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.

BLOGSCAN - GSK Lawyers Have Paxil Video Taken Down

On the Seroxat Sufferers Blog, Robert Fiddaman posted about how legal threats from attorneys for GlaxoSmithKline forced him to take down a video from YouTube which contrasted statements by Dr Alastair Benbow about the Seroxat (Paxil, paroxetine, made by GlaxoSmithKline) controversy with other versions of reality from the news media and the MHRA report. (See our most recent post here about how the MHRA concluded that GSK suppressed clinical research data unfavorable to its product.)

Also, on the Scientific Misconduct Blog, Dr Aubrey Blumsohn perceptively comments on GSK's attack on Fiddaman here. And on the Clinical Psychology and Psychiatry Blog, the anonymous blogger sagely opines here.

ADDENDUM (4 April, 2007) - Again on the Scientific Misconduct Blog, Dr Blumsohn surveyed the considerable discussion in the blogsphere of these events.

British Government Concludes GSK Suppressed Paxil (Seroxat) Data

Last year, we summarized the results of a BBC investigation broadcast on the television program Panorama that charged that GlaxoSmithKline "distorted trial results of an anti-depressant, [Seroxat in the UK, Paxil in the US, chemical name paroxetine] covering up a link with suicidal teenagers." (See also the links in that post to extensive discussion on the Clinical Psychology and Psychiatry Blog.)

The UK Medicines and Healthcare Products Regulatory Agency (MHRA) has just completed an investigation, and it is fitting to quote the BBC story about its results.

It comes after the drugs regulator announced GlaxoSmithKline would not face criminal proceedings over claims it withheld information on Seroxat.

But they warned GSK should have been quicker to raise the alarm on the risk of suicidal behaviour associated with the antidepressant in the under-18s.

GSK has rejected claims it improperly withheld drug-trial information.

The Medicines and Healthcare products Regulatory Agency (MHRA) received data from clinical trials in May 2003 showing that patients under 18 had a higher risk of suicidal behaviour if they were treated with Seroxat than if they received a placebo.

Data also showed that Seroxat was not effective for treating depression in children and adolescents.

But Professor Kent Woods, MHRA chief executive said they were disappointed GSK had not given them information earlier and that drugs firms had an "ethical responsibility".

"I remain concerned that GSK could and should have reported this information earlier than they did.

"All companies have a responsibility to patients, and should report any adverse data signals to us as soon as they discover them.

The government decided not to pursue criminal charges, mainly because of "important weaknesses in drug safety legislation in force at the time."

Also,

Health minister Dawn Primarolo said the government would take immediate steps to secure a strengthening of the law in the UK and Europe.

She also said they wanted to make it clear to all pharmaceutical companies that, "notwithstanding the limitations that may exist in the law, they should disclose any information they have that would have a bearing on the protection of health".

The Guardian reported the forceful opinions of the [UK] Mental Health Foundation chief executive, Andrew McCulloch,

It is totally unacceptable to hear that, when information can be made available at speed, young people may have taken their own lives due to a lack of transparency by a pharmaceutical company.

Woods further commented in another article in the Guardian,

I really feel there is an ethical obligation that pharmaceutical companies ought to recognise and it seems to have been lost. Twenty years ago I was a prescribing doctor and I took it for granted that if there was information relevant to the drug I was going to prescribe, then it would be available. We're talking about something which has direct relevance to health and safety.

The Guardian also noted that Woods "could not rule out the possibility that other companies were sitting on unpublished data that could cause them commercial damage."

So, in case there was any doubt, based on this UK government report, it seems very clear that GSK suppressed data about the adverse effects of Seroxat in an effort not preserve sales. This was a blatant effort to put company profits ahead of patient well-being and a slap at the integrity of the clinical science data base. This has hardly been the only case of suppression of clinical research data because it reflected poorly on some company's products or services.

And pharmaceutical executives wonder why no one trusts them anymore?

I doubt there is any way to secure the integrity clinical research short of banning all involvement by corporations with vested interests in having specific research studies come out in ways that favor their products or services.

See also the forceful comments by Dr Aubrey Blumsohn on the Scientific Misconduct Blog. He called it "a day of shame."

BLOGSCAN - More on Manipulation of Paxil Data

On the Clinical Psychology and Psychiatry blog, this post dissected allegations that GlaxoSmithKline manipulated data about suicidal ideation as an adverse effect of the drug Paxil (paroxetine , Seroxat in the UK ). (See our related post here.) The post concentrated on how key opinion leaders allayed fears about these advere effects based on summaries of data that had been processed by the company, data the company may have manipulated. Meanwhile, on the Scientific Misconduct Blog, Dr Aubrey Blumsohn noted how the current CEO of GSK chastised journalists for reporting on scientific data (unfavorable to the company) before scientists had looked at it, which makes more sense if the scientists to whom he was alluding were the sorts who are inclined to accept company processed data as is.