Side Effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial
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Only a handful of states (such as Minnesota and Vermont) require drugmakers to disclose such conflicts, and even in these states, disclosures are incomplete. In Vermont, for instance, drugmakers are allowed to keep payment records private by declaring them trade secrets. In 2005, drugmakers declared 73 percent of payments to doctors in Vermont trade secrets, the New York Times found.
Despite such extensive coverage, many medical professionals still take money from the pharmaceutical industry for both research and consulting gigs. While the most respected medical journals insist on the disclosure of these conflicts (in fine print at the end of the article), many other venues do not. Take, for example, the debate over whether black box warnings should be extended to antidepressant usage in young adults. In December 2006, the FDA held an advisory meeting to consider new findings that young adults between eighteen and twentyfive who took Paxil and eight other antidepressants were significantly more likely than those on placebo to report a suicide attempt, just as the research on children and adolescents had shown. At that hearing, opponents of the black box warnings on SSRIs cited preliminary results from a study showing what appeared to be a correlation between an uptick in national suicide rates among adolescents and a drop in the prescriptions of SSRIs among this age group. Several psychiatrists pointed to that apparent correlation as proof that the publicity over the SSRIs and the black box warnings had scared physicians from prescribing these drugs. The lack of treatment, these psychiatrists argued, may have prompted more youngsters to kill themselves.
However, when this finding was published in the September 2007 issue of the American Journal of Psychiatry, it was roundly criticized as being erroneous. The number of suicides among adolescents under the age of nineteen did indeed climb about 14 percent (from 1,737 to 1,985) between 2003 and 2004, according to statistics from the Centers for Disease Control and Prevention. The number of prescriptions for SSRIs among adolescents, however, remained essentially unchanged from 2003 to 2004 (prescription usage didn't decline until after 2004). Thus the FDA's black box warnings cannot be blamed for the apparent increase in suicides among adolescents the year before. This discrepancy in the data was not mentioned at the December 2006 FDA hearing. Nor was it disclosed that an SSRI maker (Pfizer) paid the $30,000 cost of obtaining prescription data for the AJP study, or that two lead authors of this study have financial conflicts of interest: Robert Gibbons served as an expert witness for Wyeth Pharmaceuticals (the maker of Effexor, another SSRI), and Dr. J. John Mann, a professor of psychiatry at Columbia University, has been a paid consultant to at least two SSRI makers: GlaxoSmithKline and Pfizer.
Other psychiatric researchers say that the latest upturn in suicide rates does not mean anything, given the small numbers involved and the tendency of suicide rates to fluctuate from year to year. "People who are specialists in statistics know you have to look at trends over years and years," said Julie Zito, an associate professor of pharmacy and psychiatry at the University of Maryland, who has published several articles on this subject. "For instance, you'll see that the overall trend [in suicide rates among children and adults] had been going down quite a ways before the SSRIs arrived on the scene"
In the end, the FDA did extend its black box warnings on antidepressants to young adults. But it also added language to the labels warning that "depression and certain other psychiatric disorders are themselves associated with the risk of suicide." The FDA's Thomas Laughren, now director of the Division of Psychiatry Products, said the new language had been added because of the agency's concerns about the uptick in suicide rates between 2003 and 2004. (National suicide rates for 2005 and beyond had not been released when this book went to press.)
Both Zito and Dr. Peter Lurie, deputy director of the Public Citizen Health Research Group, say that including language about untreated depression in the black box cautions on antidepressants undermines the whole point of the warning. "The important thing is that the risk of suicidal ideation is higher in the treated group than in the untreated group in randomized controlled trials, and that's what the warning should be about," Lurie says. "Whether or not untreated depression also leads to suicidal ideation is misleading and irrelevant. The FDA should not have put in that kind of language because it's intended to confuse."
IN THE YEARS since the New York State attorney general's lawsuit and the Vioxx controversy precipitated public outcry, the FDA has come under considerable pressure to toughen its stance on drug safety. According to former FDA officials at a 2006 conference, the federal agency did issue more black box warnings in 2004 than it had in previous years (although most of those warnings were for antidepressants). There is also evidence that the agency has slowed down the pace at which it approves new drugs and is approving fewer new drugs. According to the most recent statistics available from the FDA's Report to the Nation, the agency approved ninety new drugs in 2004 but only fifty-eight in 2005. And in a significant policy shift, the FDA recently began requiring drug makers to study specifically whether patients become suicidal during drug trials. For the first time, makers of drugs that treat obesity, epilepsy, heart problems, and many other conditions are being asked to include a comprehensive suicide assessment in clinical trials.
Even so, the federal agency continues to come under attack from consumers and lawmakers for not doing an adequate job of ensuring the safety of drugs, particularly those already on the market. A report by the General Accounting Office (GAO) in March 2006 found that the FDA "lacks a clear and effective process for making decisions about, and providing management oversight of," drug safety issues that arise after a medicine is on the market. The GAO said the agency's drug safety office was under the thumb of the FDA's new drugs office, which receives the lion's share of funding, and had no "independent decisionmaking responsibility" to ensure that postmarketing safety studies were conducted on already approved drugs. An equally stinging report in September 2006 by the Institute of Medicine (IOM), a group of prestigious physicians within the National Academy of Sciences that provide advice on medical issues, described the FDA as hobbled by underfinancing, poor management, and outdated regulations. The IOM report suggested that consumer advertisements of newly approved drugs be restricted for at least two years and that such drugs carry a black triangle on their labels to warn people that their safety is not certain. (Research shows that it takes years to ascertain the safety of new drugs.) The report also said the FDA should be given the authority to issue fines, injunctions, and withdrawals when drugmakers fail-as they often do-to complete required postapproval safety studies.
In an interview in August 2006, Eliot Spitzer said he was "mystified" as to why the FDA didn't just require drug companies to disclose the results of all their clinical trials so that doctors and consumers could see for themselves how safe newly approved drugs were.
"This is something that the FDA commissioner could probably do unilaterally," Spitzer said. "I don't understand why this hasn't been done"
In November 2006, Spitzer's vigorous attacks on Big Pharma, Wall Street, and lax regulatory authorities propelled him into the New York governor's office. There, he was joined by a number of his former assistant AGs from Lower Manhattan. Joe Baker became Spitzer's deputy secretary for health policy and Tom Conway was appointed general counsel to New York State's Department of Health in Albany. In September 2007, Conway recruited Rose Firestein to work with him. Seven months later, the governor who had brought them on board resigned after a federal investigation uncovered evidence that he had paid thousands of dollars to a high-priced prostitution club.
Firestein is still working with Conway in the counsel's office of the New York Department of Health. She continues to put in impossibly long hours, toiling out of an office in Lower Manhattan.
Firestein did find time, however, to design a renovation to her kitchen in Brooklyn to make it easier for her to cook safely with her limited eyesight. "She spent nights and nights measuring down to the inch and then designing and redesigning the layout on dr
aft paper," says her sister Janice. "The new kitchen is magnificent."
In January 2007, a car ran over Firestein's left foot as she stood near the curb waiting to cross the street in front of her apartment building. The accident broke three bones in her foot, but she only missed four days of work. For weeks she commuted to and from work in a cast up to her knee. "I've got tuition to pay for," she says simply, as if that were all that is needed to explain why, at the age of fifty-seven, Rose Firestein perseveres on behalf of the citizens of New York.
THE LAWSUIT FIRESTEIN and her colleagues brought against GlaxoSmithKline continues to bear rich fruit. In a case that garnered front-page coverage in 2007, Dr. Steven Nissen, a prominent cardiologist with the Cleveland Clinic, published new findings that show an increased risk of heart problems among patients taking Avandia, a commonly prescribed diabetes drug. (Avandia earned GlaxoSmithKline, its maker, more than $3 billion in worldwide sales in 2006.) Nissen's study, an analysis based on Glaxo's own clinical trials of Avandia, raised concerns in the medical community about the safety of the drug and renewed fears that the FDA did not act fast enough to alert the public about problems with a new drug. Nissen told reporters that he would not have been able to do his meta-analysis had it not been for the public registry that GlaxoSmithKline posted online as part of its settlement with the New York attorney general's office. The Avandia trials were among the first studies that Glaxo posted on the new database, and they popped up when Nissen googled the drug. "It was a treasure trove," he told Barry Meier of the New York Times, referring to the Web site that Firestein and her colleagues helped bring into being. In November 2007, the FDA put black box warnings about the increased heart risks on Avandia's label.
The New York AG's work has spawned huge ripple effects elsewhere as well. Under pressure from the International Committee of Medical Journal Editors, researchers sponsored by the drug companies are increasingly disclosing the designs of their clinical studies and results. Before the ICMJE began mandating such pretrial disclosures, the government database www.clinicaltrials.gov (the largest trial registry at the time) contained only 13,153 trials. One month after the ICMJE policy went into effect in July 2005, the number climbed to 22,714, and as of April 2007, the registry contained more than 40,000 trials, with more than 200 new trial registrations occurring weekly, according to an editorial in the New England Journal of Medicine. In May 2006, the World Health Organization climbed on board, calling for drug researchers worldwide to register on a public Web site the key protocols for all clinical studies involving humans before they are begun and to post a detailed summary of the results once they are completed. And some drug companies (in addition to GlaxoSmithKline and Forest Labs) are voluntarily posting the results of their clinical trials online, with varying degrees of detail.
The spark ignited by Eliot Spitzer's team seems to have burst into something of a national conflagration. While federal prosecutors (under the Clinton administration) launched a number of successful probes of pharmaceutical practices in the 1990s the cases against Pfizer/ Warner-Lambert and TAP Pharmaceutical Products being the most prominent examples-the pace of state investigations into the drug industry has picked up considerably since the New York AG's successful foray against G1axoSmithKline. State and federal prosecutors are now looking at everything from the improper pricing of medications for Medicare and Medicaid patients (average wholesale pricing redux) to the illegal marketing of drugs. (GlaxoSmithKline eventually settled the New York AG's AWP case in the spring of 2006 for $70 million.
Many of these investigations have zeroed in on deceptive marketing ploys. In the spring of 2007, the Justice Department hit Purdue Pharma with a $600 million fine for falsely marketing the narcotic OxyContin as a safe and nonaddictive pain medicine at a time when Purdue executives knew otherwise. Eli Lilly is now facing criminal and civil cases in several states over allegations that it concealed links between its antipsychotic drug Zyprexa and diabetes and illegally promoted Zyprexa for off-label uses. And federal and state prosecutors are continuing to investigate Johnson and Johnson for allegedly engaging in the deceptive marketing of Risperdal for off-label use in children and adolescents. Texas court records unsealed in 2006 allege that Johnson and Johnson overstated the effectiveness of Risperdal and understated its risks in order to boost sales of the drug in a pediatric population.
For the first time in decades, Big Pharma is on the defensive, and judging by the amount of money it spent on lobbying and political contributions for the 2006 elections, the industry knows it. According to the Center for Responsive Politics, companies that make drugs and medical products shelled out an all-time high of $172 million in lobbying Congress, federal agencies, and other policy makers in 2006. They also disbursed an additional $19.3 million in political campaign contributions during the 2006 election cycle. In the past, such largesse has reaped enormous benefits, in the form of federal legislation and regulations that made the FDA and other federal agencies more responsive to the wishes of the drug companies. The question now is whether the Democrat-controlled Congress will rise above the siren lure.
So far the signs are not promising. In 2007, the Democrat-controlled Congress did pass legislation that would give the FDA greater enforcement powers to ensure the safety of drugs already on the market. The law, for example, gives the FDA the power to require drugmakers to undertake clinical trials of medicines that the agency has already approved and fine those who fail to do so. It also requires the FDA to reduce the number of conflict-of-interest waivers it grants to experts who serve on its advisory boards. And it requires drug companies to register the results of new clinical trials on a publicly available Web site or face stiff penalties.
"The public needs to know about the results of clinical trials on drugs," said Senator Edward Kennedy when he introduced the bill in February 2007. "Tragically, such information was not adequately available for the clinical studies of antidepressants in children."
The 2007 legislation, however, does not apply to previously completed studies of drugs already on the market. Its limitations became glaringly evident in 2008 with the news that Merck and ScheringPlough never published studies that raised questions about the health risks of their popular cholestrol drug Zetia. By failing to disclose this research, drug companies once again gave physicians and patients a misleading view of a blockbuster drug's safety and benefits.
The new law also does nothing to change one fundamental reality: the excessive reliance of the nation's premier health agency on the industry it regulates. As part of the legislation it passed in 2007, Congress renewed the Prescription Drug User Fee Act for another five years. Instead of reducing the FDA's dependence on industry, as consumer advocates and medical ethicists have urged, Congress approved an $87.4 million increase in the annual user fees the FDA can collect from the drug industry, bringing the total of industry funds for agency operations to a projected $400 million.
With the renewal of PDUFA, consumer advocates fear that a golden opportunity to truly reform the way drugs are tested and sold has been lost. "Our position is that the agency should be fully funded out of the public purse and there should be no user fees of any kind at the FDA," said Dr. Peter Lurie, deputy director of Public Citizen's Health Research Group. "With these user fees, the agency will continue to be in hock to the drug companies."
A number of prominent medical ethicists agree. In her 2004 book, The Truth about the Drug Companies, Dr. Marcia Angell argues that user fees from drugmakers should be abolished and more public funds allocated to support the work of the FDA and the testing of new drugs. In a 2007 editorial in the New England Journal of Medicine, Dr. Jerry Avorn, author of Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs, also calls for a "national commitment to publicly supported studies of drug risks so that no company could take possession of critical findings for its own purposes."
Yet that is precisely what is continuing to happen. Even as medication becomes a way of life for more and more A
mericans, drug companies continue to control how drugs are tested, marketed, and sold in the United States. Drug trials are still largely funded by pharmaceutical companies who have a vested interest in positive research results. And many prominent doctors continue to receive millions of dollars in personal consulting income from the industry. Despite evidence to the contrary, some of these key opinion leaders persist in believing that the money they receive in no way clouds their judgment in doing research or treating patients. Such KOLs seem to feel that unlike the rest of us, they are not subject to a sad reality of human nature: money talks.
As OF May 2008, Martin Keller remains the chief of psychiatry at Brown University and a KOL in good standing with Big Pharma. To this day, Keller has denied that there is anything wrong with the results of his Paxil pediatric study or the way it was conducted. In a deposition taken in September 2006 for a lawsuit against GlaxoSmithKline, Keller insisted that the salient conclusions of his 2001 paper were accurate: that Paxil is generally well tolerated in adolescents and is significantly more effective than placebo in the treatment of depression for adolescents.