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The Deadly Corruption of Clinical Trials

When you risk life and limb to help test a drug, are you helping science—or Big Pharma? One patient's tragic, and telling, story.

Dan, age 10Dan, age 10

When Mary found out that Dan had been recruited into the CAFE study, she was stunned. "I do not want him in a clinical study," she told Olson. Just a few days earlier, Olson indicated in a petition to the court that Dan was both dangerous and mentally incapable of consenting to antipsychotic medication. How could he now be capable of consenting to a research study with the very same antipsychotics—especially when the alternative was commitment to a state mental institution?

After Dan was enrolled, he stayed at Fairview for about two more weeks. By that point, Olson thought Dan's symptoms were under control, but Mary was still very worried by his erratic behavior. She recalls meeting with the doctor: "Olson came in and sat down and opened his file and said, 'Oh, Dan is doing so well.' And I said, 'No, Dr. Olson, Dan is not doing well.' I think he was taken aback." Even so, on December 8, 2003, Dan was transferred to Theo House, a halfway house in St. Paul. He was required to sign an agreement confirming that he understood he could be involuntarily committed if he didn't continue taking his medication and keeping his CAFE study appointments.

At the halfway house, Dan often stayed in his room for days. On March 26, 2004 nearly four months after his discharge from Fairview, his thoughts were still "delusional and grandiose," according to a social worker's note. An occupational-therapy report from April 30 detailed Dan's condition: "Personal appearance disheveled. Isolated and withdrawn. Poor insight and self-awareness." Entries in a personal journal that Dan kept during this period don't show any obvious changes, suggesting that he was improving little, if at all. Mary felt he was becoming angrier. "He was so tense, with this ready-to-explode quality."

When the blind on the study was broken, researchers found that Dan was being treated with Seroquel, the drug manufactured by the study sponsor, AstraZeneca.

Olson saw things differently. "I disagree that he had significant deterioration," he testified in a 2007 deposition. However, it's unclear whether Olson actually saw Dan enough to make an informed judgment about his condition. Records suggest most of Dan's care was managed by social workers. In his deposition, Olson said he saw Dan approximately six times from the date he was admitted in November until he committed suicide in May. Whatever the doctor thought, his actions don't suggest that he felt Dan was improving. In late April 2004, as Dan's stay of commitment was about to expire, Olson recommended extending it for another six months—the duration of the CAFE study. He noted that Dan still had "little insight into his mental disorder" and might "place himself at risk of harm if he were to terminate his treatment."

Mary tried to get Dan out of the study or have his treatment changed. She called Olson and tried to see him. She wrote long, detailed letters expressing concerns about everything from Dan's diet and sleep habits to his medications. In total, she sent five letters to Olson and Dr. Charles Schulz—the chairman of the university's psychiatry department and a co-investigator on the CAFE study—communicating her alarm about Dan's condition, especially his inner rage. She received only one reply, dated April 28, from Schulz, who wrote that "it was not clear to me how you thought the treatment team should deal with this issue." Around that time, Mary left a voice message with Jean Kenney, the study coordinator, asking, "Do we have to wait until he kills himself or someone else before anyone does anything?"

Before dawn on the morning of May 8, a police officer and a Catholic priest knocked on Mary's door. Mike Howard, a family friend who lives at her house, answered. Later, in a deposition, Howard described what happened next: "Mary jumped out of her bed and went into the kitchen and stood there, and the priest extended his hand out and said, 'Mary, I'm here to tell you that Dan passed away.' And Mary just literally fell down to her knees and started to shriek and cry, and just started begging, 'Please, no, no, don't let this happen.'"

Dan had stabbed himself to death in the bathtub with a box cutter, ripping open his abdomen and nearly decapitating himself. His body was discovered in the early hours of the morning by a halfway-house worker, along with a note on the nightstand that said, "I left this experience smiling!" Later, when the blind on the study was broken, researchers found that Dan was being treated with Seroquel, the drug manufactured by the study sponsor, AstraZeneca.

 

For most of the past half-century, physicians have considered antipsychotic drugs to be among the most unpleasant chemicals in the medicine closet. Thorazine (chlorpromazine), the first antipsychotic, was developed in 1950, and while it could relieve some of the worst symptoms of schizophrenia, that relief came at a serious cost. Not only do antipsychotics often make patients feel sedated and sluggish (they used to be called "major tranquilizers"), they can also cause irreversible "extrapyramidal" symptoms, such as the shuffling gait, rigid muscles, and involuntary lip-smacking sometimes seen in patients who have been taking the drugs for years. The antipsychotics can also cause akathisia, a type of driven, agitated restlessness that ranges from unpleasant to excruciating. Until recently, psychiatrists reserved the drugs for patients with very severe mental illnesses.

By 2008, antipsychotics were the most lucrative class of drugs in America. Seroquel alone had nearly $4 billion in sales.

Over the past decade or so, however, antipsychotics have undergone an extraordinary rehabilitation. By 2008, they were the most lucrative class of drugs in America. Seroquel alone had nearly $4 billion in sales, making it the country's fifth most profitable drug. The transformation began in the mid-'90s, when pharmaceutical companies began pitching atypical antipsychotics such as Risperdal, Zyprexa, and Seroquel as more effective than older antipsychotics, but relatively free of their ugly side effects. The drugs were also very expensive—one study pegged the cost at 70 to 100 times that of an older drug—but if they didn't produce extrapyramidal symptoms, their enormous expense seemed justifiable. By the mid-2000s, atypicals were being prescribed not just for schizophrenia but also for anxiety, agitation, insomnia, attention deficit hyperactivity disorder, and depression. The most remarkable upswing came for patients diagnosed with bipolar disorder, which used to be seen as a rare illness. Once bipolar disorder could be treated with atypicals, rates of diagnoses rose dramatically, especially in children. According to a recent Columbia University study, the number of children and adolescents treated for bipolar disorder rose 40-fold between 1994 and 2003. Another study found that nearly one in five children who visited a psychiatrist came away with a prescription for an antipsychotic drug, despite early reports of alarming side effects.

Recent years have seen a backlash. The most damaging blow to the atypicals was an authoritative 2005 study funded by the National Institute of Mental Health—the so-called CATIE study—which found that the atypical antipsychotics worked no better than a much older antipsychotic called Trilafon (perphenazine), which was developed in the 1950s. The CATIE study also found that, contrary to the way the drugs had been marketed, side-effect profiles of the atypicals were generally no better than the older drug. Other research showed that atypicals were associated with significant weight gain, increased risk of diabetes, and greater possibility of death in patients with dementia. After another large analysis in The Lancet found that most atypicals actually performed worse than older drugs, two senior British psychiatrists penned a damning editorial that ran in the same issue. Dr. Peter Tyrer, the editor of the British Journal of Psychiatry, and Dr. Tim Kendall of the Royal College of Psychiatrists wrote: "The spurious invention of the atypicals can now be regarded as invention only, cleverly manipulated by the drug industry for marketing purposes and only now being exposed."

The cleverest manipulation has been with the clinical trials themselves. For years, critics have charged that pharmaceutical companies massage trials to make their own drugs look better than they really are. One common tactic is to suppress unfavorable data. A notorious example came in the 1990s, when a Wyeth safety officer overwrote the company's computer files, erasing evidence indicating that its diet drug, fen-phen, caused valvular heart disease. A less risky strategy is simply not to publish potentially damaging trials. In 2004, the Canadian Medical Association Journal described a leaked document indicating that GlaxoSmithKline had deliberately hidden two studies from regulators showing that its antidepressant, Paxil (paroxetine), could increase the risk of suicide in children. The company has paid nearly a billion dollars in legal settlements over Paxil, including $390 million for suicides and attempted suicides related to the drug. Evidence of manipulation has also emerged in many of the high-profile pharmaceutical scandals of the past decade, from Merck's pain drug Vioxx to the recent Senate investigation into GlaxoSmithKline's diabetes drug Avandia.

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