Drugging the Watchdogs (from Chapter 6)

Within the FDA, the doctors, scientists, and statisticians are dedicated to making sure the data about drugs and medical devices presented by manufacturers justify their claims of safety and efficacy. But the FDA is understaffed, underfunded, and under pressure, according to its own employees. Even worse, the FDA has fallen under the influence of the drug and medical-device industries, so much so that it was labeled “a servant of industry” by Dr. Richard Horton, the editor of the British journal The Lancet.

The FDA used to be famous for moving at a glacial bureaucratic pace. In 1980, the General Accounting Office of Congress reported that the FDA was inadequately staffed to keep up with its workload. In 1988, political action by AIDS activists drew attention to the very real need for quicker access to potentially lifesaving drugs. The ensuing political crisis resulted in the 1992 passage of the Prescription Drug User Fee Act, otherwise known as PDUFA. The drug companies agreed to pay a $300,000 fee for each new drug application; in return, the FDA’s Center for Drug Evaluation and Research promised to adhere to a speedier timetable for the new drug approval process. According to a 2002 GAO report, a little more than half the cost of reviewing new drug applications was funded by user fees from the drug industry.

New-drug approval certainly became quicker. With PDUFA funds, the FDA was able to increase the staff at the Center for Drug Evaluation and Research, or CDER, from 1300 to 2300, all assigned to expedite new-drug applications for patented (not generic) drugs. In the four years following the enactment of PDUFA, the median length of time the FDA took to decide on priority new-drug applications dropped from 20 months down to six months. At the same time, the average number of new drugs approved doubled.

Funding by drug companies may have seemed like a good idea for the cash-strapped FDA, but what about protecting the consumer from the drug companies’ influence? How unbiased can CDER be when half its budget comes from the drug companies themselves? An anonymous survey done by Public Citizen in 1998 revealed that FDA review officers felt that standards had declined as pressure to approve new drugs increased. The FDA medical officers who responded to the survey identified 27 new drugs that had been approved within the previous three years that they felt should not have been. A similar report on CDER by the inspector general of the U.S. Department of Health and Human Services, published in March 2003, found that 58 percent of the medical officers said that the six months allotted for review of priority drugs is not adequate, and that one-third of respondents did not feel comfortable expressing their differing opinions. In the FDA’s own Consumer Magazine, Dr. Janet Woodcock, director of CDER since 1994, wrote that tight deadlines for drug approval were creating “a sweatshop environment that’s causing high staffing turnover.”

The most dangerous consequence of these changes was that the number of drugs approved by the FDA but later withdrawn from the market for safety reasons increased from 1.6 percent of drugs approved between 1993 and 1996 to 5.3 percent between 1997 and 2000. Seven drugs that had been approved by the FDA after 1993 were withdrawn from the market because of serious health risks. The Los Angeles Times reported that these drugs were suspected of causing more than 1000 deaths (though the number of deaths could actually be much higher because reporting of adverse drug events to the FDA is voluntary). Even though none of these seven drugs was lifesaving, according to the Los Angeles Times, “the FDA approved each of those drugs while disregarding danger signs or blunt warnings from its own specialists.” All told, 22 million Americans, one out of every 10 adults, had taken a drug that was later withdrawn from the market between 1997 and 2000.

The blood sugar–lowering diabetes drug Rezulin is one of the drugs that were approved in haste by the FDA—and later withdrawn, but much too late for many Americans. The details of the story were first presented in 2000 in a Pulitzer Prize–winning series of investigative reports by David Willman of the Los Angeles Times. Remarkably, as quickly as medical news travels, this story had no “legs” and went largely unheeded. Three years later David Willman wrote a similar story showing that the same problems were still there.

Dr. Richard Eastman was the director of the NIH division in charge of diabetes research, and in charge of the $150 million Diabetes Prevention Program study. This large study was designed to determine whether diabetes could be prevented in people at high risk (overweight and with mildly elevated blood sugar levels) by drugs or by lifestyle interventions. In June 1996 Dr. Eastman announced that Rezulin had been selected as one of the two diabetes drugs to be included in the study—a real victory for Warner-Lambert, the manufacturer of Rezulin.

Also in 1996 Warner-Lambert submitted Rezulin to the FDA for approval, and it became the first diabetes drug to be given an accelerated review. The medical officer evaluating the new drug application, Dr. John L. Gueriguian, was a 19-year veteran of the FDA. His review recommended that Rezulin not be approved: the drug appeared to offer no significant advantage over other diabetes drugs already on the market, and it had a worrisome tendency to cause inflammation of the liver. Warner-Lambert executives “complained about Gueriguian to the higher-ups at the FDA.” Dr. Gueriguian was then removed from the approval process for this drug. When the Advisory Committee met to decide on the approval of Rezulin, they were not informed of Dr. Gueriguian’s concerns about liver toxicity. The FDA approved Rezulin in February 1997, and brisk sales soon earned it “blockbuster” status.

However, reports of fatal liver toxicity due to Rezulin soon started to appear. Notwithstanding reports of deaths in the United States as well as in Japan, and the withdrawal of the drug from the United Kingdom because of liver toxicity in December 1997, Dr. Eastman and his colleagues decided to continue treating volunteers in the Diabetes Prevention Program study with Rezulin. Only after Audrey LaRue Jones, a 55-year-old high school teacher, died of liver failure in May 1998 did Rezulin stop being given to the volunteers in the study. Warner-Lambert maintained that Rezulin was not responsible for the liver failure that led to her death.

Despite the mounting reports of liver problems in the United States, Rezulin was not withdrawn from the U.S. market until March 2000. By that time, $1.8 billion worth of the drug had been sold. The Los Angeles Times reported that, all told, Rezulin was suspected in 391 deaths and linked to 400 cases of liver failure. Looking back on his experience, Dr. Gueriguian told the Los Angeles Times, “Either you play games or you’re going to be put off limits…a pariah.”

Another FDA medical officer and former supporter of Rezulin, Dr. Robert I. Misbin, was threatened with dismissal by the FDA. His offense? He provided a copy of a letter to members of Congress from himself and other physician colleagues at the FDA expressing concern about the FDA’s failure to withdraw Rezulin from the market after the FDA had linked it to 63 deaths due to liver failure. Dr. Janet B. McGill, an endocrinologist who had participated in Warner-Lambert’s early studies of Rezulin, told the Los Angeles Times that Warner-Lambert “clearly places profits before the lives of patients with diabetes.”

In retrospect one wonders why the NIH and FDA continued to support Rezulin long after it was known to be associated with so many deaths. One particularly troubling aspect of Rezulin’s seemingly privileged treatment was provided by David Willman’s series in the Los Angeles Times: Dr. Eastman, while in charge of diabetes research at the NIH and overseeing the $150 million study in which Rezulin was included, was receiving $78,455 from Warner-Lambert on top of his $144,000 annual salary from the NIH. Between 1991 and 1997, Dr. Eastman had received, according to the Los Angeles Times, “at least $260,000 in consulting-related fees from a variety of outside sources, including six drug manufacturers.” None of this was part of the public record, but the financial relationship with Warner-Lambert had been approved by two of Dr. Eastman’s superiors. And Dr. Eastman was by no means alone. In fact, the Los Angeles Times reported that no fewer than 12 of the 22 researchers who were overseeing the $150 million government-sponsored diabetes study as “principal investigators” were receiving fees or research grants from Warner-Lambert.

One would think that, once these drug companies’ lucrative consulting contracts with high-ranking NIH officials with direct responsibility for the companies’ products had been brought to the light of day, a firewall would have been quickly erected. Hardly. In December 2003, David Willman wrote an article titled “Stealth Merger: Drug Companies and Government Medical Research,” in which he identified multiple examples of NIH officials receiving payments of hundreds of thousands of dollars from drug companies.

“Subject No. 4” died while participating in a drug study at the National Institutes of Health on June 14, 1999. She was Jamie Ann Jackson, a 42-year-old registered nurse, married and a mother of two. Mrs. Jackson was the second person who had died while participating in NIH studies of a drug named Fludara, marketed by Berlex Laboratories. This drug, which had been used to treat leukemia since 1991, was being tested to see if it helped patients with autoimmune diseases. No more patients were enrolled in the study after the second death, but the study continued with the patients already enrolled for another nine months, and terminated only when five of the remaining 12 patients developed abnormalities in their blood tests. Dr. Stephen I. Katz was the director of the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases, which was conducting the study. According to the Los Angeles Times, between 1996 and 2002 Dr. Katz received more than $170,000 in consulting fees from the German drug manufacturer Schering AG. (It was during this time period that the fatal study of Berlex’s drug Fludara was being conducted.) These details are important because Berlex is a wholly owned subsidiary of Schering AG, described as its “U.S. business unit.” Dr. Katz told the Los Angeles Times that he had been “unaware of any relationship between Berlex and Schering AG,” and therefore unaware of a potential conflict of interest. But, according to the Los Angeles Times, “Katz declined to identify when he learned that Berlex was the U.S. affiliate of Schering AG.”

Drs. Eastman and Katz were certainly not the only high-ranking officials at the NIH to receive consulting fees from the drug industry. Another official had accepted $1.4 million plus stock options over an 11-year period, while at least one of the companies for whom he was consulting was involved with the work of the laboratory he directs at the National Institute of Allergy and Infectious Diseases.

The financial conflicts of interest at the NIH are by no means isolated examples of drug company influence on the government oversight of the drug industry. Because crucial recommendations about drug approval and drug labeling are made at the FDA’s Advisory Committee meetings, federal law “generally prohibits” the participation of experts who have financial ties to the products being presented on these committees. An article in USA Today in September 2000 shows, however, that the FDA granted so many waivers—800 between 1998 and 2000—that 54 percent of the experts on these all-important Advisory Committees had “a direct financial interest in the drug or topic they are asked to evaluate.” And this 54 percent figure does not take into account that FDA rules do not even require an Advisory Committee member to declare receipt of amounts less than $50,000 per year from a drug company as long as the payment is for work not related to the drug being discussed.

The storm clouds grew even darker as the government institutions responsible for protecting the public’s interest became dependent on drug company largesse.

Reprinted by permission of HarperCollins.