Denying the Inconvenient Truth About Study 329

On 1BoringOldMan, Mickey, the semi-anonymous retired psychiatrist blogger, has updated the saga of Study 329.  The manipulation of Study 329 was a central part of the US government's case against GlaxoSmithKline that was recently settled for $3 billion and resulted in three guilty pleas by the company (look here and here.)

Mickey's previous voluminous series of posts on this subject are listed here.  He and others, most notably Dr Jon Jureidini, have attempted to get the journal that published the now widely ridiculed Study 329 retracted.  His three recent posts on the subject are:
the lesson of Study 329: an unfinished symphony…
 hide-and-go-seek… 
 a response… 

 In the most recent of these, he argued,

In this particular case, there are no facts in question. It was a negative trial, declared negative by the people who did it. The paper was ghost-written and reviewed by the sponsor before any of the twenty two authors ever saw a manuscript. The science was jury-rigged to imply a positive outcome where none was supported using well-documented sleight of hand. None of that is speculative. And the article has been a centerpiece for court settlements worth billions of dollars.

Yet, the  Journal of the American Academy of Child and Adolescent Psychiatry refused to retract the article. Mickey's opinion in the second of the posts listed above,

One can only conclude that they found this article to be an inconvenient truth, and that Dr. Andres Martin and his colleagues in the American Academy of Child and Adolescent Psychiatry believe that acknowledging that truth would do more harm than good [or maybe even found a way not to see the truth at all, though it's hard to imagine how]. Sooner or later, this whole tawdry saga is going to find its way out of the blogs and courtrooms and into the full light of day. And the question that’s going to be asked is why didn’t Medicine itself deal with the problem? Why didn’t the Journal itself retract the misinformation once they knew about it? Why didn’t the industry sponsor itself call for the retraction as part of their settlement with the DOJ? What possible reasonable reason could there be for leaving a paper that is a lie in their journal without even an expression of concern, much less a retraction? And there aren’t going to be any believable answers.

Mickey concluded the most recent post,

The loser in this story is the American Academy of Child and Adolescent Psychiatry, and ultimately psychiatry itself…

The longer inconvenient truths are ignored or suppressed, the more inconvenient, and hazardous they will ultimately become. 

ADDENDUM (26 December, 2012) - One more post on 1BoringOldMan: telling the truth as a liability…

Its conclusion

By any criteria, the conclusion to the 2001 Keller et al article is wrong ["Paroxetine is generally well tolerated and effective for major depression in adolescents"]. That’s not the reason that some of us have been so persistent in pushing for retraction. The reason is that it was wrong at the time the article was published, and they knew it was wrong, but published it anyway. We want to make a statement about the integrity of the scientific literature.

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.

Brown University Student Journalists Dare to Report on Paxil/ Seroxat, Study 329 and GSK

We have published a few posts about the controversy about the clinical research supporting the use of paroxetine (Paxil, Seroxat in the UK, made by GlaxoSmithKline) in depression (here, here, here, and here.) This controversy includes allegations that clinical research funded by GSK was manipulated, and that the company's marketing for the drug was unsupported by clinical evidence. GSK settled a case alleging fraud in the marketing of Paxil by then NY Attorney General Eliot Spitzer in 2004. A recent article provided arguments and evidence that Study 329, a clinical trial of paroxetine for adolescents, was manipulated , allegedly at least with the acquiescence of Brown University Psychiatry Chair Dr Martin Keller. [Jureidini JN, McHenry LB, Mansfield PR. Clinical trials and drug promotion: selective reporting of study 329. Int J Risk Safety Med 2008; 20: 73-81. Link here.] A book entirely devoted to this controversy, Side Effects by Alison Bass, who started reporting on the case in 1999 for the Boston Globe, was just published.

I am a still proud alumnus of Brown University (undergraduate and medical). I was a full-time faculty member at the University from 1994-2004, and am still a clinical faculty member. Despite Dr Keller's and the University's central role in the case, at least as alleged by Ms Bass and by Jureidini et al, there has only been silence about the case here in Rhode Island.

That just changed. Intrepid reporters from the Brown Daily Herald published two stories on the GSK/ Paxil/ Keller controversy. Both included some important original reporting, as well as providing clear summaries of the issues at hand.

The first article dealt mainly with Keller's alleged conflicts of interest. This article provided confirmation that Senator Charles Grassley (R-Iowa) and the US Senate Finance Committee is, in fact, investigating Dr Keller and Brown University in connection with the controversy. It also included other original reporting, including an acknowledgement from GlaxoSmithKline Director of US Media Relationships Sarah Alspach that the company had provided the committee with full information about the compensation it gave Dr Keller.

The second provided a quite clear explanation of the allegations about the manipulation of Study 329. This article also included results of an interview with Dr Jon Jureidini, the author of an article that dissected study 329, and suggested that it had been manipulated to enhance the apparent benefits of paroxetine, and diminish its apparent risks. The reporters noted that Jureidini was "confident that data in Study 329 were deliberately misrepresented." They were also able to obtain an internal GSK document that acknowledged that study 329 did not prove the efficacy of the drug.

The BDH reporters, Chaz Firestone and Chaz Kelsh, in my opinion, did a fine job, clearly explaining the issues, and digging out some new facts on the case.

Nonetheless, the BDH reporters were not able to get Dr Keller to talk to them, despite several attempts. They were not able to get anyone in the University administration to discuss any substantive aspects of the case. The highest ranking University official who would talk to them was Provost David Kertzer. He asserted that the University "can't discuss particular cases of possible claims of wrongdoing and what we do about them."

In my opinion, and as I said to the reporters, one of the most distressing aspects of this case is the refusal of Dr Keller or anyone in the University to deal with the content of the case. Very serious allegations have been made. If they can be refuted, they should be. If not, stonewalling only increases the impression that the University administration has something to hide.

Furthermore, the case raises important issues about science and clinical medicine. Universities are supposed to be where people can conduct free enquiry. There seems to be no free enquiry at Brown into the issues raised by this case. University administrators should be encouraging free enquiry. Here, they seem to be doing their best to avoid, if not stifle it.

Today, the BDH published its own editorial on the case, suggesting that Dr Keller's "actions directly affect the integrity of the University." If so, the University community should, at the very least, be discussing these actions, how they affect this integrity, and what ought to be done about it. Unfortunately, I am not optimistic that there will be an open discussion of these issues, even after the brave publication of these articles. The University administration seems to have some reason they want to clamp a lid on this case, and I am afraid they will continue to do so. The medical school faculty, lacking tenure and remembering what happened to previous dissenters like Dr David Kern, are likely to be too scared to push that lid away. Woe unto Brown.

See also comments on the Alison Bass Blog, PharmaGossip, and Pharmalot.

ADDENDUM (29 September, 2008) - See also this post on the Alison Bass blog, with links to some of the original documents relevant to study 329.

Attacking "Side Effects" with Logical Fallacies, Version 2

Side Effects by Alison Bass continues to generate controversy. As described by a reviewer in the New England Journal of Medicine,(1) the book

used the case of Paxil to expose the unsavory and self-serving relationships among members of the pharmaceutical industry, psychiatrists, and members of the FDA.

The reviewer concluded,

Bass's riveting and well-researched account of these disturbing ties should be widely read by members of the medical profession, many of whom continue to believe, despite all evidence to the contrary, that they are immune to the influence of drug companies.

We previously posted about how the book inspired one reviewer to unleash a series of logical fallacies in an apparent attempt to discredit Bass and Side Effects. Now a review by AJ Gelenberg has appeared in Health Affairs, the respected scholarly journal of health care and health policy research, which also employed its share of logical fallacies.(2)

Ad Hominem

One of Galenberg's main arguments was that Side Effects treated as black and white a story that is really about shades of gray. Furthermore, he alleged that "its hyperbole and 'villains-versus-heroes' style do no justice to a pressing public health issue." From there, he tried to discredit two of its "heroes."

One hero, a psychiatrist, admitted to a series of boundary violations with a patient that caused me to blanch. But no matter; he’s a good guy, and the author declares his intent to be pure. Another of her bigger-than-life heroes is Eliot Spitzer. The prepublication version of Bass’s book I read was written before Spitzer’s resignation as New York’s governor. I wonder if her heroes get redacted when their feet turn out to be made of clay.

Bass actually used a number of pages to address the allegations of malpractice made against the "hero" psychiatrist. But the psychiatrist's role in the book was the early raising of the hypothesis that selective serotonin uptake inhibitor (SSRI) anti-depressants may lead to suicidal ideation. Whether that hypothesis is true, and whether or not other people sought to manipulate or suppress evidence relevant to it were the real questions Side Effects addressed. The psychiatrist's conduct with a particular patient are irrelevant to their answers.

Similarly, although Elliot Spitzer did oversee the lawsuit against GlaxoSmithKline, the manufacturer of Paxil, his conduct years later that lead to his resignation as Governor of New York had nothing to do with this lawsuit or the issues it raised. Furthermore, Side Effects focused on how his staff investigated the relevant facts and pursued the lawsuit. Spitzer's role on the ground was minimal.

Thus, a single paragraph in Galentberg's Health Affairs review employed the ad hominem fallacy twice. This fallacy may be defined one "in which a claim or argument is rejected on the basis of some irrelevant fact about the author of or the person presenting the claim or argument. Typically, this fallacy involves two steps. First, an attack against the character of person making the claim, her circumstances, or her actions is made (or the character, circumstances, or actions of the person reporting the claim). Second, this attack is taken to be evidence against the claim or argument the person in question is making (or presenting)."

Guilt By Association

Later, Galenberg wrote,

I worry that Bass’s book can do harm with its broad-brush smear.

So,

Scientologists could find support for their cruel and misinformed agenda of laying waste an area of medical care that is tragically stigmatized.

Of course, anything written by anyone could be misinterpreted by someone else, or used in conjunction with yet more logical fallacies to provide erroneous support of an unrelated position. I submit that implying that Scientologists, not a group discussed or addressed in Side Effects, would be so involved was an attempt at asserting guilt by assocation. This may be defined as one "in which a person rejects a claim simply because it is pointed out that people she dislikes accept the claim."

Slippery Slope

Galenberg's worry noted above lead to a dire warning,

Worst of all, patients and their families could turn away from needed attention and further compound the neglect of psychiatric disorders.

Galenberg did not explain how Bass' book, devoted as it was to the case of the marketing and research of single drug, could undermine all of psychiatric care. Thus, this appears to be a slippery slope, defined as a fallacy "in which a person asserts that some event must inevitably follow from another without any argument for the inevitability of the event in question."

Conclusion

What Galenberg's review did not do is meaningfully address the facts presented in the book, and Bass' main interpretation of them. Side Effects argued that clinical research evidence specifically about the safety of SSRIs for children and adolescents, not adults was suppressed and manipulated. In fact, there is now considerable evidence that SSRIs may have risks for children and adolescents that were not appreciated until recently, and may not be very efficacious for younger patients. For example, the systematic review by Whittington et al included published and unpublished data from randomized controlled trials of SSRIs in children and adolescents.(3) Its abstact concluded "published data suggest a favourable risk-benefit profile for some SSRIs; however addition of unpublished data indicates that risks could outweigh benefits of these drugs (except fluoxetine) to treat depression in children and young people. The systematic review of published trials by Fergusson et al concluded there was "an association between suicide attempts and the use of SSRIs."(4)

Galenberg concluded on the regretful note,

I wish that Alison Bass had been more credible and responsible in presenting this dilemma and the underlying facts.

However, Galenberg never provided evidence or clear arguments that disputed the "underlying facts." Rather, this review, like the one by Herrmann, seemed at best to show the reviewer's distaste for Side Effects, rather than the source of that emotion.

Galenberg did allude in his review to his background,

I have consulted to the pharmaceutical industry, given lectures they have funded, and taken educational and research funds from them through my university.

He did not specify the companies for which he worked, the topic or purpose of the consultations, the nature of the lectures he gave, or the research he pursued. However, a quick search revealed that one of his colleagues in such research pursuits was Dr Martin Keller, one of the "villains," to use Galenberg's term, in Bass' book. (For example, see this article by Keller et al from 2007.[5]) The disclosures in that study included,

Dr. Gelenberg is a consultant to Eli Lilly, Pfizer, Best Practice, AstraZeneca, Wyeth, Cyberonics, Novartis, Forest, and GlaxoSmithKline; has stock options with Vela Pharmaceuticals; and has received research grants (to the University of Arizona) from Novartis.

Thus, this seems to be yet another in our series of cases of confused defenses of financial entanglements among industry and academics. Such confusion seems likely to appear in arguments made by people who themselves may have relevant conflicts of interest. As Joe Collier said, " people who have conflicts of interest often find giving clear advice (or opinions) particularly difficult."(6)

I would submit that Dr Gelenberg's review perhaps unintentionally supports the argument that physicians' and academics' financial entanglements with organizations with vested interests in promoting products, services, or ideologies should not merely be disclosed and managed, but should be materially reduced, if not eliminated.


References

1. Friedman RA. Side effects: a prosecutor, a whistleblower, and a bestselling antidepressant on trial. N Engl J Med 2008; 358: 2852. Link here.

2. Gelenberg AJ. Warning: Side Effects may include distorted vision. Health Aff 2008; 27: 1193-4. Link here.

3. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published version unpublished data. Lancet 2004; 363: 1341-1345.

4. Kirsch I, Deacon BJ, Medina-Huedo TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 5(2): e45 . Link here.

5. Keller MB, Trivedi MH, Thase ME, Shelton RC, Kornstein SG, Nemeroff CB, Friedman ES, Gelenberg AJ et al. The prevention of recurrent episodes of depression with venlafaxine for two years (PREVENT) study: outcomes from the 2-year and combined maintenance phase. J Clin Psychiatr 2007; 68: 1246-1256. Link here.

6. Collier J. The price of independence. Br Med J 2006; 332: 1447-9. Link here.

Attacking "Side Effects" with Logical Fallacies

Concerns about manipulation and suppression of the clinical research literature are gaining more traction. Recently, Alison Bass published Side Effects, a book that explored one of the more vivid cases. As described by a reviewer in the New England Journal of Medicine,(1)

She has used the case of Paxil to expose the unsavory and self-serving relationships among members of the pharmaceutical industry, psychiatrists, and members of the FDA.

The reviewer concluded,

Bass's riveting and well-researched account of these disturbing ties should be widely read by members of the medical profession, many of whom continue to believe, despite all evidence to the contrary, that they are immune to the influence of drug companies.

So it should be no surprise that Side Effects has inspired criticism from those less skeptical about such relationships. The most prominent whack was taken at it by Mark Herrmann's review in the Wall Street Journal, which deployed an interesting variety of logical fallacies to defend the pharmaceutical industry from Ms Bass' critique. Allow me to walk through them.

Appeal to Popularity

The nature of this article becomes apparent early. It started with the premise, not defended with evidence, that selective serotonin reuptake inhibitor (SSRI) anti-depressants are an unqualified social good,

Prozac improved the nation's mood when it came on the market in 1987. Earlier antidepressants had caused many side effects and were potentially lethal in overdose. Prozac appeared to be both a godsend and a blockbuster. It was effective, easy to administer and less likely to be used by depressed patients as a means to commit suicide.

This sets up the implication that any book daring to criticize such a beneficial product ought to get little credence. Thus Herrmann appears to be using an appeal to popularity, a logical fallacy defined as "a claim is accepted as being true simply because most people are favorably inclined towards the claim. More formally, the fact that most people have favorable emotions associated with the claim is substituted in place of actual evidence for the claim."

Straw Man

Next, he noted one of the earliest criticisms of SSRIs.

Soon enough a Harvard professor, Martin Teicher, published reports of six patients who developed suicidal thinking while taking Prozac, and the Church of Scientology campaigned against it.

In 1991, the Food and Drug Administration convened a committee of experts to study the matter. As it turned out, Mr. Teicher's six patients had been deeply depressed for years, medicated with multiple drugs and in several cases had attempted suicide before they first ingested Prozac. The Scientologists rested their arguments on anecdotes, not data. The committee concluded that Prozac did not trigger suicides in adults.

This is the only time that Mr Herrmann dealt with clinical evidence in his review. Note that he started with the most preliminary evidence about harms of SSRIs that were not immediately apparent after they were first marketed. At most, Teicher's anecdotes raised the hypothesis that SSRIs may be more hazardous than they originally appeared. They were hardly definitive evidence, just a clue that more evidence needed to be sought.

Mr Herrmann sought to refute this very preliminary evidence,

A pooled analysis of nearly 100,000 patients, conducted by the FDA in 2006, showed no increased suicidality for adults ages 25 to 64.

That is the last Mr Herrmann has to say about any evidence from clinical research pertaining to the efficacy and safety of SSRIs.

What he left out, however, was that Side Effects argued that clinical research evidence specifically about the safety of SSRIs for children and adolescents, not adults was suppressed and manipulated. In fact, there is now considerable evidence that SSRIs may have risks for children and adolescents that were not appreciated until recently, and may not be very efficacious for younger patients. For example, the systematic review by Whittington et al included published and unpublished data from randomized controlled trials of SSRIs in children and adolescents.(2) Its abstact concluded "published data suggest a favourable risk-benefit profile for some SSRIs; however addition of unpublished data indicates that risks could outweigh benefits of these drugs (except fluoxetine) to treat depression in children and young people. The systematic review of published trials by Fergusson et al concluded there was "an association between suicide attempts and the use of SSRIs."(3)

Thus, Mr Herrmann was setting up a straw man, defined thus, "the Straw Man fallacy is committed when a person simply ignores a person's actual position and substitutes a distorted, exaggerated or misrepresented version of that position. "

(Parenthetically, there is also controversy about the efficacy of these drugs in the treatment of adults, although this was not the focus of Ms Bass' book. See for example the meta-analysis by Kirsch et al using published and unpublished data which suggested that the drugs improve depression only slightly compared to placebo, and then only for the most depressed patients.[4])

Guilt by Association

Additionally, by grouping Dr Teicher's observations with the Scientologists' objections, Mr Herrmann seemed to be deploying guilt by association, defined as "a fallacy in which a person rejects a claim simply because it is pointed out that people she dislikes accept the claim."

Appeal to Ridicule

Ms Bass used Dr Teicher's early observations of patients given Prozac only to set the stage for her main argument. Her crucial points were that people working on behalf of GlaxoSmithKline and its predecessors suppressed and manipulated data from clinical research on Paxil (paroxetine) to make the drug appear more efficacious and less hazardous, and thus sell more of it. As my brief summary of recent published systematic reviews above implies, when some of the suppressed studies were unearthed and their data considered in addition to the published studies, SSRIs appear less efficacious and more hazardous than was previously thought.

Mr Herrmann then sought to trivialize the importance of the data suppressed as merely "inconvenient information," and to minimize GlaxoSmithKline's efforts to suppress it,

The suppressed data that Bass was addressing, particularly about rates of suicidality in children and adolescents taking Paxil, was considerably more than "inconvenient." The use of this term appears to be little more than sarcasm. Thus, Herrmann seemed to be making an appeal to ridicule, defined as "the Appeal to Ridicule is a fallacy in which ridicule or mockery is substituted for evidence in an "argument."

Red Herring

Then he asserted,

In the event, GlaxoSmithKline settled out of court and, as soon as the matter of transparency was raised, published online all of the studies of Paxil that had been submitted to the FDA, including those that showed no significant difference between the effects of Paxil and a placebo.

The implication that GSK jumped to respond immediately after the question of "transparency" was raised does not fit the facts. The GSK registry noted by Herrmann's review contains unpublished trials of paroxetine dating back at least to 1988. Questions about suicide risk due to SSRIs, specifically Prozac, were raised by Teicher in 1990. GSK published the registry as part of the settlement of a lawsuit, and then only reluctantly. Bass documented how GSK attorneys opposed a fully transparent registry as part of a settlement in 2004. Herrmann's facile language provided no facts to counter the assertion that GSK did all it possibly could to delay release of data from clinical trials that was unfavorable to its product. His argument thus appears to be a red herring, defined as " a fallacy in which an irrelevant topic is presented in order to divert attention from the original issue."

Another Straw Man

Next, Mr Herrmann then asserted that Bass was hostile to all drug company sponsored research,

For Ms. Bass the judgment of researchers, together with their data and claims, are untrustworthy if they have received money from drug companies to finance clinical trials. She is particularly hard on a professor of psychiatry from Brown University who has defended Paxil.

Actually, Bass' criticisms were far more focused. She made detailed allegations that the "professor of psychiatry" manipulated data in a particular, key trial of paroxetine in children and adolescents. She charged that after the drug failed to produce significant improvements in the pre-selected main outcome measures, the study investigators post-hoc looked for other measures until they found some by which the drug appeared efficacious. Furthermore, she charged that the investigators dropped trial patients who exhibited suicidal ideation without recording these adverse effects. (See our recent post discussing an article published after Side Effects was written that corroborates these allegations.[5]) Thus, Herrmann's appeared to raise another straw man argument.

More Red Herrings

Mr Herrmann wound up his review with a tin of red herrings. For example, he asked,

And why shouldn't companies seek advice from the best scientific minds and pay them for their efforts?

However, Bass' book discussed relationships among drug companies that went far beyond paying people to give "advice." Although spokespeople for the pharmaceutical industry have claimed that the companies' relationships with physicians and academics amount to nothing more than consulting the best and brightest for guidance, there is evidence that industry recruits "key opinion leaders," (KOLs) a title given by Ms Bass to the "professor" above, to help market the companies' products, and that KOLs early recruitment may be based on their existing sympathy to the companies and their marketing objectives. (See this post and related article by Moynihan.[6])

Herrmann's last point was that Bass

said not a word about how society suffers when the FDA approves new drugs too slowly, depriving patients of life-improving and life-saving medicine

However, the book hardly advocated a general slowdown of drug approval. In fact, as the New England Journal of Medicine reviewer pointed out, her point was more not to slow down drug approval, but to speed up recognition "the FDA knew of the risks all along but procrastinated" in warning of them.

Conclusion

Herrman concluded with the opinion that

"Side Effects" belongs to a genre of investigative journalism that involves talking to plaintiffs, their lawyers and their expert witnesses, taking their stories as gospel and denigrating the opposing view because corporate money (apparently less pure than money from the plaintiffs' side) supposedly has a corrupting effect.

"Side Effects" is lively and well-written, but readers should be warned that they may have an adverse reaction: a deep disquiet that only half the story has been told.

Maybe Mr Herrmann would benefit from the use of a mirror. His supposed review seems mainly an uncritical defense of actions that seemed more related to one pharmaceutical company's pursuit of profits than the promotion of science or the benefit of patients. At the end of his review, the Wall Street Journal noted "Mr Herrmann is a lawyer in Chicago whose firm has defended drug manufacturers in product liability cases." Thus, his review may be likened to a legal brief on behalf of a client whose conduct may be hard to defend.

References

1. Friedman RA. Side effects: a prosecutor, a whistleblower, and a bestselling antidepressant on trial. N Engl J Med 2008; 358: 2852. Link here.

2. Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove A, Boddington E. Selective serotonin reuptake inhibitors in childhood depression: systematic review of published version unpublished data. Lancet 2004; 363: 1341-1345.

3. Fergusson D, Doucette S, Glass KC, Shapiro S, Healy D, Hebert P, Hutton B. Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials. Brit Med J 2005; 330: 396. Link here.

4. Kirsch I, Deacon BJ, Medina-Huedo TB, Scoboria A, Moore TJ, Johnson BT. Initial severity and antidepressant benefits: meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 5(2): e45 . Link here.

5. Jureidini JN, McHenry LB, Mansfield PR. Clinical trials and drug promotion: selective reporting of study 329. Int J Risk Safety Med 2008; 20: 73-81. Link here.

6. Moynihan R. Key opinion leaders: independent experts or drug representatives in disguise? Brit Med J 2008; 336: 1402-3. Link here.

"Selective Reporting of Study 329"

A new study in a rather obscure journal has revealed more about the now infamous study 329. [Jureidini JN, McHenry LB, Mansfield PR. Clinical trials and drug promotion: selective reporting of study 329. Int J Risk Safety Med 2008; 20: 73-81. Link here.]

For the background, let me take the easy way out, and quote Ed Silverman from PharmaLot:

Back in 2001, an infamous study was published in the Journal of the American Academy of Child and Adolescent Psychiatry that declared Glaxo’s [GlaxoSmithKline, GSK] Paxil antidepressant - called Seroxat in the UK - [paroxetine] was “generally well tolerated and effective for major depression in adolescents.” Known as study 329, the findings were used to widely promote the drug, which became a huge seller.

Of course, the study was later held in disrepute after it was learned the results didn’t tell the whole story. In fact, 329 was one of three studies cited by former New York Attorney General Eliot Spitzer, who filed a suit charging Glaxo with “repeated and persistent fraud,” alleging the drugmaker had promoted positive findings, but hadn’t publicized unfavorable data (back story).

As it turns out, study 329, ... already had a sordid history that included ghostwriting charges (here’s some background)....

We did cover this issue in the past (here) on Health Care Renewal.

Furthermore, we can now turn to the Clinical Psychology and Psychiatry Blog for an analysis of what is new about the study by Jureidini et al. The main points were -

The study report (in the Journal of the American Academy of Child and Adolescent Psychiatry) featured results of manipulation of the measures used to assess efficacy to make the drug appear more efficacious:

• Study 329 was designed to employ 8 measures of drug efficacy. It turned out that paroxetine was not statistically significantly superior to the comparator using any of these 8 measures.
• After the study was underway, the authors added a bunch of new measures, including new instruments, and modifications of instruments used in the original 8 measures. Only when using some of these new measures did the drug exhibit any efficacy.

To summarize how the Clinical Psychology and Psychiatry blog put it:

Devising various cutoff scores on various measures on which victory could be declared, as well as examining individual items from various measures rather than entire rating scales, the authors were able to grasp and pull out a couple of small victories. In the published version of the paper, there is no hint that such data dredging occurred. Change the endpoints until you find one that works out, then declare victory.

Worse, the study report simply omitted mention of the data that serious adverse events were more common in patients treated with paroxetine than with placebo, making the drug appear safer than it really may be. Jureidini et al noted that the following phrase,

worsening depression, emotional lability, headache, and hostility were considered related or possibly related to treatment

was omitted from the published report. Furthermore, per Jureidine et al,

Suicidal thoughts and behavior were grouped under the euphemism of 'emotional lability'

Yet the final JAACAP paper only stated,

Only headache (1 patient) was considered by the treating investigator to be related to paroxetine treatment

Jureidini et al concluded,

The published conclusions of study 329 and information provided by GSK to health professionals understated adverse effect rates and emphasized post-hoc measures that were not consistent with the unpublished, protocol-defined primary and secondary outcomes.

The article by Jureidini et al adds to our understanding of the various devious ways commercial sponsors of clinical research and the supposedly independent academic investigators who collaborate with them may manipulate the design, implementation, analysis and reporting of clinical studies to make the sponsors' products look better.

As we have said again and again, patients and physicians require the best possible information about benefits and harms of treatments to make the best decisions about such treatments. When those with vested interests in supporting a particular treatment distort the information available to make such decisions, they risk harming patients. In addition, manipulation of clinical studies violates the trust of study participants who thought they were taking part to advance science or health care.

The ongoing revelations about study 329 unfortunately remind doctors and patients who skeptical they must be about how well drugs and devices really are supported by clinical research. Combined with numerous other reports of manipulation and suppression of research, they suggest that:

• medicine, and particularly academic medicine ought to do a far better job of policing itself to ensure the integrity of clinical research
• pharmaceutical, biotechnology and device companies lead by businesspeople and lacking strong corporate cultures and explicit codes of conduct supporting ethical conduct may not deserve our trust
• government regulation of drug and device companies need to be far more stringent
• consideration ought to be given to require that all clinical research be conducted at true arm's length from organizations and people with vested interests in promoting particular products or services assessed by such research
  

I must note that there is also a local angle to this. As Jureidini et al wrote, "in 1992 Martin Keller MD, Chairman of Psychiatry at Brown University, Rhode Island and colleagues successfully proposed to SKB [SmithKline Beecham, the predecessor of GSK] a multi-site study of a selective serotonin reuptake inhibitor and tricyclic antidepressant in adolescent major depression."

As PharmaLot reported, "The latest study prompted a complaint concerning possible scientific misconduct to be leveled against study 329’s lead author, Martin Keller, a psychiatry professor at Brown University, by David Egilman, a clinical associate professor in community health at Brown. We are awaiting a reply from Keller and Brown provost David Kertzer, who was sent the complaint by Egilman. UPDATE: A Brown spokesman declines to comment."

As I noted in my previous blog post, I am currently on the voluntary faculty of Alpert Medical School of Brown University. I am a former full-time faculty member, and an undergraduate and medical school alumnus of Brown. I am saddened to see the ongoing damage to the reputation of the institution from this case. I do believe that Dr Egilman's complaint warrants full, open, and transparent investigation.