LiveMint & Wall Street Journal
Clinical trials: Regulating chaos
The first in a two-part series examining the opaque world of clinical trials in India
First Published: Wed, Oct 10 2012.
A hospital in Indore has been able to get away with unethical medical trials in which 32 people have died over five years, according to the state government. This despite several investigations, a state government ban and Supreme Court strictures—a classic example of the lawless nature of the clinical trial business in India.
Lata Mehra, who works in a government-run healthcare centre, was desperate when doctors told her in 2009 that she would be on medication for the rest of her life after a heart attack. The monthly medical bill, a little less than half her salary of Rs.1,000 per month, would leave her with enough to just cover food and rent.
Then, Anil Bharani, a professor of medicine at the state-run Maharaja Yashwantrao Hospital in Indore, offered the 47-year-old a dream deal that he called a “company plan”. The Rs.1,300 a month plan would pay for the drugs and also reimburse Mehra for transportation.
What Mehra did not know was that the “company plan” was part of an unauthorized drug trial of anticoagulants. Nor was she aware that Bharani and some of his colleagues were already being investigated by the state government over allegations of misconduct in clinical trials, an investigation that eventually led to the banning of the trial by the Madhya Pradesh government in October 2010.
Regardless, Bharani continued the trials despite the ban, and Mehra unknowingly became a test case for the drugs.
The ban was imposed after it was uncovered that informed consent was not taken, and the patients subjected to clinical trials included newborns, children, pregnant women and mentally challenged persons.
The state followed up with more action, and in January barred Bharani and another doctor from conducting trials, and pulled up 12 other doctors at Maharaja Yashwantrao Hospital and 78 other private doctors for refusing to cooperate in the investigation.
That too hasn’t stopped the trials.Bharani and officials at the hospital declined comment.
The Indore case highlights glaring gaps in regulation and enforcement in India’s rapidly growing clinical trial industry. A 2011 Associated Chambers of Commerce and Industry of India report put the value of the business at Rs.8,000 crore, or $1.8 billion.
On Monday, the Supreme Court turned the spotlight on the business of clinical trials, when it threatened to impose a blanket ban on clinical trials across the country if the Union government didn’t act. The court has given the Union health ministry a month to provide the apex court with information on deaths, compensation and general practices when new drugs are tested on Indians.
“We can even issue a one-line direction that all these clinical trials which affect many people must stop forthwith,” justices R.M. Lodha and A.R. Dave said, hearing public interest cases dealing with the incidents at the Indore hospital.
The court’s order has once again drawn attention to India’s inadequate regime to regulate such trials. Not all clinical trials run in India violate norms, yet, Mehra’s experience exposes the gaps in both regulation and enforcement in clinical trials, which, in some instances, have caused deaths, in addition to violating fundamental human rights.
Mehra was more than happy with the “company plan” until her neighbour Mangilal Shreevas died suddenly, in early 2012.
“He was also a heart patient covered under the same ‘company plan’ at the same hospital and under the same doctor,” said the healthcare worker. “We took the same pills and we went to the hospital together for check-ups. After Mangilal’s death, his wife wanted his medical case sheets to lodge a complaint, but the hospital refused. I was disturbed by this and wanted a different doctor to have a look at my case sheet.”
The rest of her story is similar to that of several such participants in unauthorized clinical trials who express reservations. The doctors refused to hand over the medical file, saying it was “hospital property” and took Mehra off the “plan”. The reimbursements were discontinued.
Meanwhile, in January this year, the state government gave two doctors, Bharani and Ashish Patel, a rap on the knuckles, telling them to refrain from conducting clinical trials for six months; it also fined 12 doctors Rs.5,000 each for not cooperating with investigators.
The fines have not yet been paid, and despite the ban, the trials continue, according to petitioners Swasthya Adhikar Manch, an activist group and Dr Anand Rai, a whistle-blower who filed two separate public interest litigations (PILs) in February 2012 bringing the subject to the court’s attention.
So far, 32 people enrolled in various trials at Maharaja Yashwantrao Hospital have died between 2005 and 2010; the state government has attributed the deaths directly to the testing.
Bharani and Maharaja Yashwantrao Hospital are the targets of both a central probe by a parliamentary committee looking into irregularities in clinical trials across the country, as well as a state level investigation of ethical violations in 94 clinical trials conducted at the hospital.
Mounting evidence prompted the Supreme Court to step in. Hearing the PILs on the Indore trials, the same two-judge bench of the Supreme Court came down hard on the government and said on 17 July: “There has to be some sense of responsibility (on the part of the government). Human beings are being treated as guinea pigs. This is unfortunate.”
Meanwhile, the ethical committees that were supposed to have overseen the trials continue to function, said Amulya Nidhi, an Indore-based public health activist belonging to the Swasthya Adhikar Manch.
Complaints made to the Human Rights Commission—both state and national—are yet to yield results. In 2011, the joint director of health, Indore division, constituted a four-member committee that recommended the state impose a lifetime medical practice ban on each guilty doctor at Maharaja Yashwantrao Hospital and cancel registrations. That has had no impact.
As disturbing as the trials is the government’s apparent inability to do anything to regulate them.
In June 2011, the Madhya Pradesh economic offences wing (EOW) submitted a report on clinical trials at Maharaja Yashwantrao Hospital that established a conflict of interest, pointing out that pharmaceutical companies had sent principal investigators in several trials on “foreign trips and money was received (by doctors)”. Mint has reviewed a copy of the report.
The same month, a joint director in the state government submitted a second report advising the state government to initiate criminal proceedings against doctors for ignoring protocol.
The EOW report stated that 81 “serious adverse events” were reported in various clinical trials at Maharaja Yashwantrao Hospital.
Besides these cases, 1,833 children from the Chacha Nehru Bal Chikitsalaya (the paediatric hospital affiliated with MGM Medical College) and 233 mentally ill patients had been enrolled in clinical trials without any consent, according to documents submitted to the Supreme Court.
“As per government rules, guardians of mentally ill patients and children have to give an informed consent before they can enrol in trials,” said Nidhi of Swasthya Adhikar Manch, referring to the report.
In total, 12 doctors were named in the two reports. The EOW investigation listed Bharani (medicine), Salil Bhargava (superintendent), Ashoka Vajpayee (former superintendent), Pushpa Verma (dean), Hemant Jain (paediatrician) and Apoorv Puranik (neurologist), recommending that the Medical Council of India (MCI) initiate disciplinary action against them under Indian Council of Medical Research rules. Except for Verma, who maintained she was not involved in the drug trial controversy, none of the doctors were available for comment.
The “disciplinary measures”, including the Rs.5,000 fine, have to be compared with the Rs.5 crore that doctors earned for the trials, according to Swasthya Adhikar Manch’s PIL. Mint couldn’t independently verify this figure.
All but one of the doctors continue to practice medicine. Verma was promoted to the office of dean in January.
Over the past two years, victims and activists claim to have registered complaints at various forums, including the Central Vigilance Commission, EOW, the state police, the National Human Rights Commission, the medical education department, MCI, the Enforcement Directorate and the Central Drug Standard Control Organization. None of them seem to have had much effect.
Sarat Pandit, the joint director who submitted the 2011 report that recommends criminal proceedings against the doctors involved, blamed the delays on red tape and the involvement of too many government departments.
“Our mandate was to investigate the goings-on in Maharaja Yashwantrao Hospital and we did just that. Several irregularities in protocol and ethics were clearly established and we recommended action,” said Pandit. “The report is now lying with the government and it is up to them to act on it. The matter has now become sub judice. While several agencies are investigating the case, nothing is being done for the safety of people exposed to these doctors.”
There have been attempts to rally support for the victims. In January, Communist Party of India (Marxist) leader Brinda Karat sent a memorandum to then drug controller general of India, V.G.
Somani, seeking action against the doctors.
“Families are upset and angry, and there is a clear groundswell. It is outrageous that Indians are being used as guinea pigs,” Karat said.
Mint has seen a copy of the letter.
The Madhya Pradesh state assembly has seen about 40 questions being asked in the past two years about trials, according to whistle-blower Rai.
“When RTI (Right to Information) replies were vague, we approached local politicians to raise the issue in the state assembly,” added Rai, who worked at Maharaja Yashwantrao Hospital and first exposed the trials. “Most of the information I have was collected by this route.”
The Union government has been trying to pursue the issue without much success.
“What happened in Indore was truly horrendous,” said Keshav Desiraju, additional secretary in the health ministry, who has been trying to get more information from the state government. “They have not responded to my queries.”
The parliamentary committee, which recently exposed the alleged nexus involving the drug regulator’s office, pharmaceutical companies and doctors, is to visit Indore to investigate the matter. Its report is expected to be tabled in the winter session of Parliament.
According to the health ministry, more than 1,500 people have died in clinical trials since 2008, a figure that’s contested by public health activists. According to documents presented in the Rajya Sabha, 2,163 people have died in India due to clinical trials since 2007.
“In Indore alone, trial subjects have died as recently as February, and this does not reflect in the government investigations. The whole subject is technical, and even when deaths occur during the trial, it is very difficult to attribute it directly to the drug tested. Several committees have pointed out that doctors do not maintain proper records of severe drug events,” added Nidhi of Swasthya Adhikar Manch.
No one has been compensated yet.
And what about those like Mehra, who participated in the clinical trial to obtain critical medication and then chose to be the whistle-blower?
“This is the cost of speaking up against doctors,” she said. “They have taken me off the company plan.”
This is the first in a two-part series on clinical trials.
The dark underbelly of India’s clinical trials business
Incidents at Bhopal and Indore highlight irregularities and ethical violations in some trials
Malia Politzer | Vidya Krishnan
Updated: Thu, Oct 11 2012.
New Delhi: In 2004, doctors at the Bhopal Memorial Hospital and Research Centre (BMHRC), established exclusively for treating the victims of the 1984 gas leak, recruited unsuspecting survivors for clinical trials without their knowledge or consent; 14 participants died during the course of the trials.
Together with the episode in Indore’s Maharaja Yashwantrao Hospital (that Mint reported on 10 October), where 32 people have died in clinical trials between 2005 and 2010, this incident highlights irregularities and ethical violations in some trials conducted by clinical research firms and pharma companies—the dark underbelly of the booming clinical trial business in India.
In 2005, India introduced patent protection laws. Since then, it has become a global hub for clinical trials, drawing companies because of its ethnically diverse pool of potential test subjects, while bringing down research and development (R&D) costs by nearly 60% in phase II and III trials, according to lobby group Confederation of Indian Industry.
A phase II trial establishes the protocol for testing and a phase III one is the final testing prior to approval.
Regulatory failures have marred the clinical trial business in India, experts said, pointing to lapses in the functioning of so-called ethical committees that are required by law for each trial, contract research organizations (CROs) and the Central Drug Standard Control Organization (CDSCO).
A parliamentary panel in May found CDSCO to be in collusion with drug companies and doctors, and approving at least one drug every month without conducting clinical trials or seeking expert medical opinion. Concerns over the conduct of clinical trials prompted the same panel to look into the rapidly growing industry, and the international and domestic pharmaceutical companies sponsoring them.
“Many issues have been raised in Parliament—people being treated as guinea pigs, lack of informed consent and unattributed deaths during trials,” said Sanjay Jaiswal, a Lok Sabha member and a physician himself. “We are not against clinical trials. The issue is about how these trials are being done. Rules need to be followed.”
A report on this will be presented to Parliament in the winter session, he said.
Medical ethicists are concerned that the rapid growth— without trained manpower or a clear-cut regulatory framework —could be a “race to the bottom”, with global ramifications and not just confined to one country.
“What the media doesn’t get straight is that drug companies aren’t using poor Indians as guinea pigs for Americans,” said Arthur Caplan, a bioethicist at the New York University Langone Medical Center. “The more common thing is that say Vietnam competes with India to see if the companies will come and bring in their studies, bring in the doctors, bring some relief if the drug or vaccine works—maybe spend some money in these places, give a bribe or two to the local health ministry to recruit in the local mental hospital. So, if India tightens regulation, companies will just go to Vietnam. This is not just an India problem—it’s a global issue.”
A globalized market
International boundaries blurred substantially when the US food and drug administration (FDA) relaxed regulations allowing drug companies to submit results of foreign trials in applications for new drugs to be marketed in the US.
Between 1990 and 2008, the number of clinical trials conducted largely by US companies shot up about 24 times to 6,465 from 271, according to a 2011 article in Vanity Fair. The 20 largest US-based drug makers conduct about one-third of their phase III clinical trials outside the country, and a majority of their study sites also are elsewhere, according to American Medical News.
A large genetic pool, high-quality hospitals, English-speaking staff and low costs make India an attractive destination for pharma firms looking to conduct clinical trials.
According to CDSCO, there are an estimated 150,000 people enrolled in clinical trials in India. According to a 2011 Associated Chambers of Commerce and Industry of India (Assocham) report, nearly 100 domestic and multinational pharmaceutical companies are conducting trials in the country and the business is worth Rs.8,000 crore.
Trials in countries such as India are cheaper to run: According to a 2008 Harvard Business Review article, tracking Indian test subjects costs between $1,500 and $2,000, (Rs.79,500 and Rs.1.06 lakh today), while in the US, it would cost $20,000.
When clinical trials are conducted ethically, India’s poor also stand to gain. With only 20% of India’s 1.2 billion people covered by health insurance and 35% living below the poverty line, the bulk of the population pays from the pocket for healthcare, according to health industry data provided by Assocham.
“A lot of patients don’t have access to healthcare otherwise,” said Irene Schipper, a researcher at the Netherlands-based Centre for Research on Multinational Corporations (SOMO). “But the problem, of course, is that when the clinical trial is over, they don’t have access anymore.”
Many clinical trials aren’t conducted ethically.
Schipper is concerned that tight regulatory policies in the US and the European Union (EU) appear to be driving high-risk trials to developing countries such as India, where rules or their enforcement may be lax. In 2008, SOMO released a report, Ethics for drug testing in low and middle-income countries, cataloguing a trend of offshoring risky clinical trials to developing countries that would be prohibited by ethics committees in the EU.
In one case, AstraZaneca Plc sponsored large, multi-centred placebo-controlled trials for Seroquel XR, an anti-psychotic drug for the treatment of patients with schizophrenia. The drug was tested against a placebo, which meant that roughly half the participants—all diagnosed schizophrenics—went without any treatment for the duration of the trial.
Due to the worsening of their conditions, 8.3% of the patients receiving the placebo required hospitalization. After 173 days of placebo treatment, one 25-year-old man committed suicide. “The consequences of this practice are serious,” Schipper said in the report. “According to the Declaration of Helsinki, this type of trial can never justify the use of a placebo because it involves withholding treatment from seriously ill patients risking irreversible harm.
Nevertheless, the Dutch Medicines Evaluation Board approved Seroquel XR for the EU market.”
The multi-centre trials were conducted in India, Bulgaria, Poland, Russia and the Ukraine. While companies also continue to conduct such clinical trials elsewhere, “these days you’re seeing a lot more of these sorts of trials in India”, she said.
“At AstraZeneca, we take very seriously our responsibility towards the patients participating in our studies and our responsibility to deliver consistently high standards of ethical practice and scientific conduct in all our trials wherever they take place,” Andrew Higgins, a spokesperson for AstraZeneca, said in a statement.
“A placebo treatment does not imply a deficient standard of care. In accordance with the Good Clinical Practice rules, all patients in our clinical trials are provided with the same amount of care and are strictly monitored with the option to switch to another therapy or to be discontinued from the study where it becomes necessary,” he said.
Central to the growth of off-shoring clinical trials is the role of CROs—independent companies hired by sponsors to undertake clinical trials. Nearly 90% of trials in India are conducted by CROs, favoured by sponsors for their ability to form partnerships with local research organizations, recruit large numbers of participants and quickly conduct trials.
But medical ethicists worry this comes with a dark side. “To put it in a somewhat less polite way, the big company outsources the responsibility to the CRO. If something goes wrong, they say the CRO is completely responsible for this,” bioethicist Caplan said.
In 2011, CDSCO suspended the licence of Hyderabad-based CRO Axis Clinicals Ltd for recruiting illiterate women for a trial without obtaining proper consent. Following the incident, DCGI ordered an investigation into the operation of all 10 CROs in Andhra Pradesh.
Axis failed to respond to Mint’s repeated requests for comment.
“The problem with outsourcing to CROs is that oversight can be problematic,” said Schipper. Many CROs will divide tasks, such as administration, recruitment and research among various other CROs, making monitoring the process difficult for sponsors who are often based overseas, she said. “In our research, we’ve interviewed sponsors who have stopped using CROs entirely because they found that the cost of effectively monitoring them was greater than the money saved by hiring them.”
Caplan further worries that market incentives can drive CROs to complete trials at any cost. “There’s a conflict of interest when you hire a CRO, to act as a scientific and an ethical committee in India,” he said. “The sponsor wants the data—and wants it fast, and every day a study goes past its predicted date of completion, because they don’t have subjects enrolled, costs millions and millions of dollars—perhaps then they don’t continue to pay as much attention to informed consent or eligibility criteria.”
No functional regulatory system
Axis is not the first CRO in India to be facing hard questions: Quintiles, one of the largest global companies in the segment and based out of North Carolina, received a polite warning letter from DCGI for the clinical trials on Bhopal gas victims. “It should be noted that the studies conducted at BMHRC were approved by the Institutional Ethics Committee that was completely aware of the medical status of the patients visiting the hospital and participating in these trials,” Quintiles wrote in response to Mint’s inquiries.
Doctors, activists and researchers note that Indian ethics committees are often flawed. “Ethics committees are the front line regulators for clinical trials. If they were functional, they would be a major factor in preventing unethical trials,” said Amar Jasani, a researcher and trainer in the field of bioethics and public health. “The problem is the ethics committees are completely controlled by the institutions—they are not at all independent, the people on the committees are not trained, nor do they have the resources or independence to do their job.”
According to Jasani, Indian law allows for commercial ethics committees to be hired by the very CROs they are meant to monitor. “There’s a double conflict-of-interest,” he said. “They are governed by the CROs or the pharma companies. At the same time they are profit making—so they are more motivated by financial interest than (the safety of participants).”
While international standards governing clinical trials do exist, most are voluntary and lack regulatory teeth. The Delcaration of Helsinki, of which India is a signatory, says that potential research subjects need to be informed of the risks involved prior to participation, and reserve the right to refuse to participate.
Foreign drug authorities, such as FDA, have also made efforts to curtail unethical trials, by requiring that drug companies abide by certain guidelines. But their reach is limited. A 2010 report by the US Government Accountability Office found that FDA inspects fewer than 1% of clinical trials abroad, and that in many cases, it isn’t aware where clinical trials are being conducted until drug companies submit applications to market the new drug.
“There is no registry or international database—so I don’t think anyone knows what percentage of clinical trials are happening in the developing world. How many participants are men or women, old or young is also hard to know,” said Caplan. “We don’t have good information about what is really going on there, until there is a scandal, a problem or a death—but the overall picture is tough to know, because no one is responsible for monitoring it.”
The impact, though, is widespread: Nearly 80% of drug applications to FDA for marketing approval include tests done on foreign soil. With an FDA stamp of approval, many of the drugs end up being sold all over the world. “Seeing this as Americans exploiting Indians is not accurate,” said Caplan. “Drug companies are equally happy to sell to wealthy Indians. Drugs tested in these trials are eventually sold everywhere—studies in poor nations affect everyone.”
This is the concluding part of a two-part series on clinical trials in India.