During the last several years, there have been worldwide controversies on the issue of the role of animal experimentation in drug discovery. Whether the practitioners of drug discovery research have been judicious and rational in the use of animals as models and markers of human disease conditions has been the cardinal issue.
The developments in India spearheaded by Governmental and Non-Governmental Organisations through legislations and guidelines perpetrated by somewhat over-zealous proponents of animal welfare and countered by innumerable scientists and establishments have created tremendous confusion among the public. All the concerned parties have largely used emotions and rhetoric rather than commonsense and scientific logic while discussing and debating the issues involved.
During recent times, some of the major Research Institutes in India, such as National Institute of Nutrition (NIN) in Hyderabad, Institute of Research In Reproduction (IRR), Mumbai and National Institute of Virology (NIV), Pune, suffered as a result of the action of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), which claimed that these Institutes flouted the norms and guidelines stipulated by the Agency. All the three Institutes are unique in their respective disciplines of Nutrition, Reproduction and Virology and have over the years established themselves as major contributors to these disciplines.
Animal experiments in these institutes were scrutinized, their relevance questioned, rationality of the experimental design challenged and all aspects of access to animals from the market, the wild or through breeding, as well as the housekeeping in the animal house, where they are bred and maintained, were policed by representatives of the CPCSEA. During such action, several lacunae in their functioning were allegedly detected, and they were charge-sheeted for major offences violating the dictates of CPCSEA. The animals were released into the wild or handed over to the NGOs with the stipulation that in the latter cases, they will be maintained through their life at the expense of the Institutes.
Charges leveled by the authorities, on the Institutes and their functioning, alarmed many scientists who felt that their ability to judge the essentiality of experiments conducted and the methods employed were questioned by less informed non-scientific agencies. As a final icing on the cake, the Minister in charge of Environment, in an interview, brandished the entire Scientific Community working in Biology Laboratories, as inefficient, lacking required skills, unaware of the state-of-art developments in their research areas and above all insensitive to the need to ensure Animal welfare. Strangely, one arm of the Government, the Ministry of Environment criticized another arm of the same Government, the Ministry of Health by maligning the Drug Controller General of India, a senior member of the Health Ministry as outmoded and bureaucratic.
Even if one assumes that these extreme actions by the CPCSEA and comments by the Minister were meant to be a shock treatment which will deter further laxity in these matters by the Institutes concerned and others, it is obvious that the steps taken defied scientific logic and civil behaviour. It is little consolation that much worse behaviour leading to burning of R&D Institutes carrying out animal experiments and death threats to leading scientists have been part of the agenda of many animal activist groups in the West in recent years.
Very recently, the confrontational attitudes taken by the Ministries of Health and that for Environment led to the resignation of the two Ministers of the Government of India. These symbolic and disciplinary gestures, however, do not in any way solve the fundamental issues involved; rather they have further complicated matters and postponed a meaningful resolution of the key issues.
The issues
To understand the finer nuances of the issues involved, it is important to evaluate the evolution of the drug discovery process itself, ever since the discovery of Salvarsan by Ehrlich in the forties. It was obvious even then, that candidate drug molecules could not be directly tested in human in the absence of evidence for their safety and efficacy.
Even when in-vitro models were available, particularly for testing Anti-Infective agents, there was only questionable correlation between such tests and in-vivo use, particularly in humans. Thus, a large number of animal models were developed for a variety of disease conditions on the basis of perceived correlation between disease patterns in human and simulated disease conditions in animals. Such models were then used to study the safety and efficacy of the drug as part of the pre-clinical phase of drug development.
Controversies
Supporters of animal welfare, euphemistically termed animal activists, are of the view that most of the drug discoveries were possible without experimentations in animals and inflicting cruelty on them. Two of the oft-quoted examples of tests, considered redundant and unnecessary by many, are the LD-50 and the Draize tests, the former to determine the acute toxicity of an experimental drug. This test is still used as an indicator of potential human toxicity. Many toxicologists believe that, while it is too early to do away with this test, in the absence of a suitable alternative, the number of animals used for this test could be considerably reduced. For example, conventional LD-50 tests require up to 200 rats, dogs or other animals to be force-fed to determine the dose that would kill 50% of the animals. Recent protocols would require the use of only one-tenth of this number of animals to obtain same results.
The Draize eye irritancy test, which measures the safety of the drug to the eye or skin, is still one of the best predictors of the effect of a chemical on the human eye or skin.Modern Regulatory Agencies including the most enlightened ones, such as the US FDA, which are well aware of the need for restraint in animal experiments, feel that many procedures intended to replace or avoid animal tests are still in various stages of development and validation, and it would be unwise to replace present methods until fresh and convincing data is available on the new ones.
Animals and medical research
According Everret Koop, the Former Surgeon General of the US Government, "Virtually all major medical advances for both human and animals have been achieved through bio-medical research by using animal models to study and find a cure for a disease and through animal testing to prove the safety and efficacy of a new treatment."
Morbidity and mortality from TB, Polio, Diphtheria, several bacterial and fungal infections, Diabetes, several diseases of the Central Nervous System, such as Depression, Schizophrenia, Anxiety, Parkinson''s disease, Alzheimers and Epilepsy; Stroke and other cardiovascular diseases, have all come down dramatically due to availability of new drugs.
Many of the childhood diseases, such as Rubella and Whooping cough are now under control. Even when cure has not been possible, as in the case of Cancer or even of Pain, palliative treatments have helped improve the quality of life of the patients. In spite of all these advances that medical science has made over the years, a large number of intractable diseases still remain incurable. Cancer, several Viral diseases, Immunodeficiency disorders, including HIV/AIDS, degenerative diseases due to increasing number of ageing populations and many life-style-induced diseases fall under this category. It is clear that advances in the management of these diseases through the development of diagnostics, prophylactics and therapeutics can come about only through the continued use of animal models in medical research.
Several life-threatening terminal conditions, such as renal failures, strokes, cardiac infarcts, degene-rative musculo-skeletal diseases etc., are being treated through transplants, angioplasty, by-pass surgery, orthopaedic implants, insulin pumps and a whole range of transplantable and disposable devices were developed in the first place in animals.
Recent development of a mouse model for AIDS and the promise of an AIDS vaccine using primates will hopefully enable the management of this dreaded disease. Research on primates enabled the identification of neuritic plaques or clusters of nerve endings as causative agents for Alzheimers. Injection of Nerve Growth Factors facilitates the rejuvenation of memory-related cells in rats, an observation, which is of great relevance to Senile Dementia and Alzheimers disease.
The Heart-Lung machine, an important component of open heart surgery was developed in dogs and pigs, cardiac pace-makers were developed and tested in dogs, so too even the common sutures, clips, staples and grafts which have been taken for granted as essential components of surgical interventions. In fact all the major medical and bio-medical discoveries relied on animal research, so much so, over 50 Nobel Prize winning researchers of the last Century in Medicine and Physiology, utilised animals.
Even animals whether they are bred, domesticated or are in the wild have benefited from the advances in medical sciences, with the availability of a large number of veterinary products being available for their welfare.
In addition to products, much of our understanding of diseases, their causative organisms and the role of vectors in disease transmission relied on animal experiments.
Thus the major objectives of biomedical research, using animals are:
1) To elicit biological knowledge on diseases and health conditions to enable development of therapeutics.
2) To provide models for naturally occurring human and animal diseases.
3) To test potential therapies including diagnosis of diseases, surgical interventions and medical devices.
The Rhetoric of "Three R''s"
Most of the leading Research Organisations, practice the principles of the three R''s of animal experimentation, which are Replacement, Reduction and Refinement. These terms were coined by the British Zoologist William Russel and Microbiologist Rex Burch in 1959, when they published "The Principles of Human Experimental Techniques''. Replacement stands for use of alternative methods, eg., tests using Cell Cultures (in-vitro), Reduction stands for use of Statistics to reduce the number of animals that must be used for each experiment and Refinement for improving the experiments to reduce suffering to the animals.
According Alan Goldberg of the Centre For Alternatives to Animal testing, at the Johns Hopkins University, the Three R''s represent the common definition of Alternatives. When available, they can provide more precise and specific models for drug testing and could be more economical than animal testing. Alternatives most commonly used are Cell, Tissue and Organ Cultures and Computer assisted modeling techniques.
Ideally, in specific cases they can be used for screening drug molecules, toxicological research and even pharmacokinetic investigations on drugs to determine Absorption, Distribution. Metabolism and Excretion (ADME) studies. Currently, in the absence of adequate correlation between results from these studies and those in humans, the data from studies using alternative tests, would be unacceptable to Regulatory Agencies responsible for approvals for Clinical Trials or New Drug Introduction. In any case, based on current knowledge, only less than 20% of animal models have the potential to be replaced by non-animal alternatives.
Reduction, the second R refers to use of fewer animals, in some cases, even use of the tissue from a single animal would suffice as against hundreds used earlier.
Refinement efforts hinge on our ability to reduce pain, distress and trauma experienced by animals during the experimentation. Already the U.S. Department of Agriculture and the National Institutes of Health, Bethesda have drawn up guidelines for conducting animal experiments under the most humane conditions.
Indian Scene
The Committee For the Purpose of Control and Supervision of Experiments in Animals (CPCSEA) is today the ultimate authority for drawing up standards for procurement of animals, maintenance of Animal Houses, Animal use in Research or Production, Implementation and Monitoring of all aspects of Animal Experimentation etc. The criticisms against the CPCSEA is not so much on the scope and contents of the Guidelines per se, but more about its attitudes, approaches and implementation modalities. The Minister for Environment who is in charge of CPCSEA had mentioned that three committees will supervise the various facets of the Agency, the first, the Committee on Alternatives and Harmonisation with Global Guidelines, the second to stipulate norms for rehabilitation of the animals used in experiments, and third, on Accreditation and grading of Laboratories, based on agreed norms
Developing alternatives for animal experimentation
Indian Laboratories have no strategic plans for developing Alternatives to animal testing. They lack skills, resources, infrastructure and the will to enter this area of research.
Contrary to the general belief, the Pharmaceutical industry will be very happy if alternative testing methods are developed, which are valid and acceptable to Regulatory Agencies, since animal experiments are cumbersome and expensive. In addition access to animals of the right kind has always been a major problem.
The Laboratories in India find the guidelines of CPCSEA much too complex to implement in a defined time frame and much too bureaucratic leading to long delays for approvals. Ideally a group of knowledgeable Scientists and Managers should take an inventory of all available and currently used animal models, analyse their relevance, assess the merits of alternatives where available and suggest a systematic transformation to the new system of testing new drugs. This is an enormous task, since the efforts should be extended to all the major therapeutic areas where new drug discovery efforts are on-going or will be initiated.
Due to some of the provisions of the CPCSEA and difficulties in their implementation, several roadblocks have been created, which can slow down drug research, and since Regulatory Agencies have not yet approved most of the alternative testing methods, many Laboratories are forced to go outside India and outsource screening and toxicity testing from animal facilities available abroad. This is indeed a sad development, since India not only loses an opportunity to develop her own skills in this area, but also will lose the cost advantage over the developed countries, in the area of drug discovery and development research.
The time is ripe to review all the concerned issues and arrive at meaningful approaches acceptable to the Research Community, The CPCSEA and the Regulatory Agencies.
Of course, none of these would appease the die-hard anti-vivisectionists and animal activists, represented by e.g., PETA (People For The Ethical Treatment Of Animals), whose Director once said "A rat is a pig is a dog is a boy", implying that animal life is to be valued on par with human life and sacrifice of animals even for human welfare is unacceptable.
As the Indian Research-based Pharmaceutical Companies are entering into an era of New Drug Research to achieve global competitiveness, it would be important to ensure that their efforts are not stifled, if not nullified through short-sighted policies and practices.
- The author is one of India''s top research scientists