Healthy Skepticism Library item: 3895

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Publication type: news

Kahn J.
A Nation of Guinea Pigs
Wired.com 2006 Mar 26
http://www.wired.com/wired/archive/14.03/indiadrug.html

Notes:

Ralph Faggotter’s Comments:

When doctors at clinical meetings look at slides of clinical studies showing what percentage of subjects responded to a particular drug, do they ever stop and think about the volunteers behind these statistics?

Does it occur to them that the subjects might be mostly extremely poor people living in a third world country and willing to take on potential health risks out of ignorance and desparation?

Full text:

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 Jennifer 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.”
Jennifer Kahn (jenn_kahn@wiredmag.com) is a contributing editor. Her profile
of hacker Adrian Lamo (issue 12.04) was selected for Best American Science &
Nature Writing 2005