Criminal trials

SOME WOMEN BELONGING to Piduguralla of Guntur district in Andhra Pradesh, who underwent clinical trials by a pharmaceutical company in Hyderabad, at the Government General Hospital in Guntur. A June 2011 picture.-T. VIJAYA KUMAR

Questionable drug trials on mentally challenged persons by doctors in Indore emphasise the need for strict enforcement of medical ethics.

IN what appears to be a page out of Robin Cook's medical thriller, government and private doctors in Indore, Madhya Pradesh, reportedly carried out clinical trials of various medicines on some 233 patients who had gone to them seeking psychiatric treatment. As in Cook's famous book Coma, in which a medical student uncovers the unethical practices in a hospital and is targeted, a resident doctor with a prominent government hospital in Indore attempted to expose the unethical trials and was removed from service. The trials, using humans as guinea pigs to test medicines produced by pharmaceutical companies, were conducted between January 2008 and October 2010 without following proper guidelines.

Following a huge public and media uproar over the trials and the related deaths, 12 doctors, including six involved in the trials on mentally ill patients, were fined just Rs.5,000 each for not informing the parent hospital about the conduct of the trials and for ignoring protocols. The doctors had apparently obtained the approval from independent ethics committees attached to private hospitals. Five doctors were hauled up by the Economic Offences Wing (EOW) of the State government in 2011. But no action was taken against them. On January 1, the State government imposed a small fine on the 12 doctors. Responding to media reports on the trials conducted on mentally ill patients, the National Human Rights Commission (NHRC), which addresses matters concerning morality relating to clinical trials, issued a notice to the State government on December 23, 2011, and demanded a report within four weeks.

The matter pertaining to the drug trials on mental patients in contravention of Schedule Y of the Drugs and Cosmetics Act, which has explicit guidelines for clinical trials involving the mentally ill, and the Indian Council of Medical Research's (ICMR) Ethical Guidelines for Biomedical Research on Human Participants, was raised by Anand Rai, a former resident doctor of MGM Memorial Medical College in January 2011. Anand Rai wrote to the NHRC, which in turn referred his complaint to the State Human Rights Commission. Even after several months, no action was taken. The media then began to report the issue, following which the NHRC took suo motu cognisance of the trials.

No one took notice of his complaint, Anand Rai told Frontline. Things were moving but not fast enough.

In the third week of November 2011, the Union Ministry of Health and Family Welfare proposed amendments to the Drugs and Cosmetics Rules, 1945, relating to regulations in clinical trials. The amendments, it said, had been approved by the Drug Technical Advisory Board, a statutory committee under the Drugs and Cosmetics Act, 1940. The notification dated November 18, 2011, pertaining to the draft rules called the Drugs and Cosmetics (3rd Amendment) Rules, 2011, seeks to strengthen the regulations in favour of trial subjects but has many loopholes. Moreover, it was not given adequate publicity to elicit responses.

Public health experts noticed only recently the notification, posted on the website of the Central Drugs Standard Control Organisation (CDSCO), seeking comments from the public within 45 days. Not everyone visits the website regularly. More time should be given for responses as the proposal is beset with problems, said Anand Rai. The deadline of 45 days for sending responses has expired, but given the concerns raised, the government could consider extending the deadline in order to get more feedback on the rules.

The draft rules claim to have incorporated effective provisions to provide financial compensation to trial subjects in case of trial-related injury or death; enhance the responsibilities of the ethics committees, the sponsor and the investigator to ensure financial compensation and medical care to trial subjects who suffer injury or death; and amend the format for obtaining consent to include details such as address and occupation, and annual income of the subject so as to have information of the socio-economic status of the trial subjects.

Public health groups such as the Low Cost Standard Therapeutics (LOCOST) and Sama have criticised the proposed amendments. They have requested more time from the government so that all concerned groups can articulate their views. Under the proposal, the ethics committees have been given the responsibility of deciding the clinical trial relatedness of an injury as well as the quantum of compensation. Sama representative N.B. Sarojini and LOCOST spokesperson S. Srinivasan argued that it was not correct to hand over both issues to the ethics committees. At present there are no clear guidelines about the constitution of the ethics committees and their monitoring. Members of the ethics committees were found to be biased as they themselves conducted the trials. The so-called independent ethics committees looked into issues of protocol instead of assessing them objectively, they said. They were not part of any hospital but were often owned and operated by powerful private commercial interests, the critics pointed out.

They said a very large number of trials took place in private clinics. The ethics committees did not have the expertise required to determine the quantum of compensation based on the extent of injury, the age of the sufferer, and liabilities in case of death and, overall, had very little training in issues of ethics. Conflict of interest issues as well as institutional biases were matters that were yet to be resolved, they said. The committees had a complete say over compensation issues, including a review of disputes relating to compensation. The decision of the ethics committee after the review shall be final, the draft rules state.

Registration of clinical trials was voluntary before November 17, 2008. But the ICMR made it mandatory to register such trials with full disclosure of trial data with its Clinical Trials Registry from June 15, 2009.

In response to a question in the Rajya Sabha in March 2011 relating to the total number of clinical trials and deaths caused by such trials between 2007 and 2011, the Health Ministry gave the following information: 1,622 clinical trials were conducted between July 2007 and February 2011, and there were 288 deaths in 2008, 637 in 2009, and 597 up to August 2010. They were definitely not insignificant numbers.

The matter of trials being conducted clandestinely was raised in the State Assembly more than once where an independent legislator claimed that 1,883 persons, including children and mentally challenged persons, were subjected to drug trials between 2006 and 2010. No action was taken against any doctor during all those years. No names came out. The matter came up in Parliament. On December 20, 2011, replying to a question in the Rajya Sabha on the regulation of clinical trials, the Minister of Health and Family Welfare spoke of six cases of violation of the Drugs and Cosmetics Rules in the context of clinical trials and the action taken during the last three years.

The Minister said that following news reports about drug trials in the MGM Memorial Medical College and Maharaja Yashwantrao Hospital involving the drug Tadalafil for pulmonary arterial hypertension, the CDSCO and the State Drugs Controlling Authority conducted investigations and found that two doctors had used the drug without permission from the Drugs Controller General of India (DCGI). The Minister informed the House that the study with the drug had been initiated on September 18, 2005, when the drug had not been approved for the said indication in the country. It was approved for another indication, male erectile dysfunction, on June 10, 2003. On November 2, 2011, the Ministry directed the two doctors to stop the clinical trial of Tadalafil in pulmonary arterial hypertension and restrained them from conducting any clinical trial for a period of six months.

That was all the punishment handed out. Barring the occasional warning or temporary suspension of permission to conduct trials, the Ministry did not cite a single instance where strict action had been taken against the doctors in the last three years. Consider this. Last year, a Hyderabad-based research firm was reported to have conducted clinical trials of an anti-cancer drug at a multi-speciality hospital on poor people without their informed consent. It transpired that it had conducted bio-equivalence study on an already approved anti-cancer drug and there were certain irregularities with respect to the process of informed consent, review and the decision-making process of the ethics committee.

The firm was punished by withdrawing the permission granted for equivalence on June 22, 2011. But when it submitted corrective actions for the subject recruitment process and other procedures, it was granted a no-objection certificate to conduct the bio-equivalence study, subject to the fulfilment of certain conditions such as informed consent process, including documentation of the process through audio-video means, and conditions about the functioning of the ethics committees and the investigators. It was business as usual again.

The Indore and Hyderabad episodes are not isolated ones. Issues of informed consent involving the poor and vulnerable sections of society have always posed a problem. The compensation paid by pharmaceutical majors in case of death during trials is paltry compared with the profits they make. It was not very long ago that post-licensure clinical trials on tribal girls in Khammam in Andhra Pradesh and Vadodara in Gujarat to test the efficacy of the human papillomavirus (HPV) vaccine came under severe criticism over consent-related issues. The ICMR and the two State governments were the collaborating partners in the trial. Following reports of the death of seven girls, the ICMR suspended the trials on April 7, 2010. An inquiry committee found certain discrepancies in the conduct of the trial.

In response to a Right to Information application on November 27, 2010, seeking information about drug trials conducted by the Chacha Nehru Children's Hospital and Research Centre, Indore, over the last six years, doctors used the smokescreen of confidentiality between the sponsor and the principal investigator in order to evade an answer to the queries raised. A doctor in the medicine department of the MGM Memorial Medical College and Maharaja Yashwantrao Hospital, in response to an RTI application filed by Anand Rai, wrote that clinical trial agreements could not be publicised as that would affect scientific and business interests. He argued that the sponsoring pharmaceutical companies and the clinical research organisations (an individual or an organisation to which the sponsor may transfer or delegate some or all of the tasks and duties in a clinical trial provided such obligations are defined in writing) would be reluctant to undertake new research in the State and in the government hospitals if such information was made public.

Compared with other States, he wrote, Madhya Pradesh lagged behind in medical research. Particularly, government hospitals were far behind private clinics in this area. Delineating the benefits of medical research through drug trials, he said it encouraged foreign investment, improved scientific skill, generated employment and brought international contacts for the medical community. He stated that information could be given under limited conditions to the investigating authorities such as the EOW.

The State EOW launched an investigation only as the matter refused to die down. It found that 73 trials were carried out at the Maharaja Yashwantrao Hospital on nearly 3,300 patients, of whom 1,800-odd were children. The trials were carried out by six doctors who received pecuniary benefits from drug companies. Eighty-one trial subjects, including 18 children, suffered from serious side effects. Sixty trials were carried out in the private sector by some 40 doctors; the details of the patients were unknown. Eight Indian companies and 22 multinationals had sponsored the trials.

Anand Rai brought out some more interesting details. He said that the MGM Memorial Medical College had 27 members on its ethics committee, of whom 22 were professors in the college. The chairpersons of the committees of at least two government hospitals were veterinary doctors. The members of the ethics committee of the MGM Memorial Medical College were the principal investigators in many cases, he said. The secretary of the committee himself failed to follow the Good Clinical Practice (GCP) and ICMR guidelines, he said.

At the moment, we are discussing drug trials sponsored by large pharmaceutical companies and conducted on vulnerable sections of the population. The research subject is typically less powerful than the sponsors and investigators conducting the research. Hence, any compensation should address this imbalance and not be directed to short-term harm or injury, he said. All trial subjects should be given cashless health insurance for the rest of their lives, Anand Rai suggested. (He is now serving as a medical officer with the Health Department.)

On January 5, Brinda Karat, Communist Part of India (Marxist) leader and a former Rajya Sabha member, submitted a memorandum to V.G. Somani, the DGCI, requesting action against the clinical trials in Indore. She reminded him that it was more than a year since the trials and the violations had been exposed but the DCGI had failed to act against those involved. She said that an inquiry conducted by the EOW had found clear violations for which the licences of the doctors should have been cancelled. The State government's inquiry report had specifically recommended that the DGCI and the ICMR conduct investigations into the violations of the Drugs and Cosmetics Act and the ICMR and Medical Council of India guidelines.

Barring certain weak and cosmetic changes to the Drugs and Cosmetics Rules, relating to compensation in case of injuries to and death of trial subjects, no measures have been taken to strengthen the system in favour of those undergoing trials. Notwithstanding the Ethical Guidelines for Biomedical Research on Human Participants framed by the ICMR in 2006, norms continue to be flouted by both the public and private sectors in health care. The framework to deal with issues of compensation, consent and transparency is considered very weak, leading to several allegations, many of which seem to be well-founded, of exploitation of the poorer sections. After all, it is not the well-to-do on whom the trials are conducted. And often on the grounds of confidentiality (clinical trial agreements), agreements between the pharmaceutical company, the principal investigator and the organisation, information regarding drug trials is not given out freely. It requires dogged efforts by people like Anand Rai to bring these aspects into the public domain.