Types of clinical trial

• Randomized
• Blinded or open label
• Prospective or retrospective
• Cross-over study
 Randomized Clinical Trials
• Subjects have equal chance to be assigned to one of two
or more groups just like tossing of coin.

• One group gets the most widely accepted treatment

(standard treatment)
• The other gets the new treatment being tested
– All groups are as alike as possible;
– removes the probability of bias.
 Why is randomization important?
• So all groups are as alike as possible
• Provides the best way to prove the effectiveness
of a new agent or intervention
• The most common methods of randomization
are:
1. Simple randomization
2. Blocked randomization
3. Stratified randomization
4. Cluster randomization
 BLINDING
• Blinding, in research, refers to a practice where
study participants are prevented from knowing
certain information that may somehow
influence them—thereby tainting the results. 
• Blinding aims to reduce the risk of bias that
can be caused by an awareness of group
assignment. With blinding, out- comes can be
attributed to the intervention itself and not
influenced by behaviour or assessment of
outcomes that can result purely from knowledge
of group allocation
 How to implement blinding?
• Blinding is not a simple procedure.
• The researchers often need to engage a variety
of approaches to enhance blinding.
• These included providing treatments in
identical form, specific methods to mask
characteristics of the treatments (eg, added
flavour or colour), or use of double dummy
procedures and even simulation of an
injection
• Unblinded or open-label
It is the exact opposite of blinding, where all the
participant, clinicians, data collectors, specialists
are well known about the
treatment/intervention they receive.
• Single blinding or single-masked:
In single blinding, only a single stakeholder i.e. either
the participant or the investigator is not informed of
the nature of treatment the participant is receiving.
A trial is called single-blind if only one party is
blinded. Usually, the participant is blinded and is
unaware of the treatment they receive.
•Double-blinding or double-masked:
Double-blinded study is defined as a study, in which both study
population/ participant and data collectors/ investigators
/researchers are not aware of the kind or nature of the treatment
given and who receive the treatment.
If both ‘the participants’ and ‘the study staffs’ are blinded, it is
known as a double- blind study.
•Triple blinding:
A clinical trial or experiment in which neither the subject nor the
person governing treatment nor an individual measuring the
response to the treatment is aware of the particular treatment
received by the subject is known as triple blind. Triple blinded
studies also lengthen blinding to the data specialists.
In triple blinding, the study participant, the data investigator or
data collector and the data analyzer- all are blinded.
Only the Principle Investigator of the research might know
about the trial– may it be treatment, drugs or so on
.
 Retrospective
• A retrospective study looks backwards and examines exposures to suspected
risk or protection factors in relation to an outcome that is established at the
start of the study.
• Many valuable case-control studies, such as Lane and Claypon's 1926
investigation of risk factors for breast cancer, were retrospective
investigations.
• Most sources of error due to confounding and bias are more common in
retrospective studies than in prospective studies.
• For this reason, retrospective investigations are often criticised. If the outcome
of interest is uncommon, however, the size of prospective investigation
required to estimate relative risk is often too large to be feasible.
• In retrospective studies the odds ratio provides an estimate of relative risk.
• You should take special care to avoid sources of bias and confounding in
retrospective studies.
 Prospective
• A prospective study watches for outcomes, such as the development
of a disease, during the study period and relates this to other factors
such as suspected risk or protection factor(s).
• The study usually involves taking a cohort of subjects and watching
them over a long period.
• The outcome of interest should be common; otherwise, the number
of outcomes observed will be too small to be statistically meaningful
(indistinguishable from those that may have arisen by chance).
• All efforts should be made to avoid sources of bias such as the loss
of individuals to follow up during the study.
• Prospective studies usually have fewer potential sources of bias and
confounding than retrospective studies.
 Disadvantages of Prospective Cohort
Studies
• You may have to follow large numbers of
subjects for a long time.
• They can be very expensive and time
consuming.
• They are not good for rare diseases.
• They are not good for diseases with a long
latency.
• Differential loss to follow up can introduce bias
 Parallel Study

• A parallel study is also referred to as “between patient” or “non-

crossover” study.
• It is defined as a type of clinical study, in which two separate treatment
arms, A and B, are given so that one group receives only treatment arm
• A while another group receives only treatment arm B.
• The two treatment groups of a parallel study can either be composed of
two completely separate treatments (i.e. different drugs), or simply
different doses of the same drug.
• A major characteristic of a parallel study is randomization, which
ensures accuracy of the results and lower risk of being biased.
• Generally, a placebo or active control are used as control groups in
parallel studies.
 Design of study
• Parallel design

Group 1 Drug A effect

Group 2 Drug B effect

Advantages:
a) It’s simple and easy to implement.
b) It is universally acceptable.
c) It is applicable to acute conditions.
d) Analysis is less complicated and interpretation is
straight forward.
Disadvantages:
It does not into account the inter individual
variability
 Crossover Study
• A crossover study, also known as a crossover trial, is a longitudinal
study where subjects receive an array of different treatments or
exposures.
• In a crossover study, all subjects should receive the same number of
treatments and should be involved in the same number of periods,
which is the so-called “balance” required in practically all crossover
designs.
• Unlike the parallel study, at first one treatment group of a crossover
study receives treatment A and subsequently followed by treatment
arm B while the other group receives treatment B followed by
treatment arm A.
• Actually, in most of the crossover studies, each subject receives all
treatments.
 Cross over design

effect effect

Group 1 Drug A Drug A

Wash out period

Group 2 Drug B Drug B

effect effect
 washout period

•  A period in a clinical study during which subj
ects receive no treatment for the indication und
er study and the effects of a previous treatment
 are eliminated (or assumed to be eliminated).
 Wash out period
Half life % of drug eliminated

1st half life 50

2nd half life 50+25=75

3rd half life 75+12.5=87.5

4th half life 87.5+6.25 =93.75

5th half life 93.75+ 3.125=96.875

6th half life 96.875+ 1.5625 = 98.485

7th half life 98.485+ 0.78125= 99.2655

 Advantages:
• It removes the inter patient variability from the
comparison between treatments.
• With a proper randomization of patients to the
treatment sequences, it provides the best
unbiased estimates for the differences between
treatments
 Disadvantages:
• Carry- over effects: The residual influence of
treatments on subsequent treatment periods.
Avoided by wash out period.
• Order effects: Order in which the treatment are
administered affects the outcome.
• Period effects: The diff. between the study periods.
• Drop-outs can be higher
• Unstable patient cant be used because of drug free
wash out period
 Split person design
• Occasionally, it is possible to administer the
two interventions at the same time.
• Very similar to that of the cross-over trial,
except there is no equivalent to the periods or
to the wash-out although a carry-over (now
termed carry-across) effect is likely to be
present.
 Factorial designs
• Used when it is desired to study the influence
of a number of factors on the treatments
compared as well as their interaction with
different treatments.
• Advantages:
– A greater precision can be obtained in estimating
the overall main factor effects.
– Interaction between different factors can be
explored.
– Additional factors can help to extend validity of
conclusions derived.
• Disadvantages:
– Difficult to analyse.
– Large designs require large no of subjects.
– Between subjects design lacks statistical
Add- on Design
 Fast track process
• Fast Track Drug Development is a process that
is designed to accelerate the development and
review of drugs to treat serious conditions and
fill an unmet medical need
• The purpose fast track drugs is to get
important new drugs to the patient earlier.
 Other similar Expedited studies under FDA
program
• BREAKTHROUGH THERAPY DESIGNATION : It is a
process designed to accelerate the development and review of
drugs which may show substantial improvement over the
current therapy.
• ACCLERATED APPROVAL : These regulations allow the drugs
for serious conditions to get approved based on surrogate
endpoint.
Surrogate endpoint: Substitute measure for a clinical endpoint.
Because it can be difficult to measure clinical endpoints in studies
running for several years,
For example, in HIV-related clinical trials, HIV viral load (VL) and
CD4 T lymphocyte (CD4) count are surrogate endpoints for HIV
disease progression.
• PRIORITY REVIEW DESIGNATION : A priority review
designation means FDA’s goal is to take action on approval of
 History of Fast track process
• In 1997, FDA’s Modernization Act directed the FDA to
create a system so that the important new drugs could
reach patients even more quickly.
• Thus, then Fast track program was introduced as fast
track designation under section 506(b) of Food, Drug
and Cosmetic Act.
• Under this section, FDA may grant approval to Drug as
Fast track designation if two criteria's are Fulfilled :
– Serious Condition.
– Potential to fulfil the unmet medical need
 Feature of fast track process
• Expedite Development and Review : Once
the FDA receives a Fast track request, early
and frequently interaction with the review
team is encouraged.
• These include meetings with FDA team
including Pre-IND meetings, Design study,
Dose response concerns and use of Bio
markers.
• Rolling review : It means that the Drug
company can submit the filled or completed
section of its New Drug Application to FDA
rather than waiting until every section of its
New Drug Application gets completed.
• Ability to address emerging public health
need : Drugs under Fast track designation can
be approved or passed more quickly which
may benefit the patient as the time for drug
availability will be less.
• Showing superior effect and therapeutic
action on serious and adverse outcomes.
Approval process of fast track process

Sending a Designation submission

Receiving the Fast Track Request

FDA Review and Response

Approval
 When to Send a Designation Submission
• Sponsors may request Fast Track designation when the
IND is first submitted or at any time thereafter before
receiving marketing approval of their NDA.
• The IND and potential fast track designation may be
discussed before an IND submission in a pre-IND meeting,
but a decision on designation would await submission of
the IND.
• If a sponsor’s drug development program is granted fast
track designation for one indication and has subsequently
obtained data to support fast track designation for another
indication, the sponsor should submit a separate request.
Content of Designation Submission
• The request should contain the following information captured in
15-20 pages and ‘REQUEST FOR FAST TRACK
DESIGNATION’ should be written on cover case in Bold letters
• The name of Sponsor’s contact person and the contact details like
telephone no. , address, email etc.
• If applicable ,the Investigational New Drug Application number
should be mentioned.
• For drug products, the proprietary name and active ingredients and
for Biological products, the proper name and proprietary name
should be given.
• The name of Division or Office to which the IND has been
submitted.
• Summary of Information that support Fast
track designation request which includes the
following:
– Information for considering the drug capability to
address the unmet medical need.
– Information for considering the drug capability to
treat a serious condition
 FDA Response
• FDA will respond to fast track designation requests within 60
calendar days of receipt of the request.
• Designation letter the Agency determines that the criteria for
designation as a fast track drug development program have
been met, the designation letter will:
• State that Fast Track Designation is granted for
development of the product for use in treating the specific
serious condition.
• Point out that the sponsor should design and perform studies
that can show whether the product meets an unmet medical
need.
• Alert the sponsor to the need for the drug development
program to continue to meet the criteria for fast track
designation
 Nondesignation letter
• If the Agency determines that a fast track
designation request was incomplete or that the
drug development program failed to meet the
criteria for fast track designation, the Agency
will send a nondesignation letter to the sponsor.
• The nondesignation letter will state that fast
track designation is not granted and explain the
reasons for the Agency's decision
 Withdrawal of Fast Track Designation
• Over the years of drug development, it is expected that some
drugs which are granted Fast track designation will not meet the
Criteria for fast track later.
• This may be due to reason that new and advanced drugs are
discovered and the Fast track drug no longer shows a active
potential to address unmet medical need.
• If the sponsor recognizes that Fast track drug development
program will no longer be continued, same must be informed to
Agency.
• The Agency then send a confirmation letter to the sponsor
indicating the end of his Fast track designation. Fast Track
Approved drug
Fast Track Approved drugs
 SUMMARY
• Fast track designation is a process by which the drug for serious or
life threatening disease can be developed more rapidly and can be
easily delivered to the patients.
• In order to get fast track approval, applicant sends a submission to
agency along with the NDA containing all required information of
the drug.
• FDA issues a Designation letter or Non designation letter after
review and verification of details.
• Many Fast track drugs are approved from time to time but they can
be recalled if they show adverse effect on patients.
• Also, if sponsor feels that he no longer wants to continue fast track
program, he can inform it to Agency.