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 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."
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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."
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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."
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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?' "
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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."
Kris Hundley can be reached at firstname.lastname@example.org or (727) 892-2996.