CLINICAL PHARMACOLOGY AND PHARMACODYNAMICS

Clinical pharmacology:

Definition:
Clinical pharmacology is the science of drugs and their clinical use.
It has a broad scope, in the discovery of new target molecules, to the effects of
drug usage in whole populations.
The main objective is to promote the safety of prescription, maximize the
drug effects and minimize the side effects.
It is important that there be association with pharmacists skilled in areas of
drug information, medication safety and other aspects of pharmacy practice
related to clinical pharmacology.
Clinical pharmacology has a wide variety of branches which includes
a. Pharmacodynamics.
b. Pharmacokinetics.
c. Drug development.
d. Drug interactions.
e. Adverse drug reactions.
f. Toxicology.
A. Pharmacodynamics:
Definition:

The study of how a drug acts on a living organism, including the

pharmacologic response and the duration and magnitude of response observed
relative to the concentration of the drug at an active site in the organism.
These branches include the clinical studies. These clinical studies can be studied
under various regulatory guidelines which include,
CLINICAL STUDY DESIGN DOCUMENTATION, PRESENTATION AND
INTERPRETATION AS PER REGULATORY GUIDELINES OF EUROPEAN
COMMUNITY :

Pharmaceutical companies spend billions of dollars every year on carrying out

clinical study by conducting clinical studies for their potential products. These
studies are funded by charities, government research councils and other bodies. A
set of official guidelines has been issued in Europe that cover many aspects of
clinical trials. Any incorrect procedures lead to refusal to grant the relevant
marketing approval.
a. The most important of these guidelines is following of Guidance on Good
Clinical Practice (GCP).
b. It also sets out the basic requirements on
1. The protection of trial subjects.
2. The design of procedures to be used in the trial.
3. The recording and reporting of results.
4. The documentation that is required, and the monitoring and audit of the trial to
ensure that these requirements are being met.
Since 1990, there has also been an international process,
known as the International Conference on Harmonization of Technical
Requirements for Registration of Pharmaceuticals for Human Use (ICH), which

involves representatives of the regulatory authorities and industry associations of

Europe, Japan and the US.
The objective of the ICH is to harmonize pharmaceutical regulatory
requirements on an
International basis to minimize the possibility that tests and trials on new medicinal
products have to be repeated for the purposes of obtaining regulatory approval in
different Countries.
In broad terms, the European law states that, where an
applicant wishes to obtain marketing approval for a new medicinal product the
pharmaceutical companies must follow the follow the key points they include,
All clinical trials should be carried out in accordance with the Declaration of
Helsinki (world medical association) the freely given informed consent of each
trial subject should be obtained and documented.
The clinical trials should not begin before the authorization of ethical
committee.
All aspects of conduct of the trial should be documented in pre-established,
written procedures (e.g. written protocols) and documentation and records of
the trial should be archived for specified minimum periods of time.
The clinical study design, should include the following points:
A description of the type/design of trial to be conducted(e.g. double-blind,
placebo-controlled, parallel design) and a schematic diagram of trial design,
procedures and stages.
A description of the measures taken to minimize/avoid bias, including:
Randomization.

 A description of the trial treatment(s) and the dosage and dosage regimen of the
investigational product(s). Also include a description of the dosage form,
packaging, and labeling of the investigational product(s).
The expected duration of subject participation, and a description of the
sequence and duration of all trial periods, including follow-up, if any.
A description of the "stopping rules" or "discontinuation criteria" for individual
subjects, parts of trial and entire trial.
All records, in any form (including, but not limited to, written, electronic,
magnetic, and optical records, and scans, x-rays, and electrocardiograms) that
describe or record the methods, conduct, and/or results of a trial, the factors

affecting a trial, and the actions taken.

The act by a regulatory authority (ies) of conducting an official review of
documents, facilities, records, and any other resources that are deemed by the
authority(ies) to be related to the clinical trial should be deemed appropriate by
the regulatory authority(ies).

CLINICAL STUDY DESIGN DOCUMENTATION, PRESENTATION AND

INTERPRETATION AS PER REGULATORY GUIDELINES OF UNITED
STATES AUTHORITIES:
The U.S. Food and Drug Administration is a scientific, regulatory, and
public health agency that oversees items accounting for 25 cents of every
dollar spent by consumers.
Clinical Trial Design: Authorities conduct CLINICAL STUDY DESIGN
based on scientifically designed protocols, which balance potential risk to
the research participant with the possible benefit to the participant and to
society.
1. The study design usually performed in normal health subjects.
2. For the study of the drug analytical methods should be validated for
accuracy, precision, and sensitivity.

3. Different methods yield different results so a standard method should be

employed in the total course of study.
4. The design should be authorized by the FDA authorities for further
release in to the market.
Clinical interpretation is important in evaluation of the results of the
clinical study.
A small difference between drug product and standard, significantly produce
a very big difference in therapeutic response during the clinical
interpretation of the data.
Presentation of data:
1. According to US FDA data should be presented in graphical form and
talker forms. ANOVA is needed to determine statistical significance
between the standard and the drug designed in the pharmacological
parameters.
2. Enough care should be taken for the storage of data until it is presented
3. The guidelines taken for the study and the approvals given by the FDA
agencies should also be included with the presentation of the final data.
4. Further the drug is finally released in to the market for the usage if the
FDA satisfies with the presented data.
CLINICAL STUDY DESIGN DOCUMENTATION, PRESENTATION AND
INTERPRETATION OF REGULATORY GUIDELINES IN INDIA:
India has become hub for clinical trials among South Asian countries due to
abundant availability of large and diverse patient's pool, faster enrollment of
patients, availability of trained investigators, plenty of super specialty hospitals
with excellent infrastructure and increasingly accommodating regulatory
environment.
It is estimated that nearly 20% of all global clinical trials will be
conducted in India by 2010.

 In volume terms, it is the worlds fourth largest market in unit

sales, but ranks 13th in value terms with an annual revenue of
approximately US$ 5 billion.
The world has identified India as an emerging hub for
collaborative and outsourced research and development (R&D)
and went on to observe that Indian pharma companies had
topped drug filings with the US FDA for 2003, with a total of
126 DMFs(DRUG FILINGS), accounting for 20% of all drugs
coming into the US market, higher than Spain, Italy, Israel, and
China.
For a drug to do the clinical studies, it should be registered in
Clinical Trials Registry-India (CTRI).
In order to make clinical data available on online clinical
registry has been initiated by Indian Council of Medical
Research. (ICMR).
The 2 goals of this ICMR is the transparency and accountability
of clinical research.
In India study design was approved by Indian council of
medical research (ICMR); and ethical guidelines was provided
by the institutional ethics committee (IECs).
This study design should be according to the regulatory
guidelines framed by the ICMR and drug controller of India.
The study design should be presented to the drug controller of India for the
approval of the investigational new drug.
Interpretation of the clinical studies should be done and it should be according
to the guidelines mentioned by ICMR committee.
The interpretation should provide the adverse effects, and any toxic reactions
that are seen with the drugs that are developed.

 Drug registration is done only after the submission of the interpretation data
,and the drug was finally released in to the market.
ICH-GCP compliance for the study design:
Drugs Controller General of India (DCI) has the prominent role in overseeing
clinical trial in India along with Ethics committee.
The DCGIs office depends on external experts and other
government agencies for advice.
Additional permissions are required for the export of blood
samples to foreign central laboratories.
The Indian Council of Medical Research (ICMR) guidelines for
clinical trials insist on the setting up of ethics committees at
the institutional levels.

The IEC (Indian Ethical Committee) responsibility is to

scrutinize and approve the clinical trial before the study begins
and also to conduct periodic reviews of the progress of the trial.
The implementation of the GATT(General Agreement on Tarif
and Trade) has opened a new opportunities for India to
concentrate on the clinical trial market.
In January 2005, India adopted a new rule that will allow
pharmaceutical companies to begin phase II and Phase III trials
concurrently with trials of the same phase conducted abroad,
thereby reducing clinical development time.
With the latest amendment (20th January 2005) to the
Schedule Y of Drugs and Cosmetic Act 1945, the reporting of
adverse events from clinical trials has become clearer and
unambiguous.
Good clinical

practice

represents

the

protection of participantsin clinical trials.

requirements

for

 It also provides the detailed requirements for investigators and

sponsors with regard to planning execution, documentation,
analysis, and reporting of studies.
The above steps are taken in order to ensure the quality and
logical consistency of data findings and conclusions.
Purpose of ICH (international conference on harmonization) :
to ensure the safety and efficacy, and most efficient, and cost
efective drugs to be produced in India.
Principles of ICH:
According to ICH clinical trials should be conducted ethically
with declaration of ICMR regulatory guidelines.
The main principles include:
1.
2.
3.
4.

Rights, safety, & well being of subjects are important.

Study must be scientifically designed.
Investigators must be qualified.
Records must be maintained for accurate reporting,

interpretation, and verification.

5. Clinical trials must meet the Good Manufacturing Practices
CLINICAL TRIALS

Clinical Research Industry has billions of dollars every year on carrying out
clinical trials for their potential products, The main survival point of the
pharmaceutical industry is innovation and for introducing grown around the world
at an unbelievable rate in the past few years. Now a days Pharmaceutical
companies spend new drugs in the market, the companies have to conduct clinical
trials as per ICH GCP guidelines as well as guidelines of the country where trial is
planned.

Definition: As per Drugs and Cosmetics Rules, 1945,"Clinical trial" means a

systematic study of new drug(s) in human subject(s) to generate data for
discovering and / or verifying the clinical, pharmacological (including
pharmacodynamic and pharmacokinetic) and /or adverse effects with the objective
of determining safety and / or efficacy of the new drug."
Clinical trials are designed to help us find out how to give a new treatment
safely and effectively to people.
A clinical trial is a tool for testing a drug, device, or technique.
Clinical trials are necessary to evaluate the medicines before they enter in to
market.
These clinical trial studies were extensively done in animals and in humans to
find out the efficacy and safety of the drug product which is to be marketed.
The following phases are involved in the clinical trials which includes:
1. Phase -I.
2. Phase -II.
3. Phase -III.
4. Phase -IV.
Phase -I: clinical trials test a new biomedical intervention in a small group of
people (e.g., 20-100) for the first time to evaluate safety (e.g., to determine a
safe dosage range and to identify side effects).
These clinical trials are developed after the investigational new drug
application is submitted.
Main purpose: The main purpose of this phase is to determine drug toxicity
profile and to assess tolerability.
In most of the cases children and pregnant women and serious primary
diseases(eg: cardiac, hepatic, renal, hematological disorders) are excluded
in this phase.

 In general patients receiving contaminant drug therapy should be excluded

(eg: malignancy therapy).
Individuals with mild but stable illness may also be included in this phase.
In general out patients are not be utilized as initial recipients of
investigational new drug in this phase.
Hospital employees and volunteers may be in some cases may be utilized as
intial recipients in this phase, since they can be under the supervision of
clinical investigator.
Generally healthy human volunteers are selected for this phase studies.
The initial dose of drug is usually low i,e one tenth of the highest no-effect
dose observed during the animal studies.
The phase-I clinical trials are designed to determine the:
1. Human pharmacology of the drug.
2. Structural activity relationship.
3. Side effects associated with increasing doses.
Qualification & investigators:
Phase -1 clinical studies are performed by investigators skilled in initial
evaluation of a variety of compounds for safety and pharmacological effect.
Where the patients with a specific disease are being studied the investigator should
be expert in treating that disease.
Procedure for carrying out of phase-I clinical trials:
The procedure involved in this phase is physical examination followed by
laboratory screening tests should be performed to screen out individual with
medical abnormalities. These tests include
1. Urine analysis.

2.
3.
4.
5.
6.

Platelet estimation.
Bun (serum creatinine).
Liver functional studies.
Post prandial blood sugar
E.C.G and other drug related tests.

Prior to administration of new drugs the subjects or patients shall not been allowed
to take the OTC drugs.
Single dose studies of phase-I:
a. The phase -I studies are desirable to begin with small group eg: 5 on a drug or 5
on a placebo for a period of 5-7 days to observe the adverse effects and will
move to the larger groups.
b. The subjects should be seen at least once daily.
c. Practical examination will be performed during and post therapy and all
laboratory examinations should be repeated at least once in week.
d. The duration of drug study will be dependent up on the nature of the drug.
e. Blood levels should be tested with single and multiple doses.
f. The subjects ability to tolerate the drug & any un pleasant effects of drug are
observed and recorded.
g. Capsules without any excipients will be used for Investigational drug studies for
the case of orally administration of drugs.
h. Phase -1 study are useful in selecting different analogues of the lead compound.
If the studies demonstrate sufficient merit and if the order
of drug toxicity is low, phase-2, a study begins.

Phase -II studies:

Subjects patients selected for early phase 2 studies should ordinarily be free
from hematologic hepatic, renal, and cardiac and other serious diseases.

Carried out relatively in small group of targeted patients.

Phase -2 studies involve controlled clinical studies to evaluate the effectiveness of
drug ,this phase involves the study of side effects and toxicity symptoms that were
not shown during animal clinical trials.
Qualifications of investigators:
Only clinical experts in the disease being treated are used as investigators in phase
-2.
Procedure:
Dose response studies are performed to determine the optimum dosage
regimen for treating the disease.
During the phase, additional data are collected on the drugs pharmacokinetic
studies were undertaken to determine dose response and dosage ranging
called phase -2a studies.
Each patient is monitored for the appearance for the drug effect while the
dose is carefully increased to determine the minimum effective dose.
Then the dose is extended beyond the minimally effective dose to the level
at which a patient reveals extremely undesirable toxic or adverse effect.
The greater the range between the dose of drug determine minimally
effective and that which causes severe side effects the greater is the drugs
safe margin, called as phase-2b studies.
If the clinical results of phase -2 indicate the safe margin for the new drugs,
these studies can be ended with the approval of FDA.
Patients should ordinarily be seen by the investigators at least for 2-4
weeks.

 Specialized safety and pharmacological lab tests are performed.

When the investigational drug is altered significantly in months, to
accommodate blood analysis studies should be performed.
Routine safety tests to be done at frequent intervals, if these tests are
satisfactory then phase -3 studies were carried out.
Phase -III studies:
These are better known trials of safety and efficacy.
Include several 100-1000 patients in controlled and uncontrolled trials.
Objective:
The objective is to determine the usefulness of drug in an expanded patient
base.
This phase includes further toxicological studies that occurring the patients
during the course of study.

Procedure:
Large scale, multi center clinical studies are performed with the final dosage
from developed in phase-2.
Many additional clinicians having patients with the condition for drugs
intended use or recruited to participate in this trial.
Several dosage strength of proposed drug may be evaluated during this stage
using formulations intended to be proposed in new drug application and in
marketing.

 Sufficient information on drugs safety & effectiveness is expected to be

gathered during phase -3 to evaluate the overall benefit risk relationship of
the drug and file a complete information of the drug.
These studies are done to determine safety and efficacy of the drug product
in large population with disease or condition for which the drug was
developed.
Finally these studies concentrate on the new toxic effects that occurred in
large group of population which were not evident in previous phases of
clinical studies.
After the phase -3 studies the New Drug Application was
submitted.
Submission of New Drug Application (NDA):
An NDA is submitted to FDA for review and approval after completion of clinical
trials that show to the satisfaction of medical community that the drug product is
effective in all parameters is reasonably safe as demonstrated by animal and human
studies.
For example : of 20 drugs entering clinical testing 13-14 will successfully
complete phase-1 trials and go on phase -2, about 9 will complete phase -2, and go
to phase -3,and only one or two will clear phase -3 and on average per year only
about 20 drugs will ultimately be approved for marketing

NUMBER OF
S.NO

PATIENTS

LENGTH

PURPOSE

OF

DRUG

SUCESSFULLY
COMPLEETING

Phase -1

20-100

Several months

Mainly safety

67

Some term safety

Phase -2

Up to 100

Several months to 2 years

& mainly efficacy

45

Safety
Phase -3

100-1000

1-4 years

effectiveness and

5-10

dosage

Phase IV:
After the NDA is submitted and before approval to market the product is
obtained approval from FDA, manufacturing scale up activities occur.
Scale up is the increase in the batch size from the clinical batch, the submission
batch or both, up to the full scale production batch size using finished market
production.
The drug formulation may be modified slightly as a result of data obtained
during the manufacture scale up and validation process.
US-FDA approved drugs during recent years;
YEAR
2001
2002
2003
2004
2005
2006
2007
2008

TOTAL DRUS APPROVED

24
17
21
31
03
10
19
12

E.g. Some of the US-FDA drugs approved drugs for HIV and its complications;
APPROVED DRUG

TREATMENT FOR CONDITION

Alitertinoin

Cutaneous lesions in aids patients related to

kaposis sarcoma

Atazanavir

HIV-1

Dronabinol

For stimulation of apetite and to prevent loss of

Immunoglobulins

weight in AIDS patients

Infection prophylaxis in pediatric patients
effected with HIV.

Interferon ALFA-2a

AIDS related kaposis sarcoma.

Interferon ALFA-2a

AIDS related kaposis sarcoma.

Paclitaxel

AIDS related kaposis sarcoma.

After the FDA grants market approval of the drug, the product development

may continue.
The drug product may be improved as a result of market demands, supply, and
regulatory factors.
Some time the approved drugs are banned due to the unwanted side effects.
e.g. Analgin (for blood disorder), Rofecoxib (cardio vascular disease).
In such banned cases these use should be discouraged.

DRUG

INDICATION

CAUSE FOR BAN

Analgin

Analgesic

Bone marrow depression

Cisapride

Acidity, constipation ,GERD

Irregular heart beats

Furazolidine

Anti-diarrhoeal

Carcinogenic

Nimesulide

Pain killer, fever

Hepatotoxic

Piperazine

Anthelmenthic

Causes nerve damage

Nitro furantoin

Anti-bacterial cream

carcinogenic

DESIGN DOCUMENTATION OF CLINICAL DATA:

Factors such as age, sex disease state, food habits, Time of sample to be
administered are to be considered in study design documentation.

 The design includes:

1. Experimental design.
2. Study population.
3. Sample size and dropouts.
1. EXPERIMENTAL DESIGN:
This design includes the following sub divisions;
a. Replicated cross over design.
b. Non-replicated design.
A. Replicated cross over design.
This design is recommended when an individual bioequivalence is used to
allow the estimation of in various measurements following the four period, twosequence and two-formulation method.
For this design lots of T & R (test and reference), formulations should be used
for repeated administrations which should be separated by proper wash out
period.
The Three period design can be tabulated as follows

SEQUENCE

1
2

1
T
R

PERIOD
2
R
T

3
T
R

A greater number of subjects are tested in this type of design to obtain the efficacy
of the new drug.
B. Non-replicated design:
A conventional study design such as the standard two formulation , two-period,
two-sequence cross over design used for bio-equivalence comparision.

Here an average number of populations are used.

2. STUDY POPULATION: Unless otherwise indicated by a specific guidance

recruited for in-vivo bio equivalence studies should be 18 years, or elder and
capable of giving informed consent.
An attempt should be made to enter an heterogeneous a study population as
possible, with a reasonable balance of males and females, young and elderly
and subjects of different racial groups.
Restrictions to entry in to studies should be based solely on safety
considerations.
In some studies, it may be useful to recruit patients for whom the drug product
is intended.
In this situation sponsors/applicants should attempt to enter the patients whose
disease process is stable for the duration of the study.
IND (investigational new drug) may be required for some studies to ensure
safety of patients.
3. SAMPLE SIZE AND DROP-OUTS:

A minimum number of 12 subjects should be included in any study.

Number of subjects for this studies are based on either the population or
individual bio-equivalence approach should be estimated by stimulation,
because analytical methods/approaches for estimation are not available
Sponsors should provide a sufficient number of subjects in the study, to allow
for drop-outs, because replacement of subjects during the study could help in
the statistical model and analysis.
Sponsors who wish to replace the drop-outs during the study should be done
according to the protocol.
Additional subjects will not be allowed to enter in to the study, as it will affect
the analysis of the total study design.

PRESENTATION OF CLINICAL DATA:

The obtained data from the clinical study can be presented in the following
manner;
The drug concentration in biological fluid determined at each sampling time
should be furnished on the original scales for participating in the study.
The derived pharmacokinetic measures should also be furnished on the
original scale.
The mean, standard deviation, and co-efficient of variance for each variable
should be calculated and tabulated in the final report
In addition to the arithmetic mean and standard deviation (or co-efficient of
variance) for TEST AND REFERENCE products; and geometric means
should also be included.
The measures taken for the test subjects should be displayed in parallel with
the data obtained in their study.
The ratio of individual geometric mean of the test product to the individual
geometric mean of reference product should be tabulated side by side for
each subject.
The presentation of the clinical data should be done according to the
regulatory agencies concerned

INTERPREATION OF CLINICAL DATA:

OBJECTIVES:
To explain differences in approaches to safety data and efficacy data.
To demonstrate that adequate attention needs to be given to the assessment,
analysis, and reporting of adverse events to permit valid assessment of
potential risks of intervention.
To highlight the distinctions between rare, serious adverse events and
common, non-serious adverse events

 To define terms commonly used in the description of adverse events.

To explain methods by which causality for adverse events can be assessed.
The interpreted data should be stored in online services, and it should be
available during audits that were conducted by the regulatory agencies.
The interpretation of clinical data must also includes the total study details
that was conducted, which includes the adverse reaction of drugs, and
toxicological studies e.tc.
STATISTICAL ANALYSIS OF CLINICAL DATA
The experimental results of clinical studies can be analyzed in many ways; one of
the simplest method of analysis of clinical data is by statistical analysis method.
STATISTICAL ANALYSIS:
Statistical Analyses to be used must be clearly identified and should form basis
of the statistical model for the clinical Study.
Before 1970s clinical data was determined based only on the values of c max
values for the generic product; which should be within + or 20% of those
reference products.
During recent years FDA requires the confidence limits to the mean data , using
an analysis known as the two/one sided test procedure.
The test formulation was considered to be bio equivalent to the reference only
if
AUCtest
0.8
<

AUCref

Cmax of test

< 1.2

and

0.8
<

Cmax of ref

< 1.2

By this procedure if the test and the reference products are not bio-equivalent
they will differ by 20-25% in both AUC and in Cmax results.

 The generic manufacturer should carry out the tests at least to 90% confidence
for providing the values regarding the mean responses of the products that
should be within limits of
0.8-1.5.
Since these tests are carried out at 0.05 level of significance these can be
reliable.
In some cases the value or range (20-25%) can be given up to 30%. E.g. Antipsychotics.
Any subsequent deviation(s) should be described and justified in the Final
Report.
Results of the statistical analyses should be presented in a manner that is likely
to facilitate the interpretation of their clinical data.
FACTORIAL DESIGNS:
Factorial designs are used in experiments where the effects of different factors
or conditions on experimental results are to be elucidated.
Some practical examples where factorial designs are used are; experiments to
determine the effect of pressure and lubricant on the hardness of table
formulation, to determine the effect of disintegrant and lubricant concentration
on tablet dissolution.
Factorial designs are the choice for the simultaneous determination of several
factors and their interactions.
Definitions:
1.FACTOR:

A factor is an assigned variable such as concentration, temperature,

lubricating agent, drug treatment or diet.
The choice of factors to be included in experiment depends up on experimental
objectives.
A factor may be qualitative or quantitative.

 Quantitative factor has numerical value assigned to it, e.g the factor
concentration may be given the values 1%,2%,3% and examples of qualitative
factors are treatment, diet, batches of materials, tablet diluents.
Qualitative factors are assigned names rather than numbers.
LEVELS:
The levels of a factor are the values or designations assigned to the factor.
Examples of levels 300 and 500 for the factor temperature, 0.1 molar and 0.3
molar for the factor concentration, drug and placebo for the factor drug
treatment.
The trials that comprise factorial experiments consists of all combinations of all
levels of all factors. As an example two factor experiment would be appropriate
for the investigation of effects of drug concentration on the tablet. If both
factors were at two levels four runs would be required as follows:
SYMBOL

FORMULATION

Low drug and low lubricant concentration

Low drug and high lubricant concentration

high drug and low lubricant concentration

ab

high drug and high lubricant concentration

Here low and high refers to the factor concentration

Advantages of factorial designs:

 In the absence of interaction, factorial designs have maximum efficacy in

estimating the drug effects.
If interaction exists factorial designs are necessary to reveal and identify the
interactions.
Since factor effects are measured over varying levels of other factors,
conclusions apply to a wide range of conditions.
Maximum use is made of the data since all main effects and interactions are
calculated from all of the data.
Factorial designs are orthogonal, all estimated effects and interactions are
independent of effects of others.
For example the result obtained is only due to main effect of interest and is not
influenced by any other factors.
A simple factorial design helps in revealing the difference in action of drugs
which are tested in different locations. For e.g. if the tests performed on the
patients of Newyork and the patients of los angels give different results,
factorial design will reveal the causes for the differences such as climatic
conditions, body nature e.t.c.
Thus the factorial designs are useful in the estimation of different factors or
conditions on experiment result.