clinical trials

1. PHARMACEUTICAL VALIDATION
CHAPTER: 04
DRUG DEVELOPMENT
HOD: Dr. C SREEDHAR
PRESENTED BY: KSHITIZ K. GAUND
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2.  DRUG: (French: Drogue) It is the single active
entity present in a medicine that is used for the
diagnosis, prevention, treatment/cure of a
diseases.
OR
Drugs is any substance or products that is
intended to be used to modify or explore
physiological systems or pathological states
for the benefit of the recipient.
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3.  Synthesis /isolation of compounds.
 Preclinical studies: screening, evaluation,
pharmacokinetic and short term toxicity testing
in animal.
 Scrutiny and of grant of permission for clinical
trials.
 Pharmaceutical formulation, standardization of
chemical/biological/immuno assay of the
compound.
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4. * Clinical studies: phase I, phase II, phase III trials; long
term animal toxicity testing.
* Review and grant of marketing permission.
* Post marketing surveillance.
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5.  Natural source
 Chemical synthesis
 Rational approach
 Molecular modelling
 Combinatorial chemistry
 Biotechnology
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6.  After synthesizing/identifying a prospective
compound/series of compound , it is tested
on animals to expose the whole
pharmacological profile.
 Experiments are generally performed on a
rodent (mouse, rat, guinea pig, hamster,
rabbit) and then on large animals (cat, dog,
monkey).
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7. .
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As the evaluation progress unfavourable
compounds get rejected at each step.
Few of thousands reach to the stage when
administration can be done in man.

8.  Screening test.
 Test on isolated organs, bacterial cultures, etc.
 Test on animals models of human diseases.
 General observational test.
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9.  Confirmatory tests and analogue activities.
 Mechanism of action.
 Systemic pharmacology.
 Quantitative tests.
 Pharmacokinetics.
 Toxicity tests.
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10.  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) licence.
 The drug is formulated into a suitable dosage form and
clinical trials are carried in a logical phased manner.
 The drug is initially received under strict supervision to
minimize the risk.
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11.  Good clinical practice (GCP) has been laid out to
perform the experiments which includes
standards for the design, ethics, conduct,
monitoring, auditing, recording and analyzing
data.
 The GCP guidelines are issued by International
Conference of Harmonization(ICH).
 Adherence to GCP assures that the data and the
reported results are credible and accurate.
 The clinical studies are conventionally divided
into four phases.
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12.  The first human administration of the drug is
carried out by qualified clinical pharmacologist,
trained physician in a setting where all vital
functions are monitored and emergency,
resuscitative facilities are available.
 Subjects(mostly healthy volunteers, sometimes
patients)are exposed to the drug one by one with
the lowest estimated dose and increasing
stepwise to achieve effective dose. The total
number of subjects are 20 to 40.
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13.  The emphasis is on safety and tolerability
while the purpose is to observe the pharmaco
dynamic effects in man, and to characterize
ADME.
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14.  The phase II is conducted by the physician
who are trained as clinical investigators on
100 to 400 patients selected according to
specific inclusion and exclusion criteria.
 The primary aim is to establish therapeutic
efficacy, dose range and ceiling effect in a
controlled setting.
 Tolerability and pharmacokinetic are studied
as extension of phase I.
 These are generally carried out at 2 to 4
centres.
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15.  The phase III is carried out in a larger number
of patients ranging from 500 to 3000 by
several physician at many centres.
 The main aim is to establish the value of the
drug in relation to existing therapy.
 Safety, tolerability, and possible drug
interaction are assessed on a wider scale,
while additional pharmacokinetic data may be
obtained.
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16.  Indications are finalized and guidelines for
therapeutic use are formulated.
 A ‘new drug application’(NDA) is submitted to
licensing authority, who if convinced give
marketing permission.
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17.  After the drug has been marketed for general
use, practicing physicians are identified
through whom data are collected on a
structured Performa about the efficacy,
acceptability and adverse effects of the drug.
 Uncommon/idiosyncratic adverse effects, or
those that occur only after long term use and
unsuspected drug interaction are detected at
this stage.
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18.  Further therapeutic trials involving special
groups like children, elderly, pregnant,
patient with hepatic and renal failure may be
undertaken at this stage.
 Modified release dosage forms, additional
route of administration, fixed dose drug
combinations, etc may be explored.
 As such, many drugs continue their
development even after marketing.
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19. References: KD TRIPATHY Pharmacology book
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