The Texas TMAP Trial as Illustration of a Systematic Stealth Marketing Campaign

Before it was abruptly ended by a sudden settlement for $158 million, the trial in Texas of a suit alleging unethical marketing of the drug Respirdal (risperidone) by the Janssen subsidiary of Johnson and Johnson opened yet another window on organized stealth marketing campaigns in health care. (Note that we first discussed this case here in 2006, and that this trial and the case was ably covered in detail on the 1BoringOldMan blog.) 

Even so, given all the recent attempts to dismiss critics of the pharmaceutical industry as "pharmascolds," (e.g., here), and to otherwise uphold the current status quo in our dysfunctional health care system, I thought it would be useful to rediscuss this case to show how systematic stealth marketing threatens the ideals of rational, evidence-based health care.

Evidence-based medicine may simply be viewed as medicine based on evidence and logic tempered with humanity. A slightly longer definition is practice based on the best evidence from clinical research derived from systematic searches, critically reviewed, used to maximize individual patients' benefits and minimize their harms according to their values.

In contrast, brief summaries of sworn testimony during the trial, and of a key report by an expert witness suggested how a commercial health care organization, in this case, the Jennssen subsidiary of Johnson and Johnson, could organize a stealth marketing campaign to promote practice based on deception and falsehoods, entangled in illogic and emotional and psychological manipulation. This was all done to market a product which could not so easily be supported by evidence and logic.

Deception and Falsehoods: Suppression of Medical Research

A Bloomberg report of the last day of the trial showed how the Respirdal stealth marketing campaign used the now classic mechanism of suppression of medical research:

Johnson & Johnson officials hid three studies showing some patients using Risperdal developed diabetes while claiming the antipsychotic drug didn’t cause the disease, a witness testified.

As early as 1999, Johnson & Johnson’s Janssen unit had researchers’ findings that about half the patients taking Risperdal in a study comparing its risks to those of Eli Lilly & Co.’s Zyprexa antipsychotic drug developed diabetes after a year on the medication, Joseph Glenmullen, a psychiatrist and Harvard Medical School instructor, told a Texas jury yesterday.

That study concluded Risperdal caused 'medically serious weight gain' that led study subjects to develop diabetes, Glenmullen testified in the trial of the state of Texas’s lawsuit over Janssen’s marketing of the drug. At the same time, Janssen salespeople were telling doctors that researchers concluded the drug didn’t cause the disease, Glenmullen added.

In particular,

Glenmullen, testifying as an expert for the state, told jurors Janssen officials didn’t turn over Study 113, which found Risperdal posed a higher diabetes risk than Zyprexa, to the U.S. Food and Drug Administration when regulators began probing links between anti-psychotic medications and the disease in 2000.

The drugmaker also didn’t turn over the results of two other later studies that found Risperdal and Zyprexa posed comparable diabetes risks to the FDA.

Suppression of research is a severe threat to evidence-based medicine because it can severely bias the clinical evidence base on which it depends.
Deception and Falsehood: Ghostwriting

A summary of the 86 page report by Professor David Rothman commissioned by the Texas Attorney General published in the Houston Press provided this example of ghostwriting:

A member of J&J's Speakers Bureau, [University of Texas Professor of Psychiatry Dr Alexander] Miller collected at least $82,000 from Janssen and its contractors. He declined to comment for this story, saying he may be called as a witness in the lawsuit.

Miller was a 'guest author' for one of Janssen's ghostwritten articles. Upon receiving the manuscript, Miller wrote, 'Yes, I am happy to be included as a co-author. I made a few minor edits and comments in the manuscript.'

In addition, another article in the Houston Press summarizing the issues before the trial provided this overview of the ghostwriting process:

As described in the AG's expert witness report, a company called Excerpta Medica was hired to draft some of Janssen's Risperdal articles.

In 2003, according to Rothman, Excerpta Medica issued 'Risperidone Publication Program Status Reports,' indicating that 30 of the 145 articles to be published had authors listed as 'to be determined.'

Rothman also examined what he considered a signature ghostwritten piece meant to boost Risperdal's pediatric profile; the study is included in the 2010 parameters.

Rothman cited a barrage of e-mails between Excerpta Medica and J&J in crafting the article. At one point, an Excerpta Medica employee wrote, 'It would be very helpful to receive some guidance in relation to the flow, format and subject in this paper and whether you think this is too marketing oriented or not, in order to prepare a next draft. Besides that we would like [to] have some suggestions for external authors on this paper. Maybe [a] U.S. and a European KOL? Your input will be much appreciated.''

The article eventually appeared in a 2007 volume of the European Journal of Child and Adolescent Psychiatry. For a lead author, J&J scored a heavy hitter: Dr. Peter Jensen, former associate director of child and adolescent research at the National Institute of Mental Health, and the founding director of the Center for the Advancement of Children's Mental Health at Columbia University. Now with the Mayo Clinic, Jensen declined to comment for this story.

This indicates the scope of this particular ghostwriting initiative: 145 articles were planned.  Thus, ghostwritten articles could comprise a major proportion of the apparently scholarly literature relevant to Risperdal.  Ghostwriting is fundamentally deceptive because it allows marketing to appear in the guise of scholarly work.  Ghostwritten reviews can deceptively shift the focus from the questions that need to be addressed by the evidence-based process to benefit patients to those whose answers would benefit marketers.


Deception and Falsehoods: Key Opinion Leaders
Emotional and Psychological Manipulation: Creation of Conflicts of Interest

An important element of most stealth marketing campaigns is the creation of key opinion leaders.  These are academics or professionals who can promote products in the guise of unbiased expertise. 

A summary of the 86 page report by Professor David Rothman commissioned by the Texas Attorney General published in the Houston Press provided the example of Dr Steven Shon:

As the head of the state's mental health agency, Shon was perhaps Janssen's most crucial key opinion leader; his influence in pushing ­Risperdal was invaluable.

He accepted at least $47,000 from Janssen and its medical ghostwriter, Excerpta Medica, and signed an agreement to be a member of Johnson & Johnson's Speakers Bureau. Rothman writes, 'The medical director of the state's mental health agency should not be serving as an official spokesperson for a pharmaceutical company whose product state agencies are purchasing.'

The company paid for his trips across the country, and even overseas, to promote ­Risperdal as a safe and effective medication. (But the romance between Janssen and Shon was not without its bumps; Shon would get 'upset' if the checks he accepted from Janssen were made out to the MHMRA instead of directly to him. Apparently, those were more difficult to funnel into his personal account.)

Shon retired in 2005, allowing him to collect his taxpayer-funded pension. He moved to Las Vegas, where he's the director of psychiatry for a mental health and substance abuse clinic called Harmony Healthcare.

Shon was so influential that Janssen grew paranoid and possessive when it learned that other companies sought his partnership as well. When J&J employee Yolanda Roman heard that Eli Lilly had flown him to their headquarters on a private jet, she wrote, "Steve I suppose is enjoying the vast attention and response he can command from Industry...Obviously, Steve has the right to be served by all Industry, let's hope he remains fair [and] balanced and remembers who PLACED HIM ON THE 'TMAP' MAP."

Meanwhile, another employee busted out the caps-lock to warn that "WE WILL NOT LET LILLY OR PFIZER PREVAIL WITH OUR MOST IMPORTANT PUBLIC SECTOR THOUGHT LEADER."

Similarly, a Bloomberg report of Dr Shon's trial testimony included:

Johnson & Johnson’s Janssen unit paid a Texas mental health official to speak around the U.S. about state guidelines on prescribing antipsychotic drugs that gave preference to medicines like the company’s Risperdal, the official said.

Steven Shon accepted honorariums to fly to Arizona, Florida and New Jersey to discuss Texas guidelines developed in 1999 advising doctors that a newer class of drugs like Risperdal were a “first choice or option” for schizophrenia, he testified today in state court in Austin.

Also,

Attorneys for Jones questioned Shon, who served as medical director of the Texas Department of Mental Health and Mental Retardation until he involuntarily retired in 2006.

Shon testified that he served on Janssen advisory boards, was a board member of a Janssen publication called 'Mental Health Issues Today' and was a continuing medical education speaker in programs sponsored by the company.

Shon was asked about six trips in which he got honorariums of $3,000 from Janssen to discuss the TMAP project. In several cases, he kept those payments, he said.

In testimony yesterday, a Texas Medicaid investigator said Shon signed several consulting agreements with Janssen, and the company paid him $47,587 over several years.

Dr Shon's value to Janssen derived from his position as the respected leader of the state's mental health agency. While he was apparently paid by Janssen marketers who saw him as an ally, his marketing was all the more effective because it seemed to come from an unbiased expert. As such it was deceptive.

The Institute of Medicine report on conflicts of interest defined them as "a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary interest." The report, and indeed much of the discussion of conflicts of interest in health care assumes that most secondary interests are "-within limits - legitimate and even desirable goals." For example, an academic physician who also was a basic scientist could be paid by a pharmaceutical company to do a specific assay on samples used in research. In that case, the payments could conceivably create a risk that the academic's professional judgment in a clinical setting would be unduly favorable to the products of the company. However, the relationship hardly seems intended to cause such a bias. Notions that conflicts of interest are "inevitable" but "manageable" may stem from consideration of conflicts of interest like this.

However, conflicts of interest deliberately created as perverse incentives may be much more consequential, and as this example shows, perhaps not rare. It appears that Janssen paid Dr Shon not to do some task that was unrelated to how he fulfilled his primary entrusted responsibilities as director of mental health, but in order to influence how he fulfilled them. We have noted previous examples in which corporate marketers consider paid key opinion leaders as sales people (see posts here and here). Such conflicts are deliberately created so that the recipient of payments uses his or her entrusted responsibilities to serve the vested interests of the payer may be deceptive, as noted above.  Furthermore, by being intended to induce changes in how the payee performs his or her primary responsibilities, these conflicts are particularly likely to lead to abuse of these entrusted responsibilities. Given that the Transparency International definition of corruption is abuse of entrusted power for private gain, we need a new and more incisive term to described this variety of conflicts of interest.

The motivation of key opinion leaders by created conflicts of interest can result in powerful manipulation of the key opinion leaders, but more importantly of their audience. 

Emotional and Psychological Manipulation: Intimidation

Another Bloomberg report included testimony about how someone who attempted to blow the whistle about the Respirdal stealth marketing campaign was intimidated:

Allen Jones testified yesterday in state court in Austin, Texas, that he was an investigator in the Pennsylvania Office of Inspector General in 2002 when he looked into an unregistered bank account run by Steven Fiorello, the pharmacist. Fiorello was on a Pennsylvania committee weighing whether to require doctors to give priority to newer, more expensive drugs like Risperdal in state-funded treatment of mental-health patients, Jones said.

Jones, 57, said he found a $4,000 check from J&J’s Janssen unit to Harrisburg State Hospital that was sent “\'to the attention of' Fiorello. The check covered a Fiorello trip to New Orleans to discuss Pennsylvania’s drug guidelines. Another check for $1,766 to the hospital account was sent 'in care of' of Fiorello, Jones said. Fiorello controlled the account and didn’t register it with the state, Jones said.

'The account was used to deposit money from drug companies,' Jones said yesterday in the trial’s third day of testimony. 'There were real problems here. On many levels, the account was improper.'

Janssen also paid $2,000 directly to Fiorello as an honorarium for his speaking at a company-sponsored event in 2002, Jones said. Jones said he followed the money trail and explored efforts by Janssen to promote, on a state-by-state basis, Texas guidelines favoring drugs like Risperdal. The funds sent to the hospital account helped pay travel expenses for programs related to setting up the Texas guidelines in Pennsylvania, he said.

The state adopted the guidelines that favored Risperdal in 2003, Jones said.

Note that this testimony appears to be about yet another KOL paid to promote guidelines that would in turn promote the marketing of Respirdal. So this is yet another case of a conflict of interest apparently deliberately created to influence the individual's primary responsibility.

However, then

Jones said his boss told him to ease off his probe. He said he was told, 'Stay away from the drug companies. This is a personnel issue. Stay away from the drug companies, stay away from TMAP.


Jones said his boss said, 'Drug companies write checks to both sides of the aisle. Stay away from it.' His boss told him that 'morally and ethically I was correct, but politically, this was dead.'

Jones said that later he was removed as the lead investigator from the case, and he was 'marginalized completely.' He continued to pursue the case on his own time, and spoke to the New York Times for a story that ran Feb. 1, 2004. He said he was fired for talking to the newspaper.

So Jones was intimidated to the extent that he lost his job. Note further that the implication is that this intimidation stemmed from yet more conflicts of interest created by Janssen, payments to politicians. This underlines how stealth marketing campaigns become complex systems.

Note further that in retrospect, Jones' complaints were deemed true by a court of law and a state commission:

Fiorello, once the chief pharmacist for Pennsylvania’s public welfare department, was convicted in December 2008 of felony conflict-of-interest charges for taking payments from drug companies, including Janssen and Pfizer Inc. He was sentenced to 18 months of probation and fined $3,000. He also paid more than $27,000 in civil fines after the Pennsylvania Ethics Commission cited him.

In a sense, intimidation and created conflicts of interest are two sides of the same coin.  Both involve the deliberate imposition of incentives, either positive or negative.  These incentives are designed to further marketing aims and organizational interests, not to improve patient care or public health, or advance science.  Thus they are powerful tools of emotional and psychological manipulation.
Summary

Note that even the brief summaries of trial evidence suggested how systematic the campaign was, and how within it, the elements of deception and falsehoods (instead of evidence), and emotional and psychological manipulation (instead of logic and humanity) were predominant. This should be added to previous discussion of stealth marketing campaigns, including such examples as that of Neurontin here).

Stealth marketing campaigns are complex examples of how behavior meant to further vested interests may directly threaten evidence-based practice, physicians' professionalism, and ultimately patients' and the public's health.

There have been many calls (e.g., see recent posts here and here) for increased "collaboration" among health professionals and academics and industry.  Often they are justified by the need for "innovation," while resulting conflicts of interest are deemed "manageable."  The current examples show how the vested interests of health care organizations operating within a laissez faire, anything goes environment may make such collaboration poisonous.

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Johnson and Johnson Pleads Guilty - a Reminder of the "Lost Decade" of Nesiritide

It was just a short article in Bloomberg about yet another misstep by Johnson and Johnson....

Johnson & Johnson (JNJ)’s Scios unit agreed to pay an $85 million fine and plead guilty to misbranding the heart drug Natrecor, the U.S. said.

Scios was charged in July with misbranding the medicine because its labeling lacked adequate directions for use. Under a plea agreement reached after months of negotiation with prosecutors, Scios will be placed under organizational probation for three years in addition to paying the fine....

Although the case did involve a guilty plea, the fine actually seemed small compared to some others we have seen lately. The article made it sound like this was just a technical mis-step in labeling.

A Darker History

However, another brief paragraph hinted at a more complex background:

Natrecor, given intravenously, was one of the first drugs for congestive heart failure when it was approved in 2001, and in 2004 it generated $230 million in revenue. Sales plummeted to less than $100 million in 2006 after reviews of its use in less than 1,000 patients tied the medicine to worsening kidney function and higher death rates.

Of course, to a physician, the first sentence makes no sense. Digitalis was probably the first effective drug for heart failure, and its use was described in the 18th century. To the rest we should pay heed.

A Lack of Evidence for Benefit Outweighing Harm

In fact, in 2005, Dr Eric Topol wrote a commentary in the New England Journal that discussed Natrecor's (nesiritide's) troubled history.(1)

Here are the main points:
- Nesiritide was first tested on seriously ill, hospitalized patients with congestive heart failure.
- The drug improved one measure of physiogic function, the pulmonary capillary web pressure. However, patients given nesiritide had a not statistically significant increase in mortality, and a later significant decrease in kidney function.
- Nesiritide was thus only approved for short-term use in acutely ill heart failure patients (in 2001).
- However, its manufacturer, Scios, a Johnson and Johnson subsidiary, vigorously promoted it for out-patient "tune ups," a use for which there was no evidence that its benefits outweighed its harms.
- This use, however, was very lucrative for the company at a price of $500 per dose. So,

outpatient nesiritide use has become widespread, fulfilling sales objectives for the manufacturer and bringing in revenue for physicians. The overall sales figure for nesiritide is projected to be $700 million for 2005, nearly double last year's tally; it represents payment for more than 1.4 million treatments. Given that nearly 10 times as much drug is used for serial administration in outpatients as for the one-time use in hospitalized patients, much of this growth clearly stems from the off-label 'tune-up' application.

At that time, Dr Topol summarized the case thus:

The nesiritide story reflects some recurring themes: in other recent cases, too, major safety problems have been uncovered after a drug has been approved. Nesiritide was approved on the basis of a single trial in which surrogate end points were assessed three hours after administration. In cardiovascular medicine, we learned long ago that therapies directed at surrogate end points — such as the suppression of premature ventricular contractions or, for inotropic agents, an improved ejection fraction — can be associated with excess deaths. With the low threshold set for regulatory approval, the FDA did not demand appropriate warnings on the label regarding an increased risk of death or worsened renal function and did not require the performance of trials that would have provided definitive verification of the safety and efficacy of nesiritide.

We practice medicine in an era in which there is one pharmaceutical-company representative for every five physicians and in which companies will stretch the limits in their marketing of drugs. The boundary lines that previously separated industry from the FDA and academia have unfortunately become blurred.

No Evidence of Benefit in 2011, the End of the "Lost Decade"
Finally, in 2011, a larger study of the drug appeared.(2) It did not show that nesiritide increased mortality at 30 days, but neither did it decrease it. Essentially, it showed that the drug had no clinically important advantage over standard therapy. In an accompanying commentary, Dr Topol used the nesiritide case as an example of a "lost decade" due to "deficient clinical development of certain pharmaceutical agents."(3)

The FDA, without a prospective plan or capability to force the sponsor to perform a fitting trial after approval, unwittingly created a monster. Physicians, who prescribed nesiritide without definitive knowledge of efficacy or safety, particularly for off-label use such as for tune-up clinics, were treating patients without an adequate evidence base. The manufacturer in this case was the chief culprit because it widely promoted nesiritide in the early years after its approval but was unwilling to appropriate the resources to design and execute a compelling trial.

Summary
The sorry nesiritide case now seems to be staggering towards its conclusion with little fanfare (although the Bloomberg article noted that the legal proceedings related to it are not over.  There is a pending civil False Claims suit brought by the US Department of Justice.)

So, 10 years after the drug was widely marketed to patients for whom it would do no good, the "chief culprit" has had a pay a small financial price, relative to the revenue it received, for an offense tangential to the lost decade created for patients and physicians who thought that nesiritide might be worth using. As usual in such cases, no individual who authorized, directed or implemented the "monster" that was the dubious nesiritide marketing campaign has suffered any negative consequences.

This was just the latest in a long series of legal misadventures by the once revered Johnson and Johnson. Its most recent guilty plea for a marketing offense was only a month ago (see post here.) That blog post listed five other recent adverse legal results related to the company's marketing.

Of course, as long as the company's leaders seem immune to any sort of negative consequences for its bad behavior, and as long as its board seems happy to pay millions to the executives who preside over these messes, why should the bad behavior stop? Do we expect multi-millionaire executives to actually worry about the ethics and morals of what they are doing? - not in an era when "greed is good," at least until the whole economy collapses from the aggregated greed of its leaders.

For physicians, the nesiritide case should remind us not to deploy a test or treatment without good evidence that it actually does patients more good than harm, even if we really hope it does, and even if the company that markets it really hopes so too. 

For all of us, the case should remind us that if there are short-term monetary rewards but no penalties for unethical behavior, unethical behavior will continue.
References

1. Topol E. Nesiritide - not verified. N Engl J Med 2005; 353: 113-116. Link here.
2. O'Connor CM, Starling RC, Hernandez AF et al. Effects of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011; 365: 32-43. Link here.
3. Topol EJ.  The lost decade of nesiritide.  N Engl J Med 2011; 365: 81-82.  Link here.

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A New Venue From a Surprising Source to Discuss "External Threats to Good Decision-Making"

A new blog, entitled the Medical Professionalism Blog, signed on last week with a post emphasizing some themes that should be familiar to Health Care Renewal readers:

There is an increasing focus on the sustainability of the U.S. health care system based on current cost trends. Predictions are for the health care system to consume 19% of the GDP by 2019. How did we get here?

Some point to the overuse and misuse of health care services, inefficiencies and lack of care coordination. Others blame the lack of clinical evidence, primary care workforce and the external threats to good decision-making, such as a toxic payment system and the influence of pharmaceutical and device companies.

While there are many different ideas about what got us here and what should be done, there is wide consensus that physicians and other stakeholders must begin to develop new more effective and efficient systems of care and make wise choices that preserve our health care system’s sustainability.

We have been underlining concerns that health care professionals' values, the mission of academic medicine, and truly evidence-based practice are under a series of threats.  (For a recent, but already out of date list of threats to the academic medical mission, see this post.)  It is nice to see that that others are now alarmed by these threats and looking for ways to counter them.

So, our new colleague in the blog-sphere raised the following questions:

* What is the appropriate role of physicians and other stakeholders in preserving these resources?

* What behaviors foster and which threaten wise choices in medical decision-making?

* How can waste be removed from the system without sacrificing quality or safety?

* What system changes are needed to achieve better health care outcomes, reduce costs and improve the patient experience?

* What effect do the nature and performance of partnerships – clinician-patient, clinician-organization and clinician-society — have on professional behaviors and resource use?

Again, the importance of threats was emphasized, and concerns about conflicts of interest affecting physicians' professionals were implied. This blog will apparently have a unique focus which I hope will complement our approach on Health Care Renewal.

What we’re hearing from folks is the need to 'show me how' to answer these questions. Through analysis of promising practices, we hope to provide examples of what works – and what doesn’t.

So we welcome The Medical Professionalism Blog to our blog-roll and look forward to some interesting content.

For a final twist, I need to note that this blog's authorship appears to be unique. The Health Care Renewal bloggers, and most of our blogging friends mostly seem to include, in no particular order: academic physicians, often tenured or retired (and thus able to speak more freely), other generally senior or retired academics, independent or retired practicing physicians, journalists, independent consultants, some whistle-blowers and others who once worked in the health care establishment, and some very anonymous bloggers in the belly of the beast.  Thus, we are generally an very independent and iconoclastic, if a somewhat rag-tag lot.

However, the chief blogger on The Medical Professionalism Blog is Daniel Wolfson, who is Executive Vice President and Chief Operating Officer of the ABIM (American Board of Internal Medicine) Foundation,  and the blog itself is a project of the foundation.  Thus, this is a blog from the heart of the medical establishment, the powers that be, etc, etc.  No other blog on our blog-roll comes from a current leader of such an organization.  (One is written by someone who was a CEO of a major academic medical center/ hospital system, but who lost his job under controversial circumstances.)

It is truly refreshing to have a voice coming from the inside, so to speak, proclaim:

The Medical Professionalism Blog was created by the ABIM Foundation to stimulate conversation and highlight best practices related to professionalism....

Furthermore,

Open for considerable debate is my belief that physicians’ engagement in quality, safety and the management of health care resources ultimately improves the care they give their patients and adds to their joy of work. I look forward to hearing your point of view, even if it’s a dissenting one.

Lately, we have not heard a lot of calls for vigorous debate and dissent from the medical establishment, the powers that be, etc, etc. In fact, the anechoic effect is how we describe how such debate and dissent has been suppressed.

So it appears the The Medical Professionalism Blog may be a real breath of fresh air. We hope it can truly inspire some discussion, especially open discussion of issues which used to be not what one was supposed to talk about in polite health care company.  This could help advance the transparency which we have long been advocating.

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