Dept.

of Pharmaceutics 1 027092011
DRUG DISCOVERY NEW DRUG DEVELOPMENT PROCESS
Dept. of Pharmaceutics 2
A substance used in the diagnosis, treatment, or
prevention of a disease or as a component of a medication
recognized or defined by the U.S. Food, Drug, and
Cosmetic Act.

A drug is any chemical or biological substance, synthetic
or non-synthetic

DRUG
3
A drug is anything that affects the way an
organism works.


Drugs can be taken to enhance function, such as
a student drinking caffeine to enhance alertness.


For now we only consider drugs which are used
to cure a disease.

Continued
Dept. of Pharmaceutics 4
How Drugs are Developed
The processes of new drug discovery and
development are long, complicated and
dependent upon the expertise of a wide variety
of scientific, technical and managerial groups.

If you are new to the industry, it can prove a
significant challenge to understand the
significance of your contribution, even if you
belong to one of the teams directly involved; for
those on the periphery, the problem is magnified
to the point where team interactions and
efficiency are adversely threatened.
Drug Candidate
safety testing
Animal Studies
- relevant species
- t mice

- agonists/antagonists
- antibodies
- antisense
- RNAi
Studies of
Disease Mechanisms
Human Studies
Phases I,II, III
Target
-receptor; -ion channel; -transporter;
-enzyme; - signalling molecule
Lead Search
-Develop assays (use of automation)
-Chemical diversity
-Highly iterative process Molecular Studies
The Drug Discovery Process
Lead optimization
-selectivity
-efficacy in animal models
-tolerability: AEs mechanism-
based or structure-based?
-pharmacokinetics
-highly iterative process
Drug Approval
and Registration
Target selection &
validation
Discovery Development
Target Selection & Validation
Define the unmet medical need (disease)
Understand the molecular mechanism of the
disease
Identify a therapeutic target in that pathway
(e.g gene, key enzyme, receptor, ion-channel,
nuclear receptor)
Demonstrate that target is relevant to disease
mechanism using genetics, animal models, lead
compounds, antibodies, RNAi, etc.
Discovery
Develop an assay to evaluate activity of compounds on the target
- in vitro (e.g. enzyme assay)
- in vivo (animal model or pharmacodynamic assay)
Identify a lead compound
screen collection of compounds (compound library)
compound from published literature
screen Natural Products
structure-based design (rational drug design)
Optimize to give a proof-of-concept moleculeone that shows efficacy
in an animal disease model
Optimize to give drug-like propertiespharmacokinetics, metabolism,
off-target activities
Safety assessment, Preclinical Candidate!!!

Development
Pharmaceutical R&D
Formulation
Clinical Investigator
& patient

Clinical Pharmacology
Clinical Research
Statistics & Epidemiology
Data Coordination
Research Information Systems
Information Services
Regulatory Affairs
Project Planning & Management
Marketing
Process R&D
Chem Eng. R&D
Manufacturing
Bio Process R&D
Safety Assessment
Toxicology
Drug Metabolism
(ADME)
Pharmacology
Pre-Clinical
Clinical
Clinical
Trials
Information Learned
1. Absorption and metabolism

2. Effects on organs and tissue

3. Side effects as dosage is increased
Information Learned
1. Effectiveness in treating disease
2. Short-term side effects in health -impaired patients
3. Dose range
Information Learned
1. Benefit/risk relationship of drug

2. Less common and longer term side effects

3. Labeling information


Compassionate Use
Phase II
Several hundred health-impaired patients
Treatment Group Control Group
Phase III
Hundreds or thousands of health-
impaired patients
Investigational
New Drug
application
IND
Phase I
20 - 100 healthy volunteers take
drug for about one month
Remote data entry
Clinical
Trials
Continued
APPROVAL
PROCESS
(Ex. FDA)
Reviews,
comments, and
discussions
Drug Co./Regulatory
liaison activities
APPROVAL
Submit to
Regulatory Agencies
Advisory
Committee
Regulatory
Review Team
New Drug
Application
(NDA)

Worldwide Marketing Authorization (WMA) in other countries
Drug DiscoveryConvergence of Disciplines
Patent Law Combinatorial
Chemistry
Synthetic
Chemistry
Physical
Chemistry
Physiology
Biochemistry
Enzymology
Immunology
Pharmacology
Information
Technology
Modelling
Physiology
Safety
Assessment
Metabolism
Pharmacology
Pathology
Behavior
Novel
Molecule
Intellectual Property
Structural
Activity
Pharmacokinetic
Properties
In Vivo activity
Safety
Design
Pharmaco-
dynamics
Physiology
Physiology
Physiology
09/07/2007 Dept. of Pharmaceutics 12
Differences and Similarities of Drugs and
Medicinal Plants
Today there are at least 120 distinct chemical
substances derived from plants that are considered
important drug and are currently in use in one or more
countries in the world

Some of these drugs are simply a chemical or chemicals
extracted from plant materials and put into a capsule,
tablet or liquid.

Eg. In Germany a Cynarin drug is manufactured and
sold to treat hypertension, liver disorders and highly
cholesterol levels.

Dept. of Pharmaceutics 13
Drug/Chemical Action/Clinical Use Plant Source
Acetyldigoxin Cardiotonic Digitalis lanata
Adoniside Cardiotonic Adonis vernalis
Aescin Anti-inflammatory Aesculus hippocastanum
Aesculetin Anti-dysentery Frazinus rhychophylla
Agrimophol Anthelmintic Agrimonia supatoria
Ajmalicine Circulatory Disorders Rauvolfia sepentina
Allantoin Vulnerary Several plants
Allyl isothiocyanate Rubefacient Brassica nigra
Anabesine Skeletal muscle relaxant Anabasis sphylla
Andrographolide Baccillary dysentery Andrographis paniculata
Anisodamine Anticholinergic Anisodus tanguticus
Plant Based Drugs and Medicines
09/07/2007 Dept. of Pharmaceutics 14
Drug/Chemical Action/Clinical Use Plant Source
Anisodine Anticholinergic Anisodus tanguticus
Arecoline Anthelmintic Areca catechu
Asiaticoside Vulnerary Centella asiatica
Atropine Anticholinergic Atropa belladonna
Benzyl benzoate Scabicide Several plants
Berberine Bacillary dysentery Berberis vulgaris
Bergenin Antitussive Ardisia japonica
Betulinic acid Anticancerous Betula alba
Borneol Antipyretic, analgesic,
antiinflammatory
Several plants
Bromelain Anti-inflammatory,
proteolytic
Ananas comosus
Caffeine CNS stimulant Camellia sinensis
Plant Based Drugs and Medicines
09/07/2007 Dept. of Pharmaceutics 15
Drug/Chemical Action/Clinical Use Plant Source
Camphor Rubefacient Cinnamomum camphora
Camptothecin Anticancerous Camptotheca
acuminata
(+)-Catechin Haemostatic Potentilla fragarioides
Chymopapain Proteolytic, mucolytic Carica papaya
Cissampeline Skeletal muscle relaxant Cissampelos pareira
Cocaine Local anaesthetic Erythroxylum coca
Codeine Analgesic, antitussive Papaver somniferum
Colchiceine amide Antitumor agent Colchicum autumnale
Colchicine Antitumor agent, anti-
gout
Colchicum autumnale
Convallatoxin Cardiotonic Convallaria majalis
Curcumin Choleretic Curcuma longa
Plant Based Drugs and Medicines
09/07/2007 Dept. of Pharmaceutics 16
Drug/Chemical Action/Clinical Use Plant Source
Cynarin Choleretic Cynara scolymus
Danthron Laxative Cassia species
Demecolcine Antitumor agent Colchicum autumnale
Deserpidine Antihypertensive,
tranquillizer
Rauvolfia canescens
Deslanoside Cardiotonic Digitalis lanata
L-Dopa Anti-parkinsonism Mucuna sp
Digitalin Cardiotonic Digitalis purpurea
Digitoxin Cardiotonic Digitalis purpurea
Digoxin Cardiotonic Digitalis purpurea
Emetine Amoebicide, emetic Cephaelis ipecacuanha
Ephedrine
Plant Based Drugs and Medicines
09/07/2007 Dept. of Pharmaceutics 17
Drug/Chemical Action/Clinical Use Plant Source
Etoposide Antitumor agent Podophyllum peltatum
Galanthamine Cholinesterase inhibitor Lycoris squamigera
Gitalin Cardiotonic Digitalis purpurea
Glaucarubin Amoebicide Simarouba glauca
Glaucine Antitussive Glaucium flavum
Glasiovine Antidepressant Octea glaziovii
Glycyrrhizin Sweetener, Addison's
disease
Glycyrrhiza glabra
Gossypol Male contraceptive Gossypium species
Hemsleyadin Bacillary dysentery Hemsleya amabilis
Hesperidin Capillary fragility Citrus species
Plant Based Drugs and Medicines
09/07/2007 Dept. of Pharmaceutics 18
Drug/Chemical Action/Clinical Use Plant Source
Hyoscyamine Anticholinergic Hyoscyamus niger
Irinotecan Anticancer, antitumor
agent
Camptotheca
acuminata
Kaibic acud Ascaricide Digenea simplex
Kawain Tranquillizer Piper methysticum
Kheltin Bronchodilator Ammi visaga
Lanatosides A, B, C Cardiotonic Digitalis lanata
Lapachol Anticancer, antitumor Tabebuia sp.
a-Lobeline Smoking deterrant,
respiratory stimulant
Lobelia inflata
Menthol Rubefacient Mentha species
Methyl salicylate Rubefacient Gaultheria procumbens
Plant Based Drugs and Medicines
09/07/2007 Dept. of Pharmaceutics 19
Drug/Chemical Action/Clinical Use Plant Source
Monocrotaline Antitumor agent
(topical)
Crotalaria sessiliflora
Morphine Analgesic Papaver somniferum
Neoandrographolide Dysentery Andrographis paniculata
Nicotine Insecticide Nicotiana tabacum
Nordihydroguaiaretic
acid
Antioxidant Larrea divaricata
Noscapine Antitussive Papaver somniferum
Ouabain Cardiotonic Strophanthus gratus
Pachycarpine Oxytocic Sophora pschycarpa
Palmatine Antipyretic, detoxicant Coptis japonica
Papain Proteolytic, mucolytic Carica papaya
Plant Based Drugs and Medicines
09/07/2007 Dept. of Pharmaceutics 20
Drug/Chemical Action/Clinical Use Plant Source
Phyllodulcin Sweetner Hydrangea macrophylla
Physostigmine Cholinesterase Inhibitor Physostigma venenosum
Picrotoxin Analeptic Anamirta cocculus
Pilocarpine Parasympathomimetic Pilocarpus jaborandi
Pinitol Expectorant Several plants
Podophyllotoxin Antitumor anticancer
agent
Podophyllum peltatum
Protoveratrines A, B Antihypertensives Veratrum album
Pseudoephredrine* Sympathomimetic Ephedra sinica
Pseudoephedrine, nor- Sympathomimetic Ephedra sinica
Quinidine Antiarrhythmic Cinchona ledgeriana
Plant Based Drugs and Medicines
Dept. of Pharmaceutics 21
Drug/Chemical Action/Clinical Use Plant Source
Qulsqualic acid Anthelmintic Quisqualis indica
Rescinnamine Antihypertensive,
tranquillizer
Rauvolfia serpentina
Reserpine Antihypertensive,
tranquillizer
Rauvolfia serpentina
Rhomitoxin Antihypertensive,
tranquillizer
Rhododendron molle
Rorifone Antitussive Rorippa indica
Rotenone Piscicide, Insecticide Lonchocarpus nicou
Rotundine Analagesic, sedative,
traquillizer
Stephania sinica
Rutin Capillary fragility Citrus species
Plant Based Drugs and Medicines
Dept. of Pharmaceutics 22
Drug/Chemical Action/Clinical Use Plant Source
Salicin Analgesic Salix alba
Sanguinarine Dental plaque inhibitor Sanguinaria canadensis
Santonin Ascaricide Artemisia maritma
Scillarin A Cardiotonic Urginea maritima
Scopolamine Sedative Datura species
Sennosides A, B Laxative Cassia species
Silymarin Antihepatotoxic Silybum marianum
Sparteine Oxytocic Cytisus scoparius
Stevioside Sweetner Stevia rebaudiana
Strychnine CNS stimulant Strychnos nux-vomica
Plant Based Drugs and Medicines
Dept. of Pharmaceutics 23
Drug/Chemical Action/Clinical Use Plant Source
Taxol Antitumor agent Taxus brevifolia
Teniposide Antitumor agent Podophyllum peltatum
a-
Tetrahydrocannabinol(
THC)
Antiemetic, decrease
occular tension
Cannabis sativa
Tetrahydropalmatine Analgesic, sedative,
traquillizer
Corydalis ambigua
Tetrandrine Antihypertensive Stephania tetrandra
Theobromine Diuretic, vasodilator Theobroma cacao
Theophylline Diuretic, brochodilator Theobroma cacao and
others
Thymol Antifungal (topical) Thymus vulgaris
Plant Based Drugs and Medicines
Dept. of Pharmaceutics 24
Drug/Chemical Action/Clinical Use Plant Source
Topotecan Antitumor, anticancer agent Camptotheca acuminata
Trichosanthin Abortifacient Trichosanthes kirilowii
Tubocurarine Skeletal muscle relaxant Chondodendron
tomentosum
Valapotriates Sedative Valeriana officinalis
Vasicine Cerebral stimulant Vinca minor
Vinblastine Antitumor, Antileukemic
agent
Catharanthus roseus
Vincristine Antitumor, Antileukemic
agent
Catharanthus roseus
Yohimbine Aphrodisiac Pausinystalia yohimbe
Yuanhuacine Abortifacient Daphne genkwa
Yuanhuadine Abortifacient Daphne genkwa
Plant Based Drugs and Medicines
09/07/2007 Dept. of Pharmaceutics 25
The New Drug Development Process
(Steps from Test Tube to New Drug Application Review)


Dept. of Pharmaceutics 26
FDA will generally ask
1. Develop a pharmacological profile of the drug

2. Determine the acute toxicity of the drug in at
least two species of animals

3. Conduct short-term toxicity studies ranging
from 2 weeks to 3 months, depending on the
proposed duration of use of the substance in
the proposed clinical studies.
Dept. of Pharmaceutics 27
CFR (Code of Federal Regulations)
establishes procedure to expedite the
development, evaluation and marketing of
new therapies intended to treat people
with life-threatening and severely-
debilitating illnesses, especially where no
satisfactory alternatives exist.
Subpart E
Dept. of Pharmaceutics 28
Drug companies make every effort to use as few animals
as possible and to ensure their humane and proper care.

Generally two or more species ( one rodent, one non-
rodent).

Animal testing is used to measure how much of a drug is
absorbed into the blood, how it is broken down
chemically in the body, the toxicity of the drug and its
breakdown products metabolites, and how quickly the
drug and its metabolites are excreted from the body
Animal Testing
Dept. of Pharmaceutics 29
Short and Long Term Animal Testing
Short-term testing in animals ranges in duration from 2
weeks to 3 months, depending on the proposed use of
the substance.

Long-term testing in animals ranges in duration from a
few weeks to several years.

- Some animal testing continues after human tests begin
to learn whether long-term use of a drug may cause
cancer or birth defects.


Dept. of Pharmaceutics 30
Phase 1 Clinical Studies
Phase 1 includes the initial introduction of an
investigational new drug into human.

Phase 1 studies usually conducted in healthy volunteer.

Phase 1 studies are designed to determine the metabolic
and pharmacologic actions of the drug in humans, the side
effects associated with increasing doses, and if possible to
gain early evidence on effectiveness.

Dept. of Pharmaceutics 31
Phase 1 studies also evaluate drug metabolism,
structure-activity relationships, and the
mechanism of action in humans.

The total number of subjects included in Phase I
studies varies with the drug, but is generally in
the range of 20 to 80

Phase 1 Clinical Studies
Dept. of Pharmaceutics 32
Phase 2 Clinical Studies
Phase 2 includes the early controlled clinical studies
conducted to obtain some preliminary data on the
effectiveness of the drug for a particular indication or
indications in patients with the disease or condition.

This phase of testing also helps determine the common
short-term side effects and risks associated with the
drug.

Phase 2 studies are typically well-controlled, closely
monitored, and conducted in a relatively small number of
patients usually involving several hundred people.
Dept. of Pharmaceutics 33
Sponsor/FDA Meeting (End of Phase 2)
One month prior to the end of the Phase 2, the sponsor
should submit the background information and protocols
for phase 3 studies.

This information should include data supporting the claim
of the new drug product, chemistry data, animal data and
proposed additional animal data, results of Phase 1 and 2
studies, statistical methods being used, specific protocols
for phase 3 studies, as well as a copy of the proposed
labeling for a drug, if available.

This summary provides the review team with information
needed to prepare for a productive meeting.

Dept. of Pharmaceutics 34
Phase 3 studies are expanded controlled and
uncontrolled trials.

They are performed after preliminary evidence
suggesting effectiveness of the drug has been obtained
in Phase 2 and are intended to gather the additional
information about effectiveness and safety that is needed
to evaluate the overall benefit-risk relationship of the
drug.

Phase 3 Clinical Studies
Dept. of Pharmaceutics 35
Phase 3 studies also provide an adequate basis for
extrapolating the results to the general population and
transmitting that information in the physician labeling.

Phase 3 studies usually include several hundred to
several thousand people.

Great care is taken to ensure that this determination is
not made in isolation, but reflects current scientific
knowledge, agency experience with the design of clinical
trials, and experience with the class of drugs under
investigation


Phase 3 Clinical Studies
Dept. of Pharmaceutics 36