Drug Discovery Process - An Overview

Introduction

Drug discovery is a long and complex process as it involves multiple testing phases. The drugs are tested in thousands, but only a few of them, generally one or two, can get licensed for treatment. These drugs can be rejected at any point or phase of the discovery process based on various aspects, such as safety, quality grounds, and effectiveness. Sometimes, it may take around ten to 15 years for a compound to get into a medicine cabinet from a test tube. Drug discovery is mainly based on the knowledge of the disease’s biology, natural biological and cell processes in a healthy body, along with notable changes in the disease. All this information helps in revealing the potential targets for the drug to act on. Therefore, a new drug is discovered by having a potential knowledge of the biological molecule’s shape at an atomic level. Therefore the drug discovery process helps in bringing new products or drugs into the market through various developmental stages. This article talks in detail about the various phases of the drug discovery process.

What Are the Various Phases of Drug Discovery?

The phases of the drug discovery process are as follows:

Drug Discovery Process: This phase involves many testing and other actions, such as looking for potential leads through the collaboration of the researchers for the identification and optimization of the specific target. The main aim of these leads is to draw the effects on the specific targets in the disease and treat them effectively. This phase of research is conducted in the laboratory using biochemical assays, in silico platforms, cell cultures, and animal models. There are various sub-processes involved in this initial phase of drug discovery; these are:

1. Target Identification and Validation - When the biological activity of the selected biological target can be modified with a therapeutic molecule called a “Hit,” it is said that the biological target is “druggable.” After the identification of the target, the suitability of the target is validated by the researchers for drug development prior to the screening process for the identification of Hit.

2. High Content Screening (HCS) or High Throughput Screening (HTS) - This is a very important phase of the drug discovery process. It helps in screening a large number of molecules that can interact with the identified and validated target. An assay can be developed, which can provide detailed information about the selectivity and effectiveness of the molecule. In addition, the molecule must also have the potential to withstand all the testing requirements, which are fast and reliable. High-content screening offers much more reliable and rich data than high-throughput screening.

3. Hit Identification - The identification of the Hit is made through various methods. The Hit is discovered based on its interaction with the selected target to produce the desired therapeutic effects. The Hit is therefore identified through a large list, such as high content screening, fragment-based screening, phenotypic screening, virtual screening, and structure-based screening.

4. Assay Development and Screening - This screening is based on using high throughput microscopy to take a large number of pictures or images. The new active molecule is researched in In vitro cell models and zebrafish embryos. In this phase, HCS is used mainly for screening of secondary substances, substance profiling, lead optimization, identifying and validating effective targets, and investigation of the pharmacokinetics of the drug, which includes absorption, distribution, metabolism, and excretion of the drug. It also includes the study of the toxicity of the drug in the pre-clinical research phase.

5. Hit-To-Lead (H2L) - This is an important phase of the drug discovery process, and it mainly aims at finding the most appropriate leads for going ahead in the pathway to reach the final phase of a clinically active drug. In this process, the most refined and qualified leads are selected out of the large number through screening processes using various computer-based and In vitro approaches.

6. Lead Generation and Optimization - After the generation of H2L, the lead generation and optimization process starts. The phase focuses on improving the most promising compounds and thus enhances their effectiveness, increases adsorption, or lowers toxicity.

7. In Vivo and in Vitro Assays - This is the last stage of the early drug discovery process in which the final potential compound is screened and tested under conditions that are similar to the living cell conditions. In vivo and In vitro testing plays a major role in this process, as they are used for analyzing the toxicity and effectiveness of the compound in animal models or alternative models, such as cell cultures or zebrafish embryos.

Pre-Clinical Phase: In this phase, the identified substances in the drug discovery phase are extensively refined, optimized, and tested in laboratory, animal, and alternative models. The main aim of this phase is to provide evidence-based safety and efficacy reports before the beginning of human trials or clinical trials on humans. Also, the amount of dosage is appropriately calculated to test in humans. In addition, a sufficient quantity of the new substance should be available for trials, as earlier it was required in lesser quantities, but now the higher demands in the clinical phase require high production as well. Pre-clinical studies are demanded by the regulatory authorities before the submission of an investigational report on a new drug application to enter the clinical phase.

Clinical Phase: This phase consists of four sub-phases: I, II, III, and IV. In the first Phase, the drug candidate’s safety and tolerance are tested in a small, healthy group of 20 to 80 subjects. During this phase, the researchers look for answers to the following questions,

1. Is the drug safe to use?

2. What drug dose is safe to use and has no side effects?

3. What is the behavior of the substance in the body?

The active ingredients used in the substance are manufactured using GMP (Good Manufacturing Practices) conditions, protocols, and guidelines.

In phases, IIa and IIb, the safety, effectiveness, and tolerability of a substance are tested in a larger group of subjects. The dosage form is also developed for this phase. Phase II studies mainly include adult patients (100 to 500). Phase Ia is used to check the proof of concept or therapy concept, and phase IIb aims at finding the right dosage for the study.

In the last phase (phases III and IV), the researchers test the drug on a larger number of patients to evaluate the drug's safety and effectiveness in these patients before getting approval for a drug. In these phases, drug interactions are also tested by the doctors. These last phase studies are usually controlled studies, where some patients are given a new drug dose, and some receive the old standard dosage.

• Regulatory Approval: After the completion of clinical trials of the active substance, the entire data is collected by the researchers and analyzed. It is then further sent for review to an appropriate concerned authority. The approval of the centralized or national regulatory authority is needed before selling a vaccine or drug in a market. During this process, only one of the thousands of substances tested during the research process gets approval for clinical study and regulatory tests. Thus, only one selected compound is then finalized and approved as a vaccine or drug.

• Post-Market Monitoring: After receiving the approval for marketing from the regulatory bodies, phase IV of the drug development process starts. This is also known as post-market monitoring or post-marketing surveillance trials. In this phase, comprehensive data collection is done regarding the safety and effectiveness of the newly discovered drug. The data is collected from the patients who are taking the new drug and those who are receiving treatment with the already available drug in the market for comparison. The main purpose of this study is to assess all the long-term effects of the new drug so that the adverse effects can be noted and avoided.

Conclusion

The key factor in developing a new drug is that it should be effective against the disease, and for that, one must have a clear understanding of the disease’s pathogenesis. The drug should be safe to use, and its discovery and development should be justified keeping in mind the health and safety of the human population. Therefore, for this purpose, the effectiveness and safety of the newly discovered drugs are carefully monitored by the federal agency of the United States Department of Health and Human Services, FDA (Food and Drug Administration). The agency is responsible for promoting and protecting public health. The FDA approves the drug only after the review of the drug-related data by the Center for Drug Evaluation and Research (CDER). The drug only gets approval if its potential benefits are higher in number than some potential or known risks. FDA analyzes the drug under a very strict structured process, which includes investigating the targeted condition or disease and the available treatments, associated benefits, and risks through clinical data and strategies and planning to manage risks.