Politics Deadly Medicine-Vanity Fair Article

[Guest guest]

Prescription drugs kill

some 200,000 Americans every year. Will that number go up, now that most

clinical trials are conducted overseas—on sick Russians, homeless

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

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

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

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

lethal profit machine.

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

January 2011

TAKE TWO ASPIRIN

More and more

clinical trials for new drugs are being outsourced overseas and

conducted by companies for hire. Is oversight even possible?

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-naïveâ€

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

currently taking any drugs, and indeed may never have taken any—the sort

of people who will almost certainly yield better test results. (For

some subjects overseas, participation in a clinical trial may be their

first significant exposure to a doctor.) Regulations in many foreign

countries are also less stringent, if there are any regulations at all.

The risk of litigation is negligible, in some places nonexistent.

Ethical concerns are a figure of speech. Finally—a significant plus for

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

companies can pretty much do and say what they want.

Consent by Thumbprint

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.â€) Soon afterward the Journal of

the Royal Society of Medicine

reported an array of additional negative findings. Meanwhile, Pfizer

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

the possibility that the drug would slow the progression of dementia. It

didn’t. Sales of Celebrex reached $3.3 billion in 2004, and then began

to quickly drop.

“Rescue Countriesâ€

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-, of Gadsden, Alabama,

seemingly never met a person she couldn’t sign up to participate in a

drug trial. She enrolled more than 400 volunteers, about 1 percent of

the town’s adult population, including her entire office staff. In

return, she collected $400 a head from Sanofi-Aventis. It later came to

light that the data from at least 91 percent of her patients was

falsified. (Kirkman- was not the only troublesome Aventis

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

trial site, was addicted to cocaine. The same month his data was

submitted to the F.D.A. he was arrested while holding his wife hostage

at gunpoint.) Nonetheless, on the basis of overseas trials, Ketek won

approval.

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. 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.â€

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.â€

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-’s testing in Alabama. Cisneros later told the

congressional investigating committee that Kirkman- had indeed

engaged in fraud. “But what the court that sentenced her did not know,â€

Cisneros said, was that “Aventis was not a victim of this fraud.â€

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 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 eventâ€: 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 GlaxoKline, 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.â€

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.â€

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.â€

“Smoke and Mirrorsâ€

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 GlaxoKline went to IaÅŸi,

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.â€

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. 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. “ly,†she said, “I am mostly worried about the drug trials

that get done elsewhere now, which we have little control over.â€

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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