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Deadly Medicine
2010/12/20 20:37
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Deadly Medicine



6 Dec - 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.



Photo illustration by Chris Mueller



You wouldn’t think the cities had
much in common. Iaşi, with a population of 320,000, lies in the Moldavian
region of Romania. Megrine 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 Emajogi.”
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-naive” 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, residents of a homeless
shelter in Grudziadz, Poland, received as little as $2 to take part in a
flu-vaccine experiment. The subjects thought they were getting a regular flu
shot. They were not. At least 20 of them died. The same distorting economic
pressures exist for local hospitals or doctors, who may collect hundreds of
dollars for every patient they enroll. In theory, a federal institutional
review board is supposed to assess every clinical trial, with special concern for
the welfare of the human subjects, but this work, too, has now been outsourced
to private companies and is often useless. In 2009 the Government
Accountability Office conducted a sting operation, winning approval for a
clinical trial involving human subjects; the institutional review board failed
to discover (if it even tried) that it was dealing with “a bogus company with
falsified credentials” and a fake medical device. This was in Los Angeles. If
that is oversight in the U.S., imagine what it’s like in Kazakhstan or Uganda.
Susan Reverby, the Wellesley historian who uncovered the U.S. government’s
syphilis experiments in Guatemala during the 1940s, was asked in a recent
interview to cite any ongoing experimental practices that gave her pause.
“Frankly,” she said, “I am mostly worried about the drug trials that get done
elsewhere now, which we have little control over.”



The pharmaceutical industry, needless to
say, has a different view. It argues that people participating in a clinical
trial may be getting the highest quality of medical care they have ever
received. That may be true in the short term. But, unfortunately, the care
lasts only until the trial is completed. Many U.S. medical investigators who
manage drug trials abroad say they prefer to work overseas, where regulations
are lax and “conflict of interest” is a synonym for “business as usual.” Inside
the United States, doctors who oversee trials are required to fill out forms
showing any income they have received from drug companies so as to guard against
financial biases in trials. This explains in part why the number of
clinical-trial investigators registered with the F.D.A. fell 5.2 percent in the
U.S. between 2004 and 2007 while increasing 16 percent in Eastern Europe, 12
percent in Asia, and 10 percent in Latin America. In a recent survey, 70
percent of the eligible U.S. and Western European clinical investigators
interviewed said they were discouraged by the current regulatory environment,
partly because they are compelled to disclose financial ties to the
pharmaceutical industry. In trials conducted outside the United States, few
people care.



In 2009, according to the Institute for
Safe Medication Practices, 19,551 people died in the United States as a direct
result of the prescription drugs they took. That’s just the reported number.
It’s decidedly low, because it is estimated that only about 10 percent of such
deaths are reported. Conservatively, then, the annual American death toll from
prescription drugs considered “safe” can be put at around 200,000. That is
three times the number of people who die every year from diabetes, four times
the number who die from kidney disease. Overall, deaths from F.D.A.-approved
prescription drugs dwarf the number of people who die from street drugs such as
cocaine and heroin. They dwarf the number who die every year in automobile
accidents. So far, these deaths have triggered no medical crusades, no tough
new regulations. After a dozen or so deaths linked to runaway Toyotas, Japanese
executives were summoned to appear before lawmakers in Washington and were
subjected to an onslaught of humiliating publicity. When the pharmaceutical
industry meets with lawmakers, it is mainly to provide campaign contributions.



And with more and more of its activities
moving overseas, the industry’s behavior will become more impenetrable, and
more dangerous, than ever.



 

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