Clinical trials involve testing new drugs on human subjects in multiple phases to evaluate safety, efficacy, and appropriate dosing. The document outlines the major phases of drug development from preclinical testing through post-marketing surveillance. Phase 0 involves microdosing to determine pharmacokinetics in humans. Phases I-III test in an increasing number of subjects to further evaluate safety, efficacy, and appropriate dosing. Phase IV involves post-marketing surveillance of approved drugs. Special populations like children, elderly, and pregnant women may require distinct trial protocols.

1. DRUG DEVELPOMENT &
DISCOVERY- CLINICAL TRIALS
PRESENTED BY:
SHUBHA SHARMA
M.SC. PHARMACOLOGY
RUHS-CMS, JAIPUR

2. CLINICAL TRIALS
 Clinical trials are scientific investigations that examine and evaluate safety
and efficacy of new drug in human subjects.
 Essential to get marketing approval from regulatory authorities.
 May require upto 7 years.

3. MAJOR STAGES OF DRUG DEVELOPEMENT
Preclinical testing
IND Application
Clinical testing – phase 0 (Microdosing study)
Clinical testing – phase I (Human pharmacology and safety)
Clinical testing – phase II (Therapeutic exploration & dose ranging)
Clinical testing – phase III (Therapeutic confirmation)
New Drug Application
Clinical testing – phase IV (Postmarketing surveillance)

5. INVESTIGATIONAL NEW DRUG
APPLICATION
 When the new compound passes the preclinical pharmacological screening the
manufacturer may file a ”Preclinical New Drug or Investigational New Drug”
application (IND application)to the authorized drug control body of the country.
 Application to the CDSCO/ Drug Controller General of India (DCGI) to request
permission to begin human testing in India.
 The IND application permits the use of an investigational new drug for the sole
purpose of conducting clinical trials.

6. The IND must contain the following information :
 Information on the composition and source of the drug.
 Chemical and manufacturing information.
 All data from animal studies (pharmacokinetics, pharmacodynamics, toxicological
studies with ED50 & LD50).
 Proposed plans for clinical trials.
 The names and qualifications of investigators who will conduct the clinical trials.
 A compilation of the key data relevant to study of the drug in humans that has
been made available to investigators and their institutional review boards.
 An agreement from the sponsors to submit annual progress report.
 A certificate that ” informed consent” will be obtained from human volunteers
and that ” ethics of research in human beings”.

7.  Only when the approval is given by this body, the drug can be administered to the
men for clinical trials.
 The testing in humans is begun only after sufficient acute and subacute animal
toxicity studies have been completed.

8. PHASES OF CLINICAL TRIALS
PHASE 0
 Recent designation, also known as human micro-dosing studies.
 Developed to reduce cost and time of drug development process.
 Small sample size of 10 -15 subjects is required
 Designed to speed up the development of promising drugs.
 1/100TH of the estimated human dose, or a max. of 100ug total dose of
candidate drug, are administered to healthy volunteers and
pharmacokinetics is worked out.

9.  Why conduct micro dose studies ?
To obtain information on human pharmacokinetics as early as
possible.
Compare ADME parameters for several drug candidates where
data may be conflicting
Helps in selecting the first dose for a Phase I study
Validate animal model for pharmacology and toxicology
Pharmacoeconomics – Cost benefit analysis

10.  Goal of Phase 0 studies
To assess whether the mechanism of action defined in pre
clinical studies is achieved or not
Define specific biomarkers or targets in human studies Determine
special methods to assess the pharmacokinetics of
the drug
Develop novel models to evaluate the pharmacodynamics Define
human PK/PD data prior to phase I

11. ADVANTAGES
 Requires minute quantities of
drug – not intended to produce
any pharmacological effect; risk
of adverse events less
 Decreases time of drug
development decreases cost
significantly
 Reduces animal testing
 Helps patients and industry with
earlier availability of test drugs
LIMITATIONS
 Insufficient information on body’s
reaction to micro dose and
pharmacological dose
 Micro dosing may not be predict
kinetic parameters accurately for
drugs showing non-linear kinetics
 Metabolism and stability of
compounds
 Limited specificity

12. PHASE I
 Initial studies to determine the metabolism and pharmacologic actions of drugs
in humans, the side effects associated with increasing doses, and to gain early
evidence of effectiveness.
 20-80 Healthy Volunteers.
 These trials are NON- BLIND /OPEN LABEL.
 Performed by clinical pharmacologists in a research centre , equipped for
pharmacokinetic studies.
 Takes a year or less to complete.

13.  These trials are designed to obtain the following information:
 Safety – Determine the most significant adverse events in human
subjects.
 Tolerability – The safe dose range is determined by dose escalations
and corresponding serial lab tests.
 Pharmacokinetics – How the drug molecule is absorbed in the body
and its metabolites are distributed and eliminated from the body
 Pharmacodynamics – The effects of the drug on the body, i.e. how the
the effects of the drug vary with the plasma concentration.

14.  Types of Phase1 trials:
- Single Ascending dose studies
- Multiple Ascending dose studies
- Pharmacogenomics studies (PGx)
- ADME studies

15. Types of Phase1 trials:
-Single Ascending dose studies
- Multiple Ascending dose studies
- Pharmacogenomics studies (PGx)
- ADME studies
SINGLE ASCENDING DOSE
STUDIES
 Small group of subjects given
single dose of drug and observed
for a period of time.
 If Pk data is in line with predicted
safe values, the dose is increased
in a new group of subjects
 Continued till maximum tolerated
dose (MTD) is defined.
MULTIPLE ASCENDING DOSE
 A group of subjects receives
multiple low doses of the drug
 Samples (of blood and other
body fluids) collected at various
time points and analysed
 Gives better understanding of
pharmacokinetics and
pharmacodynamics of the drug

16.  ADME studies
Objectives:
 To assess the absorption, distribution, routes and rates of excretion
 To assess the metabolite profile and metabolite identification.
 Pharmacogenomics study
 Broadly refers to the study of drug exposure and/or response as
to variations in DNA and RNA characteristics and ,
 Contribute to a greater understanding of inter-individual
differences in the efficacy and safety of investigational drugs.

17. PHASE II
 conducted to evaluate the effectiveness of the drug for a particular indication or
indications in patients with the disease or condition under study and to
determine the common short-term side effects and risks.
 100-500 Patients with target disease
 Carried out at 2-4 centres.
 Controlled blind studies (single as well as double)
 Often take 1-2 years to complete.
 • Concerned With:
– Safety
– therapeutic Efficacy
– Drug Toxicity
– Drug Interaction

18. These trials are divided into 2 phases:
EARLY PHASE
 Small no. of patients (20-200)
 To observe potential therapeutic
benefits and side effects.
 Usually SINGLE BLIND design.
LATE PHASE
 Larger no. of patients(50-300)
 Determine optimal dose-response
range.
 Controlled DOUBLE BLIND design.

19. PHASE III
 Involves giving the drug to a large number of patients (500-3000)
 Purpose is to....
Confirms earlier efficacy results
Identify adverse events which when drug is given to a larger population
over a longer period of time
 Designed to minimize errors in the information gathered in phase I
&phase II trials.
 RANDOMIZED DOUBLE BLIND CROSS OVER design.
 Conducted by different clinicians at many centers.
 Takes an average of 3-5 years to complete.

20. Subsets of Phases :
PHASE IIIa
 Trials conducted prior to the
regulatory submission of a New
Drug Application(NDA).
 Conducted in patients in whom the
drug will be eventually intended.
 Generate additional data on both
safety and efficacy.
 Information for package insert and
labelling of medicine.
PHASE IIIb
 Clinical trial after regulatory
submission of an NDA but prior to
approval and launch.
 Supplement earlier trials, complete
earlier trials, directs towards new
trials or phase IV evaluations.
 This is a period between submission
and approval of a regulatory dossier
for marketing authorization.

21. Clinical Trials
Testing in Humans

22. NDA – New Drug Application
 If the results of all the previous testing is positive, then the pharmaceutical
company files an NDA
 Submitted to the FDA/DRA, if Phase 1, 2 and 3 trials indicate the drug is safe and
effective.
 NDA contains all of the information gathered during preclinical to phase III
 Usually contains thousands of pages.
 FDA required to make a decision within 180 days of the date the NDA is submitted
 Can take 2-3 years for FDA to review.
 Once approval is obtained to market the drug, phase IV of the trials begins.

23. PHASE IV
 Phase IV Clinical trial is also known as Post Marketing Surveillance Trial.
 It is the post licensing phase- field trials.
 Has no fixed duration.
 Phase IV trials involve the safety surveillance (Pharmacovigilance) and
ongoing technical support of a drug after it receives permission to be sold
 New age groups, races, and other type of patients will be studied.

24.  Monitor the ongoing safety of marketed drugs by reassessing drug risk
based on …
 New data collected after the drug is marketed
 By recommending ways of trying to most appropriately manage that
risk
 Includes adverse reaction reporting by the medical community of
the pharmaceutical company that markets the drugs
 Periodic sampling and testing of the drug
 Periodic inspections of the manufacturing and distribution process

25. Clinical Trials In Special Population
 Pregnant and Nursing Women
Children
Geriatric patients
Renal dysfunction
Hepatic dysfunction
Ethnic group/Vulnerable population

26. Pregnant Women:
Ideally excluded in all phases of trials.
Included if medicinal product is for use in Pregnancy.
Follow Up till term
Follow of foetus and child very important
Nursing Women:
Included for study of excretion of drug/metabolite in human milk.
Babies should be monitored.

27. Paediatric trial
Paediatric regulation requires Paediatric Investigational Plan (PIPs) to be
submitted.
 PIPs:
 Includes a description & timing of study.
 Measure for formulation acceptable in children.
 Cover all age group from birth to adolescence.
 modified at later stage as knowledge increases.
 Studies deferred until after adult studies conducted, when safe
and ethical.
Waiver for PIP: eg. Parkinson's disease.
Paediatric trial
Key considerations:
Ethical consideration always paramount.
Pk studies important to determine appropriate dose. Age appropriate
formulation.
Long term follow-up studies for effects on growth Newborns most
undeserved.

28. Geriatric Trial
Includes healthy young, healthy elderly male and female volunteers
Mostly Open-label, non randomised study, single dose.
Objective- PK and metabolism, safety tolerability
Organ impairment studies/Trials
 Hepatic impairment, Renal impairment.
 Needed as drug is substantially metabolized, eliminated via a
specific organ (>20% or if narrow therapeutic index)
 Primarily to evaluate PK and metabolism.
 Often difficult population to engage.
 Small Number Patient.
 Key influence on label.
Pharmacoeconomy in trial
 New dimension in Trial
 Differentiates two treatments of equal efficacy & safety
 Important: Health care spending is High.

29. PRINCIPLES OF GCP
(GOOD CLINICAL PRACTICE)
 Clinical trials should be conducted in accordance with the ethical principles that
have their origin in the Declaration of Helsinki, and that are consistent with GCP
and the applicable regulatory requirement(s).
 Before a trial is initiated, foreseeable risks and inconveniences should be weighed
against the anticipated benefit for the individual trial subject and society. A trial
should be initiated and continued only if the anticipated benefits justify the risks.
 The rights, safety, and well-being of the trial subjects are the most important
considerations and should prevail over interests of science and society.
 The available nonclinical and clinical information on an investigational product
should be adequate to support the proposed clinical trial.

30.  Clinical trials should be scientifically sound, and described in a clear,
detailed protocol.
 A trial should be conducted in compliance with the protocol that has
received prior institutional review board (IRB)/independent ethics
committee (IEC) approval/favourable opinion.
 The medical care given to, and medical decisions made on behalf of,
subjects should always be the responsibility of a qualified physician or,
when appropriate, of a qualified dentist.
 Each individual involved in conducting a trial should be qualified by
education, training, and experience to perform his or her respective task(s).
 Freely given informed consent should be obtained from every subject
prior to clinical trial participation.

31.  All clinical trial information should be recorded, handled, and stored in a
way that allows its accurate reporting, interpretation and verification.
 The confidentiality of records that could identify subjects should be
protected, respecting the privacy and confidentiality rules in accordance
with the applicable regulatory requirement(s).
 Investigational products should be manufactured, handled, and stored in
accordance with applicable good manufacturing practice (GMP). They
should be used in accordance with the approved protocol.
 Systems with procedures that assure the quality of every aspect of the trial
should be implemented.