This document provides an overview of ICH guidelines E9 through E12, which provide statistical and clinical trial design guidance. E9 discusses statistical principles for clinical trials, including trial context, scope, design techniques to avoid bias, sample size considerations, and data analysis. E10 covers choice of control groups in clinical trials and describes placebo, no treatment, dose-response, and active controls. E11 provides guidance for clinical trials in pediatric patients, including issues around timing, formulations, study types, age classifications, and ethical considerations. E12 relates to clinical evaluation by therapeutic category.

1. O V E R V I E W O F I C H E 9 – E 1 2 G U I D E L I N E S
ICH Guidelines
Submitted to: Mrs. Azka
Submitted by: Khushboo
M. Pharm (DRA)
2nd sem.
A10651916010

2. E9 : Statistical Principles for Clinical Trials
E10: Choice of Control Group in Clinical Trials
E11: Clinical Trials in Pediatric population
E12: Clinical Evaluation by Therapeutic Category

3. E9- Statistical Principles for Clinical Trials
A. INTRODUCTION:
 The efficacy and safety of medicinal products should be
demonstrated by clinical trials which follow the guidance in
'Good Clinical Practice: Consolidated Guideline' (ICH E6)
adopted by the ICH, 1 May 1996.
 This guidance is written primarily to attempt to harmonise
the principles of statistical methodology applied to clinical
trials for marketing applications submitted in Europe,
Japan and the United States.
 Some topics related to statistical principles and
methodology are also embedded within other ICH
guidelines. The specific guidance that contains related text
will be identified in various sections of this document.

4. i. SCOPE AND DIRECTION:
•The focus of this guidance is on statistical principles. Selected
principles and procedures related to data management or
clinical trial monitoring activities are covered in other ICH
guidelines and are not addressed here.
•This guidance should be of interest to individuals from a broad
range of scientific disciplines .
•The trial statistician should have a combination of
education/training and experience sufficient to implement the
principles articulated in this guidance.
•The principles outlined in this guidance are primarily relevant
to clinical trials conducted in the later phases of development,
many of which are confirmatory trials of efficacy.
•Many of the principles delineated in this guidance deal with
minimizing bias (see Glossary) and maximizing precision.

5. ii. CONSIDERATIONS FOR OVERALL CLINICAL
DEVELOPMENT:
TRIAL CONTEXT
1) Development plan:
The broad aim of the process of clinical development of a
new drug is to find out whether there is a dose range and
schedule at which the drug can be shown to be
simultaneously safe and effective, to the extent that the
risk-benefit relationship is acceptable.
2) Confirmatory trial:
A confirmatory trial is an adequately controlled trial in
which the hypotheses are stated in advance and
evaluated. As a rule, confirmatory trials are necessary to
provide firm evidence of efficacy or safety .

6. 3)Exploratory trial:
The rationale and design of confirmatory trials nearly always
rests on earlier clinical work carried out in a series of
exploratory studies. Like all clinical trials, these exploratory
studies should have clear and precise objectives. In
exploratory trials may sometimes require a more flexible
approach to design so that changes can be made in response
to accumulating results.

7. SCOPE OF TRIALS:
1) Population:
In the earlier phases of drug development the choice of
subjects for a clinical trial may be heavily influenced by
the wish to maximize the chance of observing specific
clinical effects of interest.
2) Primary and secondary variables:
 The primary variable should be the variable capable of
providing the most clinically relevant and convincing
evidence directly related to the primary objective of the
trial. There should generally be only one primary variable.
 Secondary variables are either supportive measurements
related to the primary objective or measurements of
effects related to the secondary objectives. The number of
secondary variables should be limited and should be
related to the limited number of questions to be answered
in the trial.

8. 3) Composite variables:
If a single primary variable cannot be selected from
multiple measurements associated with the primary
objective, another useful strategy is to integrate or
combine the multiple measurements into a single or
'composite' variable, using a pre-defined algorithm.
4) Global assessment variables:
In some cases, 'global assessment' variables (see
Glossary) are developed to measure the overall safety,
overall efficacy, and/or overall usefulness of a
treatment. Global assessment variables generally have a
subjective component. Global assessment of usefulness
integrates components of both benefit and risk and
reflects the decision making process of the treating
physician, who must weigh benefit and risk in making
product use decisions.

9. 5) Multiple primary variables:
It may sometimes be desirable to use more than one primary
variable, each of which (or a subset of which) could be
sufficient to cover the range of effects of the therapies.
6) Surrogate variables:
When direct assessment of the clinical benefit to the subject
through observing actual clinical efficacy is not practical,
indirect criteria may be considered.
7) Categorized variables:
Categorization of continuous or ordinal variables may
sometimes be desirable. Categorizations are most useful when
they have clear clinical relevance.

10. DESIGN TECHNIQUES TO AVOID BIAS:
The most important design techniques for avoiding bias in
clinical trials are blinding and randomization.
1) Blinding:
Blinding or masking is intended to limit the occurrence
of conscious and unconscious bias in the conduct and
interpretation of a clinical trial. The essential aim is to
prevent identification of the treatments until all such
opportunities for bias have passed.
2) Randomization:
Randomization introduces a deliberate element of
chance into the assignment of treatments to subjects in a
clinical trial. During subsequent analysis of the trial
data, it provides a sound statistical basis for the
quantitative evaluation of the evidence relating to
treatment effects.

11. iii. TRIAL DESIGN CONSIDERATION:
A. Design Configurations:
1) Parallel group design
2) Crossover design
3) Factorial design
B. Multicentre trials:
Multicentre trials are carried out for two main reasons.
Firstly, a multicentre trial is an accepted way of evaluating
a new medication more efficiently; under some
circumstances, it may present the only practical means of
accruing sufficient subjects to satisfy the trial objective
within a reasonable time-frame.
C. Types of comparison:
1) Trials to show superiority
2) Trials to show equivalence or non-inferiority
3) Trials to show dose-response relationship

12. GROUP SEQUENTIAL DESIGNS:
Group sequential designs are used to facilitate the conduct of
interim analysis.
SAMPLE SIZE:
The number of subjects in a clinical trial should always be
large enough to provide a reliable answer to the questions
addressed.

13. iv. TRIAL CONDUCT CONSIDERATIONS:
Trial monitoring and interim analysis
Changes in inclusion and exclusion criteria
Accrual rates
Sample size adjustment
Interim analysis and early stopping
Role of independent data monitoring committee (IDMC)

14. v. DATA ANALYSIS CONSIDERATIONS:
Prespecification of the analysis
Analysis set:
--Full analysis set
--Per protocol set
--Roles of different analysis set
Missing values and outliers
Data transformation
Estimation, confidence intervals and hypothesis testing
Adjustment of significance and confidence levels
subgroups, interactions and covariates
Integrity of data and computer software validity

15. vi. EVALUATION OF SAFETY AND TOLERABILITY:
•Scope evaluation
•Choice of variables and data collection
•Set of subjects to be evaluated and presentation of data
•Statistical evaluation
•Integrated summary

16. vii. REPORTING:
Evaluation and reporting
Summarizing the clinical database
Efficacy data
Safety data

17. E10- Choice of Control Group in Clinical
Trials
A. INTRODUCTION:
The choice of control group is always a critical decision in designing a
clinical trial. That choice affects the inferences that can be drawn from
the trial, the ethical acceptability of the trial, the degree to which bias in
conducting and analyzing the study can be minimized, the kind of
endpoints that can be studied, the acceptability of the results by
regulatory authorities, and many other features of the study, its
conduct, and its interpretation.

18. B.PURPOSE OF GUIDELINE:
 The purpose of this guideline is to describe the general principles
involved in choosing a control group for clinical trials intended to
demonstrate the efficacy of a treatment and to discuss related trial
design and conduct issues.
 The choice of the control group should be considered in the context of
available standard therapies, the adequacy of the evidence to support
the chosen design, and ethical considerations.
 The guideline then describes trials using each kind of control group in
more detail and considers, for each:
 Its ability to minimize bias
 Ethical and practical issues associated with its use
 Its usefulness and the quality of inference in particular situations
 Modifications of study design or combinations with other controls that
can resolve ethical, practical, or inferential concerns
 Its overall advantages and disadvantages

19. C.PURPOSE OF CONTROL GROUP:
 Control groups have one major purpose: to allow discrimination of
patient outcomes caused by the test treatment from outcomes caused
by other factors, such as the natural progression of the disease,
observer or patient expectations, or other treatment.
 A concurrent control group is one chosen from the same population as
the test group and treated in a defined way as part of the same trial that
studies the test treatment, and over the same period of time.
 The test and control groups should be similar with regard to all baseline
and on-treatment variables that could influence outcome, except for the
study treatment.
 Failure to achieve this similarity can introduce a bias into the study.
Bias here (and as used in ICH E9) means the systematic tendency of
any aspects of the design, conduct, analysis, and interpretation of the
results of clinical trials to make the estimate of a treatment effect
deviate from its true value.

20.  Randomization and blinding are the two techniques usually used to
minimize the chance of such bias and to ensure that the test treatment and
control groups are similar at the start of the study and are treated similarly
in the course of the study (see ICH E9).
 RANDOMIZATION:
 Assurance that subject populations are similar in test and control groups is
best attained by randomly dividing a single sample population into groups
that receive the test or control treatments.
 Randomization avoids systematic differences between groups with respect
to known or unknown baseline variables that could affect outcome.
Randomization also provides a sound basis for statistical inference.
 BLINDING:
 The groups should not only be similar at baseline, but should be treated
and observed similarly during the trial, except for receiving the test and
control drug.
 Clinical trials are often double blinded.

21.  Blinding is intended to minimize the potential biases resulting from
differences in management, treatment, or assessment of patients, or
interpretation of results that could arise as a result of subject or
investigator knowledge of the assigned treatment.
D.TYPES OF CONTROLS:
Control groups in clinical trials can be classified on the basis of two
critical attributes:
(1) the type of treatment used and
(2) the method of determining who will be in the
The type of control treatment may be any of the following four:
1) placebo,
2) no treatment,
3) different dose or regimen of the study treatment, or
4) a different active treatment.

22. PLACEBO CONCURRENT CONTROL:
 In a placebo-controlled trial, subjects are randomly assigned to a test
treatment or to an identical-appearing treatment that does not contain
the test drug.
 Such trials are almost always double-blind.
 Placebo-controlled trials seek to show a difference between treatments
when they are studying effectiveness, but may also seek to show lack of
difference (of specified size) in evaluating a safety measurement.
NO-TREATMENT CONCURRENT CONTROL:
 In a no treatment-controlled trial, subjects are randomly assigned to
test treatment or to no (i.e., absence of) study treatment.
 The principal difference between this design and a placebo-controlled
trial is that subjects and investigators are not blind to treatment
assignment.
DOSE-RESPONSE CONCURRENT CONTROL:
 In a randomized, fixed-dose, dose-response trial, subjects are
randomized to one of several fixed-dose groups.
 Dose-response trials are usually double-blind. They may include a
placebo (zero dose) and/or active control.

23. MULTIPLE CONTROL GROUPS:
 It is often possible and advantageous to use more than one kind of
control in a single study, e.g., use of both an active control and placebo.
 Similarly, trials can use several doses of test drug and several doses of
an active control, with or without placebo.
E.PURPOSES OF CLINICAL TRIALS AND RELATED
ISSUES:
Purposes of clinical trials should be distinguished:
(1) assessment of the efficacy and/or safety of a treatment and
(2) assessment of the relative (comparative) efficacy, safety, risk/benefit
relationship or utility of two treatments.
(3) Fairness of comparisons
 Dose
 Patient population
 Selection and timing of end points

24. E.ASSAY SENSTIVITY:
 Assay sensitivity is a property of a clinical trial defined as the ability to
distinguish an effective treatment from a less effective or ineffective
treatment.
 Assay sensitivity is important in any trial but has different implications
for trials intended to show differences between treatments (superiority
trials) and trials intended to show non-inferiority.
 If a trial intended to demonstrate efficacy by showing superiority of a
test treatment to control lacks assay sensitivity, it will fail to show that
the test treatment is superior and will fail to lead to a conclusion of
efficacy.

25. E11: CLINICAL TRIALS IN PEDIATRIC PATIENTS
i. GENERAL PRINCIPLE:
 Pediatric patients should be given medicines that have
been appropriately evaluated for their use.
 Obtaining knowledge of the effects of medicinal products
in pediatric patients is an important goal.

26. ii. GUIDANCE
1. ISSUES WHEN INITIATING A PEDIATRIC MEDICINAL
PRODUCT DEVELOPMENT PROGRAM:
• Data on the appropriate use of medicinal products in the pediatric population
should be generated unless the use of a specific medicinal product in pediatric
patients is clearly inappropriate.
• The decision to proceed with a pediatric development program for a
medicinal product, and the nature of that program, involve consideration of
many factors
 The prevalence of the condition to be treated in the pediatric population
 The seriousness of the condition to be treated .
 The availability and suitability of alternative treatments for the condition in
the pediatric population, including the efficacy and the adverse event profile
of those treatments.
 Whether there are unique pediatric indications for the medicinal product
 The need for the development of pediatric-specific endpoints
 The age ranges of pediatric patients likely to be treated with the medicinal
product.
 Unique pediatric (developmental) safety concerns with the medicinal product,
including any nonclinical safety issues.

27. 2. PEDIATRIC FORMULATIONS:
There is a need for pediatric formulations that permit accurate dosing and
enhance patient compliance. For oral administration, different types of
formulations, flavors and colors may be more acceptable in one region
than another. Several formulations, such as liquids, suspensions, and
chewable tablets, may be needed or desirable for pediatric patients of
different age.
3.TIMING OF STUDIES:
During clinical development, the timing of pediatric studies will depend
on the medicinal product, the type of disease being treated, safety
considerations, and the efficacy and safety of alternative treatments.
•Medicinal Products for Diseases Predominantly or Exclusively Affecting
Pediatric Patients
•Medicinal Products Intended to Treat Serious or Life-Threatening
Diseases, Occurring in Both Adults and Pediatric Patients, for Which
There Are Currently No or Limited Therapeutic Options.
•Medicinal Products Intended to Treat Other Diseases and Conditions

28. 4. TYPE OF STUDIES:
The principles outlined in ICH E4, E5, E6, and E10 apply to pediatric
studies. When a medicinal product is studied in pediatric patients in one
region, the intrinsic and extrinsic factors that could impact on the
extrapolation of data to other regions should be considered.
•Pharmacokinetics: Pharmacokinetic studies generally should be
performed to support formulation development and determine
pharmacokinetic parameters in different age groups to support dosing
recommendations.
•Efficacy: The principles in study design, statistical considerations and
choice of control groups detailed in ICH E6, E9, and E10 generally apply
to pediatric efficacy studies.
•Safety: ICH guidances on E2 topics and ICH E6, which describe adverse
event reporting, apply to pediatric studies.
•Post- marketing information: Normally the pediatric database is limited
at the time of approval. Therefore, post-marketing surveillance is
particularly important.

29. 5. AGE CLASSIFICATION OF PEDIATRIC PATIENTS:
Any classification of the pediatric population into age categories is to
some extent arbitrary, but a classification such as the one below provides
a basis for thinking about study design in pediatric patients. Ages are
defined in completed days, months, or years:
•Preterm newborn infants
•Term newborn infants (0 to 27 days)
•Infants and toddlers (28 days to 23 months)
•Children (2 to 11 years)
•Adolescents (12 to 16-18 years (dependent on region))
6. ETHICAL ISSUES IN PEDIATRIC STUDIES:
The purpose of this section is to provide a framework to ensure that
pediatric studies are conducted ethically .
•Institutional review board /Independent Ethics committee (IRB/IEC)
•Recruitment
•Consent and assent
•Minimizing risk
•Minimizing distress

30. E12: CLINICAL EVALUATION BY THERAPUTIC
CATEGORY
1.GENERAL PRINCIPLES FOR THE ASSESSMENT OF
EFFICACY:
 The primary basis of assessment of efficacy of antihypertensive drugs is
the effect of the drug on systolic and diastolic blood pressures. In the
past the primary endpoint of most studies was diastolic blood pressure.
2.STUDY POPULATION:
 The patient population studied with a new antihypertensive should
include a broad range of patients with essential hypertension. Most
patients will be in the mild to moderate range.

31. 3.ASSESSMENT OF ANTIHYPERTENSIVE EFFECT:
Studies to assess antihypertensive effect
Pharmacodynamic studies
Dose response relationship
Comparison with standard therapy
4. ASSESSMENT OF SAFETY:
ICH E1 suggests that a database of about 1500 patients (300-600 for 6
months, 100 for 1 year) is usually sufficient for chronically administered
drugs, but as suggested in that guideline, this may be too small for the
very long, very wide exposure in an asymptomatic population intended
for antihypertensive drugs.
5.CO-ADMINISTRATION WITH OTHER
ANTIHYPERTENSIVES:
As antihypertensive treatments are often used in combination, it is
important to study the efficacy and safety of the new drug in this
situation. Information on combination use can be obtained in formal
factorial studies and in combined use in the course of long- and short-
term clinical studies.

32. 6.FIXED COMBINATION PRODUCTS:
There are two approaches to the combination studies needed to obtain
safety and efficacy data to support fixed combination products. It is
essential to consult with regional regulatory authorities regarding the
specific data needed to support the specific indications.
•Factorial study.
•Studies in Non-responders to each drug.

33. THANK YOU