Features of clinical trials

What are clinical trials?

 Clinical trials are research studies that explore whether a medical strategy, treatment, or device is
safe and effective for humans.
 The Code of Federal Regulations (CFR) defined it as the clinical investigation of the drug that is
administered or dispensed to one or more human subjects
 These studies also may show which medical approaches work best for certain illness or groups of
people.  It helps in advancing the patients care.
 Clinical trial is the main stay for bringing out new drugs to the market.
 For every 10,000 to 30,000 drug molecule screened, only one reaches to the market.

 The four possible outcomes of clinical trials are:

 Positive trial: shows that the new treatment has a large beneficial effect and is superior to
standard treatment.
 Non inferior trial: shows that the new treatment is equivalent to standard treatment.

 Inconclusive trial: shows that the new treatment is neither clearly superior nor clearly inferior to
standard treatment.
 Negative trial: shows that the new treatment is inferior to standard treatment

Who are involved in clinical trials?

1. Patient / Healthy volunteer
2. Clinical Pharmacologist, Clinical Investigator & team: [Qualified and competent]
3. Institution where trials are held : [Approval required]
4. Ethical Review Board or Institutional Ethical Committee:
5. Sponsor
6. Regulatory Authorities:

Elements of clinical trials

otocol
Informed consent form:

time,

Institutional Ethical Committe

has been formally designated to approve, monitor and review biomedical
and behavioural research involving humans.

Resposibilities:
1. To protect the dignity, rights & well being of patients / volunteers
2. Ensure a competent review of the protocol
3. Advise on all aspects of welfare & safety
4. Ensure scientific soundness of the proposal

Composition of IEC
1. Chairperson
2. 1-2 basic medical scientists.
3. 1-2 clinicians from various Institutes
4. One legal expert or retired judge
5. One social scientist / representative of NGO
6. One philosopher / ethicist / theologian
7. One lay person from the community
8. Member Secretary
Key Components of a Clinical Trial
» It is a prospective study
» It is in humans
» It is designed to answer questions about a biomedical intervention or a behavioral
intervention:
• The research seeks to study something
• that the investigators will do to the subjects.
• The intervention can be either a biomedical intervention,
• such as a new drug.
• Or, the intervention can also be a behavioral intervention, such as cognitive behavior
therapy).

FEATURES OF CLINICAL TRAILS:

There is no research format or research design that is used for all clinical trials.
There are, however, four major features that are relevant to all clinical trials.
If you are proposing a clinical trial…. collaborating with other researchers… or simply reading about
trial results…
you will want to know:
• The stage of the study intervention, also known as the study phase.
• Whether the trial is a controlled study.
• Whether participants are randomized, and
• Whether participants are unaware of, or “blinded” to, treatments , and results.

these are explained below:

The Four Phases of Clinical Trials
• Phase I – The intervention is new and is being tested in a small group of people for safety
• Phase II – The intervention looks promising and is being evaluated in a larger group of people
for safety and efficacy
• Phase III – The intervention appears safe and effective and is being evaluated in a real-world
study
• Phase IV – The intervention is now in use and is being monitored for safety

What is a clinical control?

• An intervention is compared to something else, a “control”
• Compared to…
– What has been done in the past
– No treatment
– Current treatment (standard treatment)
– Similar-looking but ineffective treatment (placebo)

Uncontrolled Trials:
 Uncontrolled trials have to potential to provide a very distorted view of therapy comparison

 Especially in the hands on over enthusiastic or unscrupulous investigator  E.g. cancer trials
(Laetrile or Interferon therapy)
 It would be almost impossible to reproduce the results of an uncontrolled trial to any certainty 
Recommendation from such trials are often enthusiastic but may prove totally unrealistic

Placebo Controls
 Designed to duplicate the experience of the intervention without providing the active
component
 Recognizes that many health outcomes are dependent on the patient’s willingness to
participate and the patient’s and physician’s perception of benefit
 Can provide clear improvement in symptoms (the “placebo effect”)
 Can more accurately determine the extent to which the intervention alone affects treatment

Interventions
 The control contains an active component and is, therefore, an active control
 Active controls are frequently done in phase III trials where the intent is to understand the
benefits of a new treatment in a real-world setting

What Is Randomization?
• Randomization is the assigning of persons to the control group or the intervention groups
based on chance.
• Most experts and funding agencies consider random assignment to be an essential
feature of good clinical trial design whenever there are two or more groups.

• The key feature of randomization is that the process of randomization must be totally
unrelated to the variables of interest. For this reason,personal information, such as birth date
 or street address, is not a good a method of assigning persons to control or intervention
groups.

• Assigning persons by a number randomly generated by computer, the roll of a dice, or some
similar technique, is better.

Why is randomization necessary?

 How does the researcher decide who gets which treatment?
– every person will get the new treatment
– some persons may be willing to accept the new treatment while others are not.
 Whenever there is a good possibility that the control group and the intervention group are not
identical, there is also a good possibility that the results will differ because of some factor
totally unrelated to the treatment.

When comparing two or more forms of treatment in a clinical trial, how does the researcher decide
who gets which treatment?
 In some studies, every person will get the new treatment, such as penicillin for meningitis,
because the comparison is with historical controls, In other study designs, some persons may
be willing to accept the new treatment while others are not. Both of these situations introduce
a strong possibility of bias and confounding, which can give misleading results.
 Whenever there is a good possibility that the control group and the intervention group are not
identical, there is also a good possibility that the results will differ because of some factor
totally unrelated to the treatment.
 The standard solution to these concerns is randomization

Common Randomization Schemes

• Complete randomization
• Block randomization
• Urn randomization
• Stratified randomization
• Cluster randomization

Complete randomization
 Individuals are assigned to control and intervention groups based on a random event that is
proportional to the size of the groups
 The event could be a coin toss for two groups of equal size or a more complex computer
generated algorithm
 Resulting group sizes may not be equal (or in the desired ratio) because the process is truly
random
Suppose you wanted to randomize a group of 10 people, using a particular event......the event could
be a coin toss for two groups of equal size or a more complex computer generated algorithm.
Note that coin can come up "heads" 10 times in a row. In our case here "heads" came up 8 times.
While complete randomization is the purest approach, the resulting group sizes may not be equal,
or in the desired ratio, because the process is truly random. This is usually not a concern for large
studies, but it can be a serious problem in small studies; or if there is a requirement that study and
control groups be of equal size during the enrollment process.

Block randomization
 Also known as permuted block randomization
 Ensures that the number of subjects assigned to treatment and control groups is balanced
 Individuals are placed into small groups (blocks) and then randomly assigned to control and
intervention groups.
– Example:
 Two groups (A & B) and block size is four
 Two persons are randomly assigned to group A
 Remaining two in that block are assigned to group B
 Creates the potential for bias because the assignment of certain block members is
determined by the assignment of others.
Individuals are placed into small groups, or blocks, and then randomly assigned to control and
intervention groups. For example, suppose there are two groups (A & B) that we wish to assign
people...
If we assume the block size is ten, and the first 5 people are randomly assigned to group A......Then
the remaining five in that block are assigned to group B. This design creates the potential for bias
because the assignment of certain block members is determined by the assignment of others.

Urn randomization
 Form of “adaptive randomization” whose intent is to balance the number of individuals in each
group without specifying that an individual must be assigned to a specific group
 The chances that an individual will be assigned to a treatment or control group are allowed to
vary based on prior assignments
Again we have ten patients that we wish to use in a clinical trial. We want to split this group of ten
into two separate subgroups.
An urn contains a set number of balls of two types A and B. Upon randomization of a particular
participant a ball is drawn and replaced. If the ball is of type A, then the participants is assigned
treatment A and......a set number of type B balls are added to the urn. Notice that in this case, the
number of B balls have increased, to increase the probability of the next participant to pick the B
ball.
Conversely, if a ball of type B is drawn, the participant is assigned treatment B......and a set number
of type A balls are added to the urn to be selected by the remaining participants.
This process is repeated for the remaining participants.
Thus the composition of the urn is such that the probability of assignment is larger for the treatment
type, which has been, selected less often at any point in the trial.

Stratified randomization
 Used to guarantee that there is a balance of certain characteristics in treatment and control
groups
 Individuals are separated into subgroups (strata) based on a predetermined feature
 Randomly assigned to control and intervention groups using one of the methods mention in
previous slides
Lets assume again that we have ten patients that we wish to use in a clinical trial. We want to split
this group of ten into two separate subgroups, called strata.
Individuals are separated into strata, based on a predetermined feature. In this case, we're
separating them by their sex.
The individuals are then randomly assigned to control and intervention groups using one of the
methods mentioned in previous schmes

Cluster randomization
 Created in an attempt to deal with issues of contamination within subgroups
 Individuals are placed in subgroups
 The entire subgroup (cluster) is randomly assigned to be part of a control or intervention group
 Increasingly popular but requires an adequate number of clusters and careful design
Again we have ten patients that we wish to use in a clinical trial. We want to split this group of ten
into two separate subgroups, in this case called clusters.
In this example, patients are separated into clusters dependent on who was cared for by a certain
physician.
Then the entire cluster is randomly assigned to be part of a control or intervention group. This
approach is increasingly popular, but it requires an adequate number of clusters and a careful
design.

Blinding in Clinical Trials

Purpose of Blinding
In order to appreciate the meaning of blinding, its important to understand the purpose of blinding.
• Many clinical trials lack well-defined, objective endpoints.
For example, patients may be asked to rate their quality of life or physicians may be required
to estimate disability.
• Such measures are subject to intentional manipulation and unintentional bias.
• To help avoid these problems, researchers may seek to disguise whether the subjects are
receiving the intervention or the control treatment.
• Blinding, therefore,
is a technique that is used to reduce the possibilities of manipulation and bias.

Types of Blinding
• Unblinded or Open Label: A study where everyone knows who receives a particular
treatment is considered “unblinded” or “open label.”
• Single blind: A study where one group, comprised of either participants or observers, does
not know who receives the treatment is a “single blind” study.
• Double blind: A study where neither participants nor observers knows who receives the
treatment is a “double blind” study.
• Triple blind: Some have also used the term “triple blind” to indicate that a third party,such as
the one administering the treatment or analyzing the data, is also unaware of who receives
which treatment.