Wednesday, Dec. 20, 2000 Los Angeles Times
a New Policy Led to Seven Deadly Drugs
|By DAVID WILLMAN
Times Staff Writer
WASHINGTON--For most of its history, the United States Food and Drug Administration approved new prescription medicines at a grudging pace, paying daily homage to the physician's creed, "First, do no harm." Then in the early 1990s, the demand for AIDS drugs changed the political climate. Congress told the FDA to work closely with pharmaceutical firms in getting new medicines to market more swiftly. President Clinton urged FDA leaders to trust industry as "partners, not adversaries."
Dr. Janet Woodcock, director of the FDA's drug-review center, says the agency depends on doctors "to take into account the risks, to read the label. ... That's why drugs are prescription drugs."
The FDA achieved its new goals, but now the human cost is becoming clear. Seven drugs approved since 1993 have been withdrawn after reports of deaths and severe side effects. A two-year Los Angeles Times investigation has found that the FDA approved each of those drugs while disregarding danger signs or blunt warnings from its own specialists. Then, after receiving reports of significant harm to patients, the agency was slow to seek withdrawals.
According to "adverse-event" reports filed with the FDA, the seven drugs were cited as suspects in 1,002 deaths. Because the deaths are reported by doctors, hospitals and others on a voluntary basis, the true number of fatalities could be far higher, according to epidemiologists. An adverse-event report does not prove that a drug caused a death; other factors, such as preexisting disease, could play a role. But the reports are regarded by public health officials as the most reliable early warnings of danger.
The FDA's performance was tracked through an examination of thousands of pages of government documents, other data obtained under the Freedom of Information Act and interviews with more than 60 present and former agency officials.
The seven drugs were not needed to save lives. One was for heartburn. Another was a diet pill. A third was a painkiller. All told, six of the medicines were never proved to offer lifesaving benefits, and the seventh, an antibiotic, was ultimately judged unnecessary because other, safer antibiotics were available.
The seven are among hundreds of new drugs approved since 1993, a period
during which the FDA has become known more for its speed than its caution.
In 1988, only 4% of new drugs introduced into the world market were approved
first by the FDA. In 1998, the FDA's first-in-the-world approvals spiked to
* Only 10 months ago, FDA administrators dismissed one of its medical
officer's emphatic warnings and approved Lotronex, a drug for treating
irritable bowel syndrome. Lotronex has been linked to five deaths, the
removal of a patient's colon and other bowel surgeries. It was pulled off
the market on Nov. 28.
* The antibiotic Raxar was approved in November 1997 in the face of evidence that it may have caused several fatal heart-rhythm disruptions in clinical studies. FDA officials chose to exclude any mention of the deaths from the drug's label. The maker of the pill withdrew it in October 1999. Raxar was cited as a suspect in the deaths of 13 patients.
* The blood pressure medication Posicor was approved in June 1997 despite findings by FDA specialists that it might fatally disrupt heart rhythm and interact with certain other drugs, posing potentially severe risk. Posicor was withdrawn one year later; reports cited it as a suspect in 100 deaths.
* The painkiller Duract was approved in July 1997 after FDA medical
officers warned repeatedly of the drug's liver toxicity. Senior officials
sided with the manufacturer in softening the label's warning of the liver
threat. The drug was withdrawn 11 months later. By late 1998, the FDA had
received voluntary reports citing Duract as a suspect in 68 deaths, including 17 that involved liver failure.
Overall, Propulsid has been cited as a suspect in 302 deaths. The FDA's handling of Propulsid put children at risk. The agency never warned doctors not to administer the drug to infants or other children even though eight youngsters given Propulsid in clinical studies had died. Pediatricians prescribed it widely for infants afflicted with gastric reflux, a common digestive disorder.
Parents and their doctors had no way of knowing that the FDA, in August 1996, had found Propulsid to be "not approvable" for children. "We never knew that," said Jeffrey A. Englebrick, a heavy-equipment welder in Shawnee, Kan., whose 3-month-old son, Scott, died on Oct. 28, 1997, after taking Propulsid. "To me, that means they took my kid as a guinea pig to see if it would work." By the time the drug was pulled, the FDA had received reports of 24 deaths of children under age 6 who were given Propulsid. By then the drug had generated U.S. sales of $2.5 billion for Johnson & Johnson Co.
Questions also surround the recent approvals of other compounds that
remain on the market, including a new flu drug called Relenza. In February
of 1999, an FDA advisory committee concluded that Relenza had not been
proved safe and effective. The agency nevertheless approved it. Following
the deaths of seven patients, the FDA in January issued a "public health
advisory" to doctors.
A total of 10 drugs have been pulled from the market in just the past three years for safety reasons, including three pills that were approved before the shift that took hold in 1993. Never before has the FDA overseen the withdrawals of so many drugs in such a short time. More than 22 million Americans--about 10% of the nation's adult population--took those drugs.
With many of the drugs, the FDA used tiny-print warnings or recommendations in package labeling as a way to justify approvals or stave
off withdrawals. In other instances, the agency has withheld safety information from labels that physicians say would call into question the use
of the product.
"They've lost their compass and they forget who it is that they are
ultimately serving," said Dr. Lemuel A. Moye, a University of Texas School
of Public Health physician who served from 1995 to 1999 on an FDA advisory
committee. "Unfortunately the public pays for this, because the public
believes that the FDA is watching the door, that they are the sentry."
Once a drug is proved effective and safe, Woodcock said, the FDA depends on doctors "to take into account the risks, to read the label. . . . We have to rely on the practitioner community to be the learned intermediary. That's why drugs are prescription drugs."
In a May 12, 1999, article co-authored with FDA colleagues and
published by the Journal of the American Medical Assn., Woodcock said, "The
FDA and the community are willing to take greater safety risks due to the
serious nature of the [illnesses] being treated."
Woodcock, 52, received her medical degree at Northwestern University
and is a board-certified internist. She alluded in a recent interview to the
difficulty she feels in rejecting a proposed drug that might cost a company
$150 million or more to develop. She also acknowledged the commercial pressures in a March 1997 article.
"Consumer protection advocates want to have drugs worked up well and thoroughly evaluated for safety and efficacy before getting on the market,"
The FDA often was taking more than two years to review new drug applications. The pharmaceutical industry saw a chance to loosen the regulatory brakes and expedite an array of new products to market. The companies and their Capitol Hill lobbyists pressed for advantage: If unshackled, they said, the companies could invent and develop more remedies faster.
Dr. Rudolph M. Widmark: The medical officer retired in December 1997 after
spending 11 years with the FDA. His recommendation for a black box warning
on the label of painkiller Duract was rejected.
They started naming other diseases. They began to push that envelope."
The wielding of this single, flexible adjective--"serious"--swung wide
the regulatory door knocked ajar by the AIDS crisis.
In 1992, Kessler issued regulations giving the FDA discretion to "accelerate approval of certain new drugs" for serious or life-threatening conditions. That same year a Democrat-controlled Congress approved and President Bush signed the Prescription Drug User Fee Act. It established goals that call for the FDA to review drugs within six months or a year; the pharmaceutical companies pay a user fee to the FDA, now $309,647, with the filing of each new drug application.
The newly elected Clinton administration climbed aboard with its
"reinventing government" project. Headed by Vice President Al Gore, the
project called for the FDA, by January 2000, to reduce "by an average of oneyear the time required to bring important new drugs to the American public."
The reviewers work out of public view in secure office buildings
clustered along Maryland's Route 355. At the jet-black headquarters building, the decor is institutional, the corridors and third-floor
cafeteria without windows. The reviewers examine truckloads of scientific
One of these reviewers was Michael Elashoff, a biostatistician who
arrived at the FDA in 1995 after earning degrees from UC Berkeley and the
Harvard School of Public Health.
Last year he was assigned to review Relenza, the new flu drug developed
by Glaxo Wellcome. He recommended against approval. "The drug has no proven efficacy for the treatment of influenza in the
U.S. population, no proven effect on reducing person-to-person transmissibility, and no proven impact on preventing influenza," Elashoff
An agency advisory committee agreed and on Feb. 24 voted 13 to 4
against approving Relenza. After the vote, senior FDA officials upbraided Elashoff. They stripped
him of his review of another flu drug. They told him he would no longer make
presentations to the advisory committee. And they approved Relenza as a safe
and effective flu drug.
Elashoff and other FDA reviewers discern a powerful message. "People are aware that turning something down is going to cause
problems with [officials] higher up in FDA, maybe more problems than it's
worth," he said. "Before I came to the FDA I guess I always assumed things
were done properly. I've lost a lot of faith in taking a prescription
"Either you play games or you're going to be put off limits . . . a
pariah," said Dr. John L. Gueriguian, a 19-year FDA medical officer who
opposed the approval of Rezulin, the ill-fated diabetes drug. "The people in
charge don't say, 'Should we approve this drug?' They say, 'Hey, how can we
get this drug approved?' " Said Dr. Rudolph M. Widmark, who retired in 1997 after 11 years as a
medical officer: "If you raise concern about a drug, it triggers a whole
internal process that is difficult and painful. You have to defend why you
The pressure is such that when a union representative negotiated a new
employment contract for the reviewers last year, one of his top priorities
was to defend what he called the "scientific integrity" of their work.
"People feel swamped. People are pressured to go along with what the agency wants," said Dr. Robert S.K. Young, an FDA medical officer who in
1998 formed a union chapter to represent the reviewers. "You're paying for
Each new drug application is accompanied by voluminous medical data, enough at times to fill 1,000 or more phone books. The reviewers must master this material in less than six months or a year, while juggling other tasks. "The devil is in the details, and detail is something we no longer have the time to go into," said Gurston D. Turner, a veteran pharmacologist with the FDA's scientific investigations division who retired this year. "If you know you must have your report done by a certain date, you get something done. That's what they [top FDA officials] count, that's all they count. And that is really, to me, a worrisome thing."
The FDA did spur reviewers to move at record speed. In 1994, the FDA's goal was to finish 55% of its new drug reviews on time; the agency achieved 95%. In 1995, the goal was 70%; the FDA achieved 98%. In 1996, the goal was 80%; the FDA achieved 100%. In both 1997 and 1998, the goal was 90% and the FDA achieved 100%.
From 1993 to 1999 the agency approved 232 drugs regarded as "new molecular entities," compared with 163 during the previous seven years, a 42% increase. The time-limit goals quickly were treated as deadlines within the FDA--imposing relentless pressure on reviewers and their bosses to quickly conclude their work and approve the drugs. "The goals were to be taken seriously. I don't think anybody expected the agency to make them all," said William B. Schultz, a deputy FDA commissioner from 1995 to 1999.
Schultz, who helped craft the 1992 user-fee act as a congressional staff lawyer, added: "You can meet the goal by either approving the drug or denying the approval. But there are some who argue that what Congress really wanted was not just decisions, but approvals. That is what really gets dangerous."
Indeed, the FDA drug center's 1999 annual report referred to the review goals as "the law's deadlines." And, Dr. Woodcock, the center director, elaborated in a subsequent agency newsletter:
"In exchange [for the user fees], FDA makes a commitment to meet certain goals for review times. [The agency] has exceeded almost all of the goals, and it expects to continue to exceed them. Basically, the number of new approved drugs has doubled, and the review times have been cut in half."
The user fees have enabled the FDA to hire more medical reviewers. Last year, 236 medical officers examined new drugs compared with 162 officers on duty in 1992, the year before the user fees took effect. Even so, Woodcock acknowledged in an FDA publication this fall that the workloads and tight performance goals "create a sweatshop environment that's causing high staffing turnover."
An FDA progress report in 1998, describing the work of agency chemists,
said that "too many reviews are coming 'down to the wire' against the goal
date. . . . This suggests a system in stress." Said Nesbit, the former aide to Commissioner Kessler: "The clock is
Dozens of officials interviewed by The Times made similar observations. "The pressure to meet deadlines is enormous," said Dr. Solomon Sobel, 65, director of the FDA's metabolic and endocrine drugs division throughout the 1990s. And the pressure is not merely to complete the reviews, he said. "The basic message is to approve."
Over the last seven years, "there has been a huge shift," said Kathleen
Holcombe, a former FDA legislative affairs staffer and congressional aide
who now is a drug industry consultant. "FDA, historically, had an approach
of, 'Regulate, be tough, enforce the law [and] don't let one thing go wrong,' " Holcombe said, adding that now, "the FDA sees itself much more in
How Deaths Were Calculated
Reports of adverse drug reactions to the Food and Drug Administration are considered by public health officials to be the most reliable early warnings of a product's danger. The reports are filed to the FDA by health professionals, consumers and drug manufacturers.
The Los Angeles Times inspected all reports filed in connection with seven drugs that were
The perception of coziness with drug makers is perpetuated by potential
conflicts of interest within the FDA's 18 advisory committees, the influential panels that recommend which drugs deserve approval or should
remain on the market. The FDA allows some appointees to double as consultants or researchers for the same companies whose products they are
evaluating on the public's behalf. Such was the case during committee
Few doubt the $100-billion pharmaceutical industry's clout. Over the last decade, the drug companies have steered $44 million in contributions to the major political parties and to candidates for the White House and both houses of Congress.
The FDA reviewers said they and their bosses fear that unless the new drugs are approved, companies will erupt and Congress will retaliate by refusing to renew the user fees. This would cripple FDA operations--and jeopardize jobs.
The companies' money now covers about 50% of the FDA's costs for reviewing proposed drugs--and agency officials say that persuading Congress to renew the user fees into 2007 is now a top priority.
Yet even if the user fees remain, the FDA is prohibited from spending the revenue for anything other than reviewing new drugs. So while the budget for pre-approval reviews has soared, the agency has gotten no similar increase of resources to evaluate the safety of the drugs after they are prescribed.
"It's shocking," said Dr. Brian L. Strom, chairman of epidemiology at the University of Pennsylvania. "How can you say, 'Release drugs to the market sooner,' and not know if they're killing people? . . . It really is a dramatic statement of public priorities."
More than 250,000 side effects linked to prescription drugs, including injuries and deaths, are reported each year. And those "adverse-event" reports by doctors and others are only filed voluntarily. Experts, including Strom, believe the reports represent as few as 1% to 10% of all such events. "There's no incentive at all for a physician to report [an adverse drug reaction]," said Strom, who has documented the phenomenon. "The underreporting is vast."
Even when deaths are reported, records and interviews show that companies consistently dispute that their product has caused a given death by pointing to other factors, including preexisting disease or use of another medicine.
To be sure, a chain of events affects the safe use of a prescription
drug: The companies' conduct of clinical studies; the FDA's regulatory
actions; the doctor's decision to prescribe; the pharmacist's filling of a
handwritten prescription; the patient's ability to take the drug as
"Aggressive promotion increases exposure--and doesn't give you the time to find the problem before patients get hurt," said Dr. Raymond L. Woosley, pharmacology department chairman at Georgetown University and a former FDA advisory committee member.
When serious side effects emerge, the FDA officials have championed using package labeling as a way to, in their words, "manage" risks. Yet the agency typically has no way to know if the labeling precautions--dense, lengthy and in tiny print--are read or followed by doctors and their patients.
The FDA often addresses unresolved safety questions by asking companies to conduct studies after the product is approved. But the research frequently is not performed--prompting the inspector general of the Department of Health and Human Services to say in 1996 that "FDA can move to withdraw drugs from the market if the post-marketing studies are not completed with due diligence."
Since that report was issued, the FDA has not withdrawn any drug due to a company's failure to complete a post-approval safety study. Officials conceded this week that they still do not know how often the studies are performed.
One consequence is that greater risk is shifted to doctors and patients. For example, Woodcock and her senior aides allowed Rezulin to remain on the U.S. market nearly 2½ years after it was withdrawn in Britain in December 1997. The FDA recommended frequent laboratory testing of patients using the drug but had no scientific assurance that the tests would prevent Rezulin-induced liver failure.
"They kept increasing the number of liver-function tests you should
have," noted Dr. Alastair J.J. Wood, a former FDA advisory committee member
who is a professor of medicine at Vanderbilt University. "That was clearly
designed to protect the FDA, to protect the manufacturer, and to dump the
responsibility on the patient and the physician. If the patient developed
liver disease and he hadn't had his [tests] done, somebody was to blame and
it wasn't the manufacturer and it wasn't the FDA."
Leading industry officials say Americans have nothing to fear from the
wave of drug approvals. "Do unsafe drugs enter and remain in the marketplace? Absolutely not,"
But during interviews over the last two years, current and former FDA specialists cited repeated instances when drugs were approved with less than compelling evidence of safety or effectiveness. They also said that important information has been excluded from the labels on some medications.
Elashoff, for instance, was surprised at the labeling for a drug called Prograf, approved in 1997 to prevent rejection of transplanted kidneys. The drug first had been approved in 1994 for use among liver-transplant patients.
The new label notes that Prograf was proved effective in a study of 412 U.S. kidney transplant patients. But no mention is made of the company's 448-patient European study, in which 7% of the patients who took Prograf died--double the 3.5% death rate among those who received a different anti-rejection drug, documents show.
An auditor from the FDA's scientific investigations unit, Antoine El-Hage, examined the European study results and concluded the "data are reliable." Elashoff agreed in his review. Yet the only way for doctors or patients to find that data is to search the medical literature or seek the FDA's review documents. Excluding the European study from the Prograf label, Elashoff said, "was just a total whitewash. . . . I think any rational person would reconsider taking this drug if they knew what happened in Europe."
A spokesman for the manufacturer of Prograf said the company had no
objection to including the European study results in the labeling. William
E. Fitzsimmons, a vice president of drug development for Fujisawa Healthcare
Inc., said the decision to exclude the results was entirely the FDA's.
"We submitted that data," he said. "It came down to what the FDA was comfortable putting in the label. . . . We certainly have no interest in
trying to hide that information. We presented it at major meetings on
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