Drug Development and Testing Process

Biological products Chemical synthesis

Pharmacological & Toxicological Screening

Is the compound biologically Is the compound safe?

active?
What is the dose-response ( PK/PD)
for the activity and safety?
Go/no go

Lead compound Go No go (Kill the compound)

Preclinical study Clinical Trials FDA Approval

NDA
IND Post-marketing Surveillance
PROCESS OF DRUG DEVELOPMENT
Constraints in clinical R&D drive up costs and
the time to market of a potential molecule

The drug development process is time-consuming



and expensive:
 R&D is time consuming—It takes 10 to 15 years
File File
to bring a new drug to market.
IND Phase I Phase II Phase III NDA

Newer
 From 5,000 to 10,000 compounds must be
Technologies

screened
Discovery
Research
to yield 1 potentially
Clinical
Preclinical
ResearchDevelopment
successful
Approval
Phase
drug.
 10% or $15 to 30$ 802
billion
M is spent for preclinical
studies today.
3.5 years 1.5 years 5 years 2 years

7.41% 4.70%
 15% will be spent on preclinical studies in the
33.37%
of R&D Budget
of R&D
Budget
42.35%
of R&D Budget
of R&D
Budget

next three to five years.

Cost Per Stage


Discovery - $.5M
Product Selection - $.5M
Preclinical - $1- 1.5M
Clinical
 Phase I - $5-10M
 Phase II - $10-20M
 Phase III - $30-50M
Product Launch - $5-10M
Reasons For Drug Failure

80% can be
detected in
80% preclinical
phase

Source: 198 NCEs in clinical development by large UK companies,

1964–1985.
DRUG DISCOVERY
INDA
NDA

Candidate
molecules are
selected on the
basis of
PHARMACOLOGICAL
PROPERTIES

Drug Development Drug Approved for

Candidate Compound Marketing
PRECLINICAL DEVELOPMENT
INDA NDA

A number of non -
human studies
are performed
To satisfy all
requirements
that are to be
met before human
testing

Drug Candidate Development Drug Approved for

Compound Marketing
PRECLINICAL DEVELOPMENT PLAN
CLINICAL DEVELOPMENT
INDA NDA

Phase III :
TestPhasecompound
Phase
Multicentric III: :
Ontrial On- 80
20 100 300 -
-1000
onhealthy
is
patients testedto for
test
human
3000 volunteers
efficacy patients
, side -
Toefficacy
determine
To compare drug in
with effects
P ’clinical
kinetic
commonly , in
healthy
Psituation
’ dynamic
used tohuman
,effects
alternatives give
,,
a therapeutic
volunteers
tolerability
and for and and
indication
safety and
patients
pharmacoeconomic
determine
analysis
therapeutic dose

Drug Development Drug Approved for

Candidate Compound Marketing
PHASE IV ( POSTMARKETING
SURVEILLANCE )
INDA NDA

To study long
term adverse
effects
resulting from
use of drug in
clinical
setting

Drug Development Drug Approved for

Candidate Compound Marketing
 Strains of animal
used
 Regulatory Perspective


 IND = “Investigational New Drug” application = approval by

FDA to conduct human studies; main criterion :


 SAFETY AND LIKELY REVERSIBLE TOXICITY = allows

startof Phase I trials
 NDA = New Drug Application
PLA = Product License Agreement
 GLP-
Good Laboratory Practices
 It is a formal code for carrying out non-clinical laboratory work.( conducted per GLP as
detailed in 21 CFR Part 58.)
 AIM: To eliminate human errors far as possible. To ensure reliability of data submitted to
regulatory authorities.
 GUIDELINES:
 1. Test Facility Organisation and Personnel
 2. Quality Assurance Programme
 3. Facilities
 4. Apparatus, Material, and Reagents
 5. Test Systems
 6. Test and Reference Items
 7. Standard Operating Procedures
 8. Performance of the Study
 9. Reporting of Study Results
 10. Storage and Retention of Records and Materials

 Toxicological Studies
types -


1.Acute studies
2.Sub chronic studies
3.Chronic studies
4.Specialized studies- e.g
e)Mutagenicity
f)Carcinogenicity
g)Teratogenicity
h)Reproductive toxicity
i)Fertility studies

 ICH Safety Guidelines

S1: Carcinogenicity studies – Need ,

Testing , Dose Selection
S 2 : Genotoxicity – Regulatory , Battery of
Tests
S3A: Toxicokinetics
S3B : Pharmacokinetics
S4 : Chronic Toxicity Testing
S5A : Toxicity to Reproduction
S5B : Toxicity to Male Fertility
S6 : Preclinical Biotech derived drugs
S7A : Safety Pharmacology
S7B : QT interval prolongation
S8 : Immunotoxicity
Acute Toxicity


• Objective: To determine Maximum Tolerated Dose

(MTD) and No Observable Effect Level (NOEL)
• Duration: Typically 14 days after single dose
• Animals Required: 2 species (rodent and non-
rodent)
• Parameters:
• Mortality  Clinical pathology  Gross
necropsy
  Weight change  Clinical
observations
• Points to consider:
• Dose selection for repeat dose studies
• Choice of Species (Fialuridine)
Sub Acute Toxicity


• Objective: To determine toxicity after repeated

administration of the test material
• Duration: 14 – 28 days
• Animals Required: 2 species (rodent and non-
rodent)
• Parameters:
• Mortality  Clinical pathology  Urinalysis
• Histology  Weight change  Clinical obs
• Points to consider:
 Dosing regimen – similar to clinical
 Recovery period
 Duration of clinical trials (Phase I, II, III)
 Toxicokinetics
 Immunotoxicity
Chronic Toxicity


• Objective: In support of products used to

treat chronic conditions
• Duration: 30 days to 2 years
• Animals Required: 2 species (rodent and
non-rodent)
• Parameters:
• Mortality  Clinical pathology
• Clinical obs  Behavioral Assessment
• Histology  Weight change
• Points to consider:
 Clinical Trials (EU)
Carcinogenicity


• Objective: To evaluate the tumorigenic potential in

animals and risk to humans
• Duration: 12 months +
• Species: Mouse or Rat
• Parameters:
• Tumor development  Clinical pathology
• Clinical observations and assessment
• Points to consider:
 Considerations from:
 Pharmacology, Pharmacokinetic or Toxicology
(mechanistic in vitro and in vivo) data
 Structure-activity relationships
 Compound accumulation over long-term use
 Continuous use in humans for 6 months +

 REPRODUCTIVE TOXICITY TESTING
 For drugs use in pregnancy and women of child bearing
potential.

S. No. Segment Study

1 1 Fertility Testing:
Male and female fertility and reproductive
performance
2 2 Teratology

3 3 Peri- and Postnatal studies

 Developmental toxicity testing detects the
potential for substances to produce embryotoxicity
and birth defects. Basic parameters of this test are:



 Local Tolerance
 Dermal (skin) Irritation/Sensitization


 Eye Irritation


 Phototoxicity
 The potential for sunlight (or other light frequencies) to
transform a drug or a metabolite is:
 a useful tool for activating some drugs and
 A cause for a significant adverse effects for others
(Quinolone antibiotics).




Neurotoxicity- The hen assay determines
delayed neurotoxicity resulting from exposure to
anticholinergic substances, such as
certain pesticides. The hens are protected from
the immediate neurological effects of the test
substance and observed for 21 days for delayed
neurotoxicity. Other neurotoxicity tests include
measurements of:



 Genetic Toxicity. A large variety of tests have been

developed to measure gene mutations, chromosome
changes, and DNA activity. The most common gene
mutation tests involve:

S. No. Test Mutation Type
1 AMES TEST in bacteria (Salmonella Gene Mutation
typhimurium and E. coli)

2 In vitro in mammalian cell lines Chromosomal aberrations

3 Eukaryotes (mammalian cell lines, fungi, Gene mutations

insects)

4 In vivo tests in mammals Gene Mutations

 AMES TEST
Principle: Bacterial Reverse Mutation


 Amino acid requiring mutant strains of Salmonella

typhimurium (Histidine) and Escherichia coli (Tryptophan) are
reverted to wild forms by point mutations on exposure to a
mutagen.


 Revertent wild forms of bacteria can grow in amino acid

deficient medium unlike its mutant form.
AMES
TEST
IMMUNOTOXICITY


 Objective: To determine the potential of a

test material to induce an immune
response
 Duration: Hours to weeks (depends upon
test)
 Animals Required: 2 species (mice and
guinea pigs)
 Parameters: observable effects (pruritis,
erythema, edema, etc)
PHARMACOKINETICS TESTING
 Determination of:
1. Absorption: Plasma drug levels
 Rate and extent of drug absorption
2. Distribution: Distribution of drug in different body tissues
 Plasma protein binding
3. Metabolism: Pattern and rate of metabolism
 Metabolizing enzyme induction
 Characterization and identification of metabolites
4. Excretion: Pattern and rate of excretion
 Bioaccumulation and bioretention
5. Toxicokinetics: Application of pharmacokinetics to toxicology
On the Way……..
 ALTERNATIVES TO
ANIMAL TESTING
 1. Embryonic stem cell test, using mouse-derived cells
 To assess potential toxicity to developing embryos, has been
validated as a partial replacement for birth-defect testing in rats and
rabbits.


 2. The 3T3 Neutral Red Uptake Phototoxicity Test, which uses cells
grown in culture
 To assess the potential for sunlight-induced (“photo”) irritation
to the skin.


 3. Human skin model tests such as the validated EpiDerm™ test, is a

total replacement for skin corrosion studies in rabbits.
ALTERNATIVES TO ANIMAL TESTING
 4. The use of human skin leftover from surgical
procedures or donated cadavers can be used to measure
the rate at which a chemical is able to penetrate the skin.


 5. The use of a clinical patch test in human volunteers,

which can confirm that a chemical will not cause
irritation or allergic skin reactions.


Ref.: http://www.peta.org/factsheet/files/FactsheetDisplay.asp?ID=87
