Recent reports on the administration of an unapproved drug to cancer patients at the Regional Cancer Centre in Thiruvananthapuram has attracted attention in the media and have raised several technical, moral and ethical issues related to human trials of new drugs, generally 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 benfits 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. It is also important to put these events in the perspective of need for new and better drugs, the nature of the disease for which the experiments were carried out and the whole aspect of medical progress in the area of life threatening diseases.
Drug Discovery Process
The well-established model of new drugs discovery involves the identification of a candidate drug for development through extensive in-vitro and and animal studies, toxicological and histo-pathological investigations in rodent and mammalian species for extended periods of time, with the drug administered both by the oral and parenteral routes, studies on absorption, distribution, metabolism and excretion in animals, and trials in healthy volunteers and human beings in various phases. In spite of rapid advances in rational design of drugs including application of functional genomics and proteomics, molecular targets, combinatorial libraries and high throughput screening, neither in developmental costs nor time requirements, has drug discovery become less arduous. Costs of discovery of a single new drug has been placed at over $ 500 million and a time period of 10 to 15 years, which, of course includes the costs of failures.
Role of Clinical Research
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 % fool-proof, is the best available one at present, and historically, it has served the patients and society by delivering practically all the modern drugs which are in use today. Responsible large Corporations and Organisations involved in New Drugs Research will never by-pass the above route, nor will they belittle the known and potential risks posed by new drugs, since their first obligation is to the patients and not to the share-holders, apart from the fact that liability litigations can indeed push Corporations into bankruptsy. For example, companies which developed Silicon Breast Implants and Shiley Heart Valves went bankrupt, due to liability suits from subjects, including from those who were never harmed by their use.
Regulatory Agencies
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. The gold standard for evaluation of such data is that set by the US FDA. All the other countries , by and large, follow the U.S. standards for controlling and monitoring drug trials. 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 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. They are connected with safety issues, denial of available alternate therapies, risk to benefit ratios and the motivation of the investigator to try the drug and the patient to receive the drug and participate in the trial. 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. 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, preferably 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 in this category 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, Clioquinol, Phenyl Butazone, Troglitazone, Amidopyrine, Cisapride and even human Insulin.
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. The recent episodes of the 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.
Assessment of Benefits over Risks
Can standards for measuring risks vs benefits be different for life-threatening terminal cases of Cancer, AIDS etc, compared to ''treatable'' diseases ? Today, in spite of spending several billion dollars for the War on Cancer, except possibly for Hodgkins Lymphoma and Testicular Cancer, major breakthroughs have not been forthcoming. In such cases, could there be relaxation in standards of safety, if overall benefits outweigh risks ?
The Indian Scene
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. The general convention followed is that for drugs developed abroad, trials in a Phase earlier to what has been carried out abroad would be required in India. Exceptions, once again are made for concurrent trials and fast-track approvals depending upon the nature of the product and the medical needs. Even though India does not allow use of unapproved drugs in patients, in exceptional cases, physicians are allowed to import life-saving drugs, which have not received marketing permission in India.
The frequent allegation that unapproved drugs are clinically tested in developing countries, thereby treating the patients as guniea pigs is not valid, since no responsible Corporate body or Physician will risk such an unacceptable option. 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, since after all, everyone realises that ultimately only ethical business will sustain and will turn out to be good business.
About the author:
The author is one of India''s leading research scientists