Date: 23 January 2011
Source: www.vanityfair.com
Link: www.vanityfair.com/politics/features/2011/01/deadly-medicine-201101?printable=true#ixzz1C2T6cayL
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 Donald L. Barlett and James B. Steele•
Photo illustration by Chris 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, © Vincent O’Byrne/Alamy
(skulls); © Jason Salmon/Alamy (capsule).
You 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-naïve”
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
Many 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.”)
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 Countries”
One 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-Campbell, 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-Campbell 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.
As the months ticked by, and the number of people taking the drug climbed
steadily, the F.D.A. began to get reports of adverse reactions, including
serious liver damage that sometimes led to death. The F.D.A.’s leadership
remained steadfast in its support of the drug, but criticism by the agency’s
own researchers eventually leaked out (a very rare occurrence in this
close-knit, buttoned-up world). The critics were especially concerned about an
ongoing trial in which 4,000 infants and children, some as young as six months,
were recruited in more than a dozen countries for an experiment to assess
Ketek’s effectiveness in treating ear infections and tonsillitis. The trial had
been sanctioned over the objections of the F.D.A.’s own reviewers. One of them
argued that the trial never should have been allowed to take place—that it was
“inappropriate and unethical because it exposed children to harm without
evidence of benefits.” In 2006, after inquiries from Congress, the F.D.A. asked
Sanofi-Aventis to halt the trial. Less than a year later, one day before the
start of a congressional hearing on the F.D.A.’s approval of the drug, the
agency suddenly slapped a so-called black-box warning on the label of Ketek,
restricting its use. (A black-box warning is the most serious step the F.D.A.
can take short of removing a drug from the market.) By then the F.D.A. had
received 93 reports of severe adverse reactions to Ketek, resulting in 12
deaths.
During the congressional hearings, lawmakers heard from former F.D.A.
scientists who had criticized their agency’s oversight of the Ketek trials and
the drug-approval process. One was Dr. David Ross, who had been the F.D.A.’s
chief reviewer of new drugs for 10 years, and was now the national director of
clinical public-health programs for the U.S. Department of Veterans Affairs.
When he explained his objections, he offered a litany of reasons that could be
applied to any number of other drugs: “Because F.D.A. broke its own rules and
allowed Ketek on the market. Because dozens of patients have died or suffered
needlessly. Because F.D.A. allowed Ketek’s maker to experiment with it on
children over reviewers’ protests. Because F.D.A. ignored warnings about fraud.
And because F.D.A. used data it knew were false to reassure the public about
Ketek’s safety.”
Trials and Error
To have an effective regulatory system you need a clear chain of
command—you need to know who is responsible to whom, all the way up and down
the line. There is no effective chain of command in modern American drug
testing. Around the time that drugmakers began shifting clinical trials abroad,
in the 1990s, they also began to contract out all phases of development and
testing, putting them in the hands of for-profit companies. It used to be that
clinical trials were done mostly by academic researchers in universities and
teaching hospitals, a system that, however imperfect, generally entailed
certain minimum standards. The free market has changed all that. Today it is
mainly independent contractors who recruit potential patients both in the U.S.
and—increasingly—overseas. They devise the rules for the clinical trials,
conduct the trials themselves, prepare reports on the results, ghostwrite
technical articles for medical journals, and create promotional campaigns. The
people doing the work on the front lines are not independent scientists. They
are wage-earning technicians who are paid to gather a certain number of human
beings; sometimes sequester and feed them; administer certain chemical inputs;
and collect samples of urine and blood at regular intervals. The work looks
like agribusiness, not research.
What began as a mom-and-pop operation has grown into a vast army of formal
“contract-research organizations” that generate annual revenue of $20 billion.
They can be found conducting trials in every part of the world. By far the
largest is Quintiles Transnational, based in Durham, North Carolina. It offers
the services of 23,000 employees in 60 countries, and claims that it has
“helped develop or commercialize all of the top 30 best-selling drugs.”
Quintiles is privately owned—its investors include two of the U.S.’s top
private-equity firms. Other private contractors are public companies, their
stock traded on Wall Street. Pharmaceutical Product Development (P.P.D.), a
full-service medical contractor based in Wilmington, North Carolina, is a
public company with 10,500 employees. It, too, has conducted clinical trials
all around the world. In fact, it was involved in the clinical trials for
Ketek—a P.P.D. research associate, Ann Marie Cisneros, had been assigned to
monitor Dr. Anne Kirkman-Campbell’s testing in Alabama. Cisneros later told the
congressional investigating committee that Kirkman-Campbell had indeed engaged
in fraud. “But what the court that sentenced her did not know,” Cisneros said,
was that “Aventis was not a victim of this fraud.” Cisneros said she had
reported her findings of fraud to her employer, P.P.D., and also to Aventis.
She told the congressional committee, “What brings me here today is my
disbelief at Aventis’s statements that it did not know that fraud was being
committed. Mr. Chairman, I knew it, P.P.D. knew it, and Aventis knew it.”
Following her testimony the company released a statement saying it regretted
the violations that occurred during the study but was not aware of the fraud
until after the data was submitted to the F.D.A.
The F.D.A., the federal agency charged with oversight of the food and drugs
that Americans consume, is rife with conflicts of interest. Doctors who insist
the drug you take is perfectly safe may be collecting hundreds of thousands of
dollars from the company selling the drug. (ProPublica, an independent,
nonprofit news organization that is compiling an ongoing catalogue of
pharmaceutical-company payments to physicians, has identified 17,000 doctors
who have collected speaking and consulting fees, including nearly 400 who have
received $100,000 or more since 2009.) Quite often, the F.D.A. never bothers to
check for interlocking financial interests. In one study, the agency failed to
document the financial interests of applicants in 31 percent of applications
for new-drug approval. Even when the agency or the company knew of a potential
conflict of interest, neither acted to guard against bias in the test results.
Because of the deference shown to drug companies by the F.D.A.—and also by
Congress, which has failed to impose any meaningful regulation—there is no
mandatory public record of the results of drug trials conducted in foreign
countries. Nor is there any mandatory public oversight of ongoing trials. If
one company were to test an experimental drug that killed more patients than it
helped, and kept the results secret, another company might unknowingly repeat
the same experiment years later, with the same results. Data is made available
to the public on a purely voluntary basis. Its accuracy is unknown. The
oversight that does exist often is shot through with the kinds of ethical
conflicts that Wall Street would admire. The economic incentives for doctors in
poor countries to heed the wishes of the drug companies are immense. An
executive at a contract-research organization told the anthropologist Adriana
Petryna, author of the book When Experiments Travel: “In Russia, a doctor
makes two hundred dollars a month, and he is going to make five thousand
dollars per Alzheimer’s patient” that he signs up. Even when the most flagrant
conflicts are disclosed, penalties are minimal. In truth, the same situation
exists in the United States. There’s just more of a chance here, though not a
very large one, that adverse outcomes and tainted data will become public. When
the pharmaceutical industry insists that its drugs have been tested overseas in
accordance with F.D.A. standards, this may be true—but should provide little
assurance.
The F.D.A. gets its information on foreign trials almost entirely from the
companies themselves. It conducts little or no independent research. The
investigators contracted by the pharmaceutical companies to manage clinical
trials are left pretty much on their own. In 2008 the F.D.A. inspected just 1.9
percent of trial sites inside the United States to ensure that they were
complying with basic standards. Outside the country, it inspected even fewer
trial sites—seven-tenths of 1 percent. In 2008, the F.D.A. visited only 45 of
the 6,485 locations where foreign drug trials were being conducted.
The pharmaceutical industry dismisses concerns about the reliability of
clinical trials conducted in developing countries, but the potential dangers
were driven home to Canadian researchers in 2007. While reviewing data from a
clinical trial in Iran for a new heart drug, they discovered that many of the
results were fraudulent. “It was bad, so bad we thought the data was not
salvageable,” Dr. Gordon Guyatt, part of the research group at McMaster
University in Hamilton, told Canada’s National Post.
In addition to monitoring trials abroad, which it does not really do, the
F.D.A. is responsible for inspecting drug-manufacturing plants in other
countries, which it also does not really do. In 2007 and 2008, hundreds of
patients taking the blood thinner heparin, which among other purposes is used
to prevent blood clots during surgery and dialysis, developed serious allergic
reactions as a result of a contaminant introduced at a Chinese manufacturing
facility. It took months for the F.D.A., its Chinese counterpart, and Baxter
International, the pharmaceutical company that distributed the drug, to track
the source of contamination to Changzhou, a city of 3.5 million on the Yangtze
River.
The delay was perhaps understandable, given the manufacturing process. The
raw material for Baxter’s heparin comes from China’s many small pig farms. To
be precise, it’s derived from the mucous membranes of the intestines of
slaughtered pigs; the membranes are mixed together and cooked, often in
unregulated family workplaces. By the time the source of the contaminant was
pinpointed, many more patients in the United States had experienced severe reactions,
and as many as 200 had died. It later turned out that the F.D.A. had indeed
inspected a Chinese plant—but it was the wrong one. The federal regulators had
confused the names.
The good news was that, in this instance, the F.D.A. at least knew which
country the heparin had come from. The bad news is that it does not always know
where clinical trials are being conducted, or even the names or types of drugs
being tested, or the purpose for which they will be prescribed once approved.
Companies may withhold the foreign test data until they actually submit the
application to the F.D.A. for approval. By then the agency has lost the ability
to see whether the trials were managed according to acceptable standards, and
whether the data collected was manipulated or fabricated.
$350 per Child
If the globalization of clinical trials for adult medications has drawn
little attention, foreign trials for children’s drugs have attracted even less.
The Argentinean province of Santiago del Estero, with a population of nearly a
million, is one of the country’s poorest. In 2008 seven babies participating in
drug testing in the province suffered what the U.S. clinical-trials community
refers to as “an adverse event”: they died. The deaths occurred as the children
took part in a medical trial to test the safety of a new vaccine, Synflorix, to
prevent pneumonia, ear infections, and other pneumococcal diseases. Developed
by GlaxoSmithKline, the world’s fourth-largest pharmaceutical company in terms
of global prescription-drug sales, the new vaccine was intended to compete
against an existing vaccine. In all, at least 14 infants enrolled in clinical
trials for the drug died during the testing. Their parents, some illiterate,
had their children signed up without understanding that they were taking part
in an experiment. Local doctors who persuaded parents to enroll their babies in
the trial reportedly received $350 per child. The two lead investigators
contracted by Glaxo were fined by the Argentinean government. So was Glaxo,
though the company maintained that the mortality rate of the children “did not
exceed the rate in the regions and countries participating in the study.” No
independent group conducted an investigation or performed autopsies. As it
happens, the brother of the lead investigator in Santiago del Estero was the
Argentinean provincial health minister.
In New Delhi, 49 babies died at the All India Institute of Medical Sciences
while taking part in clinical trials over a 30-month period. They were given a
variety of new drugs to treat everything from high blood pressure to chronic
focal encephalitis, a brain inflammation that causes epileptic seizures and
other neurological problems. The blood-pressure drugs had never before been
given to anyone under 18. The editor of an Indian medical journal said it was
obvious that the trials were intended to extend patent life in Western
countries “with no consequence or benefit for India, using Indian children as
guinea pigs.” In all, 4,142 children were enrolled in the studies, two-thirds
of them less than one year old. But the head of the pediatrics department at
the All India Institute maintained that “none of the deaths was due to the
medication or interventions used in clinical trials.”
For years, American physicians gave anti-psychotic medicines to children
“off label,” meaning that they wrote prescriptions based on testing for adults,
sometimes even for different conditions. That didn’t work out so well for the
children, who, when it comes to medicine, really are not just little adults. To
provide the pharmaceutical industry with an incentive to conduct clinical
trials on children’s versions of adult drugs, Congress in 1997 enacted
legislation, known as the Pediatric Exclusivity Provision, extending the patent
life of certain drugs by six months. It worked so well that the industry has,
in the ensuing years, been able to put younger and younger children on more and
more drugs, pocketing an extra $14 billion. Between 1999 and 2007, for
instance, the use of anti-psychotic medications on children between the ages of
two and five more than doubled.
A study of 174 trials under the Pediatric Exclusivity Provision found that
9 percent of them did not report the location or number of sites of the
clinical trials. Of those that did, two-thirds had been conducted in at least
one country outside the United States, and 11 percent were conducted entirely
outside the United States. Of the 79 trials with more than 100 subjects
participating, 87 percent enrolled patients outside the United States. As is
the case with adult studies, many children’s trials conducted abroad are
neither reported nor catalogued on any publicly accessible government database.
There is no public record of their existence or their results.
In the mid-90s, Glaxo conducted clinical trials on the antidepressant Paxil
in the United States, Europe, and South America. Paxil is a member of a class
of drugs called selective serotonin re-uptake inhibitors. The class includes
Zoloft, Prozac, and Lexapro. In the United Kingdom, Paxil is sold as Seroxat.
The clinical trials showed that the drug had no beneficial effect on
adolescents; some of the trials indicated that the placebo was more effective
than the drug itself. But Glaxo neglected to share this information with
consumers; annual sales of the drug had reached $5 billion in 2003. In an
internal document obtained by the Canadian Medical Association Journal,
the company emphasized how important it was to “effectively manage the
dissemination of these data in order to minimize any potential negative
commercial impact.” The memo went on to warn that “it would be commercially
unacceptable to include a statement that efficacy had not been demonstrated.”
After the document was released a Glaxo spokesperson said that the “memo draws
an inappropriate conclusion and is not consistent with the facts.”
“Smoke and Mirrors”
It may be just a coincidence, but as controversy swirls around new drugs,
and as the F.D.A. continues to slap medicines with new warning
labels—especially the black-box warnings that indicate the most serious
potential reactions—most of the problematic drugs have all undergone testing
outside the United States. Clinical-trial representatives working for
GlaxoSmithKline went to Iaşi, Romania, to
test Avandia, a diabetes drug, on the local population. Glaxo representatives
also showed up in other cities in Romania—Bucureşti, Cluj-Napoca, Craiova, and Timişoara—as well as
multiple cities in Latvia, Ukraine, Slovakia, the Russian Federation, Poland,
Hungary, Lithuania, Estonia, the Czech Republic, Bulgaria, Croatia, Greece,
Belgium, the Netherlands, Germany, France, and the United Kingdom. That was for
the largest of the Avandia clinical trials. But there have been scores of
others, all seeking to prove that the drug is safe and effective. Some took
place before the drug was approved by the F.D.A. Others were “post-marketing”
studies, done after the fact, as the company cast about for ways to come up
with more positive results so it could expand Avandia’s use for other
treatments. Based on the initial evaluations, Avandia was expected to—and
did—become another Glaxo multi-billion-dollar best-seller.
While sales soared, so, too, did reports of adverse reactions—everything
from macular edema to liver injury, from bone fractures to congestive heart
failure. In 2009 the Institute for Safe Medication Practices, a
Pennsylvania-based nonprofit group that monitors the prescription-drug field,
linked the deaths of 1,354 people to Avandia, based on reports filed with the
F.D.A. Studies also concluded that people taking the drug had an increased risk
of developing heart disease, one of the very conditions that doctors treating
diabetics hope to forestall. The risk was so high that worried doctors inside
and outside the F.D.A. sought to have the drug removed from the market, an
incredibly difficult task no matter how problematic the medicine. As always,
the F.D.A. was late to the party. In 2008 the American Diabetes Association and
the European Association for the Study of Diabetes had warned against using
Avandia. The Saudi Arabian drug-regulatory agency yanked it from the market,
and the Indian government asked Glaxo to halt 19 of its Avandia trials in that
country. In September 2010 the European Medicines Agency pulled Avandia from
the shelves all across Europe. The F.D.A. still could not bring itself to take
decisive action. This even though the F.D.A. knew that Glaxo had withheld
critical safety information concerning the increased risk of heart attacks, and
the F.D.A. itself had estimated that the drug had caused more than 83,000 heart
attacks between 1999 and 2007. The agency settled for imposing new restrictions
on the availability of the drug in the United States. Glaxo released a
statement saying that it “continues to believe that Avandia is an important
treatment for patients with type 2 diabetes,” but that it would “voluntarily
cease promotion of Avandia in all the countries in which it operates.”
The Avandia case and others like it have prompted the U.S. Justice
Department to mount an investigation under the Foreign Corrupt Practices Act.
While it is legal for doctors in this country to accept money from drug
companies for acting as consultants, this is not the case abroad, where doctors
often are government employees, and such payments can be considered bribes.
There are other legal issues. So far, Glaxo has paid out more than $1 billion
to settle lawsuits arising from claims against Avandia and other drugs. The
Senate Finance Committee calculates that, since May 2004, seven drug companies
have paid out more than $7 billion in fines and penalties stemming from
unlawful drug dealings. Pfizer paid the largest such fine in history—$2.3
billion for promoting off-label uses of the arthritis drug Bextra.
In theory, pharmaceutical companies are barred from selling a drug for any
purpose other than the one that the F.D.A. has approved on the basis of
clinical testing. But the reality is different. The minute a drug receives the
green light from the F.D.A. for a specific treatment, the sponsoring company and
its allies begin campaigns to make it available for other purposes or for other
types of patients. The antidepressant Paxil was tested on adults but sold
off-label to treat children. Seroquel, an anti-psychotic, was marketed as a
treatment for depression. Physicians, often on retainer from pharmaceutical
companies, are free to prescribe a drug for any reason if they entertain a
belief that it will work. This practice turns the population at large into
unwitting guinea pigs whose adverse reactions may go unreported or even
unrecognized.
To secure the F.D.A.’s approval for Seroquel, which ultimately would go to
treat schizophrenia, bipolar disorders, and manic episodes associated with
bipolar disorder, AstraZeneca, the fifth-largest pharmaceutical company, conducted
clinical trials across Asia, Europe, and the United States. Among the sites:
Shenyang and more than a dozen other cities in China, and multiple cities in
Bulgaria, Estonia, Hungary, Latvia, Lithuania, Croatia, Indonesia, Malaysia,
Poland, the Russian Federation, Serbia, Ukraine, and Taiwan. The F.D.A.
initially approved the drug for the treatment of schizophrenia. But while
schizophrenia may have opened the door, off-label sales opened the cash
register. Money poured in by the billions as AstraZeneca promoted the drug for
the treatment of any number of other conditions. It was prescribed for children
with autism-spectrum disorders and retardation as well as for elderly
Alzheimer’s patients in nursing homes. The company touted the drug for treatment
of aggression, anxiety, anger-management issues, attention-deficit
hyperactivity disorder, dementia, and sleeplessness. Up to 70 percent of the
prescriptions for Seroquel were written for a purpose other than the one for
which it had been approved, and sales rose to more than $4 billion a year.
It turned out, however, that AstraZeneca had been less than candid about
the drug’s side effects. One of the most troubling: patients often gained
weight and developed diabetes. This meant a new round of drugs to treat
conditions caused by Seroquel. In an internal e-mail from 1997 discussing a
study comparing Seroquel with an older anti-psychotic drug, Haldol, a company
executive praised the work of the project physician, saying she had done a
great “smoke-and-mirrors job,” which “should minimize (and dare I venture to
suggest) could put a positive spin (in terms of safety) on this cursed study.”
After the e-mail was disclosed, in February 2009, the company said that the
document cannot “obscure the fact that AstraZeneca acted responsibly and
appropriately as it developed and marketed” the drug. In April, AstraZeneca
reached a half-billion-dollar settlement with the federal government over its
marketing of Seroquel. The U.S. attorney in Philadelphia, where the settlement
was filed, declared that the company had “turned patients into guinea pigs in
an unsupervised drug test.” Meanwhile, the company was facing more than 25,000
product-liability lawsuits filed by people who contended the drug had caused
their diabetes.
Death Toll
The only people who seem to care about the surge of clinical trials in
foreign countries are the medical ethicists—not historically a powerhouse when
it comes to battling the drug companies. A team of physician-researchers from
Duke University, writing last year in the New England Journal of Medicine,
observed that “this phenomenon raises important questions about the economics
and ethics of clinical research and the translation of trial results to
clinical practice: Who benefits from the globalization of clinical trials? What
is the potential for exploitation of research subjects? Are trial results
accurate and valid, and can they be extrapolated to other settings?” The Duke
team noted that, in some places, “financial compensation for research participation
may exceed participants’ annual wages, and participation in a clinical trial
may provide the only access to care” for those taking part in the trial. In
2007, resi
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