Spectranetics Settles

I could not let this story, which came out just before the new year, completely slip by.  As reported by the Colorado Springs Gazette:

Spectranetics, the Colorado Springs-based medical-laser manufacturer, will pay $5 million to resolve federal government allegations that the company illegally imported and marketed unapproved medical devices, the U.S. Department of Justice said Tuesday.

Spectranetics will not face criminal prosecution, although it 'has accepted responsibility for its conduct' and agreed that 'officers and employees who acted on behalf of the company engaged in multiple areas of wrongdoing,' according to a Justice Department news release.

The investigation had been under way since at least Sept. 4, 2008, when agents from the U.S. Food and Drug Administration and Immigration and Customs Enforcement raided the company’s Springs headquarters, seeking information and correspondence.

Spectranetics manufactures sophisticated medical lasers used to clear blockages in coronary and leg arteries.

At issue in the federal probe were allegations that Spectranetics imported medical devices and provided them to physicians for use in patients without federal regulatory approval, the Justice Department said.

Also, Spectranetics allegedly conducted a clinical study that didn’t comply with federal regulations, while it also promoted products for which it hadn’t received FDA approval or clearance, according to the Justice Department.

Spectranetics’ actions caused false claims to be submitted to Medicare from 2003 to 2008, the agency also alleged.

Spectranetics will pay $4.9 million in civil damages to resolve the claims, the Justice Department said. In addition, the company said it has agreed to a future forfeiture of $100,000 in cash or property.

Spectranetics has also instituted measures to prevent similar conduct and will cooperate in 'an ongoing criminal investigation,' the agency said.

Also ongoing are a class-action lawsuit initiated by shareholders, and possibly a US Securities and Exchange Commission investigation. The Gazette also noted,

The company also went through a management shake-up; then-President and CEO John Schulte resigned a few weeks after the September 2008 raid.

Another day, another settlement of charges of wrong-doing by a health care organization.  So my stock response is xataloging legal settlements seems to be a useful way to assess the sorts of bad behavior manifested by large health care organizations (see some posts here). However, as we have said frequently, such settlements, including the "corporate integrity agreements" now frequently attached to them, seem to have done little to deter bad behavior. Usually, the companies involved only need to pay fines, and no individual who performed, directed or approved unethical or illegal acts will suffer any negative consequences. I submit once again that such fines are viewed merely as costs of doing business by the affected companies, and do not deter future bad behavior.

As seems standard operating procedure for such settlements, the fine in this case was barely more than a financial speed bump, given that the company had revenues of about $104 million in 2008 (per its 2008 annual report).  At least the CEO who was in charge at the time of the admitted wrongdoing actually lost his job.  However, presumably he was able to leave with at least the 792,354 shares of stock, currently worth $5,340,466, based on today's price of $6.74, 2.5% of outstanding shares which he beneficially owned prior to his departure, according to the company's 2008 proxy statement.

I once again submit that would-be health care reformers who want to improve care, reduce costs and improve access should advocate for real negative consequences for people who implement, direct or approve the various versions of fraud, kickbacks, and miscellaneous wrongdoing, corruption and malfeasance we have discussed on Health Care Renewal.

Spectranetics Settles

I could not let this story, which came out just before the new year, completely slip by.  As reported by the Colorado Springs Gazette:

Spectranetics, the Colorado Springs-based medical-laser manufacturer, will pay $5 million to resolve federal government allegations that the company illegally imported and marketed unapproved medical devices, the U.S. Department of Justice said Tuesday.

Spectranetics will not face criminal prosecution, although it 'has accepted responsibility for its conduct' and agreed that 'officers and employees who acted on behalf of the company engaged in multiple areas of wrongdoing,' according to a Justice Department news release.

The investigation had been under way since at least Sept. 4, 2008, when agents from the U.S. Food and Drug Administration and Immigration and Customs Enforcement raided the company’s Springs headquarters, seeking information and correspondence.

Spectranetics manufactures sophisticated medical lasers used to clear blockages in coronary and leg arteries.

At issue in the federal probe were allegations that Spectranetics imported medical devices and provided them to physicians for use in patients without federal regulatory approval, the Justice Department said.

Also, Spectranetics allegedly conducted a clinical study that didn’t comply with federal regulations, while it also promoted products for which it hadn’t received FDA approval or clearance, according to the Justice Department.

Spectranetics’ actions caused false claims to be submitted to Medicare from 2003 to 2008, the agency also alleged.

Spectranetics will pay $4.9 million in civil damages to resolve the claims, the Justice Department said. In addition, the company said it has agreed to a future forfeiture of $100,000 in cash or property.

Spectranetics has also instituted measures to prevent similar conduct and will cooperate in 'an ongoing criminal investigation,' the agency said.

Also ongoing are a class-action lawsuit initiated by shareholders, and possibly a US Securities and Exchange Commission investigation. The Gazette also noted,

The company also went through a management shake-up; then-President and CEO John Schulte resigned a few weeks after the September 2008 raid.

Another day, another settlement of charges of wrong-doing by a health care organization.  So my stock response is xataloging legal settlements seems to be a useful way to assess the sorts of bad behavior manifested by large health care organizations (see some posts here). However, as we have said frequently, such settlements, including the "corporate integrity agreements" now frequently attached to them, seem to have done little to deter bad behavior. Usually, the companies involved only need to pay fines, and no individual who performed, directed or approved unethical or illegal acts will suffer any negative consequences. I submit once again that such fines are viewed merely as costs of doing business by the affected companies, and do not deter future bad behavior.

As seems standard operating procedure for such settlements, the fine in this case was barely more than a financial speed bump, given that the company had revenues of about $104 million in 2008 (per its 2008 annual report).  At least the CEO who was in charge at the time of the admitted wrongdoing actually lost his job.  However, presumably he was able to leave with at least the 792,354 shares of stock, currently worth $5,340,466, based on today's price of $6.74, 2.5% of outstanding shares which he beneficially owned prior to his departure, according to the company's 2008 proxy statement.

I once again submit that would-be health care reformers who want to improve care, reduce costs and improve access should advocate for real negative consequences for people who implement, direct or approve the various versions of fraud, kickbacks, and miscellaneous wrongdoing, corruption and malfeasance we have discussed on Health Care Renewal.

Suppression of Clinical Trials of Sumatriptan

Correspondence to the Lancet two weeks ago revealed another instance in which clinical research studies that failed to provide results favorable to a sponsor's product were suppressed. [Tfeft-Hansen  PC. Unpublished clinical trials of sumatriptan. Lancet 2009; 374: 1501-2.  Link here.]

Sumatriptan, sold as Imitrex by GlaxoSmithKline, and now available generically, is a commonly used treatment for acute migraine headaches.  A Cochrane review from 2003 concluded that multiple clinical trials versus placebo showed that the drug is a safe and effective treatment of acute migraine [link here.]  A comparison of multiple guidelines for headache treatment noted considerable variability in how guidelines were developed, but that a number recommended sumatriptan as a first-line agent based apparently mainly on trials against placebo, while noting a lack of head-to-head comparisons among sumatriptan (and other triptans) and older, simpler treatments, like non-steroidal anti-inflammatory drugs (NSAIDs).  [Schuurmans A, van Weel C. Pharmacologic treatment of migraine: comparison of guidelines. Can Fam Physician 2005; 51: 838-843.  Link here.]

Tfelt-Hansen had written a review of treatment of migraine with a combination of ergotamine and caffeine, which included a single trial comparing that combination to sumatriptan.  He noted that the results of this trial appeared on "the homepage of the Swedish Medical Agency," but were not published in a peer-reviewed journal.  The trial suggested that sumatriptan was inferior to the combination. 

Tfelt-Hansen looked up this trial in the GlaxoSmithKline trial register.  Recall that this database was the source of information on unpublished trials of Avandia (rosiglitazone, GSK) that Dr Steven Nissen and colleagues meta-analyzed to suggest that Avandia may produce adverse cardiovascular effects (see post here).   Recall also that the registry was created as part of a settlement of a lawsuit by then New York Attorney General Elliot Spitzer that accused GSK of concealing clinical research unfavorable to its drug paroxetine (Paxil, GSK).  [Steinbrook R. Registration of clinical trials - voluntary or mandatory? N Engl J Med 2004; 351:1820-1822.  Link here.]

Tfelt-Hansen's main finding was that there were six trials comparing sumatriptan to other treatments, including paracetamol (acetaminophen) plus metaclopamide (2 trials), buclizine chloride, paracetamol and codeine (2 trials), ergotamine tartrate, cyclizine HCl, caffeine (1 trial), and ergotamine tartrate plus caffeine (1 trial).  In 3 trials, sumatriptan treated patients were not significantly more likely to have relief of their headaches within 2 hours.  In 1 trial, there was a non-significant trend favoring sumatriptan.  In two trials, sumatriptan was superior to the comparison.  In 4 trials, the rate of relief after sumatriptan treatment was 50% or less. 

Tfelt-Hansen concluded:

It is easy to understand why these RCTs were never published when sumatriptan was introduced: in only one of the oral trials did more than 50% of patients have headache relief (the primary efficacy measure) after sumatriptan 100 mg for the first attack treated (table), and in the RCT with rectal sumatriptan, the drug was found inferior to ergotamine. These findings would at the time have spoiled the very positive picture of sumatriptan as a new wonder drug for migraine.

Of course, this points out that health care corporations may regard clinical trials more as marketing tools than as science. We have discussed numerous instances in which trials that did not show commercial sponsors' products in a favorable light were suppressed by these sponsors.

Individual trials only at best produce approximations of the truth about the drugs or devices they compare. Trials may be positive due to chance alone when the test or treatment under study actually has no good effects. Post-hoc suppression of "negative" trials therefore may exaggerate the benefits (and safety) of tests or treatments. Physicians and patients who try to uphold the ideals of evidence-based medicine, and base decisions on the best possible evidence can be misled when evidence unfavorable to vested interests is systematically suppressed. Suppression of evidence unfavorable to vested interests may lead to excess use of tests and treatments that really are less beneficial or more risky than the published evidence suggested, and to willingness to pay exaggerated prices for such tests and treatments. Thus suppression of evidence can lead to excess costs and bad outcomes.

Also, as we have said before, suppression of results of clinical research that are unfavorable to the vested interests of research sponsors violates the trust of research subjects.  Research subjects are often assured that their participation is for the benefit of science and health care.  Suppressing results unfavorable to vested interests distorts science and makes health care more dysfunctional.

Evidence that is purposefully suppressed is by definition hard to find. Nonetheless, we have seen several recent examples in which suppressed evidence was later revealed, and when combined with existing evidence, showed that previously hyped treatments were really not as safe and effective as was thought.  In particular, the suppression by various drug companies of evidence unfavorable to new anti-depressants they were marketing has generated some discussion (see post here).

This parade of examples suggests that stronger measures are needed to assure that clinical research is not suppressed due to the vested interests of research sponsors.  One seemingly radical, but increasingly plausible approach would ban corporations that sell health care products or services from influencing clinical research done to evaluate those products.  Would be health care reformers who really want to improve outcomes, improve access and decrease costs might want to think about how to make the evidence available about the outcomes of health care interventions more honest.

Suppression of Clinical Trials of Sumatriptan

Correspondence to the Lancet two weeks ago revealed another instance in which clinical research studies that failed to provide results favorable to a sponsor's product were suppressed. [Tfeft-Hansen  PC. Unpublished clinical trials of sumatriptan. Lancet 2009; 374: 1501-2.  Link here.]

Sumatriptan, sold as Imitrex by GlaxoSmithKline, and now available generically, is a commonly used treatment for acute migraine headaches.  A Cochrane review from 2003 concluded that multiple clinical trials versus placebo showed that the drug is a safe and effective treatment of acute migraine [link here.]  A comparison of multiple guidelines for headache treatment noted considerable variability in how guidelines were developed, but that a number recommended sumatriptan as a first-line agent based apparently mainly on trials against placebo, while noting a lack of head-to-head comparisons among sumatriptan (and other triptans) and older, simpler treatments, like non-steroidal anti-inflammatory drugs (NSAIDs).  [Schuurmans A, van Weel C. Pharmacologic treatment of migraine: comparison of guidelines. Can Fam Physician 2005; 51: 838-843.  Link here.]

Tfelt-Hansen had written a review of treatment of migraine with a combination of ergotamine and caffeine, which included a single trial comparing that combination to sumatriptan.  He noted that the results of this trial appeared on "the homepage of the Swedish Medical Agency," but were not published in a peer-reviewed journal.  The trial suggested that sumatriptan was inferior to the combination. 

Tfelt-Hansen looked up this trial in the GlaxoSmithKline trial register.  Recall that this database was the source of information on unpublished trials of Avandia (rosiglitazone, GSK) that Dr Steven Nissen and colleagues meta-analyzed to suggest that Avandia may produce adverse cardiovascular effects (see post here).   Recall also that the registry was created as part of a settlement of a lawsuit by then New York Attorney General Elliot Spitzer that accused GSK of concealing clinical research unfavorable to its drug paroxetine (Paxil, GSK).  [Steinbrook R. Registration of clinical trials - voluntary or mandatory? N Engl J Med 2004; 351:1820-1822.  Link here.]

Tfelt-Hansen's main finding was that there were six trials comparing sumatriptan to other treatments, including paracetamol (acetaminophen) plus metaclopamide (2 trials), buclizine chloride, paracetamol and codeine (2 trials), ergotamine tartrate, cyclizine HCl, caffeine (1 trial), and ergotamine tartrate plus caffeine (1 trial).  In 3 trials, sumatriptan treated patients were not significantly more likely to have relief of their headaches within 2 hours.  In 1 trial, there was a non-significant trend favoring sumatriptan.  In two trials, sumatriptan was superior to the comparison.  In 4 trials, the rate of relief after sumatriptan treatment was 50% or less. 

Tfelt-Hansen concluded:

It is easy to understand why these RCTs were never published when sumatriptan was introduced: in only one of the oral trials did more than 50% of patients have headache relief (the primary efficacy measure) after sumatriptan 100 mg for the first attack treated (table), and in the RCT with rectal sumatriptan, the drug was found inferior to ergotamine. These findings would at the time have spoiled the very positive picture of sumatriptan as a new wonder drug for migraine.

Of course, this points out that health care corporations may regard clinical trials more as marketing tools than as science. We have discussed numerous instances in which trials that did not show commercial sponsors' products in a favorable light were suppressed by these sponsors.

Individual trials only at best produce approximations of the truth about the drugs or devices they compare. Trials may be positive due to chance alone when the test or treatment under study actually has no good effects. Post-hoc suppression of "negative" trials therefore may exaggerate the benefits (and safety) of tests or treatments. Physicians and patients who try to uphold the ideals of evidence-based medicine, and base decisions on the best possible evidence can be misled when evidence unfavorable to vested interests is systematically suppressed. Suppression of evidence unfavorable to vested interests may lead to excess use of tests and treatments that really are less beneficial or more risky than the published evidence suggested, and to willingness to pay exaggerated prices for such tests and treatments. Thus suppression of evidence can lead to excess costs and bad outcomes.

Also, as we have said before, suppression of results of clinical research that are unfavorable to the vested interests of research sponsors violates the trust of research subjects.  Research subjects are often assured that their participation is for the benefit of science and health care.  Suppressing results unfavorable to vested interests distorts science and makes health care more dysfunctional.

Evidence that is purposefully suppressed is by definition hard to find. Nonetheless, we have seen several recent examples in which suppressed evidence was later revealed, and when combined with existing evidence, showed that previously hyped treatments were really not as safe and effective as was thought.  In particular, the suppression by various drug companies of evidence unfavorable to new anti-depressants they were marketing has generated some discussion (see post here).

This parade of examples suggests that stronger measures are needed to assure that clinical research is not suppressed due to the vested interests of research sponsors.  One seemingly radical, but increasingly plausible approach would ban corporations that sell health care products or services from influencing clinical research done to evaluate those products.  Would be health care reformers who really want to improve outcomes, improve access and decrease costs might want to think about how to make the evidence available about the outcomes of health care interventions more honest.

Failing to Report Adverse Effects of Treatments

We have frequently advocated the evidence-based medicine (EBM) approach to improve the care of individual patients, and to improve health care quality at a reasonable cost for populations. Evidence-based medicine is not just medicine based on some sort of evidence. As Dr David Sackett, and colleagues wrote [Sackett DL, Rosenberg WM, Muir Gray JA, Haynes RB, Richardson WS. Evidence-based medicine; what it is and what it isn't. BMJ 1996; 312: 71-72. Link here. ]

Evidence based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research.

One can find other definitions of EBM, but nearly all emphasize that the approach is designed to appropriately apply results from the best clinical research, critically reviewed, to the individual patient, taking into account that patient's clinical characteristics and personal values.

When making decisions about treatments for individual patients, the EBM approach suggests using the best available evidence about possible benefits and harms of treatment, so that the treatment chosen is most likely to maximize benefits and minimize harms for the individual patient. The better the evidence about specific benefits and harms applicable to a particular patient, the greater will be the likelihood that a particular decision based on this evidence will result in the best possible outcomes for the patient.

A new study in the Archives of Internal Medicine focused on how articles report adverse effects found by clinical trials. [Pitrou I, Boutron I, Ahmad N et al. Reporting of safety results in published reports of randomized controlled trials. Arch Intern Med 2009; 169: 1756-1761. Link here.] The results were not encouraging.

The investigators assessed 133 articles reporting the results of randomized controlled trials published in 2006 in six English language journals with high impact factors, that is, the most prestigious journals, including the New England Journal of Medicine, Lancet, JAMA, British Medical Journal, and Annals of Internal Medicine. They excluded trials with less common designs, such as randomized cross-over trials. The majority of trials (54.9%) had private, or private mixed with public funding.

The major results were:
15/133 (11.3%) did not report anything about adverse events
36/133 (27.1%) did not report information about the severity of adverse events
63/133 (47.4%) did not report how many patients had to withdraw from the trial due to adverse events
43/133 (32.3%) had major limitations in how they reported adverse events, e.g., reporting only the most common events (even though most trials do not enroll enough patients to detect important but uncommon events).

The authors concluded, "the reporting of harm remains inadequate."

An accompanying editorial [Ioannidis JP. Adverse events in randomized controlled trials: neglected, distorted, and silenced. Arch Intern Med 2009; 169: 1737-1739. Link here] raised concerns about why the reporting of adverse events is so shoddy:

Perhaps conflicts of interest and marketing rather than science have shaped even the often accepted standard that randomized trials study primarily effectiveness, whereas information on harms from medical interventions can wait for case reports and nonrandomized studies. Nonrandomized data are very helpful, but they have limitations, and many harms will remain long undetected if we just wait for spontaneous reporting and other nonrandomized research to reveal them. In an environment where effectiveness benefits are small and shrinking, the randomized trials agenda may need to reprogram its whole mission, including its reporting, toward better understanding of harms.

Pitrou and colleagues have added to our knowledge about the drawbacks of the evidence about treatments that is publicly available to physicians and patients when making decisions about treatment. Even reports of studies with the best designs (randomized controlled trials) in the best journals seem to omit important information about the harms of the treatments they test.

It appears that the majority of the reports that Pitrou and colleagues studied received "private" funding, presumably meaning most were funded by drug, biotechnology, or device companies and were likely meant to evaluate the sponsoring companies' products. However, note that this article did not analyze the relationship of funding source to the completeness of information about adverse effects.

Nonetheless, on Health Care Renewal we have discussed many cases in which research has been manipulated in favor of the vested interests of research sponsors (funders), or in which research unfavorable to their interests has been suppressed. Therefore, it seems plausible that sponsors' influence over how clinical trials are designed, implemented, analyzed and reported may reduce information about the adverse effects of their products reported in journal articles. Trials may be designed not to gather information about adverse events. Analyses of some adverse events, or some aspects of these events may not be performed, or if performed, not reported. The evidence from clinical research available to make treatment decisions consequently may exaggerate the ratios of certain drugs' and devices' benefits to their harms.

Patients may thus receive treatments which are more likely to hurt than to help them, and populations of patients may be overtreated. Impressions that treatments are safer than they actually are may allow their manufacturers to overprice them, so health care costs may rise.

The article by Pitrou and colleagues adds to concerns that we physicians may too often really be practicing pseudo-evidence based medicine when we think we are practicing evidence-based medicine. We cannot judiciously balance benefits and harms of treatments to make the best decisions for patients when evidence about harms is hidden. Clearly, as Ioannidis wrote, we need to "reprogram." However, what we need to reprogram is our current dependence on drug and device manufacturers to pay for (and hence de facto run) evaluations of their own products. If health care reformers really want to improve quality while controlling costs, this is the sort of reform they need to start considering.

NB - See also the comments by Merrill Goozner in the GoozNews blog.

High Costs and Poor Outcomes - A Lesson About the Suppression of Research

Last week, blogger Alison Bass was one of the few to comment on a new article on the risks of antidepressant medications published electronically last week by the British Medical Journal.[1] The article adds to the clinical evidence about these specific drugs. However, it also should remind us about why our health care costs seem to continue to inflate disproportionate to any improvements in health care outcomes.

Background - Why Don't Doctors Diagnose and Treat Depression According to the Evidence?

Here is the background. Since the early 1990s, based on numerous published clinical trials that showed that the newer (mainly SSRI, that is, selective serotonin reuptake inhibitor) antidepressants seemed to be quite safe and effective, authoritative guidelines have urged physicians to screen patients for depression, and have a low threshold for beginning treatment, particularly with these then new drugs. (For example, see the 1993 AHCPR guidelines,[2] and the Ambulatory Care Quality Alliance Recommended Starter Set[3].) Such guidelines targeted primary care physicians as well as psychiatrists. As a primary care physician, I often felt guilty that I didn't screen all patients, including those who did not outwardly appear depressed, for depression, and was reluctant to be the primary prescriber of antidepressants for depressed patients. I was not alone. There was evidence that many primary care physicians failed to follow these apparently evidence-based guidelines.

Suspicions that SSRIs Were Not as Effective or Safe as Thought

However, in 2004, internal documents from one drug company (Glaxo Smith Kline), published by the Canadian Medical Association Journal, suggested that the company had suppressed a study which failed to show its SSRI was effective for adolescent patients.[4] Also, then New York state attorney general Elliot Spitzer sued the company alleging it had suppressed such data.[5] Considerable anecdotal information thereafter came to light suggesting that drug companies may have suppressed data from clinical research (that is, studies done on patients, not in the laboratory) which tended to show the drugs were less effective, or more dangerous than previously thought. Many began to suspect that the drugs increased the risk of suicidal thoughts or behavior, even though one would think that if they were effective in treating depression, they should decrease such risks.

How Does Uncovering Suppressed Trials Change the Evidence About the Benefits and Harms of SSRIs?

Then, an analysis of trials of SSRIs given to adolescent patients, which included unpublished as well as published trials, did show they increased the risk of suicide.[6] But what about adult patients?

In 2008, Erick Turner and colleagues published a meta-analysis that included numerous trials of SSRIs and other antidepressants given to adult patients that had never been published, but whose results had been submitted to the US Food and Drug Administration (FDA).[7] When those trials were included in the analysis, the drugs seemed less effective than was previously believed.

The new meta-analyis by Stone et al[1] suggested how adding evidence from the suppressed trials improves our knowledge about the possible harms of these drugs. Stone et al specifically addressed whether the drugs increased the risk of suicidal thoughts or actions for adult patients. It was based on data from 372 trials that included 99,231 patients. "Most of the studies were unpublished; those that had been published in some form seldom contained information concerning suicidality in the publication." Its main result was that SSRI drugs approximately doubled the risk of suicidal behavior for patients less than 25 years old, but decreased the risk for older patients.

Suppressing Trials Distorted the Evidence-Base

Thus, the combined results of several meta-analyses suggests that SSRIs are neither as safe nor as effective for adult patients as they were previously touted to be. The drugs used to appear to be more safe and effective because the drug companies that sponsored (paid for) clinical trials of their own products suppressed the publication of studies whose results did not show their products in a favorable light. The guidelines once thought to be so authoritative are probably much to enthusiastic about the use of drugs to treat depression. It may be that those physicians who resisted pressure from these guidelines and other efforts by would-be quality improvers to diagnose more depressed patients and treat them with SSRIs weren't so dumb.

Health Policy Implications

The recently published meta-analysis of the risk of suicidal ideation or behavior due to SSRIs for adult patients[1] adds not just to the clinical evidence about the treatment of depression, but to the evidence that suppression of research by those with vested interests in its results may not be rare. There is no reason to think that suppression of research about other medical interventions used for other clinical problems does not occur just as often.

This underscores why we as a society should not have handed over control of how new drugs and devices are evaluated to the companies that stand to profit by selling them. The apparent benefits and safety of most drugs and devices brought to the market in recent years may have been exaggerated by the ability of the corporations who sponsored the research to suppress those studies that were least favorable to their products. Thus, it is very likely that doctors have over prescribed newer (and more expensive) drugs and devices based on erroneous beliefs about their safety and effectiveness, beliefs supported by an evidence base which was distorted by suppression of studies whose results did not show the results their commercial sponsors wanted to see. Furthermore, we have likely collectively paid too much for these drugs and devices based on these same erroneous beliefs. Thus, the distortion of the clinical evidence base caused by putting the makers of medical products in charge of their evaluation has likely led to increased costs and worse outcomes for patients.

Health care reformers serious about wanting to improve patient outcomes and reduce costs ought to be at the forefront of a movement to make clinical research more honest. All clinical trials completed and submitted to government regulators ought to be published in some form, so that the data they contain is available to guide clinical decisions. Going forward, all studies should be published in some form in a timely manner to prevent future research suppression. There ought to be better regulation of research sponsored, and de facto run by companies who have vested interests in the results being favorable to their products. It would not be unreasonable to prevent companies with such vested interests from running or otherwise directly influencing clinical research meant to evaluate their own products.

But here in the States, we are probably too diverted by yelling at each other about whether a "public option" is vital or nefarious to worry about such issues.. Meanwhile, expect our health care to continue to get more expensive, less accessible, and less good for patients.

ADDENDUM (25 August, 2009) - Also, see the comments by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma Blog

References

1. Stone M, Laughren T, Jones ML et al. Risk of suicidality in clinical trials of antidepressants in adults: analysis of proprietary data submitted to US Food and Drug Administration. Brit Med J 2009; 339: b2880. Link here.
2. Depression Guideline Panel. Depression in Primary Care: Volume 2 - Treatment of Major Depression. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1993. Link here.
3. Ambulatory Care Quality Alliance. Recommended Starter Set: Clinical Performance Measures for Ambulatory Care. http://www.ahrq.gov/qual/aqastart.htm
4. Kondro W. Drug company experts advised staff to withhold data about SSRI use in children. Can Med Assoc J 2004; 170: 783. Link here.
5. Wadman M. Sptizer sues drug giant for deceiving doctors. Nature 2004; 429: 589. Link here.
6. Hammad T, Laughren T, Racoosin JA. Suicidality in pediatric patients treated with antidepressant drugs. Arch Gen Psychiatry 2006;63:332-9. Link here.
7. Turner EH, Matthews AM, Linardatos E et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358: 252-260. Link here.

Pfizer Settles Trovan Case with Kano State

As reported by the Washington Post, and many news sources outside of the US, Pfizer Inc has settled another lawsuit,

Pfizer signed a $75 million agreement Thursday with Nigerian authorities to settle criminal and civil charges that the pharmaceutical company illegally tested an experimental drug on children during a 1996 meningitis epidemic.

Nigerian authorities say Pfizer's test of the antibiotic Trovan killed 11 children and disabled scores more. Pfizer says the deaths and injuries were the result of meningitis.

An attorney for the state of Kano, where the charges were lodged, said the settlement was a long time in coming but welcome because it set the record straight about Pfizer's culpability. 'People and entities can and must be held accountable for the consequences of their conduct,' the attorney, Babatunde Irukera, said. 'People around the world are no different and must be accorded the same levels of protections, always.'

Pfizer is not quite done with this case.

Charges filed against Pfizer by Nigeria's federal government, which is seeking about $6 billion in damages, are unaffected by the settlement, Irukera said. Two lawsuits related to the Trovan experiment also remain pending in New York.

The Post's article summarized the issues in the case, thus:

Details of the drug trial were first made public in December 2000 in a Washington Post investigative series. The articles reported that the trial did not conform to U.S. patient-protection standards and that the oral form of the drug used in the trial had not been previously tested in children. Pfizer had no signed consent forms for the children, the articles said, and the company relied on a falsified ethics approval letter.

Five years later, in May 2006, The Post obtained and published a confidential report that concluded that Pfizer violated Nigerian and international law in the experiment. That set in motion the criminal charges.

We first posted about this case in 2006, here. We posted about Pfizer's heretofore most recent legal settlement, here. I wonder again whether multi-million, or even billion dollar settlements have that much effect on the leadership of a company as big as Pfizer? Such settlements do not affect the leaders directly, and their financial effects one a company so big are negligible.

Be that as it may, do we need more examples to remind us that strong skepticism should be the rule when evaluating clinical research done or sponsored by pharmaceutical companies, or other health care corporations with vested interests in the research turning out a certain way? Such skepticism is warranted whatever the clinical context, whatever the product being evaluated, and whatever country in which the research is done.

Here in the US, debate has been swirling about health care reform. Many of the arguments have been about how costs can be controlled while health care quality is increased. Better research about the benefits and harms of specific drugs, procedures, devices and tests might enable physicians to choose the most appropriate care for each patient, potentially improving quality while also reducing costs. This example, plus many others discussed on Health Care Renewal, suggests that putting at least an arm's length between companies which sell drugs and devices and the clinical research meant to evaluate these drugs and devices has the potential for making better quality, less biased, more accurate clinical research available (see the topics: suppression of medical research and manipulating clinical research.)

Maybe putting this topic on our local US health care policy radar would increase the chances of achieving meaningful health care reform. Maybe if the US took the lead in separating clinical research meant to evaluate drugs, devices, procedures, or tests from the corporations selling them, the result would be a movement that would benefit health care around the world?

Practicing (Clinical Trials) Medicine Without a License

Another story of dubious clinical research, this time reported by the St Petersburg (Florida, US) Times:

Vladimir Martin called himself 'doctor' and ran 17 clinical trials of new drugs for major pharmaceutical companies before one patient noticed he didn't have a medical license.

The patient alerted the St. Petersburg Times, whose resulting story led to a state investigation. On Saturday, Martin, 43, was arrested on charges of practicing medicine without a license. He was later released from the Pinellas County Jail on $10,000 bail. The felony charge carries a maximum sentence of five years in prison and maximum fine of $5,000.

The Clearwater man, who changed his last name from Kossatchev after moving to Florida in 2003, went to medical school in the former Soviet Union and practiced in a hospital in his native Ukraine.

Ruth Weber, a 74-year-old Clearwater resident, told the Times in April 2008 that the man who called himself Dr. Martin enrolled her in a study for lower-back pain and adjusted the dosage of her medicine. Only licensed physicians are supposed to conduct such activities. Patients in the study were randomly selected to receive a new Johnson & Johnson painkiller called tapentadol, a placebo or the potent narcotic oxycodone.

Though Dr. Robert Lee Jackson, a Clearwater osteopath, was listed by the FDA as the physician conducting the study, Weber said she never saw Jackson. In weekly visits to Alliance Medical Research Group on Belcher Road, Weber said it was Martin who drew blood, doled out medication and, at one point, doubled her dosage.

Martin also conducted electrocardiograms on Weber, although his techniques were so rusty the electrodes kept slipping off, she said. Weber eventually dropped out of the study when she saw no improvement for her back pain.

A second woman, Ann Reed, told investigators she also responded to an ad for a drug study trial at Alliance Medical Research. Martin took her blood, listened to her heart and gave her medications, Reed said. Martin sometimes had to stick her four times to draw blood, she said.

Like Weber, Reed said she never saw Jackson during her trial, which involved 13 visits between May 2007 and March 2008.

Greg Panico, a spokesman for Johnson & Johnson, said the company audited Alliance Medical after the Times' story and submitted its findings to the FDA. He declined to discuss the nature of the report, but said the drug company is no longer working with Alliance Medical.

Panico also said data collected in the tapentadol study at that site was not submitted to the FDA.

The drugmaker said it reported its findings to the Sterling Institutional Review Board in Atlanta, which had been hired by Johnson & Johnson to oversee patient safety during the trial.

Despite losing the Johnson & Johnson trial, Martin told investigators in July that he was conducting four other drug studies.

A little Google searching turned up another example on ClinicalTrials.gov of a commercially funded clinical study for which the Alliance Medical Research Group enrolled patients. This was a Phase III study sponsored by Cephalon, an "Open-Label Study to Evaluate the Effect of Treatment With Fentanyl Buccal Tablets on Pain Anxiety Symptoms When Used for the Management of Breakthrough Pain." Note also that Sterling Institutional Review Board appears to be another example of a for-profit, commercial institutional review board.

Here we have another example of remarkably bad implementation of commercially sponsored and commercially supervised clinical trials.

We have posted a number of times about sloppy and mismanagement of commercially sponsored clinical research, often under the auspices of for-profit contract research organizations (CROs) and for-profit institutional review boards (IRBs). See this 2006 vintage post on the infamous study 3014 on Ketek, sponsored by Sanofi Aventis.

In my humble opinion, in the contemporary business world, many managers are driven mainly by quarterly profits. However, what works best to boost profits in the short run may not be what works to produce valid clinical research that maximizes the safety of and respect afforded human research subjects. When all the organizations involved in the research, the sponsor, the organization implementing the research, and the organization supervising research ethics are for-profit, the incentives to cut corners are multiplied. Cutting corners can jeopardize the validity of the studies, and the safety and respectful treatment of study subjects.

I again submit that making human experimental research into a commercial enterprise, mainly serving the marketing of drugs and devices, may not produce good science, and may not be good for patients. It might be a better idea to leave human research to not-for-profit organizations and health care professionals.


Hat tip to PharmaGossip.

BLOGSCAN - Trial Results Via Press Release

See posts by Gary Schwitzer on the Schwitzer Health News Blog, and by Merrill Goozner on the GoozNews Blog on a new low in disclosing results of randomized controlled trials. It seems that Dendreon, the maker of the Provenge vaccine intended to treat prostate cancer, put out a press release that said the vaccine prolongs survival, but was completely lacking in data. Even preliminary results of the trial have not yet been released, much less has anything subject to peer review appeared. Nonetheless, the usually reliable New York Times called the trial "decisive." PR has trumped clinical science.

Is Medtronic CEO Abrogating Responsibility Of His Company To Determine Device Safety?

It would appear so. If this is the case, this CEO and his board of directors should be dismissed as a danger to the public. The CEO, William A. Hawkins III, being a biomedical engineer, would take special blame for this distorted attitude.

In "Pre-emption' Cited as Major Case Is Tossed", Wall Street Journal, Jan. 7, 2009 we learn that a federal judge, U.S. District Judge Richard H. Kyle in Minneapolis, threw out lawsuits on behalf of thousands of patients with heart-defibrillator wires that have been shown to fracture and fail to function or dispatch potentially lethal shocks, concluding that a recent Supreme Court opinion made the dismissals inevitable.

Judge Kyle did allow that "the Court recognizes that at least some plaintiffs have suffered injuries from using Sprint Fidelis leads, and the Court is not unsympathetic to their plight," he wrote. Nevertheless, he said, the plaintiffs' remedy "lies with Congress."

Such a dismissal at his level is understandable on procedural grounds, but reflects problems in the laws and procedures rather than in the ability of rigorous, honest, uncorrupted medical science to help prevent such patient harm (and the need for resultant suits) in the first place.

In the article we also learn that:

At issue is the Sprint Fidelis defibrillator "lead," a wire that was the top such product world-wide when Medtronic Inc. pulled it from the market in October 2007. Defibrillators are electrical devices placed under the skin in a patient's shoulder. Connected to the heart, they have saved thousands of lives by sending out powerful jolts of electricity, restarting the normal pattern of an abnormally beating heart.

But defibrillators depend on the leads to carry that electricity to the heart, and the exceptionally thin wires have over decades tended to fail at a higher rate than the devices themselves.

The Sprint Fidelis had been surgically implanted in 268,000 patients world-wide when the Minneapolis company concluded it was fracturing at a higher rate than that of its more robust predecessor, the Sprint Quattro.When the wires fractured, some patients died, either allegedly because the defibrillator failed to dispatch electrical therapy to the heart or because the massive and multiple shocks may have caused patients' hearts to stop.

... Medtronic reports that its 42-month failure rate from all causes is 6.3%, far more than the 1.8% failure rate for its predecessor, the Sprint Quattro model 6947, at 48 months.

The obvious issue that exceptionally thin wires might fail at a higher rate in a living, moving body and heart is a key to understanding the major scientific issue here. It is one of medical and engineering common sense, both of which appear to have been lacking regarding this product (or perhaps were overruled by management fiat).

New and experimental drugs are known to pose risks. This is why pharmaceutical companies are required to do preclinical testing in animals, and, in fact, in good conscience would never presume to release a drug without years of extensive animal testing, even before the first human ever tries a new compound. It is realized that animal testing is a straightforward, first-tier way to eliminate the possibility a new drug is going to have 'hidden surprises' that could kill people.

In the WSJ we learn, however, that:

By early 2007, Sprint Fidelis was the lead used in 90% of new Medtronic patients, garnering about $1 billion in revenue since its introduction in late 2004.

The lead was marketed based not on any multiyear study in hundreds of human patients, but rather on "bench testing" of the product in a laboratory to determine how easily it might fail by putting multiple stresses on it.

Excuse me? Bench testing of a wire lead to be implanted in a beating human heart?

The key to this entire issue and how to help avoid it in the future lies in the last sentence.

That is a stunning admission if accurate.

As a physician and biomedical informaticist who did a clerkship in biomedical engineering in medical school, as an expert in building invasive cardiology information systems to in part evaluate cardiac device safety and efficacy, and as an NIH SBIR grant reviewer in the area of public health, had this been an NIH proposal for funding of development of the new wire I would have scored an application for such development of a defibrillator lead that lacked animal testing at the very bottom of the pile (lowest score).

I would also have argued vehemently at the roundtable discussion that the proposal needed revision to include such testing in a rigorous manner before it could even be considered seriously.

Apparently, private R&D in the device industry, funded by stockholders and insurance companies and patients themselves, does not undergo such rigorous review as proposals seeking public money.

If the WSJ account is accurate, and no animal testing was done, then real, live patients, not animals, became the front line for clinical testing of a new experimental device. Some paid with their lives.

If so, this is unacceptable.

The belief that bench testing (and likely computer modeling, per my post here on overconfidence in computing) of a device made with complex materials, themselves subject to the vagaries and uncertainties of materials science let alone living systems, is adequate for immediate in vivo use in humans is perhaps the biggest worldview gap between linear-thinking engineers and computer personnel on the one hand, and clinicians and life scientists on the other used to complexity and uncertainty in living systems. The linear, grade school level thinking about biomedical issues must stop.

If the WSJ account is accurate, the following questions must be asked:

• Who made the decision to not do animal testing? Why?
  
• Was input from clinicians, scientists or others that such testing should be done raised? If not, why not?
• Was such input if it occurred overridden? If it was overridden, did the managers who overrode it have appropriate biomedical backgrounds to have overridden it?
• Were profit issues a cause of lack of in vivo testing in animals of the new lead?
  
• Does biomedical engineering as a discipline forego animal testing of devices meant for human use? If so, why? If not, why was it overridden here?
  
• Did anyone in Medtronic object to release of this wire lead on the grounds of inadequate testing? If not, why not?
• If anyone did object to release, were such objections overridden, and who did the overriding based on what criteria?

We perhaps get to the root of the problem in this admission in the WSJ article - the familiar (to HC Renewal readers) issue of leadership:

Medtronic Chief Executive Bill Hawkins lauded the decision [to dismiss the lawsuits] as supporting "the principle that the U.S. Food and Drug Administration is the appropriate body to determine the safety and efficacy of innovative technologies."

Mr. Hawkins seems to be implying that Medtronic is not an appropriate body to determine the safety and efficacy of its products. It would appear he is abrogating primary responsibility for the safety of his company's product, putting that responsibility in the hands of a government agency. I can presume his Board of Directors agrees with this assessment.

This is wrongheaded, cavalier, and has been the basis of recent major individual and class action lawsuits against the pharma industry. The medical device industry should not get a pass.

It is the primary responsibility of a medical R&D and manufacturing company to do all it can to reasonably determine the safety of its experimental devices and their iterative "improvements" before seeking approval for sale and use in humans.

FDA's role is to simply assure that the determination meets sound scientific, biomedical and legal grounds. They are not, should not be, and cannot be a "safety determination subcontractor" to industry.

It seems both Medtronic and FDA failed on this case, in fact. I addressed why making FDA the ultimate arbiter of safety was, in fact, itself risible and cavalier, in my post "Staring Idiocy In The Face: The FDA As The Gold Standard, Or Tin Plated Emperor?" regarding musician Diana Levine's unfortunate loss of her arm from a misapplied drug injection.

In any case, anyone with medical training who has had responsibility for direct patient care would have little trouble understanding the principle of not passing the buck on safety. Mr. Hawkin's lack of this experience, I add, seems to show in his stunning passing of the buck for safety to government.

If I were on the board of this company, a management house cleaning would be in order.

-- SS

A 21st Century Plague? The Syndrome of Inappropriate Over-Confidence in Computing

This is a longish post that tries to tie together a number of issues regarding overconfidence in computing and healthcare IT's ills. Bear with me.

A 21st century plague might be called the "Syndrome of Inappropriate Over-Confidence in Computing" (SICC syndrome for short).

It's bad enough that we are placing major decisions about industrial policy at the tender mercies of computer models. For example, whether global warming is real or not, dependence on computer models made by scientists who cannot reliably predict the weather, or exactly where an active hurricane under comprehensive observation from sky and satellite may strike, seems presumptuous at best. It reflects a syndrome of inappropriate overconfidence in computing, a belief in "cybernetic magic" if you will.

The same overconfidence, indeed, to the point of irrational exuberance, affects other domains. One domain is healthcare IT. As I shall point out, the SICC syndrome has helped cause major problems in other domains as well. Yet the appetite for yet more computer magic appears to be spreading.

As an aside regarding global warming due to man made causes, as a ham radio enthusiast I am a bit more concerned about what might be happening on good ol' Sol, that class G2 V main sequence dwarf star (the one we see in our sky every cloudless day). Said G2 star is having a problem with generating sunspots in the beginning of its current 11 year cycle, a regular cycle observed now for centuries:

Sunspot (Wikipedia): A minimum in the eleven-year sunspot cycle happened during 2008. While the reverse polarity sunspot observed on 4 January 2008 may represent the start of Cycle 24, no additional sunspots have yet been seen in this cycle. The definition of a new sunspot cycle is when the average number of sunspots of the new cycle's magnetic polarity outnumbers that of the old cycle's polarity. Forecasts in 2006 predicted Cycle 24 to start between late 2007 and early 2008, but new estimates suggest a delay until 2009.

K7RA solar update: Last week's sunspot group was only visible for three days, December 10-12. The average daily sunspot number for all of 2007 was 12.8; if we see no sunspots for the rest of 2008, the average for this year will be 4.7. By comparison, the yearly averages of daily sunspot numbers during the last solar minimum (1995-1997) were 28.7, 13.2 and 30.7. This solar minimum is much lower than the one about 12 years ago.

Emissions caused by sunspots profoundly affect earth's ionosphere layer and thus short wave radio propagation. Those wavelengths refract or "bounce" in the ionosphere and can thus travel beyond earth's curvature.





The little mystery of the current solar clear complexion is in fact unexplainable by any science we know. Heaven knows what others effects are occurring as a result of solar mysteries such as this. The page on Sol linked above contains interesting theories on solar variations, but robust, reliable, predictive computer models for either man-made or solar-related climate change? Ha.

Regarding the SICC syndrome and healthcare IT, physicians and other clinicians at some point must realize their profession is being encroached on by one of the most arrogant occupations known to mankind, the business IT specialty (a.k.a. management information systems or MIS). A belief that mastery of IT in business, whose own track record of failure, waste and excess is far from stellar, gives one the expertise and authority to declare one's self an expert in issues deeply affecting healthcare is about as arrogant as it gets.

Worse, the arrogance is coupled with ignorance about decades of research in social informatics (the study of the social impacts of computing), observational studies, biomedical informatics and computer science research, etc. (A worst case scenario has occurred to me that people who gravitate towards business IT may lack the interpersonal skills and insights into human behaviors necessary to understand the aforementioned domains and their real world importance.) In any case, this encroachment on medicine by the business IT industry is an unwarranted, unparalleled power, territory and profiteering intrusion, a form of cross-occupational piracy.

Further, the gargantuan leap of faith -- with an almost religious fervor -- from health IT as a facilitating tool for clinicians to a tool that will "revolutionize healthcare" in the face of massive, recurrent, serious practical problems is another example of SICC. The recent Joint Commission sentinel alert on HIT is the first formal, widespread acknowledgment of this issue by a healthcare regulatory agency with real clout anywhere in the world, as far as I know.

Those who have written on this issue of HIT risk when improperly designed and implemented have taken reputational hits as alarmists. I've been writing on these same points for at least the past decade, in fact, as have others who share my concerns. I wonder how many of those who critiqued the "alarmists" would after the JC Sentinel Alert now admit their brains were running on 3 cylinders, 80 octane and wishful thinking, while ours on 8 supercharged cylinders, 96 unleaded and reality based observation.

It is perhaps symptomatic of SICC that the recent Boeing 737 accident in Denver, even without loss of life, will be investigated far more thoroughly than all HIT failures combined.

I, for one, would welcome a cessation of claims that IT will "revolutionize" any field that depends primarily on cognition, such as biomedicine, and a return to more temperate attitudes instead of the almost bellicose grandiosity about HIT we see today. That is to say, that HIT - with proper contributions from the aforementioned specialties - will facilitate better health care, not "revolutionize" it.

I also wonder how many of those who critiqued these HIT concerns had a lot of money invested in the stock market's "sure bets" in recent years.

In a Wall Street Journal article about the recent history-making $50 billion+ Madoff financial fraud, "Former Mayor, Millions Lost, Tells How He Was Lulled" (Dec. 20, 2008, subscription required) I note the following:

[Former mayor of Fort Lee, N.J., Burt Ross,who once worked as a Wall St. stockbroker himself] says he remembers being puzzled about how Mr. Madoff was able to show positive returns, even in months when the stocks Mr. Madoff's fund owned were down.

He pushed such thoughts aside. "I thought, 'Who am I to question?'" Mr. Ross says. "This guy has a formula involving computerized trading....It's like Coke. We're not supposed to know the formula."

Mystery formula for computer trading, was it! SICC syndrome incarnate. I wonder just how many people lost their life's savings on similar delusions.

The syndrome has now spread to another critical agency, the FDA. At "Computer debacle: a Broken down process at the agency - or beyond?" I had written that:

I believe [the FDA's failures in building IT systems to track drug adverse events] represent more than a "broken down process at the agency." It's a "broken-down process" in the world of IT, i.e., the belief that IT is a homogeneous industry where expertise in business computing equips one to do all computing. I would be curious to know the backgrounds of those IT personnel who were involved in the leadership, planning and development of AERS II. I would bet most had a technical focus, and I would also bet none had expertise in medical informatics.

Perhaps one day the drug industry, including the FDA, will accept the IOM's recommendations on medical informatics.

Those recommendations involved acquiring and empowering specialized people, not a resort to purported cybernetic miracles.

What does the FDA choose to do instead?

Resort to cybernetic miracles.

In "New Drugs, Virtual Tests" (Wall Street Journal, Dec. 17, 2008) we learn that:

The U.S. Food and Drug Administration plans to use new computer technology to simulate how some drugs in development are supposed to work, helping researchers and regulators spot safety and effectiveness issues before late-stage tests on humans are completed.

Entelos Inc., a Foster City, Calif., company that has developed the technology, said it will enable researchers to obtain computer-generated test results in a matter of days or weeks, compared with years required for most major clinical trials. Far more "simulated patients" also can be tested than in conventional human trials.

Under an agreement with the FDA that Entelos announced Tuesday, three drugs now being studied for heart-related conditions in large human trials will be tested by the simulation technology. Neither Entelos nor the FDA would disclose which drugs will be involved or which companies are developing them. The value of the contract also isn't being disclosed.

... "What this study is about is trying to anticipate bad scenarios before they occur," said Robert Powell, associate director in the office of translational sciences in the FDA's Center for Drug Evaluation and Research.

So, instead of reliance on building better capacity to sample data from the real world, highly speculative and (as far as I know) untested-by-clinical-trials "cybernetic miracle" simulations will be used to evaluate early drug candidates. (Disclaimer: I have no knowledge of or connections to this or any other company involved in such work. I discovered this issue as a result of reading the WSJ.)

Bad enough that insufficiently powered studies and even seemingly robust studies in domains with small effect sizes, financial interests and prejudices, and other factors may be misleading (see "Why Most Published Research Findings Are False", John P. A. Ioannidis, PLoS medicine, 2005 August; 2(8): e124).

Now computer models and in silico simulations that purport to model actual, immensely complex and poorly understood biologic and environmental factors sufficiently well to enable real world predictions will be used to influence clinical decisions. The same clinical decisions that might best made empirically in real biological systems - e.g., via in vitro and in vivo methods. That is a fantastic leap of faith. To the moon in a hot air balloon?

I note the Dec. 17 WSJ article does state that:

Mr. Powell [Robert Powell, associate director in the office of translational sciences in the FDA's Center for Drug Evaluation and Research] said regulators "wouldn't make a decision to kill a drug based on a simulation," but the findings could be used in discussions with drug companies to influence decisions such as the design of clinical trials. Eventually such information also could affect prescribing information included in drug labels.

Knowing the narrow minded, profit-motivated, often conflicted boneheads who have invested our futures in the likes of Mr. Madoff's Ponzi scheme, Fannie Mae and the like, hedge funds, profoundly arcane bundles of financial toilet paper known as "securities" based on the former sources, etc., I have very little confidence that regulators (and worse, non-scientist managers overseeing biomedical research budgets and portfolios such as here) will not use these "cybernetic miracles" in making decisions -- both pro and con -- on new drug entities and other matters.

I propose a new term, The "cyber-industrial complex" to describe these spreading SICC scenarios.

Snake oil salesmen of the 19th century had little on today's Cyber-Übermenschen.

-- SS

The Perils of Contract Research Organizations Out-Sourcing Clinical Trials

The St Petersberg Times last week published an investigative series on the out-sourcing of clinical trials to India, which raised important questions about the quality of data they produce.

Mary K. Pendergast, a former FDA deputy commissioner, said identifying a dangerous product is difficult enough. It's considerably trickier to find fraudulent clinical trial data, which could lead to the approval of dangerous drugs years later.

'It's much more time-consuming and extraordinarily tedious,' said Pendergast, who plowed through such data when she was prosecuting doctors doing drug studies in the United States. 'It's especially hard if the trial is taking place in a different country.'

Particularly when that country has a reputation for cutting corners.

The article quoted a number of people familiar with the clinical trials scene in India who suggested that corners indeed were being cut.

Amar Jasani:

In the burgeoning clinical trial business, says Amar Jesani, a doctor and medical ethicist in Mumbai, every layer of oversight is compromised by cash, and independent monitoring is nonexistent. He has resigned from supposedly independent ethics committees that rubber-stamp drug companies' proposals and overrule any objections.

Dr Arun Bhatt:

Dr. Arun Bhatt is president of Clininvent, a contract research organization in Mumbai that is running 11 trials involving 1,000 patients. He worries that Indian doctors ignore patients' reactions to experimental medicines, missing critical clues about a drug's safety.

'Most sites are not used to recognizing serious adverse events, so they are underreported,' he said with an attitude of resignation. 'Either they don't recognize, don't realize or are afraid to report this information.'

Dr Nandini Kuman:

Dr. Nandini Kumar retired in June as deputy director general of the Indian Council of Medical Research, the equivalent of the U.S. National Institutes of Health. She now works as a consultant for the agency in New Delhi, teaching doctors how to run ethical trials. Kumar is stunned by their ignorance of internationally recognized standards for conducting drug studies.

Asked what aspect of good clinical practice most surprised her students, the gray-haired, sari-clad Kumar snapped, 'Everything.'

'There are efforts to put rules in place, but at the same time there are people who just want to get the extra dollars or perks like trips abroad from doing drug trials....'

Dr S P Kalantri:

Dr. S.P. Kalantri has conducted trials for global pharma at the government hospital in Sevagram, a small town in central India. But he said he has pulled back from doing the studies.

'It's difficult to explain the complexities of trials to study participants,' Kalantri said of the hospital's mostly poor, illiterate patients. 'I think many investigators tend to take their patients for a ride. And there's an abysmal lack of know-how about clinical research among investigators.'

Dr C M Gulhati:

Dr. C.M. Gulhati, editor of an Indian medical journal, Monthly Index of Medical Specialties, said authorities cannot cope with the tsunami of trials.

'India's drugs controller general's office is both understaffed and incompetent,' he said, citing a case where the agency claimed it reviewed an 800-page trial protocol in just five days. 'How is that even possible?'

Gulhati, who fights unbridled drug testing from a dim and cluttered office above a busy Delhi shopping plaza, reeled off a litany of troubled trials:

In 2003 in Hyderabad, an unregistered study of a heart attack drug that resulted in six deaths.

In 2004 in Delhi, a first-in-human trial of a new suturing device on 13 patients without regulators' approval.

Last year, India's decision to become the only nation to allow domestic drug maker Sun Pharmaceutical Industries to market the anticancer drug Letrozole for infertility in women despite the drug's originator, Novartis, warning that it may cause fetal harm and should be used only in postmenopausal women.

And in October in Bangalore, the death of a baby during the testing of a new Wyeth vaccine.

But doing trials in India, and other less-developed countries is far cheaper and faster than doing them in developed countries. Contract research organizations (CROs) have figured this out.

Contract research organizations keep tabs on trials with regular audits. Site management organizations put an extra set of eyes in the doctor's office. Both entities dangle promises of FDA-ready studies in half the time, at 30 to 60 percent the cost in the United States. The secret? Cheap help and fast patient recruiting.

Quintiles, the world's largest contract research organization, boasts of enrolling 50 patients with diabetes in one month in India and 204 infants for a vaccine study in three days, far faster than possible in the States. In a brochure, Quintiles sums up India's allure: 'It's practically a paradise for conducting clinical trials.'

In fact, on Quintiles current web-site is an offer related to Phase II and III trials for

Accelerated Start-up and Recruitment worldwide, through a global network of investigators that includes many in nontraditional regions with large clusters of patients and few competing trials.

We have noted before that the limited oversight of CROs, which are responsible for an increasing proportion of industry-funded trials of drugs and devices, makes possible poor quality work, hence unreliable data (see most recent post here and links backward). The threat to data integrity from too hasty, too profit driven clinical research done by CROs is the third of the three major threats to the integrity of the clinical research data base. The other two, which are discussed frequently on Health Care Renewal, are suppression of clinical research, and manipulation of research design, implementation, and analysis and dissemination.

In combination, they threaten the well-intentioned and idealistic goals of evidence-based medicine, to improve clinical care by basing decisions not only on knowledge of biology and the values of patients, but on critical review of the best available clinical evidence. But given that we have become increasingly skeptical, if not outright distrustful of the integrity of the evidence, the alternative ways of making clinical decisions, basing them on theoretical (but possibly incorrect) knowledge of biology, on authority, or on tradition to me are much worse.

Doctors and patients should be vehement about the need for carefully performed clinical trials free of manipulation meant to benefit vested interests, reported honestly even if their results offend vested interests.

Another Misuse of EBM

We agree with Roy Poses' comment on the recent JAMA article about EBM, particularly regarding some of its unfortunate "misuses." In the article that stands as the defining credo of Health Care Renewal, Roy wrote:

Most physicians believe that medicine should be based on science. Evidence based medicine, (EBM) ‘‘the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients’’ [74], is a refinement of this view. Meanwhile, the scientific basis of medicine is under increasingly severe attack.

We'd like to take this opportunity to identify a misuse of EBM that, ironically, contributes to the attack on the scientific basis of medicine, and that authors Montori and Guyatt didn't consider--probably because they are unaware of it. We explain it in the following letter, submitted to JAMA in response to their article. We discuss it at more length on the other blog to which we contribute, Science-Based Medicine, referenced from the letter:

To the editor:

In their recent article, “Progress in Evidence-Based Medicine,” Drs. Montori and Guyatt include important caveats about misuses of EBM. They mention trials funded by industry. They list several, documented problems with such trials, and correctly warn that these can result in erroneous interpretations by “unsophisticated users of the medical literature.” They correctly worry about “abandoning appropriate skepticism.”

There is a related misuse of EBM that leads to erroneous interpretations even by sophisticated authors, and that calls attention to systematic problems in EBM: trials of highly implausible hypotheses. Thus, regarding the homeopathic preparation Oscillococcinum, the Cochrane Collaboration writes:

Though promising, the data were not strong enough to make a general recommendation to use Oscillococcinum for first-line treatment of influenza and influenza-like syndromes. Further research is warranted…[1]

The data, however, are not promising, and further research is not warranted. The reason is that for highly implausible treatments, existing knowledge easily trumps modestly “positive” trial data. In the case of homeopathy, each of its tenets has been more than adequately disproved, and its claim that the potency of a “remedy” increases with each dilution of the original substance, continuing well past the point at which not a molecule of that substance remains in the preparation, contradicts physical reality.[2]

Such considerations reveal at least two, related problems with the evidence of EBM as it pertains to clinical trials. The first is explicit: by relegating “physiology, bench research or ‘first principles’” to Level 5 of its “Levels of Evidence” hierarchy, EBM fails to acknowledge that consistency with firmly established knowledge is a necessary, even if insufficient, basis for accepting a hypothetical treatment as effective.[2]

The second problem is part of the culture, if not the letter of EBM: by eschewing Bayesian in favor of “frequentist” statistics, its practitioners can excuse themselves from justifying estimates of prior probability, and erroneously conclude that trial data tell us more about reality than they do.[3-5]

In January, 2008, several colleagues began the blog Science-Based Medicine, referenced below.* The name, which could just as well have been “knowledge-based medicine,” is a frank recognition of the EBM weaknesses described above. Because of our interests, Science-Based Medicine’s content is predominantly, though not entirely, concerned with implausible health claims. Its larger message, however, is that these claims call attention to fundamental ways in which EBM can be improved, such as to justify its own claim to being an arbiter of real evidence.

Kimball C. Atwood, IV

Wallace I. Sampson

10/19/2008

* Steven Novella, David Gorski, Harriet Hall, Wallace Sampson, Kimball Atwood

[1] Vickers A, Smith C. Homoeopathic Oscillococcinum for preventing and treating influenza and influenza-like syndromes. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001957. DOI: 10.1002/14651858.CD001957.pub3.

[2] Atwood K. Homeopathy and Evidence-Based Medicine: Back to the Future Part V. Science-Based Medicine 2008 (Feb. 8). http://www.sciencebasedmedicine.org/?p=42. Accessed October 19, 2008

[3] Atwood K. Prior Probability: the Dirty Little Secret of “Evidence-Based Alternative Medicine.” Science-Based Medicine 2008 (Feb. 15). http://www.sciencebasedmedicine.org/?p=48. Accessed October 19, 2008

[4] Goodman SN. Toward evidence-based medical statistics. 1: The P value fallacy. Ann Intern Med. 1999;130:995-1004.

[5] Goodman SN. Toward evidence-based medical statistics. 2: The Bayes factor. Ann Intern Med. 1999;130:1005-13.

Dr Marcia Angell on Reforming a "Broken System" of Clinical Research

This week's Journal of the American Medical Association (3 September, the paper version of which seems to arrive early at my house) is notable for having three commentaries on relationships among physicians, academic medicine, and industry. One, by David Rothman and Susan Chimonas, seemed rather optimistic, while two, by Dr Arnold Relman and by Dr Marcia Angell, were quite dark.

The latter [Angell M. Industry-sponsored clinical research: a broken system. JAMA 2008; 300: 1069-1071. Link here when available] should be required reading for anyone who worries about the issues we raise on Health Care Renewal. Dr Angell provided an excellent summary of how commercial "sponsors" have come to dominate clinical research, and thus ensure that the resulting studies favor their vested interests. My only criticism of her summary of the data was that it may actually have been too optimistic. For example, Dr Angell focused almost exclusively on pharmaceutical companies' influence on research, while the problem is even larger. Biotechnology companies, device manufacturers, and multiple miscellaneous commercial suppliers of health care goods and services also may influence research. Dr Angell's admittedly extensive list of the kinds of relationships among researchers and industry (grant support, paid consulting, service on speakers' bureaus and advisory panels, and stock ownership) was incomplete, leaving out, for example, the even more acute conflicts of interest generated by service on companies' boards of directors and service as companies' officers.

But those are quibbles. Most striking was Dr Angell's summary:

Looking at this picture altogether, it would be naive to conclude that bias is only a matter of a few isolated instances. It permeates the entire system. Physicians can no longer rely on the medical literature for valid and reliable information. This is the conclusion I reluctantly reached toward the end of my 2 decades as an editor of the New England Journal of Medicine, and it has been reinforced in subsequent years. Clinicians just do not know anymore how safe and effective prescription drugs really are, but these products are probably nowhere near as good as the published literature indicates.

I am afraid I must concur, and also concur with her summary of the effects of the substitution for valid clinical research of pseudo-evidence favoring the vested interests of "research" sponsors:

Physicians learn to practice a very drug-intensive style of medicine.

Physicians are also led to believe that the newest, most expensive brand-name drugs are superior to older drugs or generics, even though there is seldom any evidence to the effect because sponsors do not usually compare their drugs with old drugs at equivalent doses.

Physicians learn to use drugs for off-label uses without good evidence of effectiveness.

Keep in mind that the same considerations apply to devices, so that physicians also learn to practice a test- and procedure-intensive style of medicine; are led to believe that the newest tests, devices, and procedures are superior to older ones without any evidence comparing the new to the old; and physicians learn to extend the use of tests, devices, and procedures far beyond what the evidence would support.

In addition, I agree with Dr Angell's advocacy of an independent body that would administer all clinical trials of drugs. Dr Angell suggested it be an Institute within the NIH. I think it might be possible to form a not-for-profit body that would be independent of government that would do the same thing. Furthermore, that body, or another in parallel should also administer all clinical trials of diagnostic tests, devices and procedures, for analogous reasons.

Finally, Dr Angell urged academic investigators and their institutions to "be at the forefront of efforts to reform the system of clinical research and not leave it to the government and legal profession." However, as Dr Angell previously noted, a majority of medical school faculty have financial ties to drug, device, biotechnology and other health care companies, as do a majority of department chairs. As we have noted, some top leaders of academic medicine serve also as top leaders of for-profit health care corporations (see this post), and other corporations whose products have profound effects on health, even tobacco companies (see this post). Many academic leaders make a small fortune working on the side for such companies. It may be too much to expect that such leaders would be at all interested in reforming a system that has so effectively lined their pockets. For better or worse, we may need a wholesale change in the leadership of academic organizations before we can expect any real cooperation from them in transforming clinical research from being mainly a marketing exercise to once more being real clinical science.

ADDENDUM (5 September, 2008) - See also comments by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog.

Response from author of "The ADVANTAGE Seeding Trial"

In response to my earlier post "Merck scientific debate hits bottom" I received the following from one of the authors of the VIOXX seeding trial paper The ADVANTAGE Seeding Trial: A Review Of Internal Documents, Ann Intern Med 2008", Dr. David Egilman, MD, MPH.

I posted Dr. Egilman's opinions below at his request. My own thoughts follow.

Dr. Egilman also posted numerous documents to and from Merck's lawyer at this link. (The tone of some of those documents towards Dr. Egilman is particularly disturbing, such as the one here.)

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From: David Egilman, MD, MPH
To: Healthcare Renewal

I am one of the authors of the "Seeding" paper.

Merck executive Dr. Jonathan M. Edelman, Executive director, Global Center for Scientific Affairs wrote:

There's no doubt that the ADVANTAGE clinical trial had a legitimate scientific purpose. That purpose was to assess the gastrointestinal tolerability of VIOXX compared to naproxen – a commonly used arthritis medicine with known tolerability problems – in the treatment of patients with osteoarthritis in a primary care setting, and for the first time allowed patients taking concomitant aspirin to participate.

Dr. Edelman's claim that ADVANTAGE was the first trial that permitted aspirin use with Vioxx is incorrect. Study 058, which was part of Merck's application for new drug approval submitted in November 1998, permitted the use of up to 325 mg of aspirin per day. ADVANTAGE only permitted up to 100 mg per day. Study 058 was a 30 week trial. ADVANTAGE was only a 12 week trial. Study 058 involved patients older than 80, comparing Vioxx to namebutone (another NSAID) and was completed in April 1998, about 10 months before ADVANTAGE enrolled a single patient. Study 078, the ghost-written Alzheimer’s trial also permitted aspirin, began in April 1998 and was scheduled to be completed by April 2000 before the end of the ADVANTAGE trial. More patients took low dose aspirin in the Vigor trial than the Advantage trial.

Further, ADVANTAGE was not designed to test the effect of aspirin on anything. Although aspirin was permitted, the examination of aspirin effects was not included as part of the study objective which Merck described: "[t]o assess the tolerability of rofecoxib (VIOXX) compared with naproxen for treatment of osteoarthritis." On the other hand, Merck Study 136 was designed to test the effects of concomitant aspirin and NSAID use. This study revealed that Vioxx offered no GI protection to low dose aspirin users who constituted the majority of potential Vioxx users.

By November 1998, when Merck sought FDA approval for an OA indication and three months before the ADVANTAGE trial enrolled any patients, Merck had already informed the FDA it had sufficient studies to prove Vioxx was efficacious for osteoarthritis patients. Merck's osteoarthritis trials (that it used to get FDA approval for use of VIOXX in osteoarthritis patients) had compared Vioxx to 3 other NSAIDS. The VIGOR trial, which tested Vioxx and naproxen in rheumatoid arthritis patients, started at the same time as ADAVANTAGE and used twice the dose of Vioxx than was used in ADVANTAGE. VIGOR was, therefore, a more valid scientific trial to determine relative safety of the two drugs.

This request for and subsequent approval meant that Merck could claim VIOXX was as effective for pain as naproxen. Beginning long before the Advantage trial Merck claimed Vioxx was safer than all NSIADS including naproxen.

While ADVANTAGE was the first study that compared Vioxx to naproxen in OA patients, Merck had completed trials comparing the two drugs in other pain patients.

It is for these reasons that the President of Merck Research Laboratories (MRL) Dr. Scolnick characterized ADVANTAGE as "intellectually redundant."

Merck wrote:

ADVANTAGE was a double-blind, randomized, controlled clinical trial with a legitimate scientific purpose designed to answer previously unanswered questions about the use of VIOXX in osteoarthritis in a primary care setting. It was not a seeding study.

Merck’s personnel called it a seeding trial internally but in an apparent effort to hide its true purpose wrote:

“I eliminated the reference to seeding. It may be a seeding study, but let’s not call it that in our internal documents.”

Merck apparently tried to make it look like a typical science-based clinical trial to mislead IRBs and journals. All seeding trials make some claim to some usually trivial scientific purpose. For example the question of whether or not Vioxx works better on people as a function of height is a scientific question. It is of course a trivial question. In this case Merck had studies that compared Vioxx to naproxen for pain control before the Advantage trial had started. Merck also had a larger trial that tested GI toxicity.

Merck wrote:

ADVANTAGE was important because although the earlier VIOXX clinical trial program provided extensive data on efficacy and safety, it did not include naproxen as a comparison Medication.

This is not correct. Merck had a study that compared Vioxx to naproxen for pain control before the Advantage trial started. This was presented to the FDA in the original New Drug Application and was published in October 1999.

Merck wrote:

The ADVANTAGE clinical trial was designed, conducted, analyzed, interpreted and published by the scientific department of Merck's U.S. Human Health (USHH) organization, Clinical Development (CDP), in conjunction with participating investigators. CDP was part of the Medical and Scientific Affairs department of USHH and was separate from the marketing department within USHH.

A more complete picture is:

USHH was the marketing division of Merck. It included sub-divisions including sales, marketing and a medical/scientific group called CDP. CDP performed “medical” studies that could be used by marketing to increase product sales. These studies were only conducted if favorable results could increase sales. They were not done to obtain new indications for drug use and Merck did not publish or provide the FDA with some of these studies (example 106).

Mr. David Anstice, a marketing executive with no apparent scientific training or background was the President of Merck's USHH division. In contrast Dr. Edward Scolnick, a physician/scientist of international renown, was the President of Merck’s research division which was called Merck Research Laboratories. Mr. Anstice the person ultimately responsible for the Advantage trial testified:

Q. I understand that. All I'm saying is, this is the study [Advantage trial] that was initiated and conducted by marketing, right?
A. Yes, by doctors in marketing.

A picture being worth a 1000 words I provide the Merck graphic for the organization of the Advantage trial:



Here is the power point description of marketing’s role in the Advantage trial:



While the marketing division of USHH set the study “objectives” CDP was in charge of the technical aspects of study implementation.

Further proof that ADVANTAGE served little scientific purpose is the fact that Merck had already claimed that Vioxx was safer than and as effective as all NSAIDS including naproxen prior to the initiation of the ADVANTAGE.

Merck did not rely on any ADVANTAGE results to make any claim about Vioxx efficacy or safety to the FDA. The lack of scientific purpose behind ADVANTAGE is demonstrated by the fact that Merck had withheld the ADVANTAGE results from its application to the FDA that requested a label change that would allow them to claim Vioxx was safer than naproxen. Merck only produced the results after the FDA made numerous oral and written requests for the safety data discovered during the trial.

Merck claims Advantage produced important scientific information:

In the end, ADVANTAGE showed a different gastrointestinal profile between VIOXX and naproxen that was unaffected by concomitant use of aspirin. This was an important medical result for physicians. In addition to measuring the GI tolerability of VIOXX, investigators also monitored patients for adverse events, which were required to be submitted to the FDA. Therefore, in ADVANTAGE, Merck was further evaluating any potential risks of VIOXX.

In fact the trial that Merck performed to test the effect of concomitant aspirin and Vioxx use (136) showed that aspirin use thwarted Vioxx’s GI advantage. (Gastroenterology. 2004 Aug;127(2):395-402.) The conclusion Merck reached based on the Advantage result was wrong precisely because Advantage was not designed to test this question. This conclusion was based on data mining.

Merck wrote:

We also want to underscore that the scientific purpose of ADVANTAGE was properly disclosed to physicians-investigators, participants, and institutional review boards, and Merck's business interests were clearly understood.

Merck never disclosed the marketing purpose of the trial which included the fact that Marketing “set objectives.”

Merck accuses the authors of "bias.”

In this open letter to the editors of The Annals of Internal Medicine, Merck would like to put in perspective the latest article by four authors who served as paid consultants to plaintiffs' lawyers in the VIOXX litigation against Merck. We are troubled by the biased article, which contains numerous inaccuracies, and wonder about the motivation behind this attack on Merck's scientific excellence and integrity.

Merck writes that the authors were “plaintiff witnesses” and “cherry picked” documents. As far as I know, all litigation ended about a year ago. None of the authors were paid on a contingency basis, the authors received no compensation from plaintiffs to work on the papers we have written and none of the authors are working on any Vioxx litigation at this time.

If money motivation equates to bias then it is Merck and its representatives who suffer from this problem. The same cannot be said of Merck or its representatives because while the authors have nothing to gain Merck’s future earnings depend, in some measure, on its reputation for honesty.

Merck does not explain how any theoretical bias impacted on the paper. They have not come forward with contradictory documents or testimony.

The authors agree that all the documents should be made public so readers can decide for themselves if we “cherry picked.” Merck, and Merck alone, continues to block the release of the documents.

Merck would not allow us to cite documents that showed that Advantage investigators were accused of fraud and at least one was convicted. Some of this data was deleted from the published paper but readers and editors were never informed of these problems.

It should be noted that eight Vioxx patients had heart attacks during the ADVANTAGE trial compared to one patient on naproxen. Merck never informed any of these patient volunteers of the cardiovascular risks of Vioxx before or after the trial although the informed consent stated that Merck would pay for treatment of drug related side effects. Unfortunately for some, this would have been funeral costs.

Merck wrote:

It is unfortunate that the authors and journal editors chose not to contact Merck before finalizing these publications. Had any of these individuals contacted Merck, factual errors could have been avoided.

I contacted Merck's main trial lawyer Ted Mayer and provided Merck an opportunity to comment on another paper related to the Advantage trial before it was submitted for publication. I did not send a pre-publication copy to plaintiff lawyers. Mr. Mayer provided comments and i included his comments in the final version.

Merck then complained about my contact to Mr. Mayer to Judge Higbee and requested that she sanction me for contacting their lawyer and then insisted that I make no further contact with them.

-- David Egilman

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My own thoughts on all of this are as follows:

The lessons of the Annals article are clear. The scientific community and the public are simply fed up with cavalier practices in the biomedical industry. While the article may affect remaining VIOXX litigation as pointed out here, it also should have an necessary "cleansing effect" on drug R&D.

It was not clinicians and scientists outside the industry who earned it the public's animosity. It was, and continues to be, the industry itself. As Roy Poses observed, there cannot be evidence based medicine if the evidence is distorted by commercial zealotry. I think the public recognizes this.

Further, marketing personnel have no place in pre-approval, pre-marketing scientific studies such as clinical trials. If they have a scientific role, it is perhaps in post-marketing studies, especially post-marketing surveillance for adverse effects. The latter is a function the pharma industry performs poorly.

Even in that latter domain, there must be honesty and transparency, characteristics with which the biases of marketing and its leaders (e.g., towards maximizing sales) may interfere.

Merck's responses to this new Annals article seem the antithesis of science. Instead, the responses appear to be right out of the political and legal warfare playbook (where logical argument prevails - except when presenting logical fallacy is to the advantage of the protagonists) ...

The response has been this:

• ignore the arguments and evidence [in this case, emails and documents from Merck itself],
  
• issue an ad hominem attack,
  
• issue slogans ("litigation in the name of science"),
  
• present a Red Herring as a distraction,
  
• issue accusations of bias,
  
• issue accusations of cherry picking,
  
• issue accusations of the authors taking evidence "out of context", etc.

and finally:

• produce no context or new evidence of your own, hoping the above tactics will make that unnecessary.
  

All that's seemingly missing are ... puppets.

Merck seems to expect the "courtesy" of being allowed to be a participant in any issues written about its conduct, as if the authors of this paper are its employees who under employment policies must permit any pubs they produce to be reviewed internally for approval. I believe the company's executives forget that their authority ends at the front gate.

It is also an odd and even arrogant request, especially considering the way the authors' evidence (Merck's own emails and documents) was essentially ignored in the responses, and the insinuations promulgated against the authors as serving plaintiff's lawyers -- which also implies that scientific integrity and the interest of patients is not their motivation.

As I mentioned in my earlier post, this is classic ad hominem and is insulting to authors in my opinion, as well as insulting to any clinician or scientist. Why would anyone want to provide a company that acts in this manner the courtesy of pre-publication involvement in investigative journalism?

Another issue I find interesting is noted in the limitations section of the paper where it is stated that:

... we did not identify, despite an exhaustive and systematic search strategy, documents detailing discussions between the marketing and research divisions, nor could we identify documents describing contracts between Merck and collaborating companies.

As well as the Annals editor's obervations that:

... despite the large body of documents searched by the authors, they discovered few details about exactly how Merck's marketing division carried out ADVANTAGE.

This is surprising. From an information science standpoint, it would not be unreasonable to believe there might be more related to this trial of a major drug in emails or powerpoints or other documents. This document sparsity could mean that the documents did not exist, but it also raises a speculative question about the document corpus produced in Discovery.

Could "inconvenient documents" have selectively been eliminated from the corpus of documents before it was released, and therefore not be present in the corpus of documents the authors searched? Could the documents the authors did find represent ones that were "missed" by some weeding out effort?

Finally, I believe the entire tenor of Merck's responses - ignoring evidence, stating the trial was "published in a peer reviewed journal" as a Red Herring and a justification of its legitimacy while ignoring Sox & Rennie's (the Annals editors) accompanying commentary Seeding Trials: Just Say "No" , belitting the authors, etc. - is very disturbing.

From "Seeding Trials: Just Say No":

No one told Annals the true purpose of ADVANTAGE. We learned about it when we received a letter to the editor from Dr. David Egilman, who was a consultant to the plaintiffs' attorneys in the civil suits against Merck. He had access to publicly accessible trial documents, which included Merck employees' e-mail messages that disclosed the true intent of the ADVANTAGE trial ... The article provides clear evidence that the intent of ADVANTAGE was to increase prescriptions of Vioxx (the study outcome of greatest interest to Merck seems to have been Vioxx prescribing rates) ... The documents do tell us that deception is the key to a successful seeding trial.

When I review NIH grant applications, if I suspect deception I will mention it to the study section leaders, and I can assure that if deception is verified higher up the chain, that application will not get funded (at the very least). I can also assure that legitimate medical journals do not willingly publish studies involving deception.

Merck's responses to the Annals article seem to represent a belief that the public (laypeople and physicians) are stupid and gullible.

This is not science, and is not a path to a return to the corporate greatness and respect that Merck once enjoyed and had earned.

Finally, a Red Herring of my own:



-- SS