Australia linked to fatal flaws in Indian drug trials
What killed Azghar Khan?
Azghar Khan, 40, an Indian bricklayer, died suddenly in 2008. Two years later his family discovered he was part of a drug trial sponsored by the Australian government, that he and they knew nothing of.
Half an hour before his father died, Irshaad Khan was handed a sheaf of papers at the hospital bedside and told he needed to sign them. The documents were written in English, a language he did not speak, let alone read or write, but he was assured the doctor was doing all he could to save his father.
''I didn't know what they said,'' Khan says, ''but I thought these were documents we needed for his care and I wanted to save my father's life, so I signed.''
Khan's father, Azghar, was 40 years old in 2008 and in good health, after a suspected stroke three years earlier. He was working six days a week as a bricklayer when he was admitted to hospital one night with a fever.
Devastated ... Irshaad Khan signed documents thinking he was helping his family. Photo: Ben Doherty
''In the morning they told us he would be OK, but by lunchtime he was [even] more sick. At 2.30pm I was asked to sign the papers; at 3pm he died.''
Khan never found out what the papers were for, nor did he see them again. His family buried his father and dealt with the pain and upheaval of their sudden, inexplicable loss.
''Our family was devastated. This tragedy happened so suddenly. Financially, we were ruined. He was the sole breadwinner for a family of nine people. The three eldest sons, we stopped our studies and had to take jobs to support the family - that burden fell to us.''
Azghar Khan ... died in Maharaja Yeshwantrao Hospital in Indore.
Khan was forced to become a bricklayer like his father.
It was not until two years later, alerted by a whistleblower doctor, that Azghar Khan's family discovered he had been part of a drug trial, sponsored and paid for by the Australian government, at the government-run Maharaja Yeshwantrao Hospital. The illegal drug trial was run by a now-suspended doctor, Anil Bharani.
The trial, known as the VITATOPS (Vitamins to Prevent Stroke) study, was to examine the impact of B vitamins on stroke victims. It was run on thousands of subjects over several years in hospitals across the world. But in India, the trial is one of dozens at the centre of a growing controversy, because, it is alleged, patients were not told.
''It pains us that illiterate people and the children of India are being used as guinea pigs by the multinational drug companies … uncontrolled clinical trials are creating havoc in the country,'' India's Supreme Court said this month, hearing a petition from patients' rights groups and doctors.
Thousands of pages of evidence presented to the court show that poor and illiterate Indians are being signed up to clinical drug trials they do not know about or understand, and doctors are being paid handsome commissions by pharmaceutical companies to enlist as many patients as possible.
Of 39 patients in Bharani's VITATOPS study at Maharaja Yeshwantrao Hospital in Indore, four died and two experienced a ''serious adverse event''. There is no evidence that the drug trial contributed to Azghar Khan's, or any other patient's, death. The mortality rate among Bharani's patients was unexceptional for the trial, and the global trial found the drugs safe, though they did not reduce the incidence of stroke. But Indian law mandates ''post-mortem findings'' for any patient who dies during a drug trial. This was not done for Azghar Khan or others who died during the trial.
And in other trials, run by the same doctor in the same hospital, it is known that the drugs being tested killed people.
Chandrakala Bai was a dalit - the modern word for ''untouchable'', the bottom of the Hindu caste system - who went to Maharaja Yeshwantrao Hospital suffering chest pains. Typically, a low-caste Indian could expect to spend hours at the back of a queue before being seen. Instead, she was taken immediately to a private room in the hospital and given, she was told, expensive new medicines free, paid for by a special government program for families living below the poverty line.
What she was not told was that she was being enrolled in a drugs trial for tonapofylline, a heart medication being tested by the global biotech company Biogen Idec. Her relatives say she could not read or write, and was not asked to sign consent forms.
Bai developed heart arrhythmia a few days after being given the drug. She was taken off the trial and discharged from hospital a few days later. Less than a month later, she suffered a cardiac arrest and died, aged 45. Biogen's trial of Tonapofylline was later halted because of the number of recorded seizures experienced by patients.
The company says Bai's death was not formally reported to it, but a Maharaja Yeshwantrao Hospital committee has conceded her death was caused by the drug trial. Her family has received no compensation.
In the same state, other doctors are allegedly enlisting children, even infants, in drug trials without their parents' knowledge. The National Commission for Protection of Child Rights is investigating allegations from Indore man Jitendra Sargaiya that his 11-day-old daughter, Tanisha, was enrolled in a drug trial at a government children's hospital without his knowledge or consent.
He says after a trial vaccine was tested on his daughter, she was in intensive care for a month and her growth since has been affected. ''We came to know about the trial only when the matter was raised in the [Madhya Pradesh legislative] assembly [more than four years later] and our name figured on a list of victims and subjects of a drug trial,'' Sargaiya says. Sanction is rare, and scarcely a deterrent. A dozen Madhya Pradesh doctors uncovered conducting secret trials on children and patients with learning disabilities last year were fined less than $100.
Irshaad Khan says his father did not know he was part of a drug trial, and never would have assented. He says his father suffered, not necessarily because of the VITATOPS study, but because his doctors were more concerned with running the trial than treating his illness.
He worries, too, about what other medications his father might have been given. ''If it wasn't for that trial, my father would be sitting with us in this room. We went for treatment, but we were cheated. They were not concerned with his health, they just gave him these [trial] drugs and said he was being treated. They didn't try to help him. They did not have permission for that. Now he is dead.''
Over the past eight years, India has emerged as a huge, and profitable, market for clinical drug trials. In 2005, the government amended intellectual property legislation to recognise product patents, and streamlined the clinical trials process. Multinational pharmaceutical companies responded by coming to India in massive numbers, running trials directly, or more commonly through clinical research organisations, which further subcontracted the research to local hospitals.
Precise figures are hard to know, but health organisations estimate anywhere between 350,000 and 2 million Indians have been involved. For years, the trials ran without notice. But, slowly, a picture emerged of a system out of control, of patients being exploited and harmed, doctors being paid off and test results being manipulated.
Since 2005, 2644 Indians have died during clinical trials, according to an affidavit from the government's deputy drug controller general. Eighty deaths have been confirmed as having been caused by the drug being trialled, but patients' rights campaigners say few deaths are properly investigated and that the real figure is almost certainly significantly higher. Only 39 families have been compensated, in some cases as little as $1000.
In another 11,972 cases, patients suffered ''serious adverse events'' during drug trials.
The drug trials are dominated by the largest names in the pharmaceutical business: 2011 figures from the drugs controller general show, in that year alone, deaths during clinical trials conducted by, or on behalf of, Novartis, Quintiles, Pfizer, Bayer, Bristol Mayer Squibb, and MSD Pharmaceutical.
A growing list of government inquiries and reports has not checked the industry. The Madhya Pradesh government found that the ethics committees that sign off on trials are, often, the same doctors being paid by drug companies to conduct the trials.
Documents released to patients' rights campaigners under right to information laws show doctors being paid massive commissions, illegally, directly into personal bank accounts, to sign patients up to trials.
And in the national capital, Delhi, a parliamentary standing committee reported ''a collusive nexus between drug manufacturers, some functionaries of the CDSCO [Central Drugs Standard Control Organisation, the government regulator], and some medical experts''.
Essentially, drug companies are paying doctors to approve drugs, the report says, in many cases even providing them the language with which to do it. ''Is it sheer coincidence that doctors, sitting miles away from each other, gave opinions on a drug which is word-by-word identical?'' the report asks.
''There is adequate documentary evidence to come to the conclusion that many opinions were actually written by the invisible hands of drug manufacturers and experts merely obliged by putting their signatures.''
Growing disquiet at the trials came to a thundering crescendo this month when the country's Supreme Court excoriated the central government's drug controller general for the ''deep slumber'' it had fallen into, knowing, but allowing, trials to run unregulated. ''You have to protect the health of the citizens of the country. It is your obligation. Deaths must be arrested and illegal trials must be stayed.''
Dr Kritish Bopanna - president of the Indian Society for Clinical Research, which counts industry giants Bayer, Pfizer and Boehringer among its members - rejects criticism of the pharmaceutical industry. He tells Fairfax Media government torpor in devising proper regulations for the industry has been sending companies to other countries.
''Clinical research is going through tough times in this country, not because of the careless attitude of clinical researchers, but because of the careless attitude of the health ministry,'' he says. ''Government delays in approving trials are stopping innovation in this country.''
Bopanna said clinical trials were being conducted ethically and transparently in India ''with people giving informed consent''. He said the ''very occasional, one in 100, one in 1000'' incident could not be used to characterise the whole industry.
''Clinical trials are important for this country, the development of new medicines is helpful for India, and these major companies are assisting India by coming here. It is very negligent of government agencies not to pay attention to this matter.''
Indore, a Hindu-belt city of a couple of million in the central Indian province in Madhya Pradesh, is at the epicentre of India's clinical drug trial controversy. And the Maharaja Yeshwantrao Hospital is at the heart of this city's scandal.
In seven years, 73 trials have been conducted at the hospital, involving 3300 patients, 1833 of whom were children. Eighty severe adverse events have been recorded.
The patients who come to the hospital are typically poor, rural Indians. They cannot afford healthcare anywhere else. Many are illiterate or semi-literate, and almost none of them read and write English.
''They do not question what they are given, or told,'' says Dr Anand Rai, the physician who first blew the whistle on the Indore trials. ''Because in Indian culture doctor is god. People could never believe that the doctor they trust does not care about their health, only about making money from these trials.''
Rai was sacked as a senior resident of ophthalmology at the hospital when he first raised concerns half a decade ago about the number of drug trials being conducted and the way patients were being recruited. (A court later ordered he be reinstated.)
Patients, he says, would be told they were part of a ''government study'' that would provide them medicines free of charge. They were even given money to pay for travel to hospital, an unimagined perk in India's straitened public health system.
''They choose only poor, illiterate people who do not understand what is a drug trial. And they don't monitor the results properly, so drugs are being approved without proper testing. The results are flawed.''
The convener of patients' rights group Swasthya Adhikar Manch, Amulya Nidhi, said doctors on government salaries at Maharaja Yeshwantrao Hospital were paid comparatively massive amounts to run trials.
''The salary of one of these doctors is 75,000 rupees a month [$1300]. But they can get paid up to 80,000 rupees to sign up one subject to a trial. So the pull is very strong to put many patients on trials. This is a business of crores [tens of millions], the multinationals are the most powerful companies in the world.'' Nidhi's organisation has evidence of more than 200 clinical trials conducted on patients with no, or incomplete, permission.
The Madhya Pradesh government's Economic Offences Wing publicly outed six government-salaried doctors for receiving improper payments from drug companies. Five were from Maharaja Yeshwantrao Hospital.
Heading the list was Azghar Khan's doctor, Anil Bharani, who, the report said, ran 15 separate clinical trials involving 400 patients between 2006 and 2010. Thirty patients, the report said, suffered ''death and sickness due to trial''. None were compensated.
Bharani was paid 15.8 million rupees. The nearly $2 million VITATOPS trial was run by the University of Western Australia and sponsored by the Australian government's National Health and Medical Research Council; $75,000 of Australian money was sent to India to conduct trials across the country. Bharani was paid $50 for every patient he recruited.
A spokesman for the University of Western Australia says that ''all … doctors were instructed as to how subjects were to be recruited'', and that, according to the co-ordinating Indian hospital, ''all of Dr Bharani's patients received the translated Hindi version of the consent form''.
The NHMRC tells Fairfax all researchers involved in Australian trials are required to adhere to Australian standards, whether the research takes place here or overseas.
Bharani was suspended from conducting trials and has since been transferred from Maharaja Yeshwantrao Hospital. But he tells Fairfax all his trials were approved by authorities and the hospital, all patients voluntarily agreed to them and no one was harmed.
''All the clinical trials … were conducted following all the existing rules and regulations and with full attention to principles of good clinical practice,'' Bharani says. ''The patients in clinical trials received the best care because an earmarked, well-qualified team of investigators looked after them as per the protocol.''
Bharani says all of his trials were approved by government authorities and the hospital, and that all patients voluntarily agreed to the trials.
Similarly, the chairman of the ethics committee at Maharaja Yeshwantrao Hospital, Professor K.D. Bhargava, says his investigations found no evidence of wrongdoing. ''I have not found any unethical behaviour or any impropriety on the part of any of the principal investigators [doctors running trials] who got their protocols sanctioned by us,'' he says.
Irshaad Khan does not believe either of them. He says his father trusted the hospital, and Bharani, with his life. Instead his vulnerability, and his illness, was preyed upon for money.
Five years after Azghar Khan died, his family are running out of hope for compensation - ''It's not about money,'' Irshaad Khan says, ''but we want the youngest boy to be able to go to school. It was our father's wish that his children be educated'' - or even an apology. ''But we don't want other families to go through this. We were cheated. We trusted the doctors and they lied to us.''