Compensation package for clinical trial victims in the offing

India will soon quantify the amount of compensation to be paid by pharmaceutical companies, if a volunteer dies or gets injured during a clinical trial.

On October 10, the Drug Technical Advisory Board (DTAB) gave its nod to the Central Drugs Standard Control Organization (CDSCO) to prepare a "compensation chart" or extensive guidelines that will specify the amount to be paid. Ethical committees of the company will have to decide the quantum of compensation on the basis of these guidelines.

The compensation has to be paid by the trial's sponsor or its representative within 90 days of the death or injury to the victim or the next of h/his kin. In the first 30 days, the firm will have to prove to the ethics panel that the death or injury wasn't due to the drug, else it has to pay.

In India, pharma companies pay compensation "according to their will" that varies between Rs 1 lakh and Rs 10 lakhs since "no set parameters have been laid down". The CDSCO will prepare the compensation guidelines after consulting the Motor Vehicles Act, Railways and the Workers Compensation Act. Union health ministry officials say it will take another three months to notify the guidelines. "When a 70-year-old terminally ill patient dies during a clinical trial, the compensation should be less than that given to a 22-year-old in the first stage of the same ailment. The youngster could be the family's sole bread-winner and would have lived longer had it not for the adverse drug reaction. 

The guidelines will quantify who should get how much compensation," a ministry official told TOI. "Both these patients could get the same amount. However, the pharma company might have decided on an abysmally low package. Once the guidelines are in place, the division of compensation will be fair," he added. 

Families of the 22 clinical trial victims last year were paid around Rs 50 lakh by 10 pharma companies. Compensation ranged from Rs 1.08 lakh to Rs 10 lakh. Most of the families received Rs 1.5 lakh and Rs 2.5 lakh as a one-time package. Initially, the companies had not paid compensation for majority of these deaths. Then, DCGI Dr. Surinder Singh issued an ultimatum to the errant firms: pay up or all other trials would be suspended. 

The companies who paid the compensation included well-known names like Wyeth, Quintiles, Lilly, Amgen, Bayer, Bristol Mayer, Sanofi, PPD and Pfizer. Pharma companies have all along been blamed for not paying compensation to hapless clinical trial victims. The Indian Council of Medical Research recently framed draft guidelines for compensation to participants for research-related injury. Mothers, who because of clinical trials, lose or cause harm to their unborn child may be able to demand compensation from researchers conducting the trials. Compensation has to be paid, irrespective of whether injury was foreseeable/predictable, and that the research participant had freely consented in writing about participating in it.

Compensation will have to be provided to the research participants when temporary or permanent injury occurs due to participation in the clinical study. Compensation also has to be paid when the injury is caused by a procedure that has been undertaken to manage an adverse reaction occurring during the research. 

Defining "compensation", the draft says it could be in form of payment for immediate medical/surgical management of research-related injuries, compensation for research-related injuries leading to temporary or permanent disabilities or compensation to legal heir/lawful guardian in case of death. "The payment will be the responsibility of the investigator/institution," it says. Besides, the Informed Consent Document (ICD) will have to state that the research participant has the right to claim compensation in case of research-related injuries and whom to contact for it.

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Unauthorized Clinical Trials on Bhopal Victims

Ajay Shrivastav from Bhopal, the central Indian city that witnessed one of the worst industrial disasters of the world in 1984 from a deadly gas leak, is an angry man seeking justice.

A year ago, Ajay learnt that his father Ramadhar Shrivastav, a victim of the toxic gas that had engulfed Bhopal in 1984, has been subjected to clinical trials in a hospital that was meant to treat the gas victims.

"We were shocked. We are planning to move legally now against such unauthorised clinical trial," Ajay Shrivastav told IPS.

A Bhopal court last year sentenced eight former top officials of the Indian subsidiary of Union Carbide Corp (UCC) to two years imprisonment each for the 1984 gas leak that eventually killed about 20,000 and left many more incapacitated.

Several of the victims were under prolonged treatment, and some of them fell prey to unauthorised clinical trials without their knowledge.

Ramadhar Shrivastav was part of the Astra Zeneca (a global biopharmaceutical company) trial. He is too sick to speak to anyone.

"At this site in India (Bhopal), some patients were not properly consented," a spokesperson of the company told IPS, admitting that clinical trials indeed took place without patients' consent.

"These errors were discovered by AstraZeneca through monitoring processes we employ for all of our clinical studies and promptly corrected by the investigator," the spokesperson said.

"Good clinical practice requires investigators to obtain study patients' informed consent," the company said.

Earlier, Indian health activists in Bhopal gathered proof that the Bhopal Memorial Hospital and Research Centre (BMHRC), which was built with funds from Union Carbide shares confiscated as part of the criminal case on the gas leak, carried out clinical trials on gas victims without their knowledge.

Official documents show that hospital director K. K. Maudar has admitted to the Drugs Controller General of India (DCGI) that there were drug trials. The official documents show that 80 percent of those subjected to clinical trials were victims of the 1984 disaster.

"We have documents showing the details of deaths in the three trials - Fondaparinux (cardiology) and Tigicycline (gastro surgery) and Televancin trial (anaesthesiology) - that took place at BMHRC," Rachna Dhingra of the Bhopal Group for Information and Action told IPS.

"It clearly mentions that almost all people who died were gas victims."

According to the DCGI, six trials were carried out at the BMHRC while the activists say there were more such trials.

"We believe that as many as 10 drug trials were carried out by BMHRC. In their own account statement which was submitted to DCGI they clearly show that they received money for 10 different trials," says Dhingra.

The trials were conducted on 215 gas victims, according to the figures mentioned in the letter of the hospital  director to the deputy drug controller of India, Dr R. Ramakrishna, on Feb. 22 this year. The letter also gives a breakdown of the drug trials.

Dr Chandra Gulhati, editor of the New Delhi-based Monthly Index of Medical Specialties, said the BMHRC was set up in 2000 to provide super-specialty care to survivors of the tragedy and carry out research on long-term effects of the methyl-isocyanate (MIC) chemical that caused the deaths.

"But instead of concentrating on MIC-related issues, the hospital became a hot spot for conducting clinical trials on untested drugs that were primarily designed to help pharma companies," he said.

According to a World Health Organisation (WHO) bulletin report in 2008 titled 'Clinical trials in India: ethical  concerns', transnational drug companies are moving their clinical trials business to India, giving a new urgency to clinical trials registry reform.

India's powerful industry association Associated
Chambers of Commerce and Industry (ASSOCHAM) says the country is set to grab clinical trials business valued at approximately 1 billion dollars by the end of 2010, up from 200 million dollars the previous year, making the subcontinent one of the world's preferred destinations for clinical trials.

FairDrugs.org, a campaign by a worldwide coalition of health organisations and scientists led by Wemos Foundation in the Netherlands, says people living in countries like India run a high risk from pharmaceutical companies testing drugs on them unethically for the Western market.

An Indian research report published in 2009 shows several pharmaceutical companies' disregard for ethical rules.

"The Indian Centre for Studies in Ethics and Rights has examined, among other things, the way GlaxoSmithKline tested a breast cancer drug on seriously ill women in India," said Annelies den Boer of the Dutch Wemos Foundation, co-commissioner of the study with the Centre for Research on Multinational Corporations (SOMO).

Sandhya Srinivasan, a researcher who along with Sachin Nikarge documented the report for the Centre for Studies in Ethics and Rights, Mumbai, said it was found that "these trials exploited the fact that most Indians do not have access to good quality and affordable care and therefore may accept offers that might provide better quality and free treatment."

Gulhati says the clinical registration process in India should be more stringent.

"The Drugs Controller General of India should make it obligatory for all trials to be registered on the Clinical Trials Registry site before permission is granted to conduct them."

He said failure to do so should carry a penalty. "In addition, while registering trials, the composition of hospital ethics committees, which approved the trial, should be disclosed. Fewer than 40 ethics committees in India are properly constituted and functioning, which means that the safety of the subjects of clinical trials is on the  back burner."

An increasing number of hospitals are now owned by drug companies, he said. "Clinical trials at such hospitals should carry a statement of disclosure about the relationship."

According to den Boer of Wemos, "time after time we see that patients in developing countries are used to test drugs that are primarily intended for the European market. Contrary to the ethical guidelines, these patients do not benefit from the research results."

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Health Min constitutes 12 new drug advisory committees to help DCGI on new drugs, clinical trial applications

The Union health ministry has formed 12 New Drug Advisory Committees (NDAC), comprising experts in the respective fields, to advise the Drugs Controller General of India (DCGI) in matters for review of applications of new drugs and clinical trials.

Each of the panels set up to advise in matters related to review and regulatory approval of clinical trials and new drugs, except for Investigational New Drugs (INDs), relating to different therapeutic areas, has ten members. The panels were formed on reproductive and urology, cardiovascular and renal, ophthalmology, vaccines, dermatology and allergy, anaesthetics and rheumatology, neurology and psychiatry, pulmonary, oncology and haematology, gastroenterology and hepatology, metabolism and endocrinology, and antimicrobial-antiparasitic-antifungal-antiviral areas.

“The committee will advise DCGI in matters to undertake in-depth evaluation of non-clinical data including pharmacological toxicological data, clinical trial data (phase I, II, III, and IV) furnished by the applicant for approval of new drug substances of chemical and biological origin to be introduced first time in the country including vaccines and r-DNA derived products,” according to an official note by the health ministry.

The panels will also evaluate data being submitted by the applicants on global clinical trials, fixed dose combinations of two or more drugs to be introduced for the first time in the country. It will help preparing guidelines for clinical research industry in evolving acceptance criteria for marketing approval of new drugs of different therapeutic categories. The panel will also define roadmap for research industry for appropriate development of new drugs relevant to Indian population.

“While considering cases of new drugs, the committee will examine essentiality and desirability of new drugs in terms of assessment of risk versus benefit to the patient, innovation vis-à-vis existing therapeutic option and unmet medical need in India,” the note said.

Application for new drugs and global clinical trials will be evaluated by the committee either through meetings or by circulation of the applications. The term of the committees is for three years. Office of the DCGI will initially examine the applications and if any data is lacking the same will be informed to the applicant within 45 working days or else the data will be forwarded to the members of the committee in the respective areas.

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Pharma companies must compensate victims of clinical trial errors

Drug companies looking to test their experimental drugs on Indians will not find human lives cheap any more. According to an amendment to the relevant law being planned by the health ministry, the onus of proving that clinical trials did not cause death or injury will now lie with the drug company concerned. Further, in case of death or injury from such trials, the company will have an explicit legal obligation to financially compensate the victims. Currently, India has no clear, enforceable law that mandates a drug company to provide financial compensation to the affected party or his or her dependents in case of injury or death during clinical trials. Neither the Indian Council of Medical Research’s Ethical Guidelines for Biomedical Research nor the Good Clinical Practices guidelines that deal with the subject have the status of law. These guidelines spell out the obligation of the trial sponsor in case the participant incurs physical or psychological injury, but do not delve into how to deal with complications that might arise in such cases.

According to sources, the health ministry is set to mandate payment of compensation to volunteers participating in clinical trials in case of a trial-related death or injury by amending the Drugs and Cosmetics Rules.

“Under the proposed rule, it would be the responsibility of the trial sponsor on behalf of the pharma company to prove before the ethics committee that the injury or death is not on account of clinical trial within 30 days of receiving the report of the injury or death from investigator, failing which the sponsor shall be liable to pay the compensation within 60 days or as decided by the ethics committee,” a health ministry official said. The amount of compensation will be decided on a case-to-case basis by the ethics committee.

The Drug Controller General of India’s (DCGI) office has already proposed the policy changes to make drug companies and other agencies accountable in conducting clinical trials. Further, the Drug Technical Advisory Board (DTAB), the highest decision-making body on such matters, has also endorsed the proposal to make companies liable to duly compensate people suffering from trial related injuries. The DTAB, however, added that DCGI should also consider the feasibility of setting up a tribunal comprising physicians, retired judges and civil society members to decide on disputes and fix the minimum compensation. Also, the time-frame for claiming compensation could also be determined, the board suggested. The health ministry move follows an investigation earlier this year by the ministry which found that most firms undertaking clinical trials had not paid compensation to the relatives of the persons who died during the trials. Of the 671 reported deaths during clinical trials in 2010, compensation was paid only in three cases. Subsequently, the ministry sent show cause notices to over 40 drug firms including Pfizer, Bayer, Novartis and Eli Lilly seeking an explanation. When the DCGI summoned some of these firms to explain their cases in June, they reportedly opted to pay up. While most drug companies which FE contacted refused to come on record on the issue, saying it would be inappropriate to comment on a law which is still in the making, three MNCs said they adhered to internal protocols to decide the compensation once it is proven that a death or injury resulted from the trial and most cases of alleged non-payment was due to oversight of ethics committees. One of them, however, objected to the move to shift the burden of proof to the companies. “There are times when terminally ill patients enroll themselves for such trials after intimation from doctors about the seriousness of their illness. In those cases, it may become very difficult for us to establish a causal relation (between the clinical trials and the death of the patient).”

The Indian clinical research market is estimated to be between $300 to $500 million in 2010. The Indian clinical trial market which offers 30-40% savings to pharma companies compared to the US and EU (E&Y estimate of 2005), is projected to grow annually at a rate of 20%, according to Visiongain, which sees it becoming one of the most-favoured clinical trial destinations along with China by 2015.

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CHAOS IN CLINICAL RESEARCH

The recent irregularities reported in conducting of clinical trials by Axis Clinicals, a Hyderabad based CRO, in Andhra Pradesh has once again brought to focus the questionable ways in which clinical trials are being done in India by the pharmaceutical companies and their agents. The report said that the CRO conducted bio-equivalence studies for an anti cancer drug on poor women early this year without securing their informed consent. The episode came to light only last month when some women belonging to this group complained of severe body ache, joint and chest pain and extreme weakness after taking the drug. A few of them even had difficulty in walking. The office of the DCGI raided the premises of the CRO after report came in the media and suspended its license. Axis also will be disallowed from conducting all bio-availability and bio-equivalence studies at their centre for some time now. Investigation carried out by the DCGI officials found irregularities in procedures such as recruitments of subjects and in taking their informed consents. The DCGI also found that the ethics committee at the centre was not functioning independently as required under the existing ICMR guidelines. Many such violations by CROs while conducting clinical trials in India were reported in the recent past and actions were taken against the offenders. But, these offences keep occurring in various parts of the country and very few of them get reported in the media.

After the action taken against the Hyderabad CRO, the office of the DCGI decided to audit all CROs in the country to ensure that the bio-availability and bio-equivalence studies are performed strictly in accordance with the regulatory provisions and prescribed guidelines. The DCGI office has already completed auditing of CROs in Andhra Pradesh and Mumbai. The basic problem with the clinical research in the country is that the sector is not at all effectively regulated. The health ministry has been working for last ten years to put in place a set of comprehensive rules to regulate clinical research with huge flow of contract research jobs into the country. But that has not happened yet. Ethics Committees at most of the trial sites are not active with no monitoring of the trials. What the country has a set of guidelines after amendment of the Schedule Y of Drugs & Cosmetics Act and it is not yet notified. That is what emboldens the MNCs and CROs to conduct trials as they do it now. Now in the case of CROs, a set of draft rules for their mandatory registration was issued by the DCGI some time in July 2009 after it was approved by the Drug Technical Advisory Board. But the registration process is still not in place. The move to make registration mandatory for CROs was taken after finding a spate of irregularities in conducting trials in the past. In short, the slow decision making process in the health ministry is the prime reason for the whole chaos in clinical research front. The matter has to be taken up by the health minister seriously and urgently if this critical sector of the pharmaceutical industry has to function with some order.

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