Drug Development Process

Drug Development Process – Summary

Introduction:

• Drugs are key therapeutic tools in modern healthcare.
• New drug development is a major focus for pharma research.
• Early drug discoveries were often based on empirical observations (e.g., foxglove for CCF).

Definition:

Drug development is a structured process aimed at creating new, safe, and effective treatments to improve health and quality of life.

Steps in Drug Discovery:

1. Target Selection
2. Lead Identification
3. Lead Optimization
4. Product Development

Target Selection – Key Points:

• Understand the disease and its underlying cause.
• Study the mechanism of disease.
• Supports effective research and development.
• Helps design strategies to slow/reverse disease progression.

Common Drug Targets:

• Receptors
• Proteins
• Enzymes
• DNA

Target Identification:

• Targets: Receptors, proteins, enzymes, DNA, RNA, ribosomes.
• Merthods:
• Classical: Cellular & molecular biology
• Newer: Genomics & proteomics

Target Validation:

• Confirms the target is involved in the disease.
• Ensures the drug binds effectively and shows curative potential.
• Done in in-vitro and in-vivo phases.

Lead Identification:

• Identifies compounds that bind the target protein.
• Sources: Natural (plants, microbes) or compound libraries.
• Hits from screening are retested to confirm activity.

Lead Optimization:

• Chemical structure of "hit" compound is modified.
• Improves drug properties (absorption, metabolism, etc.).
• Produces a preclinical drug candidate.

Studies involved:

• Kinetics, dynamics, absorption, distribution, metabolism, excretion.

Product Development:

• Final formulation of the drug is prepared for testing and manufacturing.

Drug Discovery Approaches:

• Preclinical Testing: Pharmacological and toxicological tests.
• Clinical Testing: IND application, drug characterization, dosage form development.

Preclinical Testing/Evaluation:

• Aim: Assess drug safety and effectiveness before human trials.
• Animal testing is done due to species differences from humans.
• Two major types:
1. Pharmacological testing
2. Toxicological testing

Pharmacological Testing:

• Checks drug effectiveness and safety.
• Includes: a) Selectivity testing
  b) Pharmacological profiling
  c) Animal disease models
  d) Safety pharmacology

Selectivity Testing:

1. Screening: Assesses how specific the drug is to its target.
2. Binding Assays: Measures drug-receptor binding strength.

Pharmacological Profiling:

• Studies pharmacodynamic effects using:
1. In-vitro models: Isolated tissues (e.g., cardiac, smooth muscle)
2. In-vivo models: Whole animal studies (costly and time-consuming)

Animal Models of Disease:

• Used to mimic disease conditions.
• Includes:
1. Acute models
2. Chronic models

Animal Models in Drug Testing:

1. Acute Models:

• Mimic short-term clinical conditions.
• Example: Hot plate test for pain (analgesics).

2. Chronic Models:

• Mimic long-term diseases.
• Example: Opiate self-administration as a model for addiction.

3. Genetic Models:

• Use transgenic animals (with gene modifications) to simulate human diseases.

Safety Pharmacology:

• Evaluates life-threatening effects of a drug unrelated to its main action.
• Focuses on unexpected effects on major organs.
• Detects hazardous or dangerous effects at therapeutic doses.

Levels of Safety Testing:

1. Molecular level
2. Cellular level
3. Whole animal testing

Pharmacological Testing – Levels of Study

1.     Molecular Level

• Assesses drug’s selectivity for receptors and enzyme systems.
• Uses cell membrane fractions from organs/glands.

2.     Cellular Level

• Uses cell/tissue cultures and simulations.
• Tissues: blood vessels, heart, lungs, ileum (rat/guinea pig).

3.     Whole Animal Study

• Evaluates drug effects on organs/disease models (e.g., antihypertensive in rats).
• Ensures no serious unwanted effects.

Toxicological Testing/Evaluation

• All drugs can be toxic at some dose.
• Animal studies necessary despite species variation.
• Determines toxicity for short- and long-term use.

Types of Toxicity Studies

1.     Acute Toxicity (Short-Term)

• Single high-dose test.
• Observed over ~30 days.
• Monitors behavior, body weight, biochemical changes.

2.     Sub-Acute Toxicity

• Daily dosing for ≥2 weeks in 2 species.
• Supports initial human trials.
• Human dose often 1/10th of highest non-toxic animal dose.

3.     Chronic Toxicity

• 3–6 months (or ≥1 year for chronic use drugs).
• Monitors weight, hematology, biochemistry, urine.

4.     Reproductive Studies

• Tests effects on fertility, pregnancy, offspring development.

5.     Carcinogenicity Studies

• Long-term in rodents (mice/rats).
• Monitors tumour incidence, type, site, and survival analysis.

6.     Genotoxicity Studies

• Determine if a drug causes genetic mutations in bacteria or mammalian cells.
• Includes tests like dominant lethal mutation studies.
• In vitro methods are used to reduce animal usage, though they have limited predictive value.

INDA – Investigational New Drug Application

• A formal request to the FDA to begin human testing of a new drug.
• Submitted before starting clinical trials.
• Can be submitted by the sponsor or a CRO (Contract Research Organization).

When INDA is Required:

• Testing a new drug not previously approved.
• Drug not generally recognized as safe/effective under its labelling.

Types of INDs:

1. Investigator IND – Submitted by a physician who initiates and conducts the trial.
2. Commercial IND – Submitted by companies for market approval.
3. Emergency Use IND – For experimental drug use in urgent situations.
4. Treatment IND – For life-threatening conditions when the drug shows promise.

IND Submission Requirements:

1. Animal Pharmacology & Toxicology Data – To assess drug safety in humans.
2. Manufacturing Information – Details of composition, manufacturer, stability, controls.
3. Clinical Protocols & Investigator Details – Ensures proper study design and qualified investigators.

IND Format & Contents:

• Cover Sheet (FDA Form 1571): Sponsor details, phase info, commitments.
• Table of Contents
• Investigator’s Brochure
• Study Protocols & Investigator/IRB Info
• Chemistry, Manufacturing, Control (CMC) Data
• Previous Human Experience (if any)

Outcome of IND Submission:

• If FDA raises no objections within 30 days, clinical trials may begin.
• The Investigator’s Brochure acts as temporary labelling during trials.

DRUG CHARACTERIZATION

1. Biological Characterization

• Assesses drug efficacy and toxicity in biological systems.
• Divided into:
• Biochemical Assays: Receptor binding, enzyme inhibition, metabolism.
• Cellular Assays: Cell culture studies, tissue effects, liver metabolism.
• Whole Animal Assays: LD₅₀, organ toxicity, PK/PD, disease models.

2. Physio-Chemical Characterization

• Determines drug’s physical and chemical properties for formulation.
• Solubility, pKa, partition coefficient
• Stability, chemical structure (NMR, MS, X-ray)
• Impurity analysis (TLC, HPLC, GC)
• Polymorphism

DOSAGE FORMS

Types of Dosage Forms:

1. Tablets & Capsules
2. Injections & Infusions
3. Pessaries & Suppositories
4. Solutions, Suspensions & Elixirs
5. Ointments, Creams & Paints
6. Aerosols & Inhalers
7. Transdermal Patches

Selection Factors:

• Absorption, stability, patient compliance, therapeutic needs.

Examples:

• Tablets unsuitable if drug is acid-sensitive → use injection instead.
• Inhalers deliver drug directly to lungs but need careful dosing.
• Suppositories useful for local effects but have limited general use.
• Transdermal patches offer sustained release but may irritate skin.