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POLITICS

Deadly Medicine

Prescription drugs kill some 200,000 Americans every year. Will that number go

up, now that most clinical trials are conducted overseas—on sick Russians,

homeless Poles, and slum-dwelling Chinese—in places where regulation is

virtually nonexistent, the F.D.A. doesn’t reach, and “mistakes†can end up

in pauper’s graves? The authors investigate the globalization of the

pharmaceutical industry, and the U.S. Government’s failure to rein in a lethal

profit machine.

By L. Barlett and B. Steele - Photo illustration by Mueller

January 2011



TAKE TWO ASPIRIN

More and more clinical trials for new drugs are being outsourced overseas and

conducted by companies for hire. Is oversight even possible?

Photographs © Imagebroker/Alamy, from Image Source/Jupiter Images, ©

O’Byrne/Alamy (skulls); © Salmon/Alamy (capsule).

Y

ou wouldn’t think the cities had much in common. Iaşi, with a population of

320,000, lies in the Moldavian region of Romania. Mégrine is a town of 24,000

in northern Tunisia, on the Mediterranean Sea. Tartu, Estonia, with a population

of 100,000, is the oldest city in the Baltic States; it is sometimes called

“the Athens on the Emajõgi.†Shenyang, in northeastern China, is a major

industrial center and transportation hub with a population of 7.2 million.

These places are not on anyone’s Top 10 list of travel destinations. But the

advance scouts of the pharmaceutical industry have visited all of them, and

scores of similar cities and towns, large and small, in far-flung corners of the

planet. They have gone there to find people willing to undergo clinical trials

for new drugs, and thereby help persuade the U.S. Food and Drug Administration

to declare the drugs safe and effective for Americans. It’s the next big step

in globalization, and there’s good reason to wish that it weren’t.

Once upon a time, the drugs Americans took to treat chronic diseases, clear up

infections, improve their state of mind, and enhance their sexual vitality were

tested primarily either in the United States (the vast majority of cases) or in

Europe. No longer. As recently as 1990, according to the inspector general of

the Department of Health and Human Services, a mere 271 trials were being

conducted in foreign countries of drugs intended for American use. By 2008, the

number had risen to 6,485—an increase of more than 2,000 percent. A database

being compiled by the National Institutes of Health has identified 58,788 such

trials in 173 countries outside the United States since 2000. In 2008 alone,

according to the inspector general’s report, 80 percent of the applications

submitted to the F.D.A. for new drugs contained data from foreign clinical

trials. Increasingly, companies are doing 100 percent of their testing offshore.

The inspector general found that the 20 largest U.S.-based pharmaceutical

companies now conducted “one-third of their clinical trials exclusively at

foreign sites.†All of this is taking place when more drugs than ever—some

2,900 different drugs for some 4,600 different conditions—are undergoing

clinical testing and vying to come to market.

Some medical researchers question whether the results of clinical trials

conducted in certain other countries are relevant to Americans in the first

place. They point out that people in impoverished parts of the world, for a

variety of reasons, may metabolize drugs differently from the way Americans do.

They note that the prevailing diseases in other countries, such as malaria and

tuberculosis, can skew the outcome of clinical trials. But from the point of

view of the drug companies, it’s easy to see why moving clinical trials

overseas is so appealing. For one thing, it’s cheaper to run trials in places

where the local population survives on only a few dollars a day. It’s also

easier to recruit patients, who often believe they are being treated for a

disease rather than, as may be the case, just getting a placebo as part of an

experiment. And it’s easier to find what the industry calls “drug-naïveâ€

patients: people who are not being treated for any disease and are not currently

taking any drugs, and indeed may never have taken any—the sort of people who

will almost certainly yield better test results. (For some subjects overseas,

participation in a clinical trial may be their first significant exposure to a

doctor.) Regulations in many foreign countries are also less stringent, if there

are any regulations at all. The risk of litigation is negligible, in some places

nonexistent. Ethical concerns are a figure of speech. Finally—a significant

plus for the drug companies—the F.D.A. does so little monitoring that the

companies can pretty much do and say what they want.

Consent by Thumbprint

M

any of today’s trials still take place in developed countries, such as

Britain, Italy, and Japan. But thousands are taking place in countries with

large concentrations of poor, often illiterate people, who in some cases sign

consent forms with a thumbprint, or scratch an “X.†Bangladesh has been home

to 76 clinical trials. There have been clinical trials in Malawi (61), the

Russian Federation (1,513), Romania (876), Thailand (786), Ukraine (589),

Kazakhstan (15), Peru (494), Iran (292), Turkey (716), and Uganda (132). Throw a

dart at a world map and you are unlikely to hit a spot that has escaped the

attention of those who scout out locations for the pharmaceutical industry.

The two destinations that one day will eclipse all the others, including Europe

and the United States, are China (with 1,861 trials) and India (with 1,457). A

few years ago, India was home to more American drug trials than China was,

thanks in part to its large English-speaking population. But that has changed.

English is now mandatory in China’s elementary schools, and, owing to its

population edge, China now has more people who speak English than India does.

While Americans may be unfamiliar with the names of foreign cities where

clinical trials have been conducted, many of the drugs being tested are staples

of their medicine cabinets. One example is Celebrex, a non-steroidal

anti-inflammatory drug that has been aggressively promoted in television

commercials for a decade. Its manufacturer, Pfizer, the world’s largest drug

company, has spent more than a billion dollars promoting its use as a pain

remedy for arthritis and other conditions, including menstrual cramps. The

National Institutes of Health maintains a record of most—but by no means

all—drug trials inside and outside the United States. The database counts 290

studies involving Celebrex. Companies are not required to report—and do not

report—all studies conducted overseas. According to the database, of the 290

trials for Celebrex, 183 took place in the United States, meaning, one would

assume, that 107 took place in other countries. But an informal,

country-by-country accounting by VANITY FAIR turned up no fewer than 207

Celebrex trials in at least 36 other countries. They ranged from 1 each in

Estonia, Croatia, and Lithuania to 6 each in Costa Rica, Colombia, and Russia,

to 8 in Mexico, 9 in China, and 10 in Brazil. But even these numbers understate

the extent of the foreign trials. For example, the database lists five Celebrex

trials in Ukraine, but just “one†of those trials involved studies in 11

different Ukrainian cities.

The Celebrex story does not have a happy ending. First, it was disclosed that

patients taking the drug were more likely to suffer heart attacks and strokes

than those who took older and cheaper painkillers. Then it was alleged that

Pfizer had suppressed a study calling attention to these very problems. (The

company denied that the study was undisclosed and insisted that it “acted

responsibly in sharing this information in a timely manner with the F.D.A.â€)

Soon afterward the Journal of the Royal Society of Medicine

reported an array of additional negative findings. Meanwhile, Pfizer was

promoting Celebrex for use with Alzheimer’s patients, holding out the

possibility that the drug would slow the progression of dementia. It didn’t.

Sales of Celebrex reached $3.3 billion in 2004, and then began to quickly drop.

“Rescue Countriesâ€

O

ne big factor in the shift of clinical trials to foreign countries is a loophole

in F.D.A. regulations: if studies in the United States suggest that a drug has

no benefit, trials from abroad can often be used in their stead to secure F.D.A.

approval. There’s even a term for countries that have shown themselves to be

especially amenable when drug companies need positive data fast: they’re

called “rescue countries.†Rescue countries came to the aid of Ketek, the

first of a new generation of widely heralded antibiotics to treat

respiratory-tract infections. Ketek was developed in the 1990s by Aventis

Pharmaceuticals, now Sanofi-Aventis. In 2004—on April Fools’ Day, as it

happens—the F.D.A. certified Ketek as safe and effective. The F.D.A.’s

decision was based heavily on the results of studies in Hungary, Morocco,

Tunisia, and Turkey.

The approval came less than one month after a researcher in the United States

was sentenced to 57 months in prison for falsifying her own Ketek data. Dr. Anne

Kirkman-, of Gadsden, Alabama, seemingly never met a person she

couldn’t sign up to participate in a drug trial. She enrolled more than 400

volunteers, about 1 percent of the town’s adult population, including her

entire office staff. In return, she collected $400 a head from Sanofi-Aventis.

It later came to light that the data from at least 91 percent of her patients

was falsified. (Kirkman- was not the only troublesome Aventis

researcher. Another physician, in charge of the third-largest Ketek trial site,

was addicted to cocaine. The same month his data was submitted to the F.D.A. he

was arrested while holding his wife hostage at gunpoint.) Nonetheless, on the

basis of overseas trials, Ketek won approval.

Keywords

Politics, Pharmaceutical industry, January 2011,

Health, Medicine

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