Drug Delivery Pipeline Notes

Learning Outcomes

  • Understand the key stages in the drug discovery process, medicine design, and clinical trials.

Background on Drug Development

  • Over 90% of drugs fail to reach the market after clinical trials.
  • The estimated cost of bringing a new drug to market is approximately £5 billion.
  • Data sourced from an August 2013 survey of 100 pharmaceutical companies (Forbes).

Drug Development Process

  1. Pre-Clinical Phase
    • Includes drug discovery, preformulation/formulation, and safety/toxicity testing.
  2. Clinical Testing
    • Phases include I, II, III, and IV trials.
  3. Marketing Authorization
    • Drugs must pass rigorous testing for approval.

Drug Discovery Pipeline

  • Stages of Drug Development:
    • Target Identification
    • Target Validation
    • Lead Identification
    • Lead Optimization
Key Statistics
  • Total Compounds at Each Stage:
    • Early stages - 10,000 compounds
    • Preclinical - 250 compounds
    • Clinical - 5 compounds
    • Approved drug - 1 compound

Drug Attrition Rates

  • Stage 1 (Early Drug Discovery): 10,000 to 250 compounds
  • Stage 2 (Pre-Clinical Phase): 250 to 5 compounds
  • Stage 3 (Clinical Phase): 5 compounds to regulatory approval.

Clinical Trials Overview

  • Clinical trials evaluate drug safety and efficacy in human subjects.
  • Must have prior satisfactory quality and nonclinical safety data.
Phases of Clinical Trials
  • Phase I: 20-50 participants, focuses on safety.
  • Phase II: 50-300 participants, therapeutic exploration.
  • Phase III: 250-1000+ participants, efficacy and comparison with existing treatments.
  • Phase IV: 2000-10,000+ participants, post-marketing surveillance.

Calculation of First Dose in Humans

  • Determined using:
    1. NOAEL (No Observed Adverse Event Level) from animal studies.
    2. Human Equivalent Dose (HED) based on body surface area.
    3. Applied safety factor.

Ethical Considerations in Drug Trials

  • Compliance with ethics is paramount, following the Declaration of Helsinki.
  • Independent Ethical Committees must approve trial protocols.

Good Clinical Practice (GCP)

  • Standards for conducting clinical trials ensuring credible and accurate results.
  • Protects the rights and confidentiality of trial participants.

Drug Safety Testing

  • Toxicity studies establish safe dosage ranges and lethal doses (LD50).
  • The therapeutic window is the range of doses that provides efficacy without toxicity.
    • Therapeutic Index (TI): Defined as TI = ( \frac{LD50}{EC50} ), indicating drug safety.

Alternatives to Animal Testing

  • Advances in research for non-animal models (like Organ-on-a-chip) gaining prominence for ethical and efficacy reasons.

Future of Drug Development

  • Artificial intelligence (AI) expected to accelerate drug discovery by:
    • Target structure prediction and toxicity assessment.
    • Enhancing trial design and patient monitoring.

Case Study: COVID-19 Vaccine Development

  • Accelerated trials across multiple phases ensuring prompt availability.
  • Involvement of major pharmaceutical companies demonstrating rapid progress from research to public deployment.

Summary of Recommended Readings

  • Various articles discussing alternatives to animal testing and drug pipelines are listed for further reading.