ICH-E9 - Statistical Principles

Question 1

What does the term bias mean?

Answer 1

the term ‘bias’
describes the systematic tendency of any factors associated with the design, conduct,
analysis and interpretation of the results of clinical trials to make the estimate of a
treatment effect (see Glossary) deviate from its true value

Question 2

in ICH E9 many of the principles delineated in this guidance deal with minimising bias and maximising precision. True or False?

Answer 2

true

Question 3

The presence of bias may seriously compromise the ability to draw _______ ______ from clinical trials.

Answer 3

valid conclusions

Question 4

What is the concept of robustness?

Answer 4

Robustness is a concept that refers to the sensitivity of the overall conclusions to various limitations of the
data, assumptions, and analytic approaches to data analysis.

Question 5

What does robustness in data imply?

Answer 5

Robustness implies that the treatment effect and primary conclusions of the trial are not substantially affected when analyses are carried out based on alternative assumptions or analytic
approaches.

Question 6

A ________ _____ is an adequately controlled trial in which the hypotheses are stated in advance and evaluated. As a rule, ______ are necessary to
provide firm evidence of efficacy or safety. In such trials the key hypothesis of interest follows directly from the trial’s primary objective, is always pre-defined, and is the hypothesis that is subsequently tested when the trial is complete. In a ______ trial it is equally important to estimate with due precision the size of the effects attributable to the treatment of interest and to relate these effects to their clinical significance.

Answer 6

confirmatory trial (every word with a ____is confirmatory

Question 7

Confirmatory trials are intended to provide firm evidence in support of claims and hence adherence to ______ and ______ is particularly important; unavoidable changes should be explained and documented, and their effect
examined. A justification of the design of each such trial, and of other important statistical aspects such as the principal features of the planned analysis, should be set out in the protocol. Each trial should address only a limited number of questions

A. protocols and SOPS
b. protocol and IC
c protocol and IB
d. all of the above

Answer 7

A. protocols and sops

Question 8

Firm evidence in support of claims requires that the results of the confirmatory trials demonstrate that the investigational product under test has clinical benefits. The confirmatory trials should therefore be sufficient to answer each key clinical question relevant to the efficacy or safety claim clearly and definitively. In addition, it is important that the basis for generalisation (see Glossary) to the intended patient population is understood and explained; this may also influence the number and type (e.g. specialist or general practitioner) of centres and/or trials needed. The results of
the confirmatory trial(s) should be robust. In some circumstances the weight of evidence from a single confirmatory trial may be sufficient.

Answer 8

Just read it and study it

Question 9

The rationale and design of ______ trials nearly always rests on earlier clinical work carried out in a series of ________studies.

Answer 9

confirmatory

exploratory

Question 10

What type of trial objectives may not always lead to simple tests of pre-defined hypotheses.?

Answer 10

Exploratory

Question 11

True or False?

exploratory trials can be the basis of the
formal proof of efficacy, although they may not contribute to the total body of relevant
evidence.

Answer 11

False. Such trials cannot be the basis of the
formal proof of efficacy, although they may contribute to the total body of relevant
evidence.

Question 12

what type of trial is it best to relax the inclusion and exclusion criteria within the target population of the drug while maintaining sufficient homogenieity to permit precise estimation of representative of future users.

Answer 12

Confirmatory

Question 13

What is a primary variable (endpoint)?

Answer 13

The primary variable (‘target’ variable, primary endpoint) 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. This will usually be an efficacy variable, because the primary objective of most confirmatory trials is to provide strong scientific evidence regarding
efficacy.

may need to read more on ICH. Page 5.

Question 14

define composite variable

Answer 14

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 predefined algorithm.

Question 15

When using a composite variable does the method of combining the multiple measurements need to be specified in the protocol, and an interpretation of the
resulting scale should be provided in terms of the size of a clinically relevant benefit?

Answer 15

Yes

Question 16

True or False?
When a composite variable is used as a primary variable, the components of this variable may sometimes be analysed separately

Answer 16

True

Question 17

In a composite variable when a rating scale is used a primary variable what factors are important to address:

Answer 17

content validity (see Glossary), inter- and intra-rater
reliability (see Glossary) and responsiveness for detecting changes in the severity of disease.

Question 18

What is a global assessment variable?

Answer 18

‘global assessment’ variables (see Glossary) are developed to measure the overall safety, overall efficacy, and/or overall usefulness of a treatment. This type of variable integrates objective variables and the investigator’s overall impression about the state or change in the state of the subject, and is usually a scale of ordered categorical ratings.

Question 19

Global assessments of overall _________ are well established in some therapeutic areas, such as neurology and psychiatry.

Answer 19

efficacy

Question 20

Are gloabal assessment variables have a subjective component?

T/F?

Answer 20

True

Question 21

When a global assessment variable is used as a primary or secondary variable, fuller details of the
scale should be included in the protocol with respect to:

Answer 21

1) the relevance of the scale to the primary objective of the trial;
2) the basis for the validity and reliability of the scale;
3) how to utilise the data collected on an individual subject to assign him/her to a unique category of the scale;
4) how to assign subjects with missing data to a unique category of the scale, or otherwise evaluate them.

Question 22

Global assessment of usefulness integrates components of both

Answer 22

benefit and risk and reflects the decision making process of the treating physician, who must weigh benefit and risk in making product use decisions

Question 23

problem with global usefulness variables is that their use could in some cases lead to the result of two products being declared __________ despite having very different profiles of beneficial and adverse effects

Answer 23

equivalent

**For example, judging the global usefulness of a treatment as equivalent or superior to an alternative may mask the fact that it has little or no efficacy but fewer adverse effects. Therefore it is not advisable to use a global usefulness variable as a primary variable.
If global usefulness is specified as primary, it is important to consider specific efficacy and safety outcomes separately as additional primary variables

Question 24

Define Multiple Primary Variables

Answer 24

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. The planned manner of interpretation of this type of evidence should be carefully spelled out.

Question 25

Define Surrogate Variables

Answer 25

When direct assessment of the clinical benefit to the subject through observing actual
clinical efficacy is not practical, indirect criteria (surrogate variables - see Glossary)
may be considered. Commonly accepted surrogate variables are used in a number of
indications where they are believed to be reliable predictors of clinical benefit.

Question 26

Define Categorised Variables

Answer 26

Dichotomisation or other categorisation of continuous or ordinal variables may sometimes be desirable. Criteria of 'success' and 'response' are common examples of dichotomies which require precise specification in terms of, for example, a minimum
percentage improvement (relative to baseline) in a continuous variable, or a ranking categorised as at or above some threshold level (e.g., 'good') on an ordinal rating scale

The reduction of diastolic blood pressure below 90mmHg is a common dichotomisation. Categorisations are most useful when they have clear clinical relevance. The criteria for categorisation should be pre-defined and specified in the protocol, as knowledge of trial results could easily bias the choice of such criteria. Because categorisation normally implies a loss of information, a consequence will be a
loss of power in the analysis; this should be accounted for in the sample size calculation.

Question 27

What are two principle concerns with any proposed surrogate variables?

Answer 27

First, it may not be a true predictor of the clinical outcome of interest. For example it may measure treatment activity associated with one specific pharmacological mechanism, but may not provide full information on the range of actions and ultimate
effects of the treatment, whether positive or negative. There have been many instances where treatments showing a highly positive effect on a proposed surrogate have ultimately been shown to be detrimental to the subjects’ clinical outcome; conversely, there are cases of treatments conferring clinical benefit without measurable impact on proposed surrogates.

Secondly, proposed surrogate variables
may not yield a quantitative measure of clinical benefit that can be weighed directly against adverse effects. Statistical criteria for validating surrogate variables have been proposed but the experience with their use is relatively limited. In practice, the
strength of the evidence for surrogacy depends upon (i) the biological plausibility of the relationship, (ii) the demonstration in epidemiological studies of the prognostic value of the surrogate for the clinical outcome and (iii) evidence from clinical trials
that treatment effects on the surrogate correspond to effects on the clinical outcome. Relationships between clinical and surrogate variables for one product do not
necessarily apply to a product with a different mode of action for treating the same
disease.

Question 28

What are two of the most importnat Design Techniques to Avoid Bias?

Answer 28

blinding and randomisation, and these should be normal features of most controlled clinical
trials intended to be included in a marketing application.

Question 29

Most such trials follow a _____ approach in which treatments are pre-packed in accordance with a
suitable randomisation schedule, and supplied to the trial centre(s) labelled only with the subject number and the treatment period so that no one involved in the conduct of the trial is aware of the specific treatment allocated to any particular subject, not even as a code letter.

Answer 29

double-blind

Question 30

What are all the variable types in a study:

Answer 30

Primary and Secondary Variables
Composite Variables
Global Assessment Variables
Multiple Primary Variables
Surrogate Variables
Categorised Variables

Question 31

What is blinding?

Answer 31

Blinding or masking is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from the influence which the knowledge of treatment may have on the recruitment and allocation of subjects, their subsequent care, the attitudes of subjects to the treatments, the assessment of end-points, the handling of withdrawals, the exclusion of data from
analysis, and so on. The essential aim is to prevent identification of the treatments until all such opportunities for bias have passed.

Question 32

What is a double blind trial?

Answer 32

A double-blind trial is one in which neither the subject nor any of the investigator or sponsor staff who are involved in the treatment or clinical evaluation of the subjects are aware of the treatment received. This includes anyone determining subject eligibility, evaluating endpoints, or assessing compliance with the protocol. This level of blinding is maintained throughout the conduct of the trial, and only when the data are cleaned to an acceptable level of quality will appropriate personnel be unblinded.

Question 33

What are the differences between

single blind trials
Open-Label Trials

Answer 33

In a single-blind trial the investigator and/or his
staff are aware of the treatment but the subject is not, or vice versa.

In an open-label trial the identity of treatment is known to all. The double-blind trial is the optimal approach. This requires that the treatments to be applied during the trial cannot be distinguished (appearance, taste, etc.) either before or during administration, and that the blind is maintained appropriately during the whole trial.

Question 34

What is a double dummy technique?

Answer 34

A technique for retaining the blind when administering supplies in a clinical trial, when the two treatments cannot be made identical. Supplies are prepared for
Treatment A (active and indistinguishable placebo) and for Treatment B (active and indistinguishable placebo). Subjects then take two sets of treatment; either A (active) and B (placebo), or A (placebo) and B (active).

Question 35

Whats it important for an investigator to do in an open label and single blind trial?

Answer 35

important that the investigator’s knowledge of the next treatment should not influence the decision to enter the subject; this decision should precede knowledge of the randomised treatment.

Question 36

When is breaking the blind for a single subject ok?

Answer 36

Breaking the blind (for a single subject) should be considered only when knowledge of
the treatment assignment is deemed essential by the subject’s physician for the subject’s care. Any intentional or unintentional breaking of the blind should be reported and explained at the end of the trial, irrespective of the reason for its occurrence. The procedure and timing for revealing the treatment assignments should be documented.

Question 37

What does randomization introduce?

Answer 37

Randomisation introduces a deliberate element of chance into the assignment of treatments to subjects in a clinical trial

Question 38

T/F:

randomisation helps to avoid possible bias in the selection and allocation of subjects arising from the predictability of treatment assignments.

Answer 38

True

Question 39

What does randomization produce in treatment groups?

Answer 39

It also tends to produce treatment groups in which the
distributions of prognostic factors, known and unknown, are similar. In combination with blinding, randomisation helps to avoid possible bias in the selection and allocation of subjects arising from the predictability of treatment assignments.

Question 40

Although unrestricted randomisation is an acceptable approach, some advantages can generally be gained by randomising subjects in blocks–What are they?

Answer 40

This helps to increase the comparability of the treatment groups, particularly when subject characteristics may change over time, as a result, for example, of changes in recruitment policy. It also
provides a better guarantee that the treatment groups will be of nearly equal size. In crossover trials it provides the means of obtaining balanced designs with their greater efficiency and easier interpretation.

Question 41

When it comes to randomization, should Investigators and other relevant staff generally should be blind to the block length?

Answer 41

Yes

Question 42

T/F?

In multicentre trials (see Glossary) the randomisation procedures should be organised centrally. It is advisable to have a separate random scheme for each centre, i.e. to stratify by centre or to allocate several whole blocks to each centre.

Answer 42

True

Question 43

The randomisation schedule itself should be filed securely by the _______ or an _____ ____ in a manner that ensures that blindness is properly
maintained throughout the trial.

Answer 43

sponsor

independent party

Question 44

What is dynamic allocation?

Answer 44

Dynamic allocation is an alternative procedure in which the allocation of treatment to a subject is influenced by the current balance of allocated treatments and, in a
stratified trial, by the stratum to which the subject belongs and the balance within that stratum.

Question 45

What are the 3 main trial design configurations addressed in ICH E9?

Answer 45

Parallel Group Design

Crossover Design

Factorial Design

Question 46

What is the most common clinical trial design for confirmatory designs?

Answer 46

Parallel Group Designs

Question 47

What is a parallel group design?

Answer 47

parallel group design in which subjects are randomised to one of two or more arms, each arm being
allocated a different treatment. These treatments will include the investigational product at one or more doses, and one or more control treatments, such as placebo and/or an active comparator.

Question 48

What is a crossover design?

Answer 48

In the crossover design, each subject is randomised to a sequence of two or more treatments, and hence acts as his own control for treatment comparisons. This simple manoeuvre is attractive primarily because it reduces the number of subjects and usually the number of assessments needed to achieve a specific power, sometimes to a marked extent

Question 49

In the simplest ____ _____ ____ each subject receives each of two treatments in randomised order in two successive treatment periods, often separated
by a washout period.

(name a trial design)

Answer 49

2×2 crossover design

Question 50

What are problems with crossover designs that invalidate their results?

Answer 50

The chief difficulty concerns carryover, that is, the residual influence of treatments in subsequent treatment periods.

In an additive model the effect of unequal carryover
will be to bias direct treatment comparisons. In the 2×2 design the carryover effect cannot be statistically distinguished from the interaction between treatment and period and the test for either of these effects lacks power because the corresponding contrast is ‘between subject’. This problem is less acute in higher order designs, but cannot be entirely dismissed.

There are additional problems that need careful attention in crossover trials. The most notable of these are the complications of analysis and interpretation arising from the loss of subjects. Also, the potential for carryover leads to difficulties in assigning adverse events which occur in later treatment periods to the appropriate treatment.

Question 51

What is a good example/case of the use of a 2X2 Crossover design?

Answer 51

is to demonstrate the bioequivalence of two formulations of the same medication.

Question 52

What is a factorial design?

Answer 52

In a factorial design two or more treatments are evaluated simultaneously through the use of varying combinations of the treatments.

Question 53

What is a study type example of factorial design?

Answer 53

The simplest example is the 2×2 factorial design in which subjects are randomly allocated to one of the four possible combinations of two treatments, A and B say. These are: A alone; B alone; both A and
B; neither A nor B. In many cases this design is used for the specific purpose of examining the interaction of A and B. The statistical test of interaction may lack
power to detect an interaction if the sample size was calculated based on the test for main effects. This consideration is important when this design is used for examining the joint effects of A and B, in particular, if the treatments are likely to be used together.

Question 54

An important use of _______ Design is to establish the dose-response characteristics of the simultaneous use of treatments C and D, especially when the efficacy of each monotherapy has been established at some dose in prior trials.

Answer 54

Factorial Designs

Question 55

Why are multi-centre trials carried out? 2 reasons.

Answer 55

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.

Secondly, a trial may be designed as a multicentre (and multi-investigator) trial primarily to provide a better basis for the subsequent generalisation of its findings. This arises from the possibility of recruiting the subjects from a wider population and of administering the medication in a broader range of clinical settings, thus
presenting an experimental situation that is more typical of future use.

Question 56

If a multicentre trial is to be meaningfully interpreted and extrapolated, the usual sample size and power calculations depend upon the assumption that the differences between the compared treatments in the centres are unbiased estimates of the same quantity. It

True or False?

Answer 56

True

Question 57

What are some types of comparisions? I.E Trials to show_____

List 3 and brief description

Answer 57

Trials to Show Superiority–Scientifically, efficacy is most convincingly established by demonstrating superiority to placebo in a placebo-controlled trial, by showing superiority to an active control
treatment or by demonstrating a dose-response relationship. most common and assumed unless otherwise stated in ICH e9

Trials to Show Equivalence or Non-inferiority–without the objective of showing superiority. This type of trial is divided into two major categories according to its objective; one is an ‘equivalence’ trial (see Glossary)
and the other is a ‘non-inferiority’ trial

Trials to Show Dose-response Relationship-How response is related to the dose of a new investigational product is a question to which answers may be obtained in all phases of development, and by a variety of approaches (see ICH E4). Dose-response trials may serve a number of objectives, amongst which the following are of particular importance: the confirmation of efficacy; the investigation of the shape and location of the dose-response curve; the estimation of an appropriate starting dose; the identification of optimal strategies for individual
dose adjustments; the determination of a maximal dose beyond which additional benefit would be unlikely to occur.

Question 58

what are group sequential designs used to facilitate?

Answer 58

the conduct of interim analysis

Question 59

Does Interim Analysis trial montioring require you to break the blind?

Answer 59

Yes

Question 60

What is an interim analysis?

Answer 60

An interim analysis is any analysis intended to compare treatment arms with respect to efficacy or safety at any time prior to formal completion of a trial.

Question 61

What does the IDMC Assess?

Answer 61

An IDMC may be established by the sponsor to assess at intervals the progress of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor whether to continue, modify or terminate a trial.

The independence of the IDMC is intended to control the sharing of important comparative information and to protect the integrity of the clinical trial from adverse
impact resulting from access to trial information.

Question 62

How is the IDMC linked to the IRB/IEC?

Answer 62

Its not. The IDMC is a separate entity from
an Institutional Review Board (IRB) or an Independent Ethics Committee (IEC), and its composition should include clinical trial scientists knowledgeable in the
appropriate disciplines including statistics.

Question 63

In terms of Data Sets-

Describe Full Analysis Set

Per Protocol Set

Answer 63

In this document the term ‘full analysis set’ is used to describe the analysis set which is as complete as possible and as close as possible to the intention-to-treat ideal of including all randomised subjects. Preservation of the initial randomisation in analysis is important in preventing bias and in providing a secure foundation for statistical tests.

The ‘per protocol’ set of subjects, sometimes described as the ‘valid cases’, the ‘efficacy’ sample or the ‘evaluable subjects’ sample, defines a subset of the subjects in the full analysis set who are more compliant with the protocol and is characterised by criteria such as the following:

(i) the completion of a certain pre-specified minimal exposure to the treatment regimen;
ii) the availability of measurements of the primary variable(s);
(iii) the absence of any major protocol violations including the violation of entry criteria.

Question 64

Multiplicity may arise, for example, from __ _____ _____

Answer 64

multiple primary variables

Question 65

The calculation of ____ is sometimes useful either as an aid to evaluating a specific difference of interest, or as a ‘flagging’ device applied to a large number of
safety and tolerability variables to highlight differences worth further attention. This is particularly useful for laboratory data, which otherwise can be difficult to
summarise appropriately

Answer 65

p-values