1. NEW DRUG
DEVELOPMENT
PRESENTED BY-
DR. RAJESH. A.
KAMTANE,
2nd YEAR PG
DEPARTMENT OF
PHARMACOLOGY,

2. From the synthesis /identification of the molecule to its
marketing, a new drug takes at least 10 years and costs
500-1000 million US$.
New drug development is done as per the guidelines
laid down by Schedule Y of Drugs and Cosmetics Act
(10th amendment)2001, which were amended later in
2005.

3. STAGES IN NEW DRUG DEVELOPMENT
1.Synthesis / isolation of compound : (1-2 years)
2. Preclinical studies : (2-4 years)
3. Scrutiny and grant of permission for clinical trials : (3-6 months)
4. Pharmaceutical formulation, standardization of chemical /
biological / immuno-assay of the compound : (0.5-1 year)
5. Clinical studies : phase 1, 2, 3 and long term animal toxicity
testing : (3-10 years)
6. Review and grant of marketing permission : (0.5-2 years)
7. Post marketing surveillance : (phase 4 studies)

4. Does it
work in
double
Is it safe? Does it work? blind
trials?

5. Drug development process can be divided into 3 main
phases-
1. Drug discovery phase- during which candidate
molecules are chosen on the basis of their
pharmacological properties.
2. Preclinical phase- during which wide range of animal
studies are performed.
3. Clinical trial phase- during which the lead compound
is evaluated for safety and efficacy in human
volunteers and patients.

6. Drug Discovery Phase
Most new drugs are discovered and identified through
one of the following approaches-
1.Random Screening-
It is a sort of blind hitting procedure where new
chemical entities (natural or synthetic) are subjected to
series of pharmacological screening procedures to
explore different types of biological activity.
Such tests include studies on animal behaviour, animal
models of the human diseases and on isolated tissues.

7. Although these approaches are time consuming,
expensive and inefficient in providing fruitful results,
sometimes these are valuable, since many drugs like
morphine, atropine, digitalis, quinidine were
discovered in this way.
Cyclosporine, an immunosuppressant drug was also
discovered during routine screening of fungal products.

8. Natural Compound Collections

9. Natural Compound Library Screening

10. 2. Serendipity (happy observation, by chance)
•Sometimes a new use is discovered for an old drug or
its side effect finds a new therapeutic application.
Examples-
1. Penicillin was discovered in this way, which started
the beginning of antibiotic therapy.
2. Lignocaine (local anaesthetic) and phenytoin
(antiepileptic) were later used as antiarrhythmics .
3. Methotrexate, an anticancer drug, is also used for
psoriasis.
4. Cyclophosphamide and azathioprine (both
cytotoxic drugs) are also used to prevent tissue
rejection in kidney transplant.

11. 3. Rational drug designing-
•Two basic strategies are used in rational drug
designing---compound-centered approach and target-
centered approach.
•Promising agents, through compound-centered
approach, could be obtained from natural products.
E.g. penicillin from penicillium notatum, paclitaxel
(anticancer drug) derived from Pacific yew tree,
cyclosporine (immunosuppressive drug) obtained from
fungus.

12. •The main disadvantage in obtaining lead products from
natural source is that these are often complex molecules
which are difficult to be synthesized. It is ultimately
difficult to synthesize their modified analogues also.
Hence lead optimization becomes difficult.
•Compound centered drug designing can be followed
for synthetic products also.
•Drugs can be developed from pharmacological data
obtained from structure activity relationship of an
established drug.
E.g.--- many beta blocking drugs available today are
based on propranolol structure,
--- many ‘triptans’ are based on structure of
sumatriptan.

13. Target-centered approach---
•Biochemical or molecular targets are used to search for
promising compounds.
•Example—it was known that inhibition of angiotensin-
converting enzyme (ACE) blocks conversion of
angiotensin 1 to angiotensin 2 and hence lowers the
blood pressure. Hence it made sense to look for ACE
inhibitors (ramipril, lisinopril, etc) or for angiotensin 2
receptor antagonists (losartan, candesartan, telmisartan)
as useful antihypertensives.
•With this approach, there is high possibility of
getting useful promising agents for lead
optimisation.

14. 4. Designing of a prodrug or an active
metabolite as a drug-
•Prodrug- e.g. levodopa used in treatment of
parkinsonism.
•Active metabolite-
e.g---Paracetamol, an active metabolite of phenacetin,
was introduced as a safe analgesic this way.
---Similarly, active metabolite of procainamide, N-
acetyl procainamide, is an effective antiarrhythmic
drug which does not cause lupus-like syndrome
that occurs with procainamide.

15. •After the synthesis or isolation of compound, their purity
is ascertained by physico-chemical and analytical
studies.
•Next comes the stage of LEAD OPTIMISATION where
the aim is to identify one or two drug candidates suitable
for further investigation.

16. •Three to five years may be spent to come to this stage.
•The promising LEAD COMPOUND is then subjected to
preclinical evaluation.
•The clinical trials follow only when the results of
preclinical evaluations are encouraging.

17. PRECLINICAL STUDIES

19. PRECLINICAL EVALUATION PHASE
(ANIMAL STUDIES)
•After synthesizing / identifying a prospective compound,
it is tested on animals to expose the whole
pharmacological profile.
•Experiments are generally performed on a rodent (rat,
rabbit, mouse, guinea pig, hamster) and then on a
larger animal (cat, donkey, monkey).
•As the evaluation progresses, unfavorable compounds
get rejected at each step, so that only a few out of
thousands reach the stage when administration to
humans is considered.

20. Objectives of animal studies are to evaluate---
1.Activity
2.Toxicity
3.Selectivity and Specificity
4.Mechanism of action
5.Drug metabolism

21. •The following types of studies are performed---
1.Pharmacodynamic Studies---
•Here actions relevant to the proposed therapeutic use
(and other effects) are studied on animals.
•For e.g., antihypertensive activity of the lead compound
on dogs, cats or rats to find out blood pressure changes
and other cardiac effects like ECG changes, etc.

22. 2. Tests on isolated organs, bacterial cultures,etc---
performed to detect specific activity, such as
antihistaminic, antisecretory, antibacterial, etc.
3. Tests on animal models of human diseases---such
as spontaneously (genetically) hypertensive rats,
alloxan induced diabetes in rat or dog, etc.
4. General observational test---The drug is injected in
tripling doses to small groups of mice which are
observed for overt effects. Preliminary clues are drawn
from the profile of effects observed.

23. 5. Confirmatory tests and analogous activities---
Compounds found active are taken up for detailed
study. Other related activities. e.g antipyretic and anti-
inflammatory activity in an analgesic are tested.
6. Mechanism of action---attempts are made to find out
the mechanism of action,
e.g. whether an antihypertensive is an alpha blocker or
beta blocker, etc.

24. 7. Systemic pharmacology---irrespective of the primary
action of drug, its effects on major organ systems such
as CNS, CVS, RS, GIT are worked out.
8. Quantitative tests---the dose-response relationship,
maximal effect and comparative efficacy with existing
drug is ascertained.

25. 9. Toxicological studies---
•Aim – to determine safety of the compound in at least 2
animal species, mostly mouse/rat and dog by oral and
parenteral route.
•Types of toxicity studies are-
(1) Acute toxicity-
 Aim is to find out the acute
dose that is lethal to 50% of
the animals (LD 50).
Organ toxicity is examined by
histopathology on all animals.

26. 2. Subacute toxicity-
Aim is to identify the target organs susceptible to drug
toxicity.
The animals are maintained at the maximum tolerated
doses for a period of 1-3 months so as to allow
development of pathological changes.
Finally, animals are killed and subjected to
histopathological examination.

27. 3. Chronic toxicity-
Such studies are important if the drug is intended for
chronic use in human beings.
The duration of study may range from one to two
years.
These studies may also run simultaneously with
clinical trials, to cut short the time factor.

28. 10. Pharmacokinetic studies-
Done after toxicological studies.
Information is obtained for its pharmacokinetic
parameters (ADME, Vd, BA, t1/2)
11. Special long term toxicity-these tests are generally
performed only on drugs which cross phase 1 clinical
trials.
12. Reproduction and teratogenecity-effects on
spermatogenesis, ovulation, fertility and developing
foetus are studied.

29. 13. Mutagenecity-ability of the drug to induce genetic
damage is assessed in bacteria (Ames test), mammalian
cell cultures and in intact rodents.
14. Carcinogenecity-drug is given for long term, even
the whole life of the animal and they are watched for
development of tumours.
Standardizied procedures under ‘Good Laboratory
Practices’ (GLP) are laid down for conduct of animal
experiments, especially toxicity studies.

30. Assessment of Safety Index-
Therapeutic index
Maximum Tolerated Dose (MTD),
No Observable Adverse Effects Level (NOAEL),
No Observable Effects Level (NOEL) and
Human Equivalent Dose (HED) are determined in
species similar to humans (like monkeys), finally to
calculate First in Human Dose (FIH) which will be latter
used in phase 1 clinical trials.
FIH is 1/5 or 1/10th of HED.

31. CLINICAL TRIALS

32. Ethics Committees
• The ethics committee reviews a protocol before the
study is allowed to start. Their job is to ensure that
the risks of being in the study are not greater than
the potential benefit.

33. IRB( Institutional Review Board)
IEC (Independent Ethical
Committee)
• To ensure the rights and welfare of the participants.
• FDA regulations mandates to review the clinical trial
protocols for ethical and legal issues.

34. IRB
The investigator must furnish the IRB with the
following documents for review and approval:
• Trial Protocol
• Written Informed Consent Forms
• Written Information for Subjects (Advertisements)
• Information about compensation to patients
• Investigator Brochure
• Available (or additional) Safety Information
• Investigator’s CV
• All amendments to study protocol
34

35. IRB
The IRB’s possible responses:
• approval or favorable opinion
• modifications required for approval
• disapproval or negative opinion
• withdrawal or suspension of an earlier approval
No subjects should be enrolled until the IRB has issued
an approval (21 CFR 56.109)
35

36. Informed Consent
• Eight basic elements of informed consent (21 CFR
50.25)
1. Trial involves research, purpose of the research
2. A description of any reasonably foreseeable risks or
discomforts
3. A description of any benefits to the subject which may
reasonable be expected from the research
4. A disclosure of appropriate alternative procedures or
treatment that may be available to the subject

37. Informed Consent
5. A statement describing the extent to which
confidentiality of records identifying the subject will be
maintained.
6. An explanation as to whether any compensation and
whether any medical treatments are available if injury
occurs.
7. An explanation of whom to contact for answers to
questions about the research and research subjects’
rights .
8. A statement that participation is voluntary
37

38. Informed Consent
• Participation in clinical trials is always voluntary.
No, thank you, I’d Yes, I would
rather not participate. like to
participate.
Clinical Trials & Research 38

39. Informed Consent
• Purpose • Risks
• Medicine to be • Potential benefits
studied
• Alternatives to
• Procedures and participation
schedule
• Confidentiality
Clinical Trials & Research 39

40. What is a Clinical Trial?
Identify a health question.
Develop a plan.
Enroll volunteers and follow the plan.
Study the information collected.
Share the results with others.
Improve treatment.
Clinical Trials & Research 40

42. Objectives of a clinical trial are to establish---
1.Safety
2.Efficacy
3.Therapeutic conformation in a large population.
4.Drug metabolism in humans.
5.Unpredicted adverse reactions and new
therapeutic applications during wide use in the
community.

43. CLINICAL TRIALS-
•When a compound deserving trial in man is identified
by animal studies, the regulatory authorities are
approached who on satisfaction issue an
‘investigational new drug’ (IND) license.
•The drug is formulated into a
suitable dosage form and clinical
trials are conducted in a phased
manner.

44. •Standards for design, ethics, conduct, monitoring,
auditing, recording and analyzing data and reporting of
clinical trials have been laid down in the form of ‘Good
Clinical Practice’ (GCP) guidelines by an International
Conference on Harmonization (ICH) and Declaration of
Helsinki.
NAZI HUMAN EXPERIMENTS

45. Declaration of Helsinki-1964
1.The clinical trial must minimize the risk for
participants.
2.Provision for care of the patients.
3.Terminate the trial when the risk becomes
incompatible with the goals of the trial.
4.Adverse events to be reported immediately to
an ethical committee

46. Phases of Clinical Trials
Phase I:
Safety
(15–30 people)
A A A
A
A A
A
A Phase II:
Safety and Effectiveness
(Fewer than 100 people)
A A
A
A Phase III:
Effectiveness compared to standard of care; Safety
(More than 100 to a few thousand) A A A
A A
A
A
A A A A
A
A A A
A A A A A A A
A A
Clinical Trials & Research 46

47. Phase 0 Clinical trials
Known as
Human Micro dosing.
 To confirm whether
the drug behaves in
human subject as was
expected from pre clinical
studies.

48. Phase 0 Clinical trials
 Single sub therapeutic doses of the study drug is
given to a small number of subjects ( 10 to 15 ).
 Purpose is to gather preliminary data on best PK
and PD parameters in humans to take forward for
further development.
 It gives no data on Safety or Efficacy.

49. The clinical studies are conventionally divided into 4
phases-
Phase 1: Human pharmacology and Safety.
The objectives of this phase are---
1. To check for safety and tolerability .
2. To determine the pharmacokinetics of the drug in
humans.

50. 3.To determine a safe clinical dosage range in humans.
The common rule is to begin with 1/5th or 1/10th of
the maximum tolerated dose (mg/kg) in animals
and calculating it for an average human body weight
of 70 kg. The drug is then given in small increments till
the therapeutically effective dose is attained by clinical
observation.

51. Phase 1 trial is carried out by qualified clinical
pharmacologists/ trained physicians in a setting where
all emergency/ resuscitative facilities are available.

52. Subjects (mostly healthy volunteers, sometimes
patients) are exposed to the drug one by one (total
20-40 subjects) , starting with lowest estimated dose
and increasing stepwise to achieve the effective dose.
No blinding is done: the study is open label. i.e.
both, the investigator and the subjects know what is
being given.

53. Phase 2: Therapeutic exploration and dose ranging-
•In this phase, the drug is studied for the first time in
patients with target disease, to determine its
efficacy.
•The main purpose is to decide an end point.
e.g.
•pain relief is the end point for testing an analgesic.
•reduction in tumour size for anticancer drugs.

54. •The study is generally carried out at 2-4 centers.
•Phase 2 can be single or double blind study.

55. •Such studies are mainly conducted in two ways-
a. Parallel design---
 One group receives the new drug under trial while
other group receives control (established drug) or
placebo.
 Then results in one group are compared with those in
other group.

56. b. Crossover design---
 Here the new drug is alternated with control
(established drug or placebo) in the same patient.
 In this method, patient acts as his own control.
 This reduces the chances of erroneous results due to
individual variation amongst the patients.

57. Phase 3: Therapeutic Conformation/ Comparison-
•Generally these are randomized, double blind
comparative, controlled clinical trials.
•Conducted on a larger patient population (500-3000) by
several physicians at many centers.
•Here new drug is compared with previously established
drug or placebo, under standardized conditions.

58. •Safety, tolerability, and possible drug interactions are
assessed on a wider scale.
•Indications are finalized and guidelines for
therapeutic use are formulated.
•A ‘new drug application’ (NDA) is submitted to the
licensing authority, who if convinced gives marketing
permission, with ‘New Drug Status’

59. Launch the drug

60. Phase 4
Drug is placed in the market and patients are
monitored for side effects.

61. Phase 4: Postmarketing surveillance-
•In phase 4, data on safety, efficacy and tolerability is
collected from practicing physicians.
•Uncommon/ idiosyncratic adverse effects and
unsuspected drug interactions are detected at this stage.
•Additional indications may emerge from surveillance
data.
•The phase 4 has no fixed duration as it is the
surveillance phase.

62. •During the ‘New Drug Status’, the manufacturer is
expected to report any new information about the drug
concerning its safety.
•Such Periodic Safety Update Report (PSUR) is to be
submitted every six months for first 2 years and then
annually for the next 2 years.
•The drug may remain in ‘New Drug Status’ for several
years until the Drug Control authorities are confident
about its release to unrestricted marketing.

63. •Further therapeutic trials involving special groups like
children, elderly, pregnant, lactating women, patients
with renal/ hepatic diseases, etc (which are generally
excluded during clinical trials) may be undertaken at this
stage.