Drug discovery and development is an elaborate process involving multiple steps and requiring several years to reach the pharmacy shelf. The drug discovery usually starts with basic scientific research before it proceeds onto preclinical and clinical trials. Although different pharmaceutical companies adopt different approaches for drug discovery, the general procedure is usually common. For the ease of understanding, each of the steps involved will be sequentially discussed.
Step 1: Target identification and validation
This is the first step of the drug discovery process and involves determining the target. The term ‘target’ commonly refers to a cellular or molecular structure (such as gene, RNA transcript, proteins, or other molecules) that is linked to the disease for which the drug is being developed. Identification of the putative target often stems from academic research. Once the potential target is identified, functional information available on the target is collected from in vitro and in vivo studies. This process is referred to as target validation. The target validation process also involves the determination of the link between the target and the disease and whether the target is druggable. Therefore, a target that is well-established requires less effort to validate.
Step 2: Compound screening
Once the target is identified and successfully validated, high-throughput screening of a large number of potential drug candidates (usually a library of compounds) is performed. Screening of compounds is performed to determine the binding affinity/degree of interaction of the potential drug candidates and the validated target. For example, if the validated target is a protein kinase, potential drug candidates will be screened for their ability to inhibit the kinase activity. Often a cross-screening process is conducted to investigate whether the potential drug candidates interact with other related targets that can cause toxic effects.
Step 3: Hit validation
The potential drug candidates that show desired interaction with the target are selected. They are referred to as ‘hits’. The hits identified are then validated using several cell-based assays. These assays use different cultured cell lines and organoids to closely replicate the pathophysiological conditions. The cultured cell lines are chosen with appropriate cellular and genetic makeup. For example, genetic mutations associated with a disease can be easily incorporated in the cell lines via suitable genome editing technology. Using cell-based assays that closely replicate the in vivo conditions result in enhanced efficacy of hit validation.
Step 4: Lead identification and optimisation
Only a few identified hits can be ultimately validated. The validated hits are often referred to as ‘leads’. The leads are optimised and tested for their pharmacokinetics (including absorption, distribution, metabolism, and excretion), toxicity, and physiological stability. The testing is performed using cellular and animal models closely replicating the pathophysiological conditions. Genomic engineering is used to create a wide range of genetically engineered models that can be used to test the safety and efficacy of leads developed for genetic diseases. The testing of safety and efficacy of the selected leads using animal models is often referred to as ‘preclinical trial’. The pharmacology and toxicology testing of a new drug needs to be approved by regulatory agencies and needs to be conducted in a safe and ethical way.
Step 5: Clinical trial and approval by regulatory authorities
Once the preclinical studied are successfully concluded, the chosen candidate(s) (one or only a few compounds) proceed to clinical trials. The clinical trials are conducted among human volunteers to test the safety and efficacy with respect to current therapeutic measures, and to determine the dosage. Clinical trials consist of five phases (including phase 0). They are:
Phase 0: This stage includes the first-in-human trial performed in accordance with FDA guidelines. It usually involves the collection of pharmacokinetic data or imaging of targets without causing a pharmacological impact on a small group of 10 to 15 volunteers who are involved in this phase.
Phase 1: This phase involves 20 to 80 volunteers with the disease or condition being studied. Safety and dosage of the drug candidate are determined in this phase. Almost 70% of the drug candidates in phase 1 proceed to the next phase.
Phase 2: A few hundred participants are included in this phase. Efficacy and side-effects of the drug candidate are determined. About 33% of the drug candidates in this phase proceed to the phase 3 of the clinical trial.
Phase 3: This phase includes about 300 to 3000 volunteers. Drug efficacy and adverse reactions are monitored in this phase. About 25-30% of the drugs monitored in this phase reach the next phase of the clinical trial (i.e., drug approval).
Phase 4: Upon successful completion of phase 3 of the clinical trial, the approval from the FDA and other regulatory authorities are sought for the drug marketing. The final phase of a clinical trial is conducted to assess the post-market safety of the approved drug. Therefore, phase 4 is also referred to as the post-marketing surveillance to monitor adverse events.