[Ip-health] Vanity Fair: Deadly Medicine

Thiru Balasubramaniam thiru at keionline.org
Sat Jan 22 20:51:10 PST 2011


http://www.vanityfair.com/politics/features/2011/01/deadly-medicine-201101

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 Donald L. Barlett and James B. Steele•
Photo illustration by Chris Mueller
January 2011

Read More http://www.vanityfair.com/politics/features/2011/01/deadly-medicine-201101?printable=true#ixzz1BpXhfQoQ

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, 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.

Keywords Politics, Pharmaceutical industry, January 2011, Health,  
Medicine
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Read More http://www.vanityfair.com/politics/features/2011/01/deadly-medicine-201101?printable=true#ixzz1BpXcx3f7

------------------------------------------------------------


Thiru Balasubramaniam
Geneva Representative
Knowledge Ecology International (KEI)
thiru at keionline.org


Tel: +41 22 791 6727
Mobile: +41 76 508 0997








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