The Body Hunters: Overwhelming the Watchdogs

Second of six articles

A global boom in overseas drug experiments is changing the way new drugs are tested on humans and approved for U.S. consumers as pharmaceutical companies shift to countries where regulations are looser, costs lower and trusting patients plentiful.

Companies searching for lucrative drugs are turning abroad to hold faster human experiments, offering poorly paid foreign doctors handsome fees for every subject they recruit into tests that help speed drugs to market. In some cases, the companies test drugs deemed too risky to try out in the United States, a Washington Post investigation has found.

The globalization of drug testing has resulted in a system increasingly dominated by profit incentives, where no single regulator can see the whole picture or inspect experiments effectively, according to interviews on five continents with doctors, health officials and patients. For Americans, it means some of the newest drugs on U.S. shelves are tested at sites far removed from U.S. regulators – sometimes in countries with few inspectors and little history of examining drugs for safety and effectiveness.

"I'm scared. I'm real scared," said Stan Woollen, deputy director of the Food and Drug Administration division that monitors human drug testing, at a conference last June in San Diego. "With these huge trials that are being conducted on a faster and faster basis, maybe the system is becoming overwhelmed."

The FDA inspects only a sliver of foreign test sites and rarely does so while the tests are underway. It gets involved when a pharmaceutical company submits foreign test results to back up a request to sell its drug to American consumers – which is often years after the overseas tests are concluded.

The FDA's paper review of foreign trials is "very late in the pipeline to worry about the consumer or the patients in those trials," said Marcia Angell, former editor of the New England Journal of Medicine. And when the FDA reviews a drug this way, "it's essentially saying 'caveat emptor' ['buyer beware'] when the drug is approved for sale."

When the FDA refused to let California-based Maxim Pharmaceuticals Inc. test a new drug on Americans with liver disease – the FDA wanted more safety tests on animals first – the company went to Russia. In three weeks last year, Russian doctors screened 149 patients, but the doctors were not told about the FDA's concerns.

By going to the former Soviet Bloc, Maxim avoided a delay that could have cost millions. The firm was about to raise $20 million in a private stock sale touting its leading drug's potential. It needed to try the drug on humans quickly to speed its development.

The company said it did not evade any FDA rules and followed Russia's.

"We abided by all of their local rules," said Maxim's chairman, Larry G. Stambaugh. "Why would they care what FDA wanted?"

The Offshore Boom

Overseas drug experiments have grown at a staggering rate during the last decade.

The FDA has accepted new drug applications supported by foreign research since 1980. By last year, nearly 27 percent of them contained a foreign test result – about three times as many as in 1995.

In South America, the number of researchers registered with the FDA to conduct experiments on drugs aimed at the U.S. market grew from five in 1991 to 453 by last September. Registered East European researchers now number 429; there was only one in 1991. In southern Africa, the number has rocketed from two to 266.

Eli Lilly and Co. says that in 1994 it tested 590 patients in Africa, the Middle East, and Central and Eastern Europe. This year, it expected to test 7,309 persons in those regions, a spokeswoman said. In Latin America, about 1,000 tests are underway with predictions of "10 times that many in the next five years," said the director of clinical operation at Covance, a firm that locates test sites for drug companies.

Those numbers suggest rapid growth, but no comprehensive statistics are available. Indeed, there is virtually no public information in the United States about the number of overseas drug tests, who is participating or overseeing them, what rules they follow and what risks they pose.

The FDA aggressively protects drug companies' trade secrets. Many facets of the agency's approval process – including the details of overseas experiments – are secret. The Post obtained FDA reports of overseas inspections under the Freedom of Information Act, but the agency blacked out the names of companies and drugs not yet approved for sale. So while some reports showed problems with foreign drug research, it was not always clear what drug or company was at issue.

Securities and Exchange Commission filings, medical journal articles and medical researcher Web sites provided clues about current tests. So did interviews conducted at industry conferences, meetings and training sessions attended by Post reporters, who registered openly as journalists.

The overseas testing explosion has several causes. Americans and Europeans often don't want to join risky experiments, creating a need for alternative pools of human subjects. Meanwhile, drug companies face rising competitive pressure to develop drugs and market them faster.

An average of 4,000 people are needed to test a drug before it can be sold in the United States, according to several studies, and hundreds of drugs are developed each year, touching off intense competition for test subjects. Each day's delay getting a major drug to market costs $1.3 million in unrealized sales, by industry estimates.

Industry gatherings often give off the air of a brazen bazaar. At the annual session of the Drug Information Association, globes spun on countertops and electronic maps pulsed with lights showing countries hot for recruiting. "We've Got Patients," trumpeted one sign. "Millions of potential study participants," boasted another.

The hard-sell atmosphere unsettled some. "If John Q. Public walked off the street, they would have been appalled," said Janet F. Zimmerman, who runs Impact, a Philadelphia-area company that trains drug research teams. "It really looked like we were bargaining with the devil and trading in people."

Many drug company executives don't see it that way. They emphasize that faster testing hastens new drugs to market to save lives. The reason for putting a drug experiment in a developing nation might be as simple as "that's where the patients are," said Bert Spilker, senior vice president for the Pharmaceutical Research and Manufacturers of America. "You need patients to create new products that help us here and help people around the world. You cannot do it without test subjects."

Wall Street also has been nipping at the companies' heels. Major pharmaceutical corporations revenues grew as much as 10 percent a year throughout the 1990s and stock prices soared. It can be hard to sustain such growth in an industry in which lucrative patents last only two decades and investors pound companies that miss quarterly earnings forecasts.

To stay ahead, the big drug firms have embarked on a fast-paced, competitive search for the next bonanza drug like Viagra or Celebrex. At the same time, smaller entrepreneurs have been raking in billions from venture capitalists looking for a promising product.

With biotechnology so hot, time pressure on researchers is intense. "The quicker the better. The quicker we can complete clinical trials, the more money for our companies," Juan Pablo Guzman, who has worked on clinical trials in Latin America for Searle and Pharmacia, told colleagues at the same San Diego conference.

Sick patients have lobbied for faster drug approvals, too. "The clock is ticking rapidly and that sets up the urgency," said Nancy Nelson, a vice president of the ALS Association, an advocacy group for patients with amyotrophic lateral sclerosis, or Lou Gehrig's disease.

All of these forces help push drug tests into newly capitalist Eastern Europe, the former Soviet Union and the Third World.

Not only are patients plentiful, but experiments cost less. One Bristol-Myers Squibb executive described a complex test that cost about $10,000 per patient in Western Europe but only $3,000 per patient in Russia.

Poorer countries may also have higher prevalances of certain diseases, making tests easier to organize. Advanced cancers, for instance, may be more common in countries where early treatment isn't generally available.

And foreign patients with little exposure to medicines offer a blank slate for experimentation. Medical deprivation makes patients "better for our purposes," said Anna Romany, a Johnson & Johnson marketing director in Eastern Europe. "It's a very pessimistic outlook but a very true one."

Bound for Mexico

With such a vast global testing system, policing problems with drugs becomes enormously complex and difficult.

Glaxo Wellcome, for example, still had 7,500 people taking its drug Lotronex in worldwide tests when the company agreed last month to pull the drug from the U.S. market because of FDA safety concerns. It will take until the end of December for the company to phase out the experiments, a spokeswoman said.

Lotronex had been approved for sale by the FDA in February to treat irritable bowel syndrome. Glaxo agreed to voluntarily withdraw it in the United States based on reports to the FDA of dozens of complications and three deaths possibly linked to Lotronex. Glaxo officials say the drug did not contribute to the deaths.

In the case of five-year-old Triangle Pharmaceuticals of Durham, N.C., an adverse FDA ruling in 1997 led the company to look abroad for a more favorable regulatory climate.

Triangle hoped to hit it big with new AIDS drugs. In August 1997, after a $45 million stock offering, the start-up company bought rights to mozenavir dimosylate, a drug then in early testing.

Two months later, the FDA stepped in. Experiments on dogs had linked mozenavir to a heart arrhythmia that can cause blackouts or sudden death. The FDA imposed a "partial clinical hold," effectively halting all mozenavir trials in the United States.

Triangle eventually won permission to conduct a limited U.S. study on how the body absorbs mozenavir. For its large-scale experiments, though, the company moved overseas. It first tested the drug on a small group of Western Europeans to see if heart problems turned up. When none did, Triangle's research broadened into Mexico as well.

"With [the FDA] there was a difference of scientific opinion," said Triangle Chairman and CEO David W. Barry. "We felt that a presentation of the same data to other scientists and regulators could produce a different opinion."

Mexican health officials knew of the FDA's decision but still blessed the experiment, persuaded by the company's assurances that patients would be monitored for heart problems and informed of risks.

To date, no heart problems have been reported, although a much larger study is needed before the company can determine mozenavir's safety. Meanwhile, the drug has lived up to its promise as a potent AIDS weapon, and at least one European researcher said Triangle's decision to conduct trials abroad was justified on humanitarian grounds.

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