The lengthy process of drug discovery does not complete the process of drug development. It comprises of safety, efficacy, formulation and manufacture of the drug. Preclinical Studies are safety testing experiments involving humans in chain of studies called Clinical Trials.
These are tests performed in a controlled environment using cell cultures and animals as models. The idea is to predict what the body does to the drug candidate, by way of pharmacokinetics, or vice versa pharmacodynamics, and whether there is a potential health hazard and toxic side effects.
Pharmacokinetic testing supplies data in regard to drug absorption and transportation. It indicates the cells and organs affected, break up of enzymes, the time it takes to do so or how the metabolites are eliminated from the body. Pharmacodynamics on the other hand examine dose response, monitor biochemical and physiological changes such as enzyme activities, heart rate, blood pressure and body temperature of subjects undergoing tests. It answers important questions regarding the body’s response to the drug and the attendant toxicity in respect of the cells and organs. It also addresses the potential of a drug and its metabolites to kill or damage those cells or organs, initiate reproductive issues, cause cancer as well as birth defects and sterility. Pharmacokinetics and pharmacodynamics form the core of preclinical studies. These studies are mandatory in all countries which follow proper regulatory guidelines. Information from these studies are vital to calculate safe dosage during clinical trials. Ethical concerns and spiraling costs are impeding researchers to consider reducing the number of animal models to a minimal proportion. The United States monitor the care in case of laboratory animals by its Animal Welfare Act, which specifies that any organization receiving federal funding for research must create an Institutional Animal Care and use Committee (IACUC).
Animal models determine the effectiveness and the safety of new drug candidates. The use of KNOCK-OUTMICE or KNOCK-INMICE are tools for target validation. Knock-out mice are genetically altered to remove mouse versions of human disease genes. These genes can be knocked in to create mouse models having disease, conditions like cancer, diabetes, Alzheimer’s and Parkinson’s. Candidate drugs can then be given to humans after a thorough check of adverse side effects.
The study of safety and toxicity are done using CELL LINES, which are engineered to express genes that are responsible for adverse reactions. The decline in the use of animals is due to the creation of cell lines, which helps to speed up drug development processes. If the preclinical trials are proven to be safe, then the organization involved in research can submit an Investigational New Drug (IND) to the appropriate authorities for approval of clinical trials in humans.
Clinical trials in humans are designed to assess drug safety, proper dosage, adverse reactions and chronic toxicity. They are conducted under guidelines such as FDA’s Current Good Clinical Practice (cGCP), which ensures the safety of human test subjects, and conforms to the U.S Code of Human Research Ethics. Clinical trials are conducted in three phases and tests a large number of humans in each phase. Success in each phase leads to the next or lack of success results in the trials being halted and the drug suspended.
Since the time taken to conduct clinical trials are very lengthy, often an independent contract research organization (CRO) undertakes such ventures. They liaise with the sponsor organization and also ensure that, the volunteers subjected to these trials accept the risks involved. Participation as study subjects is voluntary, however each one of them have to sign a document called informed consent. The informed consent can be withdrawn by them at any time.
This phase represent the testing of a new drug in humans to ascertain the drug’s safety, tolerability and safe dosage range. The testing group averages between 20 to 50 volunteers who are free from disease. However when testing oncology therapeutics, patients having cancer are chosen as subjects because involving healthy patients would be too risky as the side effects of chemotherapeutic agents are very pronounced.
In this phase a large group of volunteers (100 to 300) who are suffering from the disease for which the drug is intended participate. Normally the group is divided into two distinct pairs, one studying the dosage aspect and the other the efficacy of the drug. New investigational drugs during this phase have a high failure rate because of efficacy and safety issues.
The set goal in this phase is to determine the effectiveness of the drug, and its comparison with placebos or therapies already available and marketed. Thousands of volunteers are tested over a long period of time, stretching to several years in order to confirm long term safety of the drug. The research company files a new drug or biologics application with the country’s regulatory body. In the U.S, a company would file a New Drug Application (NDA) for a small molecule drug or a BIOLOGIC LICENSE APPLICATION (BLA) for a large molecule drug to the FDA. Similarly, in Europe it can be filed with European Medicines Agency known as EMEA. On getting approval from the regulatory body, the drug can be produced mass scale in a facility so approved and then marketed. In the U.S the need to confirm to FDA’s current good Manufacturing Practice (CGMP) is mandatory to ensure purity and safety of the product. There is a acute shortage of study subjects in conducting clinical trials worldwide.
In this phase the main objective is to determine and monitor the drug’s safety and efficacy when consumed by millions of diseased patients. Sometimes acute adverse reactions are reported, since the trials have been conducted on a limited group of people. In such a scenario the company voluntarily withdraws the drug or the regulatory body does it. Further trials may or may not reinstate the concerned drug. The phases in product development or product pipeline averages 10 to 15 years for its completion. One is a thousand potential drugs will finally get approved.