BASIC AND CLINICAL EVALUATION OF NEW DRUGS

New Drug
any agent that is not yet recognized as safe and effective
for its recommended use
new chemical entity
a previously approved drug with a change in formulation or
manufacturing process
combination of two or more old drugs
a previously approved combination of drug with changes in
their usual proportions
drug with new indication, dosage form, dosage regimen or
route of administration
must be approved by regulatory bodies (ex. FDA)

Drug Development- tedious, lengthy, costly

1. Drug Discovery and Design
random screening of natural or synthetic sources
chemical synthesis or modification
rational drug design
biotechnology
Lead Compound
o product of drug screening
o prototype moiety with desired pharmacologic
activity
o potential molecule for a new drug

2. Pre-Clinical Studies
drug characterization
o physicochemical
o biological
preformulation
formulation
Biological Characterization
o pharmacodynamics
o pharmacokinetics
o toxicology
o cell-culture testing
o animal testing
Toxicological Studies
o acute toxicity
o subacute toxicity
o chronic toxicity
o reproductive toxicity and teratogenicity
o carcinogenicity
o mutagenicity
o investigative toxicology
Preformulation
o provides the framework for the drugs
combination with excipients in the fabrication
of the final dosage form
o physical description
o particle size
o melting point / boiling point
o polymorphism
o solubility and dissolution rate
o pH
o pka
o partition coefficient
o excipient compatibility
o stability
Formulation
o pilot-production
o initial dosage form for clinical trials

3. INDA
Investigational New Drug Application
to determine if the drug is sufficiently safe for clinical
trials
request to conduct clinical trials
Requirements
o drug source and composition
o manufacturing process
o results from animal studies
o clinical trial protocols
o profiles of physicians who will conduct the
clinical trials
Accelerated programs for drug approval
o for orphan drugs
used to treat orphan diseases
which are rare diseases that affect
fewer than 200,000 people in the
United States

4. Clinical Trials
most critical and demanding stage
7 9 years average
also evaluated by Institutional Review Boards (IRB)
monitored by Clinical Research Associates (CRA)
Phase 1
o safety
o pharmacokinetics
o ideal dosage range
o non-blind or open studies
o 25 50 healthy human volunteers
o conducted in research centers
o 0.5 1 year
Phase 2
o efficacy
o broader range of toxicities
o single-blind design, with placebo and
established active drug in addition to the
investigational agent
o 200 300 patients with the disease
o conducted in special clinical centers or
university hospitals
o 1 2 years
Phase 3
o safety and efficacy
o certain toxic effects may first become
apparent
o double-blind and crossover techniques
o 2000 3000 patients with the disease
o conducted in settings similar to those
anticipated for the ultimate use of the drug
o 2 3 years
Phase 0
o relationship of mechanism of action and
treatment of disease
pharmacokinetics, including
biodistribution
microdoses (1/100
th
of the dose
calculated to yield a
pharmacological effect)
no therapeutic intent
short term (7-14 days)

5. NDA
New Drug Application
full reports of all pre-clinical and clinical data
purpose: gain permission to market the new drug

6. Post-Marketing Surveillance
Phase 4
additional pharmacological & toxicological data
adverse drug reaction reporting
product defect reporting