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.”
The FDA achieved its new goals, but now the human cost is becoming clear.
A two-year Los Angeles Times investigation has found that the FDA approved… 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.
Because [deaths and other side effects] 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.
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%. 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…
And the companies have prospered… seven unsuccessful drugs alone generated U.S. sales exceeding $5 billion before they were withdrawn.
[For example, 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.
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.
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.
A total of 10 drugs [were] pulled from the market in just the past three years [article published Dec. 2000] 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.
“All drugs have risks; most of them have serious risks,” said Dr. Janet Woodcock, director of the FDA’s drug review center.
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.
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.
[T]he imperative to move swiftly, cooperatively, remains.
The impetus for change at the FDA emerged in 1988, when AIDS activists paralyzed operations for a day at the agency’s 18-story headquarters in Rockville, Md. They demanded immediate approval of experimental drugs that offered at least a ray of hope to those otherwise facing death.
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.
The political pressure mounted, and the FDA began to bow.
The emboldened companies pushed for more. They proposed that drugs intended for either life- threatening or “serious” disorders receive a quicker review.
In 1992, [FDA Commissioner] 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.
For the FDA’s medical reviewers–the physicians, pharmacologists, chemists and biostatisticians who scrutinize the safety and effectiveness of emerging drugs–a new order had taken hold.
The reviewers examine truckloads of scientific documents. They are well-educated; some are highly motivated to do their best for a nation of patients who unknowingly count on their expertise.
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.
“From the first drug I reviewed, I really got the sense that I was doing something worthwhile. I saw what a difference a single reviewer can make,” said Elashoff…
Last year he was assigned to review Relenza, the new flu drug… 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,”
An agency advisory committee agreed and on Feb. 24 voted 13 to 4 against approving Relenza.
After the vote, senior FDA officials [reprimanded] 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.
“The people in charge don’t say, ‘Should we approve this drug?’ They say, ‘Hey, how can we get this drug approved?’”
“If you raise concern about a drug, it triggers a whole internal process that is difficult and painful. You have to defend why you are holding up the drug to your bosses. . . . You cannot imagine how much pressure is put on the reviewers.”
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.
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.
“In exchange [for the user fees], FDA makes a commitment to meet certain goals for review times… the number of new approved drugs has doubled, and the review times have been cut in half.”
The [drug] 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.
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… 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.”