Discovery and Clincial Trials

What are two major regulatory hurdles in drug development

• IND (investagational new drug)

  • NDA (new drug application)

What is an IND application

A: Permission to begin testing a drug in humans using animal pharmacology, toxicology, and manufacturing data.

Q: What is an NDA application?

A: Request for FDA approval to market and sell the drug after successful clinical trials.

Q: What is the main purpose of Phase I clinical trials?

A: Evaluate safety and toxicity in 20–100 healthy participants.

Q: What is the main purpose of Phase II clinical trials?

A: Test efficacy and monitor side effects in several hundred patients with the disease.

Q: Why is Phase III called the “Valley of Death” for drugs?

A: Rare but serious side effects may appear in thousands of patients, causing many drugs to fail.

Q: What is the purpose of Phase III clinical trials?

A: Confirm safety and efficacy in large populations before NDA submission.

Q: Why should clinicians be cautious prescribing newly approved drugs?

A: Rare adverse effects may only appear after large-scale or post-marketing use.

Q: Why can vancomycin still be clinically useful despite violating Lipinski’s rules?

Route of administration matters:

• IV vancomycin bypasses poor GI absorption for systemic MRSA infections.

  • Oral vancomycin stays in the gut to treat C. diff infections.

Q: What principle does vancomycin teach about pharmacology?

A: Understand ADME and clinical context instead of blindly memorizing drug rules.

Q: Why can’t natural products usually be used directly as drugs?

A: They often have toxicity, poor ADME properties, and limited supply.

Q: How are natural products converted into usable drugs?

A: Synthetic chemistry optimizes natural “hits” into safer, scalable “lead” compounds.

what plant gave rise to morphine and codeine

poppy plant

what natural source produced vincristine

the periwinkle flower

Q: “hit” compound?

• low potency, low specificity, many off-target effects.

“lead” compound?

• optimized potency, selectivity, SAR, and ADME properties.

Q: What potency range is typical for a hit compound?

micromolar rang

what potenecy rangie is for a lead compund

nanomolar to low micromolar range

what does SAR mean

structure activity relationship

Q: Why can’t raw hit compounds go directly into animal studies?

A: They lack sufficient potency, selectivity, and optimized ADME properties.

Q: Approximately how many compounds are screened to produce one FDA-approved drug?

A: About 5,000–10,000 compounds.

Q: What are the goals of lead optimization?

A: Improve potency, selectivity, safety, and ADME properties while reducing off-target effects.