Of all activities related to medical research, clinical trials of drugs on Indian patients have attracted most attention in recent times. Critics aver than these trials are carried out on Indian patients for economic reasons of lower costs in India compared to the Western countries.
It has been reported that there have been a number of fraudulent trials being carried out in India putting patients at high risk. A parliamentary committee which went into this issue reported that of the over 200 deaths which occured during trials in the last few years, 88 per cent were due to the disease rather than the trial drug. The Health Minister mentioned in the Rajya Sabha that 22 deaths occured during trials last year and compensation for loss of life has been paid for many of them. In none of the cases was fraud or negligence established, even though in recent times there have been many reports of subjecting unwary patients to trials with fabricated informed consents and other malpractices. Such incidents have been reported from other countries as well. The US FDA every year charge sheets sponsors, investigators and CROs involved with clinical trials for misconduct and fraud.
What are the issues which should be a mater of concern to India as the country is emerging as a major outsourcing destination for clinical trials of drugs under development across the globe?
Clinical trials
Clinical trials are studies conducted in human volunteers to better treat or prevent diseases and determine whether the new treatment is both safe and effective. Such trials are approved by the regulatory agency of the Government and undertaken only after there is adequate evidence from animal experiments for their safety and efficacy.
Only well designed trials in humans will answer the many questions which arise during translation of animal data to humans. These trials are carried out in 3 phases in patients to establish their safety and efficacy. Such an accepted model of new drug development, while not 100 per cent fool-proof, is the best available one at present and used extensively by all R&D based companies as well as Institutions involved in new drug discovery and development.
In India the relevant Section in the Drugs And Cosmetics Act 1940 is Schedule Y, which not only defines new drugs , but also sets standards for drug trials and new drug introductions in the Country. The Drugs and Cosmetics Act has stipulated under Schedule Y guidelines for conducting the first human experimentation as well as later phases of trials with hitherto untested drugs and all trials carried out in India follow these Indian and International guidelines of ICH/GCP which specifies minimum ethical standards in addition to other standards of Good Laboratory and Good Manufacturing Practices.
Ethical issues in clinical research
The Helsinki Declaration of 1964 provides the guiding principles for conducting biomedical research on humans. Article 11.3 of the Declaration mandates that all patients, whether in an active treatment group or control group should receive the best possible therapy , although it allows the use of a placebo, when no such treatment exists. Article 11.6 stipulates that research in patients is justified only if it is of potential value to the patient in the best judgement of the investigator and the Ethical Committee. The Declaration also requires investigators to obtain subjects' freely given and non-coerced informed consent, in writing. These well-laid out procedures prior to initiating human trials are to-day the best possible safeguards against drug-related harm to the patients.
Tragedies still strike
In spite of all these safeguards, tragedies still strike, not only with experimental drugs , but also with marketed drugs. In fact due to the vigilance exercised by the investigators and regulatory agencies on use of experimental drugs in humans, mishaps during trials are less than in the case of marketed drugs. Right from the days of the Thalidomide disaster in 1962, which maimed over 10,000 children due to the drug's teratogenic effect, there have been several serious side effects including fatalities which were related to marketed products, such as Benoxaprofen, Practalol, Clioquinol, Phenyl Butazone, Troglitazone, Amidopyrine, Cisapride and even human Insulin. More recently the Cox 2 inhibitor Vioxx and members of the glitazone family Rosiglitazone and Pioglitazone have been indicted/withdrawn in most countries after having been in the market for several years and were blockbusters.
Deficiencies in clinical trials
In spite of all guidelines available and followed, several deficiencies still plague clinical research. They may be related to factors outside one’s control due to the unpredictability of results from animal studies being relevant to human beings as well as due to human errors in planning and execution of the trials per se, fraudulent informed consents and even deliberate frauds on the part of the stake holders , all of which do raise major concerns in the public mind.
To ensure that clinical trials are carried out in a fair, ethical and transparent manner around the world, all sponsors of trials are required to register their trials in an International Clinical Trials Platform (ICTRP) set up under U.S. Public Law 110-85.
In India, the medical profession, the drug manufacturers and the regulatory agencies have all accepted international mandatory regulations as well as ethical standards embodied in the Hippocrates Oath, Helsinki Declaration and the International Harmonisation efforts in Clinical research.
According to the International Registry of Clinical trials, a data bank maintained by the NIH in U.S. (clinical trials.gov), of the total entries of around 109,000 trials carried out in 174 countries, the Indian share very low. An Indian registry was set up under the aegis of WHO and the Infdian Council of Medical Research (ICMR) in 2008 and registration of all trials was made mandatory from June 15 of 2009. At the last count the number of entries in the Indian registry was 1871 representimg only 1.7 per cent of the global trials .At the same time China accounts for eight per cent, substantially higher than India. The fear that there is an avalanche of trials moving out to India and risking our population to trial drugs is thus unfounded.
With Indian companies entering the drug discovery research phase and India being a leader of developing countries responsible for discovery of new drugs for poor man’s diseases, it is essential that India develops expertise and experience in clinical research.
Notwithstanding all the negatives pointed out by many parties, the introduction of much needed new drugs is intimately connected with clinical research and attempts to stifle or slow down these efforts will result in major set backs to advances in medicine. The laws of the land are adequate to disallow misconduct in clinical trials and punish the perpretators as criminal offendors.
By and large, new drug research including clinical trials in India have maintained high levels of ethics, since after all, everyone realises that ultimately only maintenance of ethical standards will sustain and will turn out to be good for meaningful medical advances and healthcare benefits.
The author is a senior research scientist &
industry expert based in Chennai.