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A Nation of Guinea Pigs 

 

There's a new outsourcing boom in South Asia - and a billion people are

jockeying for the jobs. How India became the global hot spot for drug

trials.

By Jennifer Kahn 

HYPERLINK

"http://www.wired.com/wired/archive/14.03/indiadrug_pr.html'>http://www.wired.com/wired/archive/14.03/indiadrug_pr.html"http://www.wired

..com/wired/archive/14.03/indiadrug_pr.html 

 

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The town of Sevagram in central India has long been known for three things:

its heat, which is oppressive even by Indian standards; its snakes, which

are abundant; and its ashram, a derelict and increasingly malarial retreat

preserved as a tribute to Mohandas Gandhi, who lived here and was known for

tenderly relocating the poisonous vipers that slithered into his shack.

 

Despite this intemperate setting, Sevagram's hospital has a good reputation.

Though the power fails often, forcing medics to use the backlit screens of

their cell phones for illumination, the standard of care is higher than at

many of the country's public hospitals, and the facilities are comparatively

plush. At the nearby government medical center in Nagpur, for instance,

patients sometimes have to sleep on mattresses on the floor.

 

Last year, Sevagram began garnering even more cachet. A German

pharmaceutical company called Boehringer Ingelheim, whose latest

stroke-prevention drug was making its way through the clinical pipeline,

approved the town's hospital as a trial site - one of 28 in India recruiting

stroke victims to round out the company's 18,500-person study.

 

The drug regimen, known as Aggrenox, was being tested for its ability to

forestall a second stroke. S. P. Kalantri, the doctor tapped to lead the

trial in Sevagram, quickly grasped the offer's appeal. Patients in Sevagram

are poor enough that the benefits of taking part in the study would amount

to a health care windfall; among other things, Boehringer Ingelheim

guaranteed participants two physicals during each of the three years that

the trial would run. For each person enrolled, moreover, the hospital would

receive 30,000 rupees (about $665) - no small amount, given the puny budget

of the center's stroke ward, a single room of eight pallet beds. Kalantri

talked the matter over with the chair of the hospital's ethics committee,

and the two concluded that the trial drug itself, with its possible side

effects and limited efficacy, would provide little benefit to their

patients. Then they went ahead and signed up.

 

When I arrive in Sevagram on a typically sweltering October afternoon,

Kalantri is midway through a busy day. That morning, he attended to a farmer

who had been bitten on the heel by a viper while sleeping, and then to a

woman who had drunk a quart of insecticide in a suicide attempt. He also

checked on his regular patients: a man with cerebral malaria, two women with

unexplained fevers, and a stroke patient who had hemorrhaged. When I ask

what treatment he gave to the stroke victim, he seems surprised. "Nothing,"

he says. "There's nothing we can do."

 

Though hemorrhagic strokes are untreatable - drugs can't undo the damage -

Kalantri's response echoed a more persistent frustration: that patients are

too poor to pay for medicine. Because of this, one of the alluring features

of a clinical trial is that subjects are supplied with the test drug for

free. And while the medication on offer isn't always a very useful one,

there's still the chance that it will do some good.

 

This casual optimism contrasts sharply with the attitude in the West, where

the number of patients willing to sign up for clinical trials is abysmally

low. Just 3 percent of cancer patients opt to join trials, and the number of

US patients who sign up for cardiac trials has plunged by half over the past

five years.

 

Such reticence has created a problem for the pharmaceutical industry. Modern

drug design may be a sophisticated enterprise, harnessing technology that

didn't even exist a decade ago, but one part of the process remains the

same: The only way to tell how well a medication really works is to feed it

to a sick person. This process, the human clinical trial, is the largest and

creakiest part of the drug­making machine - a mammoth lab experiment that

succeeds by brute statistical force. To make it run, companies have to round

up a large number of ailing people and then convince them to swallow an

unproven remedy with uncertain side effects.

 

The experiment unfolds in three stages: Phase I, when a compound is

safety-tested on a few dozen healthy people; Phase II, conducted on a

slightly larger group of mildly ill subjects; and Phase III, which is the

most extensive. Involving thousands of subjects and taking up to seven years

to complete, Phase III trials are the make-or-break point for new medicines

and, because of their size, the hardest to fill with patients. Exacerbating

the problem is the fact that discoveries of rare side effects (including

lethal ones, like strokes and heart attacks caused by the arthritis drug

Vioxx) have pushed companies to conduct ever larger studies. In the 1980s, a

new drug typically was tested on 1,300 volunteers in a total of 30 trials.

By the mid-1990s, those numbers had swelled to 4,200 patients and 68 trials.

 

"Twenty years ago, drugs were dropping the cardiac mortality rate from 20

percent to 15 percent," says Dhiraj Narula, medical director of Quintiles

ECG, a contract-research firm that organizes trials for major

multinationals. "Today we're looking at drugs that will take you from 6

percent mortality to 5 percent. To prove an effect that subtle, in a way

that's statistically robust, you need a lot of patients in your sample." One

cardiac drug study was conducted on a whopping 41,000 subjects.

 

The result is a bottleneck that Narula argues is impeding the arrival of

important cures. Herceptin - an exceptionally effective breast cancer drug -

languished in trials for years because its maker, Genentech, reportedly

couldn't recruit enough patients to test it.

 

Like many in the pharmaceutical industry, Narula believes that the solution

to the slow pace of drug trials lies in outsourcing. As many as half of all

clinical trials are already conducted in locations far from the

pharmaceutical companies' home base, in countries like India, China, and

Brazil. And many industry analysts expect the market to skyrocket,

particularly as expanding libraries of genetic information increase the

number of drugs coming out of the lab. The consulting firm McKinsey

calculates that the market in India for outsourced trials will hit $1.5

billion by 2010.

 

Enticed by numbers like these, developing countries have been scrambling to

catch Big Pharma's eye - India most aggressively of all. Like high tech call

centers and software farms, which were meant to transform India's computer

industry by creating skilled workers and a stockpile of modern equipment,

drug trial outsourcing is seen as the fast route to economic and scientific

growth - a money train that the country can't afford to miss. With this in

mind, the government is working to advertise India's most pharmacologically

appealing qualities, notably its doctors (English-speaking and educated

abroad) and its vast number of ailing patients - 32 million diabetics alone.

Many of these patients are also, in the delicate parlance of the drug world,

"treatment naive," meaning they've never taken any medication for their

illnesses. This is a perk for trial managers, because it lowers the risk of

unforeseen drug inter­actions and avoids the troublesome process of weaning

patients off one medication and onto another.

 

Last year, the government took a more controversial step, amending a

long-standing law that limited the kind of trials that foreign

pharmaceutical companies could conduct. That law allowed companies to test

drugs on Indian patients only after the drugs had been proven safe in trials

conducted in the country of origin. In January, the government threw out

that constraint. India, the brilliant hub of outsourced labor, was

positioning itself in a newly lucrative role: guinea pig to the world.

 

The headquarters of Sevagram's Aggrenox trial, located around the corner

from the hospital's intensive care unit, is low on frills. A drooling corner

sink and two elderly computers list against the water-stained walls, under

the benevolent gaze of a small plastic bust of Gandhi. A handful of

scientific papers have been tacked to the wall, where they hang unstirred by

a sluggish fan. Since recruitment for the trial began in January 2005,

Kalantri has signed up 44 stroke victims, a quarter of the number that have

come through the hospital.

 

Nonetheless, Kalantri is uneasy about his clinical success. "Patients here

are very passive," he reflects. "They will almost never question their

doctor." Indeed, one woman who joined the trial six months ago sits

patiently for more than an hour while Kalantri translates my questions,

before revealing that she is suffering from aches and fever that are likely

malaria. Such deference is hard to imagine in US patients - a querulous

lot - and it makes Kalantri's position tricky. "Nine out of 10 times," he

says, "the patient will just ask me to make the decision about the trial for

him. So what role do I play? Am I a physician, concentrating on what's best

for the patient? Or am I a researcher interested in recruiting patients? I

try to balance the two sides, but ..." He shrugs. "It's a dichotomy."

 

Kalantri began worrying about such matters not long after he started

recruiting patients for Boehringer Ingelheim. The previous year, he had

overseen a trial for Reviparin, an anticlotting drug that improves the

health of one out of 65 cardiac patients within 30 days of a heart attack.

The trial was enormous: Nearly 16,000 patients participated, half of them

from India. When the trial ended, however, Kalantri wondered whether he had

served his patients well by enrolling them. At 800 rupees a day, the drug

they had taken was too expensive for any of them to afford. Plus, even when

it worked, it showed results for just a month. Such a minute and costly

improvement might make sense in the US, Kalantri felt, but was it really the

kind of medication that poor Indians should be testing? "The biggest

problems around here are snakebite and insecticide poisoning," he points

out. "We could really use a trial for one of those."

 

Kalantri is in a good position to observe such discrepancies. He grew up in

the neighboring town of Wardha, 15 minutes away by auto-rickshaw, and got

his training at the local medical college in Nagpur - a city whose main

claim to fame is a survey plaque declaring it to be India's geographical

center. He is a slight man, with a philosophical and conscientious manner.

His wife is a database administrator for the hospital in Sevagram, and last

year the older of their two children started attending medical school there.

Although Kalantri could probably work elsewhere - in 2004, he did a stint at

UC Berkeley, working on his master's in public health and collaborating on a

tuberculosis study that was published in The Journal of the American Medical

Association - he remains attached to the rural hospital he joined 20 years

ago. "I found my peace of mind here," he says.

 

Initially, Kalantri says, he was excited by the idea of bringing clinical

trials to Sevagram and liked the prospect of turning his hospital into a

research center. "Drug trials can teach residents proper record-keeping and

help them understand how to associate clinical care with research," he

notes. When I first called him, shortly after a record rainy season, he

mentioned that the emergency ward contained a number of patients with a

mysterious fever - one that epidemiological tests had been unable to

identify. "It would be good to study it," Kalantri murmured, sounding a bit

regretful. "Maybe we will, one day."

 

Bringing trials to India, moreover, struck him as medically important. A

Nature Genetics article had recently surveyed 29 drugs whose efficacy and

side effects varied in different racial or ethnic populations. Perversely,

testing drugs exclusively on Americans and western Europeans could almost

seem colonial.

 

Little by little, however, Kalantri began to see the problematic side of

outsourced trials. "When I try to explain that a drug is experimental, that

it might not work, the understanding is not there," he observes. "One woman

said to me, 'What do you mean, the drug might not work? All drugs work!'"

 

Poorly paid doctors can also find the financial rewards of a trial hard to

resist - particularly since pharma companies reward high enrollments with

prizes like vacations to Hawaii and Europe. "A lot of private hospital

doctors have suddenly become 'researchers,'" Kalantri notes. "They will

enroll almost anybody and recruit for almost any trial, whether or not it

helps the patient." And while the money earned from a trial in Sevagram goes

to the hospital, elsewhere it may be paid to the doctor. "A lot goes into

personal bank accounts," he says.

 

Naïveté and corruption are hardly unique to India, of course. They're the

early story of almost any developing industry, when regulation is still too

flimsy to check the horses of rapid progress. Compared to a country like

China, for instance, India is alert to the potential for exploitation and

has made at least some effort to safeguard its citizens. Programs to train

clinicians in World Health Organization-standard Good Clinical Practice - a

set of international rules covering patient rights and data management -

have sprung up around the country. In addition, all trials must ostensibly

be cleared by a local review board that includes one doctor, one lawyer, and

one pharmacist, as well as a housewife and a social worker.

 

In practice, however, policing trials is not easy. The enforcement staff of

the Drugs Controller General of India - the equivalent of the US Federal

Drug Administration - consists of just three pharmacists. And the country

has little history of keeping medical care independent of the pharmaceutical

business. The largest cardiac hospital in India, Escorts Heart Institute and

Research Centre, is a division of the massive Indian pharmco Ranbaxy.

 

"Are patients here more vulnerable?" asks Brijesh Regal, CEO of the New

Delhi-based firm Apothecaries, which runs clinical trials for pharmaceutical

companies. "Obviously. They're poor. They're illiterate." Nonetheless, he

argues, most of the problems can be attributed to the growing pains of a new

industry. He points to the thalidomide fiasco in the 1950s - women who were

given the drug for morning sickness delivered children with severe birth

defects - as evidence that every developing industry has problems. "Why are

we so concerned about India?" he asks. "If problems happened everywhere

else, they will happen here. We are a massive country without a lot of

regulatory infrastructure."

 

Regal's willingness to accept collateral damage may seem chilling, but it

has some historical precedent. The path of medical progress is strewn with

cases of questionable ethics, desperate practices, and misguided

experimentalism, if not outright exploitation. And since patients with the

fewest options are invariably the ones most likely to try (or be forcibly

volunteered for) risky new treatments, be it an artificial heart, an

unproven pill, or a radical lobotomy, they're also the ones who bear the

brunt of medicine's experimental nature. In this light, outsourcing trials

to a country where decent medical care is scarce, and medication scarcer, is

just the globalization of an old equation.

 

Kalantri, meanwhile, finds himself stuck in the uncomfortable role of

gatekeeper. "Every week, I get a call: 'Do you want to participate in this

trial?'" he says. So far, he has turned down one anti-osteoporosis trial and

another for a drug that might improve patient survival after a heart attack.

He declined, he explains, because the studies "don't make sense for India."

Finding better treatments for osteoporosis and high cholesterol is

important, he adds. "But these are diseases that will cause problems at 40

or 50. Infectious diseases like malaria and filariasis kill at 20, and

they're much more common here."

 

Kalantri is also troubled by what he sees as skewed trial demographics.

"Ninety percent of patients being recruited in India are poor," he says.

"That's the reality. Trials enroll very few patients who are rich, literate,

and capable of asking awkward questions."

 

But even as Kalantri has grown more selective, other Indian doctors are

moving in the opposite direction. And at his own hospital, Kalantri's

pickiness has been a subject of debate. "Some of my colleagues are not

exactly happy with these decisions," he sighs. "The extra money could be

used to build the department."

 

Finding a dollar amount that compensates medical centers properly - covering

costs like blood tests and the extra time a doctor must spend with study

patients, without amounting to a bribe - is tricky, Kalantri says. He

confesses that he has turned down trials because they paid too little.

Nonetheless, when a representative from Boehringer Ingelheim visited to

check up on the paperwork, Kalantri felt compelled to mention that the

amount the company was offering per patient seemed high. The rep looked at

him in surprise. "You're the first person to say that," she said, giving

Kalantri a puzzled smile. "Everyone else has asked for more."

 

Jennifer Kahn (jenn_kahn) is a contributing editor. Her profile

of hacker HYPERLINK

"http://www.wired.com/wired/archive/12.04/hacker.html"Adrian Lamo (issue

12.04) was selected for Best American Science & Nature Writing 2005

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Dear Sysman,

 

Thank you for posting this. What is extremely worrisome is that the

most risky trials will now be carried out in India. Will India go the

Africa way? We will have to wait and see.

 

Drug experimentation is always going on. Modern medicine itself is one

huge experiment that seems to have no end in sight. As our early

health planners had warned, the trusted methods of ayurveda,

homeopathy and nature cure should have been adopted to by India while

allowing modern medicine to come to some definite conclusion while

experimenting in the other countries.

 

Had we followed that advice, today we would have been a healthy,

peaceful state, and also would have been proud of our own heritage.

Indian knowledge systems would have received due attention and India

would have shown the way to the rest of the world. Our own Manmohan

Singh would have been the centre of attention and not GB.

 

Drug testing is a critical issue. But what most Indians are worried

about is the proposed testing in the genetic field. Genetic

experiments do not remain localised and havoc can very easily spread

even from the most secure labs, as genetic engineers themselves have

warned. Clearly the crying need of the day is to realise the dangerous

implications of tinkering with nature and playing God.

 

Regards,

Jagannath.

 

ayurveda, sysman <sysman wrote:

> A Nation of Guinea Pigs 

>

> There's a new outsourcing boom in South Asia - and a billion people

are

> jockeying for the jobs. How India became the global hot spot for drug

> trials.

> By Jennifer Kahn 

> HYPERLINK

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Guest guest

The post on 'Guina pigs' makes us sad that a country which gave birth

to ayurveda should open its arms to drug trials. Positive side to

this is some drug trials have shown that even placebos work, although

slightly less effective.

 

The placebo effect is one of the more interesting areas of medical

research. It touches on the power of the mind to heal the body by

tricking it into believing a sugar pill is an effective drug.

But what happens when two placebos are tested against each other in

the same trial? This fascinating question has been tested by

researchers from Harvard Medical School, who gave participants either

a sham acupuncture treatment or a sham drug to treat their arm pain.

Both groups reported a marked improvement in pain, although movement

improved more in those given the sham pill, whereas those given sham

acupuncture enjoyed better effects long term.

 

So both placebos had a positive effect - proving, yet again, the

power of our minds to influence illness.

 

Source: British Medical Journal, 2006; 332: 391-4.

 

dr bhate

 

 

 

 

ayurveda, sysman <sysman wrote:

>

>  

>

> A Nation of Guinea Pigs 

>

> There's a new outsourcing boom in South Asia - and a billion people

are

> jockeying for the jobs. How India became the global hot spot for

drug

> trials.

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