Statistical Principles for Clinical Trials E9 Flashcards
What is the broad aim of the process of clinical development of a new drug?
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.
Clinical plan(s) should be flexible enough to:
Allow for modification as knowledge accumulates.
Interpretation and assessment of the evidence from the total program of trials involves synthesis of the evidence from the individual trials. This is facilitated by ensure that common standards are adopted for a number of features of the trials such as:
- Dictionaries of medical terms
- Definition and timing of the main measurements
- Handling of protocol deviations
When would a statistical summary, overview, or meta-analysis be informative?
When medical questions are addressed in more than one trial.
As a rule, confirmatory trials are necessary to provide:
Firm evidence of efficacy or safety
In a confirmatory trial it is equally important to:
- Estimate with due precision the size of the effects attributable to the treatment of interest
- Relate these effects to their clinical significance
Firm evidence in support of claims requires that the results of the confirmatory trials demonstrate that the investigational product under test has:
Clinical benefits
In a confirmatory trial, it is important that the basis for generalization to the intended patient population is understood and explained. What does this influence?
The number and type of centers and/or trials needed.
Regarding objectives, how do exploratory trials differ from confirmatory trials?
The objectives of exploratory trials may not always lead to simple tests of pre-defined hypotheses.
True/False:
Confirmatory trials may sometimes require a more flexible approach to design so that changes can be made in response to accumulating results.
False.
EXPLORATORY trials may sometimes require a more flexible approach to design so that changes can be made in response to accumulating results.
The analysis of exploratory trials may entail data exploration; tests of hypothesis may be carried out, but the choice of hypotheses may be data dependent. This is why such trials cannot be the basis of the:
Formal proof of efficacy.
They may still contribute to the total body of relevant evidence though.
True/False:
Any individual trial may have both confirmatory and exploratory aspects.
True
By which trial phase should the inclusion and exclusion criteria relax, so that the subjects in the trials more closely mirror the target population?
Confirmatory trial
Primary Variable (Target Variable, Primary Endpoint)
The variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial.
In general, how many primary variables should there be?
One
What kind of variable will the primary variable usually be?
Efficacy variable
There should be sufficient evidence that the primary variable can provide:
A valid and reliable measure of some clinically relevant and important treatment benefit in the patient population described by the inclusion and exclusion criteria.
Generally, which variable should be the one that determines sample size?
Primary variable
Why is it important that subject outcome be carefully defined?
In many cases, the approach to assessing subject outcome may not be straightforward.
There are many possible approaches to assessing subject outcome, such as:
- Comparisons of the assessments done at the beginning and end of the interval of observation
- Comparisons of slopes calculated from all assessments throughout the interval
- Comparisons of the proportions of subjects exceeding or declining beyond a specified threshold
- Comparisons based on methods for repeated measures data
The primary variable should be specified in the protocol, along with:
The rationale for its selection
True/False:
Redefinition of the primary variable after unblinding will almost always be acceptable.
False.
Redefinition of the primary variable after unblinding will almost always be UNACCEPTABLE, since the biases this introduces are difficult to assess.
When the clinical effect defined by the primary objective is to be measured in more than one way, the protocol should identify one of the measurements as the primary variable on the basis of:
- Clinical relevance
- Importance
- Objectivity
- Other relevant characteristics
Secondary variables are either supportive measurements related to the primary objective or:
Measurements of effects related to the secondary objectives
In the protocol, what should have an explanation of their relative importance and roles in interpretation of trial results?
Secondary 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:
Composite variable, using a pre-defined algorithm.
True/False:
When a composite variable is used as a primary variable, the components of this variable may sometimes be analyzed separately, where clinically meaningful and validated.
True
When a rating scale is used as a primary variable, it is especially important to address such factors as:
- Content validity
- Inter- and intra-rater reliability
- Responsiveness for detecting changes in the severity of disease
Why in some cases are global assessment variables developed?
To measure the overall safety, overall efficacy, and/or overall usefulness of a treatment
What 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?
Global assessment variable
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:
- The relevance of the scale to the primary objective of the trial
- The basis for the validity and reliability of the scale
- How to utilize the data collected on an individual subject to assign him/her to a unique category of the scale
- How to assign subjects with missing data to a unique category of the scale, or otherwise evaluate them
What is the problem with global usefulness variables?
A problem with global usefulness variables is that their use could in some cases lead to the result of two products being declares equivalent despite having very different profiles of beneficial and adverse effects.
Is it advisable to use a global usefulness variable as a primary variable?
No
It may sometimes be desirable to use more than one primary variable, each of which could be sufficient to cover the range of effects of the therapies. It should be clear whether an impact on any of the variables, some minimum number of them, or all of them, would be considered necessary to:
Achieve the trial objectives
Surrogate Variables
Indirect criteria that can be used when direct assessment of the clinical benefit to the subject through observing actual clinical efficacy is not practical.
What are the two principal concerns with the introduction of any proposed surrogate variable?
- It may not be a true predictor of the clinical outcome of interest
- It may not yield a quantitative measure of clinical benefit that can be weighed directly against adverse effects
In practice, the strength of the evidence for surrogacy depends upon:
- The biological plausibility of the relationship
- The demonstration in epidemiological studies of the prognostic value of the surrogate for the clinical outcome
- Evidence from clinical trials that treatment effects on the surrogate correspond to effects on the clinical outcome
What are 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 categorized as at or above some threshold level on an ordinal scale?
Criteria of “success” and “response” are common examples
Dichotomization or other categorizations are most useful when they have?
Clear clinical relevance
Why should the criteria for categorization be pre-defined and specified in the protocol?
Because knowledge of trial results could easily bias the choice of such criteria
Because categorization normally implies a loss of information, a consequence will be loss of power in the analysis. This should be accounted for in what?
The sample size calculation
What are the most important design techniques for avoiding bias in clinical trials?
Blinding and Randomization
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 knowledge of treatment may have on the:
- Recruitment and allocation of subjects
- The subsequent case of subjects
- The attitudes of subjects to the treatments
- The assessment of endpoints
- The handling of withdrawals
- the exclusion of data from analysis
Through what technique can double-blind conditions be achieved when the treatment options are of completely different natures?
Double-dummy technique
In cases where the double-blind nature of a clinical trial may be partially compromised by apparent treatment induced affects, how can blinding be improved?
By blinding investigators and relevant sponsor staff to certain test results
When is the only time that breaking the blind should be considered?
When knowledge of the treatment assignment is deemed essential by the subject’s physician for the subject’s care
What is the blind review of data?
The checking of data during the period of time between trial completion and the breaking of the blind
What does block randomization help increase?
The comparability of the treatment groups, particularly when subject characterization may change over time
What does block randomization provide for crossover studies?
The means of obtaining balanced designs with their greater efficiency and easier interpretation
Investigators and other relevant staff should generally be blind to block what?
Length
Is it advisable to have a separate random scheme for each center in a multicenter trial?
Yes, it is advisable to stratify by center or to allocate several whole blocks to each center.
What kind of stratification has greater potential benefit in small trials?
Stratification by important prognostic factors measures at baseline (severity of disease, age, sex, etc.) as it may promote a more balanced allocation within the strata.
True/False:
The use of two of three stratification factors is often necessary and is more successful at achieving balance.
False.
The use of more than two or three stratification factors is rarely necessary, is less successful at achieving balance and is logistically troublesome.
Where should the randomization schedule be filed?
The randomization schedule should be filed securely by the sponsor or an independent party in a manner that ensures that blindness is properly maintained throughout the trial.
What is Dynamic Allocation?
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.
What is the most common clinical trial design for confirmatory trials?
The parallel group design
Parallel Group Design
Subjects are randomized to one of two or more arms, each arm being allocated a different treatment.
These treatments will include the investigational product at one of more doses, and one or more control treatments, such as placebo and/or active comparator.
Crossover Design
Each subject is randomized to a sequence of two or more treatments and hence acts as his own control for treatment comparisons.
The crossover design is attractive primarily because it reduces the number of:
Subjects and assessments needed to achieve a specific power, sometimes to a marked extent.
2x2 Crossover Design
Each subject receives each of two treatments in randomized order in two successive treatment periods, often separated by a washout period.
What is the chief difficulty with crossover designs that could invalidate their results?
Carryover
Carryover
The residual influence of treatments in subsequent treatment periods.
The disease under a crossover design study should be:
Chronic and stable
Factorial Design
Two or more treatments are evaluated simultaneously through the use of varying combinations of the treatments.
2x2 Factorial Design
Subjects are randomly allocated to one of the four possible combinations of two treatments.
These are: A alone, B alone, both A and B, or neither A nor B.
In many cases why is the 2x2 factorial design used?
For the specific purpose of examining the interaction or treatment A and treatment B.
How does the 2x2 factorial design make efficient use of clinical trial subjects?
By evaluating the efficacy of the two treatments with the same number of subjects as would be required to evaluate the efficacy of either one alone.
The efficiency of the factorial 2x2 study design in regards to subject number has proved to be particularly valuable for trials with a high what?
Mortality rate
What are the two reasons that multicenter trials are carried out?
- A multicenter trial is an accepted way of evaluating a new medication more efficiently. It may present the only practical means of accruing sufficient subjects to satisfy the trial objective within a reasonable time-frame.
- To provide a better basis for subsequent generalization of the study’s 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.
In multicenter trials, variation of evaluation criteria and schemes can be reduced by:
- Investigator meetings
- The training of personnel in advance of the trial
- Careful monitoring during the trial
What should be done if heterogeneity of treatment effects is found in multicenter trials?
This should be interpreted with care and vigorous attempts should be made to find an explanation in terms of other features of trial management or subject characteristics.
Bayesian Approaches
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.
Bias (Statistical & Operational)
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’.
Blind Review
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 finalizing the planned analysis.
Content Validity
The extent to which a variable (e.g. a rating scale) measures what it is supposed to
measure.
Double-Dummy
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).
Dropout
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.
Equivalence Trial
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.
Frequentist Methods
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 realizations of the same experimental situation.
Full Analysis Set
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.
Generalisability, Generalisation
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.
Global Assessment Variable
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.
Independent Data Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)
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.
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 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.
Interaction (Qualitative & Quantitative)
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.
Inter-Rater Reliability
The property of yielding equivalent results when used by different raters on different
occasions.
Intra-Rater Reliability
The property of yielding equivalent results when used by the same rater on different
occasions.
Interim 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.
Meta-Analysis
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.
Multicenter Trial
A clinical trial conducted according to a single protocol but at more than one site, and
therefore, carried out by more than one investigator.
Non-Inferiority Trial
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).
Preferred and Included Terms
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”.
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. Compliance covers such
considerations as exposure to treatment, availability of measurements and absence of major protocol violations.
Safety & Tolerability
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), andother 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.
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 protocol, and
includes detailed procedures for executing the statistical analysis of the primary and
secondary variables and other data.
Superiority 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).
Surrogate Variable
A variable that provides an indirect measurement of effect in situations where direct
measurement of clinical effect is not feasible or practical.
Treatment Effect
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.
Treatment Emergent
An event that emerges during treatment having been absent pre-treatment, or
worsens relative to the pre-treatment state.
Trial Statistician
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.
Scientifically, what is most convincingly established by demonstrating superiority to placebo in a placebo-controlled trial, by showing superiority to placebo in a placebo-controlled trial, by showing superiority to an an active control treatment, or by demonstrating a dose-response relationship?
Efficacy
In what case would a placebo-controlled trial be unethical and the scientifically sound use of an active treatment as a control should be considered instead?
For serious illnesses, when a therapeutic treatment which has been shown to be efficacious by superiority trial(s) exists.
In some cases, an investigational product is compared to a reference treatment
without the objective of showing superiority. This type of trial is divided into two
major categories according to its objective:
- Equivalence trial
- Non-inferiority trial
The equivalence (or non-inferiority) trial is not conservative in nature, so flaws in the design or conduct of the trial will tend to bias the results towards a conclusion o equivalence. For these reasons, it is especially important to minimize the incidence of:
- Violation of the entry criteria
- Non-compliance
- Withdrawals
- Losses to follow-up
- Missing data
- Other deviations from the protocol
A comparator should be:
A widely used therapy whose efficacy in the relevant indication has been clearly established and quantified in well designed and well documented superiority trial(s) and which can be reliably expected to exhibit similar efficacy in the contemplated active control trial.
True/False:
A new superiority trial should have different design features than previously conducted superiority trials in which the active comparator clearly demonstrated clinically relevant efficacy, taking into account advances in medical or statistical practice relevant to the new trial.
False.
The new superiority trial should have the SAME important design features (primary variables, the dose of the active comparator, eligibility criteria, etc.) as the previously conducted superiority trials in which the active comparator clearly demonstrated clinically relevant efficacy, taking into account advances in medical or statistical practice relevant to the new trial.
For the active control equivalence trial, both the upper and the lower equivalence margins are needed, while only what margin is needed for the active control non-inferiority trial?
The lower margin
Statistical analysis is generally based on the use of confidence intervals. what confidence intervals should be used for equivalence trials?
Two-sided confidence intervals
Statistically, equivalence is inferred when:
The entire confidence interval falls within the equivalence margins
Why might using a full analysis set bias towards demonstrating equivalence?
Because subjects who withdraw or dropout of the treatment group or the comparator group will tend to have a lack of response.
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.
What may need to be tailored to the natural ordering of doses or to particular questions regarding the shape of the dose-response curve?
The hypothesis tests
Group sequential designs are used to:
Facilitate the conduct of interim analysis
While group sequential designs are not the only acceptable
types of designs permitting interim analysis, they are the most commonly applied. Why?
it is more practicable to assess grouped subject outcomes at periodic intervals
during the trial than on a continuous basis as data from each subject become
available.
What may be used to review or to conduct the interim analysis of data arising
from a group sequential design?
An Independent Data Monitoring Committee
The group sequential design has been most widely and successfully used in what kind of trials?
Large, long-term trials of mortality or major non-fatal endpoints
The number of subjects in a clinical trial should always be large enough to provide:
A reliable answer to the questions addressed
Using the usual method for determining the appropriate sample size, the following
items should be specified:
- A primary variable
- The test statistic
- The null hypothesis
- The alternative (‘working’) hypothesis at the chosen dose(s) (embodying consideration of the treatment difference to be detected or rejected at the dose and in the subject population selected)
- The probability of erroneously rejecting the null hypothesis (the
type I error) - The probability of erroneously failing to reject the null hypothesis
(the type II error) - The approach to dealing with treatment withdrawals and
protocol violations.
Type I Error
The probability of erroneously rejecting the null hypothesis
Type II Error
The probability of erroneously failing to reject the null hypothesis
In confirmatory trials, assumptions (sample size, deviations) should normally be based on:
published data or on the results of earlier trials
Sample size calculations should refer to the number of subjects required for the
primary analysis. If this is the ‘full analysis set’ what may need to be reduced?
Estimates of the effect size may need to be reduced compared to the per protocol set
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
When the power of an equivalence trial is assessed at a true
difference of zero, then the sample size necessary to achieve this power is
what if the true difference is not zero?
Underestimated
When the power of a non-inferiority trial is assessed at a zero difference, then the sample size needed to achieve that power will be what if the effect of the investigational product is less than that of the active control?
Underestimated
The collection of data and transfer of data from the investigator to the sponsor can
take place through a variety of media, including:
- Paper case report forms
- Remote site monitoring systems
- Medical computer systems
- Electronic transfer
When capturing data, missing values should be distinguishable from what?
Value zero or characteristic absent
What can ensure that difficulties with a clinical trial are noticed early and their occurrence or recurrence is minimized?
Monitoring
What are the two distinct types of monitoring that generally characterize confirmatory clinical trials sponsored by the pharmaceutical industry?
- One type concerns the oversight of the quality of the trial
- The other type involves breaking the blind to make treatment comparisons (interim analysis)
For the purpose of overseeing the quality of the trial the checks involved in trial
monitoring may include:
- Whether the protocol is being followed
- The acceptability of data being accrued
- The success of planned accrual targets
- The appropriateness of the design assumptions
- Success in keeping patients in the trials
True/False:
Oversight monitoring requires access to information on comparative
treatment effects, and unblinding of data and therefore impacts the type I error.
False.
Oversight monitoring does NOT require access to information on comparative
treatment effects, NOR unblinding of data and therefore has NO impact on type I error.
Who is responsible for oversight monitoring?
The sponsor
What does interim analysis require unblinded access to?
Treatment group assignment and comparative treatment group summary
Inclusion and exclusion criteria should remain constant, as specified in the protocol throughout the period of subject requirement, but there are times when change may be appropriate. What are some examples?
- In long term trials, when growing medical knowledge either from outside the trial or from interim analyses may suggest a change of entry criteria .
- The discovery by monitoring staff that regular violations of the entry criteria are occurring
- Seriously low recruitment rates due to over-restrictive criteria
In trials with a long time-scale for the accrual of subjects, the rate of accrual should
be monitored and, if it falls appreciably below the projected level, what should be done?
The reasons should be identified and remedial actions taken in order to protect the power of the trial and alleviate concerns about selective entry and other aspects of quality.
What should be done if an interim check conducted on the blinded data may
reveals that overall response variances, event rates or survival experience are not as
anticipated?
A revised sample size may need to be calculated using suitably modified
assumptions, and should be justified and documented in a protocol amendment and in the clinical study report.
All interim analyses should be carefully planned in advance and described in
the protocol. Special circumstances may dictate the need for an interim analysis that
was not defined at the start of a trial. In these cases, when should a protocol amendment describing the interim analysis be completed?
Prior to unblinded access to treatment comparison data
When an interim analysis is planned with the intention of deciding whether or not to terminate a trial, this is usually accomplished by the use of:
A group sequential design which employs statistical monitoring schemes as guidelines.
Why would an interim analysis result in a study closing early?
- The superiority of the treatment under study is clearly established
- The demonstration of a relevant treatment difference has become unlikely
- Unacceptable adverse effects are apparent
Why should the execution of an interim analysis be a completely confidential process?
Because unblinded data and results are potentially involved
Regarding an interim analysis, what information should be provided to the investigator(s)?
The decision to continue or to discontinue the trial, or to implement modifications to trial procedures
Most clinical trials intended to support the efficacy and safety of an investigational
product should proceed to full completion of planned sample size accrual; trials should be stopped early only for:
Ethical reasons or if the power is no longer acceptable.
For many clinical trials of investigational products, especially those that have major
public health significance, the responsibility for monitoring comparisons of efficacy
and/or safety outcomes should be assigned to an:
External independent group, often called an Independent Data Monitoring Committee (IDMC), a Data and Safety Monitoring Board or a Data Monitoring Committee whose responsibilities should be clearly described.
If unplanned interim analysis is conducted, the clinical study report should
explain:
- Why it was necessary
- The degree to which blindness had to be broken
- Provide an assessment of the potential magnitude of bias introduced
- The impact on the interpretation of the results
The composition of the IMDC should include:
Clinical trial scientists knowledgeable in the appropriate disciplines including statistics
True/False:
There can be sponsor representatives on the IMDC, but their role should be clearly defined in the operating procedures of the committee.
True
Since sponsor staff on the IMDC would have access to unblinded information, the procedures should also address:
The control of dissemination of interim trial results within the sponsor organization
True/False:
The statistical analysis plan may be written as a separate document to be completed prior to finalizing the protocol.
False.
The statistical analysis plan may be written as a separate document to be completed AFTER finalizing the protocol.
The statistical analysis plan should be reviewed and possibly updated as a result of the what?
The blind review of the data
The statistical analysis should be finalized when?
Before breaking the blind
The set of subjects whose data are to be included in the main analyses should be defined in what section of the protocol?
The statistical section
The content of this subject documentation depends on detailed features of the
particular trial, but at least this should be collected whenever possible?
Demographic and baseline data on disease status
It is desirable to identify any important protocol violation with respect to:
- The time when it occurred
- Its cause
- Its influence on the trial result
The intention-to-treat principle implies that the primary analysis should include all randomized subjects. In practice this ideal may be difficult to achieve, so 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 randomized subjects
There are a limited number of circumstances that might lead to excluding randomized subjects from the full analysis set including:
- The failure to satisfy major entry criteria (eligibility violations)
- The failure to take at least one dose of trial medication
- The lack of any data post randomization
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:
- The entry criterion was measured prior to randomization
- The detection of the relevant eligibility violations can be made completely
objectively - All subjects receive equal scrutiny for eligibility violations; (This may be
difficult to ensure in an open-label study, or even in a double-blind study if
the data are unblinded prior to this scrutiny, emphasizing the importance of
the blind review.) - All detected violations of the particular entry criterion are excluded
In some situations, it may be reasonable to eliminate from the set of all randomized
subjects any subject who took no trial medication. Would the intention-to-treat principle be preserved despite the exclusion of these patients?
Yes, provided that the decision of whether or not to begin treatment could not be influenced by knowledge of the assigned treatment
Special problems arise in connection with subjects withdrawn from treatment after receiving one or more doses who provide no data after this point, and subjects otherwise lost to follow-up, because failure to include these subjects in the full analysis set may seriously undermine:
The intention-to-treat approach
Because of the unpredictability of some problems, it may sometimes be preferable to defer detailed consideration of the manner of dealing with irregularities until:
The blind review of the data at the end of the trial, and, if so, this should be stated in the protocol.
Per Protocol set of subjects (Valid Cases/Efficacy Sample/Evaluable Subjects)
A subset of the subjects in the full analysis set who are more compliant with the protocol
Per protocol subjects are characterized by the following criteria:
- The completion of a certain pre-specified minimal exposure to the treatment regimen
- The availability of measurements of the primary variable(s)
- The absence of any major protocol violations including he violation of entry criteria
When should the precise reasons for excluding subjects from the per protocol set be fully defined and documented?
Before breaking the blind in a manner appropriate to the circumstances of the specific trial
In confirmatory trials it is usually appropriate to plan to conduct analysis of both the:
Full analysis set and a per protocol analysis
When the full analysis set and the per protocol set lead to essentially the
same conclusions, confidence in the trial results is:
Increased
In superiority trials, what analysis set is used in the primary analysis and why?
The full analysis set, because it tends to avoid over-optimistic estimates of efficacy resulting from a per protocol analysis, since the non-compliers included in the full analysis set will generally diminish the estimated treatment effect.
During statistical analysis, outliers were found, but no procedure for dealing with
outliers was foreseen in the trial protocol, what should be done?
One analysis with the actual values and at least one other analysis eliminating or reducing the outlier effect should be performed and differences between their results discussed.
Estimates of treatment effects should be accompanied by what whenever possible?
Confidence intervals
In the choice of statistical methods due attention should be paid to the statistical distribution of what?
Both primary and secondary variables
Methods to avoid or reduce multiplicity are sometimes preferable when available, such as:
- The identification of the key primary variable (multiple variables)
- The choice of a critical treatment contrast (multiple comparisons)
- The use of a summary measure such as ‘area under the curve’ (repeated measures)
The treatment effect itself may also vary with subgroup or covariate - for example, the effect may decrease with age or may be larger in a particular diagnostic category of subjects. In some cases such interactions are anticipated or are of particular prior
interest (e.g. geriatrics), and hence a subgroup analysis, or a statistical model
including interactions, is part of the planned:
Confirmatory analysis
In most cases, subgroup or interaction analyses are what?
Exploratory and should be identified as such
The credibility of the numerical results of the analysis depends on the quality and
validity of:
The methods and software (both internally and externally written) used both for data management (data entry, storage, verification, correction and retrieval) and also for processing the data statistically.
In any clinical trial the methods and measurements chosen to evaluate the safety and tolerability of a drug will depend on a number of factors, including:
- Knowledge of the adverse effects of closely related drugs
- Information from non-clinical and earlier clinical trials
- Possible consequences of the pharmacodynamic/pharmacokinetic
properties of the particular drug - The mode of administration
- The type of subjects to be studied
-The duration of the trial.
What usually forms the main body of the safety and tolerability data?
- Laboratory tests concerning clinical chemistry and hematology
- Vital signs
- Clinical adverse events (diseases, signs and symptoms)
The common adverse event dictionary has a structure which gives the possibility to summarize the adverse event data in three different levels:
- System-organ class
- Preferred term
- Included term
For the overall safety and tolerability assessment, the set of subjects to be
summarized is usually defined as those subjects who:
Received at least one dose of the investigational drug.
Common methods to reduce the effect of the background noise of signs and symptoms are:
- Ignoring adverse events of mild severity
- Requiring that an event should have been observed at repeated visits to qualify for inclusion
- Only record events if they emerge or worsen relative to pretreatment baseline (treatment emergent)
Such methods should be explained and justified in the protocol.
It is recommended that laboratory data be subjected to both a quantitative analysis, e.g. evaluation of treatment means, and a:
Qualitative analysis where counting of numbers above or below certain thresholds are calculated.
When the conduct of the trial is over and the data are assembled and available for preliminary inspection, it is valuable to carry out the blind review of the planned analysis. This pre-analysis review, blinded to treatment, should cover decisions
concerning, for example:
- The exclusion of subjects or data from the analysis sets
- Possible transformations may also be checked, and outliers defined
- Important covariates identified in other recent research may be added to the model - The use of parametric or non-parametric methods may be reconsidered
Statistically, what is an indispensable part of the study reports?
Descriptive statistics - this should include suitable tables and/or graphical presentations
Statistical judgement should be brought to bear on the analysis, interpretation and presentation of the results of a clinical trial. To this end, who should be a member of the team responsible for the clinical study report?
The trial statistician
An overall summary and synthesis of the evidence on safety and efficacy from all the
reported clinical trials is required for a:
Marketing application
Within the study summary a number of areas of specific statistical interest arise:
- Describing the demography and clinical features of the population treated during the course of the clinical trial program
- Addressing the key questions of efficacy by considering the results of the relevant (usually controlled) trials and highlighting the degree to which they reinforce or contradict each other
- Summarizing the safety information available from the combined database of all the trials whose results contribute to the marketing application and identifying potential safety issues.
When should the meta-analysis have its own prospectively written protocol?
When a meta analytic approach is the most appropriate way, or the only way, of providing sufficient overall evidence of efficacy via an overall hypothesis test.
Why does the combination of the safety data from all human exposure to the drug an important source of information?
Its larger sample size provides the best chance of detecting the rarer adverse events and, perhaps, or estimating their approximate incidence
