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Finding a molecule that can be used to treat and manage a disease state requires a diverse approach to drug discovery. The drug discovery process comprises the identification of drug candidates, synthesis, characterisation, screening, and tests for therapeutic efficacy. The process of drug development begins, following clinical trials, when a compound achieves favourable findings. Due to the high costs of R&D and clinical trials, drug discovery and development is an expensive endeavour. From the time a novel medicine molecule is discovered until it is available on the market for treating patients, it typically takes between 12 and 15 years to develop (Deore et al., 2019). Research and development costs for an effective medicine may range from $900 million to $2 billion on average. Included in this sum are the costs associated with the tens of thousands of attempts that were unsuccessful: For every 5,000-10,000 chemicals that enter the research and development pipeline, just one eventually receives approval. A basic grasp of the R&D process can help explain why so many compounds fail to make it and why it takes so much time and work to deliver a treatment to patients. Scientific and logical geniuses, advanced laboratory and technology, and multidimensional project management are all required for success. It also requires a lot of patience and a little bit of luck.
Stages of drug discovery and development include:
- Target identification
- Target validation
- Lead identification
- Lead optimization
- Product characterization
- Formulation and development
- Preclinical research
- Investigational New Drug
- Clinical trials
Target Identification
Identifying the disease’s biological origins and prospective therapeutic targets is the first stage in the discovery of a medication. Identifying a potential therapeutic target (gene/nucleic acid/protein) and its relevance in the disease is the first step in target discovery. Following the identification of the target, the molecular mechanisms addressed by the target are characterised. Effective, safe, clinically and commercially acceptable targets should be sought. In order to identify a target, one may employ techniques derived from molecular biology, biochemistry, genetics, biophysics or other areas.
Target Validation
Molecular targets such as genes, proteins, and nucleic acids of small molecules are validated by a method known as target validation. Target validation includes: identifying the structure-activity relationship of small chemical analogues; producing a drug-resistant mutant of the supposed target; knockdown or overexpression of the presumed target; and monitoring the known signalling systems downstream of the presumed target (Imming et al., 2006). In order to demonstrate the target’s functional significance in the pathogenesis of a disease, it must be validated. Although testing a drug’s efficacy and toxicity in a variety of disease-relevant cell and animal models is tremendously valuable, the final test is whether the drug works in a clinical context.
Identification of Lead
A chemical lead is a drug-like molecule that is synthetically stable, practical, and active in primary and secondary assays with appropriate specificity, affinity, and selectivity. This entails defining the structure-activity link, as well as determining synthetic feasibility and target engagement. A drug ability assessment is frequently performed to reduce the number of compounds that fail in therapeutic development. This evaluation is critical in turning a lead chemical into a medication. A molecule must have the ability to bind to a specific target in order to be druggable, but also have a favourable pharmacokinetic profile for absorption, distribution, metabolism, and excretion. Other assays will assess the compound’s potential toxicity, such as the Ames test and cytotoxicity assay (Patidar et al., 2011).
Lead Optimization
After identifying a lead chemical, a drug candidate is designed using lead optimization. To construct a model of how chemical structure and activity are associated in terms of interactions with targets and metabolism, a prospective medication is synthesised sequentially. Lead optimization is used to identify potential compounds from hit-to-lead high throughput screening assays. During lead optimization, features such as selectivity and binding processes are assessed. Lead optimization seeks to maintain desirable attributes while enhancing lead structure. To develop a pre-clinical therapeutic candidate, lead compounds (small molecules or biologics) must be chemically modified to improve target specificity and selectivity. Toxicological and pharmacodynamic characteristics are also assessed. Obtaining data on toxicity, effectiveness, stability and bioavailability of leads is essential for determining the compound’s optimum route (Huber et al., 2005). Drug discovery researchers need quick strategies to filter potential drug candidates for downstream selectivity profiling and further analysis. To better understand and anticipate in vivo pharmacokinetics, high throughput DMPK screens have become vital in lead optimization. Optimisation is used to produce new medications with better potency and safety characteristics.
Product Characterization
The size, shape, strength, weakness, usage, toxicity, and biological activity of any novel drug molecule that demonstrates promising therapeutic action are all characteristics of the molecule to be investigated. The early stages of pharmacological investigations are beneficial in determining the mechanism of action of the compound under investigation.
Formulation and Development
When developing a new pharmaceutical product, the physical and chemical properties of active pharmaceutical ingredients (APIs) are investigated in order to provide the most bioavailable, stable, and effective dosage form possible for a certain administration route.
During pre-formulation studies the following parameters are evaluated:
- Solubility in different media and solvents
- Dissolution of the active pharmaceutical ingredient (API)
- Accelerated Stability Services under various conditions
- Solid state properties (polymorphs, particle size, particle
shape etc.)
- Formulation services and capabilities
- Formulation development of new chemical entities (NCE)
- Optimization of existing formulations
- Process development for selected dosage forms
- Novel formulations for improved delivery of existing
dosage forms
- Controlled release and sustained release formulations
- Self-emulsifying drug delivery systems
- Colloidal drug delivery systems
- Sub-micron and nano-emulsions
Preclinical Testing
Pre-clinical research involves testing drug safety and efficacy on animals before testing on humans. Regulatory authorities must approve preclinical trials. Regulatory agencies must guarantee that studies are conducted safely and ethically, and only approve pharmaceuticals that are proven to be safe and effective. The ICH established a baseline guideline for appropriate preclinical drug development (Barile, 2008). Pre-clinical trials can be general pharmacology or toxicology. Pharmacology studies medication pharmacokinetics and pharmacodynamics. Unwanted pharmacological effects must be studied in suitable animal models and monitored in toxicological investigations. Absorption, distribution, metabolism, and excretion are key pharmacokinetic factors for determining safety and efficacy. These studies provide information on absorption rate for various routes of administration, distribution, metabolism, and elimination, which affects the drug’s half-life. The drug’s half-life reveals its safety profile, which is required for regulatory approval. The drug distribution mechanism explains the medicine’s therapeutic effectiveness by determining its bioavailability and affinity. Drug metabolism include steps of biotransformation and the generation of drug metabolites. It also aids in understanding biotransformation processes and enzymes ( (Friedman et al., 2010). The drug’s toxicological effects can be evaluated in vitro and in vivo. In vitro research can look at the impact on cell proliferation and phenotypic directly. In vivo research can determine toxicological effects qualitatively and quantitatively. Many medications are species-specific, thus choosing the right animal species for testing is critical. In vivo studies to assess pharmacological and toxicological activities, including mechanism of action, are frequently employed to assist clinical investigations (Faqi, 2013).
The Investigational of New Drug Process
Drug developers must file an Investigational of New Drug application before commencement clinical research. In this application, developers must include:
- Preclinical and toxicity study data
- Drug manufacturing information
- Clinical research protocols for studies to be conducted
- Previous clinical research data (if any)
- Information about the investigator/ developer
Clinical Research
Clinical trials use human volunteers to test the safety and efficacy of medications, vaccines, other therapies, or novel ways of using existing treatments. A researcher, investigator, or manufacturer designs a study protocol for a clinical trial. Researchers generate study questions and objectives before starting a clinical trial.
Then, they decide:
- Selection criteria for participants
- Number of people take part of the study
- Duration of study
- Dose and route of administration of dosage form
- Assessment of parameters
- Data collection and analysis
The clinical research stage is broken down into phases; from phase zero to phase four.
Phase 0 clinical trial
First-in-human trials in Phase 0 are undertaken in accordance with established protocols. Phase 0 trials besides termed as human micro dose studies, they have single sub-therapeutic doses given to 10 to 15 volunteers and give pharmacokinetic data or help with imaging specific targets without exerting pharmacological actions. Phase 0 studies are used by pharmaceutical companies to determine which of their drug candidates has the best pharmacokinetic properties in humans.
Phase 1: Safety and dosage
Phase I trials have fewer healthy human volunteers than Phase II trials. Phase 1 usually involves 20 to 80 healthy volunteers with the disease/condition.
Drugs that are not tolerated by healthy persons are usually tested on patients. When a novel medicine is proposed for use in diabetics, researchers undertake Phase 1 trials on diabetics. Phase 1 studies collect data on pharmacodynamics in the human body. Researchers change dosage regimen based on animal study data to determine body tolerability and acute side effects. As a Phase 1 trial progresses, researchers learn about the drug’s mechanism of action, side effects, and effectiveness. This is critical for Phase 2 study design. Almost 70% of medications go further to the next phase.
Phase 2: Efficacy and side effects
Efficacy and safety of a medicine are assessed in Phase II trials, which are undertaken on larger groups of patients (a few hundreds). A drug’s medicinal potential cannot be determined by these tests alone. Phase 2 trials give researchers more information on safety. New Phase 3 techniques are developed based on these results. The next phase is taken by around 33% of all medicines tested. Among other things, Phase II clinical trials are used to identify therapeutic doses for Phase III investigations.
Phase 3: Efficacy and adverse drug reactions monitoring
Phase 3 trials will determine whether a product has an action benefit for a certain people. These trials use 300-3,000 individuals and are called pivotal studies. More safety data comes from Phase 3. The prior study may have missed less common adverse effects. Because phase 3 studies involve more participants and last longer, they are more likely to detect long-term or rare side effects. Only 25-30% of medicines make it to the next phase of testing. At this stage, a drug manufacturer can file a marketing application if they have proof that their drug is safe and effective for the intended use. A review team thoroughly examines all supplied data on the drug and decides whether to approve it or not.
Phase 4: Post-Market Drug Safety Monitoring
Following approval, a medication enters phase 4 clinical trials. Also known as post-marketing surveillance, these studies include drug safety monitoring and on-going technical assistance after the product has been approved. In Phase 4 studies, a variety of observational and assessment methods are utilised to evaluate the efficacy, cost-effectiveness, and safety of an engagement in real-world situations. A Phase 4 study may be mandated by regulatory authorities, or it may be done by the sponsoring corporation for competitive reasons or for other goals.
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References
Barile FA. Principles of Toxicological Testing. CRC Press, USA, 2008.
Deore A, Dhumane J, Wagh R, Sonawane R. The Stages of Drug Discovery and Development Process. Asian Journal of Pharmaceutical Research and Development. 2019; 7(6): 62-67
Faqi AS. A comprehensive guide to toxicology in preclinical drug development. Waltham, MA: Elsevier; 2013.
Friedman LM, Furberg CD, Demets DL. Fundamentals of clinical trials. 4th ed. New York: Springer Science and Business Media LLC; 2010.
Huber W. A new strategy for improved secondary screening and lead optimization using high-resolution SPR characterization of compound–target interactions. J Mol. Recogn. 2005; 18:273–281.
Imming P, Sinning C, Meyer A. Drugs, their targets and the nature and number of drug targets. Nature Reviews Drug Discovery, 2006; 5:821-834.
Patidar AK, Selvam G, Jeyakandan M, Mobiya AK, Bagherwal A, Sanadya G, Mehta R. Lead Discovery and lead optimization: A useful strategy in molecular modification of lead compound in analog design. International journal of drug design and discovery. 2011; 2(2):458-463.
