PHASE III TRIALS

G.Arun Jyothi
 Introduction
• Phase III trials are performed after preliminary evidence
of effectiveness of the drug has been obtained in phase II.
• The aim of this study is to verify drug’s effectiveness and
adverse reaction profile in larger population of patients
usually two to three thousand and longer period of time
(one to five years). Hence also referred as therapeutic
confirmatory studies.
• Phase III studies provide basis for further generalisation of
findings for launch of the drug and a basis for package
insert information.
•  Studies in Phase III are designed to confirm
the preliminary evidence accumulated in
Phase II that a drug is safe and effective for
use in the intended indication and recipient
population.
• These studies should be  intended to provide
an adequate basis for marketing approval.
• Phase III studies are randomised controlled
trials conducted at multiple centres by the
clinicians which compares completely new
treatment with the standard treatment.
• Ideal dosage regimens are obtained in phase
III and exact place of drug in therapy is
determined.
• In this phase ,data is gathered from large
numbers of patients to determine whether the
new treatment is more effective and possibly
less toxic than the current standard treatment.
• Over all to evaluate benefit risk ratio.       
• Phase III focus on patients with a specific disease,
they typically include patients of various ages,
multiple ethnicities ,and both genders, so that
the results, once obtained may be applicable to a
large number of patients population.
• Phase III trials are the most expensive ,time
consuming and difficult trials to design and run
,especially in therapies for chronic conditions.
 objectives
• Demonstrate/confirm efficacy
• Establish safety profile
• Provide an adequate basis for assessing the
benefit/risk relationship to support licensing
• Phase III trials are further divided into IIIa and IIIb.
• Phase IIIa :Trials conducted after efficacy of the medicine is
demonstrated, but prior to regulatory submission of a New
Drug Application (NDA) or other dossier.
• These clinical trials are conducted in patient populations for
which the medicine is eventually intended.
• Phase IIIa clinical trials generate additional data on both
safety and efficacy in relatively large numbers of patients in
both controlled and uncontrolled trials.
• These trials often provide much of the information needed
for the package insert and labeling of the medicine. .
• Phase IIIb: Clinical trials conducted after
regulatory submission of an NDA or other dossier,
but prior to the medicine's approval and launch.
• These trials may supplement earlier trials,
complete earlier trials, or may be directed toward
new types of trials (e.g., quality of life).
• This is the period between submission and
approval of a regulatory dossier for marketing
authorization.
• SAMPLE SIZE:1000-3000 Pts or more
• Patient Population:
• Phase III trials are conducted in patient
population for which the medicine is eventually
intended.
• Trials are also conducted in special groups of
patients e.g : renal failure ,hepatic failure etc
• Special trials such as quality of life, marketing
trials are also conducted in this phase.
 Inclusion/exclusion criteria   
• When designing a clinical research study, an
investigator must first decide who should be in
the study and who should be excluded.
• The researchers must therefore try and find a
balance between identifying those people who
are most appropriate to test a new therapy
and casting a wide enough net to ensure that
they will have enough participants to make the
results statistically significant.
 Clinical trial subjects
• Advantages :
• Following are some of the advantages of
participating in a Phase III clinical trial:
• It's a chance to receive a treatment that may be
better than anything else out there a year or two
before it hits the market.
• Treatments in Phase III trials have passed Phase I
toxicity testing, and Phase II testing has proven
them to be at least somewhat effective.
• Inclusion and exclusion criteria for Phase III trials are
generally less strict than in earlier phases.
• Since Phase III trials are generally multicenter trials,
you may have to travel a shorter distance for
treatments.
• Even if the treatment does not work for you
personally, you may take comfort in knowing that your
participation in the trial will help other cancer patients
down the road, and it will also help the advancement
of medical science.
• Disadvantages:
Some of the disadvantages of participating in a Phase III
clinical trial are:
Many people do not wish to take the chance of being
randomized into a standard treatment arm, and, in the
case of blinded trials, many people do not like being kept
in the dark about which treatment they're receiving.
• Even if one is randomized into the experimental arm of
the study, the experimental treatment may be no better
than the standard treatment, and it may be worse.
• Phase III is the first time the treatment is being
given to a large and diverse group of patients.
Adverse side effects that were not seen in
earlier phases are likely to show up in Phase
III.
• Phase III trials are often reserved for newly
diagnosed patients who have not previously
received treatment.
• Special population :: elderly, children
• (1) Geriatrics.-Geriatric patients should be included in Phase III clinical
trials (and in Phase II trials, at the Sponsor's option) in meaningful
numbers, if-
• (a)   the disease intended to be treated is characteristically a disease of
aging; or
• (b)   the population to be treated is known to include substantial
numbers of geriatric patients; or
• (c)   when there is specific reason to expect that conditions common in
the elderly are likely to be encountered; or
• (d)   when the new drug is likely to alter the geriatric patient's response
(with regard to safety or efficacy) compared with that of the non-
geriatric patient.
• (2) Paediatrics.-
 (i) The timing of paediatric studies in the new drug
development program will depend on the medicinal product,
the type of disease being treated, safety considerations, and
the efficacy and safety of available treatments.
 For a drug expected to be used in children,
evaluations should be made in the appropriate age group.
When clinical development is to include studies in children, it
is usually appropriate to begin with older children before
extending the trial to younger children and then infants.
 
• (ii) If the new drug is for diseases
predominantly or exclusively affecting
paediatric patients, clinical trial data should be
generated in the paediatric population except
for initial safety and tolerability data, which
will usually be obtained in adults unless such
initial safety studies in adults would yield little
useful information or expose them to
inappropriate risk. 
• (iii) If the new drug is intended to treat serious or
life-threatening diseases, occurring in both adults
and paediatric patients, for which there are
currently no or limited therapeutic options,
paediatric population should be included in the
clinical trials early, following assessment of initial
safety data and reasonable evidence of potential
benefit.
• In circumstances where this is not possible, lack of
data should be justified in detail.
• (iv) If the new drug is a major therapeutic
advance for the paediatric population – the
studies should begin early in the drug
development , and this data should be
submitted with the new drug application. 
• STUDY MEDICATION:
The formulation ,route of administration
should be of intended use in clinical practice.
The drug must be compared to currently
available standard treatment.
• STUDY DURATION:
These trials take many years to complete.
Phase III trials usually consists of both
short term and
long term safety and efficacy studies
• Short term safety and efficacy trials
These trials are primarily aimed at
evaluating the safety and efficacy of a new
therapy with a short duration of treatment
and comparing its efficacy with the standard
therapy . An example of this kind of trial
would be a 24 week double blined,placebo
controlled randomized trial.
• Long term safety and efficacy trial
Regulatory authorities require that the
results of long term safety and efficacy of a new
treatment be submitted before the approval to
market the drug is given.
These studies are aimed at evaluating the
long term safety and efficacy of a new
treatment. The studies have to be conducted for
a minimum period of 2 years at multiple centers.
 Clinical trials design

• These may be usually randomized, double

blind studies.
• Parallel group design.
• Crossover design.
• Factorial designs.
• Superiority trial.
• Non inferiority trial (Study of equivalency).
INTERPRETATIONS EVOLVED FROM PHASE III
TRIALS
• Patterns of responses observed in large
populations.
• Commonly observed drug interactions.
• Commonly observed non medicine
interactions e.g : with food,alcohol,etc.
• Unexpected benefit in the disease for which
the medicine was used.
• Unexpected benefits when the medicine was
given to the patients with a second clinical
problem.
e.g: patients with peptic ulcer associated with CAD
when treated with triple drug therapy ,containing
macrolide antibiotics their cardiovascular status
was improved .Then they showed roxithromycin
is effective in preventing ischemic events in
patients with unstable angina.
• Profile clinical activity in special populations
such as patients with renal or hepatic failure,
elderly and children
• Identification and characterization of common
adverse reactions (which are avoided under
controlled early trial condition)
To get phase III protocol approval following documents should be applied

• Provide a summary of all the nonclinical safety

data already submitted while obtaining the
permissions for Phase I and II trials, with
appropriate references.
• In case of an application for directly initiating a
Phase III trial complete details of the
nonclinical safety data needed for obtaining
the permissions for Phase I and II trials, must
be provided.
• Repeat dose systemic toxicity studies of appropriate duration to
support the duration of proposed human exposure
• Reproductive/developmental toxicity studies
In vitro and In vivo genotoxicity tests. Segment I
(if female patients of child bearing age are going to be involved),
and
Segment III (for drugs to be given to pregnant or nursing
mothers or where there are indications of possible adverse effects
on foetal development).
• Carcinogenicity studies (when there is a cause for concern or when
the drug is to be used for more than 6 months).
 Phase III in India
(Schedule Y requirements
• For new drug substances discovered in India,
clinical trials are required to be carried out in
India right from Phase I.
• For new drug substances discovered in countries other
than India, Phase I data as required along with the
application.
• After submission of Phase I data generated outside India
to the Licensing Authority, permission may be granted to
repeat Phase I trials and/or to conduct Phase II trials and
subsequently Phase III trials concurrently with other
global trials for that drug.
• Phase III trials are required to be conducted in India
before permission to market the drug in India is granted.
• If the drug is already approved/marketed in
other countries, phase III data should
generally be obtained on at least 100 patients
distributed over 3-4 centres primarily to
confirm the efficacy and safety of the drug, in
Indian patients.
• If the drug is a new drug substance discovered
in India and not marketed in any other
country, phase III data should generally be
obtained on at least 500 patients distributed
over 10-15 centres.
• Permission to carry out these trials shall
generally be given in stages, considering the
data emerging from earlier Phase(s)
 The Quantity of Evidence to Support
Effectiveness
• The following three sections provide guidance
on the quantity of evidence needed in
particular circumstances to establish
substantial evidence of effectiveness.
• Section 1:addresses situations in which
effectiveness of a new use may be
extrapolated entirely from existing efficacy
studies.
• Section 2
• addresses situations in which a single adequate
and well-controlled study of a specific new use
can be supported by information from other
related adequate and well-controlled studies,
such as studies in other phases of a disease,in
closely related diseases, of other conditions of
use (different dose, duration of use,regimen), of
different dosage forms, or of different endpoints.
• Section 3
• addresses situations in which a single
multicenter study, without supporting
information from other adequate and well-
controlled studies, may provide evidence that
a use is effective.
• In each of these situations, it is assumed that
any studies relied on to support effectiveness
meet the requirements for adequate and well-
controlled studies.
• It should also be appreciated that reliance on a
single study of a given use, whether alone or
with substantiation from related trial data,
leaves little room for study imperfections or
contradictory (nonsupportive) information.
• In all cases, it is presumed that the single
study has been appropriately designed, that
the possibility of bias due to baseline
imbalance, unblinding, post-hoc changes in
analysis, or other factors is judged to be
minimal, and that the results reflect a clear
prior hypothesis documented in the protocol.
• Moreover, a single favourable study among several
similar attempts that failed to support a finding of
effectiveness would not constitute persuasive
support for a product use unless there were a
strong argument for discounting the outcomes in
the studies that failed to show effectiveness (e.g.,
study obviously inadequately powered or lack of
assay sensitivity as demonstrated in a three-arm
study by failure of the study to show efficacy of a
known active agent).
• Whether to rely on a single study to support an
effectiveness determination is not often an issue in
contemporary drug development.
• In most drug development situations, the need to find an
appropriate dose, to study patients of greater and lesser
complexity or severity of disease, to compare the drug to
other therapy, to study an adequate number of patients
for safety purposes, and to otherwise know what needs to
be known about a drug before it is marketed will result in
more than one adequate and well-controlled study upon
which to base an effectiveness determination.
 New Drug Application (NDA)
• “It is an application filed with regulatory
authorities to get approval for marketing a
new pharmaceutical for sale in the country.”
• I. Goals of NDA-
• Whether the drug is safe and effective in its proposed
use(s), and whether the benefits of the drug outweigh
the risks.
• Whether the drug's proposed labeling (package insert)
is appropriate, and what it should contain.
• Whether the methods used in manufacturing the drug
and the controls used to maintain the drug's quality
are adequate to preserve the drug's identity, strength,
quality, and purity.
• The documentation required in an NDA is
supposed to tell the drug's whole story,
including what happened during the clinical
tests, what the ingredients of the drug are, the
results of the animal studies, how the drug
behaves in the body, and how it is
manufactured, processed and packaged. 
•

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