India-Guinea Pig to the World_Wired Magazine

[Guest guest]

India-Guinea Pig to the World_Wired Magazine

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and

Accountability

http://www.ahrp.org/cms/

FYI

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.

The pharmaceutical industry's dilemma: there are

few volunteers in the

drug-consuming prosperous countries--so they have

taken half their business

to underdeveloped countries.

An investigative report by Kahn who went

to India describes the new

trend in clinical trials-- " outsourcing " –in

particular to India, which is

considered the perfect human laboratory because

of its skilled, English

speaking doctors, and its impoverished population

for whom any medical

treatment is seen as an improvement. From an

expedient economic

perspective, India offers the perfect `specimens'

for clinical trials:

" Ninety percent of patients being recruited in

India are poor. Trials enroll

very few patients who are rich, literate, and

capable of asking awkward

questions. " Furthermore, because they are

" medication naive " the chances of

drug interaction don't exist.

..

The article describes stroke-prevention trials

conducted by Boehringer

Ingelheim in the town of Sevagram, and the unease

of Dr. S. P. Kalantri, who

acknowledges the ethical dilemmas presented by

the reality that many of the

drugs tested are not for illnesses most troubling

to Indians. But the lure

of money—which he insists goes to the hospital—is

hard to refuse.

(Elsewhere, doctors are depositing the

pharmaceutical company money in their

personal accounts).

" Last year, 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. "

Although the doctor and chair of the ethics

committee realized that the drug

would not be helpful to their patients, they

signed them up anyway because

the perks are too good to pass up.

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.

The Indian government changed the law to

facilitate recruitment of subjects:

" 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. "

Contact: Vera Hassner Sharav

212-595-8974

veracare@...

http://www.wired.com/wired/archive/14.03/indiadrug.html

Wired Magazine

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 Kahn

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 drug-making 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 inter-actions and avoids the

troublesome process of weaning

patients o!

ff 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. "

Kahn (jenn_kahn@...) is a

contributing editor. Her profile

of hacker Lamo (issue 12.04) was selected

for Best American Science &

Nature Writing 2005

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section 107 of the US Copyright Law. This

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[Guest guest]

India-Guinea Pig to the World_Wired Magazine

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and

Accountability

http://www.ahrp.org/cms/

FYI

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.

The pharmaceutical industry's dilemma: there are

few volunteers in the

drug-consuming prosperous countries--so they have

taken half their business

to underdeveloped countries.

An investigative report by Kahn who went

to India describes the new

trend in clinical trials-- " outsourcing " –in

particular to India, which is

considered the perfect human laboratory because

of its skilled, English

speaking doctors, and its impoverished population

for whom any medical

treatment is seen as an improvement. From an

expedient economic

perspective, India offers the perfect `specimens'

for clinical trials:

" Ninety percent of patients being recruited in

India are poor. Trials enroll

very few patients who are rich, literate, and

capable of asking awkward

questions. " Furthermore, because they are

" medication naive " the chances of

drug interaction don't exist.

..

The article describes stroke-prevention trials

conducted by Boehringer

Ingelheim in the town of Sevagram, and the unease

of Dr. S. P. Kalantri, who

acknowledges the ethical dilemmas presented by

the reality that many of the

drugs tested are not for illnesses most troubling

to Indians. But the lure

of money—which he insists goes to the hospital—is

hard to refuse.

(Elsewhere, doctors are depositing the

pharmaceutical company money in their

personal accounts).

" Last year, 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. "

Although the doctor and chair of the ethics

committee realized that the drug

would not be helpful to their patients, they

signed them up anyway because

the perks are too good to pass up.

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.

The Indian government changed the law to

facilitate recruitment of subjects:

" 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. "

Contact: Vera Hassner Sharav

212-595-8974

veracare@...

http://www.wired.com/wired/archive/14.03/indiadrug.html

Wired Magazine

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 Kahn

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 drug-making 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 inter-actions and avoids the

troublesome process of weaning

patients o!

ff 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. "

Kahn (jenn_kahn@...) is a

contributing editor. Her profile

of hacker Lamo (issue 12.04) was selected

for Best American Science &

Nature Writing 2005

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) material the use of which

has not always been specifically authorized by

the copyright owner. Such

material is made available for educational

purposes, to advance

understanding of human rights, democracy,

scientific, moral, ethical, and

social justice issues, etc. It is believed that

this constitutes a 'fair

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for in Title 17 U.S.C.

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[Guest guest]

India-Guinea Pig to the World_Wired Magazine

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and

Accountability

http://www.ahrp.org/cms/

FYI

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.

The pharmaceutical industry's dilemma: there are

few volunteers in the

drug-consuming prosperous countries--so they have

taken half their business

to underdeveloped countries.

An investigative report by Kahn who went

to India describes the new

trend in clinical trials-- " outsourcing " –in

particular to India, which is

considered the perfect human laboratory because

of its skilled, English

speaking doctors, and its impoverished population

for whom any medical

treatment is seen as an improvement. From an

expedient economic

perspective, India offers the perfect `specimens'

for clinical trials:

" Ninety percent of patients being recruited in

India are poor. Trials enroll

very few patients who are rich, literate, and

capable of asking awkward

questions. " Furthermore, because they are

" medication naive " the chances of

drug interaction don't exist.

..

The article describes stroke-prevention trials

conducted by Boehringer

Ingelheim in the town of Sevagram, and the unease

of Dr. S. P. Kalantri, who

acknowledges the ethical dilemmas presented by

the reality that many of the

drugs tested are not for illnesses most troubling

to Indians. But the lure

of money—which he insists goes to the hospital—is

hard to refuse.

(Elsewhere, doctors are depositing the

pharmaceutical company money in their

personal accounts).

" Last year, 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. "

Although the doctor and chair of the ethics

committee realized that the drug

would not be helpful to their patients, they

signed them up anyway because

the perks are too good to pass up.

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.

The Indian government changed the law to

facilitate recruitment of subjects:

" 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. "

Contact: Vera Hassner Sharav

212-595-8974

veracare@...

http://www.wired.com/wired/archive/14.03/indiadrug.html

Wired Magazine

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 Kahn

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 drug-making 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 inter-actions and avoids the

troublesome process of weaning

patients o!

ff 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. "

Kahn (jenn_kahn@...) is a

contributing editor. Her profile

of hacker Lamo (issue 12.04) was selected

for Best American Science &

Nature Writing 2005

FAIR USE NOTICE: This may contain copyrighted (©

) material the use of which

has not always been specifically authorized by

the copyright owner. Such

material is made available for educational

purposes, to advance

understanding of human rights, democracy,

scientific, moral, ethical, and

social justice issues, etc. It is believed that

this constitutes a 'fair

use' of any such copyrighted material as provided

for in Title 17 U.S.C.

section 107 of the US Copyright Law. This

material is distributed without

profit.

[Guest guest]

India-Guinea Pig to the World_Wired Magazine

ALLIANCE FOR HUMAN RESEARCH PROTECTION (AHRP)

Promoting Openness, Full Disclosure, and

Accountability

http://www.ahrp.org/cms/

FYI

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.

The pharmaceutical industry's dilemma: there are

few volunteers in the

drug-consuming prosperous countries--so they have

taken half their business

to underdeveloped countries.

An investigative report by Kahn who went

to India describes the new

trend in clinical trials-- " outsourcing " –in

particular to India, which is

considered the perfect human laboratory because

of its skilled, English

speaking doctors, and its impoverished population

for whom any medical

treatment is seen as an improvement. From an

expedient economic

perspective, India offers the perfect `specimens'

for clinical trials:

" Ninety percent of patients being recruited in

India are poor. Trials enroll

very few patients who are rich, literate, and

capable of asking awkward

questions. " Furthermore, because they are

" medication naive " the chances of

drug interaction don't exist.

..

The article describes stroke-prevention trials

conducted by Boehringer

Ingelheim in the town of Sevagram, and the unease

of Dr. S. P. Kalantri, who

acknowledges the ethical dilemmas presented by

the reality that many of the

drugs tested are not for illnesses most troubling

to Indians. But the lure

of money—which he insists goes to the hospital—is

hard to refuse.

(Elsewhere, doctors are depositing the

pharmaceutical company money in their

personal accounts).

" Last year, 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. "

Although the doctor and chair of the ethics

committee realized that the drug

would not be helpful to their patients, they

signed them up anyway because

the perks are too good to pass up.

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.

The Indian government changed the law to

facilitate recruitment of subjects:

" 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. "

Contact: Vera Hassner Sharav

212-595-8974

veracare@...

http://www.wired.com/wired/archive/14.03/indiadrug.html

Wired Magazine

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 Kahn

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 drug-making 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 inter-actions and avoids the

troublesome process of weaning

patients o!

ff 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. "

Kahn (jenn_kahn@...) is a

contributing editor. Her profile

of hacker Lamo (issue 12.04) was selected

for Best American Science &

Nature Writing 2005

FAIR USE NOTICE: This may contain copyrighted (©

) material the use of which

has not always been specifically authorized by

the copyright owner. Such

material is made available for educational

purposes, to advance

understanding of human rights, democracy,

scientific, moral, ethical, and

social justice issues, etc. It is believed that

this constitutes a 'fair

use' of any such copyrighted material as provided

for in Title 17 U.S.C.

section 107 of the US Copyright Law. This

material is distributed without

profit.