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Compensation for injury in drug trials in India

Can the new rules deliver justice, asks Sandhya Srinivasan

In the last decade, there have been many reports of unethical and illegal clinical trials in India. It is only recently that the government framed rules to monitor their conduct. In 2014, rules were devised on compensation to be paid to participants or their families in cases of injury and death in clinical trials. However, there are challenges to be met much before compensation amounts can be determined, starting from the manner in which trials are conducted extending to the procedure for assessing whether an injury is related to the trial. Some of these problems may be reduced with the planned improvements in regulation. However, trial sponsors are likely to resist regulation, participants remain vulnerable, and regulatory agencies have a poor track record in protecting people’s rights.

Following the January 2005 amendments to Schedule Y of the Drugs and Cosmetics Act (GoI 2005) regulating clinical trialsi for approval of new drugs, the multinational pharmaceutical industry rushed to India, which the government was promoting for its lower costs, available infrastructure, trained healthcare personnel, and a large population on whom trials could be conducted (Sengupta 2009). As of June 30, 2010, 666 of the 1,078 trials registered on the Indian registry for clinical trials were for drugs, the overwhelming majority sponsored by the private pharmaceutical industry (Nikarge 2010).

However, there were no regulatory mechanisms in place to protect the rights and health of the people on whom new drugs were being tested. In the absence of such rules the office of the Central Drug Standards Control Organisation (CDSCO) – the government regulatory body whose work includes governing the conduct of clinical trials towards approval of new drugs – was grossly negligent in its duties, even functioning as a “facilitator for industry” (Jesani 2013: 76).

Though Schedule Y required that trials follow the Indian good clinical practice (GCP) guidelines for clinical research (CDSCO 2001), neither document contained detailed rules on the requirements of institutional ethics committees (IECs) which review and monitor trials; on the responsibilities of investigators who conduct trials; on how injuries and deaths in trials were to be reported, investigated, and compensated, and so on. Industry exploited these loopholes, with more than a little help from the government. A government report on the functioning of the CDSCO found that it was substantially understaffed, and needed a drastic upgrade in technology, infrastructure and training to meet the job of monitoring the influx of trials. Most important, it noted “a collusive nexus between drug manufacturers, some functionaries of the CDSCO and some medical experts” (GoI 2012: para 7.36). This nexus has certainly been apparent in the reports of the last decade.

The right to compensation for trial-related injury

In India, the subject of compensation for injury or death in trial has been discussed in the course of the campaign against unethical trials and poor regulation. However, this right has nothing to do with the ethics of a trialii. Trial subjects are injured in even the best run trials. Pharmaceutical companies conduct clinical trials to gather information on a drug’s safety and efficacy, which they use to get marketing approval. People who participate in the trial take risks to provide this information. It goes without saying that participants who are injured or die in these trials have a right to medical treatment as well as compensation for any harm caused by taking this riskiii. Jesani has pointed out that all trial participants, whether on the experimental drug or a standard treatment, “are experimented upon and take risks in drug trials, and so have some right to compensation when they suffer injury or death”. (Jesani 2013: 78)

The right to compensation for injury or death in a clinical trial is enshrined in the guidelines of international bodies such as the World Medical Association’s Declaration of Helsinki that lays down ethical principles for medical research (WMA 2013). The right to compensation is also stated in Indian guidelines, though the imprecise language has worked to the benefit of pharmaceutical companies.

According to Indian GCP guidelines, subjects who suffer injury or death as a result of trial participation are entitled to be compensated “equitably for any temporary or permanent impairment or disability subject to confirmation from IEC.” (CDSCO 2001: 2.4.7). The guidelines also assert that this applies to all trials, whether conducted by “a pharmaceutical company, a government, or an institution” (CDSCO 2001: 2.4.71). The sponsor should agree, before the research begins, “to provide compensation for any serious sphysical [sic] or mental injury for which subjects are entitled to compensation or agree to provide insurance coverage for an unforeseen injury whenever possible.” (CDSCO 2001: 2.4.7.1) Prospective trial subjects should be informed of their right to compensation. Before a clinical trial starts, the researcher must provide evidence that compensation for trial-related injury will be available. The trial sponsor is responsible for ensuring that the investigator promptly reports injuries and deaths to the IEC and other competent authorities, and submits all medical and related documents.

However, the GCP guidelines do not specify details such as who determines whether or not the injury is related to the trial, how this is determined, or what an “equitable” compensation is. They only state that compensation is “subject to confirmation from IEC”.

Similarly, the guidelines of the Indian Council of Medical Research (ICMR) state: “The sponsor whether a pharmaceutical company, a government, or an institution, should agree, before the research begins, in the a priori agreement to provide compensation for any physical or psychological injury for which participants are entitled or agree to provide insurance coverage for an unforeseen injury whenever possible.” (ICMR 2006: 29). The research institution “could” set up an arbitration committee “where such a step is feasible”. (ICMR 2006: 29) However, they give no further details on the roles required to be played by the sponsor, the investigator, the IEC, and the regulator. Until recently there were no rules spelling out these requirements.

Trial sponsors call the shots

It is not surprising that sponsors of clinical trials drafted policies on compensation for injury to their own benefit. Monitoring bodies such as ethics review committees have not insisted on participants’ right to compensation for injury or death. A study interviewing investigators, members of ethics committees, and sponsors, and reviewing informed consent documents, found that “47% of investigators were either unaware of, or had not understood, the legal requirements and depended on sponsors to manage these issues.” One in four (26%) ethics committee members were unaware that compensation was required. 40% of investigators, 30% of ethics review committees and all the sponsors interviewed reported that their institutions had policies on compensation. However, these policies were almost exclusively for provision of limited medical care, or reimbursement of medical expenses. These policies did not cover compensation for time and wages lost, injury or death, though this was required by law (Thatte et al 2009)iv.

Increasing reports of unethical trials

The consequences of this lax regulatory framework soon became apparent. Reports emerged of unethical recruitment practices and unethical research: both government and private doctors, motivated by incentives from drug companies, recruiting patients for drug trials without their voluntary, informed consent; research ethics review committees approving unethical trial designs that put participants at risk of harm; particularly vulnerable groups being recruited without scientific justification for their inclusion, and without ensuring that they were able to consent; and poor patients entering trials on their physician’s advice, to obtain free treatment or better treatment (Srinivasan 2009). Reports, many of them based on investigations by advocacy organisations, also emerged of patients suffering injuries or dying in trials. It is not an accident that participants in clinical trials come from particularly vulnerable and marginalised sections of society. A few examples are cited below.

In August 2008, it was learned that 4,142 paediatric patients in the government’s All India Institute of Medical Sciences (AIIMS) – a hospital used mostly by poor patients -- had been part of clinical trialsv and 49 children died in these trials. The government disclosed this in reply to an application by Rahul Verma of Uday Foundation under the Right to Information (RTI) Act. An AIIMS representative is quoted as saying: "All the deaths can't be attributed to the trials. Some patients were suffering from conditions in which mortality was the normal outcome and we were trying to see whether a drug could improve the situation (Sinha 2008). According to the RTI reply, all deaths in clinical trials in the hospital were discussed in review meetings and data safety monitoring board meetings, notified to the trial sponsor, and reported in publications (AIIMS 2008). However, the government did not reveal the details of any investigation into these deaths: whether they had in fact been investigated and what the conclusions were. Though the government announced an inquiry in response to the public outcry following news reports, the results do not seem to have been made public.

In 2010, it was learned that over 25,000 girls had been administered a vaccine against Human Papilloma Virus (HPV) infection, in what a Parliamentary Committee report confirmed was a clinical trial (GoI 2013) vi. The trial was conducted by the international NGO PATH in collaboration with government organisations, in tribal regions of Gujarat and Andhra Pradesh, using vaccines provided by Merck, Sharp & Dohme and Glaxo SmithKline and with financial support of the Bill and Melinda Gates Foundation. At least seven girls who had been administered the vaccine died. A report published by the advocacy group SAMA Resource Group for Women and Health identified serious malpractices at many levels: government organisations collaborated with an international NGO to further the interests of private pharmaceutical companies; minors in marginalised communities were targeted for the trials; the informed consent documents were misleading and signatures on the forms were forged; there was no proper follow-up of the girls who had been vaccinated; and injuries and deaths following immunisation were not investigated, nor medical treatment provided, and so on (Sarojini et al 2010).

In 2010, it became known that the Bhopal Memorial Hospital & Research Centre (BMHRC), set up specifically to provide free treatment to survivors of the 1984 gas leak, had conducted drug trials for foreign pharmaceutical companies vii between 2004 and 2008. 215 of the 279 trial participants were gas survivors, though none of the drugs tested were for conditions specific to gas-affected people. At least 14 died.

Participants (or the next of kin of those who had died) traced by the advocacy group Bhopal Group for Information and Action (BGIA) were unaware that they had been part of a drug trial (Lakhani 2011). Even otherwise, as people dependent on free treatment, the gas survivors would have found it very difficult to refuse to be in the trial. The critically ill would have found it even harder to refuse. For example, patients in the trial of Organon/ Sanofi’s –blood thinner Fondaparinux were recruited even as they were experiencing a heart attackviii. Moreover, at least one of the trials violated the rules in place at the time: the study of Fondaparinux received DCGI approval in July 2004 and started recruiting patients in September 2004, four months before the law permitted multinational pharmaceutical trials in India.

The campaign against unethical trials

In 2012, the Indore-based organisation Swasthya Adhikar Manch and Anand Rai filed separate cases in the Supreme Court of India, calling for an investigation of clinical trials in India and appropriate action against unethical and illegal trials. They asked for information on the number and type of trials being conducted in India, the number of people who had been recruited into these trials, the number of injuries and deaths, and the medical treatment and compensation given (WP [civil] 33/2012 and WP [civil] 79/2012). The Supreme Court clubbed the two cases along with an intervention by groups in Bhopal. Public interest litigation was also filed regarding the unethical trials of the HPV vaccine (Kalpana Mehta and others in WP [civil] 558/2012 and SAMA and others in WP [civil] 921/2013).

Government reports submitted to the Supreme Court and Parliament confirmed that regulatory authorities were grossly derelict in their duty to monitor clinical trials and protect trial participants. The pharmaceutical industry, not the government, decided whether each serious adverse effect (SAEix), including death, was related to the drug, whether to pay a compensation and how much. Just 3% of deaths reported in clinical trials were attributed to the drug (Jesani 2013). Compensation amounts -- when paid -- varied according to the sponsor and were as low as Rs 50,000 (GoI 2014).There is no record of money paid to people who suffered “non-death” SAEs in a trial (Jesani 2013).

Finally, rules for the conduct of clinical trials

The PILs, along with investigations by advocacy groups, media reports and questions in parliament, have been instrumental in strengthening the regulatory framework for clinical trials in India. The new regulations (CDSCO 2014a) on the conduct of drug trials in India include those for registration of clinical trials; registration, composition and functioning of ethics review committees which reviewed and approved trials; registration of clinical research organisations; standard operating practices for inspection of clinical trial sites, audiovisual recording of informed consent, and so on.

In July 2014, the CDSCO announced a proposed online database with comprehensive information on each clinical trial, to be uploaded before applying for permission to conduct the trial, and updated daily by sponsors, researchers and IECs. This would include details of the drug being tested, the informed consent documents, IEC decisions, all participants, any SAEs, their investigation and compensation claimed and paid, if applicable (CDSCO 2014b). It is not clear how much of this information, if any, would be in the public domain. One major demand of advocacy organisations has been for the government to make such details public.

Rules on compensation for trial-related injury

In January 2013, the CDSCO introduced draft rules on compensation for serious adverse events including death in clinical trials. These rules represent a major advance from regulations elsewhere in the world. The sponsor of the trial is required to pay compensation, and not only for SAEs caused by the investigational drug, but also for those that occurred due to misconduct by the investigator or sponsor; failure of investigational drug to provide the intended therapeutic effect; use of placebo in a placebo-controlled trial; other medication (other than standard care) necessitated by the trial protocol; injury to the child in-utero, and any clinical trial procedures in the study. That is, compensation would not be limited to cases in which the SAEs were attributable to the experimental drug alone; it would be awarded in all cases in which the SAE was attributable to trial participation itself. The new rules also required that the trial sponsors provide free medical management for all injuries or illnesses suffered in these trials, whether or not they were related to the experimental drug, for as long as is required.

The finalised rules (CDSCO 2014c) were amended apparently because of pressure from the pharmaceutical industry: compensation for failure of the investigational drug, or due to the use of a placebo, can be granted only if standard treatment was available but not provided. Moreover, free medical care is to be provided only until it is established whether the injury is, or is not, related to the clinical trial x.

Timelines have been laid down for all steps in the reporting and review of SAEs, decisions on compensation, and its disbursal. The trial’s principal investigator (PI) is required to report SAEs, in a specified format, to the Drugs Controller General of India (DCGI) of the CDSCO, the institutional ethics committee (IEC) which reviewed the protocol and monitors the trial, and the trial sponsor; the sponsor is required to send a report to the DCGI. The IEC is required to review the PI’s report and submit its assessment to an expert committee, appointed in 2013 to review all cases of death in clinical trials. The expert committee receives the reports of the PI, the IEC and the sponsor to make a final assessment on whether or not the SAE is related to the trial, and sends it to the DCGI. The DCGI informs the trial sponsor if compensation is to be paid, and if so how much. The sponsor must make the payment within a given time. Formulae have also been issued for calculating the quantum of compensation for death and for serious injury but have met with widespread criticism (Ramanathan et al 2013; Ambhore et al 2014)

Need more than just a law

However, it will take more than such rules to ensure that all people injured in drug trials are even awarded this compensation, let alone receive it. There is a need to improve the conduct of trials themselves, their review and monitoring in order for the new rules to have a significant impact. Regulatory mechanisms must also compensate for the enormous disparity in the situations of sponsors and participants – their differential access to money, information, legal representation and influential ‘contacts’. The clinical trials industry is powerful and will resist regulation. The trial participant at the centre of the industry is invisible and has no voice. This situation, along with the inherent complexity of ascribing medical causality, may make it very difficult for the participants to obtain compensation even under the new rules.

Some of these problems are discussed using CDSCO’s inspection reports of three trials in Bhopal, obtained by BGIA; the report of a Parliamentary Committee on the HPV vaccine trials, and interviews with expertsxi. These reports followed exposes by advocacy organisations. The malpractices described in these reports will be just the tip of the iceberg. The workings of the clinical trials industry remain opaque, shielded by the government in the name of protecting trade secrets (Sengupta et al 2011) and participants’ confidentiality.

Shoddy research practices

Incomplete and substandard documentation, poor follow-up and delayed reporting of SAEs were among the major irregularities identified by all the experts interviewed. These were also apparent in the Bhopal and HPV trials.

The investigating team of the trial is supposed to maintain complete documentation of all aspects of the study, monitor all subjects on a regular basis and document these details, follow up outpatient as well as in-patient participants when they are discharged, and ensure that they can contact the investigator at all times of the day and night if they fall ill, or have any questions. The trial sponsor is responsible for ensuring that the investigating team complies with these requirements, by scrutinising the data submitted and conducting site visits.

However, PIs may be reluctant to report serious adverse events as they could be due to negligence. Moreover, since serious adverse event reports related to the investigational drug reduce its value to the sponsor, PIs may view such reporting as contrary to the interests of the sponsor.

Another reason for these delays is that out-patient trial subjects living far from the trial centre will find it difficult to travel to the trial centre for treatment, especially if their conveyance expenses are not compensated forxii. Treatment given at small health centres is likely to be poorly recorded, and the details will probably not be reported to the trial centre. Researchers who do not follow up with their subjects (or do not provide them with telephone numbers where they can be reached at all times of the day) will not learn about their illness or death until the next visit is due -- if in fact another visit is due. By the time they do get this information, if the subject has died, the body could have been cremated without a post mortem. Researchers who are not meticulous in following up trial participants may also just lose all contact with those who have moved to another town or city. Injuries or deaths of such subjects will not even be recorded in the trial data, resulting in an under-estimation of the number of SAEs in the trial.

In the HPV vaccine trial, researchers actually chose not to follow up the girls once they administered the vaccine. They relied, instead, on a routine surveillance – known to be grossly inadequate – for reports of any injuries or deaths, thereby violating the legal obligation to report all adverse events and deaths in a clinical trial within a specified period (GoI 2013).

The Parliamentary Committee report on the HPV vaccine trial noted that the deaths were reported to the authorities much later than required by government guidelines, “action on investigations into the causes of deaths took an unacceptably long time” and there were many “discrepancies and gaps in the investigations of the deaths” (GoI 2013: para 6.19). The medical records were inadequate, and the staff were not prepared to deal with the SAEs. The committee concluded that the possibility that the deaths were related to the vaccine could not be completely ruled out “mainly because the alternate cause of death as listed can not be fully substantiated on the basis of medical records in all the cases.” (GoI 2013: 38). The committee also questioned the accuracy of the SAE reporting; there may have been more deaths in the trial that were not reported.

The CDSCO inspections of trials in the BMHRC hospital in Bhopal found delayed reporting in all three trials (CDSCO 2010, 2011a, 2011b). In the trial of Wyeth’s antibiotic Tigecycline (conducted on hospitalised patients with serious infections), SAE reports were delayed by between 40 days and five months. Three deaths were recorded in the Wyeth trial, but there was no follow-up of a patient who suffered an SAE and sought a discharge against medical advice. So “no information was available to the inspection team for the current status with respect to condition of health of the above mentioned subject”. In the trial of Theravance’s antibiotic Telavancin, one of the deaths was reported to the IEC more than eight months after it occurred. In the trial of Organon/Sanofi’s Fondaparinux, in which six people died, at least one SAE was reported three weeks after it occurred.

Negligent ethics review committees

Schedule Y requires the IEC to review and approve the clinical trial protocol and monitor the conduct of the trial to protect the health and rights of trial subjects. The IEC has the power to halt a trial if it is felt necessary (GoI 2005) and is empowered to pay site visits (ICMR 2006). Starting in 2014, the IEC is also charged with assessing the SAE reports submitted by the PI and forwarding this assessment to the EC and the DCGI, and with awarding compensation for non-death SAEs.

It is well known that many members of IECs are investigators in industry-funded research and will have conflicts of interest when reviewing trials funded by the same company -- or even of competitor companies. It is also known that such conflicts of interest are not always disclosed (Campbell et al 2006). IEC members from within the institution may tend to give in to the views of senior colleagues and it is not uncommon for the director of the institution to be a member of the IEC.

The CDSCO inspection teams in the Bhopal trials (CDSCO 2010, 2011a, 2011b) found that none of the IECs followed standard practices on membership, terms of reference, review and decision-making procedures, review of SAEs, etc. The IEC minutes in the Fondaparinux trial indicated that the committee approved the protocol “without proper scrutiny of safety aspects”. And though IECs are required to meet after each SAE is reported, to consider whether the trial should be halted, there was no record of the IECs in the Fondaparinux and Tigecycline trials having reviewed the trial after deaths were reported.

The IEC reviewing the Fondaparinux trial would have been aware that the secretary of the IEC is married to the PI. Yet it approved an informed consent form that carries the PI’s telephone number to report injuries, and the IEC secretary’s telephone number for information on the participant’s rights: aggrieved participants would have to complain to the PI’s spouse. This obvious ethical violation seems to have been missed by the IEC.

There were two ethics committees charged with monitoring the HPV vaccine trials. The Parliamentary Committee report found both to be grossly negligent, noting that they “existed only as a formality and they did not play the role they were designated for” (GoI 2013: para 6.24). Though ethics committees are required to meet and monitor the progress of the trials and review SAE reports, “Only after reports of deaths appeared in the media, the meetings of these committees were held... This is a clear dereliction of duty on the part of the Ethics Committees.” (GoI 2013: para 6.23).

Regulators who do a whitewash job

Such serious lapses should lead regulators to at least question trial sponsors’ conclusions as to whether the death of a trial subject is related to the trial. However, when inspections are motivated entirely by public pressure, as was the case in the Bhopal and the HPV vaccine trials, the report may identify numerous violations only to absolve the investigator and others responsible.

Indeed, the CDSCO inspections in Bhopal identified lapses in all three trials, including violations by the PIs (such as late reporting, improper documentation and “improper” causality assessments) that could have affected the proper assessment of the SAEs reported. Despite noting these lapses, the investigators’ assessments – that none of the deaths were related to the trials – were accepted. At the very least, the inspection teams should have demanded a re-investigation into the SAEs. Interestingly, the reports contain many identical passages, in some cases contradicting other portions of the report, evidence of a careless copy-paste job. Clearly the inspections were a hurriedly conducted whitewash.

In the case of the HPV vaccine trials, the Parliamentary Committee report is a scathing criticism of the role of government institutions at every level: the state departments of health, the Indian Council for Medical Research, the DCGI, and even the government’s inquiry committee, whose members identified many ethical and legal violations but absolved all parties of responsibility. The Parliamentary Committee report also notes that at least two members participated in the inquiry without reporting major conflicts of interest (GoI 2013).

Difficulties assessing ‘relatedness’ of the injury

Starting in 2013, the government’s expert committee scrutinises each SAE report to assess its “relatedness” to the trial. But the assessment method is acknowledged to be imperfect and in many cases, opinions can differ on whether the death was related to the trial. In such situations, there is scope for decisions to be biased against the participant.

It was in the course of the SC case (33/2012) that the government disclosed that 3,458 people had died in clinical trials between January 2005 and December 2012, as reported by drug companies. Only 89 of these deaths were attributed to the trial, according to reports submitted by the companies. Another 14,320 “non-death SAEs” were reported, of which 506 were attributed to the trials (Legal correspondent 2014).

A detailed review of the 679 deaths reported in 2010 found that only 25 were attributed to the drug. 92 were of ‘indeterminate causality’ – ‘possible’, ‘probable’, ‘unlikely’, ‘implied’, ‘suspected’, ‘suspected to standard therapy’, ‘dubiously suspected’, ‘not suspected’, and ‘doubtful’. In an additional 30 deaths, there was no information on causality (Jesani 2013).

No explanation was given of how the sponsors made any of these assessments, why they decided that deaths with ‘indeterminate causality’ should not be compensated, and why they had not conducted causality assessments for 30 deaths. Obviously sponsors were not required to justify their assessments to the regulators.

The collective wisdom of experts

It is only in 2013 that the CDSCO started conducting its own causality assessment of deaths in clinical trials. In December 2014, it was learned that the expert committeehad examined 220 of the 370 deaths reported by trial investigators and their sponsors from January 2013. Compensation had been awarded in 21cases, based on a formula worked out by the government (Pulla 2014). Nowhere is it mentioned how the committee made its causality assessment.

At present, Schedule Y does not specify the method by which causality assessments are made. An assessment protocol is reportedly in the process of being finalised. The expert committee currently uses a method that has been described as “global introspection” or “the application of collective wisdom of experts”xiii.

Each SAE report along with all documents submitted by the PI, and the assessment made by the IEC, is scrutinised by a team from the panel of experts on the expert committee. This team usually (but not always) has a clinical pharmacologist and a subject expert (for example, in a trial of a cardiac drug, a cardiologist). It may call on another expert for an opinion, and the PI of the trial if needed. The team considers questions such as: is there a temporal relation between the drug and the SAE? Is the drug known to cause this SAE? Is the drug’s mechanism such that it might have caused the SAE? Are there other causes of this SAE? Could it be due to the natural history of the illness? Could it be a drug-drug interaction? The assessment process does not consider non-medical causes, so, for example, it would not dismiss the case of a woman in a contraceptive trial who suffers domestic violence because her husband learns of her contraceptive use, though the injury itself might be reported as an adverse event.

The team must decide if an injury is ‘related’ or ‘not related’; it may not use any other categories, even if it is unable to be completely sure if the death is – or is not – related to the trial. It must arrive at a decision by consensus.

No place for the trial participant

Neither the expert committee nor the IEC hears from trial subjects or their relatives. They will certainly have important information that the PI was not aware of or did not supply. They could have information about the injury or death itself or about possible negligence by the investigator or sponsor. While the IEC may call the participants or relatives if it is felt necessary, this is not required. The participant, who is at the centre of the clinical trials industry, who personally accepts the risks of research that is meant to generate knowledge beneficial for others, is invisible in the entire process.

Johari and others have written a detailed critique of the draft rules for compensation in which they have called for all SAEs to be investigated by an independent expert committee. This committee would, in addition to the documents provided by the investigator and sponsor, hear from participants as well as make its own inquiries. They have also criticised the narrow definition of SAE as physical harm that occurs during the trial, and called for a comprehensive understanding that includes psychological harm, social harm, loss of livelihood, and harm that becomes evident much after the trial ends xiv (Johari et al 2014).

Consensus built by influence

All the experts interviewed asserted that causality or relatedness assessment is a complex, technical issue. Very often, it is not possible to conclude with certainty whether or not a participant’s death was due to the trial. However, the expert committee does not have guidelines on how to make decisions in such cases.

Each decision in a difficult case will be influenced by the views of the experts reviewing that case. Experts can have conflicts of interest if they are also investigators for industry-sponsored trials. Their judgment is likely to be influenced by their views on the question: does the injured participant deserve the benefit of doubt? Some experts hold that unless one can say with certainty that the injury was not caused by the trial, it should be treated as caused.

If there is an unresolvable disagreement within the team of experts, it would be correct to keep the case open until the team receives additional information or expert opinion that allows it to make a final decision. However, this is, in the end, a matter of judgment, and some experts concede that the judgment of the senior-most expert could prevail.

Experts say that their most common problem is that PIs submit insufficient information. In such a situation, an expert says, “The EC is at liberty to call for more information and to keep the case on hold until it is satisfied.” What if the EC does not call for this information? What if more information is just not available? Should the EC make an assessment nevertheless? There are no explicit guidelines for these situations.

In such situations, it would be unfair to rule against the participant because the researcher and sponsor have not done their job. “In a clinical trial, documentation is a key prerequisite,” says an expert. “Subjects are supposed to be closely followed up. If this has not happened, it is a failure of the PI and the sponsor.”

Surely, when there is not enough information to decide on relatedness, the benefit of doubt should go to their next of kin.

“My personal view is that the subject should be entitled to compensation as soon as screening (for eligibility, such as a stress test) starts,” says one expert. “If the patient’s death could have been delayed if s/he had not considered participation in the trial, if s/he agreed to participate and his/her death was preponed, s/he should be entitled to compensation.” However, this view may not be shared by all the experts assessing a particular death

 

In conclusion, there are times when it is just not possible to state with certainty if a person who died in a clinical trial died due to participation in the trial. As there is no well-defined protocol for causality assessment, with instructions on how to resolve differences of opinion, or to decide with insufficient information, these decisions will depend on the views of individual experts, and the assertiveness or persuasiveness of the experts on the team. The deliberations of the EC are not made public.

A partial victory

The new rules on compensation for injury and death could be viewed as a victory for those who have been campaigning against unethical practices in the clinical trials industry. However, in the present circumstances, it is a very partial and conditional victory. The acid test is whether they help protect trial participants and deliver justice to those who have suffered. In fact, many trial participants or their families who deserve compensation for cases of death or injury will not receive compensation, for reasons spelled out above.

This commentary highlights some problems in the process leading up to establishing a trial subject’s right to compensation: the quality of documentation in a trial, reporting of injuries and deaths, functioning of monitoring mechanisms and difficulties in assessing causality.

The current discussion must continue to be located in the issues raised by advocacy organisations: the unethical and illegal practices of many trial sponsors which provoked the campaigns for regulation and transparency in clinical trials, and the wide disparity in resources and access to the law between the trial sponsors and the participants. This disparity can only be reduced if the State takes an active regulatory role in the entire process. In the case of injury or death, it must use a definition of injury that goes beyond immediate physical harm. It must also establish clear guidelines for causality assessment that include the views of trial participants and their families, and give the benefit of doubt to trial participants and their families, rather than to trial sponsors. It is essential that all aspects of this process be made public. Unfortunately, the actual record of State and administrative conduct, discussed above, does not inspire much confidence.

Acknowledgements: This comment is based on work funded by Wemos Foundation, Amsterdam, The Netherlands. I thank Rachna Dhingra and Hazra Bee of the Bhopal Group for Information and Action for making available documents obtained related to the trials in Bhopal.

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i Phase I trials collect information on the drug, including its safety and adverse reactions. They are usually conducted on a small number of healthy volunteers. Phase II trials evaluate the effectiveness and safety of a drug on a small number of patients. Phase III trials are conducted on larger numbers of people to confirm the evidence from earlier phase trials towards obtaining marketing approval of the drug. Until January 2005, India required a ‘phase lag’: phase 2 trials could be conducted in India only after the phase 3 trial had been conducted abroad. This ruled out India as a site of a multi-country trial. Multi-country trials of the same phase were permitted only for drugs with special relevance to India, such as, for example, new antibiotics for tuberculosis. In January 2005, the law was changed to permit trials of drugs being developed abroad to be tested in the same phase in India as they were abroad.

ii Compensation for research-related injury is separate from punitive compensation for the harm done because of illegal or unethical practices.

iii Unfortunately, this right is not recognised universally. In some countries, injured participants receive compensation without having to prove that the injury was caused by the trial. On the other hand, in the US, trial sponsors are not required to pay compensation for injury; they are not even required to provide medical treatment.

iv The sponsor, not the regulatory authorities, also decided on whether compensation should be paid, if one goes by the informed consent form for Organon/Sanofi’s trial of the drug Fondaparinux in Bhopal: “In the event that injury occurs as a direct result of administration of the investigational drug under study, necessary medical care will be available. However, neither free medical treatment nor any financial compensation for any illness or injury will be provided unless the study sponsor, Organon, in its discretion, approves payment for such medical care.”

v The top sponsors were the ICMR, DBT, WHO, AIIMS and Johns Hopkins. The drugs tested included Rituximab, Olmesartan, Valsartan provided by Novartis, Gene activated human glucocerebrosidase from Shire Human Genetics Therapies, USA.

viThe Parliamentary Committee report stated: “the demonstration project is a study of a pharmaceutical product carried out on humans and since the primary objectives include the study of serious adverse effects, it is clear that clinical trial rules and guidelines should apply” (GoI: 2.3).

viiAstra Zeneca, Wyeth, Pfizer, Theravance, Schering Plough, GSK and Sanofi (earlier Organon), in the departments of cardiology, pulmonary medicine, gastrointestinal surgery, anaesthesia and psychiatry. Many of these were conducted by the contract research organisation Quintiles.

viii The informed consent form of the Fondaparinux trial states: “You are being asked to participate in this trial because you are experiencing clinical signs and symptoms of a heart attack.”

ix The CDSCO defines a Serious Adverse Event (SAE) as any untoward medical occurrence that results in death, or requires inpatient hospitalisation or prolongation of existing hospitalisation or results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect.

x The rule as finalised in December 2014 is not clear: “free medical management shall be given as long as required or till such time it is established that the injury is not related to the clinical trial, whichever is earlier;”. This does not indicate that treatment will be provided free even once it is established that the injury is related to the trial.

xi The following documents provided by activists in Bhopal are referred to: CDSCO’s inspection reports of two trials in Bhopal: Tigecylcline (Wyeth Pharmaceuticals) and Fondaparinux (Organon later transferred to Sanofi Synthelabo and then GSK Ltd); the CDSCO’s warning letter for a trial in Bhopal on Telavancin (TeravanceInc); and an informed consent document template for the Fondaparinux trial. Interviews were also conducted with various experts including some members of the newly formed expert committee entrusted with assessing SAEs.

xii Both Indian GCP and the ICMR guidelines state that participants must be compensated for travel and related expenses. None of the three trials in Bhopal inspected by the DCGI compensated participants for travel and related expenses.

xiii There are alternatives to the expert opinion method, such as the causality assessment system developed by the WHO-Upsalla Monitoring Centre or the Naranjo Scale, both of which have been discussed by CDSCO experts for modification. Both scales can help arrive at judgments of ‘certain’, ‘probable’, ‘possible’ and ‘unlikely’. They would have to be converted into a ‘binary’ system to arrive at a yes or a no, or ‘related’ or ‘unrelated’, in order to make decisions on compensation. It is generally acknowledged that none of the algorithms and scales used for causality or relatedness assessment is perfect.

xiv Both the GCP and the ICMR guidelines include mental or psychological harm within the definition of injury for which compensation must be paid, but the CDSCO’s definition of SAEeligible for compensation does not mention mental harm.

Infochange News & Features, August 2015