. The value of our findings is in the overall picture that emerges from what appears to be the simultaneous use of many forms of reporting bias and spin, all within the context of a pharmaceutical company’s publication strategy, implemented for marketing purposes."
So-- it's all about the marketing, and not about the science. No big surprise here, but further documentation of what we've had reason to believe from all previous reports of this type.
Now, I sort of hate to keep beating up on editor Jeffrey Drazen of the New England Journal:
http://brodyhooked.blogspot.com/2012/09/nejm-overly-defensive-or-just-naive.html
--who as previously reported said we should not judge articles based on who sponsored the research but on the quality as depicted in the published paper. What Dr. Vedula and colleagues show us is that if a paper that's positive about a new drug shows up in Dr. Drazen's high-impact journal, we can be reasonably sure that there are 3-4 other studies with much less impressive, or even negative results, which are kept aside to be not published at all, or else published in much-lower-circulation journals many years later--or at least that's the standard business plan within the industry. And of course there's no way on this green earth that even the most fastidious reader of NEJM could ever know that. So much for being able to read a paper in the journal and then draw your own conclusions.
http://hcrenewal.blogspot.com/2012/10/when-clinical-trials-are-meant-for.html
--we are alerted to the recent publication by S. Swaroop Vedula and colleagues:
http://www.trialsjournal.com/content/13/1/136
These authors were part of the team that testified in lawsuits brought against Pfizer related to the drug Neurontin (gabapentin). As a result they had access to a trove of internal e-mails and documents. Here they report their analysis of these documents, from two separate legal actions in 2004 and 2008, providing a longitudinal account of how the company approached publication of clinical trial data on gabapentin for off-label uses. (The drug was approved by the FDA for two relatively narrow indications, epilepsy and post-herpetic neuralgia;and the company wanted to extend sales by showing that it worked also for migraine, bipolar disorders, neuropathic pain, and nociceptive pain.)
First the authors documented: "For each of the four off-label indications we included in our study, a document titled ‘marketing assessment,’ designed to examine the financial impact of seeking FDA approval for a new indication versus other methods of increasing sales for the indication, preceded clinical trials sponsored by Pfizer ..." That is, before the company or independent academic scientists had a go at designing and conducting a clinical trial, the marketing people already had their innings and decided on the overall strategy. In this instance, the key decision was not to try to gather data that would allow an aplication to the FDA to expand the approved indications for Neurontin, but to find data that would support off-label prescribing for that usage. And that key decision was made not based on the scientific results of clinical trials, but before the clinical trials were even begun. A critical difference is that if the company had approached the FDA, they would have been legally required to hand over all study results, both favoring the drug and not; while by going the off-label route, they could cherry-pick what they published, as we'll come to. (Reminder: a company cannot legally market a drug for off-label use directly, but its physician "key opinion leaders" are free to recommend off-label use so long as it seems to be at arm's length from the company. Today, drug reps can also hand out trial report reprints that support off-label use, hence the need to publish trials that are favorable.)
The other main reason, besides more control over publication, was that the patent on Neurontin was about the expire and it made no business sense for the company to expand its use just as the drug was about to go generic. In one instance, the decision as to publication of negative results seems to have been driven by the form's "evergreening" strategy, which was to roll out the "new" drug pregabalin as a me-too drug to replace gabapentin as their expensive, heavily-marketed brand-name drug. As pregabalin was about to be launched, the company may have wanted negative trials published about Neurontin, so as to lay the groundwork for later being able to claim that pregabalin was really head and shoulders better than its predecessor.
The next major finding from the authors was, "According to the internal company documents, 'affiliate-driven manuscripts' were written for Pfizer ... by [Medical Action Communications, a medical communication company] and sent to the authors for approval. Each article was coordinated by a manuscript team, consisting of representatives from the medical and marketing divisions of the company." This suggests that ghostwriting--having paid writers spin the research papers the way the company wanted them, and only then letting the scientific "authors" see the drafts of the papers--was simply standard operating procedure within the company. The entire process showed that Pfizer, and especially its marketing division, kept everyone involved in the publication of a paper on a short leash.
Finally, the authors demonstrated that the journals in which papers were published, and the timing of publication, were also chosen for maximum marketing impact--for instance, with positive results published in high-impact journals and published quickly, and with negative results showing up in low-circulation journals years later.
As the authors summarize: "In this study we also observed that publication occurred in journals with higher or lower circulations related to statistical significance of findings; delay in publishing statistically non-significant findings; tailoring of publication content to reflect key marketing messages; adding spin to scientific publications such that conclusions favoring gabapentin were emphasized and conclusions that did not favor gabapentin were explained away; and indicators of ghost authorship. Each form of bias, and spin, on its own, could be seen as a relatively minor issue. The value of our findings is in the overall picture that emerges from what appears to be the simultaneous use of many forms of reporting bias and spin, all within the context of a pharmaceutical company’s publication strategy, implemented for marketing purposes."
So-- it's all about the marketing, and not about the science. No big surprise here, but further documentation of what we've had reason to believe from all previous reports of this type.
Now, I sort of hate to keep beating up on editor Jeffrey Drazen of the New England Journal:
http://brodyhooked.blogspot.com/2012/09/nejm-overly-defensive-or-just-naive.html
--who as previously reported said we should not judge articles based on who sponsored the research but on the quality as depicted in the published paper. What Dr. Vedula and colleagues show us is that if a paper that's positive about a new drug shows up in Dr. Drazen's high-impact journal, we can be reasonably sure that there are 3-4 other studies with much less impressive, or even negative results, which are kept aside to be not published at all, or else published in much-lower-circulation journals many years later--or at least that's the standard business plan within the industry. And of course there's no way on this green earth that even the most fastidious reader of NEJM could ever know that. So much for being able to read a paper in the journal and then draw your own conclusions.
Friday, October 12, 2012
More on Sponsorship of Studies in Medical Journals
In my last post: http://brodyhooked.blogspot.com/2012/09/nejm-overly-defensive-or-just-naive.html
--I took off after an editorial in the New England Journal defending industry sponsorship of trials, saying that you should decide whether a trial is trustworthy based on reading its methods, not based on who sponsored it. My rebuttal is that many of the features that make results untrustworthy simply cannot be gleaned from reading the published report in the journal.
Here's the other side of the coin--things that make results untrustworthy that the alert reader can spot.
Again tipping my hat to Rick Bukata and Jerry Hoffman's Primary Care Medical Abstracts, I come across a study by Drs. Michael Hochman of UCLA and Danny McCormick of Harvard:
http://www.springerlink.com/content/8h66774155415128/
These guys looked at several ways of reporting results that overestimate benefits:
Drs. Hochman and McCormick then compared how likely it was that a study would report results in these ways, based on who sponsored the study. They found significant differences in two categories. Exclusively industry-sponsored studies were more likely than studies with at least some non-commercial support to report surrogate endpoints (45% vs. 29%) and disease-specific mortality (27% vs. 16%).
Now, if you wanted to defend the NEJM editorial position, you could say that readers of studies can readily see how the data are reported according to these criteria and can be wary of any study, regardless who funds it, that reports data in the less desirable way. But let's give the last word to Drs. Hochman and McCormick, in their final recommendations: "These findings highlight the need for educational efforts to ensure that readers understand the complexities of these endpoints and of relative risk reporting. ... In addition, Institutional Scientific Review Committees and regulatory agencies (e.g. the FDA) must closely examine the endpoints used in clinical trials and discourage the inappropriate use of surrogate and composite endpoints, and endpoints involving disease-specific mortality. Finally, medical journals may consider instituting editorial policies mandating the reporting of results in absolute numbers."
In other words, rather than asking readers to sift through whether the results are reported in a useful and valid fashion, medical journals like NEJM could simply refuse to publish papers that don't adhere to the highest standards. Of course, if they did, they might lose revenue as drug companies would not buy so many expensive reprints of papers that are really useful for marketing drugs--which may be one of the roots of the problem.
--I took off after an editorial in the New England Journal defending industry sponsorship of trials, saying that you should decide whether a trial is trustworthy based on reading its methods, not based on who sponsored it. My rebuttal is that many of the features that make results untrustworthy simply cannot be gleaned from reading the published report in the journal.
Here's the other side of the coin--things that make results untrustworthy that the alert reader can spot.
Again tipping my hat to Rick Bukata and Jerry Hoffman's Primary Care Medical Abstracts, I come across a study by Drs. Michael Hochman of UCLA and Danny McCormick of Harvard:
http://www.springerlink.com/content/8h66774155415128/
These guys looked at several ways of reporting results that overestimate benefits:
- Reporting relative vs. absolute risks
- Reporting surrogate endpoints rather than significant changes in health
- Reporting composite endpoints instead of reporting each endpoint of interest separately
- Reporting only disease-specific mortality instead of all-cause mortality
Drs. Hochman and McCormick then compared how likely it was that a study would report results in these ways, based on who sponsored the study. They found significant differences in two categories. Exclusively industry-sponsored studies were more likely than studies with at least some non-commercial support to report surrogate endpoints (45% vs. 29%) and disease-specific mortality (27% vs. 16%).
Now, if you wanted to defend the NEJM editorial position, you could say that readers of studies can readily see how the data are reported according to these criteria and can be wary of any study, regardless who funds it, that reports data in the less desirable way. But let's give the last word to Drs. Hochman and McCormick, in their final recommendations: "These findings highlight the need for educational efforts to ensure that readers understand the complexities of these endpoints and of relative risk reporting. ... In addition, Institutional Scientific Review Committees and regulatory agencies (e.g. the FDA) must closely examine the endpoints used in clinical trials and discourage the inappropriate use of surrogate and composite endpoints, and endpoints involving disease-specific mortality. Finally, medical journals may consider instituting editorial policies mandating the reporting of results in absolute numbers."
In other words, rather than asking readers to sift through whether the results are reported in a useful and valid fashion, medical journals like NEJM could simply refuse to publish papers that don't adhere to the highest standards. Of course, if they did, they might lose revenue as drug companies would not buy so many expensive reprints of papers that are really useful for marketing drugs--which may be one of the roots of the problem.
Thursday, September 27, 2012
NEJM: Overly Defensive, or Just Naive?
The Sept. 20 issue of the New England Journal of Medicine featured a study (http://www.nejm.org/doi/full/10.1056/NEJMsa1202397) by Dr. Aaron S. Kesselheim and colleagues, of Harvard (where else?), a part of Dr. Jerry Avorn's pharmacoepidemiology & pharmacoeconomics operation. The study addressed how practitioners judged research articles based both on methodological quality and industry sponsorship.
They showed 503 internists fake abstracts that they had manipulated according to the study variables. The good news was that these internists knew quality when they saw it; they were less willing to prescribe a new drug as the rigor of the study design diminished. The part of the study that forms the remainder of our discussion was that independent of study quality, the internists were less likely to prescribe a new drug (by a factor of about half) if the study was labeled as industry-funded compared to NIH-funded.
This latter finding unloosed an editorial from NEJM Editor-in-Chief Dr. Jeffrey M. Drazen, somewhat ominously titled,"Believe the Data" (http://www.nejm.org/doi/full/10.1056/NEJMe1207121). Dr. Drazen took serious issue with the idea that one should judge an article based on who funded the study: "A trial's validity should ride on the study design, the quality of data-accrual and analytic processes, and the fairness of results reporting. Ideally, these factors — not the funding source — should be the criteria for deciding the clinical utility." Just in case we were not sufficiently impressed, he then pulled out the moral trump card: "Patients who put themselves at risk to provide these data earn our respect for their participation; we owe them the courtesy of believing the data produced from their efforts and acting on the findings so as to benefit other patients." That is: If you decide to question the results of a study because it's industry-funded, you're being disrespectful of the patients who agreed to participate in the research.
All of which shows that Dr. Drazen is not a regular reader of this blog. Let us take just a sampling of past posts, starting with the most recent one:
http://brodyhooked.blogspot.com/2012/09/more-on-tamiflu-challenges-of-getting.html
http://brodyhooked.blogspot.com/2012/06/those-persistent-ghosts-key-loophole.html
http://brodyhooked.blogspot.com/2012/04/yet-more-ways-literature-can-mislead-us.html
http://brodyhooked.blogspot.com/2011/11/some-capsules-of-recent-pharma-related.html
(In the last-mentioned post, see the sub-entry, "Data Dredging: Which Studies Do It the Most?")
I could have listed a lot more, but the ones that I've shown basically tell the following story:
Now--let's address Dr. Drazen's moral trump card. The issue he raises about respect for research subjects is indeed an important issue. It just has nothing to do with whether the reader should be suspicious of a company-sponsored study. The real question is: when are we going to demand that truly "informed consent" for research subjects in industry-sponsored trials include disclosure of when the trial is not designed for scientific purposes and is instead designed for drug marketing purposes?
They showed 503 internists fake abstracts that they had manipulated according to the study variables. The good news was that these internists knew quality when they saw it; they were less willing to prescribe a new drug as the rigor of the study design diminished. The part of the study that forms the remainder of our discussion was that independent of study quality, the internists were less likely to prescribe a new drug (by a factor of about half) if the study was labeled as industry-funded compared to NIH-funded.
This latter finding unloosed an editorial from NEJM Editor-in-Chief Dr. Jeffrey M. Drazen, somewhat ominously titled,"Believe the Data" (http://www.nejm.org/doi/full/10.1056/NEJMe1207121). Dr. Drazen took serious issue with the idea that one should judge an article based on who funded the study: "A trial's validity should ride on the study design, the quality of data-accrual and analytic processes, and the fairness of results reporting. Ideally, these factors — not the funding source — should be the criteria for deciding the clinical utility." Just in case we were not sufficiently impressed, he then pulled out the moral trump card: "Patients who put themselves at risk to provide these data earn our respect for their participation; we owe them the courtesy of believing the data produced from their efforts and acting on the findings so as to benefit other patients." That is: If you decide to question the results of a study because it's industry-funded, you're being disrespectful of the patients who agreed to participate in the research.
All of which shows that Dr. Drazen is not a regular reader of this blog. Let us take just a sampling of past posts, starting with the most recent one:
http://brodyhooked.blogspot.com/2012/09/more-on-tamiflu-challenges-of-getting.html
http://brodyhooked.blogspot.com/2012/06/those-persistent-ghosts-key-loophole.html
http://brodyhooked.blogspot.com/2012/04/yet-more-ways-literature-can-mislead-us.html
http://brodyhooked.blogspot.com/2011/11/some-capsules-of-recent-pharma-related.html
(In the last-mentioned post, see the sub-entry, "Data Dredging: Which Studies Do It the Most?")
I could have listed a lot more, but the ones that I've shown basically tell the following story:
- Research studies paid for by industry commonly distort findings so as to favor their products.
- As a rule, the journal reader cannot tell how the results have been distorted. (As the latest entry showed, to find out what was misleading about a study that occupies 7 pages in a journal might require wading through 8500 pages of data.)
- These distortions occur in all medical journals and if anything are even more prevalent in the top-tier journals. (Probably not because these journals are badly edited, but because it's so much more of a coup if the company can land their research findings in those top journals.)
Now--let's address Dr. Drazen's moral trump card. The issue he raises about respect for research subjects is indeed an important issue. It just has nothing to do with whether the reader should be suspicious of a company-sponsored study. The real question is: when are we going to demand that truly "informed consent" for research subjects in industry-sponsored trials include disclosure of when the trial is not designed for scientific purposes and is instead designed for drug marketing purposes?
Wednesday, September 26, 2012
More on Tamiflu: The Challenges of Getting Good Evidence
I posted some time back on oseltamivir (Tamiflu) and the Cochrane systematic review that concluded that there's no good evidence that this drug prevents serious complications of influenza (despite international public health bodies having spent billions to stockpile it):
http://brodyhooked.blogspot.com/2009/12/bmj-medical-research-is-broken.html
Earlier this year, the BMJ published a further commentary from the Cochrane team, explaining further their difficulties in getting credible evidence to do their review:
http://www.bmj.com/content/344/bmj.d7898
Doshi and colleagues noted that after a good deal of fussing around, they were able to get their hands on portions of the clinical study reports from a number of trials of oseltamivir. They admitted that when this all started, they had no idea of what a clinical study report was. A clinical study report is the province of regulatory agencies; it's what the FDA looks at, for example, when deciding whether to approve a drug for marketing. Academic investigators, by contrast, including the Cochrane folks, generally deal with published study reports in medical journals. The difference can be seen when they noted, "For example, the published version of one cardiac safety trial of 400 patients is seven pages long... compared with 8545 pages for the full clinical study report."
Depite still being unable to get their hands on all the materials from all of the studies, the Cochrane team found temselves the proud possessors of 22,000 pages of documents giving highly detailed information about each study. As a result, "Our new Cochrane review update of oseltamivir engaged the equivalent of two whole time researchers (a junior and a senior) for 14 months."
In short, this account presents a sobering picture of how much we still don't know about the evidence for and against a drug even after reading what purports to be a thorough, well-done systematic review based on published studies. It probably goes without saying that very few academic teams have the resources to let two people spend all their time for 14 months reviewing a single study question.
Since I learned of this paper via the services of Primary Care Medical Abstracts, I also had the advantage of Dr. Jerry Hoffman's trenchant commentary. Jerry asked how likely it was that of the research data that remains unpublished and thus far unanalyzed, any of it supports the wider use of oseltamivir for influenza. If the world were just, there'd be roughly a 50-50 chance that any unpublished data leaned for or against the drug. Based on what we know from past experience, if a study was done and there was any way at all that the results could be spun in a manner that produced positive marketing for Tamiflu, it would probably have taken the drug company (Roche) about 7 nanoseconds to arrange for the data to be published and widely disseminated. So we have good grounds to believe that the unrevealed data is not very friendly to Tamiflu.
Nonetheless, another point that Doshi and colleagues noted in their paper is that the various government agencies cannot see eye to eye on the current data:
"In December 2009, we expressed serious doubts about the credibility of the evidence for oseltamivir because of the inaccessibility of these unpublished trials. Nevertheless, influential organisations such as the US Centers for Disease Control and Prevention (CDC) and European Centre for Disease Prevention and Control continued to cite the Kaiser et al meta-analysis....[a company sponsored study supportive of the drug] Neither agency seems to have done an independent analysis of all available evidence, even after Roche’s public offer to provide full clinical study reports. Their stance is more worrying given that another US agency unambiguously holds the opposite opinion. The FDA, which has reviewed the oseltamivir trial programme in perhaps more detail than anyone outside of Roche, states that “Tamiflu has not been shown to prevent such complications [serious bacterial infections].”... The FDA even sent Roche a warning letter in 2000 instructing it to “immediately cease dissemination of promotional materials” containing “false or misleading” claims, including statements about a reduced risk of influenza complications.... The FDA has, however, not challenged the CDC’s claims."
The Deja Vu Fan Club out there might be commenting at this point that the oseltamivir story seems to be a retread of the reboxetine story: http://brodyhooked.blogspot.com/2010/11/pfizers-reboxetine-latest-in-series-of.html
--in which only one-fourth of the study data on a new antidepressant was published, with that one-fourth favoring the drug, and the 3/4 that remained unpublished showing that the drug was both ineffective and less safe than comparable drugs.
http://brodyhooked.blogspot.com/2009/12/bmj-medical-research-is-broken.html
Earlier this year, the BMJ published a further commentary from the Cochrane team, explaining further their difficulties in getting credible evidence to do their review:
http://www.bmj.com/content/344/bmj.d7898
Doshi and colleagues noted that after a good deal of fussing around, they were able to get their hands on portions of the clinical study reports from a number of trials of oseltamivir. They admitted that when this all started, they had no idea of what a clinical study report was. A clinical study report is the province of regulatory agencies; it's what the FDA looks at, for example, when deciding whether to approve a drug for marketing. Academic investigators, by contrast, including the Cochrane folks, generally deal with published study reports in medical journals. The difference can be seen when they noted, "For example, the published version of one cardiac safety trial of 400 patients is seven pages long... compared with 8545 pages for the full clinical study report."
Depite still being unable to get their hands on all the materials from all of the studies, the Cochrane team found temselves the proud possessors of 22,000 pages of documents giving highly detailed information about each study. As a result, "Our new Cochrane review update of oseltamivir engaged the equivalent of two whole time researchers (a junior and a senior) for 14 months."
In short, this account presents a sobering picture of how much we still don't know about the evidence for and against a drug even after reading what purports to be a thorough, well-done systematic review based on published studies. It probably goes without saying that very few academic teams have the resources to let two people spend all their time for 14 months reviewing a single study question.
Since I learned of this paper via the services of Primary Care Medical Abstracts, I also had the advantage of Dr. Jerry Hoffman's trenchant commentary. Jerry asked how likely it was that of the research data that remains unpublished and thus far unanalyzed, any of it supports the wider use of oseltamivir for influenza. If the world were just, there'd be roughly a 50-50 chance that any unpublished data leaned for or against the drug. Based on what we know from past experience, if a study was done and there was any way at all that the results could be spun in a manner that produced positive marketing for Tamiflu, it would probably have taken the drug company (Roche) about 7 nanoseconds to arrange for the data to be published and widely disseminated. So we have good grounds to believe that the unrevealed data is not very friendly to Tamiflu.
Nonetheless, another point that Doshi and colleagues noted in their paper is that the various government agencies cannot see eye to eye on the current data:
"In December 2009, we expressed serious doubts about the credibility of the evidence for oseltamivir because of the inaccessibility of these unpublished trials. Nevertheless, influential organisations such as the US Centers for Disease Control and Prevention (CDC) and European Centre for Disease Prevention and Control continued to cite the Kaiser et al meta-analysis....[a company sponsored study supportive of the drug] Neither agency seems to have done an independent analysis of all available evidence, even after Roche’s public offer to provide full clinical study reports. Their stance is more worrying given that another US agency unambiguously holds the opposite opinion. The FDA, which has reviewed the oseltamivir trial programme in perhaps more detail than anyone outside of Roche, states that “Tamiflu has not been shown to prevent such complications [serious bacterial infections].”... The FDA even sent Roche a warning letter in 2000 instructing it to “immediately cease dissemination of promotional materials” containing “false or misleading” claims, including statements about a reduced risk of influenza complications.... The FDA has, however, not challenged the CDC’s claims."
The Deja Vu Fan Club out there might be commenting at this point that the oseltamivir story seems to be a retread of the reboxetine story: http://brodyhooked.blogspot.com/2010/11/pfizers-reboxetine-latest-in-series-of.html
--in which only one-fourth of the study data on a new antidepressant was published, with that one-fourth favoring the drug, and the 3/4 that remained unpublished showing that the drug was both ineffective and less safe than comparable drugs.
Tuesday, September 25, 2012
Another Example of Industry Spreading Non-Facts: Health Information Technology
While I try not to tread on the territory of our friends over at the Health Care Renewal blog, and keep this blog devoted to pharmaceutical and device industry issues, I've had occasion in the past to mention the good work of Dr. Scot Silverstein (see for example http://brodyhooked.blogspot.com/2011/03/industry-doublespeak-this-time-in-it.html). Dr. Silverstein is a highly informed critic of the bad sorts of electronic health records and other uses of health information technology (HIT), which unfortunately today may be the majority of uses. This has put him in the unhappy position of being blasted by the many hyperenthusiasts of HIT within medicine, as well as the industrial providers of HIT. As Dr. Silverstein has documented liberally in his posts, if you dare to suggest that HIT is anything less than perfection itself, the response of the enthusiasts makes the extremist-fundamentalist Muslim reaction to the recent idiotic anti-Mohammed video look like a friendly conversation over coffee.
In the recent post in question: http://hcrenewal.blogspot.com/2012/09/wsj-koppel-and-soumerai-major-glitch.html-- Dr. Silverstein mentions a recent column in the Wall Street Journal (no need for a separate link as he repeats virtually the entire opinion piece) by Stephen Soumerai and Ross Koppel, two similarly distinguished experts. In turn Soumerai and Koppel refer to a recent study out of McMaster University:
http://jamia.bmj.com/content/19/3/423.long
Cutting to the chase in all this, the bottom line is that when the politicians jumped on the bandwagon and called for massive Federal outlays to support and encourage quick adoption of HIT, they were motivated a little bit by promises that electronic records would make medical errors disappear, but no doubt even more by promises of cost savings--even to the point that they fondly imagined that they could spend billions buying HIT systems that would in the end pay for themselves in reduced costs. Just to add a personal note, if I ever believed that electronic records would save mioney, I stopped believing it after attending a meeting of department heads at my own medical center. One head estimated that the faculty now spent an extra 30% more time just completing the required electronic record tasks, and no one else disputed that estimate. I concluded that any technology that reduced physician productivity by 30% was unlikely to be a big money saver overall. (And our medical center owns one of the supposedly better HIT products.)
So the new study by O'Reilly and colleagues at McMaster looks specifically at drug ordering systems, and reviewed 31 research studies that in one way or another addressed the economics of the systems. The conclusion was that while a few studies suggested possible cost savings, the general quality of the research was poor, and one would have to conclude from the overall pattern of what us now known that there's no good evidence that electronic records save money with regard to drug ordering. Soumerai and Koppel, and Silversteion in turn, generalize this to HIT across the board and claim a lack of evidence that any of these promised cost savings are coming to fruition. Given hyped-up predictions of up to $100B in annual savings from wide adoption of HIT, this is indeed (as they used to say on the old TV sitcom) a revolting development.
What we see in the HIT industry seems to emulate a pattern we've seen many times in Pharma. A new drug is rushed onto the market because of some presumed advantage that puts it way ahead of existing drugs. (Think glitazones for diabetes, or COX-2 for arthritis.) As soon as careful studies can be carried out, the supposed advantages of the new kid on the block turn out to be illusory, and the downside starts to become glaringly apparent. But the industry is raking in too much cash to let that negative message get out, and so does its best to stonewall any disclosure of the new information. In the process it calls upon all of its lackeys inside medicine, who use their big university credentials to bolster the industry cause. In the case of Pharma, it seems usually to be the case that these "key opinion leaders" have simply been bought. HIT is different in that the issue seems to be genuine enthusiasm (not to say zealotry) among the early adopters, who then would look so silly if they admitted the validity of the new data that they dig in their heels and attack the messengers.
Dr. Silverstein repeats as often as anyone will listen that HIT holds great potential promise and that he's not against HIT. He's against poorly tested HIT that's rushed into use when it should still be considered experimental. Again, sadly, that seems to be most electronic record products now in use in the US, with more coming on line every day due to the Federal stimulus support and the Affordable Care Act.
In the recent post in question: http://hcrenewal.blogspot.com/2012/09/wsj-koppel-and-soumerai-major-glitch.html-- Dr. Silverstein mentions a recent column in the Wall Street Journal (no need for a separate link as he repeats virtually the entire opinion piece) by Stephen Soumerai and Ross Koppel, two similarly distinguished experts. In turn Soumerai and Koppel refer to a recent study out of McMaster University:
http://jamia.bmj.com/content/19/3/423.long
Cutting to the chase in all this, the bottom line is that when the politicians jumped on the bandwagon and called for massive Federal outlays to support and encourage quick adoption of HIT, they were motivated a little bit by promises that electronic records would make medical errors disappear, but no doubt even more by promises of cost savings--even to the point that they fondly imagined that they could spend billions buying HIT systems that would in the end pay for themselves in reduced costs. Just to add a personal note, if I ever believed that electronic records would save mioney, I stopped believing it after attending a meeting of department heads at my own medical center. One head estimated that the faculty now spent an extra 30% more time just completing the required electronic record tasks, and no one else disputed that estimate. I concluded that any technology that reduced physician productivity by 30% was unlikely to be a big money saver overall. (And our medical center owns one of the supposedly better HIT products.)
So the new study by O'Reilly and colleagues at McMaster looks specifically at drug ordering systems, and reviewed 31 research studies that in one way or another addressed the economics of the systems. The conclusion was that while a few studies suggested possible cost savings, the general quality of the research was poor, and one would have to conclude from the overall pattern of what us now known that there's no good evidence that electronic records save money with regard to drug ordering. Soumerai and Koppel, and Silversteion in turn, generalize this to HIT across the board and claim a lack of evidence that any of these promised cost savings are coming to fruition. Given hyped-up predictions of up to $100B in annual savings from wide adoption of HIT, this is indeed (as they used to say on the old TV sitcom) a revolting development.
What we see in the HIT industry seems to emulate a pattern we've seen many times in Pharma. A new drug is rushed onto the market because of some presumed advantage that puts it way ahead of existing drugs. (Think glitazones for diabetes, or COX-2 for arthritis.) As soon as careful studies can be carried out, the supposed advantages of the new kid on the block turn out to be illusory, and the downside starts to become glaringly apparent. But the industry is raking in too much cash to let that negative message get out, and so does its best to stonewall any disclosure of the new information. In the process it calls upon all of its lackeys inside medicine, who use their big university credentials to bolster the industry cause. In the case of Pharma, it seems usually to be the case that these "key opinion leaders" have simply been bought. HIT is different in that the issue seems to be genuine enthusiasm (not to say zealotry) among the early adopters, who then would look so silly if they admitted the validity of the new data that they dig in their heels and attack the messengers.
Dr. Silverstein repeats as often as anyone will listen that HIT holds great potential promise and that he's not against HIT. He's against poorly tested HIT that's rushed into use when it should still be considered experimental. Again, sadly, that seems to be most electronic record products now in use in the US, with more coming on line every day due to the Federal stimulus support and the Affordable Care Act.
Wednesday, September 12, 2012
Inverse Benefit in the Trenches: Primary Care Providers Treat Chronic Illness
My esteemed anthropologist colleague, Dr. Linda M. Hunt, and her graduate student Meta Kreiner at Michigan State University set out to do a study of how concepts of race influence physicians' treatment of patients with common chronic illnesses like hypertension and diabetes. Along the way they became so impressed with issues they were seeing about how drugs are prescribed that they chose to report a separate study on that latter topic. Recognizing the relevance of my own work on the Inverse Benefit Law (http://brodyhooked.blogspot.com/2011/03/synthesis-why-drug-industry-tries-to.html), they very kindly invited me to participate in the final data analysis and discussion, with the results just now appearing in the Annals of Family Medicine (http://www.annfammed.org/content/10/5/452.full).
Hunt and Kreiner interviewed 58 clinicians and 70 patients at 44 primary care clinics in Michigan, oversampling clinics treating low-income and minority patients. They also observed 107 office visits. What did they find?
First, they noted that their sample mirrored CDC data reporting that 40% of people over age 60 now take 5 medications or more; the average prescritions per patient in their sample was 4.8. While one might imagine that providers in low-income, minority-serving clinics might be a model of enlightened social awareness, they found that 72% of the clinicians they talked to had regular contact with drug reps and 62% saw more than 10 reps each week. While protesting that they always were alert for commercial bias, 77% reported finding the information they received from the reps useful.
These clinicians were basically sold on the standard practice guidelines that set target numbers for blood pressure and blood sugar, and were unfazed by the likelihood that patients would need to be on multiple medications to reach the targets--as one family physician said: "I tell most new diabetics that the sad news is that they’re going to be on 5 meds…. That’s just what’s going to happen because their cholesterol parameters are lower [and] their blood pressure parameters are lower…. It’s usually a pretty frank talk: 'You have a deadly disease and it’s going to kill you. How long you have it is up to you.' (Laughs)"
Many of these clinicians are being reimbursed in ways that include pay-for-performance bonuses for meeting targets, and this influences their practices: "I was being a little bit lackadaisical with the A1c goal as 7.0[%] or less. I wouldn’t really like to admit it, but the insurance companies making a financial carrot is probably one impetus for really cracking down on my diabetics to get them 7.0[%] or less. 7.1[%] don’t cut it…anymore. It has to be 7.0[%] or less."
Time out--a while ago I blogged about a study (http://brodyhooked.blogspot.com/2010/07/side-trip-into-diabetes-selling-wrong.html) that showed that there's reasonable evidence that patients with diabetes do well when their glycohemoglobin (A1c) level is around 7.5%, and that trying to get it super-low down to 7.0% actually does harm to patients. I also have blogged repeatedly about studies that show that diabetics are not any healthier, in the long haul, with tighter control of their blood sugar or A1c levels (http://brodyhooked.blogspot.com/2012/04/yet-more-on-broken-disease-model-of.html). Despite study after study on this topic, the drug companies continue to push drugs that lower blood sugar but fail to improve long-term outcomes; groups dependent on drug company money like the American Diabetes Association continue to promulgate guidelines that stress strict control of blood sugar; and as this study shows, physicians in practice toe the line--especially when paid to do so.
Back to the Hunt-Kreiner findings. What happens when you throw a lot of medicines at patients with diabetes and hypertension, trying to make their numbers look good in the chart? At least three bad things. First, their drugs cost a lot and some of the patients go crazy trying to pay for them. Second, the patients get a lot more adverse reactions. Third, the prescribing cascade kicks in--physicians either don't recognize the adverse reations as due to other drugs, or else feel they have no choice but to prescribe those drugs because of the guidelines; and so even more medications are then prescribed to treat the side effects of the first medications, which further raises cost and risk of side effects, and so on: "A number (24%, 14 of 58) discussed the challenge of managing multiple medications, pointing out adverse effects of common medications that may worsen other conditions, requiring even more drugs, for example, β-blockers aggravating asthma symptoms, or antipsychotics elevating blood sugar. When discussing these complicated issues, only 1 clinician mentioned prescribing fewer drugs; all the rest focused on reaching goal numbers by either adding or changing medications."
The impact this had on patients is dramatic, as one fairly typical case report showed: "Her diabetes medications cause diarrhea and bouts of hypoglycemia, which interferes with her ability to leave her home because she must eat and go to the bathroom so frequently. She also had 5 visits to the emergency department in 1 month for excruciating headaches, before they were determined to be an adverse effect of the additional hypertension medication she had been prescribed after her diabetes diagnosis. ... At her most recent appointment, her physician happily told her: 'Your blood pressure is 130/78 [mm Hg], your A1c is 7.0[%], and your cholesterol was normal. Very good!'"
As Hunt and Kreiner comment, "On the basis of current standards, the clinician classified this patient as healthy, a success story; however, this classification does not address the broader question of her well-being. Getting test numbers into the stipulated range jeopardized her employment and led to repeated hospitalizations and serious financial burden." And, I would add, with precious little evidence that at least some of these medications were improving the patient's long-term health.
Sadly, these hard-working, dedicated, and undoubtedly smart clinicians seemed both puzzled and resigned in the face of these outcomes: "I’ve got patients on 4 different medications and their blood pressure is still uncontrolled. We try sending them to the cardiologists, and they say, 'Just keep adding stuff because there’s really nothing we can do about this.'…Some people whose blood pressure that we do get normal again, they don’t function very well at all. I’m not sure why."
After all the usual warnings about not generalizing qualitative studies beyond the small sample included in the research, I worry that this peek into the trenches of clinicians actually caring for patients with common problems strongly validates the worries I have expressed in this blog in more theoretical form, especially in http://brodyhooked.blogspot.com/2011/03/synthesis-why-drug-industry-tries-to.html. The unholy alliance of drug company marketing, pay-for-performance, and unrealistic and commercially biased practice guidelines are ganging up on these patients to make them sicker rather than healthier--and the clinicians seem helpless to do anything about it.
Hunt and Kreiner interviewed 58 clinicians and 70 patients at 44 primary care clinics in Michigan, oversampling clinics treating low-income and minority patients. They also observed 107 office visits. What did they find?
First, they noted that their sample mirrored CDC data reporting that 40% of people over age 60 now take 5 medications or more; the average prescritions per patient in their sample was 4.8. While one might imagine that providers in low-income, minority-serving clinics might be a model of enlightened social awareness, they found that 72% of the clinicians they talked to had regular contact with drug reps and 62% saw more than 10 reps each week. While protesting that they always were alert for commercial bias, 77% reported finding the information they received from the reps useful.
These clinicians were basically sold on the standard practice guidelines that set target numbers for blood pressure and blood sugar, and were unfazed by the likelihood that patients would need to be on multiple medications to reach the targets--as one family physician said: "I tell most new diabetics that the sad news is that they’re going to be on 5 meds…. That’s just what’s going to happen because their cholesterol parameters are lower [and] their blood pressure parameters are lower…. It’s usually a pretty frank talk: 'You have a deadly disease and it’s going to kill you. How long you have it is up to you.' (Laughs)"
Many of these clinicians are being reimbursed in ways that include pay-for-performance bonuses for meeting targets, and this influences their practices: "I was being a little bit lackadaisical with the A1c goal as 7.0[%] or less. I wouldn’t really like to admit it, but the insurance companies making a financial carrot is probably one impetus for really cracking down on my diabetics to get them 7.0[%] or less. 7.1[%] don’t cut it…anymore. It has to be 7.0[%] or less."
Time out--a while ago I blogged about a study (http://brodyhooked.blogspot.com/2010/07/side-trip-into-diabetes-selling-wrong.html) that showed that there's reasonable evidence that patients with diabetes do well when their glycohemoglobin (A1c) level is around 7.5%, and that trying to get it super-low down to 7.0% actually does harm to patients. I also have blogged repeatedly about studies that show that diabetics are not any healthier, in the long haul, with tighter control of their blood sugar or A1c levels (http://brodyhooked.blogspot.com/2012/04/yet-more-on-broken-disease-model-of.html). Despite study after study on this topic, the drug companies continue to push drugs that lower blood sugar but fail to improve long-term outcomes; groups dependent on drug company money like the American Diabetes Association continue to promulgate guidelines that stress strict control of blood sugar; and as this study shows, physicians in practice toe the line--especially when paid to do so.
Back to the Hunt-Kreiner findings. What happens when you throw a lot of medicines at patients with diabetes and hypertension, trying to make their numbers look good in the chart? At least three bad things. First, their drugs cost a lot and some of the patients go crazy trying to pay for them. Second, the patients get a lot more adverse reactions. Third, the prescribing cascade kicks in--physicians either don't recognize the adverse reations as due to other drugs, or else feel they have no choice but to prescribe those drugs because of the guidelines; and so even more medications are then prescribed to treat the side effects of the first medications, which further raises cost and risk of side effects, and so on: "A number (24%, 14 of 58) discussed the challenge of managing multiple medications, pointing out adverse effects of common medications that may worsen other conditions, requiring even more drugs, for example, β-blockers aggravating asthma symptoms, or antipsychotics elevating blood sugar. When discussing these complicated issues, only 1 clinician mentioned prescribing fewer drugs; all the rest focused on reaching goal numbers by either adding or changing medications."
The impact this had on patients is dramatic, as one fairly typical case report showed: "Her diabetes medications cause diarrhea and bouts of hypoglycemia, which interferes with her ability to leave her home because she must eat and go to the bathroom so frequently. She also had 5 visits to the emergency department in 1 month for excruciating headaches, before they were determined to be an adverse effect of the additional hypertension medication she had been prescribed after her diabetes diagnosis. ... At her most recent appointment, her physician happily told her: 'Your blood pressure is 130/78 [mm Hg], your A1c is 7.0[%], and your cholesterol was normal. Very good!'"
As Hunt and Kreiner comment, "On the basis of current standards, the clinician classified this patient as healthy, a success story; however, this classification does not address the broader question of her well-being. Getting test numbers into the stipulated range jeopardized her employment and led to repeated hospitalizations and serious financial burden." And, I would add, with precious little evidence that at least some of these medications were improving the patient's long-term health.
Sadly, these hard-working, dedicated, and undoubtedly smart clinicians seemed both puzzled and resigned in the face of these outcomes: "I’ve got patients on 4 different medications and their blood pressure is still uncontrolled. We try sending them to the cardiologists, and they say, 'Just keep adding stuff because there’s really nothing we can do about this.'…Some people whose blood pressure that we do get normal again, they don’t function very well at all. I’m not sure why."
After all the usual warnings about not generalizing qualitative studies beyond the small sample included in the research, I worry that this peek into the trenches of clinicians actually caring for patients with common problems strongly validates the worries I have expressed in this blog in more theoretical form, especially in http://brodyhooked.blogspot.com/2011/03/synthesis-why-drug-industry-tries-to.html. The unholy alliance of drug company marketing, pay-for-performance, and unrealistic and commercially biased practice guidelines are ganging up on these patients to make them sicker rather than healthier--and the clinicians seem helpless to do anything about it.
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