A Condemnation of Suppression of Medical Research... by Ben Goldacre in the New York Times

Amazingly, this topic now seems to be in the mainstream.

The Goldacre Version in the New York Times in 2013

In his op-ed, Ben Goldacre introduced it thus:

the entire evidence base for medicine has been undermined by a casual lack of transparency. Sometimes this is through a failure to report concerns raised by doctors and internal analyses, as was the case with Johnson & Johnson. More commonly, it involves the suppression of clinical trial results, especially when they show a drug is no good.

He noted that this problems was supposed to be fixed by the registration of clinical trials, and by changes in editorial policies at medical journals:

many in the industry now claim it has been fixed. But every intervention has been full of loopholes, none has been competently implemented and, lastly, with no routine public audit, flaws have taken years to emerge.

 The Food and Drug Administration Amendments Act of 2007 is the most widely cited fix. It required that new clinical trials conducted in the United States post summaries of their results at clinicaltrials.gov within a year of completion, or face a fine of $10,000 a day.  But in 2012, the British Medical Journal published the first open audit of the process, which found that four out of five trials covered by the legislation had ignored the reporting requirements. Amazingly, no fine has yet been levied. 

An earlier fake fix dates from 2005, when the International Committee of Medical Journal Editors made an announcement: their members would never again publish any clinical trial unless its existence had been declared on a publicly accessible registry before the trial began. The reasoning was simple: if everyone registered their trials at the beginning, we could easily spot which results were withheld; and since everyone wants to publish in prominent academic journals, these editors had the perfect carrot. Once again, everyone assumed the problem had been fixed. 

But four years later we discovered, in a paper from The Journal of the American Medical Association, that the editors had broken their promise: more than half of all trials published in leading journals still weren’t properly registered, and a quarter weren’t registered at all. 

Goldacre's conclusions were:

Withholding data not only misleads doctors and patients; it’s an insult to the patients who have participated in clinical trials, believing that they were helping to improve medical knowledge. 

Medicine routinely overcomes enormous technical challenges, and there is nothing complicated about the changes needed to prevent Johnson & Johnson, or Roche — or anybody — from withholding information.

Hear, hear!

Our Version, Starting in 2003

Note that 10 years ago, in 2003, in my article on American health care dysfunction that could have been only published in Europe, (Poses RM. A cautionary tale: the dysfunction of American health care. Eur J Intern Med 2003 Mar;14(2):123-130.  Link here)  I noted that an important cause of this dysfunction is that:

the scientific basis of medicine is increasingly under attack.

The integrity of medical research has been violated by the deliberate suppression of its results.

At that time, I suggested one solution would be:

Medical schools and universities must re-affirm their support of scholarly work in the spirit of free enquiry,...

Furthermore, in one of our first posts on Health Care Renewal in December, 2004, in the context of the discovery of internal company documents (in this case, from Eli Lilly) that showed that information about the adverse effects of a drug (in this case, increased aggression associated with fluoxetine, that is, Prozac), we wrote,

The increasingly complex story of suppression of SSRI research seems to be part of a growing epidemic of suppression of medical research.

Let's say it again. Withholding data from clinical research is unethical because:
1. it breaks the promise to research subjects that their voluntary participation has scientific or social value, but undisseminated research has no value; (See Emanuel EJ et al. What makes clinical research ethical? JAMA 2000; 283: 2701-2711.)
2. it impedes scientific progress;
3. it prevents patients from receiving the best possible medical care.

But until this unethical behavior starts having negative consequences for its perpetrators, the epidemic of research suppression is likely to continue. 

Note the similarity to what Goldacre published in the Times yesterday.  You heard it here first.

Summary

To date we have published 102 posts with the label "suppression of medical research."  Obviously, Ben Goldacre's NY Times op-ed shows that suppression of research still rarely leads to negative consequences for its perpetrators.  Obviously, by making drugs, devices, and other health care interventions appear safer and more effective than they really are, suppression of medical research has lead to huge revenues for health care corporations, and has made many health care executives exceedingly rich, and many of the health care professionals and academic leaders who have enabled or implemented research suppression somewhat rich.  In the face of such perverse incentives, until we end the impunity of those who suppress medical research (and by the way, those who authorize, direct, or implement all sorts of other unethical, criminal and corrupt behavior we discuss on Health Care Renewal) things will not get better.  I can only hope that having this subject appear in a New York Times op-ed may lead to some real progress.

ADDENDUM (2 February, 2013) - see also comments on 1BoringOldMan blog. 

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.

What If the Institute of Medicine Wrote a Report and Nobody Followed it? - the Case of the Standards for Developing Trustworthy Guidelines

For over 20 years, clinical practice guidelines (CPGs) have been touted to improve health care quality and control costs.  Enormous numbers of guidelines have been developed, but with seemingly little impact on health outcomes.  While some of those leading health care organizations have predictably blamed individual practitioners for obstinately ignoring or challenging guidelines, there is increasing evidence that maybe the guidelines themselves are part of the problem.

 An Example of a Guideline that Apparently was Not Trusted

One example Dr Wally Smith and I have taught in our recurring mini-course on why physicians fail to follow guidelines (and otherwise appear not to practice in accord with others' wishes) is that of the guidelines on management of depression in primary care.  Most existing guidelines urge physicians to screen patients for (presumably mild-to-moderate) depression and treat them aggressively, with emphasis on the use of the newer anti-depressants.  These guidelines, in turn, were based on numerous published randomized clinical trials that showed that these drugs were safe and efficacious.  Yet multiple studies showed that physicians failed to follow these guidelines, and various attempts to improve their adherence did little.  So for years the assumption was that physicians at best experienced practical and system barriers to follow these guidelines, and at worst were ill-informed or irrational. 


However, information that came out gradually during the early part of the 21st century suggested that perhaps the problem was within the guidelines, not the health care professionals.  First, documents produced during New York Attorney General Eliot Spitzer's lawsuit against GlaxoSmithKline about the marketing of one of these drugs (Paxil, paroxetine) suggested that the company had suppressed clinical trial data that reflected poorly on the drug (See Kondro W.  Drug company experts advised staff to withold data about SSRI use in children.  Can Med Assoc J 2004; 170: 783.  Link here.)    These suspicions were later fleshed out  by consideration of documents further disclosed in litigation (e.g., see this post and its links).  Then several studies, most particularly that by Erick Turner and colleagues, showed that numerous trials of new anti-depressants had been suppressed, that is, never published (Turner et al. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008; 358:252-260.  Link here).  When the results of these trials were added to those that were published, the efficacy of anti-depressants was no longer so clear.  So maybe the guidelines that physicians did not follow were not trustworthy, and should not have been followed in the first place.

Would IOM Standards to Improve Guideline Trustworthiness Help?

So in 2011, the prestigious Institute of Medicine released a report on the development of  better standards to produce more trustworthy guidelines (Clinical Practice Guidelines We Can Trust.  Link here.)  We posted about that report here, but noted that it was receiving little other attention, an example of the anechoic effect. 

A few weeks ago, an article appeared documenting a study meant to assess the the trustworthiness of clinical practice guidelines published soon after the IOM report.  Its title telegraphs the results. ( Kung J, Miller RR, Mackowiak PA. Failure of clinical practice guidelines to meet Institute of Medicine standards: two more decades of little, if any progress.  Arch Intern Med 2012.  Link here.)

Methods and Results

The investigators selected a random sample of 114 individual guidelines available during June, 2011 stratified by 26 clinical topics. The versions of the guidelines used were those archived in the National Guideline Clearinghouse (NGC) maintained by the Agency for Healthcare Research and Quality (AHRQ).


The goal of the study was to "examine adherence to the IOM standards" by guidelines published after the standards were published.  Actually, the study only assessed adherence to 18 of the 25 standards espoused by the IOM (because the remaining seven were "too vague and subjective to be analyzed.")

Furthermore, the criteria used to determine if a specific guideline met each of the three items above were rather lax:

In evaluating each guideline summary, care was taken to be as liberal as possible in considering that a standard was met when the individual guideline summary provided any information pertaining to that particular standard.

Nevertheless, using these lax standards to only evaluate adherence to 18/25 guidelines, the authors found that "the overall median number of IOM standards satisfied (out of 18) was 8 (44.4%) ....  Fewer than half of the guidelines surveyed met more than 50% of the IOM standards."

An examination of the details of the study's methods reveals things are even worse than that.

Analyzing the Study's Methods to Find that Things Are Worse Than They Seem

Review of the study's methods show that they provided a very optimistic view of adherence to the IOM standards.  As noted above, the study did not look for adherence to all of the IOM standards.  Moreover, those they did consider were simplified and made less rigorous.  For example, Standard 2 from the IOM on management of conflict of interest (COI) was:

  STANDARD 2
Management of conflict of interest (COI)

2.1
Prior to selection of the Guideline Development Group (GDG), individuals being considered for membership should declare all interests and activities potentially resulting in COI with development group activity, by written disclosure to those convening the GDG.
- Disclosure should reflect all current and planned commercial (including services from which a clinician derives a substantial proportion of income), non-commercial, intellectual, institutional, and patient/public activities pertinent to the potential scope of the CPG.

2.2
Disclosure of COIs within GDG
- All COI of each GDG member should be reported and discussed by the prospective development group prior to the onset of their work.
- Each panel member should explain how their • COI could influence the CPG development process or specific recommendations.

2.3
Divestment
- Members of the GDG should divest themselves of financial investments they or their family members have in, and not participate in marketing activities or advisory boards of, entities whose interests could be affected by CPG recommendations.

2.4
Exclusions
- Whenever possible GDG members should not have COI.
- In some circumstances, a GDG may not be able to perform its work without members who have COIs, such as relevant clinical specialists who receive a substantial portion of their incomes from services pertinent to the CPG.
- Members with COIs should represent not more than a minority of the GDG.
- The chair or co-chairs should not be a person(s) with COI.
- Funders should have no role in CPG development.

However, the study boiled all this down to three items:
-  COIs stated
-  Chair has COI
-  Co-chairperson has COI

Thus the study did not address standards requiring full and complete disclosure (not just some disclosure) of all COIs; consideration of how the COIs might influence the particular guideline; divestment of specific types of conflicts of interest, that is, financial investments, and cessation of participation in marketing activities or advisor boards; minimization of conflicts of all members of the committee; and barring of participation of funders in guideline development.

Even so, the guidelines assessed did a very poor job upholding even these few liberalized standards regarding conflicts of interest.  Of the guidelines assessed, less than half, 46.8% provided ANY disclosure of conflicts of interest.  Those written by sub-specialty societies were particularly opaque in this regard.  Less than one-third, 29.3%, provided any disclosure.  Thus the majority of guidelines assessed were not at all transparent about conflicts of interest affecting the guideline development process.

Furthermore, of the 46.8% of all the guidelines which made any disclosures of conflicts of interest, 71.4% admitted their chair people HAD a conflict of interest.  Thus, only (0.468 * [1 - .714]) = 13.3% provided assurance that they fulfilled the single requirement (from standard 2.4 above) that the chair person did not have a COI.  For the guidelines written by sub-specialty societies, by a similar calculation, only 12.2% provided an assurance that the chair had no COI.  (The proportions providing assurance that the co-chair people had no COI were even lower.)  Thus the vast majority of guidelines did not clearly follow two straight-forward standards for minimizing the effects of conflict of interest, that the guideline committee chair and co-chair should not have any relevant conflicts. 

Given the miserable results concerning even minimal adherence to some of the IOM report's conflict of interest standards, it is likely that almost no published guidelines from 2011 came close to fulfilling the full set of IOM standards.  Despite the best efforts of the IOM, it appears that guideline developers have not progressed at all towards providing trustworthy guidelines. 

Summary

An editorial (Shaneyfelt T. In guidelines we cannot trust.  Arch Intern Med 2012) accompanying the article by Kung and colleagues summarized its results thus:

The same problems that have plagued guideline development continue to plague guideline development; namely, their variable and opaque development methods, their often conflicted and limited panel composition, and their lack of significant external review by stakeholders throughout the development process.   As a result, the trustworthiness of guidelines is limited.

While guidelines may have seemed to be a promising method to improve health care in the early 1990s, they have failed to live up to that promise.  Shaneyfelt was not optimistic they would improve in the future:

I am not optimistic that much will improve.  No one seems interested in curtailing the out-of-control guideline industry.

On the other hand, in my humble opinion, it is not that on one is interested in better guidelines.  It would clearly be in the best interests of patients and the public, and of health care professionals who care about the quality of their practice and the outcomes of their patients to curtail that industry.  The issue is why patients', the public's, and professional's interests were ignored.

Neither Shaneyfelt nor Kung et al discussed why there has been so little attention to patients' and the public's health, and to health care professionalism in all this.  For a quick answer, we do not have to look far on Health Care Renewal. 


In fact, the IOM report on guideline development from 2011 was a serious challenge to the powers that be in health care.  In particular, it challenged the cozy relationships that had grown up among the organizations that undertook guideline development and the health care professionals on guideline panels on one hand and organizations that stand to gain were specific guidelines to favor their products, services, and agendas on the other.  The standards mandated transparency and honesty about conflicts of interest affecting guideline committees and the organizations which assembled them, and if upheld would have greatly reduced these relationships.

Now it turns out that the guideline standards have been honored mainly in the breach.  Of course, these standards, while increasing trustworthiness, would have cost a lot of medical societies considerable commercial funding, and would have cost a lot of health care professionals on guideline panels considerable personal wealth.  These standards would probably also have cost a lot of companies whose products and services were addressed by guidelines to lose revenue.  So it is not surprising that the IOM standards were ignored.  Their implementation would have cost too many people who are financially benefiting from the status quo too much money.  And these people, that is, leaders of professional societies dependent on commercial outside funding, health care professionals and academic used to financial support from commercial interests, and health care corporations are good at making sure their interests are not ignored, even if their interests conflict with those of patients, the public, and well-intentioned health care professionals.  

So, the flouting of the well reasoned IOM guideline standards adds one more reason for patients and the general public to distrust modern health care and all those who "deliver" it, even to distrust well-intentioned health care professionals who have not been able to distinguish themselves from their colleagues who are too happy to help commercial interests while taking commercial money.  If health care professionals want to regain the public's trust, they could do worse than publicly declaring their intention to show that their practice in the future will be guided by trustworthy guidelines based on clinical research evidence and knowledge of biomedical science, drawn up by health care professionals independent of commercial interests.

When Clinical Trials are Meant for Marketing, not Science

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

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

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

Methods Summary

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

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

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

Strategies to Sell Drugs

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

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

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

How the Trials were Controlled by Marketers 

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

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

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

The marketers controlled content by controlling those who wrote it.

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

Manipulating the Dissemination (and Analysis) of Research Results

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

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

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

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

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

Summary

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

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

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

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

Back to the Future - Another Medical Device Company Accused of Hiding ICD Defects

Suppression of data about defects in and failures of implantable cardiac defibrillators (ICDs) was one of the big issues we featured in the early days of Health Care Renewal (2005-06). 

At that time, Guidant, later acquired by Boston Scientific, was accused of hiding data that certain of its defibrillator models failed, possibly leading to preventable patient deaths (see this post and follow links backward).  Boston Scientific, which acquired Guidant, settled a civil lawsuit and was put on probation in 2011 after it pleaded guilty to misdemeanor charges of failing to file required reports with the US Food and Drug Administration (see post here).   Similarly, in 2010, Medtronic settled multiple patients' lawsuits charging that it knowingly marketed a faulty ICD (see post here).

St Jude and the Obscure Riata Data

Now in 2012, A Wall Street Journal article suggested that St Jude Medical Inc hid problems with its Riata implanted cardiac defibrillator (ICD) for years.   

In December, 2010, St Jude Medical Inc issued a warning letter to doctors: Wires inside Riata defibrillator leads—cables that connect the heart to implantable defibrillators—were sometimes breaking through their insulation from the inside out.


The problem, which ultimately led to a recall last year, could cause defibrillators to send unnecessary jolts to the heart or fail to deliver lifesaving shocks to return chaotic heart rhythms back to normal. The company said it had identified dozens of cases with visible signs of the problem, and pulled Riata from the market.

For many doctors, this was the first notice of a problem with Riata.

But before that 2010 warning, physicians including Alan Cheng, director of Johns Hopkins Medicine's arrhythmia service; Samir Saba, chief of electrophysiology at the University of Pittsburgh Medical Center; and Ernest Lau at the Royal Victoria Hospital in Belfast, Ireland, say they had encountered this so-called "inside-out abrasion" in their own practices between 2006 and 2009. When these doctors brought the incidents to the attention of St. Jude they say they were told by company officials and field representatives that the incidents were isolated. The malfunctions described by the doctors didn't result in deaths.

St. Jude had been tracking the problem for several years, according to company documents collected by the Food and Drug Administration and reviewed by The Wall Street Journal. Cases involving the so-called inside-out abrasion date to at least October 2005, the documents show. Inside-out abrasion became a focus of an internal St. Jude audit, which examined multiple cases of the failure before April 2008.

The Journal article noted that more transparency about device failures might allow physicians to spot problems earlier and prevent harm to patients.

more than a dozen physicians and device-safety experts say that if St. Jude had acknowledged the inside-out failure earlier, physicians might have identified the scope of the problem sooner.


In some cases, doctors concede that they, too, believed the failures were isolated and therefore didn't act quickly to report problems to St. Jude or the FDA, which may have made it harder to spot the growing trend of failures. The leads were implanted in more than 13,000 patients since July 2008.

'Every time you have a failed lead, you assume it's an isolated event, but, you start to string together isolated events, and then you have a recall,' said Dr. Saba.

Summary

So, for Health Care Renewal, this is a straightforward case, at least so far.  Yet another health care organization, this time, a medical device company, failed to reveal data that might have reflected unfavorably on one of its products, and hence lead to decreases in short-term revenue.  However, by suppressing the information, the company may have allowed doctors to keep implanting a potentially faulty device, and exposed patients to risk, possibly of fatality. 

We have discussed many at least somewhat parallel cases of suppression of research (here), and many cases of other kinds of deception by health care organizations (here).  Yet these cases continue to occur, physicians and other health care professionals continue to be fooled by secrecy and data suppression, and patients continue to be harmed by drugs, devices, or other interventions made by people who knew, or ought to have known that they were more dangerous than they appeared to be. 

One problem may be that the people with the most influence on medical practice and health policy continue to cheer lead for the veracity of information about drugs, devices, and other health care interventions supplied by the people who most stand to gain from selling same.  A few weeks ago, the editor of the august New England Journal of Medicine, Dr Jeffrey M Drazen MD, scoffed at physicians' skepticism of pharmaceutical industry funded clinical research, claiming that there were only "a few examples of industry misuse of publications...." [Drazen JM. Believe the data. N Engl J Med 2012;  367:1152-1153.  Link here.]  In doing so, Dr Drazen seemed to ignore all the stories about suppression of medical research (some of which we have discussed here), manipulation of medical research (some discussed here), and deception (some discussed here) and secrecy (some discussed here) practiced by large health care organizations, including but not limited to drug, device, biotechnology, and health care information technology companies.

Instead, the possibility that St Jude kept hidden data about the failings of one of its ICD models reminds us how skeptical we ought to be about the information provided, or not provided by those with vested interests in selling health care goods or services.  Physicians, health care professionals, those interested in health policy, and the public at large need to collectively exert pressure on the leaders of health care organizations to promote greater transparency, especially about data reflecting on benefits and harms of health care goods and services.  . 

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.

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

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

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

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

Research Studies Designed Primarily as Marketing Vehicles

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

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

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

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

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

Manipulation of Research Design, Implementation, or Analysis

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

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

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

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

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

The Role of Key Opinion Leaders

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

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

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

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

Summary

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

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

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

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

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

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

Guidant (Boston Scientific) Gets Probation

The latest in the parade of legal settlements by health care corporations involves a new wrinkle. 

We have been writing about the case of Guidant Corporation's faulty implantable cardiac defibrillators (ICDs) in 2005, almost since the start of the Health Care Renewal blog.  A quick summary, via the Minneapolis Star-Tribune, is:

In 2005 Minneapolis Heart Institute doctors Barry Maron and Robert Hauser went public with concerns about a Guidant defibrillator called the Ventak Prizm 2 after a 21-year-old patient died when his defibrillator short-circuited and failed to revive him after he went into sudden cardiac arrest.

Guidant had known about the short-circuiting issue since 2002 and had made two attempts to fix the device, according to court documents. The company did not alert the FDA -- even though federal law requires manufacturers to report changes that may pose a health risk to patients.

In early 2004, Guidant discovered a similar short-circuiting problem in different defibrillator models called Contak Renewal 1 and 2. The company ordered its factory to stop making and shipping the models, but potentially faulty products on hospital shelves continued to be implanted in thousands of patients.

Although engineers at Guidant had recommended recalling the Contak Renewal devices, upper management rejected the proposal, court documents state. Instead, Guidant issued the 'least aggressive' form of communication, called a product update, in which sales representatives were told to tell doctors that 'nothing was broken' with the device.

Maron and Hauser met with top Guidant officials in May 2005 and urged the company to communicate the problem to doctors, but Guidant refused. The doctors then went to the New York Times, which published an article indicating that the company had known for three years that the Ventak Prizm model could short-circuit, but did not communicate that to doctors.

In June 2005, Guidant issued a public missive detailing safety issues with the defibrillators, which were later recalled by the FDA.

A longer version from a series of Health Care Renewal posts can be found here.

In 2010, Guidant, now a subsidiary of Boston Scientific, agreed to a settlement which would involve guilty pleas to misdemeanors and payment of a large ($296 million) fine, but the settlement was rejected by a federal judge who found it to be too lenient (see post here). Now the judge has approved a new version, again per the Star-Tribune,

In what is believed to be the largest criminal penalty ever imposed in a medical device case, a federal judge on Wednesday approved an agreement calling for Guidant Corp. to pay $296 million for concealing safety information about several of its heart devices.

The denouement in U.S. District Court in St. Paul ended a difficult chapter for one of the biggest players in Minnesota's signature medical technology industry. Thirteen patient deaths have been associated with faulty devices made by Arden Hills-based Guidant, which is now part of Boston Scientific Corp. The controversy lingered for almost six years and raised questions about how safety issues involving medical devices are communicated to the Food and Drug Administration, doctors and patients.

Last April, U.S. District Judge Donovan Frank rejected a previous $296 million settlement between the Department of Justice and the company. This time that fine remained intact, but Frank also called for Boston Scientific to serve three years' probation.


Boston Scientific will be required to make quarterly reports to the U.S. Probation Office regarding safety and compliance issues, as well as submit to regular, unannounced inspections of its records. Frank also called upon Boston Scientific to continue charitable programs intended to raise awareness about heart disease.

'I believe this serves not only the interests of the community and the interests of justice, but respect for the law and corporate responsibility,' Frank said.

The new wrinkle is, of course, probation. I have not previously heard of a US health care corporation put on probation in a criminal settlement. Presumably, the idea is that probation will involve court supervision of the company that might be less lenient than US Department of Justice oversight via a corporate integrity agreement.

So this is a small step forward, but once again, the extent that this settlement will deter future bad behavior seems small. Once again, although the fine imposed seems large, it is small compared to the money to be made by selling these very expensive devices. Moreover, the cost of the fine can be diffused over the entire company, and ultimately over all its employees, its stockholders, and its customers.

Since no individual will pay a penalty, and since it is likely some individuals made themselves rich or richer from the company's actions, it is likely that other individuals in the future will authorize, direct, and implement similar bad behavior to fatten their bonuses and total compensation.

Last June, we noted that some government officials were starting to talk tough about imposing penalties on individuals for misbehavior by health care corporations. In fact, in 1943, the US Supreme Court found that corporate leaders could be held responsible for corporate bad behavior, the so-called Responsible Corporate Officers doctrine. However, the laissez faire malaise that apparently infected most government officials starting in the 1980s seemed to prevent anyone from invoking this doctrine during the last 30 years of health care dysfunction. That malaise still seems to be rendering US federal law enforcement effete, at least when applied to wrong-doing by big, powerful, rich health care corporations.

So like Cassandra, fated to have her predictions always ignored, I repeat: When it comes to health care's leadership, society seems to have acceded to defining deviancy down. Until we start holding health care leaders to high standards, expect their organizations not to uphold high standards.  Further, expect organizations that did not uphold high standards in one instance to fail to uphold them in other instances.  If we really want high quality accessible, reasonably priced health care, we need true health care reform that reduces concentration of power in large organizations, and makes health care organizations' leadership accountable, ethical, and transparent. That will not be easy.

Forest Pharmaceuticals Pleads Guilty to Obstruction of Justice, No Individual Pays Any Penalty

The parade of legal settlements marches on.  The latest story is about Forest Laboratories and its marketing of Celexa (citalopram ) and Levothyroid (l-thyroxin).  Here is the most complete version, courtesy of Natasha Singer reporting for the New York Times. First, the lead sentence:

A unit of Forest Laboratories, the maker of the antidepressant Celexa, agreed on Wednesday to pay more than $313 million to settle criminal and civil complaints, including a claim that it had illegally promoted the drug for use in children.

Here are the charges:

Among the criminal charges was one that the subsidiary, Forest Pharmaceuticals, marketed Celexa, which was approved only for adult depression, to treat children and adolescents. The government also claimed that, in conjunction with the company’s off-label promotion, Forest publicized the positive results of a study on Celexa in adolescents while failing to tell doctors about a similar study that had negative results.

'Forest Pharmaceuticals deliberately chose to pursue corporate profits over its obligations to the F.D.A. and the American public,' Carmen Ortiz, the United States attorney for the District of Massachusetts, said in a statement Wednesday.

In addition, federal prosecutors accused Forest of paying doctors to induce them to prescribe Celexa and another antidepressant, Lexapro. The remuneration included 'cash payments disguised as grants or consulting fees, expensive meals and lavish entertainment, and other valuable goods and services,' the government said in its civil complaint.

Among the items that Forest sales representatives gave to doctors from 1998 to 2005, the complaint said, were tickets to St. Louis Cardinal games, which were to be 'leveraged and sold as a reward for prescriptions'; a $1,000 gift certificate to Alain Ducasse, a gourmet French restaurant, for a high-prescribing child psychiatrist; a deep-sea fishing trip off Cape Cod for a doctor and his three sons; $400 in Broadway theater tickets for a doctor and his wife; and Red Sox tickets worth $2,276 to be used for doctors in the Boston area.

So we not just off-label marketing, but suppression of clinical research (of course, a study whose results were not favorable to the product being marketed), and payments to doctors as an "inducement to prescribe."

But wait, there is more:

As part of the criminal settlement, Forest Pharmaceuticals, which is based in St. Louis, agreed to plead guilty to one felony count of obstructing justice, acknowledging that employees had lied to F.D.A. officials during a plant inspection in 2003.

The company also agreed to plead guilty to two misdemeanors, one of which covers the company’s misbranding of Celexa by marketing the antidepressant for use in children from 1998 to 2002.

The other misdemeanor covers the illegal distribution from 2001 to 2003 of an unapproved drug, Levothroid, to treat a thyroid hormone deficiency. Such thyroid pills, made by various drug makers, had been sold in the United States since the 1950s without F.D.A. approval. But in 2001, the agency told drug makers that they needed to reduce their distribution of such medications until the companies obtained agency approval to market the pills.

The criminal charges accused Forest of making a deliberate decision to continue distributing the drug in quantities exceeding the F.D.A.’s directive. After the agency sent a warning letter to Forest, the company directed employees to work until 1 a.m. to continue shipping as much Levothroid as possible, according to the criminal complaint.

So there was also obstruction of justice in the form of lying to the FDA, and selling drugs that the FDA had ordered not to be sold.

So what are the penalties?

The criminal settlement calls for the company to pay a $150 million fine and to forfeit an additional $14 million in assets. Forest will also pay more than $88 million to the federal government and more than $60 million to the states to resolve a civil complaint that its actions caused false claims to be submitted to federal health care programs. In addition, two whistle-blowers will split $14 million from the federal share of the settlement.

Forest has also entered into a five-year corporate integrity agreement, requiring an independent expert to review the company’s compliance with drug marketing regulations.

So here we go again. A large drug company was up to no good, suppressing research, paying doctors for their prescriptions, lying to the FDA, and disobeying its orders.

The penalty seemed large, over $300 million. However, Celexa was a big revenue generator at the time the events above occurred, topping $1 billion in revenue first in 2002 (per Forbes here). Furthermore, as noted by Ed Silverman on Pharmalot, it seems no individual will suffer any negative consequences for authorizing, directing, or implementing the conduct described above. Finally, as best I can tell, despite the fact that a Forest subsidiary will plead guilty to a felony, the company is not going to be barred from doing business with the government. 

So, despite pleading guilty to a felony and three misdemeanors, neither Forest as a company nor any individual working for the company will really suffer very much.  On the other hand, the leaders of Forest have been doing very well.  The company's CEO, Howard Solomon, was number 18 on Wall Street Journal list of the 25 highest paid CEOs over the last decade.  His total realized compensation was over $385 million over the last 10 years.  According to the company's 2010 proxy statement, his total compensation in 2009 was $8,267,236.  The four other highest paid executives made from just over $2.5 million to $5.3 million.

So here we go again.  Another large health care organization has been found to have done wrong, but the only penalty is a fine that whose impact will be diffused across the whole company, and ultimately be paid by its employees, its customers, including patients, and its stockholders.  Meanwhile, the people who authorized, directed, or implemented the wrong doing apparently will pay nothing and receive no negative incentives.  Furthermore, the top leaders of the company, whose huge compensation in the past was increased by the results of the wrong doing, will continue to prosper.

As we have said again and again,  we will not deter unethical behavior by health care organizations until the people who authorize, direct or implement bad behavior fear some meaningfully negative consequences. Real health care reform needs to make health care leaders accountable, and especially accountable for the bad behavior that helped make them rich.

By the way, the current case offers an avenue for those who do not like what Forest did to ask those who are supposed to be ultimately responsible for its behavior how this was allowed to happen.  The board of directors of the company is supposed to be ultimately accountable for the company's actions.  As we have noted before, these directors are supposed to "demonstrate unyielding loyalty to the company's shareholders." [Per Monks RAG, Minow N. Corporate Governance, 3rd edition. Malden, MA: Blackwell Publishing, 2004. P.200.]

The current directors of Forest Laboratories, according to the company's 2010 proxy statement, include Dr Nesli Basgoz, "Associate Chief for Clinical Affairs, Division of Infectious Diseases, Massachusetts General Hospital (MGH)," and "Associate Professor of Medicine at Harvard Medical School."  Also, it includes Dr Lester B Salans, "Clinical Professor" at Mount Sinai Medical School, not to mention Dr Peter J Zimetbaum, "Director of Clinical Cardiology" at Beth Israel Deaconess Medical Center in Boston (BIDMC), and "Associate Professor of Medicine at Harvard Medical School."   Maybe some enterprising student journalist will get to ask the good doctors how they let things at Forest get so ethically out of hand.