Year 2020 is nearing to its end. Human beings have witnessed one of the most dramatic events that has reshaped the world and brought about a paradigm shift in the thinking process. This year is surely to be etched in history, being remembered as the one that shook the very core of mankind. The scars that will be left behind will remind the future generations of the lessons that this pandemic has taught us. Our response to this pandemic will determine if our future generations will be inspired by our actions or avoid them.
As the pandemic progressed, researchers and doctors around the world started looking for a solution that could end the spread of the virus by creating herd immunity. This event prompted the researchers to speed up the process of development of vaccine. The process that is involved in the development of a drug is quite cumbersome, and involves a lot of money and time. So there are a lot of apprehensions among the common people regarding the safety and efficacy of the new vaccines that are hitting the market. Here we will try to explain briefly the steps involved in the development of any pharmaceutical product, be it a drug or a vaccine. Let us first talk about the preclinical development in some detail.
The first step in the development is to identify and validate the target which is the causative factor in the development of the disease or which facilitates the development of the infection and for which the drug needs to be developed. For example, the target of the vaccine against coronavirus is the spike protein on the virus that helps it to lodge onto human cells and subsequently infect them. The spike protein is the one that gives a crown like appearance to this virus and hence the name coronavirus. Identifying the right molecule that can progress to the preclinical development in the drug development process is a critical task and involves a lot of screening using modern technologies. Once the lead is created, the molecule can further be taken for preclinical development. In this, the molecule is tested on animals and the safety and efficacy profile is generated. The animals used are mostly mice, guinea pigs, hamsters and non-human primates like monkeys. The choice of the animal also depends on the disease that is being targeted. Modern technology in the preclinical development and the new skill sets have made it possible to reduce the number of animals used by employing in vitro (inside glass)predictive methods which can provide deeper insights in the tissue permeability, cellular transport and drug toxicity of the molecule in question. These can also help in assessing the absorption and disposition as well as the safety of the molecule. Also the development of modern disciplines such as pharmacogenomics and toxico genomics have helped us to understand drug metabolism and drug transport processes at the molecular level and the biological responses which until now were considered imprecise because of its variability and background noise.
Preclinical studies help to extrapolate the safety and efficacy outcomes of the new molecule from in vitro and non-human animal studies to a possible human effect. The number of animals used are small and hence the studies need to be validated with a large number of people which is done at a later stage in clinical trials. In fact, every drug that undergoes the preclinical development studies to analyse the eventual clinical effects results with little data that can support the animal model under study. The results of the preclinical studies help clinical scientist to arrive at a rational and ethical decision of commencing clinical trials in humans. Nowadays, the preclinical studies use a combination of older and modern technologies, the former helping in comparing with similar earlier developed drugs while the latter helping to get insights which are otherwise not available. Preclinical data also help in predicting the potential drug toxicity and for estimating first-time dose in humans. The extrapolations done are based on the algorithms developed on the basis of correlation between the exposure-response relationship in animals and humans. The selection of animal species depends on the factor that is considered in evaluating the potential interspecies differences that can influence systemic (in the body) drug exposure and target cell sensitivity. But there is no single animal species that can accurately predict the outcomes in humans.
The differences in physiology (normal body function) of different experimental animals and humans forms the basis for the eventual choice of animals in preclinical study. For example, when rats are administered antimicrobial agents, they frequently develop cecal dilation and torsion due to different microbial flora inhabiting their intestines. This finding may preclude their use as experimental animals in that particular type of drugs. The different animals used and the types of diseases in which they are used are as follows:
- Rats (Wistar and Sprague Dawley) are used in a number of studies as they are 90% genetically similar as that of humans, their body functions work in a similar way as that of humans, they breed frequently and also their genes can be manipulated easily as needed in the study. The main kinds of studies in which they are used are study of analgesics, mating behaviour and lactation studies, gastric acid secretion, hepatotoxicity, hormone bioassays, and toxicity studies.
- Mice (Swiss albino) are frequently used in drug development studies because they reproduce quickly, have shorter life spans so that several generations can be studied and since they are small, they can be housed easily and maintained with relative ease. Since they have similar nervous and reproductive systems as that of humans, they are excellent candidates for drug development studies. The main experimental studies in which they are involved are toxicology studies, bioassay of hormones, analgesics and anti-convulsant drugs, chemotherapeutic agents, genetics and cancer research and neurological studies.
- Guinea pigs have biological similarity to that of humans and were responsible for the discovery of Vitamin C. They have also been instrumental in the discovery of some of the most important vaccines. Some of the other class of drugs that are developed by using guinea pigs are antibiotics, antihistaminic drugs, anticoagulants (drugs that inhibit clotting of blood), bronchodilators, allergies, respiratory diseases to name a few.
- Gebrils, which are also known as sand rats or jirds, are also used in research. Their size lies in between that of the rat and the mouse and have been mostly employed in the research of stroke, epilepsy and heart diseases. They are very helpful in auditory studies as they have a similar hearing curve as that of humans.
- Hamsters are the third most commonly used lab animals. The 2 species that are most commonly employed are Golden or Syrian hamster and the Chinese hamster. They are used for viral studies including onco virus, influenza virus and Respiratory Syncytial Virus (RSV). Since the cheek pouches of hamsters lack lymphatic drainage, they are ideal species for tissue transplant studies. Different species of hamsters are useful in different kind of studies. Syrian hamster is mostly used in biomedical research as they are readily available. European hamster is useful in prolonged smoke inhalation studies while Chinese hamster is suitable for cytogenesis research.
- Rabbits are one of the most common non-rodent species used in labs. Louis Pasteur developed the rabies vaccine in rabbits. Many studies of cancer, glaucoma, other eye diseases, ear infections, skin conditions, diabetes, emphysema, etc. are done on rabbits. They have also been very important in the study of cardiovascular diseases, particularly hypertension and atherosclerosis. The other important areas where rabbits are employed as test animals are pyrogen testing, antifertility agents, simulation of human response to the radiation caused due to lasers, etc. They are frequently used in the testing of cosmetics using Draize test.
- Monkeys used as non-human primates as they have many similar functions as that of humans. They are suitable for undertaking psychopharmacological studies and drugs that act on the Central Nervous System (CNS), Cardiovascular System (CVS), Gastrointestinal tract (GIT) and fertility.
- Cats have contributed for a long time in the study of emotion, cardiac disease, spinal cord injury, cataract surgery, glaucoma, lupus, diabetes, spina bifida and much more. They are mostly used to study sensory systems and neuroscience. Since they have a distinct nictitating membrane, they are used to study ganglionic drugs. Since they have a long life-span, they are used in aging studies.
- Dogs are frequently used because they have smaller alimentary tracts and are quite easy to train. Frequently employed species are Beagles and Mongrels due to their manageable size, moderate hair coat and highly docile nature. They act as good models for studying diabetes mellitus, ulcerative colitis, and open heart surgery and organ transplantation.
- The other less frequently used animals are frogs, zebra fish, etc.
Recently, transgenic animals are being increasingly used in drug studies. In this technology, the genes in lab animals are replaced with the gene of interest. This help in studying specific pathways that are responsible for the disease and that can be targeted with drugs. This technology has tremendous potential to elucidate potential human outcomes early in the lead optimization and preclinical drug development stages. Also knock-out animals are used where a certain gene is totally removed and the effects of the same are studied. Athymic mice are used in immunosuppressive studies as these lack thymus and hence thymus-mediated immunity. These are also known as nude mice as they lose all the hair of their coat. Once the new molecule produces acceptable data regarding the efficacy and safety profile in animal studies that include a rodent and a non-rodent species, it is further taken for clinical trials which are divided into 4 stages.
Thus it can be seen that the drug development process is an arduous journey that a new chemical entity (NCE) takes to finally achieve the status of a drug. A lot of time, manpower, resources (both financial and human), ethical issues and legalities are involved in the whole process. The introduction of coronavirus vaccine at a record speed is truly a commendable achievement but post-marketing surveillance will play a big role in determining its side effects and even potential adverse effects in the long run. The coronavirus has presented humanity with extraordinary circumstances that need extraordinary thinking and innovation. Thanks to the resilience of the human race, we have coped quite well with the current catastrophe. Finally some light can be seen at the end of the seemingly never ending tunnel.