Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial

by Alison Bass

  Five minutes later, Casey turned the mike over to Teicher, who proceeded to talk about possible mechanisms that might propel patients on Prozac into a state of suicidal preoccupation. Referring to his published case study, Teicher explained, "The reason why I believed that we were dealing with a drug-emergent effect is because the symptomatology that [patients] developed during the time they were on fluoxetine was unlike anything they had experienced prior to or following-"

  Casey interrupted him, saying that Teicher had digressed from the first question before the committee: whether there was evidence to support a conclusion that antidepressant drugs cause the emergence of suicidal and violent behaviors. "You are expanding onto item two [whether a particular drug posed a greater risk than others] and I would like to be sure that we stay focused on question one. I am going to ask for a vote of the committee. Do you have some more to say?"

  Teicher could tell that Casey wanted him to stop talking. But he wasn't quite finished. There was too much at stake here. He proceeded to talk about a reanalysis he had just completed, which showed that pa tients on Prozac were three times more likely to have suicidal thoughts than those who were not. This time, it was Paul Leber who interrupted.

  "Again, maybe it would be useful if you would say precisely where these data that show an excess risk for fluoxetine actually are cited or published," the FDA official said. Was there a hint of sarcasm in his voice?

  "I will be happy to show you," Teicher responded. "May I show you a couple of slides?"

  "I would rather not . . . ," Casey responded. When Teicher tried to explain that he was talking about published data, the panel chair shook his head.

  "Let us stick with question number one," he said, shutting Teicher off. Casey went on to say that in his opinion, there was no credible evidence to support a conclusion that antidepressant drugs caused the emergence of suicidal thoughts or violent behaviors. Casey then called for a vote, and in a show of hands, the advisory panel unanimously agreed with him. The committee next discussed whether they should advise the FDA to put a stronger warning on Prozac. The drug's label, as Leber had noted, already warned that depression carries with it the risk of suicide and that great care must be taken to monitor patients closely. Leber made it clear that the FDA did not think a stronger warning was warranted. And the committee agreed, voting against a more explicit warning in a split 6-3 vote.

  Teicher would recall his experience that day as frustrating and somewhat surreal. Why had he not been allowed to throw up a few slides, when each of the scientists speaking on behalf of Lilly had been permitted to present numerous slides?

  An academician far removed from the shark tank of Washington politics, Teicher had no idea that powerful forces were at work in support of the pharmaceutical industry. By the fall of 1991, the FDA was under enormous pressure to expedite the approval of new drugs. AIDS activists were one group that had been demonstrating in Washington to fast-track the approval of new HIV-fighting drugs like AZT. Yet the FDA, having seen its regulatory budget slashed by the Reagan administration and then by the first Bush presidency, no longer had the staffing power to do the kind of thorough vetting of new drugs it had once been known for.

  Paul Leber himself had acknowledged those pressures in calling for the approval of Zoloft for use in treating adult depression. In two memos, one in August 1991 (before the FDA hearing on Prozac) and a second in December 1991, Leber acknowledged that the clinical evidence of Zoloft's effectiveness was weak. In an August 26, 1991, memo, he wrote that "the evidence marshaled to support sertraline's efficacy as an antidepressant is not as consistent or robust as one might prefer it to be" In a memo a few months later, Leber noted that several European regulatory authorities had not been willing to approve Zoloft (the brand name for sertraline) because of the "lack of robustness" in comprehensive clinical studies of the drug. Two placebo-controlled studies of the drug, one in the United States and one in the United Kingdom, found no difference between placebo- and Zoloft-treated patients. But "given the perceived urgency" for "expediting the public's access to new potentially promising drugs," Leber argued that Pfizer's application for Zoloft must be approved. And so it was, in the waning days of 1991. (In 2003, Zoloft would become the world's top-selling antidepressant, with annual sales of $3.4 billion.)

  In an effort to respond to the growing political pressure, the FDA also agreed to a new arrangement whereby pharmaceutical companies would pay the federal agency dues so it could hire more drug reviewers and approve drug applications faster. These dues, which came directly from the pharmaceutical industry, were called "user fees," in acknowledgment of the fact that the drug companies were essentially the users of the FDA's drug approval services. In 1992, Congress passed legislation legitimizing this arrangement: the so-named Prescription Drug User Fee Act (PDUFA). The idea behind this law was to ease the burden on American taxpayers by requiring the beneficiaries of new drug reviews-that is, the drug companies to help fund the cost of such reviews. The drugmakers, though, refused to allow their money to pay for the routine monitoring of drugs' safety once the medicines were on the market. As a result, the divisions within the FDA charged with ensuring the safety of drugs and medical devices began to shrink in importance. And as the amount of funding from the pharmaceutical industry for new drug reviews increased year after year in the face of declining financial support from Congress-the role of the FDA underwent a not-so-subtle change. By the end of the 1990s, top FDA officials were referring to the pharmaceutical industry (not the American public) as their clients or partners. Big Pharma, after all, was paying the bills. The FDA's budget numbers tell the story: In 1993, the pharmaceutical industry's $8.9 million in user-fee money accounted for just 7 percent of the FDA's drug review budget. By 2004, the industry's allocation of $232 million in user fees represented 53 percent of the agency's entire drug review budget. Many public health advocates believe that the Prescription Drug User Fee Act ultimately ended up making the nation's preeminent health agency beholden to the very industry it was supposed to regulate.

  FDA officials, however, would argue that they had no choice. By the mid-1990s, political pressure on the nation's premier public health agency had only intensified. Conservative forces led by Newt Gingrich, the Republican Speaker of the House, were pushing to dismantle the very mandate of the FDA to oversee the approval of new drugs. Pharmaceutical and tobacco companies supplied millions of dollars to fund a promotional campaign that argued that the FDA's plodding pace in approving new drugs was hurting public health. In 1996, Republican lawmakers proposed legislation that would have allowed companies to market their products without agency review, essentially gutting the FDA's oversight authority. The FDA was ultimately able to deflect this attack, but only by showing that it had significantly sped up its drug approval process. By the end of the millennium, the agency would succeed in cutting drug approval times from a peak of twenty-seven months to approximately twelve months.

  That sprint came with a price tag. A flood of questionable drugs was unleashed onto the market, many of which-like the diabetes drug Rezulin, the diet drugs Redux and Meridia, and, of course, Vioxx would later have to be recalled.

  ON THAT FINE autumn day in Rockville, Maryland, in 1991, the FDA's expert advisory panel seemed far less worried about questionable drugs than about depriving patients of a promising new treatment for depression. And indeed, the press took the panel's inaction as a ringing endorsement of Prozac and its SSRI analogues. Headlines in the nation's papers at the time say it all: FDA PANEL FINDS NO HARD EVIDENCE THAT PROZAC CAUSES VIOLENCE, PANEL FINDS LILLY'S PROZAC IS NOT LINKED TO SUICIDES, and finally, LILLY REPORTS RECORD SALES AND EARNINGS FOR THIRD QUARTER.

  A few muckraking journalists would eventually point out that of the nine committee members on the FDA"s "blue ribbon" advisory panel, five had financial ties to the pharmaceutical industry, which required the FDA to "waive" its own standards regarding conflicts of interest. Four of the six consultants also required conflict-of-
interest waivers. One of the committee members, Dr. David Dunner of the University of Washington in Seattle, had been lead investigator for Lilly in one of the four original studies that Lilly submitted to the FDA to win approval for Prozac. Dunner, Jan Fawcett, and Charles Nemeroff-the scientist who spoke so eloquently on behalf of Lilly also had lucrative consulting arrangements with the drug company. Nemeroff even owned stock in Lilly.

  The waivers these scientists were granted would become standard operating procedure for the FDA in the decade ahead. In the fall of 1991, Teicher himself required a waiver to participate in the FDA meeting. Earlier that spring, he had received an unexpected phone call from James Young, an executive with the Boston-based biotech start-up Sepracor, which was studying the two isomers of fluoxetine. Isomers are compounds that are mirror images of each other; they have the same molecular structure, but the atoms are arranged in a slightly different three-dimensional form, as if one compound were left-handed and the other right-handed. Prozac itself was a mixture of both of its isomers, known as R- and S+. Because the original mixture of these two compounds did not dissolve easily, Lilly's researchers had reformulated it as a chloride salt. As Young explained in that phone call, Sepracor was hoping that a compound made of only one of fluoxetine's isomers might have fewer side effects than Prozac and thus be a safer alternative. Young was interested in talking to Teicher because the McLean researcher had just coauthored a paper on the isomers of another drug. Teicher's lab was also known for its capability in testing the toxicity of potential drug compounds on animals (specifically rats).

  Teicher was just beginning to work with Sepracor in the fall of 1991. He had not yet received any money from the biotech, but he wanted to be completely aboveboard with the FDA. He felt it was the right thing to do. And in fact, the Sepracor contract would eventually prove to be a lucrative source of income for Teicher and his lab, one of the few bright spots in a decade marred by misfortune. Indeed, it would be easy to cast Marty Teicher's snubbing at the FDA hearing on Prozac as the beginning of his personal and professional travails.

  When the hearing finally ended at 5:40 p.m., Teicher hoped to walk back to his hotel with Stuart Montgomery and discuss the day's events with him. But Montgomery was deep in conversation with the panel chair Dan Casey and didn't seem to notice Teicher as he waited patiently to one side. Finally he struck out on his own. As he emerged from Parklawn to a still-clear sky that evening, he felt disconsolate and adrift. He was too preoccupied to take note of how quiet and peaceful the grounds had become. The Scientology demonstrators had long since decamped.

  very time Rose Firestein emerged from the Wall Street subway stop, the devastation took her breath away. Where once the towers of the World Trade Center had crowded out the sky, a giant hole in the earth now greeted her. Firestein had joined the New York attorney general's staff nine months after the planes flew into the World Trade Center, and she'd heard all the stories: How her colleagues had rushed from the building when they saw the flames shoot out of the North Tower. How Eliot Spitzer had barely made it down from the twenty-fifth floor before the towers collapsed. The crusading attorney general of New York was forced to run for his life, pursued by a choking wave of dust and debris. When Spitzer finally made it to the governor's office in Midtown Manhattan, tired and covered in ash, Governor George Pataki was so glad to see him, he gave the attorney general a big hug.

  The building where Spitzer and Firestein worked, a granite fortress known as the Equitable, was only three blocks away from Firestein's subway stop (and Ground Zero). But Firestein found she had to navigate the journey with care, sweeping her white cane in a wide arc to search out those unexpected dips in the sidewalk, the sunken sewer holes that pockmarked every block of Lower Manhattan. The cane also served as a warning sign to other pedestrians to keep their distance from the small hazel-eyed woman with hair the white blond color of corn silk.

  Firestein had lost much of her eyesight three years earlier during a trip to her childhood home in South Bend, Indiana. Her mother was seriously ill, and Rose and her siblings had decided it was time to sell the house and move the frail older woman to an assisted-living facility. Together, Rose and her younger sister, who lived nearby, settled their mother in the place where she was to spend the last four years of her life. Firestein then began the tedious job of readying her childhood home for sale. One evening at dusk, she was driving back to the house after having visited her mother when suddenly everything turned blurry. She could barely see. In a panic, Firestein pulled over to the side of the road and stopped the car. Everything in her field of vision was wavy except for one or two small vertical stripes, which constantly moved around. She sat there for a long time, trying to quiet her racing heartbeat. Something terrible had just happened, but she didn't know what. After a while, she slowly drove the rest of the way home, praying there were no reckless drivers on the road that night.

  The next day, Firestein flew home and went to see her eye surgeon. He took one look at her eyes and hustled her into a hospital operating room for surgery. The retinas in both her eyes had partially peeled off, and the surgeon worked desperately to reattach them. As he later explained, the retinal detachment was a by-product of diabetic retinopathy (Firestein, like her father, had type 2 diabetes). She was sent home with both eyes covered in gauze.

  The operation didn't take. Firestein went back to work, although she could barely read and had to write her legal briefs in two-inch-high letters, a few words to a page. A month or so later, the surgeon operated again. And again. In all, Firestein's doctor would perform ten surgeries in an effort to save at least some of her vision.

  As FIRESTEIN TURNED up Broadway on an overcast morning in late June 2004, she tried hard to focus on the terrain in front of her. In a few hours, she and her colleagues in the Consumer Frauds and Protec tion Bureau would be sitting down for the first time with attorneys for GlaxoSmithKline. It had been almost a month since the New York State attorney general's office had filed its groundbreaking civil suit against the London-based pharmaceutical company, and today's meeting was pivotal. Firestein would be playing a lead role. The lawsuit had been her idea, her baby. Over the past eighteen months, Firestein had spent countless hours poring over documents, searching the Web for clues, and talking to experts who understood the profit-driven jungle of drug research.

  The resulting lawsuit accused GlaxoSmithKline of committing "repeated and persistent" fraud by hiding from the public the results of several negative studies about Paxil, one of its bestselling drugs. Not surprisingly, the lawsuit attracted a burst of publicity when it was filed on June 2, 2004. The press coverage spotlighted what many said was a widespread practice in the pharmaceutical industry of disclosing only the results of positive studies in order to boost the sales of new drugs.

  Firestein's cane struck something hard and unyielding. She cursed under her breath. The police must have moved the barriers in front of 120 Broadway yet again, and she'd been too lost in thought to notice.

  With no eyesight in her left eye and limited vision in her right, Firestein had long consigned to memory every step of the commute between her home in Brooklyn and her closet of an office on the third floor of the Equitable. But she was less sure of her footing as one of the newest members of Eliot Spitzer's team. Firestein understood that she was something of an anomaly in the attorney general's office. While Spitzer and many of his top lieutenants hailed from law schools like Harvard, Yale, and NYU, Firestein had learned law at a state school in Indiana. She had taken classes at night, working days in Xerox's billing office to pay her own bills. Worse, she had the dubious distinction of being legally blind, although the AG's office hadn't known that when it hired her. Back then, Firestein wasn't using a cane. She figured that if she ignored her disability, the attorneys who interviewed her would too. Her strategy had worked, and now Rose Firestein was sitting atop an unprecedented legal attack on the pharmaceutical industry. She was afraid it was going to blow up-in Eliot Spitzer's face. That wou
ld not be a good outcome. Spitzer was seriously considering a run for governor of New York, and the pressure on his staff to rack up legal wins was greater than ever.

  IT WAS NOT as if Firestein doubted the rightness of what she was doing. She and her colleagues had been buoyed by the congratulatory phone calls that flooded in after they had filed their lawsuit against Glaxo in New York State Supreme Court. Some of these callers had been routed to Firestein, and even now the assistant attorney general could hear their voices, redolent with rage and disbelief. She had talked to parents whose children had tried to kill themselves and in a few cases had succeeded. They all asked her the same agonizing questions: How could their child have been allowed to take such a dangerous drug? Why were they not warned that Paxil could stir suicidal thoughts and behaviors in some children and adults? Who was looking out for their loved ones?

  The phone calls reminded Firestein of the time she had canvassed the state of Florida on behalf of foster children who were being overmedicated on drugs like Paxil, Prozac, Zoloft, and Risperdal, an antipsychotic. At the time, Firestein had been working for Children's Rights, a nonprofit organization based in New York that provided legal counsel for vulnerable children nationwide. Children's Rights had been tapped to help out on a class action suit brought by a group of local activist attorneys against the Florida Department of Children and Families. Known as Bonnie L. (after the first child listed in the complaint), the lawsuit charged the Florida children's services agency with the inadequate care and treatment of foster children in its custody. Firestein's job was to help gather evidence showing that state-funded caregivers were using psychotropic drugs as chemical straitjackets to keep hard-to-manage children docile.