The Latest Industry being Outsourced to India: Clinical Drug Trials
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 college 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. Petersburg.
"All the ingredients are there for a huge problem,'' said Dr. David 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, as 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.
Mary 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 objections.
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 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.
These 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 blackball naysayers.
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 drug trials in the United States. Its record overseas is even worse.
Christopher 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 cannot cope 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 Johns Hopkins University researcher injected an untested chemical in 27 patients at a public cancer hospital in the southern state of Kerala.
Lawyer Vincent 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."
Deaths raise questions in Indian hospital
Rahul Verma suspected he was opening a can of worms when he filed a request under India's new Right to Information Act.
Verma, whose critically ill son has been treated at All India Institute of Medical Sciences here, had heard parents complain that their children were not admitted because the hospital's beds were filled with patients in clinical trials.
So last summer Verma asked the government hospital's pediatric department these questions:
How many clinical trials have they conducted since January 2006?
How many children were involved in these trials?
How many patients died during these trials?
In the United States, a person who asked these questions of hospitals, drug companies or the FDA would get nowhere, blocked by claims of patient and corporate confidentiality. But amazingly, within a month Verma had his answers from the Delhi hospital, known as AIIMS.
Since the beginning of 2006, the pediatric department had conducted 42 trials, involving 4,142 children. Number of deaths: 49.
The news, splashed in headlines proclaiming "49 babies die,'' set off a firestorm. Though hospital officials documented that the deaths were due to underlying illnesses, even fellow researchers wondered why an overburdened public hospital, which handles about 500 pediatric outpatients a day, was taking on the extra work of clinical trials.
"Their primary objective should be to do patient care,'' said Dr. Urmila Thatte, head of clinical pharmacology at a public teaching hospital in Mumbai. "Clinical trials should not supersede that."
Dr. Vinod K. Paul, the hospital's head of pediatrics, dismissed claims that patient care had been slighted and was indignant at what he described as an attack on "the AIIMS' temple of learning and innovation." In an interview about a month after the controversy erupted, Paul itemized the causes of the 49 deaths while an assistant served tea and cookies.
A study that tried over-the-counter mouthwash to prevent sepsis in seriously ill children on ventilators accounted for 22 deaths; 21 deaths occurred in a World Health Organization-sponsored study of the potential benefit of low-cost zinc tablets for children with severe sepsis.
"Zinc tablets never kill,'' said Paul, pulling a bottle of the pills from a desk drawer and popping one in his mouth. "They keep me happy."
Serious diseases, not AIIMS' experimental therapies, killed the children, Paul said repeatedly, with the exasperation of a teacher with a slow child. Only five trials were sponsored by multinational drug companies and no one died during those trials, he said.
"I get requests from pharmaceutical companies (to do trials) every two or three weeks,'' said Paul, who said he usually rejects such offers. "We have no interest in being a colonial research entity. No way."
Outside the doors of Paul's spotless, air-conditioned office, about 4-million patients a year, among them the nation's poorest, clamor for care from AIIMS' doctors. They lie two per bed in the pediatric outpatient ward and pack a tiny emergency room off the hospital's main entrance. When an ambulance from a private hospital raced up and unloaded a critically ill newborn whose parents had run out of money, Paul's colleagues had no choice but to find space.
Verma, the father who paid 10 rupees (about 20 cents) to file his public records request, said that with space at such a premium, a government hospital shouldn't be spending time and resources on drug studies. He also said it's not clear how many of these studies involved poor, illiterate patients, whose parents who might not fully understand the nature of the trials.
Paul argues just the opposite, saying that the poverty of his patients only adds to the importance of AIIMS' research work. "Twenty-two percent of the people here make less than $1 a day," he said.
"So if I write a prescription that costs $1 a day, for that time they don't eat. If my department cannot do research, what are we here for?"
India's poor often test drugs bound for U.S. markets
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, they 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:
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 speaks 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.' "
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, put 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."
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. Now 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 testing. 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?"
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 do we find out about such things?"
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