Pharmageddon

by David Healy

  Victor took Zoloft as instructed over the next six days. His family later said that for the first day he thought the drug was helping him. By the third day, he told his sister the drug didn't suit him, and his wife noticed he was pacing and sleeping even less at night. On the fourth day, he had become shaky. On the fifth day, his birthday, he told Flora “I don't feel like myself,” “the drug is making me crazy,” and “I want to kill myself.” She urged him to continue taking the drug because the doctor had told them that it might not work for another week.

  He was due to fly to Washington the next day, November 12, the sixth day of treatment. When his brother arrived to take him to the airport, Victor was not there. He was found in his car several blocks away, dead behind the wheel from a single gun shot to his head.

  In 2001, Flora took legal action against the makers of Zoloft, alleging that Pfizer “negligently…failed to adequately warn the medical community, the general public and (her husband)…of the dangers, contraindications and side effects…of Zoloft.” Malcolm Wheeler, the lead attorney for Pfizer, contacted the new chief counsel of the FDA, Daniel Troy. Troy had joined the Department of Justice the year before, from a legal office that had done over $358,000 worth of business with Pfizer that year. Troy filed an amicus brief in the Motus case. In order to file such a brief, he had to have clearance from the solicitor general in the George W. Bush government, Paul Clements, a former partner in King and Spalding, the main law firm representing GlaxoSmithKline, who were also faced with a series of suicide cases involving an antidepressant, in this instance Paxil.

  Troy's brief argued that the California court had no jurisdiction in the case. The FDA is responsible for the labeling of drugs and if Pfizer had warned that the drug could cause people to become suicidal it would have broken the law. Troy was firing a shot across the court's bow to ensure it did not do anything that would “undermine the agency's authority to protect the public health.”57

  When considering warnings, according to Troy, the FDA has to take into account the risks posed by the untreated illness—depression. “Under-utilization of a drug based on dissemination of scientifically unsubstantiated warnings, so as to deprive patients of beneficial, possibly lifesaving treatment could well frustrate the purpose of federal regulation.”58

  This was an extraordinary and unprecedented move. This was not the conventional company argument that juries cannot possibly decide on the science of an issue such as whether a drug might cause suicide. Troy was arguing that a jury had no place in considering whether the FDA should have asked for warnings or not—and therefore the company could not be prosecuted provided it had followed the directives the FDA had given it, regardless of whatever effect the drug had or had not had on Victor Motus. This was even though, as federal law stands, companies are obliged to warn if there are hints of a problem—not just on the basis of proof of a problem.

  The idea of using a federal agency to preempt legal action in a state court was Malcolm Wheeler's brainchild. He had used it first when defending the Honda Motor Company in a 1980 case in which a plaintiff argued the company should have installed airbags even though federal regulations didn't at the time require them.59 This case went all the way to the Supreme Court who, noting that the car contained many other safety features such as seatbelts, sided with Honda.

  In the case of cars and butter as outlined earlier, it is not the job of the regulator to even begin to think about whether people should be driving cars or using butter. In the Motus case, however, the Pfizer argument was that the FDA should be thinking not just about whether drugs would be used but also attempt to ensure that they would be used, and that in this light, warnings might put a chill on this use. This opens up an extraordinary vista—and certainly not the vista Senator Kefauver had in sight when sponsoring the 1962 amendments to the Food and Drugs Act.

  When I turn the ignition key to start a car, wires have to connect to a starter motor and there has to be a flow of both oxygen and gasoline for the act of driving to become possible. For a physician to practice medicine, having a drug that works is helpful but often not essential. From time immemorial, and certainly as embodied in Pinel's famous aphorism about the art of medicine, good practice has been held to be much more likely where there is detailed knowledge about the hazards of any drug used. Semiautomatic prescribing has never been regarded as good practice.

  In arguing about the merits of safety warnings, Wheeler and Troy portrayed the issue as being the equivalent of having airbags in a car, when in fact they were arguing against a need to have the ignition wires properly connected to the starter motor or letting people know that, in some instances, the ignition wires might default to the gas tank (an instance of immediate-onset side effects), or, in a case of lateronset adverse effects, faulty brake linings that would give way after six months. Safe starting connections and functioning brakes have never been optional extras to a car in the way airbags once were; they are integral to its basic operation.

  Before there was a ruling on preemption in the Motus case, Pfizer in fact got the case thrown out, but on the basis of another astonishing defense—the prescription-only status of Zoloft that Senator Kefauver unwittingly cemented in place in 1962. In a pretrial deposition, Dr. Trostler testified that no matter what the warnings were on Zoloft, he would have gone ahead and prescribed the drug anyway. If a doctor testifies as Trostler did that he would have used the drug in a similar fashion whether there were warnings or not on it, any case against a pharmaceutical company on the basis of failure to warn about the risks of a drug that is available only by prescription collapses. The reason to make them available by prescription only was precisely this—to interpose a professional judgment between the patient and the pharmaceutical company. As a majority of his colleagues at the time also held the view that SSRIs posed no risk, Trostler was not at risk of a malpractice suit. Victor Motus, like almost everyone who dies unnecessarily on a prescription-only medicine, was the victim of a perpetrator-less crime.

  The service that pharmaceutical companies get from primary care physicians or other medical doctors, in other words, goes well beyond what most industries get from their onsite doctors. Not only can companies typically depend on doctors not to rock the boat, but they can palm off any legal responsibility for injuries caused by exposure to chemicals onto the doctors who do the prescribing. Complain about or investigate a problem and the doctor knows he is in for a rough ride. But faced with a problem that turns up later, the company gets off scot-free because doctors refuse to accept that the chemicals have caused the problem.

  DESCENT INTO THE UNDERWORLD

  Before his doctor abandoned him, Victor Motus's case led to an unearthing of a series of documents about how Pfizer had transformed clinical trials into marketing exercises, recoded patient details where the original data were inconvenient, and planted ghostwritten articles in all major journals. By focusing attention on the role of ghostwriting and company manipulations of their data it set a template for later legal actions surrounding Vioxx and other drugs.

  The Motus case also led directly to evidence of children becoming suicidal on Zoloft, ultimately triggering, in 2004, two further sets of public hearings on antidepressants and suicide in children. At the second of these FDA hearings, Tom Laughren, head of the Central Nervous System division at the FDA, presented the clinical trial data and the FDA's views of the data.

  Members of the public were then given three-minute slots to present views—seventy-three of them. Among these, a series of doctors made presentations—almost all male and all warning against the issuing of warnings. These were intermingled with a series of mothers, a modernday set of Demeters. Demeter was the Greek goddess of the Earth and of fertility whose daughter, Cora, was forcibly abducted and carried off to the underworld by Hades. Demeter protested to Zeus, who professed himself helpless, until Demeter threatened Earth with permanent winter. Zeus intervened and restored Cora to her mother as Persephone. Because Persephone had eaten some pomegran
ate seeds while in the underworld, however, she was obliged to return to Hades for the several months of winter each year.

  These modern-day Demeters similarly aimed at shaming the heavens to take action. In a presentation with mythic resonance, in the 72nd slot Mathy Downing confronted Tom Laughren:

  On January 10th, 2004 our beautiful little girl, Candace, died by hanging four days after ingesting 100 mg of Zoloft. She was 12 years old. The autopsy report indicated that Zoloft was present in her system. We had no warning that this would happen. This was not a child who had ever been depressed or had suicidal ideation. She was a happy little girl and a friend to everyone. She had been prescribed Zoloft for generalized anxiety disorder, by a qualified child psychiatrist, which manifested in school anxiety…. She had the full support of a loving, caring, functional family and a nurturing school environment.

  Her death not only affected us but rocked our community…. When Candace died her school was closed for the day of her memorial service, a service that had to be held in the school gym in order to seat the thousand or so people who attended. How ironic, Dr. Laughren, that your family attended Candace's memorial service. Our daughters had been in class together since kindergarten. How devastating to us that your daughter will graduate from the school that they both attended for the past eight years and that Candace will never have the opportunity to do so.

  Candace's death was entirely avoidable, had we been given appropriate warnings and implications of the possible effects of Zoloft. It should have been our choice to make and not yours. We are not comforted by the insensitive comments of a corrupt and uncaring FDA or pharmaceutical benefactors such as Pfizer who sit in their ivory towers, passing judgments on the lives and deaths of so many innocent children. The blood of these children is on your hands. To continue to blame the victim rather than the drug is wrong. To make such blatant statements that depressed children run the risk of becoming suicidal does not fit the profile of our little girl.60

  A few minutes earlier, Mary Ellen Winter had also confronted Laughren and the FDA about her twenty-three-year-old daughter, Beth, and brought a new player into the frame:

  Beth was looking forward to a career in communication and was experiencing some anxiety and having trouble sleeping when she consulted our family physician. He prescribed Paxil and said she would start feeling better in two weeks. Seven days later Beth took her own life.

  We, like most of you in this room, grew up with confidence in the strides made in medicine and accepted with faith antibiotics and vaccinations prescribed. We believed the FDA would always act to protect our family's well being. When my daughter went to our family GP last year, we trusted that our doctor was well educated and informed. We were wrong. We now know that pharmaceutical sales are a high stake business, driven to increase shareholder wealth. The consolidation of pharmaceutical companies like GlaxoSmithKline has resulted in increased sophistication in the quest to market and distribute pharmaceutical products. Priority has moved from health to profit. Not all doctors are equipped to understand the marketing targets they have become. The FDA has allowed our daughter to be the victim of a highly commercial enterprise that selectively releases clinical data to maximize sales efforts and seeks only to gain corporate profits….

  As residents of the State of New York, we thank our Attorney General, Elliot Spitzer, for addressing issues that the FDA has been unwilling to address…. 61

  A few weeks before, the attorney general's office in New York had opened a fraud action against GlaxoSmithKline. The brief had been prepared by the unlikeliest of heroines, Rose Firestein. Firestein was blind and in poor health, but she had a passionate concern for the abuse of children. She charged GlaxoSmithKline with fraudulent interference with the practice of medicine. The company had engineered sales of Paxil for use in treating children who were depressed through the publication of ghostwritten papers that had concealed the drug's hazards and portrayed the outcome of studies, like Study 329, as positive even though this and other clinical trials had failed to show the drug worked. Her trump card was the internal GlaxoSmithKline document I had made public at an FDA hearing on pediatric suicidality on antidepressants six months earlier that showed the company deliberately setting out to present the good bits of the evidence and suppress the rest, and to publish papers in influential journals that would lead doctors to prescribe a drug that the company had already internally recognized did not work.

  When faced by GSK's lawyers with the argument Troy made in the Motus case, that the FDA's views preempted any views a state might have, Firestein responded that New York was not attempting to argue the toss with the FDA on the labeling of the drug. When it came to the practice of medicine in the state of New York, however, the state and not the FDA had primacy. GlaxoSmithKline settled, and as part of the settlement posted on their website details of all of their clinical trials.

  Ultimately, Mary Ellen Winter, Mathy Downing, and others who testified played a part in forcing the FDA to bow and issue warnings that antidepressants might lead to suicide in children, warnings that were extended to adults in 2006. These mothers did not win because their pleas were impassioned. They won because the FDA, although still giving every sign of willingness to ignore the nineteenth bullet in the twenty-bullet gun barrel, faced with nineteen bullets there could see no way out of issuing warnings. The FDA have since gone further and issued suicide warnings for anticonvulsants and antipsychotics, as well as Champix and Zyban for smoking cessation, Roaccutane for acne, Tamiflu for flu, and Singulair for asthma, and have withdrawn from the market Rimonabant for weight loss and Cymbalta/Yentreve for urinary incontinence for this reason.

  Legal actions against pharmaceutical companies are almost nonexistent outside the United States. In part this is because patients in Europe and other countries have universal healthcare and there is much less or no need to recover the costs of treatment for an injury from a pharmaceutical company. A great deal of what the world knows therefore about how pharmaceutical companies do business—how they market drugs, ghostwrite articles, ensure trials recruit just the right number of patients so that the results for serious hazards cannot become statistically significant—stems from legal actions in the United States.

  The attempted preemptive strike engineered by Malcolm Wheeler and Dan Troy in the Motus case—that of claiming that federal regulatory agency statutes preempted any action, state or federal, against a pharmaceutical company—aimed at removing one of the few remaining impediments in the world to company abilities to do business. Although Pfizer won the Motus case by other means, other companies began to use preemption with increasing frequency, and success. A series of SSRI-induced suicides, Vioxx-induced heart attacks, and Avandia- and Rezulin-induced deaths were thrown out on this basis.

  As the argument raised was legally unprecedented, it was taken all the way to the Supreme Court.62 When preemption had first been raised in 1998, it had seemed inconceivable to most legal minds that such a defense might succeed as a matter of principle, but a decade of company arguments and lobbying had made a difference. In attempting to come to a resolution, the Supreme Court scheduled two cases. The first involved Pfizer's Rezulin, which had been approved in 1997 as a treatment to lower blood sugar and then withdrawn from the market in 2000 after being linked with an excess of deaths from liver failure. In this case in 2008, the nine justices tied 4 to 4, Chief Justice Rehnquist having recused himself on the basis that he held shares in Pfizer.63

  A second case heard in October 2008 involved phenergan, a Wyeth drug, given for nausea, which when given by injection caused an arterial spasm that led to Diana Levine losing her right arm. At the heart of the case was the issue of whether this loss stemmed from a lack of warnings regarding its proper administration.64 The issue was not whether Wyeth knew about the hazard, but rather whether the FDA had or had not specifically instructed the company to warn about the hazard and if not, whether this exculpated Wyeth—even if the company did know about the hazard. On March 4, 2009
, the Court came to a 6–3 verdict against Wyeth and against preemption.65

  For the moment therefore, the kind of documents on which Firestein based her case in New York may still occasionally come to light in actions taken by plaintiffs against drug companies. For the moment, companies remain somewhat limited in their abilities to interfere with the practice of medicine in whatever way they see fit. For the moment, the FDA has not unequivocally become the de facto regulator of medicine rather than just medicines.

  As this was happening another drama was unfolding. As part of their settlement with New York State, GlaxoSmithKline agreed to post details of all their clinical trials. This sounds better than it is: the company only posted internal study reports, not the actual data. These differ little from ghostwritten articles. They do not let anyone establish, for instance, whether a dropout from a trial was really a dropout for noncompliance or whether the child had attempted to commit suicide.

  But it is difficult to hide deaths. In 2007, Steve Nissen, a cardiologist at the Cleveland Clinic, combed through the data from trials on Avandia (rosiglitazone), GlaxoSmithKline's latest blockbuster, a successor to tolbutamide in the treatment of adult-onset diabetes, and found that, while no one trial of Avandia showed an excess of cardiac deaths, in all trials combined the drug was linked to a marked increase in such deaths.66

  The Avandia story repeats all the elements of drug disasters from tolbutamide to Paxil. When first licensed by the FDA in 1999, there was no evidence that it saved lives, but influential academics lobbied regulators and other decision makers to ensure favorable treatment for this must-have drug. The American Diabetes Association came out strongly in favor of the drug even before it was approved.67 Over the next five years, Avandia moved rapidly to blockbuster status despite warnings by the World Health Organization (WHO) in 2004 of an increased risk of death. Internal GlaxoSmithKline analyses also found increased—but nonsignificant—rates of cardiac events on Avandia in their clinical trials, but in public the company continued to argue that the drug was absolutely safe and sales continued to boom. In the face of Nissen's analysis, the company fast-tracked a major study of cardiac safety on the drug, the RECORD study, and published it claiming that it demonstrated that Avandia was safe.68 Both the FDA and European regulators agreed. But mounting concerns led to hearings at the FDA, and further investigations by FDA staff, one of whom, Thomas Marciniak, found a pattern of concealment of serious events on Avandia in the RECORD study that echoed the hiding of deaths and other serious events on SSRIs and Vioxx.69