New drug development is a highly complex, costly, and time-consuming process that can take over 10 years. It involves synthesis of new chemical entities, preclinical studies in animals and cells to evaluate safety and efficacy, followed by clinical trials in humans in 4 phases to further assess safety and efficacy. If clinical trials are successful, regulatory approval must be obtained before the drug can be marketed. The overall goal is to bring new treatments to patients while ensuring safety and effectiveness through a rigorous scientific process.

1. New Drug Development

2. What is a drug?

3. Drug
• Single chemical entity present in the
medicine used for diagnosis, prevention
or cure of a disease.
• WHO:
– Any substance or a product that is used or
intended to be used to modify or explore the
physiological systems or pathological states for the
benefit of the recipient

4. New Drug
• A substance of chemical, biological or
biotechnological origin for which adequate
data is not available for the regulatory
authority to judge its efficacy and safety for
the proposed claim.

5. Not a Easy Process
• Highly complex
• Tedious
• Competitive
• Costly (500 – 1000 million dollars)
• Commercially risky
• Time consuming (at least 10 years)

6. Stages in the new drug development
• Synthesis & isolation of compound
– New chemical entity (NCE)
– Takes 1-2 years
• Preclinical studies
– 2-4 years
• Investigational New Drug Application (IND)
– Submission & review by FDA
– 3-6 months

7. Stages in the new drug development
IND
Clinical Trials Pre clinical studies continued
•Phase 1 Plus
•Phase 2 •Long term animal toxicity
•Phase 3 •Product formulation
3 To 10 years •Manufacturing & controls
•Package & label designs
New Drug Application (NDA)
•Review & grant of marketing permission
•0.5 to 2 years
Post marketing surveillance (Phase -4)

9. Old methods of Drug Discovery
• Use crude plant / animal products / minerals to
treat disease (India, China, Egypt and Babylon)
• No study before using them. Agents were
selected on the basis of their symbolic qualities
& astrological signs
– Greek physicians used iron against weakness.
– Horn of rhinoceros as a potent aphrodisiac.
– many obnoxious remedies, like flesh, excreta &
blood of various animals were used
• Drugs were added by considerable trial and
error

10. Galen
• Concept of polypharmacy
• Mixed vegetable crude drugs from
Aelius
different sources Galenus or Claudius
• Galen’s name is retained in the Galenus (AD 129 –
200/217), better
term ‘galenical’ for preparation of known as Galen
of Pergamum
crude vegetable drugs

11. Paracelcus
• Paracelsus (AD 1493 – 1541) criticized
the polypharmacy of mixed vegetable
preparations of Galen
• Pioneered the use of chemicals and
minerals in medicine.
• He introduced the use of mercury in the
treatment of syphilis.
• "All things are poison and nothing is
without poison, only the dose permits
something not to be poisonous."

12. Important contributions
– 1847: Birth of Pharmacology as a
scientific discipline by Rudolf Buchheim at
Dorpat
– 1878: Louis Pasteur’s “germ theory” of
disease at Paris
– 1890s: The “magic bullet theory” of Paul
Ehrlich

13. Approaches to drug discovery
• Natural sources
• Chemical synthesis
• Rational approach
• Molecular modelling
• Combinatorial chemistry
• Biotechnology

14. Natural sources
• Plants
– Morphine, Ephedrine, reserpine, artermisinin,
quinine, atropine
• Animals
– Adrenaline, thyroxine, insulin, liver extract,
antisera
• Micr-organisms
– Penicillin, cephalosporin

15. Morphine from Opium
Friedrich Wilhelm
Adam Sertürner
• 1805: Friedrich Serturner, a junior
apothecary in Westphalia, Germany
isolated and purified morphine.
• He barely survived the test of its
potency on himself.
• He called the isolated alkaloid "morphium" after the
Greek god of dreams, Morpheus.
• First person to isolate the active ingredient associated
with a medicinal plant or herb

16. Indian Contribution
• Rauwolfia alkaloid form
Raulwofia serpentina as
antihypertensive and
antipsychotic drug
• Gugulipid from
Tinospora as lipid-
lowering agent

17. Chinese Contribution
• Sympathomimetic Ephedrine
from Ma huang (Ephedra
vulgaris)
• Antimalaial Artemisinin from
Quinghasou (Artemisia annua)
• Anticancer drug Camptothecin
(Irinotecan and topotecan)
from Captotreca acumunata

18. Chemical synthesis
• Randomly synthesized compounds tested for
pharmacological activity
– Barbiturates, chlorpromazine synthesized by this
approach
• Synthesis of chemical congeners
– More rational
– Me too drugs fathered by lead compounds
– Thiazide drugs from acetazolamide, TCA from
phenothiazines
– Structure activity relationship
– Enantiomers
• Serendipity

19. Loop Diazoxide
Diuretics (Anti-hypertensive)
Thiazide Diuretics
Carbimazole, Sulfonylureas
Methimazole CA inhibitors (Oral
(Anti-thyroid (Diuretics) Hypoglycaemic
Drugs) agents)
Sulthiam
SULPHONAMIDES (Anti-epileptic)
Dapsone (Anti-leprotic) Cotrimoxazole

20. Drug Discovery by Serendipity
• 1785: Withering’s discovery of Digitalis in
treating cardiac failure (dropsy)
• 1914: Wenkeback’s discovery of
antidysrhythmic effect Quinidine when
treating a patient with malaria who also
happened to suffer from atrial tachycardia.
• 1937: Use of amphetamine in treatment of
attention deficit hyperactivity disorder (ADHD)
by Bradley

21. Sidenafil as anti-impotence Drug
• Sildenafil citrate (vigra), an anti-
impotence drug. It was initially studied
for use in hypertension and angina
pectoris. Phase I clinical trials under the
direction of Ian Osterloh suggested that
the drug had little effect on angina, but
that it could induce marked
penile erections.

22. Enantiomers
• Many drugs are having two types of 3D structure
(chiral compounds)
– Enantiomeres: ‘R’ & ‘S’; l & d
– Combination of both (recemate)
• Enantiomers are non superimposable mirror
images (
• Enantiomers of chiral drugs differ in biological
activity, metabolic degradation etc.
• Single enantiomer of a drug may be better to its
racemate
• E.g dextro dopa more toxic than levo dopa

23. • Now Regulatory authority grants permission
after chiral separation of recemate drugs
when a single enantiomer is better than the
recemate preparation

24. Drugs as single enantiomers
• Antihypertensive
– (S) atenolol : 50% dose, better tolerated
– (S) metoprolol : 50% dose
– (S) amlodipine : 50% dose, better tolerated
• Proton-pump inhibitors in peptic ulcer
– (S) omeprazole (esomeprazole) : bioavailability
– (S) pantoprazole: More potent
• Anti-asthmatic drug
– (R) Salbutamol: More active, ‘S’ antagonizes ‘R’

25. Drugs as single enantiomers
• Antidepressant (SSRI)
– (S) Citalopram (escitalopram) : dose, S/E
• Chemotherapeutic Agent
– Levofloxacin (l –isomer): more active, slower
elimination
• Antihistamine
– Levocetirizine (l-isomer): 50% dose as ‘d’ form is
inactive
– Desloratadine (d-isomer) : 50% dose

26. Rational approach
• Depends on sound knowledge &
identification of specific target for drug action
• Receptor based approach ( target oriented)

27. Target oriented approach
• Receptors
– GPCR, Receptors with intrinsic ion channels,
enzyme linked receptors, Receptor regulating
gene expression.
• Ion channels
– Na+, K+, Ca++ and Cl–
• Transporters
– Na+/K+ ATPase, H+/K+ ATPase, Na+-K+-2Cl–
• Enzymes

28. Combinatorial Chemistry
• Chemical groups are combined in random
manner to yield innumerable compounds
• These compounds subjected to high through
put screening on cells, genetically engineered
microbes, enzymes, enzymes in robotically
controlled automated assay systems

29. Biotechnology
• Hormones
– Insulin, Growth hormones, Erythropoietin
• Growth factors
– GM-CSF
• Cytokines
– Interleukins
• Monoclonal Antibodies
– Trastuzumab, Rituximab, Omalizumab etc.
• DNA products
– Antisense oligonucleotides: Vitravene
• Enzymes:
– Cerebrosidase, Dornase, Galactosidase

30. Drug Development
1. Pre-clinical Study
– ADME
– Safety and Toxicity prior to human trial
– FIM (First in Man) / FHD (First Human Dose)
2. CMC (Chemistry, Manufacturing & Control)
3. Clinical Study
– Phase I, II & III
4. Registration
5. Phase IV (Post-marketing Surveillance)

31. Pre-clinical study
• Aim:
– Is it effective?
– Is it not toxic?
– Is its side effect is minimum?
• Test is done on
– Cultured cell line
– Isolated organ
– Intact animals

32. Preclinical Studies
Synthesis / Identification of Lead Compound(s)
(Thousands)
Few out of Thousands

33. Pre-clinical Studies
• Screening Tests
• Tests on isolated organs
• Tests on bacterial cultures
• Tests on animal models of human diseases
– Diabetic rats / dogs by diazoxide
– Kindled animals for anti-epileptic drugs
• General observational tests on intact animals

34. Preclinical Studies
• Pharmacokinetics
• Systemic pharmacodynamics
• Study of Mechanism of Action
• Quantitative tests
– Dose-Response Relationship
– Maximal Effect
– Efficacy testing in relation to existing drugs
• Toxicity Studies

35. Toxicity Studies
• Acute Toxicity Studies (1 – 3 days)
– LD50
– Organ toxicity
• Subacute Toxicity Studies (2 – 12 weeks)
– Therapeutic index, Eating behavior, Wt, Haematology
• Chronic Toxicity Studies (6 – 12 months)
• Special Long-term Toxicity Studies (after 1 Ph)
– Reproduction ( including Teratogenicity)
– Mutagenicity
– Carcinogenicity

36. Good Laboratory Practice (GLP)
• Embodies a set of principles that provides a
framework within which laboratory studies
are planned, performed, monitored, recorded,
reported and archived.

37. Before Clinical Studies
• Drug is formulated into a suitable dosage form
• The clinical trials are done under the guideline
of Good Clinical Practice (GCP) laid down by
International Conference on Harmonization
(ICH)

38. Investigational New Drug (IND)
• IND license is obtained after successful
completion of pre-clinical studies from
regulatory authorities.
• Regulatory Authority
– India: Drug Control General of India (DCGI)
– USA: FDA (Food and Drug Administration)

39. Good Clinical Practice (GCP)
• GCP include
– protection of human rights as a subject in clinical
trial.
– provides assurance of the safety and efficacy of
the newly developed compounds.
• Good Clinical Practice Guidelines include
standards on
– how clinical trials should be conducted,
– define the roles and responsibilities of clinical
trial sponsors, clinical research investigators, and
monitors.

40. Why Clinical Trials?
• To discover or verify:
– Pharmacodynamics (how it works)
– Pharmacokinetics (what happens to it)
– Therapeutic effects (efficacy)
– Adverse reactions (safety)

41. History of Clinical Trial
Clinical trials for cure
of scurvy in 1747
James Lind

42. JAMES LIND, CONQUERER OF SCURVY

43. Regulatory Process in Drug trial
• 1937: Use of diethylene glycol as a solvent for
sulfonamide preparation caused death of 107
in USA.
• 1938: FDA revised its old rules and made it
compulsory to demonstrated safety before
marketing

44. Regulatory Process in Drug trial
• 1959: Thalidomide
Disaster in Europe and
Australia
• 10,000 cases of severe
congenital malformation
cases were seen
Phocomelia = Greek phoco-, "seal (flipper)" +
Greek melia, "limb, extremity" = human limb like a seal's

46. Unethical trial
• In 1932, a clinical trial named Tuskegee was
conducted in patients with syphilis in USA. Study
group comprised of 400 African-American poor
men with syphilis. Control group was 200 healthy
men. The doctors offered treatment without
paying; but they only observed the patients
without treatment during many years without
telling anything. Ten years later, death rate was
two-fold in the study group. Penicillin was
developed in 1952. No patient was administered
any antibiotics including penicillin until the end of
study in 1972.

47. New York Times described this study as
“The longest clinical trial in human
body without treatment in the
medical history”

48. May 16, 1997
Tuskegee trial
President Clinton apologised from USA citizens
because of Tuskegee trial

49. Phases of Clinical Trials
• Phase I
Early Clinical Pharmacology & Safety
• Phase II
Therapeutic exploration and dose ranging
• Phase III
Therapeutic confirmation and comparison
• Phase IV
Post-marketing Surveillance / Studies

50. Phases of Clinical Trials
• In Each Phase
– Exposure to greater numbers of human
subjects to the drug
– Collection of increasing amounts of data on
safety and efficacy of the drug
I II III IV

51. PHASE I
• First study done on healthy human volunteers
(sometimes in patients)
• N = 20 – 40
• Carried out by qualified clinical pharmacologists
or trained physicians
• Venue: A place where all vital functions are
monitored and emergency / resuscitative facilities
are available
• No blinding, open label
• Duration of study: 1 yr (approximately)

52. PHASE I
• Emphasis : Safety and Tolerability
• Started with lowest estimated dose and stepwise
increased to effective dose.
• Data collection on
– Pharmacokinetics
– Systemic pharmacodynamics
– General adverse effects
• Acceptable dosing level is found
• Provisional safe dosage established

53. PHASE II
• Patients suffering from the disease
• Inclusion and exclusion criteria are fixed
• N = 100 – 400
• Carried out by physicians who are trained as
clinical investigators
• Duration: 2-3 years
• Type: Open label / Blind
• Venue: 2 - 4

54. PHASE II
• Establishment of therapeutic efficacy
• Define most appropriate dose range
and ceiling effect in a controlled setting
• Study of tolerability and
pharmacokinetics as an extension of
Phase I

55. PHASE III
• Randomized
• Placebo controlled
• Comparative
• Double-blind
• Multi-centric
• Patients study
• Involves several physicians
• N = 500 to 3000

56. PHASE III
• Value of the drug in relation to existing
therapy
• Safety, tolerability, drug interactions
• Additional information on
pharmacokinetic data
• Finalization of indication
• Formulation of guidelines for therapeutic use

57. Registration
• New Drug Application (NDA) along with the
Data (safety and efficacy) of Clinical Trials are
submitted to relevant Regulatory Authority
– India: DCGI (Drug Controller General of India)
– USA: FDA (Food and Drug Administration)
• Chirality of drug is considered by RA
• Regulatory Authority, in convinced, gives a
‘marketing permission
• Average time for approval: 2.5 yr

58. PHASE IV:
Post-marketing Surveillance (PMS)
• Clinical trials do not end with approval
• Practicing physicians are indentified and
from them data are collected on a
structured proforma regarding
– Efficacy
– Acceptability
– Adverse effects
• n = 4000 – 5000 patients or more

59. PHASE IV:
Post-marketing Surveillance (PMS)
• Uncommon adverse effects
• Long term adverse effects
• Adverse drug reactions (e.g. idiosyncrasy etc.)
• Unsuspected drug interactions
• Patterns of drug utilization
• Additional indications

60. PHASE IV:
Post-marketing Surveillance (PMS)
• Effect on special groups
– Elderly & Neonates
– Pregnancy & Lactation
– Liver &Renal impairment
• Exploration of possibilities
– Modified release dosage form
– Additional route of administration
– Fixed dose combination
• Even drugs / formulations are withdrawn from
the market if found to be injurious to health

61. Examples of drug withdrawal
• Antihistamine: Terfenadine, Astemizole for
producing “torsa de pointes”
• Selective COX-II inhibitor: Rofecoxib and
Celecoxib for producing cardiotoxicity
• NSAIDs: Nimesulide is banned for all age
groups in Western countries and for paediatric
age group in India
• Aspirin liquid formation: due to possibilities
of producing Reye’s Syndrome in children

62. Phase 0
(Human Micro-dosing)
• Offers a way of developing drugs in a
faster, more cost effective and ethical way
than ever before.