Incidents at Bhopal and Indore highlight irregularities and ethical violations in some trials
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.
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 ₹ 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, ( ₹ 79,500 and ₹ 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."