Continuing Dissection of the Infamous Study 329

On the 1BoringOldMan blog, semi-anonymous blogger Mickey has been dissecting in detail the infamous Study 329 that GlaxoSmithKline used to promote Paxil (Seroxat, paroxetine) as safe and effective for children and adolescents, when the study data, rigorously analyzed, showed that was not the case.  Study 329 was an important part of the US Department of Justice case against GSK that resulted in a record $3 billion settlement (see this post). 

The posts so far are:
A Pretty Rotten Era  
A Movement
To Make Distortion Possible
The Lesson of Study 329: the Basics
The Lesson of Study 329: Efficacy Drifts to Trends and 2s
The Lesson of Study 329: Conventions and Protocols
The Lesson of Study 329: Uh-oh
The Lesson of Study 329: Data Transparency
The Lesson of Study 329: the Authors

This does not seem to be the end of the series, but the last post yesterday did have a striking conclusion:

But, for the moment, I am stuck on the piece that is, to me, the most fundamental lesson from this story, and unfortunately many similar stories in the industry-funded clinical trial literature that fills our journals. The authors of this study did not function as physicians, clinicians, scientists, or even authors. Some were there because of their previous credentials. Others were there to build up future credentials. But they weren’t there to do what they presented themselves as doing. Researchers are practicing medicine too. I might be seen as naive to see this as the center of this story. If that’s the case, I’ll go to my grave being naive. Medicine has been my life, and this isn’t Medicine.

There’s no place or tradition for physicians, particular physicians in high places, taking part in this kind of bullshit – particularly all the while claiming otherwise. The fact that it has been a widespread practice isn’t an excuse. That’s also an even stronger indictment. There are many principled neuroscientists working in this difficult area of medical science who’ve been tarnished by this kind of pseudoscience. There are many psychiatrists and other practitioners who’ve actually trusted these deceitful articles. And there are untold numbers of patients who’ve been medicated un-necessarily or even directly harmed by this and other capricious advise coming out of these studies – this one in particular. Rather than functioning as the advisers of ill people, these were physicians who actively participated in capitalizing on patients’ illness.

However, despite the seriousness of these concerns, and their corroboration in the Justice Department document that pushed GSK to settle for so much money, my alma mater, Brown University, where Dr Martin Keller, the lead author of Study 329, was Chair of Psychiatry, has consistently refused to revisit the study, and consistently failed to publicly refute the accusations against Dr Keller, nor to accept them and take appropriate action.  The University supposedly conducted an internal investigation of the matter, but has not seen fit to make it public.  When asked again about this, Brown's new President, Christina Paxson, referred the inquiry to the public relations people:

'The recent announcement by the U.S. Department of Justice did not suggest that any further reviews of the paper by the university are immediately warranted,' Darlene Trew Crist said in a written response. 'We have no further statement to make at this time.'

Given the seriousness of the allegations, and the University's mission:

The mission of Brown University is to serve the community, the nation, and the world by discovering, communicating, and preserving knowledge and understanding in a spirit of free inquiry, and by educating and preparing students to discharge the offices of life with usefulness and reputation.

the logic of the administration's refusal to have a public discussion of this case escapes me. As I have said before (in 2008!), the appearance of continued stonewalling, now going on for years, can easily be interpreted to imply that the institution has something really big and bad to hide.

Also see comments by Alison Bass on the Alison Bass blog, and by Dr Howard Brody on the Hooked: Ethics, Medicine and Pharma blog.

ADDENDUM (4 September, 2012) - There have been two additional posts on the 1BoringOldMan blog on Study 329:
the lesson of Study 329: the hurdles…
the lesson of Study 329: naked Emperors, fractious Queens…

ADDENDUM (4 September, 2012) - See also this post on the Alison Bass blog.

ADDENDUM (5 September, 2012) - See this post on the retirement of Dr Keller by Ed Silverman on PharmaLot.

ADDENDUM (10 September, 201) - See the final two posts in the 1BoringOldMan series:
the lesson of Study 329: “we’re only as sick as our secrets”…
the final lesson of Study 329: epilogue…

His conclusion in the next to last post of the series:

Something terrible happened in psychiatry, an alliance between the pharmaceutical industry and a number of our leaders who allowed their academic credentials to be used for commercial purposes. It happened on a large scale, and in the process shamed all of us, whether we were involved or not. Many of the people we looked to to guide us fell into the role of key opinion leaders – a marketing term that meant that they could influence what we did and how we practiced. And in that new role, medical degrees, academic positions, the methods of science, and psychiatric experience became little more than marketing tools in a commercial campaign. Such was the case with Study 329 – an article that has become exemplary because it is now so painfully well known – a symbol for the failings of an era. It needs to be retracted simply because it was wrong on purpose – and we all know it. And yet no involved person, institution, or organization highlighted in that last paragraph has swallowed their pride, or guilt, or denial, or arrogance and called for retraction.

[Italics and bold typeface added for emphasis]

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.

To Sir Andrew? With a Settlement - GlaxoSmithKline to Settle for $3 Billion, CEO Said to Pursue Knighthood

Two weeks ago, reports of the largest legal settlement involving a pharmaceutical company to date in the US appeared. 

The $3 Billion Settlement

In summary, per the Philadelphia Inquirer,

In perhaps the largest penalty ever paid by a pharmaceutical company, GlaxoSmithKline said Thursday it had reached a tentative deal with the U.S. Justice Department to pay $3 billion to settle criminal and civil allegations of illegal marketing practices and pricing under a Medicaid program.

Why the deal was announced this month is not clear. Neither are all its provisions:

Glaxo said the deal would be made final in 2012, but it was unclear why it was announced now. A spokeswoman declined to say whether Glaxo would have to live by a corporate integrity agreement, which the government sometimes requires in such cases.

The Inquirer listed some possible reasons for the settlement,

As for Glaxo's latest situation, one investigation, started by the U.S. Attorney's Office in Colorado and later run on a national level by the U.S. Attorney's Office in Boston, looked at Glaxo's marketing practices related to nine of its best-selling drugs, including Paxil, Wellbutrin, and later Advair.

In a second investigation, the Justice Department looked at Glaxo's possibly inappropriate use of rules exceptions when reporting prices charged for drugs for different situations in the marketplace. Under part of the Medicaid Rebate Program, drugmakers are supposed to report the lowest price they charge most organizations, which is then used to calculate the price that Medicaid ultimately pays for its drugs.

The third investigation, also by the Justice Department, was over how Glaxo promoted the diabetes drug Avandia, which was pulled from European markets and severely restricted last fall by the Food and Drug Administration after it was shown to cause heart attacks.

As commonly occurs in such cases, GSK and its CEO averred that all the sorts of conduct that lead to this settlement are old news:

The company said in a statement that since 2008 it had 'established a new framework for compliance in the U.S., based on the company's values, policies and established industry codes of practices. It is supported by a larger compliance staff and strengthened training programs that require certification by employees.'

The changes included new incentive formulas for sales representatives, eliminating sales targets for bonuses.

'This is a significant step toward resolving difficult, long-standing matters which do not reflect the company that we are today,' Glaxo chief executive officer Andrew Witty said in the statement. 'In recent years, we have fundamentally changed our procedures for compliance, marketing and selling in the U.S. to ensure that we operate with high standards of integrity and that we conduct our business openly and transparently.'

As is also usual, none of the reports included any acceptance of responsibility for the bad conduct by GSK or any of its leaders, and certainly they did not mention any negative consequences for any persons who might have authorized, directed, or implemented the misbehavior, even giving, as is apparently true in this case, that some of the behavior was at least alleged to be criminal.

A Settlement for a Knight?

It was not clear why this settlement was announced this early in such a preliminary, and vague manner. However, a post on the PharmaLot blog suggested one motivation:

As the calendar year draws to a close, the UK government is busy readying the next list of individuals who are to be honored as members of the Order of the British Empire. These honors are bestowed on people from all walks of life who have somehow made a difference in their community. And there are various types of awards, including knighthood, that recognize a different type of contribution.

The list, however, is a closely guarded secret. Presumably, even Rupert Murdoch employees would have a hard time hacking into the treasured line up of nominees. But one name that may be under consideration is Andrew Witty, the ceo at GlaxoSmithKline. Our sources say that Glaxo minions have been encouraged to find ways to hone his image in hopes that he becomes Sir Andrew.

So one could speculate that being able to clear up these "difficult, long-standing matters," could be touted as a task that only could be accomplished by a knight. That might have been plausible if Mr Witty recently rode into town on a white horse, and then dispatched these old legal demons.

Some More History

In fact, that is not what happened. Per his official GSK biography,

Andrew Witty became Chief Executive Officer of GlaxoSmithKline plc on 21 May 2008. He is a member of the Board and Corporate Executive Team.
Andrew joined Glaxo in 1985 and held a variety of Sales and Marketing roles in the UK business.
He has worked in the Company’s International New Products groups, both in the Respiratory and HIV/Infectious disease fields and has been involved in multiple new product development programmes.
He has also worked in South Africa, The USA and Singapore where he led the Group’s operations as Senior Vice President, Asia Pacific. While in Singapore Andrew was a Board Member of the Singapore Economic Development Board, the Singapore Land Authority and in 2003 he was awarded the Public Service Medal by the Government of Singapore.
In 2003 Andrew was appointed President of GSK Europe, and joined GSK’s Corporate Executive Team.

So he has been with GSK a long time. However, the misbehavior that the current settlement is apparently designed to resolve has been going on for a long time.

As we previously posted, Paxil (Seroxat in the UK, or paroxetine), was the anti-depressant whose marketing lead GlaxoSmithKline (GSK) to settle allegations of fraud brought by then New York Attorney General Elliott Spitzer in 2004. That case included allegations of suppression and manipulation of clinical research, and was discussed in great detail in the book Side Effects by Alison Bass. We posted about various aspects of this case, e.g., more recently here, here, and here.  The case continues to echo to this day: see this post by Alison Bass about attempts to have a questionable journal article that was used to market Paxil retracted. 

Then there was Avandia (rosiglitazone), the anti-diabetic drug whose use was just restricted by the US Food and Drug Administration. This GlaxoSmithKline product inspired a "spin cycle" which provided us with endless grist for the Health Care Renewal mill. A good summary of the case appeared in September, 2010, in the British Medical Journal (Cohen D. Rosiglitazone: what went wrong: Brit Med J 2010; 341: 530-534. Link here) Once again, it appears that research was suppressed and manipulated (e.g., see here), Avandia critics were attacked by "experts" whose financial relationships with GSK were not always obvious (e.g., see here), and there were allegations that GSK executives tried to intimidate those who disagreed with them (e.g., see here and here).  All this about Avandia came out after Mr Witty became President of GSK Europe and joined the Corporate Executive Team.  While there is no reason to think he was directly responsible for any of it, as a member of this team, he ought to be accountable for the corporation's major actions, and misbehavior. 

By the way, we posted last year about another settlement by GSK, in which a GSK subsidiary pleaded guilty to criminal charges for selling adulterated drugs, including a version of Paxil.

In the Washington Post report of the $3 billion settlement, there is this quote from Dr Sidney Wolfe,

'The size of the penalties, although large, are not as large as the money [the drug companies] make and so they keep doing it over again,' said Sidney M. Wolfe, director of Public Citizen’s health research group. 'The only way this is going to stop, or get reversed, is to greatly increase the size of the penalties or to start sending some of the executives to jail, if appropriate.'

Summary

I have no idea whether there is evidence supporting criminal charges for any executives in this case. However, GSK and its leadership have not covered themselves in glory recently as shown by now three major legal settlements. I am just an American and not very knowledgeable about how the UK decides to dub people knights. However, in my humble opinion, it would be grotesque to honor the current CEO of GlaxoSmithKline with a knighthood based how his company has been lead since he became a member of its Executive Team in 2003.

I thus will end on my usual, repetitive note for such cases.... penalties that only appear to be (relatively small) costs of doing business are unlikely to deter future bad behavior. Until the people who actually authorized, directed and implemented the bad behavior have to suffer some negative consequences, expect the bad behavior to continue.

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.

ADDENDUM (18 November, 2011) -  See additional posts on attempts to have Study 329, a particularly questionable study of Paxil, withdrawn on the Fear and Loathing in Bioethics blog, the Hooked: Ethics, Medicine and Pharma blog, and on the University Diaries blog.

ADDENDUM (21 November, 2011) - See also these posts on the call for the withdrawal of Study 329 on the Alison Bass blog, and the 1BoringOldMan blog.

GlaxoSmithKline Subsidiary Pleads Guilty to Manufacturing Adulterated Drugs: Three Strikes and ...?

Paxil

First there was Paxil (Seroxat in the UK, or paroxetine), the anti-depressant whose marketing lead GlaxoSmithKline (GSK) to settle allegations of fraud brought by then New York Attorney General Elliott Spitzer in 2004.  That case included allegations of suppression and manipulation of clinical research, and was discussed in great detail in the book Side Effects by Alison Bass.  We posted about various aspects of this case, e.g., more recently here, here, and here. 

Avandia

Then there was Avandia (rosiglitazone), the anti-diabetic drug whose use was just restricted by the US Food and Drug Administration.  This GlaxoSmithKline product inspired a "spin cycle" which provided us with endless grist for the Health Care Renewal mill.  A good summary of the case appeared in September in the British Medical Journal (Cohen D. Rosiglitazone: what went wrong: Brit Med J 2010; 341: 530-534.  Link here)  Once again, it appears that research was suppressed and manipulated (e.g., see here), Avandia critics were attacked by "experts" whose financial relationships with GSK were not always obvious (e.g., see here), and there were allegations that GSK executives tried to intimidate those who disagreed with them (e.g., see here and here). 

Adulterated Drugs

And now it is adulterated drugs.  Here is the version from Bloomberg:

GlaxoSmithKline Plc, the U.K.’s largest drugmaker, will pay $750 million to settle a U.S. whistleblower lawsuit over the sale of defective drugs.

Glaxo and the U.S. Justice Department announced the agreement yesterday, resolving a false-claims lawsuit first filed in 2004 by Cheryl D. Eckard, a former global quality assurance manager for the London-based company.

'This is not something I wanted to do, but because of patient safety it was necessary,' Eckard, 51, told reporters following a Justice Department press conference in Boston. As a whistleblower, she will receive $96 million from the settlement money.

Glaxo was accused in court papers of selling tainted drugs under false pretenses. The medicines, made at a Glaxo plant in Cidra, Puerto Rico, were misidentified as a result of product mix-ups, according to papers filed in federal court in Boston. The affected drugs included the antidepressant Paxil CR and the diabetes treatment Avandamet. [Note that this is a combination drug that includes Avandia - ed]

The settlement includes a criminal fine and forfeiture totaling $150 million and a $600 million civil settlement under the False Claims Act and related state claims, the Justice Department said in a statement.

'We will not tolerate corporate attempts to profit at the expense of the ill and needy in our society -- or those who cut corners that result in potentially dangerous consequences to consumers,' Carmen M. Ortiz, the U.S. Attorney in Boston, said at yesterday’s news conference.

SB Pharmco Puerto Rico Inc., a Glaxo unit, agreed to plead guilty to charges relating to the manufacture and distribution of adulterated drugs made at the now-shuttered plant, the Justice Department said. Glaxo said in July it had agreed in principle with the U.S. to pay 500 million pounds ($791 million) to resolve the investigation.

'We regret that we operated the Cidra facility in a manner that was inconsistent with current Good Manufacturing Practice requirements and with GSK’s commitment to manufacturing quality,' PD Villarreal, a Glaxo senior vice president, said in an e-mailed statement.

Eckard’s take is the largest ever for a single whistleblower, said Patrick Burns, spokesman for Taxpayers Against Fraud, a nonprofit Washington group that publicizes the use of legal means to combat fraud against the U.S. The federal government will receive $436.4 million from the settlement and participating states will split as much as $163.6 million, the Justice Department said.

Other drugs made at the plant include Kytril, an anti- nausea medication, and Bactroban, an ointment used to treat skin infections, the Justice Department said.

'The false claims arose out of chronic, serious deficiencies in the quality assurance function at the Cidra plant and the defendants’ ongoing serious violations of the laws and regulations designed to ensure the fitness of drug products for use,' the government said in court papers.

The U.S. Food and Drug Administration in 2005 seized some Paxil CR lots after it was discovered that the pills sometimes split inappropriately, according to court papers. Some of the pills lacked an active ingredient.

It seems that not only questions about GSK sponsored clinical research about and GSK marketing of Paxil and Avandia, but the company has problems even supplying tablets that contain the pure drugs at the right dose.
Summary and Discussion

First, this is another dreary marcher in the parade of legal settlements that we have now been chronicling for years. This case has some particular features. It included a guilty plea to a crime. Although the allegations included fraud, the fundamental problem seemed to be the selling of adulterated, impure drugs.

So my first comment is that this is the latest instance of a major pharmaceutical company not being able to fulfill its most basic responsibility and reason for being, the manufacture of pure, unadulterated drugs. We previously discussed problems with adulterated drugs made by Baxter International and Johnson and Johnson. We have discussed, seemingly endlessly, how big health care corporations, including but certainly not limited to pharmaceutical companies, have engaged in various sophisticated deceptions involving marketing and clinical research to sell more products at higher prices. Now it seems that while these companies have put so much of their resources into marketing and public relations, not necessarily in honest ways, they have neglected to put the necessary expertise and resources into their most basic manufacturing functions.

So while drug industry sycophants prattle on endless about life-saving innovations, not only have industry marketing and research become less trustworthy, but now we cannot even trust the companies to supply the drug that is on the label in a pure form at the labelled dose.

My next comment is that this is the third big case involving GlaxoSmithKline reported in the last few years. (Although, like the previous cases, the events that lead to recent relevations actually occurred over the last 10+ years.) This would suggest that there is a serious problem with the culture, leadership, and governance at this corporation.

Maybe one reason such problems are allowed to fester is that in the current case, like the last two involving GSK, and as is typical for the legal settlements and crimes we have discussed before, no individuals who authorized, directed, or implemented the problematic behavior seem to have suffered any negative consequences or paid any penalty. In fact, the Guardian just pointed out:

Five of the six senior GlaxoSmithKline executives cited by a whistleblower as part of a cover-up of contamination problems at the group's Puerto Rico factory are understood to still be employed by the pharmaceuticals company.

Cheryl Eckard, who was sacked by the company as a quality control manager in 2003 after repeatedly raising her concerns with a series of GSK executives, received a $96m (£61m) reward this week as part of a $750m criminal and civil settlement between US regulators and the company.

Her evidence stated that she believed company executives refused to acknowledge the gravity of the production violations – which included the wrong strength of pills being shipped – because it would delay the approval of two new drugs by the US Food and Drug Administration.

The court documents allege that Eckard, who had recommended the factory be shut until the issues were resolved, communicated the quality violations at the plant in Cidra to David Pulman, president of global manufacturing and supply; Janice Whitaker, senior vice president of global quality; Peter Savin, vice president of global quality assurance; Diane Sevigny, director of global quality assurance, risk management and compliance; and Jonathan Box, vice president of manufacturing and supply for North America.

All five executives are believed to be still working for the London-listed company, while Pulman is also a member of the company's 18-strong corporate executive team, which includes chief executive Andrew Witty.

As we have said endlessly, penalties that only appear to be (relatively small) costs of doing business are unlikely to deter future bad behavior. Until the people who actually authorized, directed and implemented the bad behavior have to suffer some negative consequences, expect the bad behavior to continue. 

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.

See also comments on the Postscript blog.

Another Haunting Tale

Halloween is more than two months away, but the ghost stories just keep on coming. The latest version was reported by the Associated Press (with a hat tip to Prof Margaret Soltan on the University Diaries blog). To quickly summarize,

Drugmaker GlaxoSmithKline used a sophisticated ghostwriting program to promote its antidepressant Paxil, allowing doctors to take credit for medical journal articles mainly written by company consultants, according to court documents obtained by The Associated Press.

An internal company memo instructs salespeople to approach physicians and offer to help them write and publish articles about their positive experiences prescribing the drug.

Known as the CASPPER program, the paper explains how the company can help physicians with everything from 'developing a topic,' to 'submitting the manuscript for publication.'

The actual document is now available from the PharmaGossip blog here. Reviewing that document suggests that the CASPPER program was a bit different from other ghost-writing schemes (for example, see previous posts here.)

A typical ghost-writing scheme would entail ghost-writers employed by a medical education and communications company (MECC) drafting manuscripts of a scholarly-appearing review articles. The articles would be written to support the marketing of a product made by the (usually pharmaceutical) company which hired the MECC. Then, the MECC would recruit well-known medical academics as (guest) authors for the articles. The guest authors might make some minor revisions in the draft manuscripts, which would then be submitted to scholarly journals. The MECCs would handle the submission process, while maintaining the pretense that the articles were the work of the guest academic authors. The ultimate purpose of such schemes apparently would be to market the product in the guise of scholarly publication.

CASSPER, on the other hand, was meant to produce more modest articles, ostensibly written by practicing, rather than purely academic physicians. Review of the CASSPER document leads to some interesting conclusions about the project

- The project was purely a marketing project. "The objectives of CASSPER, from a publication standpoint, are to strengthen the product positioning and overcome competitive issues." The document clearly was written by marketers, and directed to pharmaceutical representatives ("drug reps.") It did not mention any involvement by GSK scientific or medical personnel. The closest it came to making a pretense about any scientific or clinical usefulness of the project was, "publication of such articles will benefit the sales force by expanding the database of published data to support PAXIL."

- It was as much about promoting closer relationships among pharmaceutical representatives ("drug reps") and doctors as about publishing articles. The project was to be implemented by drug reps, and "your participation will establish and/or strengthen your relationships with key physicians and thought leaders in the psychiatric field." The drug reps would handle, and presumably shape all communications between their physicians and the MECC.

- Articles were to arise from instigation by the drug reps, rather than from physicians' initiatives. For example, a scenario for recruiting authors began, "a physician tells you that he or she has had treatment success with PAXIL in certain indications or difficult-to-treat patient populations." Then, "ask the physician if any consideration has been given to publishing a case study based on this clinical experience."

- Although the document is somewhat ambiguous about the role of the putative author in the process, an extensive list of services available from the MECC (Complete Healthcare Communications [CHC] ) would have left little for the author to do. "The full range of editorial assistance that CASSPER can offer contributing physicians includes: developing a topic, coordinating the editorial review process, submitting to the target journal." The company's role would include "coordinating" manuscript preparation, which was defined as "development of an outline and first draft, editorial reviews, and revisions." The company would make available "published literature, available internal support, literature search results, and a database of journal submission criteria." Also, "the numerous details that CHC is prepared to coordinate ... [include] copy editing and proofreading, production of tables and graphics, preparation of the submission package, and follow-up."

So CASSPER seems to be a not really so friendly example of a newly recognized species of ghost-writing, targeted more at promoting relationships among drug reps and physicians than at producing ostensibly scholarly articles. Nonetheless, this example of the haunting of medicine is as fundamentally deceptive as previously described ghost-writing schemes. In the CASSPER project, physicians would be reduced to little more than ectoplasm, goaded by drug reps into token involvement in a writing process exclusively handled by the MECC, and mediated by the friendly appearing drug reps. I wonder whether physicians who participated escaped with any psychological independence from the drug reps who magically turned them into acclaimed "published authors?"

In any case, the disclosure of CASSPER, a ghost who was friendly only in appearance, adds more evidence about how deception and dishonesty now haunts our health care system. To achieve real health care reform, we will have to find a new group of ghost-busters. Who you gonnna call?

ADDENDUM (25 August, 2009) - See also comments by Dr Howard Brody in the Hooked: Ethics, Medicine and Pharma Blog.