Regulation failing to keep up with India's trials boom

Abstract

Ethical violations in clinical trials in India have exposed gaping holes in the country's regulatory system, which has struggled to oversee the booming industry. Amy Yee reports from New Delhi.Just 5 years ago, clinical trials in India were seen as one of the most promising sectors of the country's fast-growing pharmaceuticals industry. Analysts touted several favourable conditions: costs that were 40–60% cheaper than trials in the USA; a large pool of patients from a diverse population; and high-quality hospitals with English-speaking doctors who could oversee trials. As a result, the number of trials in India rapidly increased. In 2003, there were 40–50 clinical trials in India. In contrast, 1852 trials were registered on the government website Clinical Trial Registry India (CTRI) as of June, 2011. Across the country there are an estimated 150 000 people participating in clinical trials.However, a spate of alleged ethical violations at hospitals in the poor, landlocked state of Madhya Pradesh have created controversy over clinical trials in India and tarnished a once-bright sector. Some experts say that the trials industry overheated and outgrew controls for careful monitoring, training, and regulation.In a high-profile case of ethical violations, health activists in Indore, the commercial hub of Madhya Pradesh, last year filed formal complaints with the state and national human rights commissions, and the government regulator, the Drug Controller General of India (DCGI). As a result of the complaints, the state's Economic Offences division investigated practices at Maharaja Yeshwant Rao public hospital in Indore where 73 clinical trials were undertaken in 3300 patients, including 1833 children. A total of 81 patients, including 18 children, had serious adverse effects and even death, though there was no official conclusion that those cases were directly linked to the trials.The probe contends that volunteers did not give informed consent because the fine details of the trials were in English, among other shortcomings. Activists alleged that doctors undertaking many trials were also members of supposedly independent ethics committees. Patients were also not offered insurance or compensation in case of serious adverse effects.In a separate inquiry in Madhya Pradesh, the state fined 12 government doctors US$100 each (Rs 5000) for improper procedures in other trials. Activists are irate over these small penalties, especially compared to large sums drug makers pay doctors to cover costs of trials. For example, six doctors at Maharaja Yeshwant Rao Hospital received about $1·02 million (Rs 5·1 crore) from drug makers to undertake the 73 trials in question.Anand Rai, a medical officer with the Madhya Pradesh Government and the main whistleblower in Indore, and the Human Rights Law Network, a non-governmental organisation in Delhi, plan to file public interest litigation this month with India's Supreme Court. The small penalties “actually reinforce allegations that it's a cover up”, claims Colin Gonsalves, founder of Human Rights Law Network. “What India really needs is an investigation into the flow of money from the pharma companies to the CROs [clinical research outsourcing companies] to the doctors.”Rai said: “Doctors have deliberately violated all regulations and have reduced clinical trials to a money-spinning exercise.”After another review, a state government committee banned all new trials in Madhya Pradesh in October, 2010. The ban is still in place, though a state committee recently recommended lifting it. The state's health department last March submitted recommendations to the regulator DCGI. They called for state as well as national approval of any trials; giving state health officials rights to audit and monitor records; and requiring doctors to report serious adverse effects within 24 hours.Nata Menabde, WHO Representative to India, acknowledged that there are “significant concerns” that vulnerable populations were exploited and that informed consent processes were not adequately followed in Madhya Pradesh. Monitoring of trials must be strengthened in India along with training investigators—the doctors who run clinical trials—she added.How did the state of clinical trials in India change so quickly? The boom in clinical trials happened after a change in Indian patent laws in 2005 created rapid growth that the industry and government was unprepared to handle. Many multinational drug makers fled India in the 1980s when the country would not grant patents on pharmaceutical products. But since 2005, a stricter Indian patent regime, enacted as part of World Trade Organization negotiations, strengthened the interest of multinational drug companies in clinical trials. The number of clinical trials in India rose sharply after 2005.Trials have become a lucrative business for clinical research outsourcing (CROs) companies—the third parties that do trials on behalf of drug makers. The CRO industry generated $485 million in revenue in 2010–11 and has been growing about 12% each year, according to consultancy Frost & Sullivan. The number of CROs grew from a handful before 2005 to more than 150 today. The top 20 CROs earn more than 70% of the industry's revenues. However, there is no government registry for CROs in India.Promise of a booming clinical trials market led more companies to join the fray, even those with only expertise in the much simpler process of making generic drugs. Even companies with no pharmaceuticals background, such as large Indian conglomerates known for infrastructure or oil, formed joint ventures or launched clinical research businesses.Qualified investigators were also stretched thin and doctors were overloaded with well-paid trials. Investigators in private hospitals get paid recruitment fees of between $1500 and $3000 per patient to run trials, said a 2009 report from the Centre for Studies in Ethics and Rights in Mumbai. Doctors also often receive other benefits such as paid trips abroad to attend conferences. Such financial incentives can tempt doctors to cut corners.A 2011 letter in the Indian Journal of Medical Research from CTRI noted that many doctors are involved in multiple trials; a particular one was involved in as many as 25 clinical trials. “There is a need to be concerned about the workload on PI [principal investigators]—the number of trials an investigator is able to handle to do justice with the research”, said the letter.Vasudeo Ginde, president and managing director of DiagnoSearch Life Sciences, an Indian CRO established in 1996, estimated that India had 100–150 investigators in 2004. After the surge of new trials after 2005 “there weren't enough. Investigators were stretched thin”, said Ginde. Now he thinks there are 800–900 investigators.Some in the industry say that the India staff of CROs jumped from job to job as drug makers and other CROs offered handsome salaries. Global drug companies also “in-sourced”, or borrowed employees from experienced Indian CROs, which set off a wave of attrition. A revolving door at CROs meant many lacked expertise and were not equipped to consistently monitor investigators.However, India still has strong potential to meet demand for clinical trials, said Rajiv Rana, medical director of Merck Serono India. He noted that there are more than 700 000 medical professionals in India and more than 600 sites compliant with the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use. The Indian Government and drug industry have together “taken a number of major steps to strengthen the infrastructure for conducting clinical trials”, added Rana.In Madhya Pradesh, whistleblower Rai has filed 100 inquiries about trials in the state under India's Right to Information Act (RTI). He received 20 responses. Only government hospitals, not private ones, must respond to RTI inquiries. Documents obtained from RTI showed a wide range of both Indian and foreign companies involved with clinical trials in Madhya Pradesh. The list of eight domestic and 22 international companies include Cipla, Cadilla, and Himalaya as well as Pfizer, Merck, Novartis, Eli Lilly, GlaxoSmithKline (GSK), Boehringer Ingelheim, and Johnson & Johnson, among many others. Drug companies have done trials for strokes, heart and lung diseases, epilepsy, depression, schizophrenia, and other ailments. Across India, treatments for cancer and diabetes drugs dominate clinical trials, according to Frost & Sullivan.Pfizer and Eli Lilly did not offer comment on clinical trials in India after receiving an email inquiry. A spokesperson for GSK said: “The pharmaceutical industry is—rightly—highly regulated…We conduct all of our clinical trials to the same high scientific and ethical standards irrespective of where in the world they are held.”Indian Government regulators are trying to implement rules to strengthen ethical processes. The CTRI was set up in 2007 and registration of trials became mandatory in 2009. To add transparency, WHO in 2007 added the registry to its own global database.Meanwhile, steps to reform trials are underway. CTRI has raised concerns about strengthening ethics committees and for investigators and committee members to declare conflicts of interest.Menabde of WHO said the agency is supporting the Indian Government's efforts to strengthen investigators, regulators, registration, and procedures of informed consent. However, some are sceptical about how much the short-staffed Indian regulator can do. The 2009 report from the Centre for Studies in Ethics and Rights said: “With a staff of less than a dozen people, the DCGI apparently is unable to do more than rubberstamp the paperwork, leaving no time for the business of regulation.”Ajay Kumar Sharma, Frost & Sullivan's head of pharmaceutical and health care for South Asia said, “There are a lot of rules on paper. Rules are followed but also broken. The real problem is implementation and accountability. No one is accountable.” Ethical violations in clinical trials in India have exposed gaping holes in the country's regulatory system, which has struggled to oversee the booming industry. Amy Yee reports from New Delhi. Just 5 years ago, clinical trials in India were seen as one of the most promising sectors of the country's fast-growing pharmaceuticals industry. Analysts touted several favourable conditions: costs that were 40–60% cheaper than trials in the USA; a large pool of patients from a diverse population; and high-quality hospitals with English-speaking doctors who could oversee trials. As a result, the number of trials in India rapidly increased. In 2003, there were 40–50 clinical trials in India. In contrast, 1852 trials were registered on the government website Clinical Trial Registry India (CTRI) as of June, 2011. Across the country there are an estimated 150 000 people participating in clinical trials. However, a spate of alleged ethical violations at hospitals in the poor, landlocked state of Madhya Pradesh have created controversy over clinical trials in India and tarnished a once-bright sector. Some experts say that the trials industry overheated and outgrew controls for careful monitoring, training, and regulation. In a high-profile case of ethical violations, health activists in Indore, the commercial hub of Madhya Pradesh, last year filed formal complaints with the state and national human rights commissions, and the government regulator, the Drug Controller General of India (DCGI). As a result of the complaints, the state's Economic Offences division investigated practices at Maharaja Yeshwant Rao public hospital in Indore where 73 clinical trials were undertaken in 3300 patients, including 1833 children. A total of 81 patients, including 18 children, had serious adverse effects and even death, though there was no official conclusion that those cases were directly linked to the trials. The probe contends that volunteers did not give informed consent because the fine details of the trials were in English, among other shortcomings. Activists alleged that doctors undertaking many trials were also members of supposedly independent ethics committees. Patients were also not offered insurance or compensation in case of serious adverse effects. In a separate inquiry in Madhya Pradesh, the state fined 12 government doctors US$100 each (Rs 5000) for improper procedures in other trials. Activists are irate over these small penalties, especially compared to large sums drug makers pay doctors to cover costs of trials. For example, six doctors at Maharaja Yeshwant Rao Hospital received about $1·02 million (Rs 5·1 crore) from drug makers to undertake the 73 trials in question. Anand Rai, a medical officer with the Madhya Pradesh Government and the main whistleblower in Indore, and the Human Rights Law Network, a non-governmental organisation in Delhi, plan to file public interest litigation this month with India's Supreme Court. The small penalties “actually reinforce allegations that it's a cover up”, claims Colin Gonsalves, founder of Human Rights Law Network. “What India really needs is an investigation into the flow of money from the pharma companies to the CROs [clinical research outsourcing companies] to the doctors.” Rai said: “Doctors have deliberately violated all regulations and have reduced clinical trials to a money-spinning exercise.” After another review, a state government committee banned all new trials in Madhya Pradesh in October, 2010. The ban is still in place, though a state committee recently recommended lifting it. The state's health department last March submitted recommendations to the regulator DCGI. They called for state as well as national approval of any trials; giving state health officials rights to audit and monitor records; and requiring doctors to report serious adverse effects within 24 hours. Nata Menabde, WHO Representative to India, acknowledged that there are “significant concerns” that vulnerable populations were exploited and that informed consent processes were not adequately followed in Madhya Pradesh. Monitoring of trials must be strengthened in India along with training investigators—the doctors who run clinical trials—she added. How did the state of clinical trials in India change so quickly? The boom in clinical trials happened after a change in Indian patent laws in 2005 created rapid growth that the industry and government was unprepared to handle. Many multinational drug makers fled India in the 1980s when the country would not grant patents on pharmaceutical products. But since 2005, a stricter Indian patent regime, enacted as part of World Trade Organization negotiations, strengthened the interest of multinational drug companies in clinical trials. The number of clinical trials in India rose sharply after 2005. Trials have become a lucrative business for clinical research outsourcing (CROs) companies—the third parties that do trials on behalf of drug makers. The CRO industry generated $485 million in revenue in 2010–11 and has been growing about 12% each year, according to consultancy Frost & Sullivan. The number of CROs grew from a handful before 2005 to more than 150 today. The top 20 CROs earn more than 70% of the industry's revenues. However, there is no government registry for CROs in India. Promise of a booming clinical trials market led more companies to join the fray, even those with only expertise in the much simpler process of making generic drugs. Even companies with no pharmaceuticals background, such as large Indian conglomerates known for infrastructure or oil, formed joint ventures or launched clinical research businesses. Qualified investigators were also stretched thin and doctors were overloaded with well-paid trials. Investigators in private hospitals get paid recruitment fees of between $1500 and $3000 per patient to run trials, said a 2009 report from the Centre for Studies in Ethics and Rights in Mumbai. Doctors also often receive other benefits such as paid trips abroad to attend conferences. Such financial incentives can tempt doctors to cut corners. A 2011 letter in the Indian Journal of Medical Research from CTRI noted that many doctors are involved in multiple trials; a particular one was involved in as many as 25 clinical trials. “There is a need to be concerned about the workload on PI [principal investigators]—the number of trials an investigator is able to handle to do justice with the research”, said the letter. Vasudeo Ginde, president and managing director of DiagnoSearch Life Sciences, an Indian CRO established in 1996, estimated that India had 100–150 investigators in 2004. After the surge of new trials after 2005 “there weren't enough. Investigators were stretched thin”, said Ginde. Now he thinks there are 800–900 investigators. Some in the industry say that the India staff of CROs jumped from job to job as drug makers and other CROs offered handsome salaries. Global drug companies also “in-sourced”, or borrowed employees from experienced Indian CROs, which set off a wave of attrition. A revolving door at CROs meant many lacked expertise and were not equipped to consistently monitor investigators. However, India still has strong potential to meet demand for clinical trials, said Rajiv Rana, medical director of Merck Serono India. He noted that there are more than 700 000 medical professionals in India and more than 600 sites compliant with the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use. The Indian Government and drug industry have together “taken a number of major steps to strengthen the infrastructure for conducting clinical trials”, added Rana. In Madhya Pradesh, whistleblower Rai has filed 100 inquiries about trials in the state under India's Right to Information Act (RTI). He received 20 responses. Only government hospitals, not private ones, must respond to RTI inquiries. Documents obtained from RTI showed a wide range of both Indian and foreign companies involved with clinical trials in Madhya Pradesh. The list of eight domestic and 22 international companies include Cipla, Cadilla, and Himalaya as well as Pfizer, Merck, Novartis, Eli Lilly, GlaxoSmithKline (GSK), Boehringer Ingelheim, and Johnson & Johnson, among many others. Drug companies have done trials for strokes, heart and lung diseases, epilepsy, depression, schizophrenia, and other ailments. Across India, treatments for cancer and diabetes drugs dominate clinical trials, according to Frost & Sullivan. Pfizer and Eli Lilly did not offer comment on clinical trials in India after receiving an email inquiry. A spokesperson for GSK said: “The pharmaceutical industry is—rightly—highly regulated…We conduct all of our clinical trials to the same high scientific and ethical standards irrespective of where in the world they are held.” Indian Government regulators are trying to implement rules to strengthen ethical processes. The CTRI was set up in 2007 and registration of trials became mandatory in 2009. To add transparency, WHO in 2007 added the registry to its own global database. Meanwhile, steps to reform trials are underway. CTRI has raised concerns about strengthening ethics committees and for investigators and committee members to declare conflicts of interest. Menabde of WHO said the agency is supporting the Indian Government's efforts to strengthen investigators, regulators, registration, and procedures of informed consent. However, some are sceptical about how much the short-staffed Indian regulator can do. The 2009 report from the Centre for Studies in Ethics and Rights said: “With a staff of less than a dozen people, the DCGI apparently is unable to do more than rubberstamp the paperwork, leaving no time for the business of regulation.” Ajay Kumar Sharma, Frost & Sullivan's head of pharmaceutical and health care for South Asia said, “There are a lot of rules on paper. Rules are followed but also broken. The real problem is implementation and accountability. No one is accountable.”