Clinical Trials: Need and Ways

1. Clinical Trials: Need and Ways
Prof. Lokendra Sharma
Department of Pharmacology,
SMS Medical College
Jaipur

2. .
• .

3. Development of new
drugs/medicines/therapeutic modalities
revolutionized the practice of medicine.
The new medicine discoveries have
converted many once fatal or debilitating
diseases into almost routine therapeutic
exercises.
For example today deaths from
cardiovascular disease and stroke have
decreased by almost 50% or less over the
past 30 years

4. As the number of potential medicines
produced increases
The problem of whom to test them on
grows.
Two main groups:
Healthy volunteers and volunteer
patients (plus rarely non volunteer
patients).

5.  Studies in healthy normal volunteers can help to
find out the safety, tolerability, pharmacokinetics
e.g. anticoagulants and anaesthetic agents, their
dynamic effects.
 Otherwise the dynamic effect and thus the
therapeutic potential can only be investigated in
patients
e.g. drugs for epilepsy or antimicrobials.
Introduction of novel agents into both groups
poses ethical and scientific problems.

6. There are four reasons why medical practitioners (or
medical trainees)
1.Optimal selection of a specific dose of a medicine for a
specific patient requires a sound backup of good clinical
research.
To some extent every new administration to a patient is
an exercise in experimental therapeutics.
2.Increasingly doctors are personally involved in patient care.
3.Such studies provide an exercise in ethical and logical
thinking.
4.Good clinical research alters clinical practice.

7. Human Experiments Vs Clinical Research
 Some people are averse to the word ‘experiment’ in
relation to man, thinking man to be a guinea pig.
 That immediately implies a degree of impropriety in what
is done.
 It is better if all who are concern recognize the true
meaning of the word,
i.e. to ascertain or establish by trial (Oxford English
Dictionary),
 The benefits of modern medicine derive almost wholly
from scientific experimentation
 some risk is inseperable from much medical advances.

8. Human Experiments Vs Clinical Research
 The moral obligation of all medical
practitioners lies in ensuring that in their desire to
help patients
(the ethical principle of beneficience)
 They should never allow themselves to put the
individual who has come to seek their help at any
disadvantage
(the ethical principles of non-maleficence) as the
scientist or physician has no right to choose
martyrs for society.

9. Therapeutic Evaluation of New medicine
through Clinical Trials
When studies in animals predict that a
new molecule may be useful medicine,
i.e. effective and safe in relation to its
benefits
then the time has come put it to the test
in man.

10. The aim :
1. To assess the efficacy, safety and quality of new
medicines to meet unmet clinical needs.
2. To expand the indications for the use of current
medicines (generic drugs) in clinical and
marketing terms.
3. To protect public health over the lifetime of a
given drug.
The process of therapeutic evaluation may be
divided into pre- and post-registration phases.

11. Therapeutic Evaluation of New medicine
CONCEPT CLINIC
Phase 1
Phase 2
Phase 3
Phase 4
InVitro
Studies
Animal
Testing
Clinical Testing Marketing
4 yr
IND
8-9 yr
NDA
20 yr0 yr
to
Pre-clinical Clinical

12. Studies involving human subjects fall into
two distinct categories
1.Clinical studies: The class of all scientific approaches
to evaluate medical disease preventions,
diagnostic techniques and treatments using human
subjects(Q)
(either healthy volunteers or volunteer patients or
samples obtained from them) essentially as
experimental animals.

13. 2.Clinical Trial: It is a subset of those systematic
clinical studies that evaluate the new drug(s) in
human subject(s) to generate data for discovery
and/or verifying the clinical pharmacological
(both pharmacokinetic and pharmacodynamic)
and/or adverse effect with the objective of
determining efficacy and/or safety of the new
compound(s).
Phase 4 evaluation of marketed medicines in formal
clinical trials using the same or similar types of
protocols to those used in Phases 1 and 3 are also
referred to as clinical trial.

14. A clinical trial is a method for comparing
objectively by a prospective study the results of
two or more therapeutic procedures.
Until about 30 years ago treatment methods were
chosen on the basis of clinical impressions and
personal experiences rather than objective testing.
As a result many drugs with undoubted
effectiveness remain in use without ever having
been subjected to a control trial.
As per regulatory requirements any new drug is
now needed to have been tested in this way before
being licensed for general clinical use.

15. A clinical trial aims to compare the
response of a test group of patients
receiving
a new drug treatment (A) with that of a
control group receiving another treatment
(B).

16. Treatment (A) might be:
A new drug or a new chemical entity (NCE)
A new combination of existing drugs
An already approved drug now is used for another
indication by another route or another dosage form
Any other kind of therapeutic intervention, such as a
surgical operation
diet
physiotherapy procedure, etc.

17. Treatment (B) might be a :
currently used drug treatment
 if there is no currently available
effective treatment
a placebo or
no treatment

18. The proposed trial should be carried out, only after
approval of the Drugs Controller General of India (DCGI),
(Schedule Y of Drugs and Cosmetics Act,1940)
The investigator should also get the approval of Ethical
Committee of the Institution before submitting the
proposal to DCGI.
All the guiding principles should be followed irrespective
of whether
the drug has been developed in this country or abroad or
whether clinical trials have been carried out outside India
or not.

21. Phases of Clinical Trials
Four phases of clinical trials and medicine
development exists and are defined.
However, each of these definitions are
functional one, and the terms are not defined
on a strict chronological basis.
An investigational medicine is often evaluated
in two or more phases simultaneously in
different clinical trials.
Also, some clinical trial may overlap two
different phases.

22. Phase 1(n=20-50 subjects) Q(MTD)
 Here the drug is administered to healthy human volunteers
(Q)for the very first time
 Conducted to :
a). establish a rough idea of the dose to be
administered
b). detect the harmful adverse effects
c). determine the doses at which such ADR occurs.
 Healthy volunteers are preferred since if an unexpected and
potentially dangerous adverse effect occurs, it is more readily
manageable in an individual in good health.
 The subjects constitute a relatively reproducible model

23. Phase 1(n=20-50 subjects)
An attempt is made to establish the dose range tolerated
by volunteers for single or multiple doses.
Single dose should always be tested before repeated doses.
At least two subjects should be administered each dose.
The initial dose chosen should be very small based on the
data derived from pharmaco-kinetic, -dynamic and
toxicological studies in animals
Dose escalation should proceed very slowly. The next
higher dose should only be tested after all the clinical and
biological data on the previous dose have been analyzed.
The usual recommendation for dose escalation is to use a
geometric progression with a multiplication factor of 2
(X2). If one wants to be more cautious, the escalation
process can be by X1.5 or if one wishes to accelerate the
process it can be X4.

24. Phase 1(n=20-50 subjects)
Healthy female volunteers could be
included provided they have completed
their family or do not intend to have a
child in the future.
The volunteers should preferably be
covered under some insurance.
At least three months should lapse
between two trials in the same
volunteer.

25. Phase 1(n=20-50 subjects)(contd.)
 Phase 1 also includes metabolic and
pharmacokinetic studies with single
and then repeated administration,
although it is not an exclusive domain
of this phase.
However, pharmacokinetic trials are
usually considered phase 1 trials
regardless of when they are conducted
during a medicine development.

26. Exceptions of use of Healthy Volunteers in Phase 1
• Phase 1 trials are some times conducted in severely
ill patients, e.g.
In the field of cancer (as testing an antineoplastic drug
is considered hazardous in healthy subjects).
In less ill patients when pharmacokinetic issues are
addressed. Example is metabolism of a new
antiepileptic medicine in stable epileptic patients whose
microsomal liver enzymes have been induced by (the
received) other antiepileptic medicines.
In patient populations which may prove to be highly
susceptible to the investigational medicine such as
patients with impaired kidney or liver function.

27. Exceptions of use of Healthy Volunteers in Phase 1
This phase requires close clinical
observation and laboratory monitoring
and participation of a qualified clinical
pharmacologist is essential.
Institutions conducting Phase 1 trials
adequate facilities for clinical and
biological monitoring are mandatory.

28. Phase 2 (Exploration/Explanatory trial, n= 50-300
subjects)
Q (Efficiency )
 During Phase 2, the therapeutic potential of the new
medicine is evaluated in a small number of homogenous
patients (n=50-300 subjects)of both sexes for limited
periods
 Phase 2a Pilot Trials :
Are designed to evaluate efficacy (and safety) in selected
population of patients with the disease to be treated, diagnosed
or prevented.
Objective may focus on dose-response, type of patients,
frequency of dosing and different characteristics of safety and
efficacy.
Phase 2a may be conducted non-comparatively with neither
control group nor control treatment.

29. Phase 2 (Exploration/Explanatory trial, n= 50-
300 subjects) Q
Phase 2b Pivotal Trials :
It is well-controlled trial which evaluate efficacy
(and safety) in patients with the disease to be
treated, diagnosed or prevented.
It must be comparative, more often with a placebo
comparison first and/or comparing several different
dosages.
The Phase 2b trials provide unquestionable proof of
the compound’s therapeutic efficacy.
Phase 2 trials are usually limited to 3-4 centers

30. Phase 3 (Confirmatory Trial, n=250-1000+
subjects) Q
The purpose of this phase is to obtain adequate
data about the efficacy and safety in large and
heterogeneous population of patients.
Here, the test medicine is administered to a larger
and more varied patient population of both sexes
in multiple centers usually in comparison to a
standard proven treatment modalities or placebo if
a standard drug does not exist for disease under
study.
The duration of drug administration is increased
and may last up to 6 or up to 12 months for drugs
intended for chronic administration.

31. .
Phase 3 (Confirmatory Trial, n=250-1000+
subjects)
Phase 3a
This phase includes trials conducted after efficacy
of the medicine is demonstrated but not prior to
regulatory submission of NDA.
Here clinical trials are also conducted in special
group of patients, e.g. renal failure patients or
under special conditions dictated by the nature of
medicine or the disease.
This Phase (3a) trials offer much of the
information needed for the package inserts and the
labeling of the medicine.

32. Phase 3 (Confirmatory Trial, n=250-1000+
subjects) Q (Efficiency Comparison )
Phase 3b
 This phase is conducted after regulatory submission of an
NDA but prior to the medicine’s Phase 4 approval and
launch.
 This trial may
 Supplement earlier trials,
 Complete earlier trial, or
 May be directed towards new types of trials, e.g. QOL observations
or marketing
 Extend Phase 4 evaluation
 This phase is a period between the submission and
approval of a regulatory dossier for marketing
authorization of the new medicine

33. Phase 4 (Widespread use Trial/Field Trial)
This phase involves studies or trial conducted after
a medicine is marketed to provide additional
details of the medicine’s efficacy and safety
profile in a large number of heterogeneous
population under usual condition of use.
Here different formulations, dosages, duration of
treatment, medicines interactions and other
medicine comparison may be evaluated.
New age groups, races or other types of patients
may be studied.

34. Phase 4 (Widespread use Trial/Field Trial)
• Detection and definition of previously unknown or
inadequately quantified ADR and relative risk
factors are an important aspect of many Phase 4
studies.
• If a marketed medicine is to be evaluated for
another pharmacological effect, i.e. new
indication, then those clinical trials are considered
Phase 2 clinical trials.
• The term Post-marketing Surveillance is
frequently used to describe those clinical studies
in Phase 4 that are primarily observational or non-
experimental in nature to distinguish them from
well-controlled Phase 4 clinical trials.

35. Question ?
MTD
Efficiency comparison
Efficiency
 No EC clearance
required
 GCP not required
Small number with
highly trained clinical
pharmacologist
Normal human
volunteer
Phase I Trials
Phase 3
Phase 2
Phase 4
Preclinical phase
Phase 1
Phase 1