MONEY AND POWER RULING
HEAD AND HEART
In May 2011, British journalist Sue Reid broke a story that would shock a nation.90 It concerned a young boy from a small English village nestled in the sedentary hills of Cumbria. His name was Harry Hucknall. And from initial accounts he was your average kid: he liked football, computer games, and playing in the park. He had friends and was dearly loved by his family. There was not much to mark him out, not really. But on a Sunday night in September, that would change for good.
That evening Harry kissed his mother, Jane, and older brother, David, good night—carefully telling them that he loved them. He then went upstairs to his bedroom, locked his door behind him, took out a belt, tied it to his bunk bed, and hung himself. He was found after an hour, and later died in hospital. Harry was just ten years old.91
At the inquest into Harry’s death the coroner, Ian Smith, reported that Harry had at the time been taking “two powerful mind-altering drugs”—Ritalin and Prozac. More important, the coroner had found more drugs in Harry’s system than you would expect to find in an adult suffering from the same problem. It turns out that Harry was first given Ritalin by a child psychiatrist to help him with his poor concentration at school. He’d also been prescribed Prozac to help manage his feelings of depression.
As the inquest continued, the image of Harry as a happy boy began to disintegrate slowly. The authorities revealed that Harry had at one point self-harmed, and was also being bullied at school (he was held down and threatened with a screwdriver on one occasion). The drugs, it seems, were prescribed to help Harry manage the powerful feelings which, presumably, his situation had stoked.
Harry’s father (who had amicably separated from Harry’s mother when Harry was three) was one of the last people to find out about the drugs: “Harry was put on Prozac first, and without my knowledge,” he told Sue Reid emotionally. “I only found out about it when he came to stay for the weekend and his mother told me what dose to give him: one in the morning and one at night. ‘Are you crazy?’ I asked her. ‘That’s an antidepressant.’ I can go to work every day and pay for my child’s keep, but it seems I have little say when it comes to things like the authorities deciding to give my son drugs.”
Harry’s father was always unconvinced that his son’s problems were psychiatric. “He was just a kid,” he said to Reid, exasperated. “There was nothing wrong with him. He may have had some problems, but they were overstated.” For example, at school meetings about Harry, his teachers had said he was quiet. “My son had just recently moved house and been put into a new school where he didn’t know anybody. What did they expect? Another teacher said Harry didn’t laugh at his jokes. I asked Harry about that. He told me they weren’t very funny.”
Reid also reports how at the inquest Harry’s father challenged the psychiatrist who treated his son as to why he prescribed such powerful drugs. “This doctor said that my son had a chemical imbalance in his brain. I asked him, ‘How do you know? Did you take chemicals from his brain?’ He told me it was a theory. So based on a theory—and seeing my son five times at the most—he decided to put him on this drug Ritalin, which is as powerful as cocaine.”
Harry’s father was convinced his son’s difficulties had been wrongly medicalized and medicated. Sure, Harry had problems. But they were due to the various upheavals the boy had undergone (Harry had moved houses no less than fourteen times), not due to deficiencies in his brain. Harry’s father also believed that the drugs, rather than helping his son, had been “a major contribution” to his suicide, stating that his son had “never mentioned he wanted to kill himself before the tablets.”92
The coroner at the inquest seemed to have sympathy for Harry’s father’s claims, especially since we know that Prozac can, paradoxically enough, heighten suicidal tendencies.93 The coroner, however, could not confirm that the pills had caused Harry’s death. This was largely because it is nearly impossible to establish retrospectively in suicide cases whether it was the person’s depression or the drugs they were taking or the two combined that led them to take their life. All the coroner could say in general terms was that the combined influences of Ritalin and Prozac could not be excluded as a factor in Harry’s death, and that therefore doctors should be extremely careful when prescribing these pills to 10-year-old boys.
A few months after Reid broke this story, an independent report into the events pertaining to Harry’s suicide was published. Its verdict was that not only had the authorities demonstrably failed to improve Harry’s situation, but that there was “evidence of poor practice throughout, which included both single-agency failings and generally poor interagency communication and collaborative working.” It also stated that the interventions Harry had received were “largely adult rather than child-focused” and that there was “no evidence of Child F’s [Harry’s] voice being heard or his wishes and feelings taken into account by professionals working with him and his family.”94 Furthermore, even though Harry was given exceptionally high doses of Ritalin and Prozac, he had still never been given a psychiatric assessment and had never been classed as a “high risk” patient—this, said the report, had been a mistake. Finally, the report implicates Harry’s parents, concluding that one reason why Harry was “extremely vulnerable” and felt “unloved and unwanted” was possibly due to his parents not putting Harry’s needs before their own.
In short, and perhaps quite predictably, the report ends up leveling accusations of negligence in many directions: at Harry’s parents, at Harry’s psychiatrist, at the various bodies charged with Harry’s care, including the local agency responsible for children’s mental health (CAMHS). And this is what you’d expect in a case as complex as this: a report whose authors claim that numerous acts of neglect, rather than a single culprit, were responsible.
What you’d also expect from the report is some reference to the role psychiatric drugs played in the tragedy. But here the report is suddenly cautious: “The issues in relation to the use of such medication and the complexities involved in treating co-morbidities remain unresolved. This is clearly a national issue and central government guidance is needed to inform and direct future medical practice.” In other words, the report’s authors assumed it was beyond their jurisdiction to comment upon whether the drugs were prescribed responsibly. They also declined to comment upon whether the actual chemical properties of the drugs were a causal factor in Harry’s death. After all, the report’s compilers were not in a position to undertake a scientific assessment of their own.
But even if they were, why on earth would they? The testing of pills is a rigorous, peer-reviewed scientific process overseen by independent regulators. Surely the people who ratified drugs like Ritalin and Prozac for public use, including those undertaking the manifold clinical trials through which such drugs pass, will have therefore identified all possible dangers the drug may pose. And this information, no doubt, will be passed on to prescribing clinicians. We are talking about medical drugs, after all, and so those who supervise their development and testing cleave to the highest ethical standards, overseeing processes in which we can all confidently trust.
If this were what the authors of the report supposed, then most of us would think the supposition fairly correct. In fact, most of the time it would be correct—that is, most of the time. But there are occasions when such suppositions are fundamentally contradicted by the facts. Indeed, such occasions, as will now become clear, appear with disconcerting frequency in the realm of psychiatry.
2
In chapter 5, we encountered research showing that antidepressants work almost no better than dummy pills for the majority of patients.95 We also heard how these findings were the result of researchers like Irving Kirsch and Walter Brown performing “meta-analyses” that assessed both published and unpublished data about the efficacy of psychiatric drugs. The fact that most of the unpublished data happened to be negative may have led you to wonder whether companies were actively suppressing results that didn’t serve their financial interests.
In this chapter it is time to enter that tricky area directly, by acknowledging that pharmaceutical companies have histories of concealing evidence that they deem inconvenient. I will show that, whether this concealment is achieved by crudely suppressing negative data or by subtly manipulating research to show their drugs in the most positive light, the unpalatable truth about psychiatric drugs is that manipulation of research has been a critical reason for their popular success.
So many inconvenient facts have been sidelined or completely hidden that public debates that need to take place (about drugs inducing odd states, or long-term pathological states, or suicide states, as may have occurred in Harry’s case, as well as placebo effects) are sidelined too. This chapter is therefore about what the compilers of the report into Harry’s death either did not know or assumed they were not in a position to address. It’s about how nearly all research into psychiatric drugs is today sponsored by the pharmaceutical industry and about how this arrangement has led to the compromise of basic scientific standards, and at worst to the outright manipulation of research with the aim of maintaining or increasing company profits. The following sad procession of industry deceptions will illustrate what I mean.96
The first concerns the British pharmaceutical giant GlaxoSmithKline, who conducted three studies of its antidepressant that is called Paxil in the United States and Seroxat in the UK. These studies investigated whether this drug could reduce major depression in adolescents. But the trials were highly inconclusive. One trial showed mixed results, another trial showed that Paxil/Seroxat was no more effective than a placebo, and the third suggested that the placebo may be more effective with certain children. Despite these mixed results, the company published only the most positive study, publically declaring that the drug is effective for major depression in children.
This would have gone unnoticed had an internal company document not been leaked to the Canadian Medical Association. This showed that company officials had actively suppressed negative results from one study because, as they said, “It would be commercially unacceptable to include a statement that the efficacy had not been demonstrated, as this would undermine the profile of paroxetine [Paxil/Seroxat].” Once this information came to light, a lawsuit was filed against GlaxoSmithKline in 2004 for intentionally hiding negative findings. This was settled out of court two months later when the company paid $2.5 million for charges of consumer fraud; it is a meager sum, considering that GlaxoSmithKline made $4.97 billion in worldwide sales from the drug in 2003 alone.97
In a separate class-action suit in 2009, the pharmaceutical company Forest Laboratories was charged by the US Justice Department for defrauding the government of millions of dollars. It appeared that top executives at the company had for several years hidden a clinical study showing that their antidepressants Celexa and Lexapro were not effective in children and might even pose dangerous risks to them. At worst, these risks included causing some children to become suicidal.98 Prosecutors said that by failing to disclose the negative results, Forest had kept crucial information hidden from physicians and the wider public, preventing them from having all the information they require to make the right treatment decisions for young children.
And again, in 2010 an article in the British Medical Journal showed that the drug reboxetine, marketed as Edronax by the drug giant Pfizer, is no more effective at countering major depression than is a placebo sugar pill. Pfizer, however, withheld negative trials from publication. In fact, data on 74 percent of patients the article surveyed were actually left unpublished. The authors concluded that if the excluded data had been included, the evidence would have shown that the risks of taking the drug far exceeded the benefits. Reboxetine has been approved for marketing in many European countries (for example, the United Kingdom and Germany) since 1997, however, and is still being taken by thousands of people in the UK today.99
My final example concerns an article published by The New England Journal of Medicine in 2008 that confirmed in graphic terms precisely how widespread the suppression of negative data for psychiatric drugs actually is.100 The authors reviewed over seventy major studies of antidepressants’ efficacy, asking whether all of these studies had been published. The answer was unnerving. Out of all the studies the article surveyed, 38 showed positive results for antidepressants, and nearly every one of these positive studies had been published. But the remaining 36 studies actually showed negative results, and out of these a full 22 had been buried, 11 had been published in a form that conveyed a positive outcome, and only 3 had been published accurately.101 In other words, a total of 33 negative studies had either been buried or manipulated to convey a positive outcome.
This last article is so important because it not only shows the extent to which negative data never sees the light of day but also because it reveals that psychiatric drug research is being regularly manipulated to make negative data look positive.102 This in turn means that companies are engaging in strategies of deception greatly more sophisticated than merely hiding negative studies.
In 2005, a report by the British government’s Health Committee identified some of these strategies. The authors of the report claimed that they had heard that lax regulation and oversight had allowed pharmaceutical companies to engage in a number of practices that clearly acted against the public interest. The strategies brought to their attention included:
… that clinical trials were not adequately designed—that they could be designed to show the new drug in the best light—and sometimes fail to indicate the true effects of a medicine on health outcomes relevant to the patient. We were informed of several high-profile cases of suppression of trial results. We also heard of selective publication strategies and ghost-writing. The suppression of negative clinical trial findings leads to a body of evidence that does not reflect the true risk: benefit profile of the medicine in question.103
The former chief editor of the British Medical Journal, Dr. Richard Smith, also highlighted the proliferation of these practices in a paper titled “Medical Journals are an Extension of the Marketing Arm of Pharmaceutical Companies.” Here he described how pharmaceutical companies have manipulated drug-trial data in ways so initially undecipherable that, as he confessed, it took “almost a quarter of a century editing for the BMJ to wake up to what was happening.”104 Smith, like the authors of the 2005 government report, also outlined some of the strategies he had witnessed companies using to get the results they want:
It is not only the editor of the British Medical Journal who has spoken out. Richard Horton, editor of the Lancet, wrote in 2005 that “Journals have devolved into information-laundering operations for the pharmaceutical industry.” This position is also supported by the former editor of the New England Journal of Medicine, Marcia Angell, who lambasted the industry for becoming “primarily a marketing machine” and co-opting “every institution that might stand in its way.” In fact, the situation has so deteriorated that editors at PLoS Medicine have now openly committed to not becoming “part of the cycle of dependency … between journals and the pharmaceutical industry,” a cycle that sees journals sometimes publishing research biased in favor of company interests.106
While these editors’ complaints are reassuring, the problem is far from being solved. Companies still engage in research strategies that by most accounts massage the facts, and journals are still often publishing this research. But to allow you to truly appreciate the extent of this problem, let me first show you in a little more detail some of the unprincipled practices that cause such consternation in senior editorial ranks.
3
In May 2000, Dr. S. Charles Schulz, a psychiatrist at the very height of his powers, walks up to a podium at the annual meeting of the APA and announces a breakthrough in antipsychotic research. The breakthrough amounts to the development of a new drug that has “dramatic benefits” over its competitors. Its name is Seroquel, and because of its superiority, “patients must receive these medications first,” as he later wrote in the press release.
Two months before this commanding announcement was made, the company that manufactures Seroquel, AstraZeneca, was in disarray. It had just discovered that its latest research into Seroquel had revealed that the drug was far less effective than its archrival Haldol. The document containing this finding had been circulated among senior staff at the company, who were not sure what to do. An internal e-mail written at the time (released later by the company during litigation) captured the mood:
From: Tumas, John T A
Sent: Thursday, March, 23rd, 2000, 10:05AM
To: Goldstein, Jeffery JM; Murry, Michael MF
Subject: FW: Meta Analyses
Importance: High
Jeff and Mike,
Here’s the analyses I got from Emma. I’ve also attached a message I sent to her yesterday asking for clarification.
The data don’t look good. In fact, I don’t know how we can get a paper out of this.
My guess is that we all (including Schulz) saw the good stuff, ie the meta analyses of responder rates that showed we were superior to placebo and haloperidol, and then thought further analyses would be supportive and that a paper was in order. What seems to be the case is that we were highlighting only the good stuff, and that our own analysis [now] support[s] the “view out there” that we are less effective than haloperidol and our competitors.
Once you have a chance to digest this, let’s get together (or teleconference) and discuss where to go from here. We need to do this quickly because Schulz needs to get a draft ready for APA and he needs any additional analyses we can give him well before then.
Thanks.107
In this e-mail, the publications manager at AstraZeneca casts about for a solution. He knows the research into Seroquel “doesn’t look good,” yet Schulz has to present a paper on Seroquel at the APA’s meeting in two months’ time. If Schulz reports the negative data, the drug is presumably doomed. A way out is needed—fast.
What does the company do? How in just two months does it move from private despair over the failings of Seroquel to making a public declaration about its exceptional advantages? Does the company rapidly undertake a new study that finally secures Seroquel’s superiority? Does it re-analyze the old data only to discover that the previous, negative interpretation was wrong? The company does neither. There is no time. Even if there were time, the existing data are definitive. The drug is weaker than its competitors—that, it seems, is plain for all to see.
At this point you’d probably expect the company to cut its losses and with regret publish the whole truth. But the company does not take that route. Presumably there is too much money at stake, and anyway, perhaps there’s another way out. Sure, it’s not an ideal route to take, or even an honest one, but given the dollars that could be lost it has to be worth a go. The company therefore opts for a strategy known in drug research as “cherry-picking.”
Cherry-picking is the name given to the process by which only some of the data from a clinical trial are “picked” for publication and the rest are ignored. The huge advantage of proceeding in this way is that you can simply “pick” the data that makes the drug look effective, while leaving aside the data that don’t. This was the solution AstraZeneca chose in early 2000. Rather than admit that after a year on Seroquel patients suffered more relapses and worse ratings on various symptom scales than patients on Haldol—not to mention that they also gained on average eleven pounds in weight, which put them at increased risk of diabetes108—the company rather homed in on one shred of positive data about the drug faring slightly better on some measures of cognitive functioning. And it was on the basis of these data that public claims were made that Seroquel has “greater efficacy than Haloperidol [Haldol],” a fact they hoped would lead physicians “[to] better understand the dramatic benefits of newer medications like Seroquel.”
The company seemed to have favored the practice of cherry-picking for some time. Indeed, in the following internal e-mail, again released during litigation, we hear how cherry-picking had been used in a previously buried trial called Trial 15:
From: Tumas John T A
Sent: Monday, December 06, 1999, 11:45PM
To: Owens Judith J; Jones Martin AM – PHMS; Litherland Steve S; Gavin Jin JP
Cc: Holdsworth Debbie D; Togend Georgia GL; Czupryna Michael MJ; Gorman Andrew AP; Wilkie Allison AM; Murry Michael MF; Rak Ihor IW; O’Brian Shawn SP; Denerely Paul PM; Goldstein Jeffery JM; Woods Paul PM; De Vriese Geert; Shadwell Pamela PG
Subject: RE: EPS Abstracts for APA
Please allow me to join the fray.
There has been a precedent set regarding “cherry picking” of data. This would be the recent Velligan presentations of cognitive function data from Trial 15 (one of the buried trials). Thus far, I am not aware of any repercussions regarding interest in the unreported data.
That does not mean that we should continue to advocate this practice. There is growing pressure from outside the industry to provide access to all data resulting from clinical trials conducted by the industry. Thus far we have buried Trials 15, 31, 56 and are now considering COSTAR.
The larger issue is how do we face the outside world when they begin to criticize us for suppressing data. One could say that our competitors indulge in this practice. However, until now, I believe we have been looked upon by the outside world favorably with regard to ethical behavior. We must decide if we wish to continue to enjoy this distinction.
Best regards.109
Obviously, AstraZeneca decides not to plunge for the ethical option. Rather, it continues to risk its reputation and the health of patients by cherry-picking the positive data and burying the negative data in order to sell up the advantages of Seroquel over Haldol. This finally backfired in 2010, when so many people taking Seroquel were suffering from such awful side effects that about 17,500 of them were officially claiming that the company had lied about the risks of the drug. These claims were finally vindicated in 2010 when AstraZeneca paid out $191 million to settle a class action out of court for defrauding the public.110
4
Cherry-picking is just one practice amid a variety of goal-moving techniques employed by pharmaceutical companies. One of the other most common strategies is something called “salami-slicing.” This is when companies not only keep negative studies hidden from professionals and the general public but also publish positive studies many times over in different forms and locations. The problem with this practice is obvious: it creates the false impression that many studies have been conducted, all showing positive results, when in actual fact all the positive studies stem from only one “data set” or piece of research.
To illustrate the highly subtle way in which salami-slicing can operate, just consider for a moment a recent study that investigated how salami-slicing can work by making use of what are called “pooled analyses.” A pooled analysis is a study that literally “pools” or bundles together the results of many separate and previous clinical trials, rather like a meta-analysis does. The crucial difference between a meta-analysis and a “pooled analysis,” however, is that a meta-analysis has to include all the relevant studies that address a particular question, whereas a pooled analysis may “pool” only those studies a company chooses to include. The danger here is obvious: a company ends up picking and choosing those studies which, when pooled together, convey a desirable outcome from the company’s point of view.
To give you an example of this strategy at work, a recent study focused on forty-three “pooled analyses” conducted by Eli Lilly for its antidepressant Cymbalta (Duloxetine). It revealed that several pooled analyses were based on greatly overlapping clinical trials and presented efficacy and safety data that did not answer unique research questions, and thus appeared to qualify as “salami” publications. They also found that six clinical trials were used in more than twenty pooled analyses that were each published separately—meaning that data from six trials were disseminated in more than twenty different places.111 The authors exposing these tactics declared that “such redundant publications add little to scientific understanding,” and rather “better serve the curricula vitae of researchers and, potentially, goals of drug marketers” than they do “science and patient care.”112
An equally suspect strategy is called “washing out.” This is when a company conducts a trial comparing a placebo to an active drug, but before the trial begins, it first puts all the patients on a placebo for a specified period of time. What it then does is remove from the prospective trial all those patients who got better on the placebo. In other words, if the placebo makes you feel better, you won’t be included in the trial. This dubious practice is justified on the grounds that anyone who responds to a placebo is either not “ill” enough or has already recovered. But this justification does not even begin to address the core problem with the washout: By not allowing people who are helped by the placebo to enter the trial, you artificially inflate the numbers of people responding to the active drug compared to the placebo. Again, this dubious practice is common in psychiatric drug research.113
If you still doubt whether pharmaceutical research into psychiatric drugs is not as honest as we would like to believe, consider this final study published in the British Medical Journal. This compared the outcomes of studies funded by the pharmaceutical industry with those funded from other sources. Overall, the company-funded studies were found to be four times more likely to show results favorable to company drugs than were studies funded from other sources.114
It appears that when companies research their own products, one way or another they get—or perhaps simply choose to publish—results from which the company stands to benefit. The financial rewards of moving the goalposts, it seems, makes the temptation of doing so perhaps too strong to resist.
5
How does moving the goalposts garner huge financial rewards? The previous editor of the British Medical Journal makes it clear that publishing a positive article in a reputable journal is the most effective form of advertising a company can get:
A large trial published in a major journal has the journal’s stamp of approval … will be distributed around the world, and may well receive global media coverage, particularly if promoted simultaneously by press releases from both the journal and the expensive public relations firm hired by the pharmaceutical company that sponsored the trial. For a drug company, a favorable trial is worth thousands of pages of advertising, which is why a company will sometimes spend upwards of a million dollars on reprints of the trial for worldwide distribution. The doctors receiving the reprints may not read them, but they will be impressed by the name of the journal from which they come. The quality of the journal will bless the quality of the drug.
Publishing a positive article in a reputable journal is therefore paramount. But if journal editors know this, why aren’t they being more vigilant? After all, the articles discussed above were all published in distinguished medical journals. Smith defends the editors by arguing that, given the growing finesse of company tactics, it’s becoming increasingly difficult for editors to spot whether they are “peer-reviewing one piece of a gigantic and clever marketing jigsaw.” Furthermore, Smith also admits there are many financial pressures bearing down on editors to publish companies’ trials:
Publishers know that pharmaceutical companies will often purchase thousands of dollars’ worth of reprints, and the profit margin on reprints is likely to be 70%. Editors, too, know that publishing such studies is highly profitable, and editors are increasingly responsible for the budgets of their journals and for producing a profit for the owners. Many owners—including academic societies—depend on profits from their journals. An editor may thus face a frighteningly stark conflict of interest: publish a trial that will bring US$100,000 of profit or meet the end-of-year budget by firing an editor.115
In other words, if companies were nonprofits, and if journal editors didn’t have to rely upon pharmaceutical revenues for their subsistence, we might well see these dubious research practices disappearing overnight. But these, right now, are just fantastic conditionals. Even in Britain, where treatment is free at the point of delivery, companies are set to make vast profits each year when the right articles appear in the right journals. Companies are very successful at making this happen, since nearly all published psychiatric drug research is in someway industry-funded. Admittedly, psychiatrists still participate in much of this research, but that is no guarantee of its quality.
As the previous editor of the New England Journal of Medicine put it, increasingly doctors are used like hired hands, just supplying the patients, collecting the data, and endowing the published reports with their prestigious names and university associations. Most companies now prefer their own employees to design the studies, perform the analyses, write the papers, and decide whether and in what form to publish the results. That way the companies retain control, and therefore make use of the many subtle strategies by which their products can be cast in the best light.116
Money, then, is at the heart of the issue. It galvanizes companies to find ever more ingenious ways to sell up their pills, it can dull editors’ critical sense by the promise of high journal sales, and it can be used to win psychiatric endorsement of a pill, should the price be right.
So let’s now focus on this final point. Have psychiatrists been co-opted into supporting the pharmaceutical mega-marketing machine? And if so, in what ways have companies used their financial clout to win psychiatric support for their products?
Before I address this important question, it is only fair I first warn you that if you suffer from high blood pressure, you should probably consult a doctor before reading on.