No Needle, but the Damage was Done - A New Example of Suppression of Research about Adverse Effects of Prescription Narcotic Analgesics

This story feels personal, since as a physician who trained starting in the 1970s, figuring out how to manage patients who desperately wanted narcotics, whether to relieve pain, relieve addiction, or relieve financial distress has been a constant challenge.

Background  - Treating Pain while Avoiding "the Needle and the Damage Done"

Almost as soon as I started clinical training in medical school I came up against the problem of narcotics.  In the 1970s, narcotic addiction was a pressing problem that threw a dismal shadow over society..  In the hospital and emergency room we daily saw overdoses and the complications of narcotics addiction, including some particularly nasty infections like bacterial endocarditis,  While dealing with these, we tried to do our best to manage the severe pain of cancer and other relentless diseases with limited tools, narcotics being the most potent.

We knew that we should not let our bleak experiences with addiction to illicit narcotics prevent us from giving adequate pain medication to those with metastatic cancer.  However, it was never clear how to best to help people with chronic pain from diseases that were not so immediately deadly.  And whatever it took we wanted not to promote "the needle and the damage done."


Things did not become easier in the 1990s when we  incessantly heard about under-diagnosis and under-treatment of  pain, and how we should not be so afraid of addiction and other adverse effects when prescribing legal narcotics.  As we heard this, however, it seemed that more people with less well-defined chronic pain were coming to us seeking relief, sometimes while preoccupied with narcotics as the solution to their problems.  Yet many of these patients seemed at risk of addiction, appeared already addicted, or even appeared to be seeking drugs so they could sell them to others.

In my most recent clinical position, it seemed I was always dealing with new patients with years of obscure musculoskeletal pain who felt I was the miracle physician they were seeking, often specifically to prescribe something like Vicodin, Percodan, or Oxycontin.  When on weekend call I inevitably hear from some poor patient who had somehow run out of or lost an important medication, which turned out to be Vicodin, Percodan, or Oxycontin, and just needed a simple refill without the bother of actually seeing a doctor.  Etc, etc, etc.

How could I relieve real suffering without becoming the pusher man? 

The Over Promotion of Narcotic Pain Treatment  

Then the realization began to dawn that patients, doctors and society were being victimized by a new type of pusher man, this time dressed in a suit and working for an "ethical" drug company.  In the earlier days of Health Care Renewal, we first posted (in 2006) about allegations of deceptive and unethical promotion of fentanyl by Cephalon that lead to its overuse by patients beyond those with cancer who were its ostensible target population.  Then in 2007 came the spectacular case of guilty pleas by a subsidiary of Purdue Pharma and several of its executives for "misbranding" Oxycontin,  that is, promoting it far beyond any medically legitimate use in severe chronic pain.  Following that various investigations, well chronicled in the Milwaukee Journal Sentinel, showed how pharmaceutical companies employed deceptive marketing techniques, subverting medical education and research, and creating conflicted key opinion leaders and institutionally conflicted disease advocacy groups, to push more "legal" narcotics  For example, see the Journal Sentinel reports the subversion of :  medical schools and their faculty; .medical societies, disease advocacy groups, and foundations; and guideline writing panels.  In 2012, we posted about how a drug company paid key opinion leader admitted to second thoughts about his role promoting narcotics.

The realization that that overtreatment of chronic pain, now matter how sketchy, never mind the adverse effects of narcotics, was driven by greed and marketing did not make managing chronic pain and patients who wanted narcotics easier.

One strategy we used was to try to find drugs nearly as effective as narcotics (although we began to realize that narcotics are also notw as effective as we thought) but less addictive.  The latest story by the indefatigable John Fauber of the Milwaukee Journal-Sentinel suggests that strategy too was subverted.

 Suppression of Research about Addiction to Tramadol

One workaround I sometimes attempted was to prescribe tramadol (e.g., Ultram, Janssen), an opioid which was promoted as non-narcotic and non-addicting.  However, like many quick pharmaceutical solutions to difficult problems promoted in the last few years, that did not often seem to work as well as expected.  Now, per Mr Fauber, it appears that

the FDA failed to heed a key piece of research indicating tramadol had the potential to be abused when it first appeared on the U.S. market in 1995. The drug was not placed under the Controlled Substance Act.

Despite recent research affirming its abuse potential, restrictions on prescribing it are no more stringent than for Lipitor or Viagra.

The Controlled Substance Act places drugs into five progressively restrictive categories based on their abuse potential. At the top of the list are drugs such as heroin. At the other end are cough medicines with limited amounts of codeine.
In deciding tramadol need not be on the list, the FDA based its decision largely on research in which the drug was injected as well as reports from Europe, where it had been on the market for years, that showed very little abuse.

However, the agency also had unpublished research showing that when given to opioid abusers orally in high doses, rather than being injected, it produced opiate-like effects that were similar to those from oxycodone, the narcotic in OxyContin, one of the most abused drugs in America. 

Oops.  Here is more detail about the suppressed research,

Tramadol was first introduced in Germany in 1977.

Data from Germany had suggested it was only about one-tenth as potent as morphine when injected. Other data showed that after years of use in Germany and other countries there was very little abuse of the drug.

However, in the early 1990s, researchers at Johns Hopkins University did a study in which high doses of the drug were given orally to opioid abusers. Taken that way, tramadol acted much differently than when injected.

At very high doses it produced opiate-like effects that were similar to high-dose oxycodone.

Taken by mouth, the drug is transformed in the liver to a metabolite known as M1, which is able to attach to and activate opioid receptors in the brain. It is M1 that is believed to produce the desirable, opiate-like effect.

In 1994, Ortho-McNeil, part of the R.W. Johnson Pharmaceutical Research Institute of Johnson & Johnson, sought approval from the FDA to sell its brand-name version of the drug, Ultram, in the United States.

The Johns Hopkins study never was published, but the company said it was provided to the FDA.

Also, oops.  The FDA decided not to list the drug as a controlled substance, realized more thought might be needed in the future, but did not appear too worried about who would be doing the thinking.  

That was when the FDA allowed Ortho-McNeil to fund its own committee, separate from the FDA, that would monitor the country for problems with the drug.

While it was called an 'independent steering committee,' Ortho-McNeil paid for the group's work and also paid consulting fees to its members.

Sidney Schnoll, a former member of the committee, said he could not remember how much the committee members were paid. In total, the program cost Ortho-McNeil about $15 million a year, said Schnoll, now an executive with Pinney Associates, a Bethesda, Md., company that works with drug and opioid companies.

'There was absolutely nothing independent about this group,' said Andrew Kolodny, a New York addiction specialist and advocate of tighter controls on opioids.

From early on, Ortho-McNeil's marketing plan for tramadol meant keeping it off the list of controlled substances where it would have difficulty competing against other narcotic painkillers such as Tylenol 3 and Tylenol 4, Schnoll said in a 2009 interview. Both Tylenol products contain codeine and are schedule 3 drugs.

The Schnoll interview was done by two professors, one from the University of Florida and one from Rensselaer Polytechnic Institute in New York, as part of a project at University of Michigan Substance Abuse Center.

'There were equally good products that were cheaper on the market,' Schnoll said, according to a transcript of the interview. 'So they really wouldn't have much of the market. They wanted to see if it would be possible to get the drug onto the market as a non-controlled substance.'

After a decade, the eight-member Ortho-McNeil committee dissolved itself in December 2005, without ever having recommended that tramadol be put under the Controlled Substances Act.

Oops, again.  Meanwhile, the adverse effects of tramadol were becoming more apparent.

An analysis by the Journal Sentinel and MedPage Today found that tramadol use is up dramatically since 2008, the earliest year for which data is available. It rose from 25 million prescriptions that year to nearly 40 million in 2012, according to data from IMS Health, a market research firm.

In 2011, the drug was linked to 20,000 emergency department visits around the country. In Florida alone, there were 379 overdose deaths involving tramadol that year, up from 106 in 2003, according to the DEA.

In Milwaukee County, 20 people died of a drug overdose involving tramadol from 2010 through October 2013, according records from the Medical Examiner's Office. In most of those cases, tramadol was one of several opioids that had been taken.

Final oops.  Perhaps no needles were involved, but the damage was being done.  

Summary - Goddam the Pusher Man

The over-promotion of addictive narcotics for pain relief has become an instructive example of deceptive and unethical practices used by commercial health care firms seeking revenue no matter what it takes to get it.  Just the latest article on tramadol illustrated the use of paid key opinion leaders and more broadly, the creation of conflicted medical academics for marketing objectives (here, apparently, obfuscating the dangers of the product); the suppression of clinical research (for the same reason); and at least raised the possibility of regulatory capture.  It seems unlikely that whoever made the decisions to use the tactics worried about adverse effects including loss of the integrity of research, subversion of academic medicine, ;undermining medical decision making, and obviously most importantly direct harm to patients.  (I would note that the decision makers appeared to be working for Johnson and Johnson, a company which seems to have a growing history of questionable behavior.)  

Health care professionals should at least learn that the pusher man does not always look like a character out of Easy Rider.

Vested Interests and Their Influence on Physicians- New Understanding from Cognitive and Social Psychology

Evidence-based medicine proposes patient care decisions based on the best evidence from critically reviewed clinical research, knowledge of biology and the biopsychosocial context, and patients' values and preferences.  Yet physicians often fail to make evidence-based decisions, despite many efforts to educate, or incentivize them to do so.  We used to think that the main reason was physicians' lack of knowledge and understanding of EBM, and human cognitive limitations that make such evidence-based thinking difficult.  However, now we realize that physicians are deluged by  attempts to influence their decisions so as to favor vested interests, whether or not that is good for patients.

We have discussed various kinds of deception used in marketing meant to increase physicians' prescriptions for drugs, and recommendations for devices and health care services.  Physicians have not proved to be very resistant to these methods.

Now a new article provides a different perspective on how marketers use cognitive and social psychology to manipulate physicians.(1)  Sunita Sah's and Adriane Fugh-Berman's introduction stated,

Physicians often believe that a conscious commitment to ethical behavior and professionalism will protect them from industry influence.  Despite increasing concern over the extent of physician-industry relationships, physicians usually fail to recognize the nature and impact of subconscious and unintentional biases on therapeutic decision-making. Pharmaceutical and medical device companies, however, routinely demonstrate their knowledge of social psychology processes on behavior and apply these principles to their marketing. 

The article then listed a number of findings from social (and cognitive) psychology that marketers may use to their advantage on naive physicians.

Psychological Mechanisms Promoting Acceptance of Conflicts of Interest and Dubious Marketing Ploys

First, marketers may take advantage of cognitive biases and psychological mechanisms that allow physicians to accept marketing maneuvers while denying the effect of marketing on their decision making.

Confidence and Over-Confidence

People are strongly influenced by messages delivered with confidence and do not take the trouble to ascertain the accuracy of these messages if doing so requires effort or money.

I would add that many humans, including physicians, are also over-confident in the accuracy of their own judgments.  (In 1989 we showed  that physicians often were excessively confident in their judgments of patients' outcomes, in particular, about survival of critically ill patients.)(2)

Of course, marketers often state their messages with great confidence regardless of their accuracy.

So physicians need to try to restrain their own over-confidence, and be more skeptical of the confidence of others. Maybe this would just be an exercise in simple humility.

Self-Serving (or Ego) Biases

People tend to believe that the results of their decisions, or of their groups' decisions, are better than average.  This can be called the Lake Wobegon effect (from Garrison Keilor's fictional town in which all the children are above average.)

We and others have shown that physicians may be overly optimistic about the outcomes of their own (versus others') patients, or their clinical units' (versus others') outcomes, again in the context of predicting survival of critically ill patients.(3)  We have also posted about how corporate boards of directors seem to almost always think that their hired executives are better than average, at least when determining their executive compensation.

Similarly, Sah and Fugh-Berman wrote,

Physicians believe that their own prescribing behavior is unaffected by industry influence, although they concede that other physicians are susceptible to such influence.

Furthermore,

Social psychology research confirms that people have a 'bias blind spot,' namely, they are more likely to identify the existence of cognitive and motivational biases in other than in themselves.

But, as Dana and Lowenstein wrote,

It cannot both be true that most physicians are unbiased and that most other physicians are biased.

So, to put it bluntly, physicians ought to be more humble about their own ability to resist outside influences and the resulting biases. Again, some simple humility might help.

Cognitive Dissonance

Sah and Fugh-Berman pointed out that

While articulating and believing in the importance of scientific objectivity, physicians' biases to accept industry gifts create cognitive dissonance; that is, discomfort that arises from discrepancy between conflicting beliefs, or between beliefs and behaviors.

So,

Cognitive dissonance theory specifies three methods - not mutually exclusive - by which people manage or reduce dissonance.  Changing one of the dissonant beliefs, opinions or behaviors (possibly a difficult or painful process that requires sacrificing a pleasurable behavior or treasured belief); Lowering the importance of one of the discordant factors which can be accomplished by denial - forgetting or rejecting the significance of one or more of the conflicting cognitions; and adding consonant elements that resolve or lessen the dissonance (this may involve rationalizations to buffer the dissonance between conflicting cognitions.)

Physicians may use denial and rationalization to reduce cognitive dissonance caused by their concurrent desire for relationships with marketers and others with vested interests on one hand, and their professionalism and its obligation to put patients' needs first on the other hand.  Sah and Fugh-Berman cited Chimonas and colleagues,

Denial included (a) avoiding thinking about the conflict of interest; (b) rejecting the notion that industry relationships affect physician behavior, and (c) disavowing or universalizing responsibility for problems that arose from conflicts of interest ('there's always a conflict of interest...').  Rationalizations included (a) asserting techniques that would help maintain impartiality and (b) reasoning that meetings with drug reps were educational and benefited patients.

We have discussed various public justifications for accepting conflicts of interest by physicians and other health care decision makers that employed a variety of logical fallacies along these lines.

So physicians need to re-examine their treasured beliefs and the gratification they get from relationships with industry (as opposed to those with patients, colleagues, friends and families).  They could remember the advice that no one can serve two masters.

Sense of Entitlement

Physicians' sense of entitlement, especially given the increasing stress upon them, may be used to rationalize relationships with drug, device and biotechnology companies since these corporations seem to be among their few friends (versus insurance companies, government agencies, and sometimes hospital administrations whom physicians feel may be more burdensome.).  So, in one study,

Implicitly reminding physicians of the burdens of medical training and their working conditions more than doubled reported willingness to accept gifts....

So physicians need to reconsider that to which they feel entitled.  This is the third instance in which some humility might help. 

Principles of Influence Used by Marketers

Markets seem to also be well acquainted with the six principles of influence and persuasion identified by Cialdini and colleagues.

Reciprocity

The norm of reciprocity - the obligation to help those who have helped you - is one of the guiding principles of human interaction

This is the foundation of the effect of relatively small conflicts of interest, such as giving of small gifts.

Physicians pay off industry gifts through changes in their practice

Furthermore,

Gifts associated with a subtle implicit request may be more likely to achieve compliance than gifts that call for explicit reciprocation. 

So physicians need to be wary of Greeks, or anyone else bearing gifts, even those less conspicuous than wheeled horses.

Commitment and Consistence

Consistency is highly valued in our society and associated with rationality and stability.  After committing to a decision or opinion, people justify that choice or opinion by remaining consistent with it.

So marketers try to get physicians to make small commitments to leverage larger ones.  This is

why drug reps, ask, for example, 'will you try my drug on your next five patients?'

So physicians should remember there is no virtue in commitment to erroneous beliefs.  "A foolish consistency is the hobgoblin of little minds." - Ralph Waldo Emerson

Social Proof

This is basically the deliberate deployment of the logical fallacy of the appeal to common practice.

Social proof, also referred to as social validation or conformity, is the practice of deciding what to do by looking at what others are doing.

So,

If accepting industry gifts is a cultural norm in medicine, physicians will continue to do so.  The opinions of colleagues are often used by industry representatives to sway physicians to adopt a particular therapy. 

This may be why industry works so hard to sign up health care academics.

Trainees in an institution, for example, are affected by the institution's stated policies but also - and sometimes more so - by what they see their mentors do.

So physicians, who often pride themselves on independence, need to be skeptical about the need to follow the crowd.

Liking or Rapport

The more you like someone, the more you are apt to follow their advice, even if your feelings towards them have been manipulated.

This is obviously why drug representatives, for example, are so nice to physicians.

Physicians often feel overworked, underpaid, and unappreciated [ed note -  and their is plenty of evidence, some of which we have discussed on this blog, that this is not unreasonable.]  Drug reps dispense sympathy, flattery, food, gifts, services and income-enhancing opportunities and seek to ask nothing in return but scholarly consideration of the benefits of drugs.

So physicians need to reconsider who really are their friends, and be skeptical of "friends" with something to sell. 

Authority and Security

This is basically the deliberate deployment of the logical fallacy of the appeal to authority.  The best example is industry's efforts to recruit key opinion leaders, that is health professionals who are perceived as authority figures, but have really been hired to market.

From an industry perspective, the best KOLs radiate status and authority while successfully convincing their peers (and perhaps themselves) of their illusory independence and lack of bias.

Note that

KOL speakers not only influence audience members' prescribing behavior, but also - as predicted by cognitive dissonance theory - become more convinced themselves of the benefits of the products they endorse.

So physicians need to be skeptical of those claiming to be authorities, especially when they are connected with people who have something to sell.

Summary

We used to strongly believe (and Dr Wally Smith and I used to teach a course to the effect that) the major barrier to true evidence-based practice was the cognitive limitations that physicians share with all humans.  We thought in terms of cognitive biases and the inappropriate use of cognitive heuristics leading physicians to inaccurately judge the probabilities of diagnoses and medical outcomes, and thus make less than optimal decisions.

Now it seems apparent that the deliberate influencing of health professionals' judgments and decisions by external actors, mainly those interested in selling more products and services, but sometimes by those with ideological or political motives, is currently a much more important challenge to evidence based practice.  It looks like the influencers may be very knowledgeable about human cognitive limitations and how social psychology influences judgment and decisions, and may use this knowledge to pursue their vested interests, at the financial and physical expense of patients, and ultimately the public.

 True health care reform would encourage professional education designed to increase resistance to external influences that put self-interest ahead of patients' and the public's health, and careful regulation that would decrease some of the more dangerous practices used.  Of course, much more resistance might be achieved if physicians used a little more common sense when dealing with people who are obviously trying to sell them on goods, services, or ideas.  A good proportion of the deceptive methods discussed above could be countered by remembering the usefulness of humility, skepticism, and a few simple aphorisms.   

Again, as we have written repeatedly, not only should all conflicts of interest be disclosed for the sake of honesty, but physicians and other health professionals ought to consider repudiating most of all of them, maybe at some personal expense, but in the interest of re-establishing their commitment to putting the patient, not their own self-interest, or the vested interests of others, first.  
 

References

1.  Sah S, Fugh-Berman A. Physicians under the influence: social psychology and industry marketing strategies.  J Law Med Ethics 2013; 14:  . Link here:

2. Poses RM, Bekes C, Copare F, Scott WE.  The answer to "what are my chances, doctor?"  depends on whom is asked: prognostic disagreement and inaccuracy for critically ill patients.  Crit Care Med 1989; 17: 827-833.  Link here.

3. Poses RM,  McClish DK, Bekes C, Scott WE, Morley JN. Ego bias, reverse ego bias, and physicians' prognostic judgments for critically ill patients. Crit Care Med 1991; 19: 1533-1539.  Link here.

Doctors' Dubious Excuses for Taking Pharmaceutical Companies' Money

Pro Publica has updated their database of payments by pharmaceutical payments to physicians and organizations.  It now has data from 15 companies totaling more than $2 billion from 2009 to 2012.

To accompany Pro Publica's report, a number of news outlets wrote about payments given to local or regional doctors.  These included, in semi-random order, the Los Angeles Daily News (via the Inland Valley Daily Bulletin), the Salt Lake (City, Utah) Tribune, the San Jose (California) Mercury News, NewsChannel5 in Nashville, Tennessee, the Pasadena (California) Star-News, the Bergen and Passaic, New Jersey Record Herald via NorthJersey, the Philadelphia Inquirer, and the Columbus (Ohio) Dispatch.

The combined reports showed that many physicians, including prominent academics and community practitioners, are still getting a lot of money from pharmaceutical firms.  Since Pro Publica was only able to get data from some US drug companies, albeit those who accounted for 47 percent of US drug sales, it is likely that many more doctors than those in the data base got such payments, and the doctors in the data base may have gotten more money from companies that do not report their payments.  In addition, it is likely that many more doctors get similar payments from medical device companies, health care information technology companies, and other for-profit corporations that promote health care products and services.  

We had discussed Pro Publica's initial reporting from its database here.  While there is evidence that most payments to doctors by pharmaceutical companies are intended to promote marketing, we discussed here how some doctors rationalized their payments as fully professional and proper.

Now the updated reporting has provided many examples of - not to put too fine a point on it - physicians making dubious excuses for their acceptance of payments, often large, from pharmaceutical companies. Their themes included

It's Education, What Could Possibly Go Wrong?

From Pro Publica,

[Dr Rakesh] Jain, of Lake Jackson, Texas, has earned $582,049.  [Dr Vladimir] Maletic, of Greer, SC, made $527,850, according to Dollars for Docs.

So,

Jain said he loves teaching and delivers the same lectures about drugs and medical conditions regardless of whether a drug company is paying him.

'I am not a marketer, I am an educator,' Jain said.

Also

Maletic said he speaks about treatments for mood disorders, schizophrenia and sleep-wakefulness disorders because he believes that 'good quality education about pharmaceutical products may be beneficial to both physicians and their patients.'

The LA Times found someone with a similar opinion.

'Pharmaceutical companies used to take doctors to dinner, but that was banned years ago,' said Dr. Arthur Chanzel Jeng, an infection control specialist at UCLA-Olive View Medical Center in Sylmar.  'Now they must provide some educational content.'

Jeng was paid $80,500 by Pfizer last year for several speaking engagements. As an infection control specialist at Olive View, he and others in his field are concerned about drug resistant diseases and the limited number of antibiotics. Drug companies have little incentive to produce new antibiotics, he said, so if they do, physicians in his field want to know more about the drugs. That's why he agrees to speak.

'We (speakers) provide education when a new antibiotic does get released,' he said. 'There needs to be education among doctors on how to use this new antibiotic.'

In addition, the Salt Lake Tribune noted that 

[Dr Eliot] Brinton received two of the single largest payments in Utah, both in excess of $85,000, for promoting drugs by GlaxoSmithKline, ProPublica’s database shows. He describes the lectures as educational and based on science.

'I love the science and I love to teach. And doctors are glad to better understand the drugs and how to use them. I’m careful not to act as a cheerleader,' he said. 'If I’m a shill for the drug company I lose my integrity and integrity is really all I have to offer my patients and the drug companies.'

The physicians above all asserted that since their activities were "educational," they must be worthwhile.

Note that the ostensibly educational activities described above all appear to be "drug talks," that is talks sponsored by the drug companies, probably through speakers' bureaus, and given probably not as part of formal, accredited continuing medical education.  Since the publication of "Dr Drug Rep" in the New York Times in 2007, the public has learned that such talks mainly include content provided by the pharmaceutical companies, and are meant by the companies as marketing exercises.  From that case we also learned that physicians who deviate from the marketing message do not last long on speakers' bureaus.  (See posts here and here.) 

In addition, pharmaceutical companies often pay physicians deemed to be "key opinion leaders," whose opinions are promoted supposedly for their brilliance and erudition.  However, as noted here and here, the companies buying their services believe they have bought the services of sales people.    Evidence about key opinion leaders actually performing like marketers has come from documents revealed during litigation (e.g., see this recent example of a huge monetary settlement made of charges that GlaxoSmithKline, a major multinational drug company committed fraud among other things, and in the course of its unethical activities used key opinion leaders as marketers).   Also, see the Neurontin marketing plan (see post here), and the Lexapro marketing plan (see post here) for examples of how company keaders view key opinion leaders as marketers.

Given the volume of evidence about drug talks, speakers' bureaus, and the marketing purposes of key opinion leaders, the assertion that because they were in some sense educational, these doctors' corporate financed talks were worthwhile is at best a silly excuse.

More formally, it may arise from a logical fallacy.  The doctors appeared to be arguing that education is an unalloyed good.  However, obviously not all education is good education, or unbiased education. Specifically in this case, logic, and evidence from several cases in which pharmaceutical companies' intentions as documented in communications revealed in litigation (see examples here) suggest that these companies pay physicians for education that they believe serves marketing purposes.Thus the doctors seem to be using the composition fallacy, the logical fallacy that an entire class (in this case, all of education) can be judged by some of its members (examples of unbiased, accurate, good education.) 

It's Research, What Could Possibly Go Wrong? 

Similarly, the doctors who get paid to do research say it's all about the research.  The Salt Lake Tribune reported on

CRI LifeTree Research, which has received at least $3.4 million in drug company payments since 2009, according to ProPublica. 

Co-founder Lynn Webster, an anesthesiologist, is listed as having received the single largest payment in the state: $1,687,771 from Cephalon, a big maker of pain medications. Only three other doctors in the country received more from Cephalon.

Nationally, Webster is among the top 50 for single largest payments received, behind marquee hospitals, such as the Mayo Clinic, Cleveland Clinic and Duke and Harvard Universities.

A nationally recognized expert in pain management, Webster is under investigation by the U.S. Drug Enforcement Administration, which is looking into opioid overdose deaths of patients of his former pain clinic. A Senate Committee is probing his financial ties to Big Pharma.

Webster insisted,

Research payments to him cover overhead and other costs, including his salary as a lead researcher, he said. 

'Research inevitably leads to better education, better systems and better therapies — things that are indispensable for medical advancement and quality care,' he said. 

The Pasadena Star-News provided this version,

Pasadena-based plastic surgeon John Edward Gross received more than $770,000 from Allergan, the maker of Botox and some breast implants.

In 2011-12, Allergan paid Gross to conduct research, consult, serve on health care panels and business travel.

'What I'm doing for Allergan is to advance breast surgery,' said Gross, a board certified surgeon and a former chemical engineer. 'Much of the research you do is industry-supported. They have a motivation to make better and new products.'

It is pretty amazing to see the notion that all clinical research is irreproachable in print.  We and others have documented huge numbers of cases and volumes of evidence that clinical research may be manipulated, and, if necessary, suppressed to support the commercial goals of those who make products or provide services assessed by such research.  In fact, the prestigious Institute of Medicine's report on Conflict of Interest in Medical Research, Education and Practice included the recommendation (4.1) that "individuals may not conduct research with human participants if they have significant financial interest in an existing or potential product or a company that could be affected by the outcome of research."  Given the volume of this evidence, the assertion that all pharmaceutical company clinical research should be irreproachable is just plain silly.

Again, formally the physicians' arguments, if they should be dignified with that name, seem to arise from the same logical fallacy discussed above.  The underlying argument seems similar to that made above about education: "I am doing research.  All research is good, unbiased, helpful to patients.  So what I am doing is good, unbiased, helpful research."  So it appears the composition fallacy again was in play.

It's Not Really My Money

The San Jose Mercury News provided this example,

The database links Dr. Gurkirpal Singh to more than $248,000 in Pfizer payments it lists for speaking, consulting, travel and meals since 2009. He said all the money went to Institute of Clinical Outcomes Research and Education in Palo Alto, where he is the chief scientific officer. Singh said the money paid for research.

'I receive nothing -- let me be very clear on that,' said Singh, who is an adjunct clinical professor at Stanford University.

The Columbus Dispatch added,

 Dr. Henry Nasrallah, a psychiatrist at the University of Cincinnati, netted $647,341 in speaking and consulting fees from drug companies, ranking him as Ohio’s top recipient of such payments over that four-year period. Cincinnati’s College of Medicine put that money toward his $222,232 annual salary.
'The (pharmaceutical) companies have a signed agreement with the university for my activities, not with me personally,' Nasrallah wrote in an email to The Dispatch.

'This is another reason why I maintain scientific and clinical impartiality about the various drugs I teach, because I do not have a direct personal gain,' wrote Nasrallah, a former chairman of Ohio State University’s psychiatry department.

Really, the boss doesn't care whether he brings in any money?

These doctors seem to be denying that money is fungible.  In other words, they seem to be arguing that money going to the organizations that pays them is different from money going directly to them, and that their bosses do not in fact care whether their activities bring any revenues to the organization.  This just flies in the face of common sense.

Someone Needs to Pay

NewsChannel5 was able to interview the top earner on the Pro Publica list, Dr Jon W Draud, who said among other things, 

it was only fair to accept payments for his speaking engagements because it makes up for what he would otherwise make while working at his practice.

 'It's not essential, I suppose, but I consider it a reasonable, fair compensation for being gone and traveling, and spending time away from my home and family,' Draud said.

If Dr Draud was providing education, a useful service, it seems reasonable that someone should pay for it.  However, he appears to beg the question of who should pay for it?  Underlying this question is the concern that since it was pharmaceutical companies, not students, who were paying, the education was being done primarily to benefit the former, through marketing, rather than the latter.  The apparent argument, that because it is not reasonable to get paid for services, any source of payment is acceptable, is again just plain silly. 


Who Cares About Money?

NewsChannel5 also reported that Dr Draud said

 accepting so much money did not create a conflict of interest between him and his patients. He said the information he gives out was not biased towards the drug companies.

However, the Institute of Medicine report on Conflict of Interest in Medical Research, Education and Practice defined conflict of interest as "circumstances that create a risk that professional judgments or actions regarding a primary interest will be unduly influenced by a secondary interest."  Asserting that receiving over $1 million could not create even a risk that his educational presentations were biased towards the interests of those who gave him that money seems like simple denial.  

The FDA Said it Was True

Top earner Dr Draud also said according to NewsChannel5,

 It has to be vetted by the FDA as being fair, balanced and non-biased toward the pharmaceutical company....

From the Philadelphia Inquirer, re Dr Warren S Joseph, a podiatrist who received over $650,000

Joseph acknowledged the payments in an email to Philly.com.

'All of my lectures given for the Pharma industry follow strict FDA guidelines and are consistent with the corporate integrity agreements entered into between the companies and the government,' Joseph said. 'There is full disclosure of this fact at all lectures.'

 These justifications appear to be just plain wrong.  As far as I know, the US Food and Drug Administration does not pre-approve "drug talks" given by physicians for pharmaceutical companies.

By the way, the statement by Dr Joseph approaches self parody.  As we have discussed, corporate integrity agreements are usually the products of legal settlements of charges of wrongdoing.  Drug companies do not sign such agreements because of previous good behavior.  Moreover, I have never heard of such an agreement that required pre-approval of drug talks, either. 

 Trust Me, I'm an Expert

 As reported by NorthJersey,

One of the top recipients in North Jersey was Thomas Dayspring, an internist and expert in cholesterol management, who earned just under $400,000 from Merck and GlaxoSmithKline. Dayspring said he was paid for lectures at conferences for doctors arranged by the drug companies, as well as continuing medical education programs.

'I’ve logged over 2 million miles, all over the world and in all 50 states,' said Dayspring, who served as the director of the North Jersey Institute of Menopausal Lipidology in Wayne until last summer. 'Guys like me who are nationally known attract a big audience. Not every speaker can trot out a CV like mine.'

New Jersey, you gotta love it.  The most charitable characterization of this is an appeal to authority, albeit an amazingly egotistical one. 

Summary

 Two years after Pro Publica's report, pharmaceutical companies are continuing to pay substantial sums to physicians and other health professionals, nominally for education and research.  Because these arrangements are financially beneficial to the professional recipients of the money, and likely financially beneficial via their marketing effects  to the companies that provide the money , it should be no surprise that they are continuing in the absence of any regulatory restrictions.

What is saddest about the latest reporting is the silliness of the excuses made by the conflicted physicians.  Professionals with four years of education post-college, and multiple years of experience, and who are often respected as academics or practitioners ought to be able to reason and argue better than they did in the examples above.  Of course, people who make a lot of money often come to believe they really deserve it.  And conflicts of interest produce conflicted thinking.  As Joe Collier wrote in the BMJ, " people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult." (Look here.)

The IOM  report  on conflicts of interest suggested full disclosure of all payments that could be considered conflicts of interest, banning clinical research by conflicted individuals, prohibiting academic physicians from giving "drug talks" whose content was provided by industry, and developing methods to fund continuing medical education independent from industry.  This report, and its recommendations have gotten scant attention, maybe because they would threaten a status quo that enriches conflicted health professionals and the companies that create these conflicts.  However, in my humble opinion, implementing all the report's recommendations would only be a beginning down the road of restoring the integrity of clinical care, teaching, and research.  

Oh, the Prices we Pay ... for Questionable Drug Marketing to Enrich Corporate Insiders - the Case of Questcor's H P Acthar Revisited

In 2007, we first discussed the case of the amazing pricing of H P Acthar, a very old drug of questionable usefulness, as an example of the irrationality of health care prices in the US, and of the failure of the organizations that ought to resist outrageous pricing in our mixed, pseudo-market based health care system to do so.  A recent New York Times article has updated this case.

Background

As we wrote in 2007, ACTH (adrenocorticotrophic hormone) is a naturally occurring hormone that stimulates the activity of the adrenal gland, which produces cortisol and other glucocorticoid and mineralocorticoid hormones.   ACTH produced from pigs' adrenals was first marketed as a biologic agent in the 1940s.  It was used for some conditions that appear to benefit from the effects of increasing cortisol production induced by ACTH.

It has been traditionally used to treat infantile spasms, a rare but distressing condition, and exacerbations of multiple sclerosis (MS).  However, since the drug was introduced so long ago, it was never subject to rigorous controlled trials to assess its efficacy and adverse effects for these indications.  Furthermore, since the 1940s, synthetic glucocorticoid hormones have become widely available as generic drugs.  Yet these slightly newer drugs have never been rigorously compared to ACTH for infantile spasms or MS.  The most recent review (edited in 2009) by the Cochrane Collaboration found that steroids and ACTH have some evidence in their favor for the treatment of acute MS, but found no evidence showing that ACTH was superior.  [Filippini G, Brusaferri F, Sibley WA, Citterio A, Ciucci G, Midgard R, Candelise L. Corticosteroids or ACTH for acute exacerbations in multiple sclerosis. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD001331. DOI: 10.1002/14651858.CD001331].  Also, the most recent review (edited in 2009) of treatment of infantile spasms concluded, "it is not clear which treatment [including ACTH] is optimal." [Hancock ED, Osborne JP, Edwards SW. Treatment of infantile spasms.  Cochrane Database of Systematic Reviews 2008, Issue 4. Art. No. : CD001770. DOI: 10.1002/14541858.CD001700.pub2.]

The Pricing of H P Acthar

Possibly because some physicians thought ACTH might be useful for some patients with two conditions, infantile spasms and acute exacerbations of MS, ACTH has remained on the market.  It was manufactured by a single company, Aventis, (now part of Sanofi-Aventis), the successor to Rhone-Poulenc-Rorer.  In 2001, Aventis sold the rights to manufacture ACTH, with the trade name H P Acthar, to a new, small biotechnology company, Questcor.  In 2007, Questcor raised the price of ACTH from $1650 per vial to more $23,000 per vial.  That got the attention of the Philadelphia Inquirer, on whose article we based our commentary. We used the price increase as an example of how pricing in health care has become untethered from any sort of clinical reality, and wondered why insurance companies and the US government seemed willing to pay this outrageous price for an old drug with little evidence from clinical research to support its use.  But the issue then seemed, like many others we have discussed , to become anechoic, until the very end of 2012.


Now the  New York Times story has provided an example of how health care corporations can do very well without doing anyone, except corporate insiders, much good.  It included instances of many of the kinds of ethically questionable practices we have discussed over the years on Health Care Renewal.

Deceptive Marketing

Per the NY Times,

Questcor did almost no research or development to bring Acthar to market, merely buying the rights to the drug from its previous owner for $100,000 in 2001. And while the manufacturing of Acthar is complex, it accounts for only about 1 cent of every dollar that Questcor charges for the drug.

Moreover, the tiny 'orphan' market soon became much bigger. Before long, Questcor began marketing the drug fo multiple sclerosis, nephrotic syndrome and rheumatologic conditions, even though there is little evidence that Acthar is more effective for those other conditions than alternatives that are far cheaper. And the company did so without being required to prove that the drug actually works. That is because Acthar was approved for use in 1952, before the Food and Drug Administration required clinical trials to show a drug is effective for a particular disease. Acthar is essentially grandfathered in. 

Today, only about 10 percent of the drug’s sales are for infantile spasms. The new uses, Mr. Bailey has told analysts, represent multibillion-dollar opportunities for Acthar and Questcor, its sole maker. 

The results have been beyond even the company’s wildest dreams. Sales of Acthar, which accounts for essentially all of Questcor’s sales, totaled nearly $350 million in the first nine months this year, up 145 percent from the period a year earlier. In the same period, Questcor’s earnings per share nearly tripled, to $2.12. In the five years after the big Acthar price increase in August 2007, Questcor shares rose from around 60 cents to about $50, in one of the best performances of any stock in any industry. 

So Questcor leadership was clever enough to use loopholes in the law to promote ACTH for particular kinds of patients without any good evidence that it did those patients any good.  Furthermore, Questcor used several questionable tactics 

in this promotion.

Manipulated Research

Apparently Questcor leaders decided they needed some sort of minimal research results to promote their products, so as the Times reported,

Because Acthar was approved for these conditions decades ago, Questcor has not had to do large clinical trials to show that the drug works. It has paid for some small studies, mainly by individual doctors, who then publish a paper that the sales force can present to doctors. 

The study that justified calling on rheumatologists involved five patients with rare conditions, all of them treated by a single doctor. All the patients had much improvement on Acthar after failing to benefit from more standard therapies, the doctor, Todd Levine, said in a Questcor conference call.

Too call the research Questcor sponsored minimalist would be too polite.  A case series of five patients, lacking any control group proves almost nothing.  It proves less when the research is done in an unblinded  fashion by a single doctor who presumably was invested in the outcome being favorable for his sponsor's product.  (I suppose some might quibble with calling this research manipulated, but I contend but doing such crude research when it would be possible to do something much more credible amounts to manipulation.)

Suppression of Research

Moreover, it seems that even such rudimentary studies sometimes failed to produce the wanted results.  In these cases, the Times reported that Questcor simply suppressed them.

Still, it appears that at least a couple of small studies that may have raised questions about the drug have been suspended. 

'From my standpoint it just didn’t work,' said Dr. Sungchun Lee, a Phoenix nephrologist who stopped a small study testing Acthar as a treatment for nephrotic syndrome. 'I think they were O.K. with me stopping because we weren’t getting the results,' he said. 

Another study that was terminated sought to determine whether multiple sclerosis patients who did not have a good response to steroids should be treated with either another round of steroids or with Acthar. The study was halted midway through 'to analyze data,' according to the summary of the trial on the federal clinical trial database. 

Use of Paid Key Opinion Leaders

Despite the lack of good clinical evidence in support ACTH, there are some physicians who defend its use.  One example in the Times article was a physician who is paid by Questcor

But some doctors say Acthar can be effective in cases that are not well treated by steroids. They say that there is emerging evidence that Acthar does more than just stimulate the body to produce its own steroids. 

'It really looks like the ACTH does bring something different to the table that standard steroids don’t,' said Dr Ben W Thrower, director of the multiple sclerosis institute at the Shepherd Center, a hospital in Atlanta. Dr. Thrower, who is a paid speaker for Questcor, said his institute had tried Acthar for about 60 of its 3,000 patients, ones who did not respond to steroid treatment. Acthar made the symptoms subside in about half of them.

Where to begin?  Just because ACTH is different does not mean it is better.  Since MS is a disease whose symptoms wax and wane, patients who fail standard treatment may get better on their own, and without a control group, it is impossible to say whether the ACTH given to such patients was the reason they got better. 

Creation of Institutional Conflicts of Interest for Disease Specific Foundations

Questcor's ACTH also has support from a disease specific foundation, but one that Questcor has also supported financially.

Dr Lawrence Brown, a neurologist at the Children's Hospital of Philadelphia, and the president of the Child Neurology Foundation, says of Questcor: 'They have gone out of their way to help every kid who needs the medicine to get it quickly and efficiently.'

This year, the foundation awarded its first corporate citizenship award to Questcor. Dr. Brown says Questcor’s donations — the amount has not been disclosed — to the foundation didn’t influence the award.

Who could be so naive to think that giving an organization funding might influence its actions?  After all, human response to financial incentives is the basis for most current economic thinking.

Insiders Get Rich

Admittedly, these questionable tactics did lead to an increase in "shareholder value,"  As the company's proxy statement boasted in 2011,

While we generated strong financial returns in 2011, we are most proud of our patient focus and investments in Questcor which we believe will generate sustainable value to our shareholders, employees, patients and all of the communities that we serve. We believe that our patient focus and commitment to generating sustainable value to all of our constituencies results in strong value creation for our shareholders.

However, as of today, Qustcor's share price has dropped to $26.74 from a peak of 53.42 in June, 2012, with most of the drop in December, 2012, around the time the Times article came out, according to Google Finance.  So whether share holder value will turn out to have increased in the long run is not clear. 

Meanwhile, some Questcor employees did very well.  The largess started with some drug representatives,

Questcor sales representatives who are lucky enough or skillful enough to have a big prescriber in their territory can reap bonuses of $50,000 a quarter, according to former employees of the company.

More highly placed corporate insiders did even better.

Executives are paid well, too. In 2009, Mr. Bailey, [the CEO]  hired his daughter Kirsten Fereday as director of business analytics and evaluation, a job that paid $275,000 in cash and stock last year. 

 Left out of the Times article, somewhat surprisingly, was what the top executives make.  Information from up to 2011 is publicly available, however, in proxy fillings.

In the company's 2012 proxy statement, we find the following figures for total compensation:
Don M Bailey, President and CEO - $4,546,230, up 192% of his compensation in $1,554,503 in 2009
Michael H Mulroy, Senior Vice President, Chief Financial Officer and General Counsel -  $1,749,891 (his first year)
Stephen L Cartt, Chief Operating Officer -  $2,298,308, up 168% from $855,460 in 2009
David J Medeiros, Executive Vice President and Chief Technical Officer - $1,232,556, up 78% from $692,188 in 2009
David Young Pharm D, Chief Scientific Officer - $1,948,804 up 182% from $1,066,159 in 2009

In addition, by 2011, Mr Bailey, the CEO, had acquired 1.92% of the company's total stock, 3,834,910 shares, today worth $102,545,490.

Finally, per the Times,

one group of shareholders has done pretty well for itself. Over the last two years, as the company’s share price mainly soared, Questcor insiders have sold more than $100 million of stock. 

Summary

 So, in summary, a small biotechnology company drastically increased the price of its only product, a drug which has never been subject to modern clinical trials, and whose efficacy has never been proven.  Its marketing tactics have included manipulation and suppression of research, and payments to physicians and non-profit organizations.  Although its most breathtaking price increases were made in 2007, they attracted little public attention until five years later.   Meanwhile, corporate insiders, from drug representatives to top executives and their relatives, have done very well for themselves.

In the US, there a lot of people who advocate free market based health care for its efficiency and innovation.  For example, see "Yes, Mr President, a Free Market Can Fix Health Care," published by the Cato Institute, in which its Director of Health Policy Studies proclaimed, "The great advantage of a free market is that innovation and more prudent decisionmaking means that fewer patients will fall through the cracks," and then "a free market can and would control costs, expand choice, improve health care quality, and make health coverage more secure." [italics added for emphasis]

Unfortunately, the case of Questcor's ACTH makes it seem that in the current US system, which is supposedly more market based than systems in many other countries, the efficiency and innovation is characteristic of the marketing of corporate health care, not of the health care itself.  Here is a stellar example of how clever, and not always very scrupulous marketing can be used to sell a very old drug with little demonstrated clinical value for a stratospheric price, enriching corporate insiders, perhaps enriching stockholders (although, not so much lately, and we will see how they do in 2013), at the expense of the public who pays taxes and insurance premium.  This case suggests a need for more attention to market failures and less insistence on market fundamentalism.  Of course, it also suggests the continuing need for health care professionals, policy makers, patients and the public to be extremely skeptical about heavily promoted commercial health products.

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.     

BLOGSCAN: Key Opinion Leader Admits to being a Marketer

Without any notable shame, and as a guest blogger on KevinMd.  The post was about other physicians can become big-time KOLs by using social media, and refers to another post which indicates that pharmaceutical companies look for physicians who are big prescribers of their products and have a lot of influence to, guess what, help market their products.  Although the blogger refers to ethics more than once, how it is ethical to trade on the trust physicians get for their professional vows to put patients first to market products (that may not always be good for patients) remains beyond me.

ADDENDUM (27 August, 2012) - See also comments by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog.  

Giant GSK Settlement Provides Reminder of the Pervasiveness of Stealth Marketing

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

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

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

No individuals have been charged in any of these cases.

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

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

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

Manipulation of Clinical Research

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

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

Manipulation of Study Endpoints

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

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

Manipulation of Data

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

Manipulation of Dissemination

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

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

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

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

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

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

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

Suppression of Clinical Research

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

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

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

Bribing Physicians to Prescribe

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

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

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

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

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

Use of Key Opinion Leaders as Disguised Marketers

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

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

Consulting Fees as Kickbacks

In general,

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

In particular,

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

Also,

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

Manipulation of Continuing Medical Education

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

Furthermore,

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

Summary

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

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

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

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

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

In fact, as the New York Times reported,

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

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

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

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

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