Pharmageddon (22 page)

In a number of states, Texas among them, legislators have the power to rule that guidelines such as TMAP's must be applied in the care of any patients receiving treatment in public facilities. The logic is that evidence-based guidelines, if they really do reflect reality, can be expected to be cost-effective over time. The legislators in Texas meet infrequently, are poorly paid, and are intensively lobbied. Perhaps because of such lobbying, or because pharmaceutical lobbyists were able to show the legislators position papers endorsed by experts, in 1999 the state of Texas endorsed, with no dissenting views, the TMAP guidelines for schizophrenia, mood disorders and for children, thus requiring state hospital doctors to prescribe the newer drugs first.

The TMAP guidelines were subsequently adopted by executive decision in a large number of other states.
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In this way companies have effectively produced a situation in which a growing number of patients on Medicaid and other programs end up being put on and maintained on the newest and most costly of drugs.

The consequences are worth looking at. In 2004, eighth-graders in Pflugerville, Texas were screened by psychologists. Aliah Gleason, a thirteen-year-old, ticked the box for suicidality on one of the tests—probably a probe such as, Have you ever wished you were dead. Even though she was regarded as a live wire in class, this tick led to a referral to a psychiatrist and removal from her family by the child protection services. She was admitted to Austin State Hospital and within hours she was receiving the very best treatment—and did so for the next nine months. This involved all the latest antipsychotics, antidepressants, and mood stabilizers, as mandated by TMAP, costing a small fortune. These were administered not individually but in cocktails of up to five different medications daily. She gained huge amounts of weight, developed a range of side effects, and showed no evidence of progress. It took nine months for her family to get her back and begin to get her off treatment.
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Between 1997 and 2004, Texas Medicaid spending on antipsychotics rose from $28 million to $175 million. In the months of July and August 2004, over 19,000 adolescents in Texas were given antipsychotics, even though pharmaceutical companies had not applied for licenses to market these drugs for use in minors.

In 2003, Zyprexa pulled in $4.3 billion in sales in the United States, 70 percent of which came from state health insurance and other public health programs. It will probably come as no surprise that within all the major companies there are divisions aimed at maximizing the effectiveness of company marketing in the public sector. And it may be no accident that, in 2009, research revealed that children being treated under Medicaid were four times more likely to get antipsychotics than children not covered by Medicaid.
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Surely nothing similar could happen within Britain's socialized system of medicine, where the key guidelines are produced by NICE, which had been set up with a brief to make recommendations as to the most cost- effective treatments for both physical and mental illnesses? The panelists framing NICE guidelines, whether for cardiac treatments, arthritis management, or psychiatric conditions, have access to the resources of the Cochrane collaboration, the independent organization set up by Iain Chalmers initially in Britain but now with centers in all Western countries that systematically reviews the published evidence—taking pains to obtain all the published evidence and eliminate all evidence that has been duplicated to inflate artificially the apparent benefits of one drug over another. When assembling guidelines, NICE also ensures that it has a range of nonmedical participants to balance out any bias the doctors involved may have in favor of the latest treatment.

Despite this, the 2002 NICE guidelines for the use of antipsychotics came to the same conclusions as TMAP: newer agents like Risperdal and Zyprexa should be used before older ones.
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Lilly responded to this news by incorporating symbols of NICE and NICE statements into its ads for Zyprexa, which was now supposedly a medication NICE endorsed. NICE had done for Lilly what we've seen the FDA had indicated would be illegal in the United States for the company to do for itself.

How come? The first point is that while NICE had access to all the published evidence through the resources of the Cochrane collaboration, this really didn't amount to any more than they would have been provided by the pharmaceutical companies had they asked. The Cochrane Center had made it clear that there was a great deal of duplicate publication. The four initial trials of Zyprexa in schizophrenia for instance had given rise to 234 publications of one sort or another—almost entirely company written.
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While whittling the publications down to establish just how many trials there had been did help to qualify the apparent benefits of Zyprexa, it made no difference in NICE's overall evaluation.

What might have made a difference lay elsewhere in the vast amount of data from the four Zyprexa trials that simply could not be found in any of the 234 publications—there was nothing on suicides, diabetes, or cholesterol and little on weight gain. Not one publication hinted that patients given Zyprexa in these trials for schizophrenia had the highest suicide rate in clinical trials history; suicide was in fact rare in schizophrenia before the advent of the antipsychotics.
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Not one publication mentioned that patients in these trials went on to develop diabetes at a rate triple the background rate in the general population, when diabetes was almost unheard of in schizophrenia before the antipsychotics.
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The publications concealed the extent of weight gain in the patients given Zyprexa, whose weight often ballooned by anything from 20 to 140 lbs. These and subsequent publications also failed to reveal that, regardless of diagnosis, Zyprexa raised cholesterol levels more than almost any other drug in medicine—though Zyprexa had received a patent in part based on company claims that it would be less likely than other antipsychotics to raise cholesterol levels.

The figures for suicides, cholesterol, and diabetes were all buried in reports submitted by the company to the FDA. Even furnished with these reports to the regulator, it is difficult to establish what the true figures are and a good deal of data seems to be missing.
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But NICE and TMAP didn't have the data and didn't even have these reports that were submitted to the regulator—they were working only from the published evidence. Based on a thorough assessment of the publications alone, NICE came to the conclusion the newer antipsychotics were no better than older agents. But the published evidence still suggested the new drugs provided a better quality of life and a lower burden of side effects than the older drugs, whereas the raw data point to just the opposite conclusions.

Against this background, NICE also had to manage a dynamic situation. First, how would clinicians and patient lobby groups, who had been bombarded for years with hundreds of publications extolling the virtues of Zyprexa and Risperdal and claiming these drugs liberated patients from some of the terrifying problems caused by the older agents, respond to a recommendation from NICE to use older drugs—had they chosen to give it? The 234 Zyprexa publications and further hundreds from the other new antipsychotics (Risperdal, Seroquel, Abilify, Geodon) played a great part in generating this pressure. Some of the panelists may privately have thought the older drugs were as good as the new ones, but it was difficult to offer evidence for this point of view, especially since they had no access to some of the most telling data. If NICE had come down favoring the older drugs, company-sponsored patient groups, told they should have the older drugs, would likely holler rationing, and even use this supposed rationing as an argument for desocializing healthcare. Second, just as journals do not publish articles critical of the pharmaceutical industry for fear of a legal action, so also NICE knew it stood to be dragged into a legal action if it came to a decision that was not based on published evidence. And since then, in the case of guidelines for Alzheimer's disease, it has found itself sued even though its decision is based on the published evidence.

Rumor has it that NICE was also faced with a British government that was in receipt of communications from several pharmaceutical companies threatening to pull out of the UK if the guidelines were not favorable to its products.
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The NICE guidelines came out in 2002. Three years later two large independent studies, one American and one European, were published showing that older antipsychotics were as effective and tolerable as any of the newer agents, and superior to some of them.
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But if doctors wanted to follow the evidence and prescribe one of the older agents, they would have found a series of guidelines standing in their way, as these are only updated periodically.

THE GREATEST DIVIDE IN ALL OF MEDICINE

Having been invited to a number of guideline meetings, I had a chance in 1997 to convene one. As the secretary of the British Association for Psychopharmacology, I organized the first consensus conference to look at issues surrounding the prescription of psychotropic drugs to children. The growing number of prescriptions being written for ADHD (attention deficit hyperactivity disorder) had triggered the meeting, but on the day, the treatment of depression in children was the primary focus of attention.
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There was an important difference between this and the pediatric guideline meetings that came later. In 1997, except for ADHD, there were few published clinical trials. Furthermore when it came to depression, the clinical wisdom as of 1996 was that unhappiness in childhood was not the same as depression in adults—it was not something for which pills were the accepted answer. As a result when authoring the final document, the premium was on treating the child rather than the condition. Clinicians were recommended to lay out all the treatment options—drug and nondrug—for patients and their parents and if the first treatment didn't seem to be working they were advised to switch to alternate treatments even if not among those the doctor preferred. This was guidance rather than a guideline.

One feature of the meeting became intriguing later on. I had invited all panelists and a number of pharmaceutical companies. SmithKline Beecham were present as were a number of the clinical investigators for Study 329, SmithKline's trial of Paxil in depressed children outlined in the previous chapter. This study had been completed at the time the guidelines were written but I didn't know about it and possibly very few others did and there was not a single mention of any Paxil study on the day of the meeting.

Two years later, in 1999, TMAP issued guidelines endorsing the use of SSRIs in children who were depressed.
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By this time a trial of Prozac in children had been reported and it was known that several other trials were underway. In 2002, the FDA endorsed Prozac for treating depression in children. The FDA had also issued a tentative approval to GlaxoSmithKline for the use of Paxil in children and was likely to do so for Zoloft. An article that had appeared in
Newsweek
to coincide with World Mental Health day in 2002 claimed there were three million depressed adolescents in the United States, who were supposedly at substantially increased risk of career failure, divorce, alcoholism or other substance misuse, and suicide, all of which could, according to the
Newsweek
article, be averted by the new SSRIs just about to be approved.
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There was no hint here that unhappiness in childhood might be different than adult depression. The thrust of the article was that a failure to treat with medication would be equivalent to failing to give an antibiotic to a child with a life-threatening infection.

When the FDA approved Prozac, Paxil, and Zoloft for use in adults in the early 1990s, they noted that the drugs were likely to be used to treat children and encouraged companies to run studies to establish the safety of the drugs in children. Sales of SSRIs for children had been creeping up steadily through the 1990s on the back of over seventy published “open studies” of these medicines—all claiming the drugs were marvelous. Open studies are ones in which a doctor knows what the drug is and the patient may be told as well. They invariably report positive results for a drug, but companies cannot use this kind of study to get marketing approval from FDA; they can only use randomized studies.

Because there were so few good studies for any drugs in children, in 1998 the FDA Modernization Act (FDAMA) offered pharmaceutical companies a six-month patent extension for a drug if they submitted studies that examined safety issues in children. They didn't have to prove safety. They just had to test for it. If the drugs showed hazards, the company still received the patent extension but would have to incorporate the hazard information in the label.
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This offer of patent extension gave the companies a hefty incentive to submit studies to the FDA on the effect of their drugs on children. A six-month patent extension for a Paxil or Zoloft meant easily over $1 billion in additional revenues. And there was every chance that the FDA would miss the problems.

As a result, in 2003 when NICE set about drawing up a guideline on the treatment of childhood depression, six randomized trials of SSRIs in children had been published.
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The new guidelines were set to endorse the use of Prozac and other SSRIs for children.
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The use of these drugs was increasing rapidly in Europe and this endorsement would likely have opened a floodgate.

In the case of Prozac there were two Lilly trials. Graham Emslie from Texas, who had participated in drawing up the TMAP guidelines for children, was involved in both. In clinical trials, it is customary to specify a primary measure of the success of treatment—such as the score on a particular rating scale or blood test—and if the drug fails to beat placebo on this measure, the trial is considered negative. On this basis, the first Emslie study, which started in 1990 but was only published in 1998, was a negative study even though the published article claimed it was a positive study.
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