Pharmageddon (36 page)

THE RULE OF DOUBT

The question of whether Prozac was in fact causing serious problems unleashed on the FDA a set of public and media concerns to rival those that had broken around tolbutamide in 1970. In 1991 the agency organized public hearings on the issue, which gave rise to a dramatic clash between the personal histories of a range of patients and randomized trial data supplied by Lilly, the makers of Prozac. But in marked contrast to their handling of tolbutamide, the FDA introduced an extraordinary argument that would have brought howls of medical outrage in the 1970s but produced not a peep of protest in the 1990s.

If the FDA did the right thing and warned about risks, agency representatives argued, it might paradoxically increase the number of deaths. Even if some people became suicidal on Prozac, senior officials within the FDA and academics linked to Lilly claimed, their numbers would be smaller than the number of deaths likely to occur among people who because of the existence of a warning would be deterred from seeking treatment in the first place. Prominent warnings about risks of suicide, in other words, might lead to an increase in the number of deaths.
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There is an astonishing ethical calculus here. In the case of the antidepressants, even the FDA had doubts about whether the drugs worked. There was absolutely no evidence they reduce suicides—all the clinical trial evidence pointed to an increase in risk, so much so that the major companies were engaged in various subterfuges to minimize public attention on the problem.

Given the completely predictable vigor of pharmaceutical company marketing that has led doctors to switch patients to the latest branded drugs, such as from ibuprofen or naproxyn to Vioxx or from hypoglycemics such as metformin to Rezulin and Avandia almost from the day they are launched, not warning patients appropriately in these cases amounts to a covert vaccination program—we want to see as many people on these new drugs as possible. But unlike vaccination, as the use of blockbuster drugs has spread, whether for osteoporosis, lowering blood sugar, or mood stabilization, the human cost that clinical trials of these drugs point to is increasingly paid by people who do not stand to benefit.

When it comes to the injuries produced by other industrial products, it is now clear that companies have been quite prepared to sponsor studies designed to bring in results that cast doubt on claims that chemicals from vinyl chloride to lead pose any health risks. Recent legal actions involving Paxil and birth defects have unearthed documents suggesting that lawyers for GlaxoSmithKline have liaised with academics to generate studies that could in similar fashion be used to counter any claims that Paxil might cause birth defects.
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This suggests that tactics honed in the battles over industrial pollution in the 1950s are being deployed within medicine today.

The most striking example of company willingness to put profits before all else came at the end of the 1960s, when in response to concerns about smoking and lung cancer, the tobacco companies sponsored a series of papers showing that from 1900 to 1960 respiratory and cardiac deaths fell and life expectancy rose in tandem with increased tobacco consumption. This use of apparently scientific data (but misleading analysis) was part of a campaign to sow doubt about a link between smoking and disease, caught exquisitely in company admissions that “doubt is our product.”
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But the ultimate use of the “doubt is our product” strategy faces us now in the form of company arguments that doubt about a hazard means it can be disregarded. As long as the data do not point to a statistically significant increase in heart attacks on Vioxx or deaths on statins or biphosphonates, the companies argue that doubt remains, and while doubt remains the drug must be regarded as being, in effect, free of hazards. The FDA and most doctors join them in this argument—to add warnings would, according to the American Psychiatric Association, have “a chilling effect on appropriate prescribing for patients.”
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A PREEMPTIVE STRIKE

When it comes to other chemicals and the problems they pose, no company can buy up all doctors and hence they have to cope with the abilities of doctors to spot new hazards and their preparedness to speak out about these hazards. But when it comes to drugs, the interests of doctors, regulators, and companies are now so closely allied that pharmaceutical companies have been able to deploy an extraordinary legal maneuver.

When in 1991 the FDA talked about the public health consequences of deterring patients from treatment with antidepressants, it was a view aired in the course of a public debate. It wasn't public policy. The regulators and drug companies were still notionally managing the labels on drugs rather than determining the treatment of patients. A few years later a case in Southern California, the Motus case, made it clear that efforts were underway to shift public policy in the direction of actively supporting treatment with drugs.

In early November 1998, Victor Motus, a prominent member of the Filipino community in Southern California, had a few nights of poor sleep. He owned an architectural firm, was president of the local school district board, and had just launched his campaign for a seat on the Cerritos city council. He was due to go to Washington to receive an award from President Clinton for work done for the local school. With his wife, Flora, he owned numerous rental properties, an antique store, and he held an 80 percent ownership interest in two restaurants. Even without all this, a few nights of poor sleep were hardly surprising in a fifty-one-year-old man.
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The only health problem Motus had was type 2 diabetes that he managed by a combination of diet and medication. When he developed problems sleeping, Flora made an appointment with a general practitioner, Dr. Trostler, on November 6, 1998 for her husband to obtain sleeping pills. During the visit, mention was made of financial problems with one of his restaurants, and even though there was no prior medical history to point to depression and little wrong clinically, educated by companies like Pfizer to think that sleep difficulties commonly pointed to a depressive disorder, in which case antidepressants would be a more appropriate treatment than hypnotics, Trostler gave Victor a sample pack of the antidepressant Zoloft—something unlikely to help his sleep. The Motuses were told that Zoloft might take several weeks to work.

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.”
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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.”
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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.
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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.