Author Name: Boutika
Profession: clinical Research
Introduction:
Drugs are chemical agents that alter the physiological or psychological functions of living organisms. They are used in various ways, such as for diagnosis, treatment, and prevention of diseases, or to promote well-being.
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Drug discovery is a massive process that leads to the development or introduction of a new molecule into the market for the benefit of society. It takes around 12–15 years for a drug molecule to be fully established as a new drug candidate. Just imagine the expenditure required to finally bring it to market. It takes more than $1 billion to carry out this drug discovery process.
Process:
The process of drug discovery involves several key steps, which include:
Pre discovery
Pre clinical research
Clinical research
Regulatory approval process
Post-Marketing Surveillance
Now, let's learn about them one by one.
Pre discovery:
In the past, discoveries were often made by chance or by testing a wide range of traditional medicinal plants and remedies. Researchers would then use classical pharmacology to determine whether any of these substances had therapeutic effects.
Today, the process is more focused. Scientists first identify a few promising molecules, called 'HITs,' through targeted screening. They then use advanced medicinal chemistry to evaluate these molecules, selecting the most potent one as a 'lead.' Finally, they optimize this lead to reduce or eliminate any potential side effects.
1. Target Identification:
Target identification is the first key stage in drug discovery, especially for the target-centered approach. It refers to the specific binding site of a drug in vivo, through which the drug exerts its action.
2. Target Validation:
Target validation is the initial stage of drug exploration, providing deeper insights into the pathogenesis of target-related diseases.
3. Lead Discovery:
Once a disease-associated molecular target has been identified and validated, the initial screening process begins to identify more promising candidates. This involves limited optimization or a structure-activity relationship (SAR) study to find compounds that bind effectively to the target.
4. Lead Optimization:
After identifying hits, the next step is to optimize these lead compounds with promising biological activity. This process ends with the identification of the best analog, enhancing potency, selectivity, and safety.
Pre clinical research:
Once potential drug candidates are identified, they undergo pre clinical testing. The primary goal of this stage is to ensure their safety for human trials by conducting rigorous safety assessments using both in vitro and in vivo methods.
1. In Vitro:
In vitro evaluation is conducted in test tubes or laboratory settings, where potential drug candidates are tested for receptor characterization, receptor binding, enzyme inhibition, secondary messenger analysis, cytokine activity, etc.
2. In Vivo:
In vivo evaluation is conducted in living organisms such as rats and mice to assess pharmacological and toxicological properties. This helps determine a safe and effective drug dose, facilitates animal-to-human dose conversion, and establishes the maximum recommended starting dose.
Generally, in vivo studies are performed on two mammalian specie which are one rodent and one non-rodent. The drug is administered via two different routes that will be used in human trials.
All these data obtain from pre clinical study are required in IND Submission.
Clinical Trials :
Clinical trials involve investigations in human subjects to discover or verify the clinical, pharmacological, and pharmacodynamic effects of an investigational product. They aim to identify any adverse reactions and study the ADME (Absorption, Distribution, Metabolism, and Excretion) of the investigational product to determine its safety and efficacy.
In simple terms, clinical trials are conducted to scientifically evaluate the safety and effectiveness of a new investigational compound based on proven data.
Phases of clinical trail:
Phase 0
Phase 1
Phase 2
Phase 3
Phase 4
Phase 0 :
Phase 0 is an exploratory trial phase used to gather information on the pharmacodynamics and pharmacokinetics of an investigational drug at a sub-therapeutic dose. It is conducted on 10–15 healthy volunteers for a short duration.
Phase 1 :
Phase 1 aims to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a drug in humans for the first time. It is conducted on a small group of 20–100 healthy volunteers or patients over a period of 1 to 1.5 years. This phase consists of two sub-phases:
• Phase 1a: Focuses on single ascending dose studies.
• Phase 1b: Focuses on multiple ascending dose studies.
The primary objective of Phase 1 is to identify the maximum tolerated dose with minimal and common side effects.
Phase 2 :
Phase 2 focuses on assessing the efficacy and side effects of the drug in a moderate group of 200–400 patients over a period of 1–2 years. This phase consists of two sub-phases:
• Phase 2A: Known as proof of concept studies, it focuses on exploring various doses to find the most effective dose with the least side effects based on the previously identified maximum tolerated dose (MTD).
• Phase 2B: Known as definite dose-finding studies, it focuses on confirming the best dose identified in Phase 2A.
Phase 3 :
Phase 3, also known as the pre-marketing phase, is designed to assess the efficacy of the new intervention by demonstrating whether or not the product offers a treatment benefit to a specific patient population in comparison with the current gold standard treatment. It is a larger, longer-duration phase that focuses on dose-response relationships, the efficacy and safety of the drug, and the drug's efficacy in combination with other drugs. This phase usually lasts from 1 to 4 years and involves 400–4,000 patients. A successful Phase 3 trial is essential for acquiring regulatory approval for a new drug application and marketing.
Phase 4 :
Phase 4, also known as Post-Marketing Surveillance (PMS), begins after a drug has received approval from the regulatory licensing authority. This phase focuses on monitoring the safety and efficacy of the drug in a broader population across multiple centers and countries. The primary aim of Phase 4 is to detect rare or long-term side effects that may not have been identified during earlier phases of clinical trials. It also helps to gather more data on the drug's performance in real-world settings, providing valuable insights into its use in diverse patient populations over extended periods.
Regulatory approval process :
Regulatory agencies like the FDA (Food and Drug Administration) and EMA (European Medicines Agency) review the drug's safety and efficacy data. Applications like the Investigational New Drug (IND) and New Drug Application (NDA) are crucial milestones for obtaining market approval.
Post-Marketing Surveillance :
Post-Marketing Surveillance (PMS) is a crucial part of Pharmacovigilance, but it is not the same as Phase 4 clinical trials. While Phase 4 trials involve interventional studies to further assess the drug’s safety and efficacy, PMS studies are typically observational or non-interventional studies conducted under approved conditions and within the intended patient population.
PMS is a mandatory process, requiring the marketing authorization holder (MAH) of a newly approved drug to submit a Periodic Safety Update Report(PSUR) in a specified format. The reporting timeline is as follows:
• Every six months for the first two years
• Annually for the next two years
A drug remains classified as a "new drug" for four years after approval, during which PMS ensures ongoing safety monitoring in real-world conditions.
Conclusion:
The drug discovery and development process is a testament to human ingenuity and perseverance. It bridges the gap between laboratory research and real-world medical application, offering hope to millions. As technology and science converge, the horizon looks promising for faster, more efficient, and personalized therapeutic solutions.
Citations:
1. Postgraduate Pharmacology - Authors: Sogata Sarkar, Vartika Srivastava, Manjushree Mohanty
2. Drug Discovery and Development - Authors: H. P. Rang and R. J. Flower
3. Drug Discovery Series - Publisher: Royal Society of Chemistry
4. Drug Discovery: Practices, Processes, and Perspectives - Authors: R. Larsson, A. L. Hill, and B. A. Cox
5. https://www.frontiersin.org/journals/drug-discovery/articles/10.3389/fddsv.2023.1201419/full
6. https://en.wikipedia.org/wiki/Drug_discovery
7. https://pmc.ncbi.nlm.nih.gov/articles/PMC5725284/
8. http://www.niperhyd.ac.in/images/services/Scientificjournal/2.pdf
9. https://www.ncbi.nlm.nih.gov/books/NBK92015/
10. https://www.nature.com/articles/s41573-020-00114-z
11. https://analyticalsciencejournals.onlinelibrary.wiley.com/journal/10982299
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