IN recent months there have been a spate of reports that raise concerns about the conduct of clinical trials on human subjects in India. These ranged from reports of a number of deaths in trial subjects in the All India Institute of Medical Sciences in 2008, to the gross ethical violations alleged in trials of a vaccine to prevent cervical cancer among adolescent girls in Andhra Pradesh and Gujarat in 2010. There have also been reports of growing number of deaths in trial subjects that led, in one instance, to the Drug Controller General of India stepping in to stop the concerned trial in Bangalore. What is disturbing about all these reports is the absolute lack of transparency regarding how these trials are being conducted. The government, when forced by media reports to make a statement, has chosen to maintain this veil of secrecy to the extent possible.
These reports, raising misgivings about the way clinical trials are being conducted in India, coincide with a very rapid expansion of the number of clinical trials conducted in the country. The flood gates opened in 2005 when India changed the rules regulating clinical trials in the country. To understand how this happened we need to understand the process involved while conducting clinical trials.
CLINICAL TRIALS AND ETHICS
When new drugs are researched, they need to be tested on human subjects before they are given a marketing approval by drug regulatory agencies. Before a new drug is tested on human subjects, they have to be tested on animals to establish the safety and efficacy of the drug. However, this is not enough to establish the safety and efficacy of the drug in humans. The final step involves testing the drugs among human subjects. These tests are carried out in four phases. In the first phase of human trials, the drug is tested on a small number of human subjects to show that the drug is indeed safe for human consumption. Generally phase I trials are conducted on healthy subjects and the intent is to establish the safety of the drug. Phase II and III are conducted on subjects who have a condition that may benefit from the use of the drug, and thus these trials are designed to establish that the drug is effective in treating a particular disease. Phase IV trials are also called post-marketing surveillance and are designed to collect data from an even larger sample of patients, after the drug is introduced.
Because clinical trials are essentially experiments that are conducted on human beings, all countries have rules that regulate how these trials should be conducted. Globally, the Helsinki declaration, sets the benchmark of how such rules should be framed. All rules related to drug trials are concerned with the ethics of how trials are conducted. The first, and perhaps the most important aspect of these rules, are those related to “informed consent”. Because trials are an experiment they carry a potential risk. So it needs to be ensured that those who participate in clinical trials should be aware of the risks and should formally consent to be part of the trial after the risks are explained in details. The concept of informed consent is also premised on the assumption that trial subjects consent to be a clinical trial subject without being coerced, directly or as a consequence of the circumstances in which the person might find himself. The second fundamental concern about ethics in clinical trials is that trials should be allowed in a population who would later benefit from the introduction of the drug that is tested. In other words clinical trials should not be permitted where trial subjects in a particular country or community are used as mere guinea pigs.
There are several other critical issues that determine whether a trial is ethical. In recent years, a major concern has related to “placebo” controlled trials. A placebo is a substance that has no significant effect on a human subject – it could be a capsule containing a small amount of salt or sugar, for example. In placebo controlled trials, some trial subjects are given the placebo while others are given the drug that is being studied. Through this route researchers can decide if the drug is a better alternative to no treatment. However placebo trials are unethical if a treatment already exists for the disease for which the new drug is being tested, for it means that those who are given the placebo are being denied treatment, even though a treatment for the disease exists. The Helsinki declaration clearly states that in general placebo trials should be avoided if treatment already exists. However there is no unanimity on this among researchers. Laws in the US, for example, have different standards for placebo controlled trials depending on whether the trials are being conducted in the US or being conducted in a third country.
CHANGE IN LAW OPENS FLOOD-GATES
Before 2005, the Indian law was designed to actively discourage the use of Indians as mere subjects for experimentation by foreign companies. The law required that if a foreign company wished to conduct trials in India, it needed to repeat the trials from the same phase in India as had already been conducted in locations outside India. Thus if a company had already conducted phase I trials outside India, it could not directly start phase II trials in India – it would have to conduct phase I trials again in India, before permission was conducted to conduct phase II trials in the country. This allowed Indian regulatory agencies greater control over the kind of trials being conducted in India and was a vital tool for protection of trial subjects against unethical trials. In 2005, however, this requirement was waived (by and amendment to schedule Y of the drugs and cosmetic rules) and concurrent phase II and III trials were allowed. This means that a phase II or III trial can be conducted concurrently in India, along with similar trials in other centres in the world, even if the drug has not undergone a phase I or II trial in India.
The result of this change in the law has been spectacular. In 2005, less than a 100 trials were being conducted in India. The number jumped to over 250 by 1997-98 and is projected to exceed a 1000 by the end of 2010. It is now estimated that one in four clinical trials in the world are conducted in India, and the turnover for the industry is expected to touch US$ 1.52 billion by 2010. The Association of Indian Contract Research Organisations (ACRO) chairman Dr S P Vasireddi is quoted as claiming: "We have now a share of 24 per cent while China has 33.3 per cent of the global business."
REASONS BEHIND BOOM IN CLINICAL TRIALS
What explains this boom in clinical trials in the country? Does it indicate a rapid expansion of capability and capacity for conducting medical research in the country? Unfortunately the answer to this is largely in the negative. While capacity and capability have increased, the sudden rise in number of trials far outstrips the enhancement in capacity and capability. Even industry sources admit that at present levels there is a need for about 5,000 new professionals trained in good clinical practice (GCP) in the industry to augment the 600 odd who are available in the country. What is perhaps an even bigger concern is that regulatory capacity has not kept pace with the sudden spurt in clinical trials. While the law was changed in 2005, it was only in late 2009 that the government deemed it prudent to make it mandatory to register clinical trials in the country. While rules now specify that all clinical trials need to be overseen by institutional ethics committees, the constitution and functioning of these ethics committees are fraught with numerous problems. Primary among these is the issue of conflict of interest -- ethics committee members can have vested interest in ensuring that a trial is given permission because they have links with the company or the local contractor or the researcher who is engaged in promoting the trial. Further, there is little interaction between ethics committees in different locations, thereby allowing the practice of "ethics committee shopping": sponsors whose trial is rejected by one ethics committee approach a different centre for approval.
The sudden boom in clinical trials, in fact, can be explained precisely because of the incapacity to regulate clinical trials. Companies are rushing to India to conduct trials which they would have problems in justifying in their home countries. This is happening in a situation where most patients in India are particularly vulnerable because they have poor or no access to public health facilities. Thus, poor and vulnerable patients sign up for trials as they see this as the only opportunity to access treatment for their disease. A study done by the Mumbai based Centre for Studies in Ethics and Rights quotes a survey that showed that just 11 per cent of trial subjects enrolled to advance scientific knowledge. In contrast the rest joined the trials because they were looking for better or free treatment, or they were advised by their treating physician to enroll. Five per cent even admitted that they joined because they were paid money to do so! Poor access to public health in India has another advantage that trial sponsors seek to exploit – most Indians are treatment naïve, that is they have not been exposed to treatments before enrolling in a trial. In other words, all that is wrong with the public health system in the country has become the primary motive force for India becoming the favoured destination of clinical trials in the world.
MIDDLEMEN MILK THE SYSTEM
The story would not be complete without a mention of the prime movers of the clinical trials industry in India. There has been a mushrooming of Clinical Research Organisations (CROs) and Site Management Organisations (SMOs) in the recent past. To put it bluntly, they are the middlemen or fixers who grease the machinery and ensure that more and more clinical trials are outsourced into India. They liaise between the drug companies and the clinical researchers (many of them of extremely dubious quality). They ensure that the drug regulatory authorities are kept happy, they draw up the protocols, advise the researchers as to how patients are to be recruited and even help in formation of the ethics committees. Their prime motivation is not an interest in research but the billions of dollars that are flowing into the industry. When researchers are drawn from the private sector, they are paid on a pro rata basis depending on the number of subjects who are recruited. Such payments can range from $1,500 (Rs 70,000) to $3,000 (Rs1,40,000) per patient.
Recently, in a reply to a question in parliament, the ministry of health reported that deaths among clinical trial subjects increased from 132 in 2007 to 637 in 2009, and 462 deaths had already been reported till June 2010. While deaths can occur among clinical trial subjects (largely in cases where the subjects are suffering from terminal diseases such as cancers), such a rapid increase is a cause for concern. The concern is compounded by the fact that there appears to be an absolute lack of transparency in reporting regarding how trials are being conducted and the outcomes of these trials.
This is not to suggest that good quality researchers are not present in India and that excellent research is not being conducted in several centres. Unfortunately these would constitute a small minority of the total number of clinical trials being conducted in the country. Given the huge and growing concerns about the dubious quality and ethical gaps regarding most clinical trials being conducted, there is a danger that the entire system of clinical research will stand discredited in the global arena. If this is to be avoided drug regulatory authorities and the Indian Council of Medical Research must step in to ensure transparency, ethics and quality in clinical research. At the same time, there is a clear need to separate the unethical and the incompetent from genuine researchers. Only better regulation with much larger regulatory capacity and resources can ensure this. Finally, there is also an urgent need that CROs and SMOs be regulated and perhaps phased out of the entire system of conducting clinical research in the country.
Courtesy: www.pd.cpim.org
These reports, raising misgivings about the way clinical trials are being conducted in India, coincide with a very rapid expansion of the number of clinical trials conducted in the country. The flood gates opened in 2005 when India changed the rules regulating clinical trials in the country. To understand how this happened we need to understand the process involved while conducting clinical trials.
CLINICAL TRIALS AND ETHICS
When new drugs are researched, they need to be tested on human subjects before they are given a marketing approval by drug regulatory agencies. Before a new drug is tested on human subjects, they have to be tested on animals to establish the safety and efficacy of the drug. However, this is not enough to establish the safety and efficacy of the drug in humans. The final step involves testing the drugs among human subjects. These tests are carried out in four phases. In the first phase of human trials, the drug is tested on a small number of human subjects to show that the drug is indeed safe for human consumption. Generally phase I trials are conducted on healthy subjects and the intent is to establish the safety of the drug. Phase II and III are conducted on subjects who have a condition that may benefit from the use of the drug, and thus these trials are designed to establish that the drug is effective in treating a particular disease. Phase IV trials are also called post-marketing surveillance and are designed to collect data from an even larger sample of patients, after the drug is introduced.
Because clinical trials are essentially experiments that are conducted on human beings, all countries have rules that regulate how these trials should be conducted. Globally, the Helsinki declaration, sets the benchmark of how such rules should be framed. All rules related to drug trials are concerned with the ethics of how trials are conducted. The first, and perhaps the most important aspect of these rules, are those related to “informed consent”. Because trials are an experiment they carry a potential risk. So it needs to be ensured that those who participate in clinical trials should be aware of the risks and should formally consent to be part of the trial after the risks are explained in details. The concept of informed consent is also premised on the assumption that trial subjects consent to be a clinical trial subject without being coerced, directly or as a consequence of the circumstances in which the person might find himself. The second fundamental concern about ethics in clinical trials is that trials should be allowed in a population who would later benefit from the introduction of the drug that is tested. In other words clinical trials should not be permitted where trial subjects in a particular country or community are used as mere guinea pigs.
There are several other critical issues that determine whether a trial is ethical. In recent years, a major concern has related to “placebo” controlled trials. A placebo is a substance that has no significant effect on a human subject – it could be a capsule containing a small amount of salt or sugar, for example. In placebo controlled trials, some trial subjects are given the placebo while others are given the drug that is being studied. Through this route researchers can decide if the drug is a better alternative to no treatment. However placebo trials are unethical if a treatment already exists for the disease for which the new drug is being tested, for it means that those who are given the placebo are being denied treatment, even though a treatment for the disease exists. The Helsinki declaration clearly states that in general placebo trials should be avoided if treatment already exists. However there is no unanimity on this among researchers. Laws in the US, for example, have different standards for placebo controlled trials depending on whether the trials are being conducted in the US or being conducted in a third country.
CHANGE IN LAW OPENS FLOOD-GATES
Before 2005, the Indian law was designed to actively discourage the use of Indians as mere subjects for experimentation by foreign companies. The law required that if a foreign company wished to conduct trials in India, it needed to repeat the trials from the same phase in India as had already been conducted in locations outside India. Thus if a company had already conducted phase I trials outside India, it could not directly start phase II trials in India – it would have to conduct phase I trials again in India, before permission was conducted to conduct phase II trials in the country. This allowed Indian regulatory agencies greater control over the kind of trials being conducted in India and was a vital tool for protection of trial subjects against unethical trials. In 2005, however, this requirement was waived (by and amendment to schedule Y of the drugs and cosmetic rules) and concurrent phase II and III trials were allowed. This means that a phase II or III trial can be conducted concurrently in India, along with similar trials in other centres in the world, even if the drug has not undergone a phase I or II trial in India.
The result of this change in the law has been spectacular. In 2005, less than a 100 trials were being conducted in India. The number jumped to over 250 by 1997-98 and is projected to exceed a 1000 by the end of 2010. It is now estimated that one in four clinical trials in the world are conducted in India, and the turnover for the industry is expected to touch US$ 1.52 billion by 2010. The Association of Indian Contract Research Organisations (ACRO) chairman Dr S P Vasireddi is quoted as claiming: "We have now a share of 24 per cent while China has 33.3 per cent of the global business."
REASONS BEHIND BOOM IN CLINICAL TRIALS
What explains this boom in clinical trials in the country? Does it indicate a rapid expansion of capability and capacity for conducting medical research in the country? Unfortunately the answer to this is largely in the negative. While capacity and capability have increased, the sudden rise in number of trials far outstrips the enhancement in capacity and capability. Even industry sources admit that at present levels there is a need for about 5,000 new professionals trained in good clinical practice (GCP) in the industry to augment the 600 odd who are available in the country. What is perhaps an even bigger concern is that regulatory capacity has not kept pace with the sudden spurt in clinical trials. While the law was changed in 2005, it was only in late 2009 that the government deemed it prudent to make it mandatory to register clinical trials in the country. While rules now specify that all clinical trials need to be overseen by institutional ethics committees, the constitution and functioning of these ethics committees are fraught with numerous problems. Primary among these is the issue of conflict of interest -- ethics committee members can have vested interest in ensuring that a trial is given permission because they have links with the company or the local contractor or the researcher who is engaged in promoting the trial. Further, there is little interaction between ethics committees in different locations, thereby allowing the practice of "ethics committee shopping": sponsors whose trial is rejected by one ethics committee approach a different centre for approval.
The sudden boom in clinical trials, in fact, can be explained precisely because of the incapacity to regulate clinical trials. Companies are rushing to India to conduct trials which they would have problems in justifying in their home countries. This is happening in a situation where most patients in India are particularly vulnerable because they have poor or no access to public health facilities. Thus, poor and vulnerable patients sign up for trials as they see this as the only opportunity to access treatment for their disease. A study done by the Mumbai based Centre for Studies in Ethics and Rights quotes a survey that showed that just 11 per cent of trial subjects enrolled to advance scientific knowledge. In contrast the rest joined the trials because they were looking for better or free treatment, or they were advised by their treating physician to enroll. Five per cent even admitted that they joined because they were paid money to do so! Poor access to public health in India has another advantage that trial sponsors seek to exploit – most Indians are treatment naïve, that is they have not been exposed to treatments before enrolling in a trial. In other words, all that is wrong with the public health system in the country has become the primary motive force for India becoming the favoured destination of clinical trials in the world.
MIDDLEMEN MILK THE SYSTEM
The story would not be complete without a mention of the prime movers of the clinical trials industry in India. There has been a mushrooming of Clinical Research Organisations (CROs) and Site Management Organisations (SMOs) in the recent past. To put it bluntly, they are the middlemen or fixers who grease the machinery and ensure that more and more clinical trials are outsourced into India. They liaise between the drug companies and the clinical researchers (many of them of extremely dubious quality). They ensure that the drug regulatory authorities are kept happy, they draw up the protocols, advise the researchers as to how patients are to be recruited and even help in formation of the ethics committees. Their prime motivation is not an interest in research but the billions of dollars that are flowing into the industry. When researchers are drawn from the private sector, they are paid on a pro rata basis depending on the number of subjects who are recruited. Such payments can range from $1,500 (Rs 70,000) to $3,000 (Rs1,40,000) per patient.
Recently, in a reply to a question in parliament, the ministry of health reported that deaths among clinical trial subjects increased from 132 in 2007 to 637 in 2009, and 462 deaths had already been reported till June 2010. While deaths can occur among clinical trial subjects (largely in cases where the subjects are suffering from terminal diseases such as cancers), such a rapid increase is a cause for concern. The concern is compounded by the fact that there appears to be an absolute lack of transparency in reporting regarding how trials are being conducted and the outcomes of these trials.
This is not to suggest that good quality researchers are not present in India and that excellent research is not being conducted in several centres. Unfortunately these would constitute a small minority of the total number of clinical trials being conducted in the country. Given the huge and growing concerns about the dubious quality and ethical gaps regarding most clinical trials being conducted, there is a danger that the entire system of clinical research will stand discredited in the global arena. If this is to be avoided drug regulatory authorities and the Indian Council of Medical Research must step in to ensure transparency, ethics and quality in clinical research. At the same time, there is a clear need to separate the unethical and the incompetent from genuine researchers. Only better regulation with much larger regulatory capacity and resources can ensure this. Finally, there is also an urgent need that CROs and SMOs be regulated and perhaps phased out of the entire system of conducting clinical research in the country.
Courtesy: www.pd.cpim.org
