Pharmageddon (23 page)

A second study published in 2002 was also negative. After the first week of the study, all children who had a bad reaction to Prozac or a good response to placebo were excluded.
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It is common for a company to load the dice in its favor by excluding anyone who responds to placebo in the initial phase of the trial, but it was almost unheard of at the time to take the extra step and exclude patients who reacted poorly to the experimental drug during the first week of their exposure to it. If they dropped out of the study, they should be counted as dropouts for adverse events, not eliminated from the study calculations entirely. This novel tactic has since been increasingly copied in company trials of drugs for asthma, hypertension, and other conditions.

In the case of Paxil, the key study and the largest of the SSRI trials was Study 329, which as outlined in
chapter 4
was a negative study that Sally Laden of Scientific Therapeutics Information transformed into an article demonstrating the remarkable efficacy and safety of Paxil. In addition to Study 329, Study 377 had also been undertaken in the 1990s but remained unpublished. Two further studies were presented at academic meetings in 2002; both claimed that Paxil was safe and

effective.
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The third of the major SSRIs was Zoloft. The FDA requires two controlled studies to let a drug on the market. Pfizer ran two studies. In each Zoloft failed to beat placebo.
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Just as with Study 329, these studies were ghostwritten. In this case they were published in the
Journal of the American Medical Association
and in the process transformed into one positive study—Zoloft was deemed effective and well tolerated. The design of these trials did not encourage the detection of any problems resulting from Zoloft, but even so, compared to children on placebo, there was a doubling of the rate of behavioral problems, including suicidality and aggression, in children on Zoloft and a tripling of the dropout rate for side effects.
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By 2003, then, a series of articles all claimed the SSRIs worked, and so an impending endorsement by NICE did not seem surprising. GlaxoSmithKline had applied to the British regulator (the Medicine and Healthcare Products Regulatory Agency, MHRA) for a license to market Paxil for childhood depression. But in October 2002 and Spring 2003 two BBC investigative journalism programs had questioned the benefits of Paxil.
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Astonishingly, MHRA turned down GlaxoSmithKline's application to license Paxil, and in support of their move took the unprecedented step of posting on its website the details of fifteen controlled trials on antidepressants undertaken by a number of companies in pursuit of a license for treating pediatric depression. Depending on the way one reads the studies, between twelve and fourteen of these fifteen studies suggested the drug being tested didn't work and overall the studies showed a doubling of suicidal acts on the drugs compared to placebo. It was clear from these posted studies that there were yet further data that GlaxoSmithKline had not sent to the regulator.
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NICE was faced with two problems. First, they worked from the published data but the MHRA posting made it clear there were many more studies. Of the at least fifteen studies conducted, only six had been published. The unpublished studies were all negative. The second problem was that even the published Paxil, Prozac, and Zoloft studies, it was now clear, had been manipulated so that essentially negative studies were transformed into positive studies, hiding the fact the drugs didn't work and masking the problems of treatment. These revelations led researchers from NICE to pen an award-winning editorial in the
Lancet
, lamenting “depressing research.”
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This pointed to the impossible position any guidelines agency was in if companies withheld trials and distorted the data to the extent that had happened in the case of the pediatric antidepressant trials. It was left unsaid, but the position for doctors whose legitimate concerns about giving drugs like Paxil to children might conflict with the guidelines, had they been instituted, would have been even worse. The position for the children would of course have been worst of all.

For a brief moment, some of those in NICE who had gone through this crisis toyed with the idea of insisting that the status of any evidence that came from company trials be downgraded. Up to this point, the rules of evidence-based medicine had been that the results of clinical trials trumped everything else. Now it had become clear that companies were selective in what trial data they released, and thus company data appeared to be worth a lot less than had previously been assumed.
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But NICE dropped the idea of downgrading company trials. Could they be sure that a rule made on the back of the issue of antidepressants for children would hold water when it came to, say, trials of antihypertensives or analgesics or drugs for osteoporosis? If company evidence were to be downgraded, to what rung in the ladder should it be relegated—above or below the opinions of experts? Just how worthless was company evidence? And having dragged pharmaceutical companies into trials by insisting upon their necessity in order to gain a license, was this really the time to give them a slap in the face? Far better, surely, to work to improve company trials.

There had, moreover, apparently been one positive outcome of the debacle. The Paxil data that MHRA made public confirmed the message of an internal GlaxoSmithKline memo that had come to light in the BBC investigations: that Study 329 had shown Paxil was not effective, so only the good bits of the data would be published. At hearings the FDA held in February 2004 on prescribing antidepressants for children I made it public. It found its way from there to the offices of New York's Attorney General, who sued GlaxoSmithKline for fraud, and as part of the settlement, the company agreed to register all its trials on the web.

The idea of a clinical trial register took off. Journals indicated that they would in future only publish accounts of trials that had been registered with a central trial register beforehand and been given a unique identifier. Such an identifier would have made it easier to establish that only four trials underpinned the 234 publications on Zyprexa. But clinical trial registers and Glaxo's posting to its website do nothing to change the basic problem, which is that companies still do not made the raw data from these trials available.

NICE finally did issue a guideline on pediatric depression in 2004: they recommended against using SSRIs as a treatment. In 2004, the FDA held a further regulatory hearing in September to follow up the February hearing. These hearings on antidepressants and suicidality in children led to the highest level of warning, a black box warning, being put on the drugs indicating that they might trigger suicidality. The FDA meanwhile did not license Paxil or Zoloft or other antidepressants for use in children.

Far from this being a case of all's well that ends well, however, the use of antidepressants in children shows how far our scientific standards have slipped and how this impinges on our ability to care for some of the most vulnerable people there are. These studies of antidepressants in children offer the greatest known divide in medicine between what published reports in the scientific literature say on the one side and what the raw data in fact show, but there is no reason to think this problem doesn't extend to other treatments in other areas, from drugs for osteoporosis to treatments for asthma, female sexual dysfunction, PTSD, or other disorders. There was another landmark also—this was the only known case where all of the published studies were ghostwritten or company written.

The fifteen controlled studies of these new antidepressants should stand as a celebrated example of what controlled trials are there for—to stop bandwagons in their tracks. But instead, between ghostwriting and selective publication of the data, companies have turned controlled trials into their primary means to turbocharge sales. The published papers endorsing the use of Paxil, Prozac, and Zoloft remain in print in the best journals and continue to fuel a boom in off-label sales of these drugs to children.
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There have been efforts to get Study 329 retracted but these have failed.
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It continues to be built into guidelines supporting the use of antidepressants for children.

Erick Turner, formerly a reviewer with the FDA, has demonstrated that a third of the studies undertaken to get current antidepressants on the market for adults remain unpublished but even more worryingly a third of those published were studies the FDA regarded as negative but, like Study 329, companies published as positive.
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In other areas of medicine, where the problem has not been forced out into the open, companies can use their published studies to capture guidelines as they had almost done in the case of antidepressants given to children and, as we shall see in the next section, they continue to do in other domains. But even when the guideline is not captured, such studies and their publications transform the way we view things. In the case of antidepressants and children, for example, there is no longer any appreciation that childhood unhappiness might be anything different from adult depression. Someone attempting to express such a view today would find it difficult to get acceptance in anything other than a marginal journal.

THE CAPTURE OF THE BIPOLAR GUIDELINES

Classic manic-depressive illness, which typically leads to periods of hospitalization, was and still is rare. The recent invention of bipolar disorder obscures this but reveals much about how companies capture guidelines. When patients with the classic illness were admitted to hospital, either manic or depressed, they were typically too ill to be recruited for a controlled trial. This is not as problematic for good clinical care, including care that involves pharmaceuticals, as it may sound, however. Clinical trials rarely lead to discovery of any new drugs. Chlorpromazine, for instance, the first of the antipsychotics, was discovered in the early 1950s in Paris as a treatment for mania—but it was discovered because it made such an obvious difference to the patient in front of the doctor's eyes, not because a clinical trial showed it had an effect.
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For the ensuing forty years, no one in medicine saw a need to conduct a trial for something as obviously beneficial as giving these antipsychotics to manic patients.

That there had been no randomized trial data for these older drugs for mania opened up a golden opportunity for pharmaceutical companies to push these older drugs out of the market, when in the 1990s the companies came out with a series of new, albeit, as it turned out, no more effective and actually more hazardous antipsychotics. The way forward led through treatment guidelines.

Here's how it happened in the case of bipolar disorder. The first step was to run short-term trials involving patients with much less severe conditions, and less certain diagnoses, using rating scales that may have reflected little more than how highly sedating were the drugs being tested. A strong sedative will always produce a “signal” on a rating scale for mania—the patient will be less active, less talkative, less disinhibited while under the influence of the drug. This is all it takes to get FDA approval for company claims their drug is antimanic. As a result of these trials all guidelines from the first formulated by TMAP in 1998 to a set of NICE guidelines in 2006 recommend the use of on-patent antipsychotics—but not any of the older antipsychotics.
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The second step was to run debatably ethical trials elsewhere, such as one Janssen ran in 2003 and 2004 on Risperdal for mania in India.
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This trial became the subject of a BBC investigation into the ethics of studies for Western treatments outsourced to India. Did patients know they were involved in research? Did they consent to it? Did they know that once their participation was over they would be removed from drugs that might have been helping them? And it wasn't just ethics that was at issue. The correspondence in the columns of the
British Journal of Psychiatry
on the validity of this study was more extensive than for any other study the journal has published.
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In this newly globalizing clinical trial world, everyone faces a future in which the bulk of the evidence that dictates clinical practice when it comes to the use of statins, antihypertensives, painkillers, antibiotics, and practically everything else from mental health to respirology will come from settings that are very different from those in which the treatment will be given. There are likely to be many consequences for clinical practice, not least because both efficacy and side effects of different medicines may vary markedly in different ethnic groups.

As a result of the trials undertaken in India and elsewhere, only the new antipsychotics had randomized controlled trial support. The older agents hadn't. The straitjacket of current notions of evidence-based medicine, as applied by guideline bodies like TMAP or NICE, places published evidence from controlled trials above everything else—almost to the absurd point of not using a parachute until a study is undertaken to indicate formally its usefulness. What's more, the marketing departments of companies depend on our fascination with the supposed ironclad science of controlled trials and use it to capture the process of developing guidelines.

The third step involves something close to checkmate. In the case of manic-depressive illness the only agent with an established prophylactic effect is lithium. But modern guidelines also variably recommend Zyprexa, Depakote, and other new antipsychotics or anticonvulsants even though these are not licensed for this purpose. This has essentially happened because Abbott heavily advertized Depakote as a mood stabilizer in the first instance and the companies with follow- up anticonvulsants and antipsychotics followed suit. The term “mood stabilizer” generates expectations of a prophylactic effect even though none has been shown. Claiming Depakote was prophylactic would have been illegal—but there was no need for Abbott or other companies to tempt the law when a prestigious guideline recommends Depakote for a use the regulator would not let the company claim. In this case, bound by the law, the FDA is a lot more stringent than the guideline makers. This is advertising that's hard to beat.