Trial markets

Published : Jul 13, 2012 00:00 IST

Women who underwent clinical trials speak to district officials at the Government General Hospital in Guntur in Andhra Pradesh. A file picture.-T.VIJAYA KUMAR

Women who underwent clinical trials speak to district officials at the Government General Hospital in Guntur in Andhra Pradesh. A file picture.-T.VIJAYA KUMAR

The Parliamentary Committees report touches upon some important aspects of unethical drug trials, but health activists say that is not enough.

The 59th report of the department-related Parliamentary Standing Committee on Health and Family Welfare, especially its suggestion for a separate report on clinical trials given the unprecedented growth in drug trial markets, was well received by various health groups. The report, which was tabled in Parliament on May 8, essentially dealt with the functioning of the Central Drugs Standard Control Organisation (CDSCO).

Responding to a query in Parliament in March, the Minister for Health and Family Welfare informed that as per the information given in the Clinical Trials Registry maintained by the Indian Council of Medical Research (ICMR), the target Indian sample size in clinical trials had shown an upward trend in 2009 and 2010 but had declined in 2011. The number of clinical trials permitted by the Drugs Controller General of India (DCGI), in the past three years were 453 (2009), 505 (2010) and 271 (2011). The number of serious adverse events (SAE) of deaths in all clinical trials in the past three years stood at 637, 668 and 438 respectively. He also informed that two clinical trials had been conducted without the DCGIs permission in the past two years. But as no adverse event of death was reported, no compensation was paid.

While there is little doubt that clinical trials are necessary for the advancement of medicine and for the approval and testing of new drugs, in recent times there have been several instances of conflict of interest as well as violation of the ethical guidelines pertaining to informed consent of trial subjects. A national consultation on the regulation of drug trials in September last year organised by Sama, a resource group for Women and Health, underscored the need for better infrastructure for regulation, review of ethical practices and monitoring to regulate clinical trials, especially in the context of pharmaceutical companies outsourcing drug trials to Contract Research Organisations.

The problem is rather deep-rooted and, as the status report points out, may need a completely new report. The 59th report does not cover the whole gamut of unethical drug trials but has touched upon some important aspects. The extent of the problem can be gauged from an illustration. When Dr Anand Rai, the Indore-based health activist who filed a public interest petition in the Supreme Court on clinical trials, sought information through a Right to Information application about data (such as trial site code and hospital names) on trial sites from the Directorate-General of Health Services, the DGHS office wrote back to him saying that it had not maintained composite data of such reports in respect of trial sites.

Anand Rai told Frontline that as per Schedule Y of the Drugs and Cosmetics Rules, any unexpected SAE occurring during a clinical trial should be communicated within 14 days by the sponsor to the licensing authority and to other investigators participating in the study. In Appendix XI of the Rules, he said, the sponsor and the investigator were both required to submit details of the SAE and the investigator was required to give an undertaking to inform all SAEs to the sponsor and the ethics committee. On March 23, Anand Rai received a reply from the DGHS office giving details of the number of SAE deaths in clinical trials in 2008, 2009, 2010 and 2011, which were 288, 637, 668 and 438 respectively. On the query about data on the trial sites (hospital names), and the States where they were conducted, the office held that such data were not maintained by the Directorate. Where are the data then about where the trials have been conducted? asked Anand Rai. He was informed that as per available data, there were 22 cases of death related to clinical trials in 2010 and as per information received by the sponsor/Contract Research Organisations, compensation was paid in all 22 cases of deaths related to clinical trials.

It was interesting that at least 10 major multinational pharmaceutical companies featured in the list prepared by the DGHS and the rate of compensation ranged from a minimum of Rs.1.08 lakh to a maximum of Rs.20 lakh. The average rate was, however, Rs.1.5 lakh. In one single case, the amount had been enhanced to Rs.20 lakh following the recommendation of the Ethics Committee. In Section 3 of Appendix XI of the Rules (Data elements for reporting SAEs occurring during a clinical trial), under the sub-section on details of suspected adverse drug reactions, it is clearly specified that the setting for instance, hospital, out-patient clinic, home or nursing home has to be mentioned. Following reports early this year about clinical trials being conducted on mentally ill persons in Indore by psychiatrists attached to the Mahatma Gandhi Medical College and Mental Hospital ( Frontline, February 10, 2012), the CDSCO found after an investigation that the subjects had been enrolled as per inclusion and exclusion criteria of approved protocol and were found to be mentally sound. The psychiatrists had conducted 11 clinical trials between January 2008 and October 2010 in their private clinics. Only in one case, the investigator did not have the original consent form at the site.

It may be recalled that of the 78 doctors who were found conducting these trials, the State government penalised only 12, with a fine of Rs.5,000 each. While replying to a question in Parliament about these trials, the Health Minister said that while Schedule Y of the rules and Good Clinical Practice (GCP) guidelines recognised that mentally challenged and mentally differently abled persons, who were incapable of personally giving consent, were considered vulnerable subjects, there was no prohibition under the said rules and guidelines that clinical trials could not be conducted on such patients. For enrolling such patients, informed consent was required from a legally acceptable representative of the patient. The Minister did not specify whether this was done in all the cases or that whether economic compulsions were behind the cases of informed consent. In any event, this was a loophole that needed to be corrected.

On June 12, Anand Rai again wrote to the Central Information Commission stating that clinical trial was a sensitive issue and that 2,031 deaths had occurred since 2008 and that there were thousands of SAEs while compensation had been paid only in 22 cases. Representing the Swasthya Sewa Samarpan Samity, Anand Rai and Kalpana Mehta, of the Madhya Pradesh Mahila Manch, said that the parliamentary committee report mirrored their experience as health activists. Truly, in this era of globalisation Indian citizens are being squeezed from both ends. They feature only in cost-cutting exercises. On the one hand they are being subjected to unnecessary trials to cut the cost of pre-approval global trials of multinational drug companies, while the trials that would give them safe and effective drugs are being waived off, a statement issued by them said.

The committee, they observed, had done a long-overdue review of the CDSCO and hoped that the action taken would match the inquiry and remove the gross anomalies to make drug control responsive to the needs of the people. The activists said that the worst fears that the DCGI was acting in favour of the pharmaceutical companies was confirmed by the mission statement of the CDSCO, which was about meeting the aspirations, demands and requirements of the pharmaceutical industry. Even market-oriented economies ran their respective departments in the interest of public health.

We are happy that the committee has stated that (it) is of the firm opinion that most of the ills besetting the system of drugs regulation in India are mainly due to the skewed priorities and perceptions of CDSCO. For decades together it has been according primacy to the propagation and facilitation of the drugs industry, due to which, unfortunately, the interest of the biggest stakeholder, i.e. the consumer, has never been ensured, the statement said. It expressed concern over the committees findings that overworked and under-qualified staff of the CDSCO arbitrarily waives off trials and allows the companies to default on regulatory requirements...

Welcome move

Other health activists and organisations, too, have welcomed the committees recommendations, which they felt had been arrived at after a rigorous investigation into the flawed system of drug regulation. The committee also makes a case for unambiguous and clear guidelines for a range of issues related to clinical research particularly related to approval of new drugs and the selection processes of outside experts for this purpose; highlighting the importance of identification of all possible biases and potential conflicts of interest, read a statement jointly issued by the Jan Swasthya Abhiyaan, Sama, LOCOST Therapeutics, the Delhi Science Forum, the Centre for Trade and Development, Prayas (a non-governmental organisation in Chittorgarh), the Drug Action Forum, the All India Peoples Science Network and several individuals. They said the committee had rightly questioned the approval of new drugs without the mandatory Phase 3 clinical trials under the guise of public interest and called for an urgent scrutiny of the arena of clinical trials as a separate issue. This is a welcome move; with the increasing scale and scope of the clinical trial industry in India, there is an urgent need for further independent inquiry into this area, the statement read.

We are encouraged that the committee has concluded that there is an urgent need to increase the minimum number of subjects in Phase III pre-approval clinical trials. The committee has recommended that while approving Phase III clinical trials, the DCGI should ensure that such trials are spread across the country so as to ensure a truly representative sample. Besides, trials should be conducted in well-equipped medical colleges and large hospitals with round-the-clock emergency services to handle unexpected serious side-effects and with expertise in research and not in private clinics, Anand Rai and Kalpana Mehta said in their statement.

Interestingly, at the consultation organised by Sama and others last September, V.M. Katoch, Secretary and Director-General of the ICMR, observed that there was an urgent need to strengthen the regulatory mechanisms in the area of clinical trials and that there was a need to revise the guidelines. He said that the changes in the 2006 guidelines would take the form of a draft Bill. The experiences of the human papilloma virus (HPV) vaccine projects in Andhra Pradesh and Gujarat had brought to light a number of issues and problems relating to the execution of clinical trials. Despite common ICMR guidelines, he said, there were differences in the performance of projects across different States. He also posed the question whether the same institute making the guidelines could also play the role of a regulatory body or act as a partner. At the same time, if it does indeed become a partner, how can it then monitor the performance? he asked.

Replying to a question in the Rajya Sabha on a stringent piece of legislation to curb unethical clinical trials, the Union Minister for Health and Family Welfare informed that proposals had been approved by the Drug Testing Advisory Board (DTAB) to carry out amendments to the Drugs and Cosmetics Rules. This included the enhancement of the responsibilities of the ethics committees, sponsor and investigator in order to ensure that financial compensation and medical care were provided to trial subjects who suffered trial-related injury or deaths.

But the Minister was silent on the composition of the ethics committees wherein there have been cases of conflict of interest. He said that an amendment to the format for obtaining informed consent of trial subjects with details of address, occupation, annual income, and so on to get information on their socio-economic status would be made.

If any amendments are to be made to the Drugs and Cosmetics Rules or the ambit of the GCP guidelines is to be widened, it has to be done after broad consultations with all the stakeholders and not just with the pharmaceutical companies. As of now, health activists have demanded that the Ministry take action on the recommendations of the department-related report instead of constituting new committees to look into the inquiries that have already been conducted.

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