Clinical Trial Industry: No Accountability? :

The Indian government has been promoting the country as an attractive site for outsourced clinical trials. However, there is no regulatory mechanism in place while a bill on clinical research has been hanging fire for five years. There is an urgent need to protect trial participants who are vulnerable to exploitation by the drug companies, the contract research organisations and investigators.

COMMENTARY

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Clinical Trial Industry:	research. The selling point is that it costs less in India, and that we have the
No Accountability? Sandhya Srinivasan	infrastructure, trained humanpower and plenty of “treatment naïve” (untreated) patients. The government has promised to fast-track clearance of applications from drug companies, and to set up the moni-

The Indian government has been promoting the country as an attractive site for outsourced clinical trials. However, there is no regulatory mechanism in place while a bill on clinical research has been hanging ﬁre for ﬁve years. There is an urgent need to protect trial participants who are vulnerable to exploitation by the drug companies, the contract research organisations and investigators.

Sandhya Srinivasan (sandhya199@mtnl.net.in) is executive editor, Indian Journal of Medical Ethics, and consulting editor, Infochange News and Features.

Economic & Political Weekly

august 27, 2011

n June this year, it was found that families of those who had died in clinical trials were not paid compensation (Sinha 2011). According to the drug companies’ reports to the Drugs Controller General of India (DCGI), 670 people died in trials in 2010 and 25 of the deaths were related to participation in the research. Compensation was received in only ﬁve deaths, and treatment expenses were paid or reimbursed for only eight participants. Eventually 22 families received compensation (Press Information Bureau 2011). We do not know what happened to the remaining families, or whether treatment and compensation was given to those who suffered trial-related injury.

Since the amendment of Schedule Y of the Drugs and Cosmetics Act (Ministry of Health and Family Welfare 2005), permitting the conduct of clinical trials of foreign drugs in the same phase1 as in other parts of the world, the government has promoted India as a site for outsourced

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toring mechanisms necessary for foreign regulatory bodies.2

Size of the Industry and Trends

Various projections have been made of the size of the clinical trials industry in India, with one estimate putting it at up to $1 billion by 2014 (van Huijstee and Schipper 2011). Though the US and western Europe still contain the vast majority of clinical sites, according to an industry monitor, phase 2 and 3 trials which must recruit more patients – and fast – are moving to eastern Europe, and, most recently, Asia (Karlberg 2011).

India has the third largest number of phase 3 industry-sponsored trials in Asia after Japan and South Korea and before China, with 14.3% of such trials in the region; Bangalore ranks fourth for the number of such trials (Karlberg 2011). The writer states: “Based on multinational trials sites, India will be the most utilised Asian country for industry-sponsored trials, i e, being more popular than Japan” (p 63).

COMMENTARY

Though the regulatory changes encouraging foreign clinical trials in India came into force in January 2005, it was only in June 2009 that the DCGI required registration of clinical trials on the Clinical Trials Registry of India (CTRI), after which there has been a steady rise in the number of trials on that database. The Centre for Studies in Ethics and Rights noted that 1,078 trials were registered as of June 2010. Of these, 782 were sponsored by pharmaceutical companies. They were conducted at 4,292 sites across India, led by Ahmedabad, Bangalore, Chennai, Hyderabad, Mumbai, New Delhi and Pune (Clinical Trials Watch 2010). Of the 670 trials open for recruitment as of 31 December 2010, 68% (456) were sponsored by drug companies, the highest number (100) for cancers (Clinical Trials Watch 2011).

Ethical Double Standards

India may also be an attractive option for drug companies looking to outsource research that would be difﬁcult to conduct in their own countries. For example, placebocontrolled trials can deprive patients of effective treatment. The US Food and Drug Administration (USFDA) requires placebocontrolled trials as proof of a drug’s efﬁcacy, but ethics committees there may be reluctant to permit such trials when it concerns a serious condition like schizophrenia. The World Medical Association’s (WMA) Declaration of Helsinki, with ethical guidelines for clinical research, has been the subject of battles on the use of placebo-controlled trials. The 2008 version restricts their use. In order to bypass the WMA’s authority, in 2008, the USFDA removed the requirement that clinical trials submitted to it must abide by the Declaration (Macklin 2009).

Though Indian law requires clinical trials to abide by the Declaration of Helsinki, many trials violate it, and the government may face pressure to formally do away with it.

Vulnerability of Trial Participants

Media reports on patients’ vulnerability are reinforced through research. A survey by the contract research organisation Excel Life Sciences of participants in their trials3 found that 26% were looking for free or higher quality care. Indeed, interviews with doctors suggest that poor people may enter trials to get treatment; those at private hospitals may seek free care and government hospital patients will want better care. The high cost of drugs (for example, for cancer) induces patients to enter trials to get treatment – especially if their doctors tell them that the experimental drug is better than nothing.

Of Excel’s total participants 5% enrolled for the money. Bioequivalence trials4 recruit healthy volunteers for substantial payments, and people may be induced to enrol for a fee, ignoring any risks of participation. Further, 76% were recruited by their family doctors who were also the trial’s investigators and 21% were referred by the family doctor. They may have been reluctant to refuse their doctor’s advice.

The doctor-investigators may be a bit too eager to recruit. Private doctors receive payment for each patient recruited and retained through each stage of the trial’s duration. Doctors in government hospitals are reported to receive fringe beneﬁts such as trips abroad (Srinivasan 2009). There can be a conﬂict between the interests of the doctor and the patient s/he advises to join a trial.

Contract Research Organisations

International clinical trials are largely conducted by contract research organisations (CROs), the mediators between drug companies, investigators, trial subjects and regulatory authorities. The CROs advertise that they do everything from obtaining permissions and conducting the trial to writing up the ﬁndings and submitting data for marketing approval. They have been known to use ethically questionable recruiting techniques such as organising health camps, ﬁnancing patient support groups, and placing staff in hospitals to gain access to medical records (Srinivasan 2009).

There is no registry of CROs in India. A study of the sector estimated that between 130 and 200 CROs operate in the country. They may work with insufﬁciently trained personnel, and inadequate supervision from ethics committees and regulatory authorities, conducting trials on vulnerable populations who are unable to give informed consent (van Huijstee and Schipper 2011).

Indeed, since 2005, reports have regularly emerged of unethical research practices. In the past few months, a Hyderabadbased CRO was reported to have administered women a cancer drug without their informed consent (The Hindu 2011); doctors at a government hospital at Indore are reported to have conducted 76 clinical trials on over 3,000 patients, receiving Rs ﬁve crore in the process (Singh 2011); and survivors of the Bhopal gas disaster seeking treatment at the Bhopal Memorial hospital were enrolled in drug trials without their knowledge (Pioneer 2011). Deaths in clinical trials have been traced back to inappropriate recruitment practices such as including an ill child in a trial limited to healthy volunteers (Pandeya 2008) and offering large payments inducing people to enrol in more than one trial (Ramana 2008).

Rules regarding registration of the CROs were drafted in 2009. In January 2011, these were published in the government gazette (MoHFW 2011), and six weeks were given for the public to respond. However, this process has not moved forward.

The DCGI’s ofﬁce is expected to review all applications for conducting clinical trials, and visit sites to ensure that the trial is conducted according to good clinical

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Economic Political Weekly

COMMENTARY

practices. But 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.5 The DCGI’s ofﬁce recently advertised 50 posts that involved the handling of everything from scrutinising papers, developing an archiving and retrieval system, to drafting guidelines and inspecting clinical trial sites – but all were on four-month contracts (Central Drugs Standard Control Organisation 2011).

The ‘Adverse Event’

An adverse event (AE) is deﬁned as “any untoward medical occurrence...during treatment...that does not necessarily have a relationship with the treatment being given”. A serious adverse event is an AE “associated with death, inpatient hospitalisation..., prolongation of hospitalisation...persistent or signiﬁcant disability or incapacity, a congenital anomaly or birth defect, or is otherwise life threatening” (DCGI, DGHS, CDSCO 2011).

Along with the increase in the number of trials registered on the CTRI, there has been an increase in the number of deaths reported in these trials: 132 in 2007, 288 in 2008 and 637 in 2009 (PIB 2010). In 2010, 670 deaths were reported in clinical trials. There were many more “serious adverse events” (SAEs) but these numbers have not been made public. The Drugs and Cosmetics Act requires that all unexpected SAEs6 be reported to the sponsor within 24 hours, to the ethics committee within seven working days, and to the DCGI and other investigators within 14 days, and that action be taken. However, at present the SAE records are reportedly maintained manually and there is no follow-up of reports. The ethics committees that function as the local monitors may be untrained and under-resourced.

In fact, it may be up to the drug company on whose behalf the trial is conducted to monitor a trial and halt it when it is harming participants.

The quality of SAE reporting was ﬂagged by the committee investigating the human papillomavirus (HPV) vaccine trial involving 25,000 girls. No system was in place to report and investigate the AEs and while the deaths in the trials were “most probably unrelated to the vaccine” in some cases the cause of death could not be “established with certainty” as postmortem results and detailed medical records were unavailable. Nor was treatment available for girls who reported side effects though the non-governmental organisation (NGO) running the trial had insurance for itself (GoI 2011).

Compensation for Injury

Various documents – the Drugs and Cosmetics Act, the ICMR ethical guidelines, the Indian good clinical practice guidelines (CDSCO undated) and the draft SAE reporting guidelines – require study subjects to be provided medical treatment and compensation for trial-related injury. Yet a survey found that 47% of investigators and 26% of ethics committee members were unaware of, or did not understand, this requirement. Again, 40% of investigators, 30% of ethics committee members and all trial sponsors had policies on compensation but mainly to provide immediate medical relief or reimburse expenses, not to compensate for disability or death. The researchers reviewed informed consent forms and found that compensation was not mentioned; even reimbursement was to be given only if treatment was not already covered by other medical insurance, or only after insurance was exhausted.

In 2008, the Indian Council of Medical Research (ICMR) along with the Federation of Ethics Review Committees in India and the Indian Society for Clinical Research drew up draft guidelines on compensation for research-related injury (Bavdekar and Thatte 2009). The document requires trial sponsors to provide treatment for research-related injury and compensation for disability or death. It spells out how compensation should be determined and given, by whom and in what time frame, and how to handle disputes. This draft seems to have died a natural death as it is no longer available on the ICMR website.

Ethics Review and Monitoring

The ethics committee (EC) is entrusted with reviewing research proposals and monitoring research (ICMR 2006). There is little research on whether ECs are equipped for this, but available information suggests that many are not (Mudur 2005, WHO-ICMR 2007). The inquiry report on the HPV vaccine trials (GoI 2011) raised questions about the ethics of taking consent from hostel superintendents, and administering a vaccine to thousands of girls without a system for reporting and treating serious adverse events – issues that should have occurred to the various local and international ECs that cleared the trials. The committee also found many irregularities in the informed consent forms which would have been picked up if the EC had monitored properly.

A recent phenomenon is that of the private research ethics committee often constituted by drug companies or CROs to review proposals for a fee. The proﬁt motives of these private boards pose a conﬂict of interest: they may be inclined to conduct superﬁcial reviews since they beneﬁt from the review fees (Ledford 2007). Further, since approval from private ECs is not tied to any particular site or institution, researchers can get approval from a private EC in one city and conduct the research in another city where there is no scope to monitor the research. Also, when research is not tied down to any one institution, sponsors can shop around for the right ethics committee.

Finally, while guidelines for the constitution and functioning of ECs exist, there

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COMMENTARY

is no way to ensure that these guidelines are followed. Ethics committees are still not registered, they need not make their discussions public, and they are not held liable for their decisions. In essence, the ECs can function as a law unto themselves or to their institutions or funders.

Conclusion

The government has encouraged clinical research without ﬁrst putting a regulatory structure in place. A bill governing clinical research as a whole (GoI 2006) has been around for more than ﬁve years. Draft rules on various aspects such as registering the CROs, reporting research-related injury and ensuring compensation have been discussed for some time. There are lacunae to be ﬁlled and contradictions to be resolved but this must be done – with public involvement in this process – and the laws enforced. This is only the ﬁrst step towards protection of trial participants, but one that needs to be taken urgently.

Notes

1 Phase 1 trials are generally on healthy volunteers and collect information on the drug’s safety. Phase 2 trials evaluate its effectiveness and safety on a small number of patients. Phase 3 trials are conducted on a few hundred patients to conﬁrm the drug’s safety and efﬁcacy and towards obtaining marketing approval. Phase 4 trials are conducted once the drug enters the market and monitor for serious side effects that would become evident only when the drug is used by very large numbers of people. Before 2005, foreign drugs had to be tested at one phase prior to the phase tested elsewhere. In 2005, the law was amended to permit concurrent phase trials in India.

2 Su Si , at a c

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Si

, at a c

ference of the Institute of Clinical Research (India), Mumbai, 10-11 October 2008.

3 Presentation by Dan Mcdonald, vice president, business development, Excel Life Sciences, at a meeting of the Institute of Clinical Research (India), Mumbai, 10-11 October 2008.

4 A bioequivalence trial compares a generic formulation to the branded drug.

5 The DCGI’s ofﬁce is headless at present after the 20 July interim order by the Madras High Court staying the extension of the DCGI’s term.

6 Expected adverse events are those that will occur because of the condition under study.

References

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