Role of clinical research in drug discovery

RECENT REPORTS on the administration of an unapproved drug to cancer patients at the Regional Cancer Centre in Thiruvananthapuram have attracted attention in the media and have raised several technical, moral and ethical issues related to human trials of new drugs, referred to as clinical research.

While deliberating on these matters, one needs to appreciate in a broader perspective, the nature and character of the process of drug discovery, which relies very heavily on trials of experimental drugs in human volunteers and patients. The issues involved in the debate are clear; among them are charges that rules and regulations have been by-passed, patient interests have been sacrificed, patients from developing countries are being used as guinea pigs and personal, professional and pecunary benefits were sought.

Even the most ardent critics of the events at the Centre would admit that none of the above is unambiguously true and that the picture is not as clear as made out to be in some quarters.

However impressive the data on animal experiments are with respect to safety and/or efficacy of an experimental drug, the role of validation through human experiments cannot be minimised.

This is because; most of the disease models developed in animals do not simulate the human diseases, in aetiology, progression or prognosis.

The metabolic enzymes involved may be different in animals and consequently the metabolites formed in-vivo also could be significantly different. This is significant, since in the case of many drugs, the active drug could very well be the metabolite rather than the original molecule.

Since the first priority in drug discovery is to ensure that the new moiety is safe to the patients, Phase 1 Clinical trials are meant for establishing safety in humans, by understanding the profile of the drug and its behaviour in healthy volunteers and patients. Phase 2 of the trial concentrates on dose-searching for efficacy in selected patients, while Phase 3 is devoted to multi - centric trials, if warranted, in comparison with a placebo(non- drug) and/or a competitive drug.

Only when all these phases are successfully completed in a statistically significant number of cases can the drug be approved for marketing.

The drug is further evaluated after it is marketed through post- marketing surveillace studies to ensure that unacceptable adverse reactions do not present themselves in the field. Such an accepted model of new drug development, while not 100 per cent fool-proof, is the best available one at present.

The responsibility for ensuring that all mandatory requirements for human trials, rests with the Drug Regulatory Agency of the Country where the drug is to be marketed. The first major milestone is the approval of an Investigational New Drug (IND) Application , based on pre-clinical data, for initiating the first trials in humans. Section Y of the Drugs And Cosmetics Act 1940 not only defines new drugs , but also sets standards for drug trials and new drug introductions in the Country.

The Drug Controller General has recently issued guidelines for conducting the first human experimentation with hitherto untested drugs ( IND Format).

Ethics in human experimentation

There are several ethical and moral issues involved in carrying out the administration of experimental drugs to humans.

To ensure that vested interest groups do not influence the decision to try new drugs for the first time in humans, institutions undertaking the trials have to have their own ethical committee , consisting of members from the public, including jurists and media representatives.

The committee's recommendations based on all ethical and moral considerations and human rights, are binding on the Institute.

The Helsinki Declaration of 1964 provides the guiding principles for conducting biomedical research on humans.

These well-laid out procedures prior to initiating human trials are today the best possible safeguards against drug-related harm to the patients.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 in this category are less in the case of marketed drugs.

As a general rule, assessment of the risk involved and ensuring an acceptable risk-benefit ratio is based on the nature and stage of the disease, availabilty of alternates and the extent of the projected benefits from the drug.

Recent episodes of death of a healthy volunteer during the trial of an anti-asthma drug by Johns Hopkins University and the death of Jesse Gelsinger who participated in a gene therapy trial for a rare genetic disorder are examples of cases , where even with maximum vigilance, mishaps did occur.

The general convention followed in India is that for drugs developed abroad, trials in a phase earlier to what have been carried out abroad would be required in India.

Exceptions, once again are made for concurrent trials and fast- track approvals.

The frequent allegation is that unapproved drugs are clinically tested in developing countries, thereby treating the patients as guniea pigs.

It is possible that due to the nature of the disease and its endemicity, certain drugs have to be necessarily tested in certain populations around the globe.

By and large, new drug research and medical practices have maintained high levels of ethics.

M. D. Nair

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