Successful Drug Development depends on Pre-clinical and Clinical Trials

 

Pre-clinical and Clinical Trials are must for every drug that we use today. It has gone through rigorous multi-step process of testing and evaluation to explore everything about the drug. It takes a lot of time, effort and resources to know about the risks and benefits of a particular drug before it reaches a patient. The drug development process comprises of two pivotal components namely preclinical studies and clinical trials. Before a drug is tested in human subjects (or clinical trials), it is important to know about the safety, effectiveness and optimal use on people. For this, preclinical studies are conducted in both in vitro and in vivo models that provides information and evidence about the candidate drug’s biological effect. The testing of a drug in pre-clinical studies is done in non-human subjects that can be animal/model organisms or cell lines. It covers information about the pharmacodynamics and pharmacokinetics of the novel agent including organ system toxicity, besides potential hazards of carcinogenicity, mutagenicity, and teratogenicity. The preclinical findings form the basis of clinical research and allow researchers to estimate a safe starting dose for human testing. Majority of the drugs that undergo laboratory or animal testing never even make it to the next step of drug development, i.e., clinical trials.

Clinical trial is the systemic study of new drug(s) in human subject(s) to generate details for verifying clinical pharmacological effects and adverse effects with an objective of determining safety and efficacy of the new drug. Drug studies in human subjects are conducted only after the primary data of the novel drug gathered from preclinical studies is reviewed by a local institutional review board (IRB) and Drugs Controller General of India (DCGI) grants permission for the same. At this stage, the DCGI decides whether it is reasonably safe for the pharmaceutical company to further conduct testing in humans. The IRB is responsible for the approval of the clinical trial protocols and consists a team of physicians, statisticians and researchers to ensure that the clinical trial is ethical, protects patients’ rights and is appropriate to answer all the queries asked from both scientific and statistical point of view. Clinical trials involve healthy human volunteers or patients and is used to learn if the new treatment is more effective and/or has acceptable level of adverse effects as compared to the standard treatment. Traditionally, clinical trials are divided into four stages and the number of subjects participating increases in each subsequent trial phases.

Phase-0 or microdosing study is an exploratory investigational new drug study that involves a small number of candidates, around 10-15 people. It does not give any drug safety or efficacy data, but helps decide which pharmacokinetic parameters will be the best to take forward in the next phases. Also, this phase ensures the early bioavailability, half-life and pharmacodynamics of drug to minimize the losses if the drug fails in later stages. Usually, drugs undergoing phase-0 trials often skip phase I. The next phase I is the dose escalation, tolerability studies that has a primary goal of dose ranging to find the best dose with fewest side effects for the novel drug. This phase involves 20-100 healthy volunteers and establish maximum tolerated dose, pharmacodynamics and pharmacokinetics. To evaluate the effectiveness of the drug for a particular indication(s) in patients and to determine common short term side effects and risks, phase II or therapeutic exploratory studies are conducted. It includes 100-300 participants with a particular disease and lasts for several months to 2 years. In this phase, the drug is not presumed to have any therapeutic effect whatsoever and required to be proved all over in phase II. Phase II are therapeutic confirmatory trials, involving large population of 1000-2000 individuals to confirm Phase II findings This phase is essential as it provides an adequate basis for marketing approval. This phase is conducted before the new drug is approved for its use in the general public. Once the drug is approved, post approval research and monitoring or Phase IV are conducted to closely monitor long term safety and efficacy of the drug marketed, while comparing with already approved drugs. Additional Phase IV is sometimes conducted that involves research on the collected data instead of dosing or monitoring.

Therefore, preclinical trials explore the potentially hazardous drug in nonhuman animals and provides the first substantial, biological data that forms the foundation for clinical studies. Preclinical phase not only protects human volunteers for toxic exposure but also provides researcher an opportunity to explore detailed safety/toxicology profile of the novel drug. Further, clinical trials lead the deserving candidate drugs to the therapeutics and extrapolate preclinical safety and efficacy findings to human system where the drug is finally used.

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