Secret reports seen by The Independent reveal that drug trials funded by western pharmaceutical firms at the Indian hospital set up for survivors of the Bhopal disaster violated international ethical standards and could have put patients at risk.
Some 14 patients died during the three trials examined by the reports. In one trial, for an antibiotic, five out of seven patients died during the trial or soon after it finished. While there is no suggestion that every death merits compensation, critics say there has been no adequate investigation into whether compensation was appropriate in any of the cases. None has ever been paid.
At least eight other trials were carried out on hundreds of Bhopal gas victims. The Independent has evidence of patients who were unaware that they were taking part in a trial at all. The conduct of the trials has exposed the hospital to furious criticism from activists who say that survivors have been used as guinea pigs without proper informed consent.
The reports on the three trials at the Bhopal Memorial Hospital and Research Centre (BMHRC) – carried out on behalf of Theravance, Sanofi, and Wyeth, which is now a part of Pfizer – shine a spotlight on serious ethical violations which experts say are endemic in India. BMHRC is the country’s only hospital dedicated to treating the surviving half a million people affected by the deadly gas leak which campaigners say killed 25,000 in December 1984. The hospital made more than 10m rupees (£140,000) from British, US and French drug companies for carrying out the trials for treatments that have since been approved for use in Europe and the US.
The Bhopal trials were first exposed by the leak of a memorandum sent by the hospital trustees – several of whom also served on the ethics committee that would have approved the studies – ordering “all current and proposed trials to be immediately stopped”.
The public outcry in Bhopal at the memo triggered three inspections by the Indian drug regulator, which found numerous failings in the trials. The secret inspection reports seen by The Independent criticised the hospital’s ethics committee for failing to protect patients by approving trials without proper consideration of potential safety hazards.
None of the 14 deaths in the three inspected trials were independently investigated and several were not reported to authorities within legally imposed time limits. Not a penny was given to patients to compensate them for travel expenses, inconvenience or loss of income. The inspectors failed to talk to any of the patients or families to check whether proper informed consent had been obtained.
The reports also show that doctors doubled up as trial facilitators, making it harder for their patients to say no.
A subsequent state government inquiry, widely criticised by local media, found no evidence of wrongdoing after speaking to three patients who came forward in response to newspaper adverts. The hospital admits that the majority of gas victims it treats are illiterate.
The controversial decision by the hospital trustees and drug regulator to sanction the hospital as a site for clinical trials highlights serious concerns about what critics see as inadequate protection for patients in a country growing more popular with drug companies.
More than 1,500 drug trials involving 150,000 patients have started across India since 2009. The Independent yesterday revealed that at least 1,730 patients died between 2007 and 2010. Many of these patients were seriously ill and could have died regardless of the trial. But campaigners argue that often no proper inquiry takes place – and when compensation is paid, it is unduly low.
Moreover, in the Bhopal case, medical experts have questioned the scientific value of testing drugs on gas victims when the long-term affects of exposure to Methyl Isocyanate (MIC) are poorly understood. The drug companies unanimously defended this decision and said it was up to doctors to assess if patients were medically suitable to participate.
Several of the Bhopal trials were outsourced to contract research organisations (CROs), Indian and multinational, which get regulatory and ethics approval, recruit patients and oversee the trial at arms-length from the drugs companies.
Drug companies often put the blame for negligence on CROs, making it near-impossible for poor people to hold Western companies to account when violations are exposed, according to the Dutch NGOs Somo and Wemos.
But Rachna Dhingra, head of the International Campaign for Justice for Bhopal, insisted that the drugs companies should bear responsibility, called the conduct of the trials “disgusting and appalling” and demanding legal action against the firms involved. “The people of Bhopal have been doubly victimised by the unethical trials,” she said.
The three inspections known to have been carried out by the Drugs Controller General of India (DCGI) should make uncomfortable reading for an industry which insists that ethical and scientific standards are uniform across the world.
One study named “Attain”, sponsored by Theravance and run by the CRO Quintiles, compared two antibiotics to treat hospital-acquired pneumonia – a potentially life-threatening condition. Three patients died during the trial, two others soon after. Again, it is not possible to determine whether the deaths were the result of participation. The hospital made a profit of 623,820 rupees after study costs are accounted for.
Serious shortfalls were found with the ethics committee, medical records, quality assurance protocols and training procedures. Information about some of the deaths was inadequate; the study was not reviewed by the ethics committee despite the fact that the death rate was unusually high. After the inspection, warning letters were sent out to both companies. What action was taken, if any, is unknown.
Theravance reiterated that it had “hired a CRO to manage the study in compliance with applicable laws, rules and regulations at multiple study sites in India, including BMHRC”.
In another of the three trials, an antibiotic study carried out by Quintiles on behalf of Wyeth, now a part of Pfizer, 32 out of 34 patients were gas victims. Participants in the “Tiger” trial suffered five “serious adverse events” and three deaths. The deaths were classed as “unrelated” to the investigational drug without independent or laboratory tests, and were not eligible for compensation. BMHRC made a profit of 1,936,158 rupees.
Pfizer insists it conducted only two trials there; the hospital says it received money for four. Pfizer said the studies were “conducted by doctors at the hospital” and were carried out “with the informed consent of the study participants and with oversight by the hospital’s ethics committee. The standards were no different than for trials conducted in the US, the EU, or elsewhere in the world.” Compensation is always approved by principal investigators, ethics committee and regulator, the company added.
The Oasis-6 cardiac trial, in which six Bhopal patients died, highlights the problem of assigning responsibility. GSK purchased the test drug, fondaparinux, from the French company Sanofi-Synthelabo (now Sanofi-Aventis), in 2004 when the trial had already started in India. Under its contract, GSK say Sanofi remained responsible for the conduct of the study, while it was responsible for evaluating the data. A CRO was employed in India; the study co-ordinator was in Canada.
Sanofi refused to answer detailed questions but said: “Sanofi’s clinical trials are conducted ethically and are in line with Good Clinical Practice guidelines, and are conducted under the supervision of the institutional ethics committee.”
GSK said: “We conduct our clinical trials to the same high standards irrespective of where they are held. With regards to [the Oasis 6] study, GSK was not the sponsor … The study would have been run in strict accordance to a protocol.”
The Oasis 6 inspection concluded that the deaths were reported to the ethics committee, but again this did not trigger a necessary review. Yet the committee chair at that time, retired professor of cardiology Dr Ramesh Bhargava, told The Independent that “there were no adverse effects or deaths” reported.
Committee meeting minutes seen by The Independent show that discussions about potential trials were superficial and brief. In one meeting, three trials were approved and one rejected. One committee member, Kusum Arendekar, told The Independent that decisions about clinical trials were left up to medical staff because “they knew best”.
The workings of such committees are another area of difficulty. There are only two accredited institutional ethics committees in India. Most are like the one in BMHRC, recruited by the hospital management, working without a standard operating procedure and little insight into how patients should be protected, says Dr Amar Jesani, the editor of the Indian Journal of Medical Ethics.
The principle investigator in the Oasis 6 trial, Dr Skand Trivedi, is also head of cardiology. He is married to the secretary of the ethics committee, Dr Prabha Desikan, who plays a key role in approving trials. Dr Desikan was a sub-investigator in at least one trial she approved. “A family member on the IRB is a serious conflict of interest,” said Dr Jesani. “A person on the IRB should have no part of the trial. These are bare minimums.”
The Independent spoke to patients from a cardiology study known as PLATO, on behalf of AstraZeneca. The patients said that they were never told that they had participated in the trial. One participant, a 53-year-old woman who wished to remain anonymous, said: “I thank God that nothing happened to me and I don’t want any trouble with the hospital, so I would rather just try and forget it.”
AstraZeneca said: “We have strict processes in place to monitor all of our clinical studies on an ongoing basis to ensure patients have been properly consented. Through this, it was discovered that some patients at BMHRC were not properly consented during the PLATO trial. These errors were promptly corrected by the investigator.”
Quintiles, the world’s biggest CRO, actively recruited patients at BMHRC in four studies and conducted preliminary work in three others. It said in a statement that “clinical staff visited the sites on a regular basis to ensure the studies were conducted as dictated by the protocol and in accordance with international and national ethical guidelines.”
BMHRC and its doctors who conducted the trials refused to answer any questions from The Independent.
Case study: ‘Of course I’m angry. I didn’t even know what a clinical trial was until it was already over’
Ramadhar Shrivastave, 64, a former electrician, first knew he had participated in the Plato clinical trial, sponsored by the British company AstraZeneca, when a local journalist presented him with documents in June 2010.
Mr Shrivastave has suffered from vision and digestive problems since the Bhopal gas disaster in 1984, but first registered with BMHRC in November 2007 after a heart attack. He was admitted to ICU and treated with an angioplasty – a technique used to mechanically unblock arteries – before being discharged. He was given two bottles of unlabelled pills by a doctor he hadn’t met before, and asked to sign a form which was written in English, and which he didn’t understand.
For about two years, Mr Shrivastave and his wife Kamlesh said, the same doctor rang every month to remind him to collect his pills; each time he signed a form which contained the names and signatures of 10 to 15 other people. He was never given any verbal or written details about the trial. Despite his poor health, Mr Shrivastave took a bus to BMHRC every month because a rickshaw cost 100 rupees (£1.25) each way, which was unaffordable; he received no money towards transport costs.
“Suddenly, one day, Madam Doctor told me that the course of medication was finished and I didn’t need to come back,” he said. “Instead I could collect my other medication from a nearby BMHRC satellite unit. I didn’t even know what a clinical trial was until my son explained to me after all this came out.”
The hospital refused Mr Shrivastave’s request to see his medical notes but The Independent has seen a copy of his discharge summary, which confirms his participation in the Plato trial. The family still fear he could be reliant on the hospital again. “If he becomes ill, then we would have no choice but to go back; we cannot pay for hospital treatments,” Mrs Shrivastave said.
The trial drug, Ticagrelor, was approved in Europe in December 2010 for the treatment of heart attacks and unstable angina.
“Of course I’m angry. I’ve been angry ever since I found out,” Mr Shrivastave said. “But what can I do? We are poor people. If I had money I would have filed a case against them straight away, but we don’t have money. If I’d known it was a drug trial I never would have agreed. How can I ever trust them again? These people should do trials on their own families, not poor people like me. God has saved me twice: first I survived the gas disaster and now this.”
Case study 2: ‘The doctors said that they always did trials for new drugs, and there was nothing to worry about’
Sanjay Munshi, 35, has lived near the Union Carbide factory all his life, and suffers from chronic respiratory and eye problems. He was recruited onto a trial sponsored by US company, Progenics, on his first admission to BMHRC in 2007 for bowel surgery. He was suffering from chronic constipation as a result of a rectal prolapse.
The night before his surgery, two doctors talked to him about a drug trial and gave him 10 pages in Hindi to read. “I didn’t understand a lot of it,” he said. “I got scared, but the doctors said there was no need to worry, that they always did trials for new drugs, and there was nothing to worry about. But I was scared, I have young children, what if something goes wrong, what would my family do?”
The junior doctors tried to reassure him. “They said ‘what do you know about your surgeon? You don’t know much about him but he is good. You don’t have to know about the medicine, it is good.’ Everything was arranged so I was worried that if I said no, I would ruin their plans and maybe my operation wouldn’t be done properly, so I didn’t say no.”
He was so afraid that he ‘stole’ the consent form and gave it to his younger brother who had come to visit. “I told him to take the paper, so that if something goes wrong, you will know what happened. When the doctor came to ask for the form I pretended the nurse had taken it, so they gave me another one which I signed. I didn’t know what the new drug was for, what the side effects might be; they just told me it would be fine.”
Progenics says it has a letter approving the trial but information provided by BMHRC to the Indian Parliament does not mention it. The CRO Progenics contracted to conduct the trial, subcontracted out at least part of the work to another CRO in Mumbai, including ethics approval by its own commercial committee. Yet Progenics admit that “It is a standard industry practice to work with a central IRB [ethics committee] when conducting a clinical trial.”
A spokeswoman added: “The CRO acting on Progenics’ behalf monitored the study site throughout the trial as required by its contract, and conducted an audit of the trial activities.”
The drug, Methylnaltrexone, was approved by the European Medicines Authority in July 2008 to treat constipation caused by opiate medications, such as morphine. The BMHRC trial was part of a separate study but the drug was found to be ineffective in treating post-surgery bowel complications.
Mr Munshi was never told about any of that. He stayed in hospital for around 10 days after the surgery and was given an injection of the drug every day. “After I was discharged I came back for blood tests, but nobody ever mentioned the drug trial again, I’ve no idea what happened to that drug. I am angry, and I am shocked that the hospital or doctors made money, but I am happy that God saved me.”