Drug Discovery and Development

Pre-Discovery: HIT Identification

• What biological process causes the disease?

• Identify your target to treat

• Scientists Identify:

  • Receptors

  • Enzymes

  • Ion Channels

  • Transporters

  • Genes

Drug Discovery: Lead Compound

A molecule with promising biological activity that can be further optimized

Drug Discovery: Methods of Lead Discovery

• Natural Product Discovery (e.g., Paclitaxel from Pacific Yew)

• High-Throughput Screening

  • Compound Library → Robotic Screening → Hit Identification

• Virtual Screening (e.g., COVID-19 drug repurposing studies)

• Rational Drug Design (e.g., Imatinib, Oseltamivir)

• Drug Repurposing (e.g., Sildenadfil for Erectile dysfuntion and Minoxidil for Hair growth)

Drug Discovery: Lead Optimization

• Goal: Improve the molecule before animal testing

• Scientists Modify:

  • Potency

  • Selectivity

  • Solubility

  • Stability

  • Toxicity

Preclinical Studies

• Purpose: To evaluate the safety, pharmacology, and Toxicity, of the lead compound before testing in human subjects

• Key Studies:

  • Pharmacokinetics (ADME)

  • Toxicology (Acute, Subacute, and Chronic Toxicity)

  • Special Studies (Genotoxicity, Carcinogenicity, Reproductive Toxicity)

Preclinical Studies: In Vitro Studies

• Performed in test tubes or cell cultures

• Cytotoxicity Assays, Receptor Binding Studies, Antimicrobial Testing

Preclinical Studies: In Vivo Studies

Performed in Animals (e.g., mice, rats, rabbits, dogs)

Investigational New Drug (IND) Application

• Before clinical trial

• Submitted by regulatory authorities before human testing

• Contains the preclinical data, manufacturing information, and clinical protocol

Clinical Studies

To evaluate the safety, efficacy, and optimal dosage of the drug substance in humans

Clinical Studies: Clinical Trial Phase I

• Parameter/Assessed: Initial Safety

• Type of Subjects: 20-100 healthy volunteers

• Key Questions

  • Is it safe?

  • What does is tolerated

• Goal: Safety

Clinical Studies: Clinical Trial II

• Parameter/Assessed: Safety, Efficacy

• Type of Subjects: 100-300 patients (with illness)

• Key Questions

  • Does it work

  • What dose is effective?

• Goal: Efficacy

Clinical Studies | Clinical Trial Phase III

• Parameter/Assessed: Safety, Efficacy

• Type of Subjects: >300 patients

• Key Questions

  • Compare with placebo and standard treatment

• Goal: Confirm Efficacy

Regulatory Reviews

Submission of:

• New Drug Application (NDA)

• Biologics License Application (BLA)

  • For Vaccines

Commercialization

• Acquisition and control of materials

• Provision of Facilities, Utilities, and Equipment

• Production (including packaging and labeling)

• Quality control and assurance

• Release

• Storage

• Distribution (excluding wholesaler activities)

Post-Marketing Surveillance

To Detect:

• Rare adverse effects

• Long-term safety

• Real-world effectiveness

Drug Development Attrition

Most drugs fail because of:

• Lack of efficacy

• Toxicity

• Poor pharmacokinetics

• Commercial consideration