Promoting Amphetamines for Over-Eating - What Could Possibly Go Wrong?

Every day seems to bring the latest breathlessly touted innovation in modern health care.  The endless hawking of new health care wonders is beginning to inspire some skepticism, but maybe not enough.

The Promotion of Vyvanse for Binge Eating Disorder


For example, at the end of January, 2015, reports of the first ever drug therapy for binge eating disorder appeared.  For example, see Jonathan Rockoff writing in the Wall Street Journal

Shire PLC’s drug Vyvanse became the first drug approved for sale in the U.S. to treat some of the estimated 2.8 million adults who have a binge-eating disorder.

Rather ominously, the article described this disorder thus,

Patients regularly eat more food than they need, often when they aren’t hungry and until they feel uncomfortably full, the FDA said. The condition can lead to weight gain, obesity and related health problems.

Furthermore, it appears to be common,

An estimated 2.8 million adults in the U.S. are binge eaters, two times more than those who have the eating disorders anorexia and bulimia combined, according to Shire.

However, now there is a pharmaceutical solution!

In two pivotal studies, binge eating episodes declined to an average of one day a week among patients taking Vyvanse capsules for 12 weeks, down from an average of five days a week, Phil Vickers, Shire’s head of research and development, said in an interview.

'The approval of Vyvanse provides physicians and patients with an effective option to help curb episodes of binge eating,' Mitchell Mathis, director of the FDA’s division of psychiatry drug products, said in a statement.

Because the disease is common, that may mean a lot of money for Shire

For Shire, the approval could eventually add 'several hundred million' dollars in sales, and help the company reach its goal of $10 billion in yearly sales by 2020, said Flemming Ornskov, the company’s chief executive. Vyvanse is the company’s top-selling drug, notching $1.1 billion of the company’s $4.3 billion in total sales during the first nine months of last year.

The only hitch is that all those long suffering victims of binge eating disorder have to be found, and presented with this wonderful new alternative:

One challenge: increasing the numbers of patients diagnosed as binge eaters. Shire estimates that just 3% of Americans with the disease have been diagnosed under the mental-disorder criteria, Dr. Ornskov said.

Brief coverage of the initial approval of Vyvanse appeared in the NY Times. Bloomberg also weighed in, adding to the urgency by underlining how seriously the FDA had handled this:

'Binge eating can cause serious health problems and difficulties with work, home and social life,' Mitchell Mathis, director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research, said in a statement.

The FDA gave Vyvanse priority review, a designation for drugs with promise to 'provide a significant improvement over available therapies,' the agency said.

Among the major media covering the rollout, only Reuters noted a potential fly in the ointment in this  article,

Vyvanse is an amphetamine which, like other amphetamines, carries the potential for abuse and addiction. They also have been associated with increase blood press sure and heart rate, sudden death, stroke, heart attack, insomnia and psychiatric side effects such as hallucinations and mania.

What Really is the Clinical Evidence Supporting Vyvanse for Binge Eating Disorder?


So Vyvanse is actually lisdexamfetamine, and having been a child when the slogan "speed kills" referred to methamphetamine, not driving automobiles fast,  I thought it might be worth looking into the evidence that this somewhat new amphetamine, a relative of that infamous "speed," was now deemed a wondrous treatment for eating too much.

In particular, a recent article in JAMA Psychiatry reported results of one of the two trials Shire did of Vyvanse for binge eating disorder.(1)  The study by McElroy et al randomized patients with binge eating disorder to one of four groups, to receive the drug at dosages of 30, 50, or 70 mg/ day or placebo.  The investigators followed patients for 11 weeks.  The main outcome variable was the number of binge eating days per week reported by the patients.

Patients in all groups were binge eating during approximately 4.5 days/ week at the beginning of the study.  At 11 weeks, the average number of binge eating days/ week declined in all groups, dropping 3.3 days/ week for the placebo group, 3.5 for the 30 mg group, 4.1 for the 50 mg group, and 4.1 for the 70 mg group.  Thus, by this measure, the difference between patients given placebo versus patients given maximum dosage of the drug was an average decrease of 0.8 binge eating days a week.  That does not seem like a very big effect size, or in other words, it seems that the drug had only a small effect on binge eating compared to placebo.

That impression was reinforced by looking at some other study outcomes.  The average numbers of binge eating episodes per week at 11 weeks were 1.1 for placebo, 1.2 for the 30 mg group, 0.5 for the 50 mg group, and 0.5 for the 70 mg group.  Again, patients given the maximum dose of the drug had only a slightly smaller number of binge eating episodes than those given placebo, reinforcing the impression that the drug is not very effective.

A graph of binge eating days/ week measured over time makes things clearer.  It showed that all groups, including patients given placebo, markedly reduced their reported binge eating over the 11 week period.  Since the study did not allow any patients to get any other treatment for binge eating other than placebo or the study drug, this again suggests that the drug was not much better than placebo.  Further, the apparent reduction in binge eating by patients given placebo suggests a number of possibilities:
-  Just paying more attention to patients by putting them in a trial could lead to marked decreases in binge eating, or
-  People in binge eating trials could tend to report they are improving, whatever treatment they get, or
-  Binge eating may not be a stable phenomenon, and its intensity could vary over time, or
-  It may be difficult to make a reliable diagnosis of binge eating disorder.

In summary, at best, the trial showed that Vyvanse only caused small reductions in binge eating, and that binge eating may decrease spontaneously, or at least when patients are given more attention or scrutiny.  Thus, even putting the best face on the evidence from a trial done by the maker of Vyvanse does not greatly support the benefits of this drug.

In addition, according to evidence-based medicine advocates, the benefits of a treatment must be balanced with its potential harms.  In this study, about 5% of patients given any dosage of Vyvanse had to discontinue its use because of adverse effects.  3/196 patients initially randomized to Vyvanse had serious adverse effects, and one patient died, apparently of an amphetamine overdose.  Oddly, the article declared that the one death, due to methamphetamine overdose, was thought by a study investigator not to be related to treatment with another amphetamine, lisdexamfetamine.  That makes little sense, given that in a randomized controlled trial, the presumption is that differences in groups given different treatments were caused by these treatments.

In addition, patients given Vyvanse (lisdexamfetamine) had higher rates of various symptoms that are commonly associated with amphetamines, including insomnia, nausea, constipation or diarrhea, anxiety, feeling jittery, palpitations, and sleep disorder.

This suggests that the relatively small apparent benefits of the drug must be weighed against rates of adverse events that are not negligible, especially given the short amounts of time patients were followed. So this study did not show that the benefits of Vyvanse clearly outweigh its harms.

Finally, there were many problems with this trial that further cloud its validity, or applicability to patients (generalizability):
-  Patients were diagnosed using DSM-4 criteria, rather than the new DSM-5 criteria
-  Patients with any other psychiatric illness were excluded, limiting the applicability of its results.
-  Patients with an ostensibly chronic disease were only followed for 11 weeks, so the effects of this drug given for the treatment duration that might be needed to treat a chronic problem are unknown
-  The loss to follow-up rate, about 5% for treated patients decreases precision of the results given the relatively small effect size
-  The study was done at a large number of sites, initially 32, given the size of the patient population (starting at 260), and one site was dropped because of an "investigation," raising questions about the quality of the study implementation and data collection

So, in my humble opinion, even this Shire sponsored study, which was responsible for half the evidence used to support the approval of Vyvanse for binge eating disorder, provided only weak and questionable evidence that the benefits of the drug outweigh its harms in the short term, and no evidence about long-term use of the drug.  

However, no media coverage so far has addressed the weakness of the clinical evidence supporting the use of Vyvanse.  I have yet to see any other attempts at a rigorous, skeptical review of the clinical trial evidence supporting Vyvanse in this application.  Instead, the media reporting so far seems to have accepted the word of the manufacturer's executives, who obviously have an interest in promoting the drug.  (See the WSJ article above which just repeats assertions by a Shire executive.

Why So Much Enthusiasm about a Type of Drug with Such a Bleak Past?

This lack of skepticism was particularly baffling given the nature of the drug that was being promoted, and its long and unfortunate history.  As I noted, the amphetamines have proved to be dangerous drugs when abused, and they are abused frequently.

The beginnings of widespread amphetamine abuse grew out of previous efforts to promote these drugs for obesity (which can be, of course, a consequence of eating too much).  As documented by Cohen and colleagues(2),

The discovery of amphetamine energized the weight loss industry. Introduced as the Benzedrine inhaler in 1932 by venerable Philadelphia firm Smith, Kline, and French, the American Medical Association (AMA) soon recognized Benzedrine as a  treatment of narcolepsy, postencephaletic Parkinsonism, and certain depressive psychopathic conditions. Several clinical studies first published in the late 1930s demonstrated amphetamine’s anorectic effect. The Clark & Clark Company of Camden, NJ, established in 1941, was one of the earliest manufacturers of diet pills combining amphetamine sulfate and thyroid along with phenobarbital, aloin, and atropine sulfate to counteract untoward effects.

These rainbow pills were used with great enthusiasm, however,

adverse events, including deaths, began to be reported to the FDA as early as the 1940s. In the early 1950s, additional adverse reactions including deaths prompted a detailed investigation by the agency.

By the 1960s, the problem was acute,

Efforts had been in place at least since the 1965 Drug Abuse Control Amendments to increase accountability of the use of amphetamine in medical practice. Diversion of the drug for recreational use and the concomitant public health concerns had been recognized as a serious problem by the 1950s, but prescribing amphetamine— whether alone, as part of the rainbow regime, or for indications other than weight loss—continued to rise in the 1960s.  Under the Comprehensive Drug Abuse Prevention and Control Act of 1970, which established different schedules for certain drugs based on their medical value vis-á-vis their abuse potential, amphetamine was relegated to Schedule II. This status mandated even greater hurdles for the prescribing and dispensing of the drug as well as production ceilings. In the 1970s, FDA also reconsidered obesity as a safe and effective use of amphetamine and its congeners, ruling that amphetamines were effective but only safe for short-term use, which essentially 'marginalized the anorectics and contributed to the eventual decline in their use.'

That is, until they were resurrected as a treatment for attention deficit disorder in children, and then their use was extended to adult patients with so-called adult ADHD, and now to patients with binge eating disorder.


Given this history, the rapid approval of Vyvanse by the FDA, without the benefit of an expert panel, especially given that it was for a supposedly common disorder of adults, is very curious, and worrisome.  As Dr Daniel Carlat said (quoted on the WBUR CommonHealth blog),

 

'I’m concerned that the FDA’s approval of Vyvanse for binge eating disorder is going to worsen our problems with stimulant abuse,' Carlat says.

'Vyvanse is a derivative of Dexedrine. We’ve seen epidemics of Dexedrine abuse in the past when it was used to help people diet. I predict that the FDA has just opened the gates to another similar epidemic – after all, binge eating disorder is a subjective diagnosis that could be potentially expanded to cover many millions of people.'

Why So Much Enthusiasm about Treating Such a Doubtful Diagnosis?

As Dr Carlat noted above, it is not so obvious that binge eating disorder should be considered to be a disease.  Starting with first principles, its definition is very vague and subjective.  According to the Alliance for Eating Disorders, the DSM-5 criteria for it are:

• Recurrent episodes of binge eating. An episode of binge eating is characterized by both of the following:
  • eating, in a discrete period of time (for example, within any 2-hour period), an amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances
  • a sense of lack of control over eating during the episode (for example, a feeling that one cannot stop eating or control what or how much one is eating)
• The binge-eating episodes are associated with three (or more) of the following:
  • eating much more rapidly than normal
  • eating until feeling uncomfortably full 
  • eating large amounts of food when not feeling physically hungry 
  • eating alone because of feeling embarrassed by how much one is eating
  • feeling disgusted with oneself, depressed, or very guilty afterwards
• Marked distress regarding binge eating is present.
• The binge eating occurs, on average, at least once a week for three months.
• The binge eating is not associated with the recurrent use of inappropriate compensatory behavior (for example, purging) and does not occur exclusively during the course Anorexia Nervosa, Bulimia Nervosa, or Avoidant/Restrictive Food Intake Disorder.

"An amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances?"  In this case, how are "larger," "most people," and "similar circumstances" defined, and by whom?  If I go out to eat with friends, and am the only one who has desert, or soup, for that matter, does that qualify?  Similarly subjective are "a sense of lack of control," and "eating more rapidly than normal."

In fact, the DSM-5 which ordained the new binge eating disorder diagnosis has been roundly criticized for embodying "diagnostic hyperinflation," turning aspects of the human condition, symptoms, and behavioral variants into disease.  Dr Allen Frances, who has been one of its prime critics, described "binge eating disorder" thus,

 Excessive eating 12 times in 3 months is no longer just a manifestation of gluttony and the easy availability of really great tasting food. DSM-5 has instead turned it into a psychiatric illness called Binge Eating Disorder.

Perhaps the enthusiasm to make binge eating disorder a disease had to do more with the financial relationships among the authors of DSM-5 and pharmaceutical companies that wanted to market drugs for the problem.  An article by Cosgrove and colleagues(3) noted that members of the DSM-5 work group that approved binge eating disorder as a disease included three people with financial relationships with Eli Lilly, maker of Cymbalta, three people with relationships with GlaxoSmithKline, maker of Lamictal, and one person with a relationship to Shire, maker of Vyvanse.  

Yet the discussion of Vyvanse in the big media outlets did not address these past questions about the validity of the binge eating diagnosis for which it is now being promoted. 

The Over-Marketing of Binge Eating Disorder to Promote Vyvanse

This week, however, at least some skepticism about other aspects of Vyvanse's promotion appeared in a major media outlet.  Just a few weeks after that initial coverage, the NY Times published a somewhat more skeptical take on the promotion of Vyvanse.  It noted that Shire was underwriting celebrity endorsements without disclosing its financial backing of them,

The retired tennis player Monica Seles spent this month making the rounds of television talk shows, appearing on everything from 'Good Morning America' to 'The Dr. Oz Show' to share her personal struggle with binge eating.

'It took a while until I felt comfortable talking about it,' she said in a People magazine interview, explaining that she secretly devoured food for years while she was a professional athlete. 'That’s one of the reasons I decided to do this campaign: to raise awareness that binge eating is a real medical condition.'

But that is not the only reason. Ms. Seles is a paid spokeswoman for Shire, which late last month won approval to market its top-selling drug, Vyvanse, to treat binge-eating disorder,...

Shire also was funding patient groups as part of its promotional efforts,

And patient advocacy groups — freshly infused with donations from Shire — began driving social media traffic to a company website that provides advice on how to raise the issue of binge eating with a doctor.

Furthermore, Shire has been trying to raise awareness of the new binge eating disorder diagnosis in ways that obfuscate its promotional interests,

Shire appeared to be following a familiar drug industry playbook by promoting awareness of a disorder, in this case binge eating, before more directly marketing its treatment. A company website, BingeEatingDisorder.com, makes no mention of Vyvanse but provides detailed information about how to talk about the disorder with a doctor, including a printable symptom checklist and sample opening lines to start the conversation. The site also tells patients 'don’t give up' if a doctor initially resists.

Some experts in prescription-drug abuse said the content was troubling because it appeared to coach patients about how to receive a diagnosis for a relatively uncommon condition, or shop for a new doctor if they were not successful.

Note Shire's use of undisclosed payments to celebrity spokespeople and patient advocacy groups and a disease awareness website whose connection to the company's drug was obscured suggests the operation of a stealth marketing campaign.  Furthermore, the article noted that Shire has been accused of deceptive marketing in the past, and specifically for its marketing of Vyvanse and another stimulant.

In 2011, the F.D.A. cited Shire, which is based in Dublin, for misleading advertising, and last fall the company paid $56.5 million to settle federal charges that it improperly promoted Vyvanse, Adderall and other drugs. Among the allegations, which Shire denied, was that the company played down Vyvanse’s addiction potential and said it would prevent car accidents, divorce, arrests and unemployment.

 We posted about that settlement here. 

The article also emphasized concerns about this new pushing of amphetamines,

 With the approval of Vyvanse for binge eating, 'now we have another reason for the public to learn about the glories of amphetamine — it’s very worrisome,' said Dr. Lawrence H. Diller, a behavioral pediatrician in Walnut Creek, Calif., who has written about A.D.H.D. drugs. 'My hat’s off to Shire. They’ve done it again.'

Also,

Several drug safety and addiction experts said the approval was of particular concern because of amphetamines’ troubled history as a treatment for weight loss. Vyvanse is converted by the body into an amphetamine when it is swallowed. 

From the 1940s through the 1970s, the drugs were commonly prescribed to overweight people who then became addicted. After public outcry and tighter government controls, companies stopped selling amphetamines as obesity treatments and their use is now tightly restricted. In 2012, the F.D.A. approved Qsymia, a drug combination that treats obesity and contains the amphetamine phentermine, although unlike Vyvanse, it is classified by the federal government as having a low potential for abuse.

The F.D.A. expressly forbade Shire from promoting Vyvanse as an obesity drug, but some drug safety experts said they worried its weight-loss attributes could be attractive to people who habitually overeat. The company says about 80 percent of people with the disorder are overweight or obese. Weight loss and appetite suppression are a common side effect of amphetamines.

'There’s so many reasons to be concerned about this,' said Dr. Andrew Kolodny, the chief medical officer of Phoenix House, a drug treatment organization.

He questioned why the F.D.A. approved the new use of Vyvanse so swiftly and said that given amphetamines’ troubled past, more caution was necessary.  'We had a horrible experience with amphetamines in this country, so the fact that this would just get rushed through without even bringing it before an advisory committee is especially concerning,'  he said.

However, the NY Times article still did not address the lack of good evidence that the drug provided a substantial benefit even in terms of just reducing binge eating, and questions raised whether binge eating disorder is a valid diagnosis. 

Summary

Once again we see the overenthusiastic promotion of the latest wonder drug, starting with uncritical media reports that parroted drug company executives.  At least this time some skepticism appeared about how an apparent stealth marketing campaign was organized, and about how the drug's riskiness was soft-pedaled. 

However, so far there has been little skepticism about the efficacy of the drug.  In fact, close reading of the report of one major trial showed that at best it has minimal efficacy, and even the evidence for that is weak and sketchy.  Furthermore, major news media have been hesitant to cite the real questions that have been raised about the nature of the disease for which the drug was advocated.

Most concerning is that this promotion was of an amphetamine, a type of drug with a very dark past, a type of "hard drug" responsible for major abuse problems, and known to cause particularly bad side effects, a type of drug whose illicit use has been previously sparked by over-enthusiastic marketing for dubious indications.

So once again I get to say that physicians need to be much more skeptical about the new "innovations," often promoted as miracle cures, that seem to appear weekly.  Attempts to educate physicians about clinical epidemiology, the principles of evidence based medicine, and just simply how to read a clinical research article with an appropriately skeptical and critical eye seem to have fallen by the wayside.  Furthermore, the diminishing number of health care journalists with diminishing resources may not be able to sufficiently skeptical of the marketing and public relations hype surrounding new drugs and devices.  Physicians and journalists need to have the courage to be more skeptical, and the public, who may trust journalists and physicians to cut through the bloviation, need to advocate for better training of physicians and journalists.

Finally, health care professionals and the public at large have been told to trust government regulators to only approve medicines that are safe and effective.  Yet the US Food and Drug Administration increasingly seems too cowed to challenge the pharmaceutical industry, and did not seem to exert much critical thinking before approving an amphetamine for over-eating.  The public and health care professionals ought to be advocating intensely for regulators that are less captured by the industry they are supposed to oversee.

As we have said until blue in the face, true health care reform would bring some skeptical thinking and regard for evidence and logic into the health policy discussion.

For our closing musical inspiration, or warning, note the chorus in "Amphetamine Annie" by Canned Heat...




"Speed Kills"

References

1.  McElroy SL, Hudson JI, Mitchell JE et al.  Efficacy and safety of lisdesamfetamine for treatment of adults with moderate to severe binge eating disoder: a randomized clinical trial.  JAMA Psychiatry 2015;   Link here.
2.  Cohen PA, Goday A, Swann JP. The return of rainbow diet pills.  Am J Pub Health 2012; 102: 1676-1686. Link here.

3.  Cosgrove L, Krimsky S, Wheeler EE et al.  Tripartite conflicts of interest and high stakes patent extensions in the DSM-5.  Psychother Psychosom 2014; 83: 106-113.   Link here.

11:09 AM

Giant GSK Settlement Provides Reminder of the Pervasiveness of Stealth Marketing

The latest  and biggest legal settlement involving health care to hit the news, that of GlaxoSmithKline (GSK) and the US government, has many familiar elements. As summarized by the New York Times,

In the largest settlement involving a pharmaceutical company, the British drugmaker GlaxoSmithKline agreed to plead guilty to criminal charges and pay $3 billion in fines for promoting its best-selling antidepressants for unapproved uses and failing to report safety data about a top diabetes drug, federal prosecutors announced Monday. The agreement also includes civil penalties for improper marketing of a half-dozen other drugs.

As was the case for nearly every other legal settlement we have discussed,

No individuals have been charged in any of these cases.

Thus, how well even such a large settlement will deter future wrong-doing is not clear.

Nonetheless, the documents released with it provide good documentation about how pervasive systematic, deceptive stealth marketing campaigns have become in health care. 

In particular, the official "complaint" filed by the US Department of Justice emphasized all these elements in the stealth marketing of paroxetine (Paxil, Seroxat in the UK) to adolescents.

Manipulation of Clinical Research

We have frequently discussed how health care corporations, particularly pharmaceutical, biotechnology and device companies, now sponsor  the majority of clinical research.  Their control of the design, implementation, analysis and dissemination of clinical research allows manipulation that increases the likelihood that the results will be favorable to their vested interests, usually the products and services they sell. 

We have previously discussed the manipulation of Study 329 to promote the marketing of Paxil (look here and here).  However, the US DOJ document makes these concerns more official.  It included:

Manipulation of Study Endpoints

Study 329 was a randomized controlled trial of Paxil vs imipramine vs placebo for depression in adolescents. The two primary endpoints pre-specified to the US Food and Drug Administration were "the degree to which a patient's Hamilton Rating Scale for Depression ('HAM-D') total score changed from baseline"; and "the patient's 'response' to medication, as defined as (a) a 50% or greater reduction in the patient's HAMD-D score, or (b) a HAM-D score of less than or equal to 8." However, initial analysis by GSK failed to show that Paxil improved either of these two end-points. The company concluded "it would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of [Paxil]."

So the analysis emphasized secondary outcomes, the "Study 329 investigators later added several additional efficacy measures not specified in the protocol. Paxil separate statistically from placebo on certain of these measures." Adding numerous post-hoc measures increased the likelihood of finding a difference on at least one due to chance alone.

Manipulation of Data

Initial analysis of the data suggested that patients given Paxil experienced 11 serious adverse events, including five that appeared related to suicidal ideation or action. When the FDA later reexamined the data, "upon closer examination the number of possible suicide-related events among the Study 329 Paxil patients increased beyond the five patients GSK described in the JACAAP article as having 'emotional lability.' While collecting saftey information for the FDA, GSK admitted that there were four more possible suicide-related events among Paxil patients in Study 329. In addition the FDA later identified yet another possible suicide-related event in the Study 329 Paxil patients, which was also not among the 11 serious advents listed in the JAACAP article. Thus, altogether, 10 of the 93 Paxil patients in Study 329 experienced a possible suicidal event, compared to one in 87 patients on placebo. This is a fundamentally different picture of Paxil's pediatric safety profile than the one painted by the JAACAP article...." 

Manipulation of Dissemination

The report describing the results of Study 329 (Keller MB, Ryan ND, Strober M et al.  Efficacy of paroxetine in the treatment of adolescent major depression: a randomized controlled trial.  J Am Acad Child Adolescent Psychiatry 2001; 40: 762-772.  Link here. ) was written under the control of GSK. "In April 1998, GSK hired Scientific Therapeutics Information, Inc (STI) to prepare a journal article about Study 329. GSK worked closely with STI on the article by providing a draft clinical report to 'serve as a template for the proposed publication.'"

The published report of Study 329 "mischaracterized the results." "Although the ... article identified the study's two primary endpoints in the abstract, the article did not explicitly state that Paxil failed to show superiority to placebo on either of the primary efficacy measures." Also, "the article did not explicitly identify the two protocol-specified primary outcome measures - or that Paxil failed to show superiority to placebo on these two measures. Instead the article claimed that there were eight efficacy measures and that Paxil was statistically superior to placebo on four of them." In addition, "while the article listed the five protocol-defined secondary endpoints, the text of the article omitted any discussion regarding three of the secondary measures on which Paxil failed to statistically demonstrate its superiority to placebo and instead focused on the five secondary measures that GSK added belatedly and never incorporated into the Study 329 protocol. The article claimed that these finve secondary measures had been identified 'a priori,' therefore incorrectly suggesting that all secondary endpoints had been part of the original study protocol." In other words, the final published articles contained multiple outright falsehoods about the drug's efficacy that exaggerated that efficacy.

Furthermore, initial analysis showed that patients given Paxil had more serious adverse events than others. An initial draft of the study article stated, "serious adverse events occurred in 11 patients in the paroxetine group, 5 in the imipramine group, and 2 in the placebo group." These included "headache during down-titration(1 patient), and various psychiatric events (10 patients): worsening depression (2); emotional lability (e.g., suicidal ideation/ gestures, overdoses), (5); conduct problems or hostility (e.g., aggressiveness, behavioral disturbance in school) (2); and mania (1)." As noted above, the number of suicide related events was actually double that noted in this draft as "emotional lability."  However, the published version of the report "falsely state[d] that only one of the 11 serious adverse events in Paxil patients was considered related to treatment...."  Nor did it mention the true number of events related to suicidal ideation or action.

The article only "listed at most five possibly suicidal events among Paxil patients, brushed those off as unrelated to Paxil, and conclude that treating children with Paxil was safe."

Later, GSK marketing materials described the results of the study thus,

This 'cutting-edge,' landmark study is the first to compare efficacy of an SSRI and a TCA with placebo in the treatment of major depression in adolescents. Paxil demonstrates REMARKABLE Efficacy and Safety in the treatment of adolescent depression."

Thus the conrol exerted by GSK over the published article, despite its apparent academic authorship, enabled it to promote a drug that was not efficacious and had major adverse events as remarkably safe and effective, a totally deceptive result that would mislead any health care professional who used the article to guide clinical practice. 

Suppression of Clinical Research

GSK sponsored two other studies of Paxil in pediatric populations, Studies 377 and 701. As stated in the Department of Justice's Criminal Complaint against GSK,

GSK Did Not Publicize the Results of Studies 377 and 701
43. GSK learned the results of Study 377 in 1998 and the results of Study 701 in 2001. Paxil failed to demonstrate efficacy on any of the endpoints of either study.
44. GSK did not hire a contractor to help write medical articles about the results of Studies 377 and 701, as it had with Study 329.
45. GSK did not inform its sales representatives about the results of Studies 377 and 701.

Thus, GSK managed to conceal the fact that the majority of the studies it sponsored about Paxil used for adolescent patients showed no evidence that the drug worked, again seriously distorting the evidence-base on which clinicians made decisions, and doubtless leading to the use of a dangerous, ineffective drug by numerous vulnerable patients.

Bribing Physicians to Prescribe

GSK's sales representative reflected in their call notes their use of money, gifts, entertainment and other kickbacks to induct doctors to prescribe GSK drugs....

One really creative way to pay physicians to be exposed to marketing:

For example, in or about 2000 or 2001, GSK used 'Reprint Mastery Training Programs' or 'RMTS' to further promote drugs by purporting to pay physicians to train sales representative to review reprints of studies. Although the training was purportedly for the representatives, in fact, the sales force was already familiar with the materials. GSK typically paid physicians $250 to $500 to review the reprints.

Thus GSK simply paid physicians to use its drug, a practice characterized as kickbacks in the official complaint.  An article in the Guardian noted that the US Attorney involved in the case put it even more bluntly,

The sales force bribed physicians to prescribe GSK products using every imaginable form of high-priced entertainment, from Hawaiian vacations [and] paying doctors millions of dollars to go on speaking tours, to tickets to Madonna concerts.

Use of Key Opinion Leaders as Disguised Marketers

GSK also created a group of national 'key opinion leaders' ('KOLs') who were paid generous consulting fees. GSK selected many of these physicians based on their prescribing habits and influence within the community and used the speaker fees paid to these physicians to induce and reward prescribing of GSK's products. GSK used these individual to communicate marketing messages focused on the drug's marketing campaigns at the time, including off-label uses. Some physicians on GSK's speaker's board have been paid more than a million dollars for speaking on behalf of the company and recommending its drugs.

Thus key opinion leaders were paid specifically to market drugs, and as a reward, a bribe for prescribing drugs.

Consulting Fees as Kickbacks

In general,

In order to induce physicians to prescribe and recommend its drugs, GSK paid kickbacks to health professionals in various forms, including speaking or consulting fees, travel, entertainment, gifts, grants, and sham advisory boards, training,....

In particular,

During 2000 and 2001 at least, GSK also utilized events termed 'advisory boards' or consultant meetings and forums to disseminate its promotional message. Although these boards were purportedly composed of 'thought leaders' for the purpose of obtaining advice from the physicians, in fact, the 'advisory boards' were little more than promotional events coupled with financial inducement to prescribing and influential physicians.

Also,

GSK typically paid the physician between $250 and $750 to attend each local 'advisory' meeting. The payments did not reflect the value of services. The physician was not required to do anything but show up. GSK had no legitimate business reason to hire thousands of 'advisors' to 'consult' with the company about a single drug.

Manipulation of Continuing Medical Education

GSK also used so-called CME and CME Express programs and other sham training for marketing purposes, and to promote off-labe uses for the GSK prescription drugs.

Furthermore,

These CME programs purported to be independent eduaction free of company influence, but in fact functioned as GSK promotional programs disguised as medical education. GSK maintained control and influence over the purportedly independent CME programs through speaker selection, and influence over content and audience, among other things. Although third party vendors were usually also involved, they served only as artificial 'firewalls' that did not insulate the program from GSK's influence.

Summary

The legal documentation of the GSK settlement demonstrated how one drug company used an integrated, systematic campaign incorporating deception and bribery to sell drugs. Its elements included manipulation and suppression of the clinical research it sponsored, paying key opinion leaders to be disguised drug marketers, outright payments to physicians to prescribe drugs, and manipulation, again using payments to physicians, of supposedly independent continuing medical education. 

Note that while I summarized the elements of the stealth marketing campaign to sell Paxil, particularly for use in pediatric patients, the US government complaint also documents similar activities used to sell other drugs.  Furthermore, other stealth marketing campaigns have come to light through legal action, and many other instances of manipulation and suppression of clinical research, use of KOLs as disguised marketers, kickbacks and bribes, and manipulation of CME have been documented.

This means that any claims that:
- commercially sponsored clinical research provides clear, unbiased data that should drive clinical decisions
- health care professionals and academics paid as consultants by commercial health care firms are not influenced by these payments, and can provide clear, unbiased opinions
- commercially sponsored medical education provides clear, unbiased teaching
unfortunately must be viewed with extreme skepticism. This is particularly unfortunate given that most clinical research is now supported by commercial sponsors, and the majority of influential academics in medicine get some form of payments from the health care industry (look here).

Of course, there are some physicians who consult for commercial firms who actually provide clinical or scientific advice or assistance, and some commercially sponsored activities are honest. But we must wonder what garden path all those advocates for increasing industry "collaboration" to promote "innovation," and who regard conflicts of interest as "inevitable" and "manageable" are taking us down (e.g., look here and here).

Although the current settlement will require a huge payment, as I have said many times before (as early as 2008, here), do not expect such settlements to deter future bad behavior like that listed above.  The cost of the settlement will actually be spread among all company shareholders, all company employees, and likely patients and taxpayers.  However, the settlement will entail no specific negative consequences to the people who authorized, directed, or implemented the bad behavior.  In particular, executives whose remuneration was swollen by proceeds from the sales of affected drugs, and the health care professionals who willingly accepted what the US Attorney called bribes will not pay any sort of penalty.  The bad behavior listed above was doubtless personally very profitable for some people.  Unless people who indulge in such behavior face the possibility of penalties worse than their expected gains, expect such bad behavior to continue.

In fact, as the New York Times reported,

critics argue that even large fines are not enough to deter drug companies from unlawful behavior. Only when prosecutors single out individual executives for punishment, they say, will practices begin to change.

'What we’re learning is that money doesn’t deter corporate malfeasance,' said Eliot Spitzer, who, as New York’s attorney general, sued GlaxoSmithKline in 2004 over similar accusations involving Paxil. 'The only thing that will work in my view is C.E.O.’s and officials being forced to resign and individual culpability being enforced.'

True health care reform would strive to eliminate important conflicts of interest affecting clinical research and medical education.  Specifically, it would prevent corporations that sell health care products or services from controlling clinical research meant to evaluate these products or services.  It would seek to eliminate serious conflicts of interest affecting health care professionals.  Finally, it would prevent vested interests from controlling medical education.  Not that I expect any such reform in the near future, it would be too threatening to those who have personally benefited from the current system.

Hat tip to Dr Howard Brody whose Hooked: Ethics, Medicine and Pharma blog scooped me on the details of the settlement relevant to study 329.

ADDENDUM (11 July, 2012) - see also this post on the 1BoringOldMan blog.

5:00 AM

"More Marketing Than Science" - An Anonymous Confession About Deceptive Marketing Published in the British Medical Journal

The British Medical Journal just published an anonymous article by a pharmaceutical company insider that explained once again how pharmaceutical companies turn research studies, apparently scholarly articles, and medical education into stealth marketing efforts.  (See Anonymous.  Post-marketing observational studies: my experience in the drug industry.  Brit Med J 2012; 344: 28.  Link here.)

We have previously discussed examples of health care corporate insiders confessing their individual efforts to turn medical research and education into marketing.  For example, peruse this.  We have also discussed how documents made public through litigation have revealed marketing plans for specific drugs that used apparently academic, educational, or scholarly publications and venues to market without revealing this transformation.  For example, see the Neurontin marketing plan (see post here), and the Lexapro marketing plan (see post here).  We have also discussed numerous examples of manipulation of particular research studies by those with vested interests, and outright suppression of studies whose results did not favor such vested interests.

Yet I suspect majorities of health care academics and professionals, health care policy makers, and the public at large do not realize, or would not admit that the evidence base for making health care decisions, and the general academic and professional discourse has been so corrupted.  So it is worthwhile to review once again how an insider summarized this corruption.

Research Studies Designed Primarily as Marketing Vehicles

In general, the anonymous author suggested that at least some studies were done for marketing, not scientific purposes:

some of the studies I worked on were not designed to determine the overall risk:benefit balance of the drug in the general population. They were designed to support and disseminate a marketing message.

Whether it was to highlight a questionable advantage over a 'me-too' competitor drug or to increase disease awareness among the medical community (particularly in so called invented diseases) and in turn increase product penetration in the market, the truth is that these studies had more marketing than science behind them.

Furthermore, the studies were supervised not by physicians or scientists, but by marketers in the marketing department,

Although the medical department developed the publication plans, designed the study, performed the statistical analysis, and wrote the final paper (which when published was passed on to marketing and sales to be used as marketing material), the marketing team responsible for that product were directly involved in all stages. They also closely supervised the content of other educational 'scientific' materials produced in the medical department and intended for potential prescribers. Instructions from marketing to the medical staff involved were clear: to ensure that the benefits of the drug were emphasised and the disadvantages were minimised where possible.

Manipulation of Research Design, Implementation, or Analysis

The author described how the marketers manipulated research studies so they would produce the results desired from a marketing perspective, regardless of their underlying truth,

Since marketing claims needed to be backed-up scientifically, we occasionally resorted to 'playing' with the data that had originally failed to show the expected result. This was done by altering the statistical method until any statistical significance was found. Such a result might not have supported the marketing claim, but it was always worth giving it a go to see what results you could produce. And it was possible because the protocols of post-marketing studies were lax, and it was not a requirement to specify any statistical methodology in detail. On the other hand, the studies were hypothesis testing (such as cohort studies, case-control studies) rather than hypothesis generating (such as case reports or adverse events reports), so playing with the data felt uncomfortable.

Other practices to ensure the marketing message was clear in the final publication included omission of negative results, usually in secondary outcome measures that had not been specified in the protocol, or inflating the importance of secondary outcome measures if they were positive when the primary measure was not.

So to summarize, the marketers would control the statistical analyses, promoting multiple analyses to attempt to come up with the "right" result that would support the marketing message (although the more kinds of analyses one tries, the more likely one is likely to come up with false results by chance alone). Presumably the marketers did not care whether or not the results were really true, which is perhaps why even they felt "uncomfortable" in some circumstances.

They would also foster the suppression of negative results, and the dredging of data for extra outcome measures when analysis showed no advantage in terms of the real primary outcomes. Suppression of negative results could be viewed as plain lying. Deliberate analysis of multiple end-points again risks identifying random error as true results.

The Role of Key Opinion Leaders

The author described how key opinion leaders, that is, health care professionals thought to be especially influential on practice or policy, were hired to become marketers presumably without revealing this intention.

Every big international observational study had a large advisory board. This was critical since the success of a newly launched drug in the market would depend on how many key opinion leaders were part of the study. Not only would they add credibility to the results, but they would also be key in influencing decision makers and other prescribers. In regional studies with thousands of patients, the study’s advisory board was formed by at least one key opinion leader from each country in that region, ensuring that areas important in terms of possible sales were covered. The contributions of the key opinion leaders to the study were always positive, but in my experience more directed towards designing new studies to answer their specific clinical questions rather than critically appraising our results and conclusions. In general, the relationship was amicable. We took them to the best hotels and restaurants during our advisory board meetings, and they appeared as authors in our research. Later, they would act as the company’s 'ambassadors,' giving conferences, teaching doctors, or talking to the media about the benefits of the drug.

Note that even the anonymous author could not bring him or herself to call the key opinion leaders salespeople, or marketers, but used the ambiguous wterm "ambassadors." Nonetheless, the role of key opinion leaders described would clearly be that of marketers or salespeople. However, it is extremely doubtful that any of these KOLs felt they had to declare that they were paid salespeople when presenting at conferences, teaching doctors, or talking about the media.

I would suggest that their actions would therefore fit Transparency International's definition of ethical corruption, "abuse of entrusted power for private gain." The KOLs are entrusted to be professional, and in many cases, scholarly. Using a professional or scholarly guise to act as a salesperson appears to be abuse of that entrusted power, in my humble opinion. In nearly every case, KOLs are paid, often handsomely, by the companies whose products they are selling. Thus, key opinion leaders acting as described by the anonymous author appear to be ethically corrupt.

Summary

The evidence of unethical marketing practices by commercial health care firms is mounting. Although I am most familiar with evidence from the US, there is mounting evidence that these practices are global, often done by companies that are not US based, and meant to influence practice and policy world-wide.

As the evidence mounts, it becomes increasingly clear that many such marketing practices are corrupt, at least in an ethical sense. Whether they may break laws in particular countries is a question for someone else.

The latest BMJ article is a reminder how skeptical the shrinking group of health care professionals who do not have conflicts of interest, are not biased in favor of particular products, and who put patients' interests first must be about ALL published research, scholarly publications, and apparently educational activities. Advocates of true evidence-based medicine must be extremely careful to try to use the least biased and manipulated parts of the evidence-base.

The mounting evidence suggests that at a minimum, all research reports, scholarly articles, media reports, conferences, and educational programs should provide full, detailed disclosure of all conflicts of interest. Perhaps having to make a declaration like "I am paid 50,000 Euros a year by the marketing department of company X to help market drug Y" before a supposedly educational talk would make some health care professionals think twice about such relationships.

However, even such detailed disclosure may not be sufficient to hamper marketing practices that now appear overtly corrupt. In my humble opinion, it is time to consider a global ban on the funding or influencing of human research by companies and other organizations which stand to gain financially according to the results of the research, or whose products and services are subject of such research. It is also time to consider a global ban on the funding or influencing of health care education by such organizations.

However, so many people are making so much money from the current practices that I doubt such proposals would get much support, or even public notice beyond this humble blog.

9:41 AM

Know-Nothing, or Industry Shill? You Be The Judge.

I have not been writing much the past few weeks due to other concerns, and will probably not write much this summer.

However, I have been commenting on various posts on other blogs.  One resultant thread stands out as yet another example of a likely industry shill or sockpuppet defending the state of health IT, oddly at a blog on pharma (same blog as was the topic of tmy post "More 'You're Too Negative, And You Don't Provide The Solution To The Problems You Critique', This Time re: Pharma").

Industry-sponsored sockpuppetry is a form of stealth marketing or lobbying, through discreditation of detractors, although in a perverse form.

The following exchanges meet the sockpuppetry criteria once pointed out by business professional and HC Renewal reader Steve Lucas in 2010 in a post about an industry sockpuppet caught red-handed through IP forensics here:

... In reading this thread of comments I have to believe [anonymous commenter moniker] "IT Guy" is a salesperson. My only question is: Were you assigned this blog or did you choose it? We had this problem a number of years ago where a salesperson was assigned a number of blogs with the intent of using up valuable time in trying to discredit the postings.

In my very first sales class we learned to focus on irrelevant points, constantly shift the discussion, and generally try to distract criticism. I would say that HCR is creating heat for IT Guy’s employer and the industry in general.

I find it sad that a company would allow an employee to attack anyone in an open forum. IT Guy needs to check with his superiors to find out if they approve of this use of his time, and I hope he is not using a company computer, unless once again this attack is company sanctioned.

In the hopes that continued exposure of this nonsense can educate and thus help immunize against its effects, I present this:

At "In the Pipeline", a blog on medicinal chemistry (the science of drug making) and other pharma topics, a rebuttal to a claim that over 500,000 people (not 50K) might have died due to VIOXX was posted entitled "500,000 Excess Deaths From Vioxx? Where?"

That 500K possibility appeared on a UK site 'THE WEEK With the FirstPost' at "When half a million Americans died and nobody noticed."  The author of the FirstPost piece started out by raising the point made by publisher Ron Unz that life in China might be more valued than that in the U.S., where major pharma problems and scandals generally meet what this blog calls "the anechoic effect."  (In China, Unz noted, perpetrators of scandalous drug practices actually get arrested and suffer career repercussions.)

FirstPost notes:

ARE American lives cheaper than those of the Chinese? It's a question raised by Ron Unz, publisher of The American Conservative, who has produced a compelling comparison between the way the Chinese dealt with one of their drug scandals – melamine in baby formula - and how the US handled the Vioxx aspirin-substitute disaster ... (Unz) "The inescapable conclusion is that in today's world and in the opinion of our own media, American lives are quite cheap, unlike those in China." 

Not to argue to merits of the order of magnitude-expanded VIOXX claim, which I disagree with, but having concern for the general state of ethics in biomedicine in the U.S., I posted the following comment at the comment thread of the rebuttal post at "In the Pipeline" at this link:

6. MIMD on May 30, 2012 11:38 AM writes...

While I agree the VIOXX numbers here are likely erroneous, the point of the cheapening of the value of American life is depressingly accurate.

For instance, look how readily companies lay people off, ruining them, and perhaps forcing them out of the workforce forever.

Also, currently being pushed by HHS is a medical device for rapid national implementation known to cause injury and death. The government is partially financing it to the tune of tens of billions of dollars, probably with Chinese money no less.  [Either that, or with freshly-printed money adding to the trillions of $ in our deficit - ed.]

There are financial penalties for medical refuseniks (non-adopters).

However, FDA, the Institute of Medicine and others readily admit in publication thay have no idea of the magnitude of the harm because of lack of data collection, impediments to information diffusion and even legal censorship of the harms data. In effect, we don't even know if the benefits exceed the harms, and FDA and IOM admit it. FDA in fact refers to the known injuries and deaths from this device as "likely the tip of the iceberg."

Perhaps to some it's no longer a big deal if people are injured and/or die in data gathering for this medical enterprise.

E.g., see "FDA Internal Memo on H-IT Risks", and the Inst. of Medicine report in the same issues here.

It's all for the greater social good, they might say.

 

The following anonymous reply ensued:

10. Watson on May 30, 2012 1:47 PM writes...

@6 You keep using that word - "device" - I do not think it means what you think it means

 

I replied:

11. MIMD on May 30, 2012 3:48 PM writes...

 #10

'medical device' is the term chosen by FDA and SMPA (EU).
But that's a distraction from the points I raise in the linked post about the experiment.

To which this confused misdirection came forth from the ether:

12. Watson on May 30, 2012 4:46 PM writes...

The linked article is discussing the poor state of "medical device records" because of a lack of uniform specifications with respect to Health Information Technology, i.e. how these technologies code data and the challenges of making the data obtained uniform across a wide variety of implementations and vendors. [Erroneous, incomplete misdirection - ed.]

It seems that the concern, far from being that Health Information Technology is "killing" people, is that the Medical Device Records may contain duplicate reports for adverse health events because of health care providers encoding the data more than once for each event.  [What in the world? - ed.] This problem with replication exists because there are different health record systems where this data needs to be input, and perhaps the same patient uses different physicians who have different systems, but all of which are required to report adverse events. [I have little idea what this even means - ed.]

In other words, "Health Information Technology" is not some monolithic "device", and your conflation of "HIT" which is more properly an abstract term with the "devices" which are used to generate some forms of patient data is in my view the real distraction. [The "real" distraction from the ethical issues of the HIT experiment is terminology about medical devices?  Misdirection again from the ethical issue, and of a perverse nature - ed.]

Yes, some of the "devices" (a blood pressure monitor for example) may have underlying issues, which the FDA regulations for "medical device records" are designed to identify. The FDA, as a governmental entity has no constitutional power to mandate certain devices or implementations are to be used.  [Now we're in la-la land of misinformation and distraction- ed.] The power that the FDA does have is to inspect that the manufacturer of a device keeps appropriate medical device records (e.g. a lot of syringes, or a batch of formulated drug) and addresses any complaints about the device to the satisfaction of the FDA.

My replies:

17. MIMD on May 31, 2012 8:51 PM writes...

#12

It seems that the concern, far from being that Health Information Technology is "killing" people, is that the Medical Device Records may contain duplicate reports for adverse health events because of health care providers encoding the data more than once for each event

Yes, fix just that little problem and then the problems with clinical IT are solved! (Actually,I'm not even sure what you're referring to, but the evidence is that fixing it as you suggest is the cure.)  [Sarcasm - ed.]

The FDA, as a governmental entity has no constitutional power to mandate certain devices or implementations are to be used.

You are also right about FDA. They were completely toothless even in this situation.  [Sarcasm again - ed.]

18. MIMD on May 31, 2012 9:10 PM writes...

#12

In other words, "Health Information Technology" is not some monolithic "device", and your conflation of "HIT" which is more properly an abstract term with the "devices" which are used to generate some forms of patient data is in my view the real distraction.

Those who conducted the Tuskegee experiments probably felt the same way.

It's all about definitions, not ethics, and not data - which FDA as well as IOM or the National Academies, our highest scientific body, among others, admits, as in the linked posts in #6, is quantitatively and structurally lacking on risks and harms.

I don't really mean to laugh at you, not knowing how little you really know about the Medical Informatics domain, but you bring to mind this Scott Adams adage on logical fallacy:

FAILURE TO RECOGNIZE WHAT’S IMPORTANT
Example: My house is on fire! Quick, call the post office and tell them to hold my mail!

And with that, I move on, letting others enjoy the risible comments from surely to follow! :-)

I could not have been more correct.

In typical industry shill/sockpuppet fashion comes this, with clear evidence of a not-so-clever liar which I've bolded:

19. Watson on June 1, 2012 12:35 AM writes...
@18

I read the articles you originally linked to, and my comments were based upon trying to interpret your meaning from those selections. I worked in the industry and had to deal with GMP, and had to make sure to follow all of the guidelines with respect to medical device manufacturing and electronic records. I understand the terminology very well. Luckily, I never had to deal with "health IT", but I did have to pore over enough pages of Federal Register legalese to know that what is sufficient is not necessarily what is best.  [Right.  See below - ed.]

Is that risible enough for you?

The link that you provided in @17 was a much more concrete example, and if you had referenced it in your original post, would have cleared up much of the confusion that I (and I assume @9) faced in understanding what it was you were trying to convey. It would have been useful if you had explained which device or devices you were talking about. If you had more than conjecture to back up the Chinese money trail, and if you had provided an example of a company that has been damaged by being a refusenik, those would have supported your argument as well. [Continuing haphazardly with the irrelevant as a distraction in an attempt to shift the focus from the ethical issue of nationally implementing HIT in a relative risk-information vacuum, having weakly conceded the main argument's been lost - ed.]

Straw man and ad hominem fallacies are pretty transparent around here, and I wish you the best with both. [Another attempt at diversion - ed.]

I assure you that I recognize what's important, that I have ethics, and that I care about people having reliable healthcare. [This seems a form of post-argument-lost attempt to seize the moral high ground - ed.]

I then point out the nature of what is likely a bold-faced lie.  Someone who's read the Federal Register in depth would likely know FDA's authority is not a "Constitutional power", as bolded below: 20. MIMD on June 1, 2012 6:44 AM writes... @19 The FDA taxonomy of HIT safety issues in the leaked Feb. 2010 "for internal use only" document "H-IT Safety Issues" available at the link in my post #6 is quite clear: - errors of commission - errors of omission or transmission - errors in data analysis - incompatibility between multi-vendor software applications or systems This is further broken down in Appendices B and C, with actual examples. Both this FDA internal report and the public IOM report of 2011 (as well as Joint Commission Sentinel Events Alert on health IT of a few years ago, and others) make it abundantly clear there is a dearth of data on the harms, due to multiple cultural, structural and legal impediments to information diffusion. Yes, it's in the linked IOM report at #6 entitled "Health IT and Patient Safety: Building Safer Systems for Better Care". See for instance the summary pg. S-2 where IOM states about limited[ed] transparency on H-IT risk that "these barriers to generating evidence pose unacceptable risks to safety." Argue with them, not me. Back to my original point: national rollout of this medical device (whatever you call it is irrelevant to my point, but see Jeff Shuren's statement to that effect here) under admitted conditions of informational scarcity regarding risks and harms represents a cheapening of the value of patient's lives. Cybernetics Over All. As to your other misdirection, spare me the lecture. It's not ad hominem to call statements like "The FDA, as a governmental entity has no constitutional power to mandate certain devices or implementations are to be used" for what they are - laughable (and I am being generous). FDA's authority is statutory, not written in the Constitution. Same with their parent, HHS. To get quite specific, on human subjects experimentation, which the H-IT national experiment is, the statutory authority for HHS research subject protections regulations derives from 5 U.S.C. 301; 42 U.S.C. 300v-1(b); and 42 U.S.C. 28. [The USC or United States Code is the codification by subject matter of the general and permanent laws of the United States.  HHS revised and expanded its regulations for the protection of human subjects in the late 1970s and early 1980s. The HHS regulations on human research subjects protections themselves are codified at 45 CFR (Code of Federal Regulations, aka Federal Register) part 46, subparts A through D. See http://www.hhs.gov/ohrp/humansubjects/guidance/. - ed.] A real scientist would have known things like this before posting, or have made it their business to know. Tell me: are you in sales? Not to point fingers, but with your dubious evasion of the ethical issue that was the sole purpose of my post, and your other postings using misdirection and logical fallacy to distract, you fit that mindset. You certainly don't sound like a scientist. Any med chemist worth their salt (pun intendend) would have absorbed the linked reports and ethical issues accurately, the first time. I then pointed out I've moved this 'discussion' to the HC Renewal Blog, as it is not relevant per se to pharma, the major concern of In the Pipeline. Industry shill/sockpuppet (as in the perverse example at this link) or just a dull, ill-informed but opinionated person who happens to read blogs for medicinal chemists, where layoffs have been rampant in recent years, takes issue with my attacks on those practices, and defends health IT like a shill? You be the judge. Whether a shill or know-nothing contributed the cited comments, it is my hope this post contributes to an understanding of pro-industry sockpuppetry. -- SS

4:52 AM

Polly Want a Million (Plus)

We have frequently posted about attempts to justify financial relationships among physicians and medical academics on one hand, and pharmaceutical, biotechnology, device and other health care corporations, on the other. Some defenders of such relationships now have gone so far as to start their own society, whose meeting was covered and commented on by fellow "pharmascolds," including Dr Daniel Carlat and Dr Howard Brody. The usual justification of these relationships is that they are necessary for "innovation" and the onward progress of medical science, education, and care. I have yet to see any logic or evidence to back up these assertions, nor have I seen anyone defend these relationships who does not also have personal financial relationships of their own with health care corporations. (See examples here, here, and here.)

Meanwhile, cases of individual physicians and academics whose lucrative relationships with industry seem to generate huge conflicts of interest continue to surface. The latest example ferreted out by investigators working for US Senator Charles Grassley (R - Iowa) is that of Dr David Polly. (Recall that Dr Polly was one of the strongest defenders of Dr Thomas Kuklo, who was accused of falsifying clinical research results in a way that seemed to favor the product of his own corporate benefactor [see post here].)

The main points were reported by David Armstrong and Thomas M Burton in the Wall Street Journal,

In May 2006, University of Minnesota spine surgeon David Polly urged a Senate committee to fund research into the severe arm, leg and spine injuries suffered by soldiers in Iraq and elsewhere.

Dr. Polly told the committee he was testifying on behalf of the American Academy of Orthopaedic Surgeons and referenced his prior work caring for soldiers as a surgeon at the Walter Reed Army Medical Center.

What Dr. Polly didn't disclose during his testimony was that his trip to Washington was paid for by Medtronic Inc., the big medical-device maker whose bone growth product, called Infuse, has been used to treat soldiers, according to company records.

Dr. Polly and colleagues in Minnesota subsequently received a $466,644 Department of Defense grant for a two-year study beginning in February 2007 to evaluate Infuse in cases where an injury is also infected, according to the university.

Dr. Polly was paid $1.14 million by Medtronic for consulting services from 2004 to 2007.

Details of Dr. Polly's consultant billing were provided by Medtronic to Sen. Charles Grassley, an Iowa Republican who has been scrutinizing the relationship between academics and industry.

Although there have now been many reported cases of medical academics who collected large payments from health care corporations, the services they provided in exchange for the money have not always been very clear. Defenders of financial relationships among physicians and medical academics and industry have argued that most payments were for valuable research, education, or health care activities. However, Senator Grassley's office provided the details of Dr Polly's invoices, and several of the news articles so far described what he did for the money. Per the Wall Street Journal article,

In total, Dr. Polly billed Medtronic for more than $50,000 in lobbying-related costs. He made trips to Washington in 2005 and 2006 and called on several members of Congress, according to the records.

According to billing records, Dr. Polly's billing rate was $4,750 for an eight-hour day in 2007, and he billed as many as 13,000 minutes a quarter -- or 216 hours over three months. In some months, he conducted at least some Medtronic business on nearly every day.

His consulting log indicates that on one occasion he spent one minute to wake up a Medtronic executive, although he listed 'no charge' for that service. He did bill Medtronic for the 30 minutes he spent in the car with that executive after waking him up.

An accompanying post on the Wall Street Journal Health Blog provided more information:

Did you ever wonder what doctors do to earn big consulting contracts from medical device companies and pharmaceutical concerns?

Records released by Medtronic to Sen. Charles Grassley, a longtime critic of the ties between academics and and health-care companies, provide a rare and detailed glimpse into the daily billings of a consultant — in this case, spine surgeon David Polly of the University of Minnesota.

Polly collected more than $1 million in four years of work for Medtronic, according to the records, which you can take a look at here.

The services he provided were many, but among them, Polly was paid to write articles for medical journals; write a chapter in a book and a book outline; recruit patients for publicity efforts; attend Medtronic national sales meetings; travel to conferences in Japan, Paris and elsewhere; lead training and educational sessions for physicians; and lobby Congress.

Polly also billed for at least two phone calls with Medtronic CEO William Hawkins as well as charging the company $2,000 when Mr. Hawkins visited an operating room. In October, 2003, he billed the company $12,000 for attending a medical meeting of the North American Spine Society, at $4,000 a day.

There are also scores of entries for work billed in five-minute increments, usually to send email or return phone calls. The bill for each five-minute charge? $49.48 a pop.

So did the $1.2 million Medtronic spent on Dr Polly's services inspire any "innovation?" Did it lead to any scientific progress or improved health care? I am not sure.

It is clear, however, that a good chunk of this money went to support marketing, advocacy, and lobbying. The items in bold italics above were clearly in support of marketing, advocacy and lobbying, not science, medical education, or patient care. (To give Dr Polly the benefit of a doubt, some other items listed above could have been related to research, education, or patient care, although this is not indisputable.)

So the case of Dr Polly corroborates my deep skepticism of the financial relationships among physicians and medical academics on one hand, and corporations that sell health care goods and services on the other. We "pharmascolds," - a preferable term might be health care skeptics - suspect that many of these relationships are really about stealth marketing and advocacy. The companies often pay to market their products and services, or advocate positions to the companies' advantage, but prefer that their salespeople and advocates are cloaked in academic guises, and wreathed in the rarefied aura of respected academic institutions. (Note that some of us are just as skeptical about relationships among academic institutions and other health care not-for-profit organizations on one hand, and such corporations on the other, for analogous reasons.)

While the leadership of our formerly distinguished medical academic institutions remains infiltrated, if not dominated by people earning many thousands of dollars from health care corporations, I must remain skeptical about how much of these institutions supposedly academic output is actually stealth marketing and stealth health policy advocacy.

At the very least, medical academics, medical academic institutions, and other health care not-for-profits or NGOs should reveal in detail what payments they get from companies selling health care products or services, and how these payments could relate to the companies' marketing or lobbying efforts. In the US, some such disclosure would be mandated by the proposed "Sunshine" legislation now being considered by the US Congress. (By the way, note that this problem is hardly confined to the US, and needs global, not just American attention.)

However, physicians (at least physicians in full-time private practice, academic positions, and employed by mission-oriented not for profit organizations) should go further, and consider whether receiving industry money is worth the ongoing damage it does to our professionalism and our professional reputations. Medical schools, universities, health care foundations, disease advocacy groups, and other health care not-for-profits and NGOs should also go further, and consider whether receiving industry money is worth the ongoing damage it does to their missions, and their institutional reputations.

See also comments by Prof Margaret Soltan on the University Diaries blog.

10:07 AM

Pseudo-Evidence Based Medicine Threatens Health Care Reform Based on "What Works"

As I posted yesterday, the increasingly noisy debate about health care reform in the US has not dealt much with the issues we often discuss on Health Care Renewal. These include problems in how health care organizations are led which threaten physicians' and other health care professionals' core values using tactics including perverse incentives, deception, and intimidation.
Last night, however, President Obama held a news conference mostly devoted to health care issues, in which he stressed the importance of changing not just how health insurance works, but how health care decisions are made. As Newsweek's "The Gaggle" blog reported,

Can I guarantee that there are going to be no changes in the health care delivery system? No. The whole point of this is to try to encourage changes that work for the American people and make them healthier. The government already is making some of these decisions. More importantly, insurance companies right now are making those decisions. And part of what we want to do is to make sure that those decisions are being made by doctors and medical experts based on evidence, based on what works, because that's not how it's working right now.

So what the President seems to be advocating is making health care more evidence-based, perhaps in the formal sense of evidence-based medicine.

As a card-carrying evidence-based medicine advocate, I certainly agree, but let me reiterate that 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. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice. Increased expertise is reflected in many ways, but especially in more effective and efficient diagnosis and in the more thoughtful identification and compassionate use of individual patients' predicaments, rights, and preferences in making clinical decisions about their care. By best available external clinical evidence we mean clinically relevant research, often from the basic sciences of medicine, but especially from patient centred clinical research into the accuracy and precision of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens.

Furthermore,

Evidence based medicine is not 'cookbook' medicine. Because it requires a bottom up approach that integrates the best external evidence with individual clinical expertise and patients' choice, it cannot result in slavish, cookbook approaches to individual patient care. External clinical evidence can inform, but can never replace, individual clinical expertise, and it is this expertise that decides whether the external evidence applies to the individual patient at all and, if so, how it should be integrated into a clinical decision.

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.

So far, so good. I believe the proper application of "real" (as described above) evidence-based medicine has the potential to improve patient outcomes while moderating health care costs. However, we have pointed out how problems arising from concentration and abuse of power in health care threaten the evidence-based medical ideal.

First, there are major problems with the development of the sort of clinical research evidence required by the EBM process. We have discussed how clinical research is frequently manipulated by those with vested interests in producing results that favor the products or services that they sell. The critical review process inherent in EBM is meant to cope with less than optimally designed and implemented research. However, the process was designed to cope with honest mistakes and inevitable trade-offs, not deliberate manipulation by vested interests.

Worse, we have discussed how vested interests may engineer the suppression of research when manipulation fails to produce the desired results. The EBM process assumes that the research on which decisions should be based is an unbiased sample of research that was done (and done to advance science, not commercial or ideological interests). When research whose results are unwanted by vested interests is suppressed, the resulting distortion of the evidence base may irretrievably bias the EBM process.

Finally, we have posted about how vested interests have distorted the discussion, dissemination, and teaching of the results of clinical research. They may develop systematic stealth marketing campaigns, often employing supposed "key opinion leaders," who are paid on the side by marketers, and using "medical education and communication companies"as marketing fronts whose publication strategies include deceptive tactics such as "ghost-writing."

Thus, a rising tide of "pseudo-evidence based medicine" threatens to overwhelm even the most conscientious physicians trying to practice evidence-based medicine.

So, while I applaud President Obama's advocacy of reforming health care to emphasize what the best evidence suggests really works, I do not think this effort will get far unless we deal with the rising tide of pseudo-evidence based medicine. As a minimum, we need full and detailed disclosure of all the relationships among vested interests and medical research and education, and a much greater role for research and education that is not subsidized by corporations bent on using research and education to market their products and services.

7:27 AM