Special Report: Drug Safety Can Drug Firms Be Trusted?

By Christine Gorman

Even to a nation grown accustomed to multibillion-dollar business frauds, the allegations are shocking. A Scottish psychiatrist has charged Upjohn of Kalamazoo, Mich., with falsifying scientific evidence regarding the safety of the sleeping pill Halcion (annual worldwide sales: $240 million). The accusation has prompted a federal investigation. Dow Corning Wright of Arlington, Tenn., stands accused of failing to report that its silicone-gel breast implants were associated with severe side effects -- including the development of autoimmune disorders like rheumatoid arthritis and lupus. That product and similar implants made by other manufacturers have been placed in 1 million to 2 million American women. If fraud has occurred, the cost cannot be compared with chicanery in other industries, for at stake is more than the customers' investment. It is their health and, in some cases, their very lives.

The charges of fraud have struck an industry already reeling from allegations of deception, greed and insufficient attention to their products' safety. The Food and Drug Administration is currently investigating an alleged cover-up by Hoffmann-La Roche of the lethal effects of its liquid anesthetic Versed, which has been linked to 40 deaths from respiratory failure. And while fraud has not been alleged against Pfizer, the New York City-based company will set aside $500 million for problems arising from one of its now discontinued artificial heart valves, which exhibit a sometimes fatal tendency to crack inside the body.

Meanwhile, Eli Lilly is battling several lawsuits that claim, on the basis of scant evidence, that the antidepressant Prozac can cause extreme agitation, suicidal tendencies and even an impulse to murder.

A critical social contract between manufacturers, regulators and the public seems to be unraveling. "I just don't trust the drug companies as much as I once did," says New York City real estate agent Peggy Mathews. "Halcion and silicone implants stand out like beacons, putting us all on the alert." She has reason to worry, says Dr. Sidney Wolfe, a consumer activist who heads Public Citizen's Health Research Group. "The heart of the problem is the dangerous amount of control the industry has over testing. Hundreds of people have been killed and thousands injured because data have been falsified."

Is Wolfe just crying wolf? Or has a pervasive corruption -- which the FDA seems powerless to stop -- spread throughout the pharmaceutical and medical- device industries? Upjohn and Dow Corning strenuously deny any wrongdoing.They point out, rightly, that only a small proportion of consumers report problems with their products, and that it is naive to expect perfection in so large and complex a business. In the U.S. alone, there are 3,000 types of drugs on the market and more than 1.5 billion prescriptions written every year. A small number of incidents with a handful of drugs is hardly an indictment of the entire system.

In addition, say some drug-industry experts, the system has a built-in incentive for companies to be honest about their products' quality. "The negative fallout of dangerous drugs is much worse in many cases than not getting the drug approved to begin with," says Dr. Kenneth Kaitin, assistant director of the Center for the Study of Drug Development at Tufts University. "If a drug has to be pulled from the market, it's very bad for public relations, financially and in every possible way. It just doesn't make sense that they would intentionally conceal real problems."

That kind of thinking had been the basis for a relationship of trust between the medical-products industry and the FDA. Historically, the agency has counted on the pharmaceutical firms, when they apply for approval of a new drug or device, to carry out the necessary testing themselves and to do it honestly. Though agency panels scrutinize the results of industry research, they rarely demand the raw data, relying instead on the analyses and conclusions drawn by the company. The FDA simply does not have the personnel or the budget to do all the research itself -- nor would it be practical for it to do so. "That road leads to madness," says Dr. Jere Goyan, dean of the school of pharmacy at the University of California, San Francisco, and former head of the FDA. The FDA is designed to act as a brake, not a developer.

But relying on drug marketers to analyze research data has serious drawbacks. Raw data are often ambiguous; the medicine vial can be half empty or half full. Considering that it can take an investment of $200 million and 10 years to bring a drug from the lab bench to the pharmacy, manufacturers have a powerful incentive to look on the bright side, particularly when problems turn up late in the game after millions have been expended. "They definitely have rose-colored glasses," admits Robert Temple, chief of the FDA's office of drug evaluation.

Still, the system mostly seems to work. Last year the government carried out 203 random inspections of clinical investigators and discovered just eight , studies that were significantly flawed. (Offending researchers can be permanently barred from submitting any drug tests to the FDA.) The low rate of skulduggery has remained constant since 1962, which helps explain why there has historically been a "gentlemanly working relationship between the FDA and industry," says Dr. Norman Anderson, a professor at the Johns Hopkins University School of Medicine who has served on numerous science advisory panels for the FDA.

The silicone breast-implant scandal may, however, change that relationship. Anderson's own trust in the system was shattered on Dec. 12, when he sat down and read scores of Dow Corning documents, including 17 internal memos dating as far back as the mid-1970s, about silicone-gel breast implants. The information surfaced during a liability suit in Michigan. When he finished, Anderson wrote and hand-delivered both the documents and an urgent letter to the FDA demanding that all such implants be promptly removed from the marketplace. "This appeal is not made lightly," Anderson wrote. He noted that Dow Corning officials had assured an FDA review panel, of which Anderson was a member, that the company had disclosed all relevant information on implants. "I am now in possession of unprotected court documents which indicate this was not true." Anderson's conclusion: the memos leave "little doubt of ((Dow Corning's)) misrepresentation of the facts."

The resulting furor rattled the FDA like no scandal since the thalidomide scare of the early 1960s. Following Anderson's appeal, the agency declared a moratorium on all silicone-gel implants, pending further review. "It's the ultimate case as to why you need a strong agency," says FDA Commissioner David Kessler. Now, says Kessler, "the honor system is out the window." He promises that companies will be subject to intensive audits in which investigators will scrutinize how data are analyzed and presented by the manufacturers. Says he: "People have to know that we have the will and resolve to deal with those who have crossed the line."

Brave words from a bureaucrat with limited power. Although the FDA is entrusted with guaranteeing the safety of all medical drugs and devices in the U.S., it is poorly armed for the job. For example, unlike almost every other federal agency, the FDA lacks the legal clout to subpoena a company's internal records if a problem is suspected. Congress woke up to the problem last fall, at Kessler's prodding, and introduced a bill that would have enabled the ( agency to seize corporate documents. The threat of a presidential veto halted the measure, though the new revelations about Halcion and breast implants seem likely to revive the initiative.

The drugs scandals of the '90s are prompting other calls for heightened regulation. One proposal, currently making its way through Congress, would give the FDA commissioner emergency powers to pull any drug from the market. At present, about all he can do is jawbone a recalcitrant company into withdrawing a dangerous product. "It's easier for the Consumer Products Safety Division to recall a toaster than for the commissioner of the FDA to recall a dangerous drug," grouses a Capitol Hill staff member. Even so, the measure is strenuously opposed by both the Pharmaceutical Manufacturers Association and the White House, which sees it as burdensome regulation.

Would-be reformers are also pushing the FDA to adopt a more strenuous review of drugs after they have been approved for marketing. Such postapproval monitoring is already being tried in Canada, Britain and Sweden, where officials can tap into data from a national health-care system. The reasoning behind the push is quite straightforward. Clinical trials typically include a few thousand people and can therefore pick up only the most obvious and prevalent side effects. Once a drug enters the market, hundreds of thousands or even millions of people start using it, often for sustained periods of time -- when more subtle or long-term risks may come to light. Such was the case with "beta-blocker blues," a syndrome of fatigue and mild depression sometimes associated with regular use of a popular category of heart drugs called beta blockers. The syndrome went undetected in clinical trials.

Currently the FDA relies on spontaneous reporting of postmarketing problems by physicians who prescribe the drugs or manufacturers who may receive complaints from doctors. It is a seriously flawed system, says Joe Graedon, author of several consumer-oriented books about prescription drugs. First, says Graedon, if a patient has a problem -- say an upset stomach or itching skin -- he or she may not make the connection to a drug or medical device. Second, even if the patient does make the link, the doctor may dismiss it. Third, a physician simply may not take the time to report a suspicious problem to the FDA or drug manufacturer. "It means extra time, extra paperwork, and there is always the fear of litigation." Graedon believes the FDA should contract with large medical groups -- major HMOs, for instance -- to keep data bases on adverse reactions.

The Bush Administration might even be persuaded to go along with this extra regulatory step. For several years now, it has been pressuring the FDA to streamline its approval process. Agency officials have been reluctant, and the recent scandals have proved them right. But streamlining approval may make more sense if postapproval surveillance is beefed up.

Drug companies are marshaling their forces to oppose increased government oversight. Those that stand accused are also conducting somewhat belated counteroffensives to limit the legal damage and repair their frayed reputations. Dow Corning, which has been widely criticized for reacting insensitively to the implant debacle, announced that it has retained former Attorney General Griffin Bell to lead an independent investigation into its development and marketing of implants. The company has also agreed to make public 90 additional documents and to ensure that it provides accurate information to the thousands of women calling the company for advice.

Upjohn is meanwhile reassuring physicians that reported problems with Halcion occur only at high doses and if the drug is taken for long periods of time. At the FDA's request, Upjohn revised the drug's package insert to warn patients not to extend its use beyond 10 days without consulting their physician. Last week the firm filed a libel suit against its Scottish accuser, Dr. Ian Oswald, and the British Broadcasting Corporation for televising allegations of fraud. Upjohn is also actively appealing the British Department of Health's decision last fall to ban Halcion.

The negative publicity has affected the whole industry, prompting several companies to curry favor with the public. Last month Bristol-Myers Squibb announced that it will donate 17 different brands of blood pressure- and cholesterol-lowering drugs for use by patients whose doctors will certify that they have no insurance or other means of paying. In addition, Bristol Myers, Syntex and Merck have announced that they will provide 12.5% price rebates on drugs dispensed in federally financed public health programs for the poor.

All the goodwill gestures in the world seem unlikely to deflect the growing movement toward further government regulations of the pharmaceutical industry. Experts caution, however, that hastily written rules, even if they are produced with the best of intentions, can backfire. The Orphan Drug Act, for instance, was passed in 1983 to encourage the development of drugs for rare diseases. The law provides an extra economic incentive, in the form of a seven-year monopoly, to companies that market products for maladies that afflict fewer than 200,000 people. Though it has done some good, it has also been widely blamed for the outrageous prices of certain medications, including aerosolized pentamidine for AIDS patients, and for allowing some companies to make a killing when an "orphan drug" has turned out to be useful for a common disease. Congress is working on revising the measure.

Despite such regulatory pitfalls, the time is ripe for putting some teeth into the FDA. A profit-driven system cannot be so dependent on trust, particularly when lives hang in the balance. Doctors and their patients also bear some responsibility for using drugs wisely. "All drugs have risk," observes physician-activist Wolfe. "Most of the time the benefits outweigh the risks. But there is abysmal ignorance on the part of the public about side effects." In a culture that has long been addicted to the quick fix, a healthy respect for the power of the pill -- negative as well as positive -- may prove to be the best medicine of all.

CHART: NOT AVAILABLE

CREDIT: TIME Graphic by Steve Hart

CAPTION: HALCION

SIICONE-GEL BREAST IMPLANTS

PROZAC

VERSED

BJORK-SHILEY HEART-VALVE

GENERIC DYAZIDE

With reporting by Mary Cronin and Andrew Purvis/New York and Dick Thompson/Washington