ICH E9 Clinical Trial Statistics

Question 1

Bias, Definition in Clinical Trials, Sources (4)

Answer 1

The systematic tendency of any factors associated with the:

1. design (e.g., lower risk subject receives more placebo)
2. conduct (e.g., protocol violation and subject exclusion)
3. analysis and
4. interpretation

of the results of clinical trials to make the estimate of a treatment effect deviate from its true value.

Question 2

Robustness, Definition in Clinical Trials

Answer 2

The sensitivity (tolerability) of the overall conclusion to various limitations of the data, assumptions, and analytic approaches to data analysis.

High robustness implies treatment effect and primary conclusion of the trial are not substantially affected by the alternative assumption or analytic approaches.

Question 3

Development Plan, Broad Aim

Answer 3

Determine 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 ( for the subject and indication).

Question 4

Clinical Development, Considerations
Confirmatory vs Exploratory Trials

Answer 4

Confirmatory trials: Hypothesis testing of predefined hypothesis. Significant results are sufficient to demonstrate efficacy.

Exploratory trials: Hypothesis generating from data and testing of post hoc hypothesis. Significant results contribute but cannot be the sole basis of the formal proof of efficacy.

Question 5

Clinical Development, Scope of Trials (7)

Answer 5

1. Population: from more defined to more relaxed inclusion/exclusion criteria to approach the indicated population.
2. Primary and Secondary Variable: predefined, clinically relevant, scientifically valid main and supportive results
3. Composite Variables: Integrated various measurements into a single variable (index) using a predefined algorithm (e.g., rating scales for arthritis evaluation)
4. Global Assessment Variables: Recapitulate clinician assessment of the overall safety and efficacy, reported a scale of ordered categorical ratings (poor, normal, well).
5. Multiple Primary Variables: A predefined sets o results, each or a subset of which are sufficient to cover the range of therapeutic effects.
6. Surrogate Variables: Indirect criteria with predictive power used in lieu of clinical assessment due to practicality.
7. Categorized Variables: Predefined and specified dichotomization/categorization of continuous or ordinal variables

Question 6

Clinical Development, Designs Techniques to Avoid Bias (2)

Answer 6

1. Blinding: intended to limit the occurrence of conscious and unconscious bias in conduct and interpretation of trial.
2. Randomization: introduces a deliberate element of chance into the treatment assignment to avoid bias arising from predictability in clinical trials.

Question 7

Clinical Development, Design Configuration

Answer 7

1. Parallel Group Design
2. Crossover Design
3. Factorial Designs

Question 8

Multicenter Trials, Statistical Analysis for Multicenter, Treatment Effects

Heterogeneity vs Homogeneity:
Treatment x Center Interaction Test

Answer 8

Heterogeneity and homogeneity across centers should be considered in statistical analysis:

Heterogeneous treatment effect across centers:
Treatment x Center Interaction is needed, else the main effect is controversial. (Heterogeneity should be explained by analysis or trial.)

Homogeneous treatment effect across centers:
Treatment x Center Interaction reduces efficiency of the test for main effect.

Note: Treatment-by-Center Interaction isolates effect of each center instead of treating all centers as a whole.

Question 9

Multicenter Trials, Statistical Analysis for Multicenter, Treatment Effects

Fixed Model vs Mixed Models

Answer 9

Fixed Model: Assume center and treatment-by-center effect to be universal. Heterogeneity of centers are observed and explained.

Mixed Models: Consider center and treatment-by-center effect to be random. Heterogeneity of centers are integrated in the analysis.

Note: Mixed model are especially relevant when the number of sites is large.

Question 10

Trial Statistics, Type of Comparison

Answer 10

Statistics of trials to demonstrate:

1. superiority (i.e., relative to placebo, active comparator, or various dose)
2. equivalence (e.g., bioequivalence trials, two sided) and non-inferiority (e.g., active control trials, one sided)
3. dose-response relationship (all trial stages)

Question 11

Statistical Analysis, Equivalence and Non-inferiority Trials, Statistical Test Precautions for Type I Errors

Inappropriate method
Appropriate method

Answer 11

To avoid type I errors, or falsely claiming equivalence or non-inferiority, the statistical analysis:

MUST NOT base observing a non-significant test results of the hull hypothesis that there is no significant difference between the investigational product and the activator.

Instead, it SHOULD based on one-sided test to demonstrate the distribution of investigational product effect is significantly above the lower equivalence margin for non-inferiority (and simultaneously significantly below the higher equivalence margin for equivalence)

Question 12

Statistical Analysis, Group Sequential Designs

Answer 12

Grouping subject outcomes for assessment at periodic intervals, commonly used in interim analysis of large long-term trials (i.e., Kaplan Meier analysis for mortality)

Question 13

Sample Size, Power Analysis
General Considerations: alpha and beta levels
Special Considerations: Group Sequential Design

Answer 13

Conventional standards:
Type I error: < 0.05
Type II error: < 0.1 or < 0.2

In group sequential design:
re-estimation of sample size is possible, when effect size and variability deviate from the original estimates.

Question 14

Clinically Acceptable vs Clinically Relevant

Answer 14

Clinical Acceptable: Describe the significant agreement between the groups that makes clinically indistinguishable in equivalence and non-inferiority trials.

Clinically Relevant: Describe the significant difference between the groups which are clinically meaningful in superiority trials

Question 15

Data Capture and Processing, Important Considerations NA

Answer 15

Must ensure distinguishing:

Missing Values,
Value “0”, and
Characteristic Absent

Question 16

Trial Conduct Considerations, Trail Monitoring and Interim Analysis, Monitoring Types (2)

Answer 16

Types of monitoring charactering confirmatory clinical trials by companies

1. Oversight of the quality of the trial: no unblinding required and no risk of bias.
2. Analysis for treatment comparison (i.e., interim analysis): requires unblinding, necessitates statistical plan in protocol.

Question 17

Trial Conduct Considerations, Changes in Inclusion and Exclusion Criteria, Scenarios (3)

Answer 17

Inclusion and exclusion criteria generally remains as pre-specified, except for where justified:

1. growing internal/external medical knowledge
2. regular violations of entry criteria by staff
3. low recruitment rates due to over-restrictive criteria

Inclusion and exclusion criteria necessitates protocol amendment and approval.

Question 18

Trial Conduct Considerations, Accrual Rates

Answer 18

Appreciably falling accrual rate must be remediated to protect the power of the trial.

Question 19

Trial Conduct Considerations, Sample Size Adjustment

Answer 19

The potential need for re-estimation of the sample size should be envisaged in the protocol.

Question 20

Trial Conduct Considerations, Interim Analysis and Early Stopping, Early Termination Scenarios by Interim Analysis with Group Sequential Design (3)

Answer 20

The goal of such an interim analysis is to stop the trial early if:

1. Superiority of the treatment is clearly established (requires more evidence)
2. demonstration of a relevant treatment difference has become unlikely
3. unacceptable adverse effects are apparent (requires less evidence)

Question 21

Trial Conduct Considerations, Interim Analysis and Early Stopping,

Fixed Alpha vs Flexible Alpha Spending Function Approach

Answer 21

To control for Type I error,

Fixed Alpha: Predefined Alpha level divided equally among interim and final analysis based on preliminary data (can be too inefficient or too conservative if true effect size is greater or smaller than expected).

Flexible Alpha: Varying alpha over time and across interim and final analyses based on accumulating data.

Question 22

Trial Conduct Considerations, Interim Analysis and Early Stopping,

Unplanned Interim Analysis Disclosure (4)

Answer 22

Unplanned Interim Analysis should be avoided, as it may flaw the results of a trial and possibility weaken confidence in the conclusion drawn. However, if conducted the clinical study report must disclose:

1. Reason for why it was necessary
2. Extended of unblinding
3. Magnitude of the bias introduced
4. Impact on the interpretation of result

Question 23

Trial Conduct Considerations, Role of Independent Data Monitoring Committee (IDMC)

Answer 23

Recommends whether to continue, modify or terminate a trial based on interim analysis of trial progress, safety and efficacy data.

Note: Independent nature of IDMC is intended to control the sharing of important comparative information and to protect the integrity of the clinical trial.

Question 24

Data Analysis Considerations, Pre-specification of the Analysis

Confirmatory vs Exploratory Trials

Answer 24

The statistical section of the protocol should include principals of the statistic analysis, for

Confirmatory trials: all the analysis pre-specified in protocol (and amendments if needed)

Exploratory trials: more general principles and directions

Question 25

Data Analysis Considerations, Analysis Sets

Principles for the Analysis Set Selection (2)

Answer 25

Unless data on all subjects are complete (which is rarely the case), decisions concerning the analysis set should be guided by the following principles to select analysis set:

1. to minimize bias
2. to avoid inflation of type I error

Question 26

Data Analysis Considerations, Analysis Sets

Full Analysis Set, Practical Definition

Answer 26

In practice, full analysis set, describes the analysis set which is as complete as possible and as close as possible to the intention-to-treat ideal of including all randomized subjects.

** Intention-to-treat principal: primary analysis should include all randomized subjects.

Question 27

Data Analysis Considerations, Analysis Sets

Full Analysis Set, Justified Exclusion, Scenarios (3)

Answer 27

1. eligibility violations (failure to satisfy major entry criteria)
2. compliance violations (failure to take at least one dose of trial medication)
3. Other variable violations (lack of any data post randomization)

Question 28

Data Analysis Considerations, Analysis Sets
Full Analysis Set,
Justified Exclusion by Eligibility Violations, Justified Scenarios (4)

Answer 28

Only under following circumstances, the subject may be excluded without the possibility of introducing bias:

1. the entry criterion was measured prior to randomization
2. the detection of the relevant eligibility violations can be made completely objectively
3. all subject receive equal scrutiny for eligibility violation
4. all detected violation of the particular entry criterion are excluded

Question 29

Data Analysis Considerations, Analysis Sets
Full Analysis Set,

Partial Medication Compliance, Scenarios (3)

Answer 29

1. No medication taken: Ok to exclude if non-compliance is not due to specific assignment
2. Withdrawn after some medication: include as per the intention-to-treat principle (analysis with imputation, modeling, and qualitative techniques requires justification).
3. Complete medication regimen: Include as per the intention-to-treat principle

Question 30

Data Analysis Considerations, Analysis Sets

Per Protocol Set, Criteria (3)

Answer 30

“Per protocol set” = “valid case” = “efficacy sample” = “evaluable subjects”:

a subset of the subjects in the full analysis set who are more compliant with the protocol specified criteria:

1. the completion of a certain pre-specified minimal exposure to the treatment regimen
2. the availability of measurements of the primary variables
3. the absence of any major protocol violations including the violation of entry criteria.

Question 31

Data Analysis Considerations, Analysis Sets

Roles of the Different Analysis Sets

Selection of Full vs Per Protocol Set
For Superiority vs equivalence/non-inferiority Trials

Answer 31

Comparing results from Full vs Per Protocol sets explores the sensitivity of conclusions to the choice of the set of subjects analyzed.

Superiority Trial: Full set analysis
Equivalence/non-inferiority Trail: Per protocol analysis

Question 32

Data Analysis Considerations, Missing Values and Outliers

Answer 32

Missing values and outliers are typically inevitable in practice. Therefore, the methods for handing missing values and outliers need to be pre-defined in protocol and refined during the blind review.

Question 33

Data Analysis Considerations, Data Transformation

Answer 33

Data transformations (square root, log) and data derivatives (delta, %change, AUC, ratio) should conform to the standards in the specific clinical areas.

Question 34

Data Analysis Considerations,
Estimation, Confidence Intervals, and Hypothesis Testing

Answer 34

Estimation of treatment effects,
confidence intervals of effect distribution, and hypothesis testing for primary (and secondary) variables,

should be specified in the statistical section of the protocol

Question 35

Data Analysis Considerations,
One-sided vs Two-sided Alpha

Answer 35

In regulatory settings, when justified to use one-sided test, the alpha for one-sided test is set at half of which for two-sided test to limit the probability of type I error and claim statistical significance:

One-sided test: p < 0.025
Two-sided test: P < 0.05

Question 36

Data Analysis Considerations,
Adjustment of Significance and Confidence Levels
Multiplicity Examples (3)

Answer 36

Adjustment to the type I error should always be considered when multiplicity is present, such as in

1. multiple primary variables
2. multiple comparisons of treatment
3. repeated evaluation over time and interim analysis

Question 37

Data Analysis Considerations,
Special Consideration for Covariates Analysis

Answer 37

Adjustment for covariate is sometimes an integral part of the analysis, but should only be done for covariates measured before randomization (as covariates can be affected by treatment).

Question 38

Data Analysis Considerations,
Integrity of Data and Computer Software Validity

Answer 38

Methods and software (internal and external sources) for data management, processing, and statistical analysis should be reliable and subject to quality control.

Question 39

Data Analysis Considerations,
Subgroups, Interactions, and Covariates
Exploratory vs confirmatory Analysis

Answer 39

Subgroup analysis by a statistical model including interactions with covariates, are mostly exploratory, unless specifically planned as confirmatory.

** Conclusion of treatment efficacy or safety based solely on exploratory subgroup analysis are unlikely to be accepted.

Question 40

Evaluation of Safety and Tolerability, Scope of Evaluation

Pharmacovigilance Studies, Negative vs Positive Statistics

Answer 40

Exploratory (and even confirmatory) studies demonstrating safety and tolerability (by lack of adverse findings) generally lack power.

Studies demonstrating superiority or equivalence of safety and tolerability (compared to other drug or dose) should be supported by confirmatory trials similar to efficacy claims.

Question 41

Evaluation of Safety and Tolerability, Choice of Variables and Data Collection,

Adverse Event Data Standardization

Answer 41

Consistent methodology is recommended for data collection and evaluation throughout the clinical development program to facilitate combining of safety data from different trials.

Question 42

Evaluation of Safety and Tolerability, Set of Subjects to be Evaluated and Presentation of Data,

Set of Subject, Definition in Safety and Tolerability Evaluation

Answer 42

Set of Subject in safety and tolerability evaluation:

those subjects who received at least one dose of the investigational drug.

Question 43

Evaluation of Safety and Tolerability, Set of Subjects to be Evaluated and Presentation of Data,

Incidence of Adverse Events, Expression

Answer 43

Conventional expression:

Incidence Proportion =
(#Subject with AE) / (#Subject at Risk)

or, depends on context:

Incidence Proportion =
(#Subject with AE) / (#in Person-years)

Question 44

Evaluation of Safety and Tolerability, Set of Subjects to be Evaluated and Presentation of Data,

Substantial Background Noise of Signs and Symptoms,

Treatment Emergent vs Threshold Method

Answer 44

In case of substantial background noise of sign and symptoms for safety evaluation, adverse events are recorded only if they meet the following condition:

Treatment Emergent: AEs emerge or worsen relative to pretreatment baseline (e.g., as in psychiatric trials)

or,

Threshold Method: AEs reach significant severity or frequency

Question 45

Evaluation of Safety and Tolerability, Statistical Evaluation

Hypothesis Testing vs Confidence Intervals

Answer 45

The use of confidence intervals (CI) is preferred to hypothesis testing in non-inferiority or equivalence for demonstrating safety profile (to evidence any low frequencies of occurrence)

Question 46

Evaluation of Safety and Tolerability, Integrated Summary

Risk and Benefit Analysis, Clinical Development

Answer 46

Risk and benefit analysis to determine the overall usefulness of a drug should be performed for the entire clinical trial program as wells as for a single trial.

Question 47

Reporting, Evaluation and Reporting, Blind Review Coverage (5)

Answer 47

1. exclusion of subject and data
2. possible transformation
3. outlier definition
4. important covariates emerged
5. parametric vs non-parametric

Blind review should be distinguished from the later unblind analysis

Question 48

Reporting, Evaluation and Reporting, Full Analysis Pre-specified Plan Details Procedures (5)

Answer 48

During the pre-specified plan, data validation, presentation and tabulation should be finalized for:

1. subject selection
2. data selection and modification
3. data summary and tabulation
4. estimation
5. hypothesis testing

Question 49

Reporting, Evaluation and Reporting, Unplanned Subgroup Analysis,

Efficacy vs Safety Reporting

Answer 49

The efficacy claimed from unplanned subgroup analysis should be reported with caution for over-interpretation.

However,

The possibility for non benefit or adverse effect from such unplanned subgroup analysis should be reported as a conservative approach.

Question 50

Summarizing the Clinical Database, Meta-analysis,
Summary Statistic Combining All Trials, Aspects (3)

Answer 50

1. demography and clinical features of the populations under treatment for all trials
2. efficacy result evaluations for consistency across all trials
3. safety summary from combined database of all trials

Question 51

Summarizing the Clinical Database, Meta-analysis,
Standardization for Combining All Trials Compatibility, Aspects (2+4)

Answer 51

1. A common dictionary for medication/medical history/AE recording
2. A common definition of primary and secondary variables
3. Measurement for key efficacy variables
4. Timing of assessment relative to randomization/trail entry
5. Procedures for protocol violation and deviation
6. definition of prognostic factors

Question 52

Summarizing the Clinical Database, Meta-analysis, Area of Focus for Ensuring Analysis Reliability (4)

Answer 52

1. possibility of Bias associated with selection of trials
2. homogeneity of trial results
3. proper modeling of the various source of variation
4. Sensitivity of conclusions to the assumptions and selections

Question 53

Summarizing the Clinical Database, Meta-analysis, Efficacy Data

Answer 53

Individual clinical trails should always be large enough to satisfy their objectives.

Trials can be combined reliability for treatment effect size, only with appropriate meta-analytic techniques.

Question 54

Summarizing the Clinical Database, Meta-analysis, Safety Data

Answer 54

Combination of safety data from all related trials provides the best chance of detecting rarer adverse events and estimating approximate incidence.

Question 55

Summarizing the Clinical Database, Meta-analysis, Safety Data

Quantitative Risk Benefit Assessment

Answer 55

Survival Analysis:

The risks associated with identified adverse effects should be appropriately quantified to allow a proper assessment of the risk/benefit relationship.

Question 56

Bayesian Approaches

Approaches to data analysis that provide a ____ probability distribution for some parameter (e.g. treatment effect), derived from the observed data and a ____ probability distribution for the parameter. The ____ distribution is then used as the basis for statistical inference.

Answer 56

Approaches to data analysis that provide a posterior probability distribution for some parameter (e.g. treatment effect), derived from the observed data and a prior probability distribution for the parameter. The posterior distribution is then used as the basis for statistical inference.

Question 57

Bias (Statistical & Operational)

The systematic tendency of any factors associated with the ____, ____, ____ and ____ of the results of a clinical trial to make the estimate of a treatment effect deviate from its true value. Bias introduced through deviations in conduct is referred to as ‘____’ bias. The other sources of bias listed above are referred to as ‘____’.

Answer 57

The systematic tendency of any factors associated with the design, conduct, analysis and evaluation of the results of a clinical trial to make the estimate of a treatment effect deviate from its true value. Bias introduced through deviations in conduct is referred to as ‘operational’ bias. The other sources of bias listed above are referred to as ‘statistical’.

Question 58

Blind Review

The checking and assessment of data during the period of time between ____ (the last observation on the last subject) and the ____, for the purpose of finalising the ____.

Answer 58

The checking and assessment of data during the period of time between trial completion (the last observation on the last subject) and the breaking of the blind, for the purpose of finalising the planned analysis.

Question 59

Content Validity

The extent to which a variable (e.g. a rating scale) measures what it is ____ to measure.

Answer 59

The extent to which a variable (e.g. a rating scale) measures what it is supposed to measure.

Question 60

Double-Dummy

A technique for retaining the blind when administering supplies in a clinical trial, when the two treatments cannot be made ____. 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).

Answer 60

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 61

Dropout

A subject in a clinical trial who for any reason fails to ____ in the trial until the last visit required of him/her by the study protocol.

Answer 61

A subject in a clinical trial who for any reason fails to continue in the trial until the last visit required of him/her by the study protocol.

Question 62

Equivalence Trial

A trial with the primary objective of showing that the response to two or more treatments differs by an amount which is ____. This is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence margin of ____ differences.

Answer 62

A trial with the primary objective of showing that the response to two or more treatments differs by an amount which is clinically unimportant. This is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence margin of clinically acceptable differences.

Question 63

Frequentist Methods

Statistical methods, such as ____ and ____, which can be interpreted in terms of the ____ of certain outcomes occurring in hypothetical repeated realisations of the same experimental situation.

Answer 63

Statistical methods, such as significance tests and confidence intervals, which can be interpreted in terms of the frequency of certain outcomes occurring in hypothetical repeated realisations of the same experimental situation.

Question 64

Full Analysis Set

The set of subjects that is as close as possible to the ideal implied by the ____ principle. It is derived from the set of ____ subjects by ____ and ____ elimination of subjects.

Answer 64

The set of subjects that is as close as possible to the ideal implied by the intention-to- treat principle. It is derived from the set of all randomised subjects by minimal and justified elimination of subjects.

Question 65

Generalisability, Generalisation

The extent to which the findings of a clinical trial can be reliably ____ from the subjects who participated in the trial to a broader ____ and a broader range of ____.

Answer 65

The extent to which the findings of a clinical trial can be reliably extrapolated from the subjects who participated in the trial to a broader patient population and a broader range of clinical settings.

Question 66

Global Assessment Variable

A single variable, usually a scale of ____ categorical ratings, which integrates ____ variables and the investigator’s ____ about the state or change in state of a subject.

Answer 66

A single variable, usually a scale of ordered categorical ratings, which integrates objective variables and the investigator’s overall impression about the state or change in state of a subject.

Question 67

Independent Data Monitoring Committee (IDMC)

An independent data-monitoring committee that may be established by the sponsor to assess at intervals the ____ of a clinical trial, the ____ data, and the critical ____ endpoints, and to recommend to the sponsor whether to ____, ____, or ____ a trial.

Answer 67

An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Question 68

Intention-To-Treat Principle

The principle that asserts that the effect of a treatment policy can be best assessed by evaluating on the basis of the ____ to treat a subject (i.e. the planned treatment regimen) rather than the ____ treatment given. It has the consequence that subjects allocated to a treatment group should be followed up, assessed and analysed as members of that group irrespective of their ____ to the planned course of treatment.

Answer 68

The principle that asserts that the effect of a treatment policy can be best assessed by evaluating on the basis of the intention to treat a subject (i.e. the planned treatment regimen) rather than the actual treatment given. It has the consequence that subjects allocated to a treatment group should be followed up, assessed and analysed as members of that group irrespective of their compliance to the planned course of treatment.

Question 69

Interaction (Qualitative & Quantitative)

The situation in which a treatment contrast (e.g. difference between investigational product and control) is ____ on another factor (e.g. centre). A quantitative interaction refers to the case where the ____ of the contrast differs at the different levels of the factor, whereas for a qualitative interaction the ____ of the contrast differs for at least one level of the factor.

Answer 69

The situation in which a treatment contrast (e.g. difference between investigational product and control) is dependent on another factor (e.g. centre). A quantitative interaction refers to the case where the magnitude of the contrast differs at the different levels of the factor, whereas for a qualitative interaction the direction of the contrast differs for at least one level of the factor.

Question 70

Inter-Rater Reliability

The property of yielding ____ results when used by ____ raters on different occasions.

Answer 70

The property of yielding equivalent results when used by different raters on different occasions.

Question 71

Intra-Rater Reliability

The property of yielding ____ results when used by the ____ rater on different occasions.

Answer 71

The property of yielding equivalent results when used by the same rater on different occasions.

Question 72

Interim Analysis

Any analysis intended to compare treatment arms with respect to efficacy or safety at any time ____ to the formal completion of a trial.

Answer 72

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

Question 73

Meta-Analysis

The formal evaluation of the ____ evidence from two or more trials bearing on the ____ question. This most commonly involves the statistical combination of ____ from the various trials, but the term is sometimes also used to refer to the combination of the ____.

Answer 73

The formal evaluation of the quantitative evidence from two or more trials bearing on the same question. This most commonly involves the statistical combination of summary statistics from the various trials, but the term is sometimes also used to refer to the combination of the raw data.

Question 74

Multicentre Trial

A clinical trial conducted according to a ____ protocol but at more than one site, and therefore, carried out by more than one investigator.

Answer 74

A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more than one investigator.

Question 75

Non-Inferiority Trial

A trial with the primary objective of showing that the response to the investigational product is not ____ inferior to a comparative agent (____ or ____ control).

Answer 75

A trial with the primary objective of showing that the response to the investigational product is not clinically inferior to a comparative agent (active or placebo control).

Question 76

Preferred and Included Terms

In a hierarchical medical dictionary, for example MedDRA, the included term is the ____ level of dictionary term to which the investigator description is coded. The preferred term is the level of ____ of included terms typically used in reporting frequency of occurrence. For example, the investigator text “Pain in the left arm” might be coded to the included term “Joint pain”, which is reported at the preferred term level as “Arthralgia”.

Answer 76

In a hierarchical medical dictionary, for example MedDRA, the included term is the lowest level of dictionary term to which the investigator description is coded. The preferred term is the level of grouping of included terms typically used in reporting frequency of occurrence. For example, the investigator text “Pain in the left arm” might be coded to the included term “Joint pain”, which is reported at the preferred term level as “Arthralgia”.

Question 77

Per Protocol Set (Valid Cases, Efficacy Sample, Evaluable Subjects)

The set of data generated by the subset of subjects who ____ with the protocol sufficiently to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to ____, availability of ____ and absence of major protocol ____.

Answer 77

The set of data generated by the subset of subjects who complied with the protocol sufficiently to ensure that these data would be likely to exhibit the effects of treatment, according to the underlying scientific model. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of major protocol violations.

Question 78

Safety & Tolerability

The safety of a medical product concerns the ____ to the subject, usually assessed in a clinical trial by laboratory tests (including clinical chemistry and haematology), vital signs, clinical adverse events (diseases, signs and symptoms), and other special safety tests (e.g. ECGs, ophthalmology). The tolerability of the medical product represents the degree to which ____ can be tolerated by the subject.

Answer 78

The safety of a medical product concerns the medical risk to the subject, usually assessed in a clinical trial by laboratory tests (including clinical chemistry and haematology), vital signs, clinical adverse events (diseases, signs and symptoms), and other special safety tests (e.g. ECGs, ophthalmology). The tolerability of the medical product represents the degree to which overt adverse effects can be tolerated by the subject.

Question 79

Statistical Analysis Plan

A statistical analysis plan is a document that contains a more technical and detailed elaboration of the principal features of the analysis described in the ____, and includes detailed procedures for executing the ____ of the primary and secondary variables and other data.

Answer 79

A statistical analysis plan is a document that contains a more technical and detailed elaboration of the principal features of the analysis described in the protocol, and includes detailed procedures for executing the statistical analysis of the primary and secondary variables and other data.

Question 80

Superiority Trial

A trial with the primary objective of showing that the response to the investigational product is superior to a comparative agent (____ or ____ control).

Answer 80

A trial with the primary objective of showing that the response to the investigational product is superior to a comparative agent (active or placebo control).

Question 81

Surrogate Variable

A variable that provides an ____ measurement of effect in situations where ____ measurement of clinical effect is ____ feasible or practical.

Answer 81

A variable that provides an indirect measurement of effect in situations where direct measurement of clinical effect is not feasible or practical.

Question 82

Treatment Effect

An effect attributed to a treatment in a clinical trial. In most clinical trials the treatment effect of interest is a ____ (or contrast) of two or more treatments.

Answer 82

An effect attributed to a treatment in a clinical trial. In most clinical trials the treatment effect of interest is a comparison (or contrast) of two or more treatments.

Question 83

Treatment Emergent

An event that emerges during treatment having been ____ pre-treatment, or ____ relative to the pre-treatment state.

Answer 83

An event that emerges during treatment having been absent pre-treatment, or worsens relative to the pre-treatment state.

Question 84

Trial Statistician

A statistician who has a combination of education/training and experience sufficient to ____ the principles in this guidance and who is responsible for the statistical aspects of the trial.

Answer 84

A statistician who has a combination of education/training and experience sufficient to implement the principles in this guidance and who is responsible for the statistical aspects of the trial.