Paul Dieppe of the University of Bristol attempts to explain aspects of the VIOXX matter using complicity theory. His article is interesting reading and thanks to Pharmagossip for the link.
I think deciphering why things happen is a bit like interpreting poems to discern what did the author really mean. It is an interesting exercise and often we seem to feel better when we "know" why things happen but in the end is it anything more than speculation?
Dieppe says in part:
"Complicity works like that. All those with a vested interest in an enterprise get sucked into the rhetoric associated with it, and they soon ' believe' in everything that is going on within that enterprise. If personal financial gain is involved, corruption may also occur."
How much they believe and how much "they go along to get along" is hard to determine but it is clear that people in groups do things they would never do on their own.
Thursday, June 29, 2006
Thursday, June 22, 2006
'Unanticipated" effects of the quality movement-JAMA commentary
Dr. Robert M. Wachter, of UCSF, is well known in medical circles for his writing and activities in the hospitalist phenomenon. In the June 21, 2006 issue of JAMA he writes about the quality and IT "revolutions".
His comments about the unforeseen effects of the quality movement resonant with me and likely many real life physicians who may have found the quality activities impeded their work as doctors.I quote:
" More typically, individuals and institutions begin to focus on improving their performance on the variable measure, in doing so turning away from others. This "playing for the test" is not only expected; in some cases it is the point of the whole exercise."
He comments on the most egregious examples of IT gone bad with the Cedars-Sinai debacle and the tragic increase in pediatric deaths occurring after the introduction of a commercial computer system.(Han,YY et al,Pediatrics,2005:116-1506-1512.)
With those facts on the table I find the following puzzling:
"Importantly,until the science of guidelines development and quality measurement improves, the systems must preserve physician's' ability to apply the art of medicine when patients do not fit the templates, such as in those patients with multisystem illness or rapidly changing disease course."
Of course, physicians must have the final say in clinical management,they cannot be replaced with computers and algorithms. The individual physician must be able to deal with the unique particulars of the case at hand. Wachter's use of the word "until" makes me flinch. He seems to believe that someday computers and IT system and EBM and algorithms will get to the point when physicians will not have to apply the art of medicine and will not be allowed to do so. We cannot escape the contingencies of life and medicine by all encompassing algorithms and computer prompts. I don't really think that Dr. Wachter thinks we can escape them but I worry about that "until".
His comments about the unforeseen effects of the quality movement resonant with me and likely many real life physicians who may have found the quality activities impeded their work as doctors.I quote:
" More typically, individuals and institutions begin to focus on improving their performance on the variable measure, in doing so turning away from others. This "playing for the test" is not only expected; in some cases it is the point of the whole exercise."
He comments on the most egregious examples of IT gone bad with the Cedars-Sinai debacle and the tragic increase in pediatric deaths occurring after the introduction of a commercial computer system.(Han,YY et al,Pediatrics,2005:116-1506-1512.)
With those facts on the table I find the following puzzling:
"Importantly,until the science of guidelines development and quality measurement improves, the systems must preserve physician's' ability to apply the art of medicine when patients do not fit the templates, such as in those patients with multisystem illness or rapidly changing disease course."
Of course, physicians must have the final say in clinical management,they cannot be replaced with computers and algorithms. The individual physician must be able to deal with the unique particulars of the case at hand. Wachter's use of the word "until" makes me flinch. He seems to believe that someday computers and IT system and EBM and algorithms will get to the point when physicians will not have to apply the art of medicine and will not be allowed to do so. We cannot escape the contingencies of life and medicine by all encompassing algorithms and computer prompts. I don't really think that Dr. Wachter thinks we can escape them but I worry about that "until".
Wednesday, June 21, 2006
Are Phase IV trials really "seed" trials-another way to manipulate physician behavior?
Dr. Bruce M. Psaty, a prominent clinical epidemiologist from Seattle, plunges into the topic of Phase IV drug trials in the June 21, 2006 issue of JAMA.
Phase IV trials are post marketing trials that,quotes Psaty, were discussed in a 1994 NEJM article by former FDA head David Kessler as a main technique to promote "me too" drugs.
Kessler said:
...because they are, in fact, thinly veiled attempts to entice doctors to prescribe a new drug being marketed by the company,they are often referred to as "seed trials"...[features include]the use of a design that does not support the stated research goals,the recruitment of investigators not because they are experts or leading researchers but because they are frequent prescribers of competing products [and] sponsorship of the studies by the company's sales and marketing division rather than its research department."
Clearly these seed trials are not high quality studies.Psaty talks about what distinguishes high quality studies. Randomization is not enough.
Psaty says that blood pressure drugs are commonly promoted in these trials.
"industry has supported thousands of small short-term randomized trials..."
Most of these seed trials proudly promote themselves as "randomized" and many are but randomization does not equate to a quality trial nor to one that asks a worthwhile scientific question or is otherwise well designed. As Psaty says other features need be present such as blinding,completeness of followup,ascertainment of outcomes to name a few.Randomization is not a sufficient condition for a trial to be worthwhile and/or meaningful and non-trivial.
At times,big pharma and the contract research organizations have taken some of the concepts and rhetoric of EMB and misused them to promote various products by funding and executing these largely bogus seed trials which may have influenced not only the physicians who participate in them but the other physicians who hear from the "thought leaders" how these randomized trials favor one brand over the other. A veneer of evidence based medicine is glued over what is no more than a promotional activity. If big pharma may have corrupted the EBM process, how should the physicians who take part in them be characterized?
Two nouns come to mind; dupes and co-conspirators and I wish I could think of some less pejorative words as alternatives. Some are simply naive and do not understand what is really going on. Some of the academics, however, probably cannot plead ignorance. They either know better or at least in recent years should know better.
Phase IV trials are post marketing trials that,quotes Psaty, were discussed in a 1994 NEJM article by former FDA head David Kessler as a main technique to promote "me too" drugs.
Kessler said:
...because they are, in fact, thinly veiled attempts to entice doctors to prescribe a new drug being marketed by the company,they are often referred to as "seed trials"...[features include]the use of a design that does not support the stated research goals,the recruitment of investigators not because they are experts or leading researchers but because they are frequent prescribers of competing products [and] sponsorship of the studies by the company's sales and marketing division rather than its research department."
Clearly these seed trials are not high quality studies.Psaty talks about what distinguishes high quality studies. Randomization is not enough.
Psaty says that blood pressure drugs are commonly promoted in these trials.
"industry has supported thousands of small short-term randomized trials..."
Most of these seed trials proudly promote themselves as "randomized" and many are but randomization does not equate to a quality trial nor to one that asks a worthwhile scientific question or is otherwise well designed. As Psaty says other features need be present such as blinding,completeness of followup,ascertainment of outcomes to name a few.Randomization is not a sufficient condition for a trial to be worthwhile and/or meaningful and non-trivial.
At times,big pharma and the contract research organizations have taken some of the concepts and rhetoric of EMB and misused them to promote various products by funding and executing these largely bogus seed trials which may have influenced not only the physicians who participate in them but the other physicians who hear from the "thought leaders" how these randomized trials favor one brand over the other. A veneer of evidence based medicine is glued over what is no more than a promotional activity. If big pharma may have corrupted the EBM process, how should the physicians who take part in them be characterized?
Two nouns come to mind; dupes and co-conspirators and I wish I could think of some less pejorative words as alternatives. Some are simply naive and do not understand what is really going on. Some of the academics, however, probably cannot plead ignorance. They either know better or at least in recent years should know better.
Sunday, June 18, 2006
Could the SMART trial have been better designed to bring about the results that GSK did not want?
More than one pulmonary disease specialist has referred to the SMART trial as the [not so] SMART trial. Its design is subject to criticism both in terms of what was offered to the patient volunteers and what was likely to happen in terms of results?
GSK was faced with the task of designing and executing a large clinical trial that had been brought about because of concern that salmeterol might be harmful to some patients with asthma. An earlier trial in Great Britain had shown a numerical increase in salmeterol treated patients that was not statistically significant. One lingering popular explanation for any possible increase in salmeterol treated patient death is that these patients were either under poor control at the beginning of the trial and/or perhaps used the medications improperly or inadequately.
So, what did they do?They recruited patients by advertisements, insuring a high proportion of patients who might not have been receiving good physician care, gave them either salmeterol or placebo and then provided only monthly telephone followup. At this point we have a group of patients, many of whom were not under good control or receiving regular physician hands-on follow up, who were given a medication that was purportedly possibly harmful and not monitored other than by telephone calls. They could not be accused of "cherry-picking" their study subjects in this trial.
This "phase one " recruitment ended when it appeared the trial would need over 60,000 participants (over twice what the original power computation indicated because of the relatively low mortality rate in both the control and treatment arms) and the recruitment process shifted to study investigators who recruited their own patients.This change brought about a situation at least resembling how the drug might be used in clinical practice.
There was a marked difference in the outcomes based on the method of recruitment. 13 of the 16 asthma related deaths occurred in patients recruited in phase one ( figure 2 in the SMART article in CHEST).There were about 15,00 patients in phase one versus about 11,000 in phase
2. The report's table 7 indicates that there were no statistically significant differences between salmeterol and placebo in any of the primary or secondary outcome measures in the phase 2 patients.
If there had been no phase 1 recruitment, there would likely be no black box warning on salmeterol containing products. It should be noted that this trial was terminated early by GSK. Only half of the subjects had been enrolled and the predefined criteria for terminations had not been met.The reasons given were the disproportionate number of events in African Americans and difficulty in enrollment.
What about the effect of prior or concomitant treatment with an inhaled corticosteroid (ICS) on salmeterol treatment outcomes? This is how salmeterol is currently used according to guidelines. As the study authors said " SMART was not adequate to determine whether or not ICS use affected the incidence of the key outcome events."
To me, the most robust finding of SMART is that asthma treatment is much better when a patient in under a physcian's care than when a prescription is given to a patient and he is told that they will be contacted by phone to see how they are doing.
GSK was faced with the task of designing and executing a large clinical trial that had been brought about because of concern that salmeterol might be harmful to some patients with asthma. An earlier trial in Great Britain had shown a numerical increase in salmeterol treated patients that was not statistically significant. One lingering popular explanation for any possible increase in salmeterol treated patient death is that these patients were either under poor control at the beginning of the trial and/or perhaps used the medications improperly or inadequately.
So, what did they do?They recruited patients by advertisements, insuring a high proportion of patients who might not have been receiving good physician care, gave them either salmeterol or placebo and then provided only monthly telephone followup. At this point we have a group of patients, many of whom were not under good control or receiving regular physician hands-on follow up, who were given a medication that was purportedly possibly harmful and not monitored other than by telephone calls. They could not be accused of "cherry-picking" their study subjects in this trial.
This "phase one " recruitment ended when it appeared the trial would need over 60,000 participants (over twice what the original power computation indicated because of the relatively low mortality rate in both the control and treatment arms) and the recruitment process shifted to study investigators who recruited their own patients.This change brought about a situation at least resembling how the drug might be used in clinical practice.
There was a marked difference in the outcomes based on the method of recruitment. 13 of the 16 asthma related deaths occurred in patients recruited in phase one ( figure 2 in the SMART article in CHEST).There were about 15,00 patients in phase one versus about 11,000 in phase
2. The report's table 7 indicates that there were no statistically significant differences between salmeterol and placebo in any of the primary or secondary outcome measures in the phase 2 patients.
If there had been no phase 1 recruitment, there would likely be no black box warning on salmeterol containing products. It should be noted that this trial was terminated early by GSK. Only half of the subjects had been enrolled and the predefined criteria for terminations had not been met.The reasons given were the disproportionate number of events in African Americans and difficulty in enrollment.
What about the effect of prior or concomitant treatment with an inhaled corticosteroid (ICS) on salmeterol treatment outcomes? This is how salmeterol is currently used according to guidelines. As the study authors said " SMART was not adequate to determine whether or not ICS use affected the incidence of the key outcome events."
To me, the most robust finding of SMART is that asthma treatment is much better when a patient in under a physcian's care than when a prescription is given to a patient and he is told that they will be contacted by phone to see how they are doing.
Monday, June 12, 2006
Will a recent Meta-analysis be the tipping point to remove LABAs from the market?
Long acting bronchodilators (LABAs) have long been accused of increasing the number of asthma related deaths. My 12/23/2005 posting gave a brief summary of events up to that time.
Concern about LABAs was exacerbated by two studies that lead the FDA to issue a black box warning in November 2004.
A 16 week study from Great Britain, the Salmeterol National Surveillance Study (SNS) of 25,180 patients, found 12 deaths in the salmeterol group versus 2 in the placebo group a finding that was obviously numerically greater but not statistically significant.
Of greater concern was the SMART trial. This was a 28 week trial with 26,350 patients which demonstrated a 4.3 fold increase in asthma related deaths,( 13 versus 3) in the salmeterol treated group.
At least one important piece of information was not available from SMART. In the FDA statement we find this statement:
"The data from the SMART trial was not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk."
We really need to know if inhaled steroids mitigate or eliminate the putative increased risk from LABAs.Current recommendations essentially depend on that as the recommendation is to not start a LABA for asthma treatment until the patient is receiving at least moderate doses of steroids.
A recent meta-analysis published in the Annals of Internal Medicine seems to provide that missing information. Dr. Shelley R. Salpeter et al pooled results from 19 trials with 33,826 patients and found that LABAs ( not just salmeterol) increased exacerbations requiring hospitalizations (O.R. 2.6) and asthma related deaths (O.R.3.5). When the authors looked at the trials in which more than 75% of the participants were taking inhaled corticosteroids, the O.R. for hospitalizations was still increased at 2.1 ( 1.3 - 3.4).
While this may not be a slam dunk to answer all we need to know or to settle the issue, it is bound to raise the level of concern to a higher notch. Unfortunately, the authors do not give us more information about that part of their analysis nor do they include it in their article summary.However, in their concluding paragraph they say : " Concomitant inhaled corticosteroids do not adequately protect against adverse effects "
The LABA controversy will not be settled by this meta-analysis. A recent article from Australia quotes a Cochrane systematic review of LABA use in asthma and concludes they are safe and effective. As the editorial in the Annals noted, Evidence Based Medicine exhorts us to use the best evidence. Determining what is best sometimes is no easy matter. The medical literature dealing with the long acting beta agonists is extensive and replete with contradictory data. Since deaths from asthma are relatively uncommon, many physicians who use Advair and other LABA containing medications have not seen serious complications in their patients and typically observe better control in those patients requiring LABAs. It is not surprising that-as noted in the Salpeter article-the Black Box warning has not altered physicians's prescribing habits. Whether those habits should be changed or not seems to still be an open question.
Concern about LABAs was exacerbated by two studies that lead the FDA to issue a black box warning in November 2004.
A 16 week study from Great Britain, the Salmeterol National Surveillance Study (SNS) of 25,180 patients, found 12 deaths in the salmeterol group versus 2 in the placebo group a finding that was obviously numerically greater but not statistically significant.
Of greater concern was the SMART trial. This was a 28 week trial with 26,350 patients which demonstrated a 4.3 fold increase in asthma related deaths,( 13 versus 3) in the salmeterol treated group.
At least one important piece of information was not available from SMART. In the FDA statement we find this statement:
"The data from the SMART trial was not adequate to determine whether concurrent use of inhaled corticosteroids provides protection from this risk."
We really need to know if inhaled steroids mitigate or eliminate the putative increased risk from LABAs.Current recommendations essentially depend on that as the recommendation is to not start a LABA for asthma treatment until the patient is receiving at least moderate doses of steroids.
A recent meta-analysis published in the Annals of Internal Medicine seems to provide that missing information. Dr. Shelley R. Salpeter et al pooled results from 19 trials with 33,826 patients and found that LABAs ( not just salmeterol) increased exacerbations requiring hospitalizations (O.R. 2.6) and asthma related deaths (O.R.3.5). When the authors looked at the trials in which more than 75% of the participants were taking inhaled corticosteroids, the O.R. for hospitalizations was still increased at 2.1 ( 1.3 - 3.4).
While this may not be a slam dunk to answer all we need to know or to settle the issue, it is bound to raise the level of concern to a higher notch. Unfortunately, the authors do not give us more information about that part of their analysis nor do they include it in their article summary.However, in their concluding paragraph they say : " Concomitant inhaled corticosteroids do not adequately protect against adverse effects "
The LABA controversy will not be settled by this meta-analysis. A recent article from Australia quotes a Cochrane systematic review of LABA use in asthma and concludes they are safe and effective. As the editorial in the Annals noted, Evidence Based Medicine exhorts us to use the best evidence. Determining what is best sometimes is no easy matter. The medical literature dealing with the long acting beta agonists is extensive and replete with contradictory data. Since deaths from asthma are relatively uncommon, many physicians who use Advair and other LABA containing medications have not seen serious complications in their patients and typically observe better control in those patients requiring LABAs. It is not surprising that-as noted in the Salpeter article-the Black Box warning has not altered physicians's prescribing habits. Whether those habits should be changed or not seems to still be an open question.
Wednesday, June 07, 2006
Growing consensus not to use beta-blockers as initial choice for blood pressure treatment
Fueled largely by the results of the blood pressure arm of ASCOT, various authoritative medical organizations are demoting beta-blockers (BBs) from their former role as first line treatment for elevated blood pressure. NICE (the British National institute for Health and Clinical Excellence) and the British Hypertension Society have recently published guidelines that recommend BBs not be used as first line BP treatment except in cases of angina and HBP or in patients with excessive sympathetic tone or if they cannot tolerate ACEs or ARBs. They also recommend that if a patient is already on beta-blockers and a second BP drug is needed that the additional drug not be a diuretic because of the increased risk of diabetes.(Apparently the argument that since an increased mortality was not seen in ALLHAT patients who developed diabetes it is somehow OK if some medications trigger diabetes did not have much credence with the panel)
For those of us enamored by pathophysiology I refer back to a earlier posting that briefly reviewed data suggesting that beta-blockers are not as good as we once thought because-at least in part- of their failure to lower the central blood pressure while the ACEs and ARBs do.
For those of us enamored by pathophysiology I refer back to a earlier posting that briefly reviewed data suggesting that beta-blockers are not as good as we once thought because-at least in part- of their failure to lower the central blood pressure while the ACEs and ARBs do.
Saturday, June 03, 2006
A nap and a cup of coffee-What a concept.
I have posted before on the excessive sleepiness awareness "educational" programs that are appearing on the free doctor dinner programs and in various publications, there was a interesting juxtaposition of reading material arriving in my mail box.
The Annals of Internal Medicine ( June 6, 2006 issue) featured two articles on the effect of naps and coffee on "real life" situations and an editorial (" Naps and Drugs to Combat Fatigue and Sleepiness") by a well known and prolific sleep researcher, Dr. Christian Guilleminault. ( Annals Internal Medicine-volume 144,number 11 p. 856)
The other was a special issue of Internal Medicine World Report on the topic of excessive Sleepiness (ES). (ES has joined the ranks of conditions designated by an abbreviation and may soon rival ED in the level of promotional material produced.) The Report offered free CME and the authors credited with its material were an academic family doctor teamed with PhD sleep researcher from University of Michigan. The readers are told that the supplement was provided by "CME Outfitters,LLC" and was supported by an educational grant from Cephalon, Inc.,the manufacturer of modafinil (trade name Provigil).
The readers of the supplement are told that in order to accurately diagnose ES a detailed sleep history is necessary. A 14 item list of questions is suggested and the readers are told that it is critical to ask patients about the quality and quantity of sleep. It seems that ES is not only wide spread but it is said to be under recognized so we should seek it out in our patients.The list of "alertness-promoting agents" is reviewed and not surprisingly modafinil seems to be the best choice.
One of the Annals' article dealt with nighttime driving and demonstrated that either a nap or a caffeine containing beverage reduced the number of impaired driving events.A study involving interns showed that naps lead to less sensation of fatigue. Both sets of results conform with common sense and everyday experience (and with references noted in the articles and the editorial) and neither seems particularly monumental and I cannot help but wonder if this was a slow news day at the Annals editorial offices.
I found one of Dr. Guilleminault's editorial comments thought provoking. Apparently some of the interns did not really nap during their nap time.Some worked on the charts and others continued to take call for their own patients. He says :
"Clearly a 'medical culture element' (responsibility for one's own patients) was conflicting with the napping concept." He continues, " Perhaps it is time for medical housestaff to give the same weight to their responsibility to be alert as they do to their responsibility to be available to their patients.".
I will need more time to mull that over. I thought being responsible for your patients was a good thing.
The editorial is supportive of the use of napping and coffee to battle fatigue and sleepiness and is less enthusiastic about modafinil "The shortcomings of modafinil raise questions about the use of pharmacologic agents..."
Those comments are not surprising as a NEJM article and editorial last year seemed to indicate that modafinil was about as good as a big dose of coffee.
The Annals of Internal Medicine ( June 6, 2006 issue) featured two articles on the effect of naps and coffee on "real life" situations and an editorial (" Naps and Drugs to Combat Fatigue and Sleepiness") by a well known and prolific sleep researcher, Dr. Christian Guilleminault. ( Annals Internal Medicine-volume 144,number 11 p. 856)
The other was a special issue of Internal Medicine World Report on the topic of excessive Sleepiness (ES). (ES has joined the ranks of conditions designated by an abbreviation and may soon rival ED in the level of promotional material produced.) The Report offered free CME and the authors credited with its material were an academic family doctor teamed with PhD sleep researcher from University of Michigan. The readers are told that the supplement was provided by "CME Outfitters,LLC" and was supported by an educational grant from Cephalon, Inc.,the manufacturer of modafinil (trade name Provigil).
The readers of the supplement are told that in order to accurately diagnose ES a detailed sleep history is necessary. A 14 item list of questions is suggested and the readers are told that it is critical to ask patients about the quality and quantity of sleep. It seems that ES is not only wide spread but it is said to be under recognized so we should seek it out in our patients.The list of "alertness-promoting agents" is reviewed and not surprisingly modafinil seems to be the best choice.
One of the Annals' article dealt with nighttime driving and demonstrated that either a nap or a caffeine containing beverage reduced the number of impaired driving events.A study involving interns showed that naps lead to less sensation of fatigue. Both sets of results conform with common sense and everyday experience (and with references noted in the articles and the editorial) and neither seems particularly monumental and I cannot help but wonder if this was a slow news day at the Annals editorial offices.
I found one of Dr. Guilleminault's editorial comments thought provoking. Apparently some of the interns did not really nap during their nap time.Some worked on the charts and others continued to take call for their own patients. He says :
"Clearly a 'medical culture element' (responsibility for one's own patients) was conflicting with the napping concept." He continues, " Perhaps it is time for medical housestaff to give the same weight to their responsibility to be alert as they do to their responsibility to be available to their patients.".
I will need more time to mull that over. I thought being responsible for your patients was a good thing.
The editorial is supportive of the use of napping and coffee to battle fatigue and sleepiness and is less enthusiastic about modafinil "The shortcomings of modafinil raise questions about the use of pharmacologic agents..."
Those comments are not surprising as a NEJM article and editorial last year seemed to indicate that modafinil was about as good as a big dose of coffee.
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