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ICH E9

Statistical Principles for Clinical Trials

QuestionAnswer
E9 was finalized under ______ in _________. step 4; February 1998
I: The focus of this guidance is on statistical principles. It does not address the use of specific ____________. Specific procedural steps to ensure that principles are implemented properly are the responsibility of the sponsor. statistical procedures or methods
I: The principles outlined in this guidance are primarily relevant to clinical trials conducted in _________, many of which are confirmatory trials of efficacy. the later phases of development
I: The term '_____' 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 deviate from its true value. bias
I: _______ 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. Robustness
II: A _____________ 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 ______. confirmatory trial; efficacy or safety
II: The results of the confirmatory trial(s) should be _______. In some circumstances the weight of evidence from a single confirmatory trial may be sufficient. robust
II: The rationale and design of confirmatory trials nearly always rests on earlier clinical work carried out in a series of ______. exploratory studies
II: Any individual trial may have both ____________ aspects. confirmatory and exploratory
II: The ________ should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial. primary variable (‘target’ variable, primary endpoint)
II: The primary variable should generally be the one used when estimating the _______. sample size
II: To avoid multiplicity concerns arising from post hoc definitions, it is critical to specify in the protocol the ________ of the primary variable as it will be used in the ______. precise definition; statistical analysis
II: Redefinition of the primary variable after _____ will almost always be unacceptable, since the biases this introduces are difficult to assess. unblinding
II: If a single primary variable cannot be selected from multiple measurements related to the primary objective, another useful strategy is to integrate or combine the multiple measurements into a single or ______ variable, using a _______. 'composite'; pre-defined algorithm
II: Global assessment variables integrate objective variables and the __________ about the state or change in the state of the subject, and is usually a scale of _________. investigator’s overall impression; ordered categorical ratings
II: What are the two principal concerns with surrogate variables (indirect criteria): (1) may not be a true predictor of the clinical outcome of interest (2) may not yield a quantitative measure of clinical benefit that can be weighed directly against adverse effects
II: The most important design techniques for avoiding bias in clinical trials are _______________. blinding and randomization
II: The essential aim of _______ is to prevent identification of the treatments until all such opportunities for bias have passed. blinding
II: In an ______ trial the identity of treatment is known to all. open-label
II: The reasons for the degree of blinding (double, single, open-label) adopted should be explained in the protocol, together with steps taken to ________ by other means. minimize bias
II: the blind review of data refers to the checking of data during the period of time between _________ and __________. trial completion (the last observation on the last subject); the breaking of the blind
II: Randomisation introduces a _________ into the assignment of treatments to subjects in a clinical trial. deliberate element of chance
III: What three trial design configurations are detailed in 'Trial Design Considerations'? parallel group design, crossover design, and factorial design
III: The design configuration in which subjects are randomized to one of two or more arms, each arm being allocated a different treatment. parallel group design
III: The design configuration in which each subject is randomized to a sequence of two or more treatments, and hence acts as his own control for treatment comparisons. crossover design
III: The main difficulty of a crossover design trial is the ___________ in subsequent treatment periods. the residual influence of treatments
III: A common, and generally satisfactory, use of the 2×2 crossover design is to demonstrate the bioequivalence ____________. two formulations of the same medication
III: In a _______________ two or more treatments are evaluated simultaneously through the use of varying combinations of the treatments. factorial design
III: What are the two main reasons for carrying out multicentre trials? (1) may present the only practical means of accruing sufficient subjects (2) to provide a better basis for the subsequent generalisation of its findings
III: What three things can help reduce variation of evaluation criteria in multicentre trials? (1) investigator meetings, (2) training of personnel in advance of the trial, (3) careful monitoring during the trial
III: Scientifically, efficacy is most convincingly established by demonstrating _________ to placebo in a placebo-controlled trial, by showing superiority to an active control treatment or by demonstrating a dose-response relationship. superiority (a superiority trial)
III: The appropriateness of placebo control vs. ________ should be considered on a trial by trial basis. active control
III: It is vital that the protocol of a trial designed to demonstrate ____________ contain a clear statement that this is its explicit intention. equivalence or non-inferiority
III: For equivalence trials, _________ confidence intervals should be used. two-sided
III: For ________ trials a one-sided interval should be used. non-inferiority
III: Dose-response trials may serve a number of objectives, amongst which the following are of particular importance: (5 things) (1) confirmation of efficacy (2) the investigation of the dose-response curve; (3) estimation of appropriate starting dose; (4) identification of optimal strategies for dose adjustments; (5) determination of a maximal dose
III: _________ are used to facilitate the conduct of interim analysis. Group sequential designs
III: Group sequential designs are the most commonly applied because it is more practicable to __________. assess grouped subject outcomes at periodic intervals than on a continuous basis as data from each subject become available.
III: The number of subjects in a clinical trial should always be large enough to _____________. provide a reliable answer to the questions addressed
III: The sample size of an equivalence trial or a non-inferiority trial should normally be based on the objective of obtaining a confidence interval for the treatment difference that shows that the treatments differ at most ________. by a clinically acceptable difference
III: The exact sample size in a group sequential trial cannot be fixed in advance because it depends upon _______ in combination with the chosen stopping guideline and the true treatment difference. the play of chance
III: In data capture, __________ should be distinguishable from the ‘value zero’ or ‘characteristic absent’. ‘Missing values’
IV: What are the two distinct types of monitoring that generally characterize confirmatory clinical trials in the pharmaceutical industry? (1) oversight of quality of clinical trial (2) breaking the blind to make treatment comparisons (interim analysis)
IV: Over what period of the clinical trial does quality oversight usually take place? from selection of trial site(s) to cleaning of the last subject's data
IV: Interim analysis trial monitoring requires unblinding and therefore necessitates that the protocol detail the statistical plans for the interim analysis to prevent _____________. certain types of bias
IV: In long term trials there will usually be an opportunity to check the assumptions which underlay the original design and __________. sample size calculations
IV: ________ is any analysis intended to compare treatment arms with respect to efficacy or safety at any time prior to formal completion of a trial. interim analysis
IV: Special circumstances may dictate the need for an interim analysis not defined in the protocol. In these cases, a protocol amendment describing the interim analysis should be completed prior to _________ to treatment comparison data. unblinded access
IV: The execution of an interim analysis should be a _____ process because unblinded data and results are potentially involved. completely confidential
IV: In terms of the interim analyses results, _______ should only be informed about the decision to continue or to discontinue the trial, or to implement modifications to trial procedures. investigators
IV: Most trials trials should be stopped early only for _____ or if the _______. (1) ethical reasons, (2) the power is no longer acceptable
IV: For many clinical trials, the responsibility for monitoring comparisons of efficacy and/or safety outcomes should be assigned to an ____________. external independent group (Independent Data Monitoring Committee, Data Safety Monitoring Board, or Data Monitoring Committee)
IV: 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 __________ a trial. continue, modify or terminate
IV: The _________ may be written as a separate document to be completed after finalizing the protocol. statistical analysis plan
V: The frequency and type of protocol violations, missing values, and other problems should be documented in the __________ and their potential influence on the trial results should be described. clinical study report
V: Decisions concerning the analysis set should be guided by these two principles. 1) minimizing bias, and 2) avoiding inflation of type I error
V: The ________ principle implies that the primary analysis should include all randomized subjects. Compliance with this principle would necessitate complete follow-up of all randomized subjects for study outcomes. intention-to-treat
V: There are a limited number of circumstances that might lead to excluding randomised subjects from the full analysis set including: (3 things). (1) the failure to satisfy major entry criteria (eligibility violations), (2) the failure to take at least one dose of trial medication, (3) the lack of any data post randomization
V: Subjects who fail to satisfy an entry criterion may be excluded from the analysis without the possibility of introducing bias only under the following circumstances: (4 things) (1) entry criterion measured prior to randomization (2) detection of eligibility violations can be made objectively (3) all subjects receive equal scrutiny for eligibility violations (4) all violations of the particular entry criterion are excluded
V: __________, ranging from the carrying forward of the last observation to the use of complex mathematical models, may also be used in an attempt to compensate for missing data. Imputation techniques
V: The _________ 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 'per protocol'
V: A severe bias may arise from the analysis of the per protocol set due to the fact that ________________ to the study protocol may be related to treatment and outcome. participant adherence
V: What should be done if no procedure for dealing with outliers was foreseen in the trial protocol? an analysis with all values and an analysis with outliers eliminated should both be conducted and differences between the results should be discussed.
V: The decision on whether and how to transform a variable should be influenced by the preference for a scale which facilitates ___________. clinical interpretation
V: It is important to clarify whether __________ tests of statistical significance will be used, and in particular to justify prospectively the use of ___________. one- or two-sided ; one-sided tests
VI: For the overall safety and tolerability assessment, the set of subjects to be summarised is usually defined as those subjects who _____________. received at least one dose of the investigational drug
VI: The incidence of a certain adverse event is usually expressed in the form of a _________ relating number of subjects experiencing events to number of subjects at risk. proportion
VII: All subjects who entered the trial should be accounted for in the __________, whether or not they are included in the analysis. clinical study report
VII: ___________ statistics form an indispensable part of clinical study reports. Descriptive
VII: An overall summary and synthesis of the evidence on safety and efficacy from all the reported clinical trials is required for a _______. marketing application
VII: Under exceptional circumstances, a _________ approach may also be the most appropriate way, or the only way, of providing sufficient overall evidence of efficacy via an overall hypothesis test. meta analytic
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. Bayesian Approaches
Glossary: 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
Bias introduced through deviations in conduct is referred to as ________ bias. 'operational'
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 finalist the planned analysis. Blind review
The extent to which a variable (e.g. a rating scale) measures what it is supposed to measure. content validity
A technique for retaining the blind when administering supplies in a clinical trial, when the two treatments cannot be made identical. double-dummy
A trial with the primary objective of showing that the response to two or more treatments differs by an amount which is clinically unimportant. equivalence trial
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. Frequentist methods
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 randomized subjects by minimal and justified elimination of subjects. Full analysis set
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. Generalisability
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. Global assessment variable
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. intent-to-treat principle
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. magnitude; direction
The property of yielding equivalent results when used by different raters on different occasions. inter-rater reliability
The formal evaluation of the quantitative evidence from two or more trials bearing on the same question. meta-analysis
Any analysis intended to compare treatment arms with respect to efficacy or safety at any time prior to the formal completion of a trial. interim analysis
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. per protocol set (valid cases, efficacy sample, evaluable subjects sample)
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. non-inferiority trial
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). Superiority trial
A variable that provides an indirect measurement of effect in situations where direct measurement of clinical effect is not feasible or practical. surrogate variable
Created by: wickerfurniture