Non-HIV drug trials in India

[Guest guest]

One has some reason to hope that things are a bit different with HIV drug trials, but I suspect the larger prevention trials might be a bit laxer. Read according to your interest and time.

 

Bob Roehr

 

 

 

http://www.tampabay.com/news/business/article934677.ece

TAMPA BAY TIMES

The latest industry being outsourced to India: clinical drug trials

By Kris Hundley, Times Staff Writer

Published Thursday, December 11, 2008 5:07 PM

NEW DELHI Two hours after opening, the pediatric waiting room at All India

Institute of Medical Sciences is like the anteroom to hell. Families,

anxious, restless, sweaty in the soupy air, cram into plastic chairs, crouch

in corners, crowd doorways, clog up aisles. Cries jangle off the ceiling.

Feces litter the floor. Signs in the corridor attempt to impose order on the

chaos:     Don't spit. Don't feed the monkeys. Don't pay bribes.

This overstretched government hospital and medical colleg

e treats about

4-million people a year. It's also one of a growing number of Indian

hospitals that use their patients to gather data on experimental drugs

destined for Western markets. It recently was revealed that 49 children have

died during clinical trials at the institute. Though the hospital blamed the

deaths on underlying illnesses, the news triggered unease about a

drug-testing phenomenon, propelled by mountains of money, that has swept

India with little publicity. As the world flattens, India is not just

answering our tech calls. Global drug companies are tapping its population

of nearly 1.2-billion to test the safety and effectiveness of compounds

that, if approved, will end up in medicine cabinets in the United States.

The upshot: the distance has been compressed between a patient trying a new

diabetes drug in New Delhi and the retiree who will buy that prescription in

St. sburg.

"All the ingredients are there for a huge problem,'' said Dr. Ross, a

former FDA medical officer.

"First of all the data must be applicable to the U.S., where the population

may differ in clinically significant ways," he said. "And the FDA has to

have the capacity to go over and inspect the data. If not, you're asking for

trouble."

In the past three years, the FDA has inspected just eight of the thousands

of trial sites in India.

Poor oversight invites problems in an overseas drug pipeline,=2

0as Americans

learned after deaths from Chinese-made blood thinners this year. In a rare

proactive move, the FDA slammed the door on 30 generic drugs from one of

India's biggest drug makers in September after finding problems at its

factories.

K. Pendergast, a former FDA deputy commissioner, said identifying a

dangerous product is difficult enough. It's considerably trickier to find

fraudulent clinical trial data, which could lead to the approval of

dangerous drugs years later.

"It's much more time-consuming and extraordinarily tedious,'' said

Pendergast, who plowed through such data when she was prosecuting doctors

doing drug studies in the United States. "It's especially hard if the trial

is taking place in a different country."

Particularly when that country has a reputation for cutting corners. In

India, cops execute suspected criminals in so-called "encounters." Laws

against selectively aborting female fetuses are ignored. And those "No

bribes" signs in public hospitals? Bhupali Magare, whose uncle was recently

hospitalized in Mumbai, just shrugged.

"Everybody pays bribes," she said.

In the burgeoning clinical trial business, says Amar Jesani, a doctor and

medical ethicist in Mumbai, every layer of oversight is compromised by cash,

and independent monitoring is nonexistent. He has resigned from supposedly

independent ethics committees that rubber-stamp drug companies' proposals

and overrule any objec

tions.

Said Jesani: "We're sitting on a time bomb that may explode at any time."

.. . .

Drug makers spend hundreds of millions of dollars bringing a promising

compound to the stage where it can be tested on humans - only to be stymied

when subjects in developed countries are slow to sign up.

So the companies have moved offshore in search of subjects, and now nearly

half of all studies are conducted outside the United States. Brazil, Russia

and China have been popular trial locales, but India is moving up fast,

aggressively courting the drug study business.

Its pitch? Thousands of English-speaking doctors and millions of people

suffering everything from exotic diseases to ailments common in the West -

diabetes, cancer, heart disease. With two-thirds of the nation living on

less than $2 a day and health insurance rare, these patients are often

"treatment-naive," presenting a clean slate to pharmaceutical companies. An

added bonus: suing doctors is almost unheard of in India.

Asif Iqbal brought his 61-year-old father from Kolkata (Calcutta) to Mumbai

to be treated for brain cancer. When the doctor said his father might live

longer if he enrolled in a clinical trial, Iqbal signed the forms though

they were in English, a language he does not understand.

"I surrendered to the doctor,'' Iqbal, 30, said through an interpreter, as

he pulled the unintelligible papers from a worn plastic bag. "

I said, 'I am

a lay person, you are god to me.' ''

To accommodate pharmaceutical companies' needs, a cottage industry of site

managers and trial monitors has sprung up so rapidly no one can keep count

of the players. Contract research organizations keep tabs on trials with

regular audits. Site management organizations put an extra set of eyes in

the doctor's office. Both entities dangle promises of FDA-ready studies in

half the time, at 30 to 60 percent the cost in the United States. The

secret? Cheap help and fast patient recruiting.

Quintiles, the world's largest contract research organization, boasts of

enrolling 50 patients with diabetes in one month in India and 204 infants

for a vaccine study in three days, far faster than possible in the States.

In a brochure, Quintiles sums up India's allure: "It's practically a

paradise for conducting clinical trials."

Everybody wants a piece of an industry estimated to top $1-billion by 2010.

But as a gold-rush mentality grips India's booming clinical trial business,

even its proponents are having second thoughts.

Dr. Arun Bhatt is president of Clininvent, a contract research organization

in Mumbai that is running 11 trials involving 1,000 patients. He worries

that Indian doctors ignore patients' reactions to experimental medicines,

missing critical clues about a drug's safety.

"Most sites are not used to recognizing serious adverse events, so they=2

0

are

underreported,'' he said with an attitude of resignation. "Either they don't

recognize, don't realize or are afraid to report this information."

Dr. Nandini Kumar retired in June as deputy director general of the Indian

Council of Medical Research, the equivalent of the U.S. National Institutes

of Health. She now works as a consultant for the agency in New Delhi,

teaching doctors how to run ethical trials. Kumar is stunned by their

ignorance of internationally recognized standards for conducting drug

studies.

Asked what aspect of good clinical practice most surprised her students, the

gray-haired, sari-clad Kumar snapped, "Everything."

"There are efforts to put rules in place, but at the same time there are

people who just want to get the extra dollars or perks like trips abroad

from doing drug trials,'' Kumar said as monsoon rains pounded outside her

cramped office and the power kept winking off. "My work is like a drop in

the ocean."

.. . .

Though demand has far outstripped the country's supply of researchers and

monitors - a shortfall of up to 50,000 trained clinicians according to one

government report - that hasn't slowed the surge.

The number of registered clinical trials being conducted in India has nearly

doubled in the past year, to more than 800 ongoing or completed, according

to www.clinicaltrials.gov.

Thes

e studies are being conducted at massive public hospitals, like the All

India Institute of Medical Studies in Delhi, where doctors take on the extra

work despite a waiting room overrun with patients.

Trials are a lucrative sideline for private oncologists like Dr. Chiraq

Desai, who shares a modern office with five other doctors in the dusty

northwestern city of Ahmedabad. A year ago, Desai made a presentation to

Pfizer executives in New Jersey, touting a patient population in India that

is "willing and compliant." Today he's running 20 trials on 67 subjects.

Dr. S.P. Kalantri has conducted trials for global pharma at the government

hospital in Sevagram, a small town in central India. But he said he has

pulled back from doing the studies.

"It's difficult to explain the complexities of trials to study

participants,'' Kalantri said of the hospital's mostly poor, illiterate

patients. "I think many investigators tend to take their patients for a

ride. And there's an abysmal lack of know-how about clinical research among

investigators."

.. . .

On the ground in India, it is impossible to find anyone running, monitoring

or auditing clinical trials who is not on the payroll of the drug makers.

Doctors are paid according to the number of patients they enroll. Local

ethics boards, set up to ensure patient safety, are often comprised of

colleagues who approve each others' projects and blackball20naysayers.

C.J. Shishoo, former dean of India's oldest pharmacy college, runs an

independent ethics committee in Ahmedabad. He lost the business of two big

clients when he objected to how they were running their studies.

"They just went elsewhere,'' Shishoo said of the drug companies he

alienated. "I'm very much concerned. Life here is a little cheap."

Shishoo was not surprised to hear of the offer made to Afsar Khan, a

motorcycle mechanic in Mumbai. Khan and his uncle were told that a new drug

from America could cure their diabetes, but it would cost them each 100,000

rupees (about $2,000). Unable to pay, the men walked away. A few weeks later

they got a much different offer: Try the drug and we'll pay you 25,000

rupees ($500).

"That made us suspicious, so we backed away,'' said Khan, who makes about

6,000 rupees ($120) a month. Unable to afford Western drugs for his

diabetes, Khan, 46, is now treated by a hakim, a practitioner of traditional

Islamic medicine, at his mosque. "I have blackouts and pain in my knees," he

said. "But I can live with it."

Government regulators on both sides of the globe are supposed to be the

final backstop on the safety of clinical trials. But that hasn't happened in

India. Despite being stung by controversies involving the testing behind

drugs like Vioxx, Avandia and popular antidepressants, the FDA inspects

fewer than 1 percent of all dr

ug trials in the United States. Its record

overseas is even worse.

DiFrancesco, an FDA spokesman, said the agency puts no cap on

the percent of patient data that can be submitted for drug approval from a

single country, despite its inability to keep an eye on the process. The FDA

hopes to open offices in New Delhi and perhaps Mumbai by year-end, he said.

India's top drug regulator, Dr. Surinder Singh, said the FDA is training 24

Indian officials to conduct random audits of trial sites, to begin as soon

as this month. His predecessors made similar promises of imminent

inspections, which went unfulfilled, in 2006 and again in 2007.

Singh, India's drugs controller general, has rolled out the welcome mat for

foreign drug companies, promising to review applications in two to six weeks

and push his ossified operation, as he put it, "from the Stone Age to the

Clone Age."

As proof of his commitment, Singh said recently he will remove restrictions

prohibiting foreign companies from conducting Phase I, or first-in-human,

studies in India. That announcement caused pause even among those who could

profit from the business.

"We are not ready to do Phase I trials of global quality yet,'' said

Clininvent's Bhatt. "They are very risky. We should not rush into them."

Dr. C.M. Gulhati, editor of an Indian medical journal, Monthly Index of

Medical Specialties, said authorities cannot20cope with the tsunami of

trials.

"India's drugs controller general's office is both understaffed and

incompetent,'' he said, citing a case where the agency claimed it reviewed

an 800-page trial protocol in just five days. "How is that even possible?"

Gulhati, who fights unbridled drug testing from a dim and cluttered office

above a busy Delhi shopping plaza, reeled off a litany of troubled trials:

In 2003 in Hyderabad, an unregistered study of a heart attack drug that

resulted in six deaths.

In 2004 in Delhi, a first-in-human trial of a new suturing device on 13

patients without regulators' approval.

Last year, India's decision to become the only nation to allow domestic drug

maker Sun Pharmaceutical Industries to market the anticancer drug Letrozole

for infertility in women despite the drug's originator, Novartis, warning

that it may cause fetal harm and should be used only in postmenopausal

women.

And in October in Bangalore, the death of a baby during the testing of a new

Wyeth vaccine.

"It's a total farce," said Gulhati, who could not think of a single case of

an Indian doctor disciplined for mishandling a trial. "When I complain

people have broken the law, they ask 'What harm have I done?' "

.. . .

One well-known scandal occurred about eight years ago, when a s Hopkins

University researcher injected an untested chemical in 27 patients at a

public=2

0cancer hospital in the southern state of Kerala.

Lawyer Panikangulara represented an illiterate coolie laborer with

throat cancer who unknowingly enrolled in the trial after signing a form in

a language he did not understand. India's court dismissed his claim of a

human rights violation, citing a statute of limitations of one year from the

time of the injection. By the time the court ruled, the patient was dead.

"There was an institutional commitment to protect other institutions at the

expense of the rights of individuals," Panikangulara said. "The question of

human rights violation was never even on the agenda."

Asked whether India today offers a safer environment for clinical drug

studies, the lawyer leaned back and smiled.

"Are you talking about safety for the patient or the corporation?" he asked.

"For the corporation, it's 100 percent safe. For the patient, that is a

matter for study and investigation. It's a sad situation here."

Kris Hundley can be reached at hundleysptimes or (727) 892-2996.

About these stories

Times staff writer Kris Hundley spent three weeks this fall in India on a

World Affairs Journalism Fellowship administered by the International Center

for Journalists. The fellowship is sponsored by the Ethics and Excellence in

Journalism Foundation. Hundley was one of eight journalists from around the

country to be awarded a 2008 World Affairs Fellowship

..

Her proposal to research drug testing in India stemmed from several stories

she wrote on U.S. clinical trials in the St. sburg Times in 2007. For

more information on that series, written with Times staff writer Rob Farley,

see links.tampabay.com.

What they're saying:

Dr. Nandini Kumar, former deputy director general of the Indian Council of

Medical Research in New Delhi: "I am not very confident right now about how

ethically it (a trial) would be conducted."

Dr. Chirag Desai, oncologist in Ahmedabad, who is conducting 20 trials:

"There is pressure from the pharma industry for doing things. Until Indian

regulators, investigators and ethics committees mature, possibly the

patients are vulnerable."

Dr. Vinod K. , head of pediatrics at All India Institute of Medical

Sciences, New Delhi: "There is money-driven research, with private doctors

who receive 100,000 rupees ($2,000) for each patient they get."

Y.K. Sapru, retired executive director of & Ltd. (India),

now chief executive of non-profit Cancer Patients Aid Association: "Despite

all the credos which are written down in pharmaceutical company's worldwide:

'We stick to honesty, we are all for god.' All that is bull----. The manager

who follows that will lose his job ... and his bonus."

Dr. S.P. Kalantri, a public hospital physician in Sevagram, a small village

in central India: "We see 200 patients with snake

bites every year and lose

10 percent of them. We see 300 to 400 pesticide poisonings (attempted

suicides) and we lose 20 percent of them. The drugs and treatments for both

are fairly expensive. But no one seems interested in these problems."

Veena Jaguste, director of development operations in Mumbai for Amgen, which

is conducting nine trials in India with 300 patients: "For a well-managed

study (the data is) as good or in some cases maybe even better (than from

U.S. studies)."

 

http://www.tampabay.com/opinion/essays/article934654.ece

St. sberug Times

OUR DRUGS, THEIR BODIES

By Kris Hundley, Times Staff Writer

Thursday, December 11, 2008 4:53 PM

Reporting a story on drug studies in India recently, I had plenty of

interviews with people at the top. Doctors, government officials,

entrepreneurs who make their living running clinical trials leaned over

polished conference tables in modern, air-conditioned offices in some of

India's biggest cities. They assured me that India is capable of running

world-class studies on new medicines destined for the U.S. market. No

problem.

But finding the people at the bottom rung, those testing the drugs or the

experimental procedures, was more difficult. They are all around you, yet

they are invisible. They are often poor and illiterate. If something goes

wrong in a trial, the

y don't hire a lawyer, they just go home. They

disappear into a haze of patient confidentiality.

Under international guidelines for clinical trials of new drugs and

treatments, there are rules to protect these patients. Consent forms,

oversight committees, ethics reviews. The people at the top in India

reassured me those protections were rock-solid. But the people at the

bottom, when I finally found them, said otherwise.

Here are a few of their stories:

Asif Iqbal: CLUELESS ABOUT CRITICAL TREATMENT

When Asif Iqbal's father was diagnosed with brain cancer in July, the two

men immediately left their village outside Kolkata (Calcutta) and headed to

Mumbai. They found free lodging at an ashram, a community run by

orange-robed monks. They found hope at the government's Tata Memorial

Hospital.

Iqbal, the eldest son, was told his 61-year-old father had limited options,

so the family quickly agreed to what the doctor described as an experimental

treatment.

Earnest, intense, worn with worry, the 30-year-old son said the new

treatment involved brain surgery followed by chemotherapy and radiation.

Though his father now lay weak in a hospital bed, the doctor promised his

life would be prolonged.

"They said without it, he would have maximum three months to survive,'' the

son said.

But the consent forms Iqbal signed on his father's behalf were in English, a

language he neither spe

aks nor reads. "If they had been in Bengali, I could

have followed them," he said through an interpreter, almost apologetically.

Sitting in the garden at the monk's ashram at sunset, Iqbal pulled the

consent forms from a tattered shopping bag. They indicate that the trial had

nothing to do with chemo or radiation. It simply tracked the infection rate

in patients whose heads were not shaved before brain surgery.

Told this, the son looked puzzled, then resigned.

"The doctor told me shaving heads was the old process, that not shaving is

the latest,'' he said as the sunlight faded. "I just told the doctor, 'Do

what is good. You are god to me.' "

Ramsakhi Devi: HER CANCER ULTIMATUM: ENROLL OR GO HOME

At the monk's ashram in Mumbai, Ramsakhi Devi sat on the bottom bunk of a

metal frame bed, cocooned in a sea-green sari. Her thin arms were wrapped

around her legs, a feeding tube taped to her nose. Occasionally her fingers

swept the dark swell of her left cheek, feeling again where the cancerous

tumor once was. She watched warily, lips tightening with pain, as her son,

Bablu Gupta, explained how they ended up here, a 48-hour train ride from

their home in West Bengal.

The doctors at the government cancer hospital had removed his mother's tumor

then given her an option: sign up for a clinical trial or go home. Devi, a

55-year-old widow who can neither read nor write,20put her thumbprint on the

consent form, which was in English and Hindi. Her youngest son, suddenly in

charge at age 21, signed on her behalf. Anxious to see his mother cured, he

said he understood the terms of the trial. But he did not.

The form says there were three treatment options. Gupta was aware of just

one.

The form says patients have the right to drop out of the trial at any time.

Gupta said his mother was told she had to complete the grueling month-long

cycle of chemo and radiation if she wanted to be "fully cured."

But the treatment left his mother weak, nauseated and more dependent on

Gupta than ever. The young man, who has tended his mother during eight

months in Mumbai, tried to be hopeful.

"She's better than before," Gupta said as his mother pulled her sari over

her face and turned away. Dropping his voice, he added, "If you say

something about the treatment, the doctors become unhappy."

Kamlesh Solanki: HE'S TESTED ALL KINDS OF PILLS FOR A PRICE

The crowded slums of Ahmedabad in northwest India are prime recruiting

ground for the area's generic drug makers, who need healthy subjects for

Phase I, or first-in-human testing of new drugs. Among those who have

responded to the call is Kamlesh Solanki.

A member of India's Dalit, or untouchables, caste, Solanki has volunteered

for about nine Phase I trials of new generic drugs since 2001. No

w 24, he's

consumed pills for everything from heart problems to acid reflux in studies

that involved X-rays, frequent blood tests and overnight stays. The most

complicated trial paid 7,500 rupees ($150), a godsend in an area where

farmers earn about 50 rupees ($1) a day.

He said he never suffered side effects but knew others who did. "They assure

you that after the test you will be very much okay.''

Solanki, who lives with his father and two brothers in a room the size of a

single-car garage, said he was treated well at the testing centers. "There

is total AC, TV, videos, and a thick cushion on the bed,'' said Solanki, who

sleeps under a fan on a thin mat at home. "The food is excellent."

He was once so gung-ho about the studies that he became a recruiter, getting

100 to 200 rupees ($2-$4) for each enrollee. But Solanki turned sour on the

business two years ago. As masses of desperate people compete for trial

slots, pay has dropped dramatically, he said, to as little as 3,000 to 4,000

rupees ($60-$80). Now working as a lathe operator in a factory, making about

4,000 rupees a month, Solanki has a growing unease about his past as a lab

rat.

In late 2002, an unemployed laborer from south of Ahmedabad died after being

involved in the Phase I testing of a generic antidepressant. The drugmaker,

Sun Pharmaceutical Industries Ltd., denied the death was related to the

testi

ng. But the incident made young men like Solanki think twice about the

deflated price tag being put on their lives.

"I know they pay more for such trials in the U.S.," said Solanki, who never

told his family about the trials. "Do they think we are worth less?"

Maheshbhai Macwana:  "We give our bodies to them''

In Dholka, a village in northwest India, three men sat in a lawyer's office

recounting their experiences with Phase I trials. Maheshbhai Macwana, 42,

was the veteran, having enrolled in a half-dozen studies.

Macwana, who now has a temporary government job, said financial desperation

drives the trial business. "We live here on a dribble a day," he said as a

donkey brayed in the village square and power looms clattered in the nearby

homes of Muslim weavers. "The companies are taking advantage of our economic

condition. We give our bodies to them."

He needs, but cannot afford, medications for liver and stomach problems. All

he can do is sell his body to test drugs he does not need.

As he ages, he's started worrying about the long-range effect of

participating in multiple tests. But when his 17-year-old son recently got

hit by a car and broke his leg, Macwana had little choice: go into debt or

enroll in a trial. Embarrassed by his poverty, he wonders if anyone in the

wider world cares.

"Are there any international regulations for conducting trials? How d

o we

find out about such things?"

Patient protections Under international guidelines:

.. Trial subjects must be given a consent form in a language they understand,

fully explaining the experimental nature of the trial and all possible side

effects.

.. Patients can drop out of a trial at any time.

.. Volunteers in Phase I or first-in-human trials are usually paid enough to

compensate them for their time, but not enough to be an incentive. Subjects

in later trial phases sometimes receive a token amount of money for time and

travel and generally get the trial drug for free.

.. The consent form should clarify who is responsible for paying for any

injuries sustained as a result of the trials.

Source: FDA, CenterWatch

Kris Hundley traveled to India on a World Affairs Journalism Fellowship

administered by the International Center for Journalists. The fellowship is

sponsored by the Ethics and Excellence in Journalism Foundation. Kris can be

reached at hundleysptimes or (727) 892-2996.

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