Subject: FDA a "partner" of the pharmaceutical industry. 2 9 06

 Wednesday, December 20, 2000

 How a New Policy Led to Seven Deadly Drugs

 Medicine: Once a wary watchdog, the Food and Drug Administration set out
 to become a "partner" of the pharmaceutical industry. Today, the public
 has more remedies, but some are proving lethal.

 By DAVID WILLMAN, Times Staff Writer
 http://www.latimes.com/news/nation/reports/fda/


      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. 

 with the 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." 

 *** sidebar ***
 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." 

 BRIAN WALSKI / Los Angeles Times
 *** end sidebar  ***

      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      Seven drugs approved since 1993 have been withdrawn after reports of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 66%.

 *** sidebar ***
 Video: Willman reacts to receiving the Pulitzer Prize for this report.
 Real | Quicktime
 *** end sidebar ***

      The drug companies' batting average in getting new drugs approved
 also climbed. By the end of the 1990s, the FDA was approving more than 
 80%
 of the industry's applications for new products, compared with about 60%
 at the beginning of the decade.
      And the companies have prospered: The seven unsuccessful drugs alone
 generated U.S. sales exceeding $5 billion before they were withdrawn.
      Once the world's unrivaled safety leader, the FDA was the last to
 withdraw several new drugs in the late 1990s that were banned by health
 authorities in Europe.
      "This track record is totally unacceptable," said Dr. Curt D.
 Furberg, a professor of public health sciences at Wake Forest University.
 "The patients are the ones paying the price. They're the ones developing
 all the side effects, fatal and non-fatal. Someone has to speak up for
 them."  

      The FDA's faster and more lenient approach helped supply pharmacy
 shelves with scores of new remedies. But it has also yielded these fatal
 missteps, according to the documents and interviews:
      * 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 diet pill Redux, approved in April 1996 despite an advisory
 committee's vote against it, was withdrawn in September 1997 after
 heart-valve damage was detected in patients put on the drug. The FDA 
 later
 received reports identifying Redux as a suspect in 123 deaths.
      * 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.
      * The diabetes drug Rezulin was approved in January 1997 over a
 medical officer's detailed opposition and was withdrawn this March after
 the agency had linked 91 liver failures to the pill. Reports cite Rezulin
 as a suspect in 391 deaths.
      * The nighttime heartburn drug Propulsid was approved in 1993 
 despite
 evidence that it caused heart-rhythm disorders. The officials who 
 approved
 the drug failed to consult the agency's own cardiac specialists about the
 signs of danger. The drug was taken out of pharmacies in July after 
 scores
 of confirmed heart-rhythm deaths. 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.


 *** sidebar ***
 Michael Elashoff: The biostatistician was upbraided by senior FDA
 officials after he recommended against the approval of Relenza, a new flu
 drug. An agency advisory committee agreed with him, but the drug was
 approved by the FDA as safe and effective.
 BRIAN WALSKI / Los Angeles Times
 *** end sidebar ***

      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 'Lost Compass'
      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.

   

      Present and former FDA specialists said the regulatory decisions of
 senior officials have clashed with the agency's central obligation, under
 law, to "protect the public health by ensuring . . . that drugs are safe
 and effective."
      "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."
      The FDA's shift is felt directly in the private practice of 
 medicine,
 said Dr. William L. Isley, a Kansas City, Mo., diabetes specialist. He
 implored the agency to reassess Rezulin three years ago after a patient 
 he
 treated suffered liver failure taking the pill.
      "FDA used to serve a purpose," Isley said. "A doctor could feel sure
 that a drug he was prescribing was as safe as possible. Now you wonder
 what kind of evaluation has been done, and what's been swept under the
 rug."
      FDA officials said that they have tried conscientiously to weigh
 benefits versus risks in deciding whether to approve new drugs. They 
 noted
 that many doctors and patients complain when a drug is withdrawn.
      "All drugs have risks; most of them have serious risks," said Dr.
 Janet Woodcock, director of the FDA's drug review center. She added that
 some of the withdrawn drugs were "very valuable, even if not lifesaving,
 and their removal from the market represents a loss, even if a necessary
 one."
      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."
      Compared to the volume of new drugs approved, they wrote, the number
 of recent withdrawals "is particularly reassuring."
      However, agency specialists point out that both approvals and
 withdrawals are controlled by Woodcock and her administrators. When they
 consider a withdrawal, they face the unpleasant prospect of repudiating
 their original decision to approve.
      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," Woodcock wrote in the Food and Drug Law Journal. "On the other
 hand, there are economic pressures to get drugs on the market as soon as
 possible, and these are highly valid."
      But this summer--following the eighth and ninth drug
 withdrawals--Woodcock said the FDA cannot rely on labeling precautions,
 alone, to resolve safety concerns.
      "As medical practice has changed . . . it's just much more difficult
 for doctors to manage" the expanded drug supply, Woodcock said in an
 interview. "They rely upon us much more to make sure the drugs are safe."
      Another FDA administrator, Dr. Florence Houn, voiced similar concern
 in remarks six months ago to industry officials: "I think the lessons
 learned from the drug withdrawals make us leery."
      Yet the imperative to move swiftly, cooperatively, remains.
      "We are now making decisions more quickly and more predictably while
 maintaining the same high standards for product safety and efficacy," FDA
 Commissioner Jane E. Henney said in a National Press Club speech on Dec=