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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