This document discusses the process of drug development from sources and discovery through clinical trials and regulatory approval. Key points covered include preclinical research involving animal studies to assess toxicity and efficacy. Clinical trials have four phases from initial small human studies to large trials to confirm safety and effectiveness. New drug applications are submitted to regulatory agencies like the FDA for review and approval before marketing. Ongoing monitoring occurs after approval to identify any rare or long-term adverse effects.

1. DRUG DEVELOPMENT
By Dr PARUL PREETY
1st yr PGT
DEPT OF
PHARMACOLOGY

2. TOPICS TO DISCUSS
• DRUG SOURCES , INVENTION & DISCOVERY
• PRE CLINICAL RESEARCH
• IND APPLICATION
• CLINICAL TRIALS
• NDA/ BLA APPLICATION
• FDA APPROVAL
• POST MARKETING SURVEILLANCE

4. SOURCES DETAILS EXAMPLES
PLANTS SEEDS, BARKS, LEAVES , RESINS FROM
TREES, ROOTS, GUM
MORPHINE, QUININE,
DIGITALIS, ATROPINE
ANIMALS GLANDS, ORGANS, TISSUES INSULIN, HEPARIN
MINERALS EARTH, SOIL IODINE, ZnO, MgSO4, MILK OF
MAGNESIA, SOLGANAL, KMnO4
MICRO-ORGANISMS BACTERIA, FUNGI PENICILLIN, ERYTHROMYCIN,
BACITRACIN
SYNTHETIC NUCLEUS OF DRUG & CHEMICAL
STRUCTURE IS ALTERED
ASPIRIN, EMETINE BISMUTH
IODIDE, SULPHONAMIDES
SEMI-SYNTHETIC NUCLEUS OF DRUG RETAINED BUT
CHEMICAL STRUCTURE IS ALTERED
APOMORPHINE, ETHINYL
ESTRADIOL, METHYL
TESTOSTERONE
BIO-TECHNOLOGY USING GENETIC ENGINEERING (GENE
THERAPY)
HUMAN INSULIN, GROWTH
HORMONE, INTERFERON, MAb

5. DRUG INVENTION
• ME TOO METHOD
• SERENDIPITY METHOD/ ACCIDENTAL
DISCOVERY
• FUNTIONAL BASED APPROACH
• RATIONAL DRUG DESIGN

6. • ME TOO ANALOG/ FOLLOW UP DRUGS/
MOLECULAR MODIFICATION- chemical
modifications of known active molecules.
Pharmaceutical companies modify the structure in
such a way that :
- avoids patent restrictions
- retain activity
- improved the therapeutic properties
• SERENDIPITY METHOD/ ACCIDENTAL
DISCOVERY
e.g- discovery of penicillin in 1928 by Alexander Fleming

7. • FUNCTIONAL BASED APPROACH- it is done
without prior identification of a drug target.
e.g.-
• RATIONAL DRUG DESIGN- a process in which
finding of new medication based on knowledge
of biologic target.
It involves design of small molecules that are
complementary in shape & charge to biological
target.
poppy juice (opium) containing
morphine
For pain relief & dysentery
control
Mushroom & deadly night shade plant Professional poisoners
Arsphenamine as “salvarsan” For syphilis

8. • Types of rational drug designing:
1)Receptor based drug design- design a drug candidate
that will have multiple sites of complementary interactions
with the biological targets.
2) Pharmacophore based drug design- generate new
ligands which have the same necessary chemical groups in
the same 3D location.

9. DRUG DISCOVERY
It is screening for biologic activity of large number
of natural products , banks of previously
discovered chemical entities, or large libraries of
peptides , nucleic acids and other organic
molecules.

10. STAGES OF DRUG DISCOVERY
TARGET
IDENTIFICATION
TARGET
VALIDATION
LEAD
DISCOVERY
LEAD
OPTIMISATION
PRE- CLINICAL
STUDIES

11. Target identification: a process of identifying
the direct molecular target i.e., protein,
nucleic acid, enzymes, etc.
• First step in drug discovery.
Target validation: the process by which the
predicted molecular target is verified, to check
binding capacity.

12. HIT COMPOUND LEAD COMPOUND
HIT – A molecule with confirmed structure, confirmed activity
identified in high throughput screening & are thus known to
react with target.
LEAD- A chemical compound that has pharmacological or
biological activity likely to be therapeutically useful.

13. LEAD OPTIMISATION
• Lead optimization is an operationally diverse stage of
the drug discovery process in which the chemical
structures of compounds or biologics are modified to
improve target specificity and selectivity, plus
pharmacodynamic, pharmacokinetic and toxicological
properties to produce a preclinical drug candidate.
Done by- X-ray crystallography
- Nuclear Magnetic Resonance
• Lead optimization (LO) is one of the most expensive
and time-consuming stages of the drug development
process.

15. PRE CLINICAL RESEARCH
Once a lead compound is found, drug development
begins with preclinical research to determine the safety
and toxicity of the drug.
Researchers determine the following about the drug:
• Absorption, distribution, metabolism, and excretion
• Potential benefits and mechanisms of action
• Best dosage, and route of administration
• Adverse events
• Effects on gender, race, or ethnicity groups
• Drug interactions
• Effectiveness compared to similar drugs

16. Limitations of preclinical testing
• Time consuming ( 2-6 yrs maybe required to
collect & analyse data on toxicity for testing)
• Expensive
• Large number of animals maybe needed. It
raises ethical issues.
• Rare adverse effects are unlikely to be
detected in preclinical testing.

17. IND APPLICATION
• It is the means by which a pharmaceutical company
obtains permission from FDA to start human clinical
trials and to ship an experimental drug across state
lines before a marketing application for the drug has
been approved.
• It contains information:
-Animal pharmacology & preclinical data: PK, PD,
TOXICITY
-manufacturing process, stability of shelf life,
chemical composition
-protocol of clinical trials & investigator
information

18. • 3 types of IND application:
INVESTIGATOR
IND
EMERGENCY USE
IND
TREATMENT IND
Submitted by physician
to proposed studying:
An unapproved drug
 an approved product
for a new indication
To obtain authorisation
for use of an
experimental drug in an
emergency situation
Submitted for
experimental drugs
showing promise in
clinical testing for
serious and immediate
life threatening
conditions.
Submission of IND:
-After IND is submitted the sponsor must wait for 30 days before starting clinical trials,
for the FDA to provide a response.
-The FDA’s main goal is to review for unreasonable risk and proper clinical safety
studies.

21. Phases of clinical trials
PHASE 0
PHASE 1
PHASE 2
PHASE 3
PHASE 4

22. The U.S. NIH identifies seven ethical principles that
must be satisfied before a clinical trial can begin:
1. Social and clinical value
2. Scientific validity
3. Fair selection of subjects
4. Informed consent
5. Favourable risk-benefit ratio
6. Independent review
7. Respect for potential and enrolled subjects (NIH,
2011).

24. Advantages of microdosing-
• Less chance of adverse effects
• Short duration
• Less number of volunteers
• Reduced cost & drug development time
Limitations-
• only PK parameter: not safety or efficacy
• Laboratory parameter are limited & expensive
• Agents having different kinetic characteristics
between microdose & full dose are not evaluated by
phase 0 trials

25. PHASE 1
• First in human
• 10-100 participants
• Usually healthy volunteers ; occasionally
patients with advanced or rare diseases.
• Safety & tolerability
• open label/ no blinding
• Time taken- 1-2 yrs
• Approximate expenditure- U.S $ 10 million
• Success rate- 50%

26. PHASE 2
• First in patient
• 50-500 participants
• Patient- subjects receiving experimental drug
• Randomised & controlled ( can be placebo
controlled); may be blinded
• Efficacy & dose ranging
• Time- 2-3 yrs
• Expenditure- U.S $20 million
• Success rate- 30%

27. PHASE 3
• A few hundred to a few thousand participants
• Patient – subject receiving experimental drug
• Randomised & controlled ( can be placebo
controlled ) ; may be blinded
• Confirm efficacy in larger population (
THERAPEUTIC CONFIRMATORY)
• Time- 3-5 yrs
• Expenditure- U.S $ 50-100 million
• Success rate- 25- 50%

28. FDA REVIEW
In US following types of application are
submitted for approval of drug for marketing
depending upon the type & nature of drug.
- NDA- New Drug Application
- BLA- Biologic License Application
- ANDA- Abbreviated New Drug Application

29. NEW DRUG APPLICATION (NDA)
Application to permit the sale & marketing of a
new drug by FDA.
Facts needed for application-
- patent & manufacturing information
- drug safety & efficacy
- reports on design , compliance &
conclusions of completed clinical trials.
- drug susceptibility to abuse
- proposed labelling & directions for use

30. • BLA- a request for permission to introduce, or deliver for
introduction, a biologic product into interstate commerce.
• ANDA- an application for a U.S. generic drug approval for
an existing licensed medication or approved drug.
(After expiration of the patent, any company may produce the
drug, file ANDA, demonstrate required equivalence, and,
with FDA approval, market the drug as a generic product
without paying license fees to the original patent owner.)
GOAL OF ANDA-
- To reduce the price of drug
- To reduce the time of development
- increase the bioavailability of drug

31. FDA APPROVAL
• FDA approval of a drug means that data on
the drug's effects have been reviewed by
CDER ( centre for drug evaluation & research),
and the drug is determined to provide
benefits that outweigh its known and
potential risks for the intended population.

32. POST MARKETING SURVEILLANCE/
PHASE IV
It is done to assure the efficacy & safety of drugs
after its marketing.
• No fixed duration/ patient population.
• Open label / no blinding
• Starts immediately after marketing.
• Report all ADRs
• Help to detect: - Rare ADRs
- drug interactions
- new uses of drugs

33. PERIODIC SAFETY UPDATE REPORTS
(PSUR)
• PSUR are pharmacovigilance documents
intended to provide an evaluation of risk-
benefit balance of a medicinal product for
submission by marketing authorisation
holders at defined time during post
authorisation phase.
• It summarises the benefits and risks of drug.

34. ORPHAN DRUGS
• A pharmaceutical agent developed to treat
medical conditions which, because they are so
rare, wouldn't be profitable to produce
without govt assistance.
• Orphan drug amendment 1983 – provides
incentives for development of drugs for
treatment of rare diseases.

36. REFERENCES
• Brunton LL, I lilal-Dandan R, Knollman BC(Eds):Goodman and
Gilman's The Pharmacological Bci5is of Therapeutics: 13th
edn: McGraw-Hill,New York
• Katzung B.G.(Ed.),Ed. Bertram
G. Katzung.eds. Basic & Clinical ... Basic & Clinical
Pharmacology, Fourteenth Edition.
• Pharmacology and pharmacotherapeutics : by R.S. Satoskar,
Nirmala N. Rege, Raakhi K. Tripathi, S.D.Bhandarkar.. 25th
edition. Elsevier
• Tripathi, K. D. (2018). Essentials of medical pharmacology (8th
ed.). Jaypee Brothers Medical.
• Rituparna maiti : post graduate topics in pharmacology