AR - Drug Discovery & Development I

Question 1

Q1: What are the four main stages in therapeutic drug development? (4)

Answer 1

1. Discovery & Development – Identify potential drug compounds and evaluate their basic properties.
2. Preclinical Research – Lab and animal testing to assess mechanism of action, efficacy, PK, and toxicity.
3. Clinical Research – Human testing in Phases I–III to evaluate safety and effectiveness.
4. Regulatory Review & Post-Marketing Surveillance – Agencies (FDA/MHRA/EMA) assess drug for approval and continue monitoring after market launch.

Question 2

Q4: What is LADMET and what does it represent in drug development? (6)

Answer 2

• Liberation – Drug release from dosage form.
• Absorption – Entry into bloodstream.
• Distribution – Movement to tissues/organs.
• Metabolism – Chemical breakdown (mainly in liver).
• Excretion – Elimination via urine/feces.
• Toxicity – Potential harmful effects

Question 2

Q3: What are key research questions addressed during drug development? (8)

Answer 2

• ADME – How is the drug absorbed, distributed, metabolised, and excreted?
• Therapeutic benefit and proposed mechanism of action.
• Optimal dosage and administration route.
• Adverse effects and toxicity profile.
• Population-specific responses (gender, race, ethnicity).
• Drug-drug interactions.
• Comparative effectiveness vs. other therapies.
• Pharmacokinetics and pharmacodynamics (PK/PD) models

Question 3

Q2: How are new drug candidates typically discovered? (4)

Answer 3

• New insights into disease mechanisms guide rational design.
• High-throughput screening of compound libraries for activity.
• Repositioning existing drugs with unexpected benefits.
• Emerging technologies such as gene editing or targeted delivery tools.

Question 4

Q5: What must be demonstrated during preclinical studies before human trials? (6)

Answer 4

• Mechanism of Action (MOA)
• Efficacy in disease-relevant animal models
• Pharmacodynamics – effect of drug on body
• Pharmacokinetics – what the body does to the drug
• Toxicity – adverse effects, LD50, organ damage
• Compliance with GLP (Good Laboratory Practices)

Question 5

Q6: What practices are required under GLP for preclinical research? (8)

Answer 5

• Clear study protocols and objectives
• Qualified personnel
• Standardised facilities and equipment
• Defined SOPs (standard operating procedures)
• Accurate study reports and documentation
• Quality assurance systems
• Ethical animal care practices
• Use of both in vitro and in vivo models

Question 6

Q7: Why are animal models essential in biomedical research? (6)

Answer 6

• Animals share >95% of genes with humans (e.g., mice).
• Mimic human physiology and organ systems.
• Suffer from similar diseases (e.g., cancer, asthma, infections).
• Essential for developing vaccines, antibiotics, and surgeries.
• Enable study of PK, efficacy, and long-term toxicity.
• Ethically regulated, often used with in vitro/computer models.

Question 7

Q8: What are major breakthroughs made possible through animal studies? (5)

Answer 7

• Herceptin (breast cancer) – developed from mouse antibodies.
• HAART for HIV – enabled by animal testing.
• Insulin therapy – tested in rabbits and dogs.
• Tamoxifen – reduced breast cancer mortality by 30%.
• Vaccines – polio, HPV, meningitis, etc.

Question 8

Q10: What happens in Phases I–III of clinical research? (6)

Answer 8

• Phase I – Test safety, dosage, and PK in 20–100 healthy volunteers.
• Phase II – Assess efficacy and side effects in 100–500 patients.
• Phase III – Confirm results in 1,000–5,000 patients; compare with existing therapies.
• All phases follow GCP (Good Clinical Practice).
• Trials include controls, randomisation, and blinding to reduce bias.
• All data used for New Drug Application (NDA) submission.

Question 9

Q9: What must occur before moving a drug to clinical trials? (4)

Answer 9

• Submission of IND (Investigational New Drug) application.
• Design of clinical protocols (phases, dosing, endpoints).
• Define eligibility criteria and sample sizes.
• Approval from regulatory authorities (FDA, MHRA, EMA).

Question 10

Q12: Why do many drug candidates fail or slow down in development? (7)

Answer 10

• Poor pharmacokinetics (e.g. low bioavailability).
• Toxicity issues identified in preclinical or clinical stages.
• Lack of efficacy in target population.
• Market-related concerns (cost, competition).
• Synthetic complexity – hard to manufacture.
• Ambiguous toxicology findings.
• Target has limited therapeutic window or disease is too complex.

Question 11

Q11: What information is included in a New Drug Application (NDA)? (5)

Answer 11

• Full clinical trial data from Phases I–III.
• Reports on toxicity, pharmacokinetics, and efficacy.
• Proposed labeling and usage instructions.
• Safety updates and drug abuse potential.
• Patent, compliance, and manufacturing details.

Question 11

Q13: What was the TGN1412 disaster and what did it teach us? (3)

Answer 11

• TGN1412 – anti-CD28 superagonist tested in humans in 2006.
• Caused cytokine storm in all 6 volunteers at Northwick Park, UK.
• Highlighted the critical gap between animal models and human immune response – led to updated regulations for first-in-human trials.