Drug Development and Approval Process

INTRODUCTION

• Drug development involves synthesizing numerous drug molecules to discover new drugs.
• The primary employer of organic chemists is drug manufacturers.

DRUG DEVELOPMENT

In Vitro Testing

• Initial testing occurs in vitro, using test tubes to assess biological activity.
• Example:
  • Test tubes are set up with pathogenic bacteria and nutrients.
  • A potential antibiotic is added to one tube, while the other serves as a control.
  • After incubation, clear solutions indicate antibiotic activity, while cloudy indicates failure.
• Cloudiness can be measured using a spectrophotometer.

High Throughput Screening

• To enhance efficiency, high throughput screening tests use multi-well plates (96+ wells).
• Allows testing of multiple antibiotic candidates simultaneously.
• Current systems can evaluate up to 100,000 samples per day.

Animal Testing

• Drugs passing in vitro tests proceed to testing on animals (mice, rats, rabbits) for positive effects on disease symptoms.
• Promising drugs undergo the Ames test for carcinogenicity before human trials.

Clinical Trials

1. Phase I Trials:
   • Conducted on healthy human volunteers.
   • Focuses on toxic effects and metabolism, monitored closely over a short period (days/weeks).
2. Phase II Trials:
   • Involves patients who can benefit.
   • Monitors drug dosages, adverse effects, efficacy versus placebo in a double-blind manner.
3. Phase III Trials:
   • Larger patient groups over extended periods (months or years).
   • Higher costs and detailed data analysis required.

Approval Success Rate & Costs

• Approximately 15% of drugs from clinical trials achieve FDA approval.
• Drug market entrance costs range from $350 million to $2.6 billion (2014 estimates).
• Controversial balance between thorough pre-market testing and timely drug release.

Phase IV Monitoring

• After FDA approval, drugs may require further monitoring (Phase IV) for safety and efficacy.
• Follow-up monitoring effectiveness varies.

DRUG MARKETING

• Patent protections last for 20 years; companies extend these through further testing and legal disputes against generics.
• Post-FDA approval marketing campaigns are extensive (e.g., $382 million for erectile dysfunction drugs in 2004).
• Less than 1 in 100,000 drug molecules from initial synthesis reach marketing.
• Blockbuster drugs generate billions, but only 30% recoup development costs.

Patents & Market Strategy

• Evergreening:
  • Strategy to extend exclusivity through overlapping patents or minor modifications to existing drugs.
  • Example: Lyrica (pregabalin) versus Neurontin (gabapentin).

Unforeseen Effects & Off-Label Uses

• Human trials often reveal other drug effects (e.g., Minoxidil for hair growth, Sildenafil for erectile dysfunction).
• Unlabeled uses are prevalent but illegal for companies to advertise.
• Example: Gabapentin (Neurontin) widely prescribed for off-label uses despite penalties for off-label marketing by Pfizer.

DRUG TERATOGENICITY

• Teratogens: Molecules that increase birth defect risks.
• Limited ethical data on drug effects on pregnancy.
• New labeling (since July 2015) will include risks during pregnancy and breastfeeding.

Drug Category Ratings

• Category A: No significant risk in well-controlled testing.
• Category B: No evidence of defects in studies; insufficient human data.
• Category C: Adverse animal effects; insufficient human data; use if benefits outweigh risks.
• Category D: Clinical evidence of risk; may be prescribed if benefits outweigh risks.
• Category X: Substantial risk; should not be used in pregnancy (e.g., Accutane, thalidomide).

DRUG ABUSE POTENTIAL

• Federally regulated by the DEA with five schedules based on abuse potential:
  • Schedule I: No accepted medical use (e.g., heroin, LSD).
  • Schedule II: High abuse potential (e.g., oxycodone, morphine).
  • Schedule III: Moderate potential (e.g., anabolic steroids).
  • Schedule IV: Low potential (e.g., diazepam).
  • Schedule V: Lowest potential (e.g., pregabalin).

DRUG NAMING CONVENTIONS

• Chemical names are rarely used; generic and trade names are standard.
• Trade names are often heavily marketed.
• Example:
  • Chemical: N-acetyl-para-aminophenol
  • Generic: Acetaminophen
  • Trade: Tylenol

COMMON PRESCRIPTION ABBREVIATIONS

• ac: before meals
• pc: after meals
• bid: twice daily
• tid: three times daily
• qid: four times daily
• qd: every day
• hs: at bedtime
• PRN: as needed
• PO: by mouth
• NPO: nothing by mouth
• SC: subcutaneous
• OTC: over the counter

CRITICAL THINKING QUESTIONS

1. Outline four key points in the drug approval process timeline and the usual timing of patent applications.
2. Contrast Phase I and II clinical trials focusing on differences and similarities.
3. Examine the key differences between Phase II and Phase III clinical trials.
4. Discuss the purpose of Phase IV clinical trials.
5. Describe the DEA schedule system for drug abuse potential; provide examples for each schedule.
6. Compare the teratogen category system against its replacement.
7. Identify conflicts between drug companies and patients in drug development; describe the government's role.
8. Distinguish between trade names and generic names, giving three examples each.