The "King of Pain" Recants - Pharmaceutical Paid Key Opinion Leader Admits It Was All "Misinformation"

This may be a first.  A Wall Street Journal story announced that the "key opinion leader" who played a pivotal role in the promotion of  aggressive use of narcotics to treat non-malignant chronic pain has had a change of heart.  

Background - Embracing Narcotics

In the long ago time when I was in medical school, the wisdom was then that narcotics (that is, drugs like morphine or heroin, the latter not legal) should only be used in severe acute pain, like that due to bad trauma or occurring post-operatively, or for the pain of terminal illnesses, like cancer.  The reason their use was so restricted was that the drugs were believed to cause frequent adverse effects, from severe constipation, to addiction, to respiratory depression and death.

However, starting in the 1990s, the conventional wisdom changed.  Suddenly, the focus was on the under-treatment of chronic, but not malignant pain, and it became permissible, or even preferable, to use potent narcotics for this purpose.  Physicians like me who were very conservative in their use of narcotics were chastised for under-treating pain.

The Wall Street Journal article explained how this radical change in approach was apparently engineered by a few key opinion leaders, particularly Dr Russell Portenoy.  It opened,

Two decades ago, the prominent New York pain-care specialist drove a movement to help people with chronic pain. He campaigned to rehabilitate a group of painkillers derived from the opium poppy that were long shunned by physicians because of their addictiveness.

Dr. Portenoy's message was wildly successful. Today, drugs containing opioids like Vicodin, OxyContin and Percocet are among the most widely prescribed pharmaceuticals in America. 

The article provided graphics showing that per capita prescription narcotic use has more than tripled since 1999, 

A Change Driven by Wishful Thinking, not Evidence

Unfortunately, as the article made clear, the radical change that seemed so odd to some of us physicians who were trained before the 1990s was not driven by any good evidence from clinical research.

Per the WSJ,

Because doctors feared they were dangerous and addictive, opioids were long reserved mainly for cancer patients. But Dr. Portenoy argued that they could be also safely be taken for months or years by people suffering from chronic pain. Among the assertions he and his followers made in the 1990s: Less than 1% of opioid users became addicted, the drugs were easy to discontinue and overdoses were extremely rare in pain patients. 

However, Dr Portenoy's contention seemed to be based only on a small case-series of patients, lacking any sort of control group, and too small and likely too selective to generalize, particularly to patients with chronic, non-malignant pain.(Portenoy RK, Foley KM.   Chronic use of opioid analgesics in non-malignant pain: report of 38 cases. Pain 1986; 25:171-86.  This article does not seem to be available online.)

In 1986, at the age of 31, he co-wrote a seminal paper arguing that opioids could also be used in the much larger group of people without cancer who suffered chronic pain. The paper was based on just 38 cases and included several caveats. Nevertheless, it opened the door to much broader prescribing of the drugs for more common complaints such as nerve or back pain. 

 Dr Portenoy also cited

the statistic that less than 1% of opioid users became addicted.

Today, even proponents of opioid use say that figure was wrong. 'It's obviously crazy to think that only 1% of the population is at risk for opioid addiction,' said Lynn Webster, president-elect of the American Academy of Pain Medicine, one of the publishers of the 1996 statement. 'It's just not true.'

The figure came from a single-paragraph report in the New England Journal of Medicine in 1980 describing hospitalized patients briefly given opioids.

The reference here appears to be a letter to the New England Journal of Medicine ( Porter J, Jick H. Addiction rate in patients treated with narcotics. New England Journal of Medicine 1980; 302:123.  Link here.)  This was literally one paragraph long, so the methods of the research it reported cannot be rigorously evaluated.  In any event, the letter appears to have retrospectively documented an observation of hospitalized patients who were given at least a single dose of narcotics, and thus appears not relevant to the effects of long-term narcotics on patients with chronic pain. 

Thus, Dr Portenoy's enthusiasm for aggressive use of narcotics in non-malignant chronic pain was never based on any good evidence from well designed and performed randomized controlled trials with long-term followup that showed that narcotics were safe and effective in this setting.  At best, Dr Portenoy's and colleagues' contentions that narcotics should be liberally utilized for such patient were based on wishful thinking, not good evidence.


A Change Driven by Stealth Marketing

The WSJ article documented how Dr Portenoy was a prime mover in what appeared to be deceptive stealth campaigns to market narcotics for chronic, non-malignant pain.  Dr Portenoy's 1986 case-series

opened the door to much broader prescribing of the drugs for more common complaints such as nerve or back pain.

Charming and articulate, he became a sought-after public speaker. He argued that opioids are a 'gift from nature' that were being forsaken because of 'opiophobia' among doctors. 'We had to destigmatize these drugs,' said Dr. Portenoy.

He rose to chairman of pain medicine and palliative care at Beth Israel Medical Center in New York. His small office is studded with awards and evidence of his offbeat sense of humor. He prominently displays a magazine mock-up that jokingly dubs him 'The King of Pain.'

At medical conferences, his confident, knowing manner helped smooth the way for his message. Before an audience of government regulators, he once joked that he might tell a patient at low risk of abuse: 'Here, [have] six months of drugs. See you later,' he said, according to a Food and Drug Administration transcript. Amid laughter, he added, 'It's just hyperbole. I don't actually do that.'

Steven Passik, a psychologist who once worked closely with Dr. Portenoy and describes him as his mentor, says their message wasn't based on scientific evidence so much as a zeal to improve patients' lives. 'It had all the makings of a religious movement at the time,' he says. 'It had that kind of a spirit to it.'

So Dr Portenoy became a respected opinion leader.  His influence was demonstrated by how he generated disciples

 Dr. Portenoy's ideas about opioids reached into mainstream medicine and attracted outspoken advocates. In a 1998 talk in Houston, Alan Spanos, a South Carolina pain specialist, said patients with chronic noncancer pain could be trusted to decide themselves how many painkillers to take without risk of overdose. According to a recording, Dr. Spanos said he understood that a patient would simply 'go to sleep' before stopping breathing. While asleep, he said, the patient 'can't take a dangerous dose. It sounds scary, but as far as I know, nobody anywhere is getting burned by doing it this way.'

Dr Portenoy was affiliated with organized efforts that facilitated the marketing of narcotics for chronic malignant pain.  The marketing used clinical practice guidelines to push narcotics

Dr. Portenoy helped write a landmark 1996 consensus statement by two professional pain societies that said there was little risk of addiction or overdose among pain patients. 

The campaign enlisted government regulators, and thus seemed to include an element of regulatory capture,

One of Dr. Portenoy's chief complaints was that doctors were reluctant to prescribe opioids because they feared scrutiny by regulators or law enforcement. In the second half of the 1990s, he and his followers campaigned successfully for policies to change that.

In 1998, the Federation of State Medical Boards released a recommended policy reassuring doctors that they wouldn't face regulatory action for prescribing even large amounts of narcotics, as long as it was in the course of medical treatment. In 2004 the group called on state medical boards to make undertreatment of pain punishable for the first time.

This case demonstrated the direct involvement of pharmaceutical companies who sold narcotics,

That policy was drawn up with the help of several people with links to opioid makers, including David Haddox, a senior Purdue Pharma executive then and now. The federation said it received nearly $2 million from opioid makers since 1997. The federation says it derives the majority of its funding from administering medical licensing exams, credential verification, and data services.

A federation-published book outlining the opioid policy was funded by opioid makers including Purdue Pharma, Endo Health Soluttions Inc, and others, with proceeds totaling $280,000 going to the federation. .

 The campaign also involved an important hospital accrediting organization

In 2001, the Joint Commission, [JCAHO] which accredits U.S. hospitals, issued new standards telling hospitals to regularly ask patients about pain and to make treating it a priority. The now-familiar pain scale was introduced in many hospitals, with patients being asked to rate their pain from one to 10 and circle a smiling or frowning face.

The Joint Commission published a guide sponsored by Purdue Pharma. 'Some clinicians have inaccurate and exaggerated concerns" about addiction, tolerance and risk of death, the guide said. "This attitude prevails despite the fact there is no evidence that addiction is a significant issue when persons are given opioids for pain control.'

A Change Leading to Personal Enrichment

Meanwhile, Dr Portenoy was personally profiting from his relationships with pharmaceutical companies

Over his career, Dr. Portenoy has disclosed relationships with more than a dozen companies, most of which produce opioid painkillers. 'My viewpoint is that I can have those relationships, they would benefit my educational mission, they benefit in my research mission, and to some extent, they can benefit my own pocketbook, without producing in me any tendency to engage in undue influence or misinformation,' he said.

Dr. Portenoy and Beth Israel declined to provide details of their funding by drug companies. A 2007 fundraising prospectus from Dr. Portenoy's program shows that his program received millions of dollars over the preceding decade in funding from opioid makers including Endo, Abbott Laboratories, Cephalon, Purdue Pharma and  Johnson & Johnson.  

He currently also appears to be on the advisory boards of  Zars Pharma Inc,  Relevare Therapeutics, and Cytogel Pharma.

Thus, it seems that Dr Portenoy fit the usual definition of key opinion leader.  He was regarded as an authority in his area and his opinions were obviously influential.  He was paid by health care corporations with interests in selling their goods or services, in this case, narcotic drugs, and was using his influence to promote individual patient care decisions and policy decisions that facilitated the widespread use of these drugs. 

A Change Leading to Sick and Dead Patients

Since the campaign to "destigmatize" narcotics began, the US has seen what many have called an epidemic of narcotic adverse effects.  The WSJ article provided graphs showing that narcotic related deaths and hospital admissions both increased more than five times since 1999.   As the WSJ put it,

 some specialists now question whether the drugs should be prescribed so freely for months or years to people with chronic pain that isn't related to cancer, as Dr. Portenoy proposed 25 years ago. "People lost sight of the fact that these are dangerous drugs that are highly addictive," said Jane Ballantyne, a pain specialist at the University of Washington. She once agreed with Dr. Portenoy and proponents of broad opioid use but now believes they need to be used more selectively.

Dr Portenoy Recants

What is most remarkable about this case is that it seems to be the first in which a highly influential industry paid key opinion leader has publicly had a change of heart.

Now, Dr. Portenoy and other pain doctors who promoted the drugs say they erred by overstating the drugs' benefits and glossing over risks. 'Did I teach about pain management, specifically about opioid therapy, in a way that reflects misinformation? Well, against the standards of 2012, I guess I did,' Dr. Portenoy said in an interview with The Wall Street Journal. 'We didn't know then what we know now.'

I would note there is some sophistry there.  There was never good evidence for narcotics' effectiveness or safety for patient with chronic, non-malignant pain.

In fact, Dr Portenoy also admitted that, sort of,

'Data about the effectiveness of opioids does not exist,' Dr. Portenoy said in his recent Journal interview. To get a painkiller approved, companies must prove that it is better at reducing pain than a sugar pill during short trials often lasting less than 12 weeks. 'Do they work for five years, 10 years, 20 years?' Dr. Portenoy said in the Journal interview. 'We're at the level of anecdote.'

Again, it is not that the data that supported the use of the drugs has disappeared, or that new data has been developed that contradicts the old data.  There never has been any good data, that is, from well designed and performed randomized controlled trials that demonstrate that the benefits of narcotics outweigh their harms for patients with chronic, non malignant pain.  It does not exist now and it never existed.

Dr Portenoy also admitted,

'I gave innumerable lectures in the late 1980s and '90s about addiction that weren't true,' Dr. Portenoy said in a 2010 videotaped interview with a fellow doctor. The Journal reviewed the conversation, much of which is previously unpublished.

In it, Dr. Portenoy said it was 'quite scary' to think how the growth in opioid prescribing driven by people like him had contributed to soaring rates of addiction and overdose deaths. 'Clearly, if I had an inkling of what I know now then, I wouldn't have spoken in the way that I spoke. It was clearly the wrong thing to do,' Dr. Portenoy said in the recording.

So not only did the Wall Street Journal article describe how the overuse of narcotics for chronic, non-malignant pain came from wishful thinking energized by the possibility of corporate and personal profit, it showed how the chief medical cheer leader for these drugs now admits he was wrong.


Summary

In summary, it appears that the huge increase in the use of narcotics to treat chronic, non-malignant pain was never based on clear convincing evidence from well-designed studies.  At best it was based on irrational enthusiasm and wishful thinking by some very vocal and persuasive advocates.  These advocates seemed to become "key opinion leaders," that is, influential people who promoted the use of pharmaceuticals while they were being paid by pharmaceutical companies, and were likely involved in what appears to be systematic stealth marketing campaign by the pharmaceutical companies that make narcotics.  These campaigns included production of clinical practice guidelines promoted as authoritative, and enlistment of accrediting organizations and government regulatory agencies.

One particularly disturbing part of this story was the involvement of numerous people and organizations  entrusted by society to promote good medical care.  It shows how physicians, other health professionals, and the public at large must be very skeptical of vocal advocates of new, aggressive, "innovative" approaches, of clinical practice guidelines even those developed by apparently prestigious professional societies, of accrediting organizations, and of government regulators.  That is discouraging, and could lead to the cynical approach of simply not trusting anyone.

I would note, however, that two ways the headlong rush to over-use of narcotics could have been derailed would have been:
-  employment of extreme skepticism of people paid by narcotics manufacturers advocating increased use of these drugs, no matter how distinguished, scholarly, or influential these people appear to be.  This suggests the need for general skepticism of people with financial relationships with health care corporations pushing the goods or services these corporations provide, or pushing policies that would aid the selling of those goods or services
-  a rigorous evidence-based medicine approach, meaning making clinical and policy decisions based on the best evidence found by systematic search from rigorously evaluated clinical research about the benefits and harms of these decisions, informed by patients' values.  Such an approach would have revealed there was never any good clinical evidence to support long-term use of narcotics for chronic, non-malignant pain, the particular "innovation" being pushed in this case.

So I would argue that the case of the legal narcotics pushers underlines the need for utmost transparency about conflicts of interest affecting people and organizations that advocate for particular approaches to health care, and to the management of individual patients; continuing movement to bar at least the most egregious conflicts, as per the Institute of Medicine report on the topic (look here); and the need for the very skeptical, rigorous application of true evidence-based medicine approaches.  

Finally, I must note that this seems to be the first time that a prominent, highly influential key opinion leader  has recanted.  Maybe he will write an article entitled "Dr Drug Pusher?" - just joking, but at least one former  key opinion leader did write the confessional  "Dr Drug Rep."  Maybe this is the beginning of a movement toward health care based on logic and evidence rather than wishful thinking, irrational enthusiasm, or ideology, or even worse, on deception or personal enrichment.     

"The Scent ... of a Casino" - Clinical Research Results as Fodder for Insider Trading

"The scent and smoke and sweat of a casino are nauseating at three in the morning. Then the soul-erosion produced by high gambling - a compost of greed and fear and nervous tension - becomes unbearable and the senses awake and revolt from it." - Ian Fleming.  Casino Royale.  1953

A major theme of this blog has been threats to the integrity of clinical research.  When I started out as a young naive academician in medicine, I viewed clinical research through the lens of evidence-based medicine, as primarily a means to develop better evidence to aid in the care of patients, and secondarily a way to advance science and public health.  Yet in the past 20 to 30 years, clinical research has become commercialized.  Now most randomized controlled clinical trials are done to support the licensing of drugs and devices for particular indications.  Furthermore, clinical research has become de facto a primary avenue of marketing of drugs and devices.  So we have discussed endlessly how clinical research has been manipulated by those with vested interests in selling drugs and devices, and may be suppressed when even such manipulation fails to produce results desired by commercial sponsors.

If that was not bad enough - and it is - now there is evidence that clinical research has become the roulette wheel in an investment casino.  This is the lesson provided by new US government charges that giant hedge fund SAC Capital used insider knowledge to trade drug company stocks.


Let me try to provide a narrative of the key elements of the case.

The Key Players

Matthew Martoma was a " former student at Harvard Law School, ... [who] co-wrote papers on medical ethics before seeking a business degree at Stanford University and joining a little-known Boston hedge fund."  Then, "in 2006, at age 32, Martoma made it to SAC Capital Advisors LP and gained the attention of the firm’s billionaire owner Steven A. Cohen."(1)

Dr Sidney Gilman is

an 80-year-old neurologist with expertise in neurodegenerative disorders, including Alzheimer’s disease. According to his biography on the University of Michigan website, Gilman first served on the faculty at Harvard and Columbia and then had a long and distinguished career at the University of Michigan, where he was the chair of the department of neurology for many years. He is a member of the Institute of Medicine of the National Academy of Sciences and a past president of the American Neurological Association. In other words, he’s a bigshot.

Gilman moonlighted as a consultant, working for an expert networking firm, where he provided advice to the financial industry (and which eventually led to the insider trading case), and for Elan Pharmaceuticals. In addition to his consulting for Elan, he also served as the chair of the Safety Monitoring Committee for a phase II clinical trial of a highly promising (at the time) Alzheimer’s drug, bapineuzumab, under development by Elan and Wyeth.(2)

The owner of SAC Capital, a hedge fund worth $14 billion, is Steven A Cohen, "a prodigious art collector, an investor in the New York Mets, a supporter of Mitt Romney’s presidential campaign."  His "career ... has reached mythic status on Wall Street. Over the last 20 years, Mr. Cohen has amassed a multibillion-dollar fortune by posting returns averaging 30 percent a year. SAC has grown into a firm with about 1,000 employees around the world."(3)

The Maneuver


Per the NY Times(4), 

The doctor met Martoma as a consultant for an expert- networking firm based in Manhattan and had sessions with Martoma from mid-2006 to July 2008, according to the government.

Gilman worked for Gerson Lehrman Group’s Scientific Advisory Board starting in 2002,... 

Also according to the NY Times(5)
 

Dr. Gilman’s consulting work for Mr. Martoma earned him about $108,000, according to court filings. Based in part on Dr. Gilman’s leaks about positive developments related to the clinical trials of a new Alzheimer’s drug, SAC accumulated a roughly $700 million position in the stocks of Wyeth and Elan, according to the government.

The S.E.C. said that the fund’s owner, Mr. Cohen, took a large position in Wyeth and Elan in his personal portfolio based on Mr. Martoma’s recommendation. Mr. Cohen maintained his holdings even though there was significant internal debate about the wisdom of such a large position in the drug makers, the government said.

Furthermore, per Larry Husten writing in Cardiobrief(2),

 While serving on the Safety Monitoring Committee of the trial, from the summer of 2006 through mid-July 2008, Gilman had access to the safety (but not the efficacy) data from the trial. Throughout this period he leaked the positive safety information to his contact at SAC (the enormous hedge fund), which then began to accumulate a large position in both Elan and Wyeth.

So, allegedly based on information from Dr Gilman, the high-ranking academic physician doubling as a data monitoring committee chair for a drug trial, paid for these services by Elan, SAC Capital and Mr Cohen made a large investment in Elan and Wyeth, the companies sponsoring the trial.

But then, again per Husten(2),

 Later in June, Elan chose Gilman to present the full trial data at ICAD. Gilman did not become privy to this data until the middle of July when Elan gave him the full results of the trial. The results, in sharp contrast to the earlier view in the press release, were decidedly negative, offering little hope that the drug would be considered effective. Gilman apparently understood this, because he immediately gave the results to the hedge fund, which then rapidly and dramatically reversed its long position on Wyeth and Elan.

Specifically, per the New York Times(5), after

Dr. Gilman told Mr. Martoma that patients were experiencing serious side effects, prosecutors say. Afterward, Mr. Martoma e-mailed Mr. Cohen, telling him 'it’s important' that they speak. They spoke on the phone for nearly 20 minutes, the government says, and Mr. Martoma told his boss that he was no longer 'comfortable' with the investments.

The following day, SAC reversed course. Mr. Cohen’s head trader sold the firm’s entire inventory of roughly 10.5 million shares of Elan and about seven million shares of Wyeth, the government said. Once it had dumped the shares, SAC built a short position in the two stocks, betting their value would drop.

According to the S.E.C., the trader, Mr. Cohen and Mr. Martoma kept the sales confidential. The trade, wrote the head trader in an e-mail to Mr. Cohen, 'was executed quietly and efficiently over a four-day period through algos and darkpools' — referring to trades using algorithms and to trading platforms that do not have the same reporting requirements as the stock exchanges — 'and booked into two firm accounts that have very limited viewing access.'

After the companies announced the results of the trials, Elan’s stock fell about 42 percent and Wyeth’s about 12 percent.

The trading allowed SAC to avoid about $194 million in losses and earn about $83 million in profits on Elan and Wyeth, according to prosecutors.

At the end of 2008, Mr. Martoma received a bonus of about $9.3 million, the S.E.C. said.

So, having bet heavily on Elan and Wyeth based on Dr Gilman's initial information that the trial was showing positive results, SAC Capital and Mr Cohen then bet heavily against these companies based on Dr Gilman's new information that the trial would end up not showing such results.  Because they had this information allegedly before it was made public, these bets yielded huge profits.  Mr Martoma, the conduit between SAC Capital and allegedly Mr Cohen, made millions.  Dr Gilman made over a hundred thousand.

The Charges

Per Bloomberg(4),

Martoma, 38, was accused by prosecutors in Manhattan federal court with playing a lead role in what they called the most lucrative insider-trading scheme in history, given the $276 million profit he allegedly helped the hedge fund achieve.

The government started off taking a tough approach, per the NY Times(5),

FBI agents arrested Mr. Martoma, 38, early Tuesday morning at his home in Boca Raton, Fla. He was released on bail after making an appearance in Federal District Court in West Palm Beach. Mr. Martoma, who has been unemployed since leaving SAC in 2010, is expected to appear in federal court in Manhattan on Monday and enter a plea.

 In addition, Dr Gilman, per Bloomberg(1), "has entered into a non- prosecution agreement with prosecutors in which he agreed to testify before a federal grand jury and to forfeit $186,761, money which he was paid by Elan for his consulting work."

Mr Cohen has not been charged.  However, according to John Cassidy writing in the New Yorker(6),

the complaints do assert that Cohen, identified as 'Portfolio Manager A,' personally authorized many of Martoma's trades, and pocketed the bulk of the profits they generated.  In a statement accompanying the indictment [US Attorney Preet] Bharara was careful to state that S.AC., and by extension Cohen, reaped enormous rewards from the criminal wrongdoing, even though they weren't being charged.

the complaints do assert that Cohen, identified as “Portfolio Manager A,” personally authorized many of Martoma’s trades, and pocketed the bulk of the profits they generated. In a statement accompanying the indictment, Bharara was careful to state that S.A.C., and by extension Cohen, reaped enormous rewards from the criminal wrongdoing, even though they weren’t being charged.

Read more: http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html#ixzz2DdLAchwv

Read more: http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html#ixzz2DdKdZcAY

In addition, there is now some likelihood that there will be legal actions against SAC Capital.  The company has reportedly received a "Wells notice" that the SEC is considering pursuing such action.  In addition, according to the New York Times(7), "an additional action against SAC, or even Mr. Cohen, could involve accusations of fraud based on the so-called control-person liability theory, meaning that it was in 'control' of Mr. Martoma when he engaged in insider trading."

the complaints do assert that Cohen, identified as “Portfolio Manager A,” personally authorized many of Martoma’s trades, and pocketed the bulk of the profits they generated. In a statement accompanying the indictment, Bharara was careful to state that S.A.C., and by extension Cohen, reaped enormous rewards from the criminal wrongdoing, even though they weren’t being charged.

Read more: http://www.newyorker.com/online/blogs/johncassidy/2012/11/sharks-circle-around-hedge-fund-big.html#ixzz2DdKdZcAY

Summary

At one point, I would have simply regarded the trial of bapineuzumab as a clinical scientific experiment meant to determine if a promising new therapy would work for the important clinical problem of Alzheimer's disease, and incidentally as means to learn more about the biology of that disease.  More recently, I would have regarded the trial as primarily a means for Elan and Wyeth to persuade the US Food and Drug Administration to approve this drug as a treatment for this disease, and then if so, a means for these companies to market it.  I would have been skeptical about the value of the clinical evidence supplied by the trial to support use of this drug, but would not have dismissed this evidence out of hand.

Now it appears that a major role of this trial was to be a roulette wheel in a Wall Street casino.  Big bettors on this wheel included people who may have had advance knowledge about the slot in which the ball would land.

Ideally, clinical research ought to be done by people who have no particular interest in the results turning out one way or the other.  Obviously, clinical investigators as humans may have opinions about how studies might turn out.  However, they should not be in positions to gain or lose money according to the results, or to be intimidated by those with interests in having the studies obtain particular results. Our current system in which many clinical studies are funded by organizations with interests in how the results turn out has lead to numerous cases of manipulation of study results, and sometimes suppression of studies whose results could not be manipulated successfully in the desired direction.  Such threats to study integrity make it difficult to make the best clinical decisions for individual patients, distort health policy, and break the trust of patients who volunteered to participate in the studies.

Now it appears that short-term stock trading that bets on the results of clinical research, sometimes informed by insider information about these results, could be another powerful external influence on clinical research that could additionally threaten its integrity.  Furthermore, as we speculated seven years ago (see this post and links backward), fear of insider trading may be making clinical research more opaque, and this opacity may allow even more control of research by sponsors (companies funding it) rather than investigators.

We have previously suggested that real consideration ought to be given to taking clinical research out of the hands of organizations, particularly health care corporations, that have vested interests in the direction of the results.  Knowledge that clinical research is increasingly becoming a casino for stock traders and hedge funds, and that research results are becoming the stuff of insider trading should further prompt this consideration. 


References
1.  Burton K, Kishan S, Van Voris B. Cohen's 'Elan Guy' Martoma dropped ethics for hedge fund.  Bloomberg, Nov 23, 2012.  Link here.  
2.  Husten L. The doctor and the center of the insider trading scandal.  Cardiobrief, Nov 27, 2012.  Link here.
3.  Lattman P. S.E.C. weighs suit against SAC Capital.  New York Times, Nov 28, 2012.  Link here.
4.  Van Voris B, Hurtado P. Insider crackdown uses SAC manager in health-care pivot.  Bloomberg, Nov 21, 2012.  Link here.
5.  Lattman P. Insider inquiry inching closer to a billionaire.  New York Times, Nov 20, 2012.  Link here.
6.  Cassidy J. It's time for Obama to bite the hedge-fund sharks.  New Yorker, Nov 21, 2012.  Link here.
7.  Lattman P. S.E.C. weighs suit against SAC Capital.  New York Times, Nov 28, 2012.  Link here. 

When Clinical Trials are Meant for Marketing, not Science

The development of the randomized controlled clinical trial (RCT) was one of the major scientific advances in clinical medicine.  RCTs provide a major part of the evidence underlying evidence based medicine.  RCTs provide a major source of data used by the US Food and Drug Administration, and similar agencies in other countries, to decide whether to approve drugs or devices to manage particular clinical problems.  Unfortunately, with the rise of the RCT came a rise in attempts to suppress and manipulate clinical trials by those with vested interests, often in selling the products and services the trials can evaluate.

Many of the examples we have discussed were of attempts at manipulation or suppression of clinical trials originally done to provide evidence for product approval, or even ostensibly to advance clinical science.  Yet a relatively new article covering evidence revealed from litigation about the drug gabapentin (Neurontin) originally made by Parke-Davis, first a part of Warner Lambert, now part of Pfizer suggests that many clinical trials may not be done to advance science, or even just to provide data to regulators, but only to market products.

The article is Vedula SS, Goldman PS, Rona IJ, Greene TM, and Dickersin K. Implementation of a publication strategy in the context of reporting biases: a case study based on new documents from the Neurontin litigation.  Trials 2012; 13: 136.  Link here.

Methods Summary

The article described a case study based on documents revealed in 2008 litigation.  The purpose of the study was:

to describe the implementation of a publication strategy for off-label marketing of gabapentin, within the context of reporting biases and spin of Pfizer and Parke-Davis’s clinical trial findings, for four off-label uses: migraine prophylaxis, treatment of bipolar disorders, neuropathic pain, and nociceptive pain. 

The study examined documents revealed through the 2008 litigation.  It concentrated on documents relating to the marketing of Neurontin for four off-label indications, that is, for four potential reasons to use the drug which had not yet been approved by the US FDA.  It focused on documents discussing strategies for marketing for these indications, and then documents about particular company sponsored RCTs done for these indications.

Strategies to Sell Drugs

The documents examined by the investigators showed that Parke-Davis prepared "marketing assessments" for four possible indications for Neurontin.  The assessments discussed two possible strategies.  The "indication strategy" would be to conduct trials for the purposes of providing data to the FDA in the hope that the FDA would then approve the new indication for the drug.  The "marketing strategy" would be, in the words of an internal company memo quoted in the study, to conduct clinical trials and

to disseminate the information as widely as possible through the world’s medical literature

In other words, the publication strategy involved using RCTs first for marketing, rather than scientific or regulatory purposes.

How the Trials were Controlled by Marketers 

The publication strategy involved not simply doing trials and publicizing their results, but controlling the messages conveyed by the trials to make sure they primarily supported marketing.  This was done by having the company's marketing department control the content of the trial reports.

 A Neurontin Publications Subcommittee (NTN PSC) was formed within Pfizer and Parke-Davis to implement a publication plan. Minutes from meetings between the NTN PSC and Medical Action Communications (MAC), a medical writing company, indicate that a list of key messages, guiding the content of published reports related to the trials of gabapentin for off-label indications, was developed based on a branding guide

Thus it appeared to be that marketers, not physicians or scientists were in control of supposedly scholarly research publications appearing in medical journals.

The marketers controlled content by controlling those who wrote it.

 A standard operating procedure related to publication of affiliate-driven manuscripts was identified in internal company documents dated October 16, 2002, and it sheds further light on the publication planning process (see Figure 3). (The term affiliate in this context refers to Pfizer’s foreign affiliates, that is, corporations related to Pfizer by either shareholdings or other means of control, including subsidiary, parent, or sibling corporations). According to the internal company documents, 'affiliate-driven manuscripts' were written for Pfizer and Parke-Davis by MAC and sent to the authors for approval. Each article was coordinated by a manuscript team, consisting of representatives from the medical and marketing divisions of the company. The documents also indicate that all affiliate-driven manuscripts should be forwarded to the NTN PSC for review. One of the objectives of manuscripts being reviewed by the NTN PSC was to ‘ensure that they are in-line with current product messages and areas of interest’

Manipulating the Dissemination (and Analysis) of Research Results

Note that the control of publication by marketers describe above involved ghost-writing of articles by medical education and communications companies (MECCs).  Later the article explained that these ghost writers were "not appropriately acknowledged" in the resulting published articles.

The Vedula et al study article provided examples of "spin" in the writing of again supposedly scholarly research publications used in fact to support marketing, and controlled if not composed by marketers.

 We identified spin in publications related to 8/12 trials included in our analysis.... We classified the following as spin: emphasis in the published report on outcomes that were not specified in the study protocol (Study 879–201) ...; conclusions that did not match study findings described in the internal company research report (Study 945–220) ...; extensive rationale to explain away statistically non-significant (unfavorable to the sponsor) findings (Study 945–209; 945–291; No study number - Gorson) ...; conclusion of treatment effectiveness from an uncontrolled study (Study 945–250) ...; emphasis on statistically significant secondary outcomes despite negative findings for the primary outcome (Study 945–271) ...; and an explicit description of an attempt to spin study findings (as described in internal company emails) (Study 945–306).

Note that while most of these examples of spin involved manipulation of the dissemination of study results, that is, doubtful, biased or fallacious arguments based on apparently unbiased data, they also involved manipulation of the analyses (in italics). 

The article also described manipulation of dissemination involving the timing of publication, including delaying publication of an article despite the wishes of the study's investigators because the results were not statistically significant, and hence not favorable for marketing. 

Summary

Documents revealed by litigation about Neurontin in 2004 provided insights about how pharmaceutical and presumably other kinds of health care corporations may conduct systematic, deceptive stealth marketing campaigns to promote their products and services (look here).  We noted that initial media coverage of documents revealed in the 2008 litigation also suggested the existence of a systematic "publication strategy" to control dissemination of results of particular trials, while suppressing trials whose results could not easily be spun to provide support of marketing objectives (look here).

Now the new paper by Verdula et al fill out our knowledge of this case.  The paper suggests that randomized controlled clinical trials may be done not to advance science, or even convince regulators, but primarily to market their sponsors' products.  Thus some significant proportion of the clinical research literature, the literature that physicians and other health professionals have relied upon to make evidence-based decisions for their patients, may exist mainly for marketing purposes.  Even the most rigorous methods used by clinical epidemiologists to review research are meant to discover problems that arose from human error or the inevitable trade-offs made when research is done in the real world, but not deliberately introduced biases and defects meant to promote vested interests.  Thus it is not clear that even the most "evidence-based" medical decisions are based on real scientific evidence rather than the spinning of marketers.

Thus health care professionals, policy makers, researchers, and the interested public need to be even more skeptical about arguments made to promote innovative treatments and other clinical interventions.  However, it is not clear that even rigorous skepticism can defend the integrity of evidence based medicine from marketing disguised as clinical research.

Going forward, we must consider erecting an impregnable barrier between clinical research and those whose primary interest is to make money by selling health care goods and services.  If we do not do that, we will forever need to worry that we really have no idea what "works in medicine," and whether any particular test, treatment, or program provides benefits that outweigh its harms. 

Pseudo-Evidence Based Medicine Should be a Global Health Concern

We have frequently advocated for evidence-based medicine (EBM) , that is, medicine based on judicious use of the best available evidence from clinical research, critically reviewed and derived from systematic search, combined with biomedical knowledge and understanding of patients' values and preferences.  However, EBM risks being turned into pseudo-evidence based medicine due to systematic manipulation and distortion of the clinical research evidence base.  Dr Wally Smith wrote about pseudo-evidence based medicine, which he defined as "the practice of medicine based on falsehoods that are disseminated as truth," in the British journal Clinical Governance (Smith WR. Pseudoevidence-based medicine: what it is, and what to do about it. Clinical Governance 2007; 12: 42-52. Also see this post).  

Now it appears that this issue is causing concern in the Cochrane Collaboration, the main voluntary international group promoting EBM.  An article from December, 2011 in the Indian Journal of Medical Ethics outlined why we need to question the trustworthiness of the global clinical evidence base.  (See Tharyan P. Evidence-based medicine: can the evidence be trusted.  Ind J Med Ethics 2011; 8: 201-207.  Link here.)  It merits further review.

The Role of Vested Interests

Dr Tharyan, its author, emphasized that a major threat to the integrity of the clinical research data base is the influence on clinical research of those with vested interests in marketing particular products, e.g., drugs, devices, etc.

The motives for conducting research are often determined by considerations other than the advancement of science or the promotion of better health outcomes. Many research studies are driven by the pressure to obtain post-graduate qualifications, earn promotions, obtain tenured positions, or additional research funding; many others are conducted for financial motives that benefit shareholders, or lead to lucrative patents.

The Importance of Pervasive Conflicts of Interest

Early on, the author discussed how the distortion of the clinical research data base arises from the pervasive web of conflicts of interest in medicine and health care:

This hijacked research agenda perpetuates further research of a similar nature that draws more researchers into its lucrative embrace, entrenching the academic direction and position statements of scientific societies and academic associations. Funders and researchers are also deterred from pursuing more relevant research, since the enmeshed relationship between academic institutions and industry determines what research is funded (mostly drugs at the expense of other interventions), and even how research is reported; thus hijacking the research agenda even further away from the interests of science and society.

The article then goes on to show how the influence of vested interests may distort the design, implementation, analysis, and dissemination of research.

Distortion of Research Design and Implementation

The Research Question

Dr Tharyan noted

The majority of clinical trials conducted world-wide are done to obtain regulatory approval and a marketing licence for new drugs. These regulations often require only the demonstration of the superiority of a new drug over placebo and not over other active interventions in use. It is easier and cheaper to conduct these trials in countries with lower wages, lax regulatory requirements, and less than optimal capacity for ethical oversight. It is therefore not surprising that the focus of research does not reflect the actual burden of disease borne by people in the countries that contribute research participants, nor address the leading causes of the global burden of disease. Some 'seeding' trials, conducted purportedly for the purpose of surveillance for adverse effects, are often only a ploy to ensure brand loyalty among participating clinician-researchers.

Insufficient Sample Size

The article stated,

Many trials do not report calculations on which the sample size was estimated, often leading to sample sizes insufficient to detect even important differences between interventions (for primary, let alone secondary outcomes)

I would add that such small trials are particularly bad at detecting important adverse effects of the interventions being promoted.

Excessively Stringent Enrollment Criteria

As Dr Tharyan wrote,

Most RCTs funded by industry and academia are designed to demonstrate if a new drug works, for licensing and marketing purposes. In order to maximise the potential to demonstrate a 'true' drug effect, homogenous patient populations; placebo controls; very tight control over experimental variables such as monitoring, drug doses, and compliance; outcomes addressing short term efficacy and safety; and methods to minimise bias required by regulatory agencies are used to demonstrate if, and how, the drug works under ideal conditions.

The problem is that very few patients in clinical practice resemble those enrolled in such trials, so the generalizability of the trials' results is actually dubious. Ideally, clinicians practicing evidence-based medicine could refer to trials that include patients similar to those for whom they care.

Practical or pragmatic clinical trials are designed to provide evidence for clinicians to treat patients seen in day-to day clinical practice, and evaluate their effectiveness under 'real-world' conditions. These trials use few exclusion criteria and include people with co-morbid conditions, and all grades of severity. They compare active interventions that are standard practice, and in the flexible doses and levels of compliance seen in usual practice. They utilise outcomes that clinicians, patients, and their families consider important, such as satisfaction, adverse events, return to work, and quality of life). Recommendations exist on their design and reporting , but such trials are rare.

Comparisons to Placebo, not the Other Interventions Clinicians Might Realistically Consider

Per the article,

Industry sponsored trials rarely involve head-to head comparisons of active interventions, particularly those from other drug companies, thus limiting our ability to understand the relative merits of different interventions for the same condition.

The result may thus be a number of studies showing particular interventions appear to be better than nothing, but few if any studies that would help clinicians decide which intervention would be best for a particular patient.

Inappropriate Comparators

However,when studies are done comparing the intervention of interest to other active interventions, the details of the choice of comparators are often managed so that the comparators are likely to appear to be worse.

Even if active interventions are compared in industry-sponsored trials, the research agenda has devised ways in which the design of such trials is manipulated to ensure superiority of the sponsor’s drug. If one wants to prove better efficacy, then the comparator drug is a drug that is known to be less effective, or used in doses that are too low, or used in non-standard schedules or duration of treatment. If one wants to show greater safety, then the comparator is a drug with more adverse effects, or one that is used in toxic doses. Follow up, also, is typically too short to judge effectiveness over longer periods of time.

Meaningless Outcomes

A favorite tactic used in the design of trials influenced by vested interests is to choose outcomes that are likely to show results favorable to the product being promoted, but have no meaning for patients or clinicians. There are three ways this is commonly done.

The first is to use rating scales that are very sensitive to small perturbations, but not meaningful in terms of how patients feel or function:

The choice of outcome measures used often ensures statistically significant results in advance, at the expense of clinically relevant or clinically important results. Outcomes likely to yield clinically meaningless results include the use of rating scales (depression, pain, etc.). These scales yield continuous measures usually summarised by means and standard deviations, rather than the dichotomous measures clinicians use such as: clinically improved versus not improved. These rating scales, however extensively validated, are hardly ever used in routine clinical practice. A difference of a few points on these scales results in statistically significant differences (low p values), that have little clinical significance to patients.

Another is to use surrogate outcomes,

Other outcomes commonly used are surrogate outcomes; outcomes that are easy to assess but serve only as proxy indicators of what ought to be assessed, since the real outcome of interest may take a long time to develop. These are mostly continuous measures that require smaller sample sizes (blood sugar levels, blood pressure, lipid levels, CD4 counts, etc.). These measures easily achieve statistical significance but do not result in meaningful improvements (reduction in mortality, reduction in complications, improved quality of life) in patients’ lives, when the interventions are used (often extensively) in clinical practice.

Finally, there are composite outcomes,

The use of composite outcomes, where many outcomes (primary, secondary and surrogate outcomes) are clubbed together (e.g.: mortality, non-fatal stroke, fatal stroke, blood pressure, creatinine values, rates of revascularisation) as a single primary outcome, can also mislead. Such trials also require smaller sample sizes, and increase the likelihood of statistically significant results. However, if the composite outcome includes those of little clinical importance (lowered blood pressure, or creatinine values), the likelihood of real benefit (reduction in mortality, or strokes, or hospitalisation) and the potential for harm (increase in non-fatal strokes or all-cause mortality) are masked.

Distortion of Analysis

Relative Instead of Absolute Risks

A favorite trick is to emphasize relative risks rather than absolute risks. For example if a trial reduces the risk of a bad outcome from 2 of 10,000 patients (0.02%) to 1 of 10,000 patients (0.01%), the relative risk reduction is 50%, but only 1 of 10,000 patients experienced a benefit.

The use of estimates of relative effects of interventions, such as relative risks (RR) and odds ratios (OR) with their 95% confidence intervals, provides estimates of relative magnitudes of the differences and whether these exclude chance, as well as if these differences were nominal or likely to be clinically important.

However, even relative risks can be misleading since they ignore the baseline risk of developing the event without the intervention. The absolute risk reduction (ARR) is the difference in risk of the event in the intervention group and the control group, and is more informative since it provides an estimate of the magnitude of the risk reduction, as well the baseline risk (the risk without the intervention, or the risk in the control group). Systematic enquiry demonstrates that on average, people perceive risk reductions to be larger and are more persuaded to adopt a health intervention when its effect is presented as relative risks and relative risk reduction (a proportional reduction) rather than as absolute risk reduction; though this may be misleading.

Sub-Group Analysis

Another statistical trick used to present favourable outcomes for interventions is the use of spurious subgroup analyses, where observed treatment effects are evaluated for differences across baseline characteristics ( such as sex, or age, or in other subpopulations). While they are useful, if limited to a few biologically plausible subgroups, specified in advance, and reported as a hypothesis for confirmation in future trials; they are often used in industry-sponsored trials to present favourable outcomes, when the primary outcome(s) are not statistically significant.

A major statistical point is that the more ways one subdivides the study population, the more likely it is to find a difference between those receiving different interventions by chance alone.

Distortion of Dissemination

Poor Exposition

As noted by Dr Tharyan,

Evidence also shows that the published reports are not always consistent with their protocols, in terms of outcomes, as well as the analysis plan, and this again is determined by the significance of the results. Harms are very poorly reported in trials compared to results for efficacy; and are also often suppressed or minimised.

Ghost-Writing

Also, those with vested interests may try to ensure maximally favorable dissemination by employing ghost-writers,

Other tactics used to influence evidence-informed decision making include ghost-writing, where pharmaceutical companies hire public-relations firms who 'ghost-write' articles, editorials, and commentaries under the names of eminent clinicians; a strategy that was detected by one survey in 75% of industry-sponsored trials, where the ghost author was not named at all, and in 91% when the ghost author was only mentioned in the acknowledgement section. Detecting such conflicts of interest is difficult, since they are rarely acknowledged due to the secrecy that shrouds the nexus between academia and industry in clinical trials.

Industry-sponsored trials often place various constraints on clinical investigators on publication of their results; these publication arrangements are common, allow sponsors control of how, when, and what is published; and are frequently not mentioned in published articles.

Ghost-writers under the direct control of those with vested interests could more efficiently bias their writing in favor of their sponsors than could even academics constrained by contractual obligations to sponsors.

Suppression of Research

When all else fails, the most crude example of distorted dissemination is suppression of studies that despite all the manipulations noted above fail to produce favorable results for the product being promoted:

A considerable body of work provides direct empirical evidence that studies that report positive or significant results are more likely to be published; and outcomes that are statistically significant have higher odds of being fully reported, particularly in industry funded trials.

By the way, the latest demonstration of suppression of research was a study by Turner et al (Turner EH, Knoepflmacher D, Shapley L. Publication bias in antipsychotic trials: an analysis of efficacy comparing the published literature to the US Food and Drug Administration database. PLoS Medicine 2012; 9(3): e1001189. Link here) It showed that of 24 trials of atypical antipsychotics registered in the US FDA database, 15/20 (75%) of the published trials were positive, that is, had results in favor of the sponsors' drugs according to the FDA review, but only 1/4 (25%) of the unpublished trials were positive. In other words, 15/16 of positive trials were published, but only 5/8 non-positive ones were.

Summary

Thus, Dr Tharyan provided a nice summary of many of the ways that the clinical research data base can be manipulated or distorted to serve vested interests. Such distortions risk the transformation of evidence-based medicine into pseudo-evidence based medicine.

We have repeatedly discussed (see links above) most of these issues. Because we are located in the US, and speak mainly English, this blog may have given the impression that the lack of trustworthiness of the clinical research evidence base is primarily a US problem. The article by Tharyan emphasizes, however, that it is a global problem.

While this problem now seems to have the attention of the Cochrane Collaboration, it seems to be relatively anechoic in global health circles. It appears to be no more prominent on the agendas of global health organizations than is health care corruption (look here.) Yet the two issues are highly related. Most of the distortions in the global clinical evidence database may be driven by conflicts of interest. Conflicts of interest are risk factors for corruption. Distortions of the global clinical research data base that lead to use of expensive, but ineffective or dangerous interventions when other options would work as well or better leads to needless suffering and death, and by unnecessarily raising the costs of care, decreases access, especially for the poor.

Also note that conflicts of interest may be one reason that all these problems remain so anechoic (look here).

True global health care reform requires addressing health care corruption, but also conflicts of interest and their role in the distortion and manipulation of the clinical research data base. I still live in hope that that some academic health care institutions, professional societies, health care charities and donors, and patient advocacy groups will gain enough fortitude to stand up for accountability, integrity, transparency, and honesty in health care.

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.

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.

What the November, 2009, Breast Cancer Screening Argument Obscured

In November, 2009, a rancorous argument about screening mammography for women aged 40-49 was touched off by the publication of updated guidelines(1), supported by a systematic literature review(2) by the US Preventive Services Task Force (USPSTF).  The guidelines suggested that yearly mammographic screening for women in that age group should not be automatic, but a decision made for individual patients after discussion between the patients and their doctors.  This was based on a critical review of the best available data which suggested that the benefits of screening acrue to only a few patients.  1904 women would have to start screening and continue for multiple rounds to prevent one cancer death over 11-20 years of follow-up.  These benefits had to be balanced against a number of potential risks, including the risks of treatment of cancers that might never behave malignantly, and the at least theoretical risk of generating new cancers through radiation exposure from mammography. 

These seemingly reasonable recommendations generated heated responses.  The debate, to be charitable, seemed to be at its core about how one should weigh benefits and harms in making individual and health policy decisions.  Since different people value different outcomes differently, I was not sure at the time how to make a meaningful contribution to this debate, or whether the debate had to do with the issues we usually discuss on Health Care Renewal.

I should note that the USPSTF guidelines never said "do not screen" women under age 50, or that the government should not pay for such screening.  They did say "the decision to start regular, biennial screening mammography before the age of 50 years should be an individual one and take pateint context into account, including the patient's values regarding specific benefits and harms."  It is hard to see how anyone could argue with that as an expression empowering patients' choices and values.  (For further discussion about how the recommendations were actually modest and reasonable, see Partridge and Winer.)(3)

Now that the dust has settled, it may be useful to reflect further on this.  Doing so suggests that the rancorous US debate mainly obscured rather than illuminated the major issues regarding mammography screening, particularly about our lack of clear evidence from clinical research needed to make the best individual and  policy decisions about mammography. 

It seems to me that the main questions one must answer to make an individual or policy decision about screening mammography are:

Does it improve longevity?

This is not the same as asking whether mammography reduces mortality from breast cancer.  It is theoretically possible that while decreasing mortality due to breast cancer, screening and its downstream consequences increases mortality from other causes.  At least in theory, screening may detect small tumors that would never grow or metastasize.  Treating such tumors could sometimes lead to premature death due to complications of surgery, radiation, or chemotherapy.  Furthermore, screening also involves periodically exposing large numbers of women to radiation, which may sometimes cause new tumors.  So reducing breast cancer mortality does not automatically mean that overall longevity would be improved.

There have been eight major trials of breast cancer screening which included women younger than 50. (See reference 2.)  None demonstrated a statistically significant increase in overall survival (that is, an increase unlikely to have been due to chance alone) due to screening.

Does it reduce suffering, improve functioning or generally improve quality of life?

To my knowledge, no major trial attempted to answer this question.  No such data is mentioned in the USPSTF systematic review.

Do the above benefits outweigh all its potential harms and risks?

So we cannot answer this question, because the benefits that might be most meaningful to patients (overall survival, symptom reduction, functional improvement, overall quality of life improvement) have not been clearly measured.

A Lack of Relevant Evidence

So the USPSTF guidelines, like other relevant guidelines, were based on the evidence that is available.  Since the evidence did not directly answer the most important questions, the guideline writers were left doing the best they could with evidence that only indirectly addressed the main issues.  No wonder they ended up unable to make a clear recommendation, and leaving the decisions to individual discussions, and individual discussions that would necessarily hinge on guesses about the unknown. 

One would think that a big point of discussion about breast cancer screening would be why after eight trials enrolling a total of about 350,000 patients reported over 20 years we still cannot answer the big clinical questions.  A related point for discussion in the US is why only one, and the earliest trial was conducted here.  If we here in the US think breast cancer screening is such a major concern (and we should think so), why have we been unable to mount a single important trial of it since the HIP trial conducted more than 30 years ago?

Instead, the rancorous debate in the US included...

Anecdotes, Some Irrelevant

The press found a number of women who said they would not be alive were it not for screening mammography before age 50.  With all due respect, one cannot tell whether an individual whose tumor was found on screening mammography would still have been diagnosed early enough for succesful treatment in the absence of screening mammography.  (And also with all due respect, we have no idea whether there also are cases of women who died as a result of treatments of tumors that never would have progressed, or cases of women who died of tumors caused by radiation from multiple mammograms.)  Reasoning from single cases when people, diseases, and treatment results vary so much is likely to mislead. 

It is somewhat ironic that some of the cases cited were of women who had breast cancer diagnosed before age 40, even though the debate was supposedly about screening from ages 40-49.  For example, in an inflammatory article that suggested that some "oncologists" might want the USPSTF sent to the prison at Guantanamo Bay, Washington Post editorialist Dana Milbank cited cancer activist Nancy Brinker, who mentioned her sister "whose breast cancer was found with a mammogram at age 37," (and apparently who tragically is no longer alive).(4) 

Going Well Beyond the Evidence

As noted above, no trial has shown that screening mammography for women under 50 increases overall longevity.  We all hope it does, but so far, there is no clear evidence that it does. 

Yet multiple media reports included assertions that screening mammography saves lives.   For example, the breast cancer activist mentioned above said, "mammography saves lives," apparently including mammography under age 50.(4)  An op-ed column by Dr Alan Kaye, chairman of radiology at Bridgeport Hospital, asserted "large, multinational research studies have shown that mammography saves lives in all age groups covered by the current guidelines."(5)  I would challenge him to show me a single such study that found a statistically significant increase in overall survival for patients under 50.  A Texas radiologist stated, "I diagnosed a 40-year old woman with breast cancer last week.  If she had waited 10 years, with pre-menopause breast cancer she would have been dead."(6)  Unfortunately, since she was just diagnosed, how can he be certain that she will survive any given amount of time?  How could he know that the cancer might not have become manifest, absent that single mammogram, later while still treatable? 

I do not want to be too hard on patients who do not appreciate that the outcomes of testing and treatment for breast cancer are not certain.  However, one would hope that physicians would be able to deal with this uncertainty.

Conflicted Opinions

Some of the more strident discourse came from those who may have had financial vested interests in promoting screening mammography.  Fugh-Berman and Bell pointed out numerous "fact-free emotionally charged statements" made by people who appeared to "reading from the same script-book."(7)  They identified that many of the loudest critics of the USPSTF guidelines were affiliated with not-for-profit organizations with impressive names, but also with substantial financial support from corporations that make products used in mammography.  Also, some had personal financial relationships with such corporations. 

An op-ed article by former US Food and Drug Agency (FDA) commissioner Dr Andrew von Eschenbach and Ms Nancy Desmond distorted the USPSTF guidelines to mean "most women should delay screening until they are 50," and claimed that was based on cost concerns, not clinical evidence.(8).  Desmond is the CEO of and von Eschenbach is now a senior advisor to the Center for Health Transformation.  The Center's members include numerous pharmaceutical and device manufacturing corporations, including several that make mammography equipment (e.g., GE Healthcare and Siemens).

Summary

Cancer, especially breast cancer, has major emotional connotations, and can be a difficult issue to deal with from many people.  The conflicting emotions cancer brings out in many patients may understandably affect their physicians, as well as friends and family.  Nonetheless, physicians, other health policy professionals, and health policy experts can serve patients better if they do not allow the patients' understandable affective responses cloud their understanding of the clinical and scientific issues. 

Yet the late 2009 debate in the US about screening mammography included many responses in which emotion seemed to overwhelm reason.  It may also be that some such responses came from people who had vested interests, or whose employers had vested interests that supported the emotional, rather than the reasoned approach.  Meanwhile, no one seemed to acknowledge that a big reason we are still debating this topic is that we have not made the effort or expended the resources to do good trials of sufficient size to answer the questions that need answering.  Of course, such trials might provide answers that would upset some people, or threaten others' incomes.  (As one news article pointed out, mammography is now a $5 billion a year industry in the US.)(6)

So my end of annus horribilis 2009 message on Health Care Renewal is to better serve our patients, from 2010 onward we health care professionals need  to try harder to put evidence and logic ahead of our own emotions, and certainly ahead of our financial self-interest.  

Note that numerous bloggers have taken on this topic, so see posts on Respectful Insolence, GoozNews,  Health Care Organizational Ethics, and the Evidence in Medicine blog.
References

1. US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement.  Ann Intern Med 2009; 151: 716-726. [link here]
2. Nelson HD, Tyne K, Naik A et al. Screening for breast cancer: an update for the U.S. Preventive Services Task Force.   Ann Intern Med 2009; 151: 727-737.  [link here]
3. Partridge AH, Winer EP. On mammography - more agreement than disagreement.  N Engl J Med 2009; 361: 2499-2501. [link here]
4. Milbank D. Feeling farther from the finish.  Washington Post, Nov 24, 2009.  [link here] 
5. Kaye A. An alarming retreat on early detection.  Hartford Courant, Nov 25, 2009 [link here]
6.  Jacobson SJ. Dallas-area clinics ignore proposed rules, still push for mammograms. Dallas News, Nov 27, 2009.  [link here]
7. Fugh-Berman A, Bell A. Mammography and the corporate breast.  Bioethics Forum, Nov 24, 2009.  [link here]
8. von Eschenbach A, Desmond N. Government panels can't put price on human life. Associated Press, Nov 24, 2009.  [link here]