2.1 Stages of drug discovery and development

Drug discovery and development is a complex, multi-stage process. It starts with identifying disease targets and screening potential compounds. The most promising leads then undergo rigorous preclinical testing to assess safety and efficacy before moving to human trials.

Clinical trials are the cornerstone of drug development, progressing through three main phases. These trials evaluate safety, efficacy, and optimal dosing in increasingly larger patient populations. Regulatory approval is the final hurdle before a new drug can reach patients.

Drug Discovery

Target Identification and Lead Compound Selection

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• Target identification involves identifying specific molecules (proteins, genes, or RNA) involved in disease processes
• Utilizes various techniques including genomics, proteomics, and bioinformatics to identify potential targets
• High-throughput screening tests thousands of compounds against the identified target
• Lead compound emerges as the most promising molecule showing desired effects on the target
• Structure-activity relationship (SAR) studies optimize lead compounds for improved potency and safety
• Medicinal chemistry techniques modify lead compounds to enhance their drug-like properties (solubility, stability)

Preclinical Studies and Safety Assessment

• In vitro studies evaluate compound's mechanism of action and potential toxicity using cell cultures
• In vivo studies assess drug effects in animal models to determine efficacy and safety profiles
• Pharmacokinetic studies analyze drug absorption, distribution, metabolism, and excretion (ADME)
• Toxicology studies determine potential adverse effects and safe dosage ranges
• Formulation development optimizes drug delivery method (oral tablets, injectables, topical creams)
• Good Laboratory Practices (GLP) ensure quality and integrity of preclinical data

Clinical Trials

IND Application and Phase I Trials

• Investigational New Drug (IND) application submitted to FDA for clinical trial approval
• IND includes preclinical data, manufacturing information, and clinical protocols
• Phase I trials assess drug safety and tolerability in healthy volunteers (20-100 participants)
• Determine pharmacokinetics and pharmacodynamics in humans
• Evaluate side effects and establish maximum tolerated dose
• Usually conducted in specialized clinical pharmacology units
• Typically last several months and have a single-ascending dose design

Phase II and III Clinical Trials

• Phase II trials evaluate drug efficacy in patients with target disease (100-300 participants)
• Determine optimal dosing regimens and further assess safety profile
• Often include randomized, controlled study designs
• Phase III trials confirm efficacy and monitor long-term safety (1000-3000 participants)
• Compare new drug to current standard treatments or placebos
• Evaluate drug in diverse patient populations and multiple clinical sites
• Generate data on drug interactions and special populations (elderly, children)
• Can last several years and involve complex study designs (double-blind, multi-arm)

Regulatory Approval

NDA Submission and FDA Review Process

• New Drug Application (NDA) compiles all data from drug discovery through clinical trials
• Includes comprehensive information on drug chemistry, manufacturing, and controls
• Presents detailed analysis of clinical efficacy and safety data
• FDA review teams (medical officers, statisticians, pharmacologists) evaluate NDA
• Advisory committee meetings may be held to discuss complex or controversial applications
• FDA issues Complete Response Letter for applications requiring additional information

FDA Approval and Post-Marketing Surveillance

• FDA approval grants permission to market the drug for specific indications
• Labeling negotiations finalize prescribing information and patient medication guides
• Risk Evaluation and Mitigation Strategies (REMS) may be required for drugs with serious safety concerns
• Post-marketing surveillance (Phase IV) monitors drug safety in real-world use
• Adverse event reporting systems collect data on unexpected side effects
• Post-approval studies may be required to address specific safety or efficacy questions
• Periodic safety update reports submitted to regulatory agencies
• FDA can require label changes or market withdrawal based on post-marketing data