clinical pharmacology and new drug development is must know medical student Hope my presentation will help

1. Clinical Pharmacology & Drug
Development
Dr. Javed Akhtar
JR-II
Department Of Pharmacology
k.G.M.U, Lucknow

2. • The term was coined by Prof. Harry Gold in
1950s.
• Prof. Louis Lasagna started 1st Department Of
Clinical Pharmacology, at Johns Hopkins
University in 1954 and is known as “Father Of
Clinical Pharmacology”
• Clinical pharmacology is the scientific
discipline that involve all aspects of the
relationship between drugs and human

3. • It involves scientific study of drugs in man,
their rational use which includes safety and
efficacy of medicines, consideration to cost,
availability
• The discipline was started in India in 1960s.
Since then, it has been contributing to
development of new drugs, clinical research,
clinical trials for new drug, new drug
regimens, pharmacogenetics, etc.

4. • The main objective is to promote the safety of
prescription, maximize the drug effects and
minimize the side effects
• The aim of clinical pharmacology is to
generate data for optimum use of drugs and
the practice of ‘evidence based medicine’

5. Clinical Pharmacology consists of multiple
branches listed below:
• Pharmacodynamics - what drugs do to the
body and how. This includes not just
the cellular and molecular aspects, but also
more relevant clinical measurements
• Pharmacokinetics - what happens to the drug
while in the body. This involves the body
systems for handling the drug

6. – Absorption - process of the drug moving into the
bloodstream
– Distribution - transmission of the drug from one
location to the other in the human body
– Metabolism - the process of how the drug is
metabolized in the liver of the human body
– Excretion - the process of how the drug expels,
happens in the liver and kidneys.

7. • Rational Prescribing - using the right medication,
at the right dose, using the right route and
frequency of administration for the patient, and
stopping the drug appropriately
• Adverse Drug Effects - determining the side
effects of medicine
• Toxicology - deals with the negative effects on a
living system caused by chemicals

8. • Drug interactions - the study of how drugs
interact with each other. Two drugs may
negatively or positively effect the drug effects.
• Drug development - usually culminating in some
form of clinical trials and marketing authorisation
applications to country-specific drug regulators
• Pharmacogenomics - studying human genome to
learn interaction of drugs with genetics

9. Role Of Clinical Pharmacologist
1. Optimizing drug use: PK study, evaluation of
toxicity
2. Clinical evaluation of drugs: conduct clinical
trial, drug interaction study
3. Academics: promotion of EBM
4. Role in patient care: TDM, dose adjustment
5. Role in drug regulation: policy making for
regulatory guidelines

10. Rational prescribing
As per the WHO — ‘rational use of medicines
requires that the patients receive medication
appropriate to their clinical needs in doses that
meet their own individual requirements for an
adequate period of time, and at the lowest cost
to them and to their community’

11. The criteria to evaluate rational prescribing are:
1. Appropriate indication
2. Appropriate drug
3. Appropriate dose, route and duration
4. Appropriate patient
5. Correct dispensing with appropriate
information
6. Adequate monitoring

12. Factors Influencing Prescribing

13. Irrationalities In Prescribing

14. Irrationalities In Prescribing
• It is helpful to know the commonly encountered
irrationalities in prescribing so that a conscious
effort is made to avoid them
• Use of drug when none is needed; e.g. anti-
biotics for viral fevers and nonspecific
diarrhoeas
• Incorrect route of administration: injection when
the drug can be given orally
• Compulsive coprescription of vitamins/tonics

15. Impact Of Irrational Prescribing

16. Evidence Based Medicine
There is gradually transform in the practice of
medicine from ‘experience based’ wherein
clinical decisions are made based on the
experience (or rather impression) of the
physician to ‘evidence-based’ wherein the same
are guided by scientifically credible evidence
from well designed clinical studies.

18. • Evidence-based medicine is the process of
systematically finding, evaluating and using
contemporary research findings as the basis of
clinical decisions
• Results of well designed multicentric
interventional trials are forming the basis of
constantly evolving guidelines for disease
management

19. Grades Of Strength Of Evidence

20. NEW DRUG DEVELOPMENT
• Drug development now is a highly complex,
tedious, competitive, costly and commercially
risky process
• From the synthesis/identification of the
molecule to marketing, a new drug takes at
least 10 years and costs 500–1000 million US$

21. Stages In New Drug Development

22. Approaches To Drug Discovery/
Invention
• Exploration of natural sources
• Random or targeted chemical synthesis
• Rational approach
• Molecular modelling
• Combinatorial chemistry
• Biotechnology

23. Preclinical Studies/Non Clinical
Studies
• After synthesizing/identifying a prospective
compound
• It is tested on animals to expose the whole
pharmacological profile
• As the evaluation progresses unfavourable
compounds get rejected at each step, so that
only a few out of thousands reach the stage
when administration to man is considered

24. The following types of tests are performed
1.Screening tests These are simple and rapidly
performed tests to indicate presence or absence
of a particular pharmacodynamic activity that is
sought like analgesic or hypoglycaemic activity
2.Tests on isolated organs, bacterial cultures,
etc. These also are preliminary tests to detect
specific activity, such as antihistaminic,
antisecretory, vasodilator, anti-bacterial.

25. 3.Tests on animal models of human disease
Such as kindled seizures in rats, spontaneously
(genetically) hypertensive rats, alloxan induced
diabetes in rat or dog, etc.
4.Confirmatory tests and analogous activities
More elaborate tests which confirm and
characterize the activity. Other related activities,
e.g. antipyretic and anti-inflammatory activity in
an analgesic are tested

26. 5.Systemic pharmacology
Irrespective of the primary action of the drug, its
effects on major organ systems such as nervous,
cardiovascular, respiratory, renal, g.i.t are
worked out
6.Quantitative tests
The dose-response relationship, maximal effect
and comparative potency/efficacy with existing
drugs is ascertained

27. 7.Pharmacokinetics
The absorption, tissue distribution, metabolism,
excretion, volume of distribution and half- life of
the drug are quantified
8. Toxicity tests
The aim is to determine safety of the compound
in at least 2 animal species, mostly mouse/rat by
oral and parenteral routes

28. a) Acute toxicity: Single escalating doses are
given to small groups of animals that are
observed for overt effects and mortality for 1–3
days. The dose which kills 50% animals (LD50) is
calculated. Organ toxicity is examined by
histopathology on all animals
b) Subacute toxicity: Repeated doses are given
for 2–12 weeks. Animals are examined for overt
effects, food intake, body weight, haematology,
etc. and organ toxicity

29. c) Chronic toxicity: The drug is given for 6–12
months and effects are studied as in subacute
toxicity. This is undertaken concurrently with
early clinical trials
d) Reproduction and teratogenicity: Effects on
spermatogenesis, ovulation, fertility and
developing foetus are studied.
.

30. e) Mutagenicity: Ability of the drug to induce
genetic damage is assessed in bacteria,
mammalian cell cultures and in intact rodents
f) Carcinogenicity: Drug is given for long-term,
even the whole life of the animal and they are
watched for development of tumours

31. Schedule Y(Drug And Cosmetic Rules)
• Contains requirement and guidelines for clinical
trials
• It specifies the requirements and give provisional
view point of Indian regulatory authority for
permission to import and/or manufacture for sale
or to undertake clinical trial.
• Rules 122A, 122B, 122D, 122DA, 122DAA
• Application of permission: to be applied in form
44

33. • 122-A Application for permission to import
new drug
• 122-B Application for approval to manufacture
new drug
• 122-D Permission to import or manufacture
FDC

34. • 122-DA Permission to conduct clinical trials for
new drug / investigational new drug
• 122 -DA A Definition of CLINICAL TRIAL
• 122- DA B Reports of Serious Adverse Events
(SAEs) including deaths and compensation
• 122-DA C specific requirement for permission
to conduct clinical trial(liable to inspection by
CDSCO)
• 122 DA D Requirement of DCGI for ethics
committees reviewing clinical trial protocol

35. Clinical trials
Clinical trial means ‘a systematic study of new
drug(s) in human subject(s) to generate data for
discovering and/or verifying the clinical,
pharmacological (including pharmacodynamic
and pharmacokinetic) and/or adverse effects
with the objective of determining safety and / or
efficacy of the new drug’

36. Clinical trial
• Begin only when
– all the preclinical studies have been completed
– an approval has been received from the drug
regulation authority (DRA)
• India - Central Drug Standard Control
Organization (CDSCO)/Drug Controller General of
India (DCGI)
• Prior to the conduct of a clinical trial, an
IND(Investigational New Drug) application must
be filled

37. Phase 0: Microdosing studies
• Very low doses, generally about 1/100th of
the estimated human dose, are administered
to healthy volunteers
• These subpharmacological doses are not
expected to produce any therapeutic or toxic
effects, but yield human pharmacokinetic
information.

38. • Costly phase 1 human trials could be avoided
for candidate drugs which would have later
failed due to unsuitable human
pharmacokinetics
• Microdose pharmacokinetics may be quite
different from that at pharmacological doses
• The phase 0 studies have not yet been
technically fully developed or adequately
evaluated.
• They are neither established nor mandatory.

39. Phase I: Human pharmacology and
safety
• Designed to assess the safety, tolerability,
pharmacokinetics and pharmacodynamics
• Subjects: total 20– 80 subjects
• Mostly healthy volunteers
• Sometimes patients(anticancer drugs, AIDS
therapy)
• Starting with the lowest estimated dose and
increasing stepwise to achieve the effective
dose

40. Phase I: Human pharmacology and
safety
• Unpleasant side effects are noted and an
attempt is made to observe the
pharmacodynamic effects in man
• The human pharmacokinetic parameters of
the drug are measured for the first time.
• No blinding is done: the study is open label

41. Subset of phase 1
1. Single ascending dose (Phase Ia)
– small groups of subjects are given a single dose
of the drug while they are observed and tested
for a period of time to confirm safety
– With increasing the dose in each group it will
continued until pre-calculated pharmacokinetic
safety levels are reached, or intolerable side
effects start showing up (at which point the drug
is said to have reached the maximum tolerated
dose (MTD))

42. 2. Multiple ascending dose (Phase Ib)
– Investigate the pharmacokinetics and
pharmacodynamics of multiple doses of the
drug
– In these studies, a group of patients receives
multiple low doses of the drug
– While samples (of blood, and other fluids) are
collected at various time points
– Analyzed to acquire information on how the
drug is processed within the body

43. Phase II: Therapeutic Exploration And
Dose Ranging
• Subjects: 20–500 patients selected according
to specific inclusion and exclusion criteria.
• The primary aim is establishment of
therapeutic efficacy, dose range and ceiling
effect in a controlled setting
• Tolerability and pharmacokinetics are studied
as extension of phase I

44. Phase II: Therapeutic exploration and
dose ranging
• The study is mostly controlled and
randomized, and may be blinded or open label
• It is generally carried out at 2–4 centres
• The candidate drug may get dropped at this
stage if the desired level of clinical efficacy is
not obtained

45. Subset of Phases
• Phase II a:
– Early phase
– designed to assess dosing requirement
– 20- 200 patients
– Pilot clinical trials to evaluate efficacy and safety in
selected populations of patients with the disease
or condition to be treated, diagnosed, or
prevented
– Single blind comparison with standard drug

46. • Phase II b:
– Late phase
– Designed to study efficacy
– 50- 300 patients
– Pivotal clinical trials to evaluate efficacy and safety
in patients with the disease or condition to be
treated, diagnosed, or prevented.
– These clinical trials usually represent the most
rigorous demonstration of a medicine’s efficacy
– Double blind compare with placebo or standard
drug

47. Phase III: Therapeutic confirmation/
comparison
• Therapeutic confirmatory trials
• Large scale, multicentre, Randomised, Controlled
trials
• Target population: 500 to 3000 patients
• Takes 2 to 5 years
• To establish efficacy of the drug against existing
therapy in larger number of patients, method of
usage and to collect safety data etc
• Make comparisons between the new treatment
and standard therapy and/or placebo

48. Subset of phases
• Phase III a
– Trials conducted after efficacy of the drug is
demonstrated but prior to regulatory submission
of a New Drug Application (NDA)
– Generate additional data on both safety and
efficacy in relatively large numbers of patients.
– Provide information needed for the package inside
and labeling of the drug

49. • Phase III b:
– Clinical trials conducted after regulatory
submission of an NDA ,prior to the drug’s approval
and launch.
– These trials may supplement earlier trials or
complete earlier trials, or may be directed toward
new trial.
– This is the period between submission and
approval; a regulatory dossier for marketing
authorization.

50. NDA: New Drug Application
• Proposal to approve a new drug for sale
• Sufficient evidences provided to FDA/DCGI to
establish:
– Drug is safe and effective.
– Benefits outweigh the risks.
– Proposed labelling is appropriate.
• NDA contains all of the information gathered
during preclinical to phase III
• Can take 2-3 years for FDA to review

51. Phase IV: Post Marketing Surveillance/
Studies
• Done after drug has been marketed
• No fixed duration/patient population
• Open label(no blinding)
• It is done to detect unexpected adverse
effects and drug interactions
• Also to explore new uses for drugs

52. Phase IV: Post Marketing
Surveillance/ Studies
• Periodic Safety Update Reports
– to be submitted every six months for the first two
years after approval of the drug
– For subsequent two years need to be submitted
annually and may be extended if necessary.
• Harmful effects discovered may result in
restriction or no longer sold