trial and protocol design

1. Trial and Protocol Design

2. • List Key concepts in trial designs
• Recognize the various types of trial designs
• Describe protocol and their contents

3. Introduction
• ICH-GCP sets forth the specific requirements
for clinical trial designs. ICH-GCP guidelines for
clinical trial and protocol designs are
discussed in this lesson.

4. ICH requirement for Trial Design
• According to ICH-GCP, clinical trials:
– Should be scientifically sound and described in a clear,
detailed protocol
– Should be designed , conducted and analyzed according to
sound scientific principles to achieve the specified
objectives
– Require that the sponsor use qualified individuals (i.e.
biostatisticians, clinical pharmacolost and physicians, etc)
as appropriate throughout all the stages of the trial
process.

5. Introducation
• As a Monitor/Clinical Monitor, Research
Associate (CRA), you will work with different
types of clinical trials. This slide describes the
types of clinical trials and which types are
conducted during each phase. It also provides
review of the phases of clincal trials.

6. Types of trials• The different types of trials are:
– Treatment trials: are tests of experimental treatments,
new combinations of drugs or new approaches to surgery
or radiation therapy.
– Prevention trials: Look for better ways to prevent disease
or to prevent a disease from returning. The approaches
may include medicines, vitamins, minerals or lifestyle
changes
– Diagnostic trials are conducted to find better tests or
procedures for diagnosing a particular disease condition.
– Screening trials tests the best way to detect certain
diseases or health conditions
– Quality of life trials (Also called as supportive care trials)
explore ways to improve comfort and the QOL for
individual with a chronic illiness

7. Types of trials..cont
• Another category of trials are
– Bioavailabity
– Bioequivalence
– These are designed to provide that 2 medicinal
products are bioequivalent if
• They are pharmaceutically equivalent
• Their bioavailability after administration in the same doses
are similar
• They have essentially the same efficacy and safety
Brief overview as how these studies are conducted

8. Phase 1 trials
• Phase I- First stage of testing trials on Humans
(20-80) healthy human volunteers
Take up to six months to 1 yr to complete
Data on safety & tolerability
Pharmacokinetics and Pharmacodynamics
In some case patients are used e.g. Anti-HIV
trials, Anto cancer trials

9. Phase II
• First time, patient are exposed to experimental
drugs and are performed on the larger group (50-
300)
• They explore, how well patients will respond to
drug (i.e. efficacy), include studies on safety of
the drug and also determine the most
appropriate dose of the drug to be used in
patients. These usually take one year to three
years to complete.

10. Phase III
• More complex in design and large subject (300
to 1000 and above)
• They confirm the data on safety and eficasy
generated from previous trials.
• Generally take 2 to 3 years or longer to
complete
• IIIa- Before regulatory submission
• III b- After regulatory submission, but before
marketing approval is granted.

11. Phase IV
• - Conducted after the drug is approved.
• Subjects are general public who are taking this
drug
• Subject number may range from 1000 or more
and may last months to year depending upon
indication of the drug.
• Long term safety and efficacy- Rare AEs/SAEs

12. Key concepts in trial designs
• Randomization is a method of assigning trial
subjects to different treatment groups using
an element of chance. This approach
eliminates selection bias that might
undermine the realiabity of comparison
between two groups.

13. Stratification
• Is a particular type of randomization for
specific subgroups, for example, stratification
for country/site, severity of disease or age.

14. Blinding/Masking
• Refers to a procedure in which one or more
parties to the trial are kept unaware of what
treatment group they are assigned to.
• Single –blinding – subject is unaware
• Double blinding – Subject/PI/CRA unaware
• Open labeled – All are aware
• Blinded and unblinding teams- for trials
unblinded is difficult…steps to prevent
unblinding

15. Comparator (Product)
• The comparator (Product) is an
investigational or marketed product or
placebo that provides the control for a clinical
trial.
• A placebo is an inactive pill, liquid or powder
that has no treatment value. However its
good to know the recipients of placebo, as
some people might be allergic and this needs
to be mentioned in informed consent.

16. Control Group
• Control group in clinical trials allow
researchers to separate outcomes caused by
treatment from outcomes caused by other
factors.

17. Fixed Dose Vs. Titrated Dose
• Fixed dose trials are trials in which subjects
continue to receive fixed maintenance dose
throughout the trial. (Single arm of fixed doses
or multiple arms
• In dose titration trials, the dose of the study
drug/comparator can be titrated/adjusted
until a particular end point is reached.

18. Types of trial design
• Parallel trial design, the trial patients
continue to receive the same drug
• Drug A------------------------------------Drug A
• Drug B------------------------------------Drug B
» 3 months>>>>

19. Cross-Over Design
• In cross-over designs, all subjects have
opportunity to get both the study drugs due
to crossover mid way.
• In crossover design, each subject acts his or
her its own control
• Crossover designs cannot be used, when drug
is tested to check efficacy
• Crossover designs, can be used for more than
2 treatment

20. Cross-Over Design
• Used for drugs, with high inter-subject
variability (e.g. in BA/BE studies)

21. Cross-Over Design
• The washout period is used for elimination of
initial drug from the body. However, the
effects of the first drug may persist in the
body.

22. Trial designs in protocols
• Several types of clinical trial controls are
discussed in this section.
• Multiple control groups may be used in a
single trial.
• Trial designs are heart of any protocol, a well
designed study design, helps to get the
required results.

23. Concurrent Controlled Clinical
Trials
• In a concurrent control clinical trial, the test
and control groups are chosen from the same
population, and are treated in the same
manner over the period of time

24. Historical Control Trials
• Historical Control Trials are used in unusual
cases when a similar group of patients studied
previously are used as control subjects (This is
not generally recommended, but used usually
for academic projects etc)
– Prospective (Future) Control
– Retrospective Control

25. Placebo Control Trials
• In a placebo control trials, subjects are randomly
assigned to the test treatment or to an identical
appearing treatment that does not contain the test
drug. The use of placebo control does not mean that
control group is untreated.
• In many placebo controlled trials, the investigational
treatment and placebo are each added to a common
standard therapy. These are known as "add-on"
studies.

26. Active (Positive) Control Trial
• In an active (Positive) control trial, subjects
are randomly assigned to the test treatment
or to an active control treatment

27. Dose response control trials
• In a dose response control trials, subjects are
randomized to one of several fixed dose
groups
– 20 mg
– 40 mg
– 60 mg
– 80 mg
– Placebo

28. Trial Designs in Protocol
• According to ICH-GCP, the scientific integrity
of the trial depends substantially on the trial
design. The ICH-GCP guidelines provide
specific information about standards for
designing, conducting, recording and
reporting trials that involve the participation
of human subjects.
• This section discusses some of the trial design
requirements mandated by ICH-GCP

29. A description of the trial design in
the protocol should include:
• A specific statement of the primary endpoints and secondary
endpoints, if any to be measured during the trial
• The type/design of the trial to be conducted (i.e. Double
blind, placebo controlled, parallel design)
• A schematic diagram of the trial design, procedures and
stages
• The measures to be taken to minimize or avoid bias, including
randomization and blinding
• The trial treatment(s), dosage and dosing regimn of the
Investigational Product (IP)

30. The description of the trial design
should also include:
• The expected duration of all the subject participation and a
description of the sequence and duration of all trial periods,
including follow ups , if any
• The stopping rules or discontinuation criteria for individual
subjects, part of the trial and the entire trial
• Accountability procedures for the (IP), including the
placebo(s) and comparator(s), if any
• Maintenance of trial treatment randomization codes and
procedures for breaking the codes.
• The identification of any data recorded directly on the CRF
and considered to be source data

31. Quiz
• As per ICH-GCP, the protocol contains which of the following
(Select all that apply)
A) A summary of findings from non-clinical studies that
potentially have critical significance and from clinical trials
that are relevant to the trials
B) A description of the ideal investigative site to select
C) The procedures to follow-up with subjects withdrawn from
Investigational product treatment/trial treatment
D) A description of the informed consent process

32. Quiz
2) Trial design can include all of the following
controls except
a)- Placebo vs active investigational product
b)- Parallel design, comparator controlled,
randomized
c)Crossover design ensuring that the subject
receives placebo both times
d)Concurrent vs historical control

33. Quiz
• 3) The protocol will contain a description of
the measures taken to minimize bias,
including a statement that the subject will be
informed of the treatment group they are
assigned to
• - True
• -False