Dangerous Medicine

Thirteen dangerous prescription drugs have been withdrawn from the market in the last decade -- but not before hundreds of patients died and thousands were injured. Yet no congressional committee has investigated why the U.S. Food and Drug Administration approved these dubious medicines or why they were not withdrawn right away.

In fact, just this past May, Congress opted instead to renew the arrangement that's a major source of the problem. For 10 years, drugmakers have provided much of the FDA's own funding by paying "user fees." In exchange, the FDA speeds up its regulatory reviews. If this Faustian bargain was a factor in the recent drug calamities, Congress was not about to find out. Instead, the lawmakers allowed the drug companies and the FDA to decide, in closed-door negotiations, how much the industry would have to pony up this time around and just what concessions it would get from its regulators in return. Then Congress tacked the agreement onto an unstoppable bioterrorism bill and -- without a hearing, debate or vote in any committee -- passed it.

The legislators' indifference reflects the immense power of the drug industry, even though drug regulation can be a life-and-death matter. Among drugs recently withdrawn from the market were the infamous diet pills Pondimin and Redux, manufactured by Wyeth-Ayerst Laboratories, then a division of American Home Products Corporation. When taken in the deadly "fen-phen" combination, the drugs regularly caused heart-valve damage, and many patients who took them developed a devastating lung disorder that's fatal in more than 50 percent of cases. These two drugs generated the most massive wrongful-conduct litigation against a pharmaceutical manufacturer in American history, as a result of which the corporation expects to pay claims and legal costs totaling, thus far, $13.2 billion.

And that's only one story. Los Angeles Times reporter David Willman won a Pulitzer Prize last year for his investigation exposing the costs of FDA speedups. Placed under unremitting time pressure, regulators frequently approve drugs without regard to their dangers.

Surely something here needs fixing. But all Congress seems to want from the FDA is what former Commissioner Jane E. Henney assured the Senate it was getting: an agency that "enhances U.S. competitiveness in global markets ... and strengthens the domestic economy as a whole by inviting increased foreign investment" in the U.S. drug market.

Not so long ago, things were drastically different. Public-health disasters used to spur lawmakers to action. The slaughterhouse scandals at the turn of the last century prompted the FDA's creation. More than 100 deaths from a poisonous "elixir" spurred the 1938 passage of legislation requiring that drugs be proven safe before they can be marketed. The thalidomide tragedy led Congress to pass legislation in 1962 requiring the FDA to ensure that drugs are effective as well as safe.

From the mid-1960s through much of the 1980s, Congress played an integral part in drug safety. Lawmakers meticulously probed the regulatory histories of dubious drugs, uncovered FDA weaknesses and ordered corrections. It was congressional investigators who discovered that the FDA, when it approved Eli Lilly's anti-arthritis drug Oraflex in 1982, had missed six reports in its own files warning of serious liver and kidney disease. After the drug went on the market, congressional investigators alerted the FDA that the manufacturer was not reporting deaths and adverse reactions in a timely fashion. Both Eli Lilly and Hoechst AG, which was doing the same thing with its antidepressant Merital, were criminally prosecuted. In other instances, such as the one involving the catastrophically defective Dalkon Shield IUD, massive civil litigation was built on the findings of congressional overseers.

Nowadays, however, Reps. W. J. "Billy" Tauzin (R-La.), chairman of the House Committee on Energy and Commerce, and James C. Greenwood (R-Pa.), who leads the committee's investigative panel, seem to construe oversight not as protecting lives but as protecting investments. They are currently investigating whether the biotechnology company ImClone Systems Inc. misled investors about the FDA approval prospects for its anticancer drug Erbitux. They have yet to investigate a drug-safety issue.

Unfortunately, this shift in priorities has been bipartisan. Drug-safety oversight began to decline in the late 1980s when the Democrats controlled the House. The real nosedive in 1992 -- when user fees were first authorized -- also occurred on the Democrats' watch. With those industry fees, the FDA was able to hire nearly 600 people to expedite new drug applications, increasing the existing staff by 60 percent. But in exchange, the industry insisted that the FDA hasten new drug approvals to meet deadlines that would become more stringent each year. Moreover, user-fee revenues could only be spent on new drug reviews, and the legislation required diversion of public funds to new drug approvals at the expense of FDA safety programs.

After the Republicans took control of Congress in 1994, lawmakers indentured to the pharmaceutical industry went even further, targeting the FDA as their prime example of regulatory excess. Then–House Speaker Newt Gingrich dubbed the agency "the leading job-killer in America" and its activist commissioner at the time, Dr. David A. Kessler, a "thug" and a "bully." The right-wing Washington Legal Foundation accused the agency of committing homicide by denying Americans access to new drugs. The Pharmaceutical Research Manufacturers Association flew dying patients to Washington to plead for less thorough testing of new medicines.

Soon only a handful of legislators -- led by Sen. Edward Kennedy (D-Mass.) -- opposed proposals to "reform" the FDA. Kennedy called these plans a "blueprint for demolition, not modernization." Congress, he said, was being "driven by powerful and well-funded interests [to] gut the regulatory agency that stands between them and increased profits." He won some modifications, but he couldn't stop the train.

In 1997, Congress reauthorized user fees as part of a "modernization" package that reduced the legal standard for new drug reviews: Instead of requiring two clinical trials, the FDA could accept just one. The new law also allowed manufacturers to promote drugs for "off label" uses the FDA had never approved. Other provisions greased the fast track; none enhanced the safety of the drug-review process. It was the first time in its 91 years that the Food and Drugs Act's public-health protections had been rolled back.

The 1997 law codified the FDA's fast-track procedure for reviewing new drugs, and it continued to prohibit the spending of user-fee revenues to monitor drugs once they were on the market. With government appropriations for the FDA essentially flat, the effect was to deny the agency the ability to monitor the new drugs it was speeding to market. Nonetheless, Sens. Kennedy and Jack Reed (D-R.I.) were the only senators to vote against the measure.

By 1995, the median time for FDA review of "priority" drugs -- those offering significant therapeutic advances over available medicines -- had already been reduced to a record low of six months. In 1996, the agency approved 53 new drugs, almost twice the largest number approved in any previous year.

By 1997, Congress should have been examining to what extent those numbers reflected compromised safety rather than increased efficiency. Was the FDA taking big risks only in desperate situations, or in ordinary ones, too? Congress, however, was largely responsible for the problem.

Industry's investments in politicians had by then skyrocketed. Total political contributions from pharmaceutical and health-products businesses rose 86 percent, from more than $7 million to more than $13 million, just from the 1994 to the 1996 election cycle, according to the Center for Responsive Politics. From 1997 to the present, pharmaceutical and health-products companies have spent $51 million on campaign contributions, more or less doubling their spending in each successive election cycle. And between 1997 and the last available report (in June 2000), pharmaceutical-manufacturing companies spent at least $322 million -- more than any other industry -- on lobbying Congress and the president. It's surely no coincidence that in five years, congressional "oversight" of FDA drug regulation has been confined to four hearings -- three in the House and one in the Senate -- each of which was called to ensure that the FDA continues to expedite its drug approvals.

The FDA's pace, as a result, has been frantic. In the words of Dr. Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research, the push for speed has created a "sweatshop environment that's causing high staffing turnover." And, of course, in the parts of the FDA that are not user-fee funded, staffing problems have been worse. In the current fiscal year, the FDA has only 10 professionals trained as physicians or epidemiologists to assess the safety of the thousands of medicines now being sold, and to review the hundreds of thousands of "adverse event" reports that regulators receive each year. The division responsible for policing false and misleading prescription-drug advertising has only 14 people to review 32,000 pieces of promotional material annually.

Ten years ago, Dr. Alan Lisook, then a senior FDA investigator, admitted to The New York Times that the agency had no good way to tell when clinical study summaries submitted by pharmaceutical manufacturers misrepresented underlying patient-safety data. Because regulators base their decisions on the summary information, this flaw struck at the very heart of their ability to ensure drug safety. Yet the FDA today still does not have a single employee responsible for auditing the accuracy and completeness of such data.

The user-fee reauthorization that Congress passed in May has been presented as a reform. Even Kennedy celebrated it on the Senate floor as meeting "our obligation to assure the safety" of drugs brought to market quickly. But the accolades are misplaced. True, Congress has finally agreed to increase public funding for the FDA's understaffed divisions, and industry negotiators for the first time agreed to allow a portion of user-fee revenues to be spent on drug-safety monitoring and drug-advertising review. But what's still not allowed is crucial.

The FDA is prohibited from drawing on user-fee funds to monitor the safety of any drug submitted for review before October -- so the overwhelming majority of drugs on or entering the market cannot be scrutinized using these funds. In the few cases where user-fee-supported monitoring is allowed, it is limited to only two years (three years if the drug presents unusual risk concerns). The FDA is barred from relying on user-fee dollars to monitor side effects that were unanticipated at the time of approval. For the first time, the agency may spend user-fee money to check a manufacturer's compliance with a post-marketing safety plan. But if unanticipated safety concerns arise after marketing begins, user-fee revenues may not be used to assess them. The safety of drugs already on the market is hardly thus ensured by this legislation. And the safety of new drugs is not even addressed.

In the meantime, under congressional and industry pressure, the number of new drugs approved by the FDA has soared. In 1988, only 4 percent of all new drugs introduced throughout the world were cleared for marketing in the United States before they were approved elsewhere. Last year, 80 percent of all new drugs were approved here first. But is this a good thing? The FDA's Woodcock concedes that "'U.S. first in the world' means our population is placed at greater risk because we are [initially] going to discover" adverse drug reactions here, rather than learn about them as they crop up elsewhere.

For drugs that represent no significant therapeutic advance, this hardly seems a risk worth taking. Yet among the 13 dangerous drugs withdrawn from the U.S. market in the last decade, not one filled an otherwise unmet medical need. The diabetes drug Rezulin, produced by Parke-Davis, a unit of Warner-Lambert, was approved in 1997 on a fast track despite warnings from an FDA medical officer that it could cause liver and heart damage. Moreover, it was kept on the market for three years despite mounting evidence of its deadly liver toxicity -- and even though at least nine safer diabetes drugs of comparable effectiveness were already available. The nonsteroidal inflammatory drug Duract, a Wyeth-Ayerst product, which was also known to cause liver damage, was approved although 19 similar drugs were already on the market. The anesthetic Raplon, produced by Organon, was implicated in reports of fatal lung muscle spasms but approved anyway. What's more, its risks were understated in the information sent to physicians -- despite the fact that equivalent anesthetics were available.

For pharmaceutical companies whose patents are expiring on blockbuster drugs, there is much to gain from rushing even unnecessary new drugs to market. But the FDA should not be complicit in this business strategy, nor should Congress force it to be.

Some in the House -- notably Reps. Sherrod Brown (D-Ohio), Bart Stupak (D-Mich.) and Henry Waxman (D-Calif.) -- have questioned the wisdom of forcing the FDA to financially depend on, and to promote, the U.S. pharmaceutical industry. But these minority party members are not empowered to run investigations or hearings. The one legislator with the power to finally step into the breach is Kennedy, the Senate's liberal stalwart and chairman of the Health, Education, Labor, and Pensions Committee. Earlier this year, Kennedy considered holding hearings on drug safety. When renewal of the user-fee program whisked through Congress, those plans were shelved, perhaps indefinitely.

But the need for congressional attention is, if anything, greater now than ever. The FDA lacks authority to levy civil penalties for violations of the nation's drug laws, to subpoena industry records when it's necessary to investigate industry wrongdoing, or to mandate drug recalls. Under the bill just passed, companies that don't perform the mandated follow-up research on drugs the FDA approves "pending further study" still won't be fined or otherwise penalized. Instead, the FDA will now have the authority to post their names on its Web site and try to embarrass them into compliance.

The pharmaceutical industry and the legislators beholden to it will bitterly resist investigations of the FDA's pressure-filled drug-approval "sweatshop." And many lawmakers will be loath to examine too closely the effects of their own ideological preoccupations. But the drug calamities of recent years raise real doubts about the FDA's ability to uphold safety standards in an environment where global competitiveness and industry profitability are the reigning concerns. Such incidents instill no confidence in the agency's willingness to say no to distinctly toxic and questionably necessary drugs. It is Congress that put the FDA in this position, and it is Congress that must investigate and undo the damage.

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