ACRP-CP Exam Flashcards by Anna Fite

Specific procedural steps to ensure that statistical principles are implemented properly are the responsibility of

the sponsor/experienced statistician

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clinical trials conducted in the later phases of development are

confirmatory trials of efficacy

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In addition to efficacy, confirmatory trials may have as their primary variable:

a safety variable (e.g. an adverse event, a clinical laboratory variable or an electrocardiographic measure) OR a pharmacodynamic or a pharmacokinetic variable (as in a confirmatory bioequivalence trial)

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early phases of drug development consist mainly of clinical trials that are

exploratory in nature

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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

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Bias introduced through deviations in conduct is referred to as

Operational bias

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Statistical bias examples include

Trial design, during conduct or analysis of the trial

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sensitivity of the overall conclusions to various limitations of the data, assumptions, and analytic approaches to data analysis. ________ implies that the treatment effect and primary conclusions of the trial are not substantially affected when analyses are carried out based on alternative assumptions or analytic approaches

Robustness

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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 Method

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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.

Bayesian Approaches

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The broad aim of the process of clinical development of a new drug is to find out whether there is a __________ at which the drug can be shown to be simultaneously safe and effective, to the extent that the risk-benefit relationship is acceptable.

dose range and schedule

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Interpretation and assessment of the evidence from the total __________ of trials involves synthesis of the evidence from the individual trials

programme

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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.

Meta-Analysis

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A _______ trial is an adequately controlled trial in which the hypotheses are stated in advance and evaluated. As a rule, ________ trials are necessary to provide firm evidence of efficacy or safety. In such trials the key hypothesis of interest follows directly from the trial’s primary objective, is always pre-defined, and is the hypothesis that is subsequently tested when the trial is complete.

Confirmatory trial

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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, Generalisation

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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

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The rationale and design of confirmatory trials nearly always rests on earlier clinical work carried out in a series of __________ studies. Such trials cannot be the basis of the formal proof of efficacy, although they may contribute to the total body of relevant evidence.

Exploratory

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The _____________ should be the variable capable of providing the most clinically relevant and convincing evidence directly related to the primary objective of the trial. There should generally be only one ______________.

Primary variable

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Primary variables could be:

Efficacy, safety and tolerability, quality of life, and health economics

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_____________ are either supportive measurements related to the primary objective or measurements of effects related to the secondary objectives.

Secondary variables

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If a single primary variable cannot be selected from multiple measurements associated with the primary objective, another useful strategy is to integrate or combine the multiple measurements into a single or __________ variable, using a pre- defined algorithm

composite

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

Content validity

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

Inter-Rater Reliability

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

Intra-Rater Reliability

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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

_____________ variables generally have a subjective component. When a _____________ variable is used as a primary or secondary variable, fuller details of the scale should be included in the protocol with respect to: 1) the relevance of the scale to the primary objective of the trial; 2) the basis for the validity and reliability of the scale; 3) how to utilise the data collected on an individual subject to assign him/her to a unique category of the scale; 4) how to assign subjects with missing data to a unique category of the scale, or otherwise evaluate them.

Global assessment

When direct assessment of the clinical benefit to the subject through observing actual clinical efficacy is not practical, indirect criteria (______________) may be considered.

Surrogate variables

A variable that provides an indirect measurement of effect in situations where direct measurement of clinical effect is not feasible or practical. It may not be a true predictor of the clinical outcome (safety and efficacy) of interest. Secondly, proposed _____________ may not yield a quantitative measure of clinical benefit that can be weighed directly against adverse effects.

Surrogate variables

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

Dichotomisation or other categorisation

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

dichotomisation/categorizations

The most important design techniques for avoiding bias in clinical trials are ________________, and these should be normal features of most controlled clinical trials intended to be included in a marketing application.

blinding and randomisation

The essential aim of ____________ is to prevent identification of the treatments until all such opportunities for bias have passed.

Blinding

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

double-blind

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

single-blind

In an __________ trial the identity of treatment is known to all.

open-label

Difficulties in achieving the double-blind ideal can arise: the treatments may be of a completely different nature, for example, surgery and drug therapy; two drugs may have different formulations and, although they could be made indistinguishable by the use of capsules, changing the formulation might also change the pharmacokinetic and/or pharmacodynamic properties and hence require that bioequivalence of the formulations be established; the daily pattern of administration of two treatments may differ. One way of achieving double-blind conditions under these circumstances is to use a _____________ technique. 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).

'double-dummy'

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.

The blind review

____________ introduces a deliberate element of chance into the assignment of treatments to subjects in a clinical trial. During subsequent analysis of the trial data, it provides a sound statistical basis for the quantitative evaluation of the evidence relating to treatment effects.

Randomization

In multicentre trials, the randomisation procedures should be organised __________. It is advisable to have a separate random scheme for each centre, i.e. to stratify by centre or to allocate several whole blocks to each centre. More generally, ___________ by important prognostic factors measured at baseline (e.g. severity of disease, age, sex, etc.) may sometimes be valuable in order to promote balanced allocation within strata; this has greater potential benefit in small trials.

centrally; stratification

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

Multi-center trial

The most common clinical trial design for confirmatory trials is the ________________ in which subjects are randomised to one of two or more arms, each arm being allocated a different treatment. These treatments will include the investigational product at one or more doses, and one or more control treatments, such as placebo and/or an active comparator.

parallel group design

In the __________ design, each subject is randomised to a sequence of two or more treatments, and hence acts as his own control for treatment comparisons. In the simplest 2×2 _________ design each subject receives each of two treatments in randomised order in two successive treatment periods, often separated by a washout period.

crossover

Potential problems with crossover design:

Carryover, that is, the residual influence of treatments in subsequent treatment periods. Loss of subjects Also, the potential for carryover leads to difficulties in assigning adverse events which occur in later treatment periods

A common, and generally satisfactory, use of the 2×2 __________ design is to demonstrate the bioequivalence of two formulations of the same medication.

crossover

The crossover design should generally be restricted to situations where losses of subjects from the trial are expected to be _______.

small

In a __________ two or more treatments are evaluated simultaneously through the use of varying combinations of the treatments. The simplest example is the 2×2 __________ in which subjects are randomly allocated to one of the four possible combinations of two treatments, A and B say. These are: A alone; B alone; both A and B; neither A nor B. In many cases this design is used for the specific purpose of examining the interaction of A and B. Another important use of the ____________ is to establish the dose-response characteristics of the simultaneous use of treatments C and D, especially when the efficacy of each monotherapy has been established at some dose in prior trials.

factorial design

Multicentre trials are carried out for two main reasons:

Efficiently and generalizability of findings

Such a trial would be a confirmatory trial in the later phases of drug development and would be likely to involve a large number of investigators and centres.

Multi-center

Trials that avoid excessive variation in the numbers of subjects per centre and trials that avoid a few very small centers (in multi-center trial) have advantages if it is later found necessary to take into account the _____________ of the treatment effect from centre to centre, because they reduce the differences between different weighted estimates of the treatment effect. (This point does not apply to trials in which all centres are very small and in which centre does not feature in the analysis.)

heterogeneity

In the simplest multicentre trial, each _____________ will be responsible for the subjects recruited at one hospital, so that ‘centre’ is identified uniquely by either investigator or hospital.

investigator

The statistical model to be adopted for the estimation and testing of treatment effects should be described in the ___________.

protocol

If ___________ of treatment effects is found, 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. In the absence of an explanation, ____________ of treatment effect as evidenced, for example, by marked quantitative interactions (see Glossary) implies that alternative estimates of the treatment effect may be required, giving different weights to the centres, in order to substantiate the robustness of the estimates of treatment effect

heterogeneity

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

Interaction (Qualitative & Quantitative) Quantitative; qualitative

Multicentre trials has been based on the use of fixed effect models (variables considered are fixed and non random). _______ models may also be used to explore the heterogeneity of the treatment effect. These models consider centre and treatment-by-centre effects to be random, and are especially relevant when the number of sites is large.

Mixed

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 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).

Non-inferiority 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.

Equivalence trial Bio equivalence trials are in this category

There are well known difficulties associated with the use of the active control equivalence (or non- inferiority) trials that do not incorporate a placebo or do not use multiple doses of the new drug. These relate to the implicit lack of any measure of ___________ (in contrast to superiority trials), thus making external validation necessary.

internal validity

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.

Full analysis set

____________ 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.

Dose-response

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

_________________ designs are used to facilitate the conduct of interim analysis

Group sequential

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.

Independent Data Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)

The number of subjects (sample size) in a clinical trial should always be large enough to provide a reliable answer to the questions addressed. This number is usually determined by the ______________ of the trial. If the sample size is determined on some other basis, then this should be made clear and justified.

primary objective

Sample size calculations should refer to the number of subjects required for the _______________. If this is the 'full analysis set', estimates of the effect size may need to be reduced compared to the per protocol set.

primary 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. Compliance covers such considerations as exposure to treatment, availability of measurements and absence of major protocol violations.

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

The sample size of an _________________ 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

equivalence trial or a non-inferiority trial

The exact sample size in a _______________ cannot be fixed in advance because it depends upon the play of chance in combination with the chosen stopping guideline and the true treatment difference.

group sequential trial

The process of data capture through to database finalisation should be carried out in accordance with _____ (see ICH E6, Section 5).

GCP

Two distinct types of monitoring that generally characterize confirmatory clinical trials sponsored by the pharmaceutical industry:

1. oversight of the quality of the trial 2. breaking the blind to make treatment comparisons (i.e. interim analysis)

The _______ (or appropriate amendments prior to a first analysis) contains statistical plans for the interim analysis to prevent certain types of bias

protocol

Changes to ____________ should be made without breaking the blind and should always be described by a protocol amendment which should cover any statistical consequences, such as sample size adjustments arising from different event rates, or modifications to the planned analysis, such as stratifying the analysis according to modified ____________ criteria.

inclusion/exclusion

In trials with a long time-scale for the accrual of subjects, the ______________ should be monitored and, if it falls appreciably below the projected level, 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. In a multicentre trial these considerations apply to the individual centres.

rate of accrual

The goal of such an interim analysis is to ___________ if the superiority of the treatment under study is clearly established, if the demonstration of a relevant treatment difference has become unlikely or if unacceptable adverse effects are apparent.

stop the trial early

Trial stopping guidelines and their properties should be clearly described in the protocol or amendments. The potential effects of early stopping on the analysis of other important variables should also be considered. This material should be written or approved by the __________________________

Data Monitoring Committee

The execution of an interim analysis should be a completely __________ process because unblinded data and results are potentially involved. All staff involved in the conduct of the trial should remain blind to the results of such analyses _____________ should only be informed about the decision to continue or to discontinue the trial, or to implement modifications to trial procedures.

confidential Investigators

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 __________________________ whose responsibilities should be clearly described.

an Independent Data Monitoring Committee (IDMC), a Data and Safety Monitoring Board or a Data Monitoring Committee

When a ___________ assumes the role of monitoring efficacy or safety comparisons and therefore has access to unblinded comparative information, particular care should be taken to protect the integrity of the trial and to manage and limit appropriately the sharing of information. The _____________ should assure and document that the internal monitoring committee has complied with written standard operating procedures and that minutes of decision making meetings including records of interim results are maintained.

Sponsor

An _____ may be established by the sponsor to assess at intervals the progress of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor whether to continue, modify or terminate a trial. The _____ is a separate entity from an Institutional Review Board (IRB) or an Independent Ethics Committee (IEC), and its composition should include clinical trial scientists knowledgeable in the appropriate disciplines including statistics. When there are sponsor representatives on the _______, their role should be clearly defined in the operating procedures of the committee (for example, covering whether or not they can vote on key issues).

IDMC

When designing a clinical trial the principal features of the eventual statistical analysis of the data should be described in the statistical section of the _________. This section should include all the principal features of the proposed confirmatory analysis of the primary variable(s) and the way in which anticipated analysis problems will be handled. In case of _________ trials this section could describe more general principles and directions.

protocol; exploratory

A ______________________ 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.

statistical analysis plan

The ____________________ may include detailed procedures for executing the statistical analysis of the primary and secondary variables and other data. The plan should be reviewed and possibly updated as a result of the blind review of the data (see 7.1 for definition) and should be finalised before breaking the blind. 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.

statistical analysis plan

If the blind review of statistical data suggests changes to the principal features stated in the protocol, these should be documented in a _______________. Otherwise, it will suffice to update the statistical analysis plan with the considerations suggested from the blind review. Only results from analyses envisaged in the protocol (including amendments) can be regarded as confirmatory.

protocol amendment

The set of subjects whose data are to be included in the main analyses should be defined in the _________ section of the protocol.

statistical

Possible amendments to the way in which the analysis will deal with protocol violations should be identified during the __________.

blind review

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 (see ICH E3).

clinical study report

Decisions concerning the analysis set should be guided by the following principles :

1) to minimise bias, and 2) to avoid inflation of type I error.

The _______________ principle implies that the primary analysis should include all randomised subjects. Compliance with this principle would necessitate complete follow-up of all randomised subjects for study outcomes. In practice this ideal may be difficult to achieve, for reasons to be described.

intention-to-treat

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. Will follow all subjects despite full compliance

Intention to treat

The term ______________ is used to describe the analysis set which is as complete as possible and as close as possible to the intention-to-treat ideal of including all randomised subjects.

full analysis set

There are a limited number of circumstances that might lead to excluding randomised 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 and the lack of any data post randomisation.

Subjects who fail to satisfy an ______________ may be excluded from the analysis without the possibility of introducing bias only under the following circumstances: (i) the ____________ was measured prior to randomisation; (ii) the detection of the relevant eligibility violations can be made completely objectively; (iii) 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, emphasising the importance of the blind review.) (iv) all detected violations of the particular _________ are excluded.

entry criterion

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

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

per protocol

The problems that lead to the exclusion of subjects to create the per protocol set, and other _____________________, should be fully identified and summarised. Relevant _____________________ may include errors in treatment assignment, the use of excluded medication, poor compliance, loss to follow-up and missing data. It is good practice to assess the pattern of such problems among the treatment groups with respect to frequency and time to occurrence.

protocol violations

In ________________ trials it is usually appropriate to plan to conduct both an analysis of the full analysis set and a per protocol analysis, so that any differences between them can be the subject of explicit discussion and interpretation. In some cases, it may be desirable to plan further ___________ of the sensitivity of conclusions to the choice of the set of subjects analysed.

confirmatory; exploration

When the full analysis set and the per protocol set lead to essentially the same conclusions, ______________ in the trial results is increased, bearing in mind, however, that the need to exclude a substantial proportion of subjects from the per protocol analysis throws some doubt on the overall validity of the trial.

confidence

The full analysis set and the per protocol set play different roles in_________ trials (which seek to show the investigational product to be superior), and in __________ or __________ trials (which seek to show the investigational product to be comparable, see section 3.3.2). In __________ trials the full analysis set is used in the primary analysis (apart from exceptional circumstances) 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. However, in an ___________ or ___________ trial use of the full analysis set is generally not conservative and its role should be considered very carefully.

superiority; equivalence; non-inferiority

Missing values represent a potential source of ______ in a clinical trial. Hence, every effort should be undertaken to fulfil all the requirements of the protocol concerning the collection and management of data. In reality, however, there will almost always be some missing data. A trial may be regarded as valid, nonetheless, provided the methods of dealing with missing values are sensible, and particularly if those methods are pre-defined in the protocol. Same with ___________.

bias; outliers

The statistical section of the protocol should specify the ____________ that are to be tested and/or the treatment effects which are to be estimated in order to satisfy the primary objectives of the trial. The statistical methods to be used to accomplish these tasks should be described for the primary (and preferably the secondary) variables, and the underlying statistical model should be made clear. Estimates of treatment effects should be accompanied by ________________, whenever possible, and the way in which these will be calculated should be identified

hypotheses; confidence intervals

When ____________ is present, the usual frequentist approach to the analysis of clinical trial data may necessitate an adjustment to the type I error. ____________ may arise, for example, from multiple primary variables (see Section 2.2.2), multiple comparisons of treatments, repeated evaluation over time and/or interim analyses (see Section 4.5).

multiplicity

The __________ 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 ______________ of the medical product represents the degree to which overt adverse effects can be tolerated by the subject.

Safety and tolerability

Laboratory tests concerning clinical chemistry and haematology, vital signs, and clinical adverse events (diseases, signs and symptoms) usually form the main body of the ____________________ data. The occurrence of serious adverse events and treatment discontinuations due to adverse events are particularly important to register (see ICH E2A and ICH E3).

safety and tolerability

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”.

Preferred and included terms

The adverse event dictionary has a structure which gives the possibility to summarise the adverse event data on three different levels:

system-organ class, preferred term or included term (see Glossary).

For the overall safety and tolerability assessment, the set of subjects to be summarised is usually defined as those subjects who received at least ____ dose of the investigational drug.

one

In situations when there is a substantial background noise of signs and symptoms (e.g. in psychiatric trials) one should consider ways of accounting for this in the estimation of risk for different adverse events. One such method is to make use of the ___________ concept in which adverse events are recorded only if they emerge or worsen relative to pretreatment baseline.

treatment emergent

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

Treatment emergent

The overall usefulness of a drug is always a question of balance between ____________ and in a single trial such a perspective could also be considered, even if the assessment of ____________ usually is performed in the summary of the entire clinical trial program. (See section 7.2.2)

risk/benefit

As stated in the Introduction, the structure and content of clinical study reports is the subject of ______.

ICH E3

As stated in the Introduction, the structure and content of clinical study reports is the subject of ______.

ICH E3

Safety and tolerability variables should be collected as comprehensively as possible from these subjects, including type of adverse event, severity, onset and duration (see ______). Additional safety and tolerability evaluations may be needed in specific subpopulations, such as females, the elderly (see ______), the severely ill, or those who have a common concomitant treatment. These evaluations may need to address more specific issues (see ______).

ICH E2B ICH E7 ICH E3

Further, an adverse event experienced after a ______________, such as use of an excluded medication, may introduce a bias. This background underlies the statistical difficulties associated with the analytical evaluation of safety and tolerability of drugs, and means that conclusive information from confirmatory clinical trials is the exception rather than the rule.

protocol violation

In the majority of trials investigators are seeking to establish that there are no clinically unacceptable differences in safety and tolerability compared with either a comparator drug or a placebo. As is the case for non-inferiority or equivalence evaluation of efficacy the use of ________________ is preferred to hypothesis testing in this situation.

confidence intervals

An overall summary and synthesis of the evidence on safety and efficacy from all the reported clinical trials is required for a __________________.

marketing application

A precise description of the treatment effect reflecting the clinical question posed by the trial objective. It summarises at a population-level what the outcomes would be in the same patients under different treatment conditions being compared.

Estimand

A numerical value computed by an estimator.

Estimate

A method of analysis to compute an estimate of the estimand using clinical trial data.

Estimator

Events occurring after treatment initiation that affect either the interpretation or the existence of the measurements associated with the clinical question of interest. It is necessary to address ___________________ when describing the clinical question of interest in order to precisely define the treatment effect that is to be estimated.

intercurrent events

Data that would be meaningful for the analysis of a given estimand but were not collected. They should be distinguished from data that do not exist or data that are not considered meaningful because of an intercurrent event.

Missing data

Classification of subjects according to the potential occurrence of an intercurrent event on all treatments. With two treatments, there are four principal strata with respect to a given intercurrent event: subjects who would not experience the event on either treatment, subjects who would experience the event on treatment A but not B, subjects who would experience the event on treatment B but not A, and subjects who would experience the event on both treatments.

principal stratification

In this document a ________________ refers to any of the strata (or combination of strata) defined by principal stratification.

principal stratum

A series of analyses conducted with the intent to explore the robustness of inferences from the main estimator to deviations from its underlying modelling assumptions and limitations in the data.

Sensitivity analysis

A general description for analyses that are conducted in addition to the main and sensitivity analysis with the intent to provide additional insights into the understanding of the treatment effect.

Supplemental analysis

It remains undisputed that _______________ is a cornerstone of controlled clinical trials and that analysis should aim at exploiting the advantages of _________________ to the greatest extent possible.

randomization

The framework outlined in the _______ addendum gives a basis for describing different treatment effects and some points to consider for the design and analysis of trials to give estimates of these treatment effects that are reliable for decision making (whether estimating an effect in accordance with the ITT principle always represents the treatment effect of greatest relevance to regulatory and clinical decision making). Secondly, issues considered generally under data handling and “missing data” (see Glossary) are re-visited.

ICH E9 (R1)

ICH E9 introduced the _______________________ principle in connection with the effect of a treatment policy in a randomised controlled trial, whereby subjects are followed, assessed and analysed irrespective of their compliance to the planned course of treatment, indicating that preservation of randomisation provides a secure foundation for statistical tests.

Intention-To-Treat (ITT)

Multiple consequences arising from the ITT principle can be distinguished. Firstly, that the trial analysis should include ____ subjects relevant for the research question. Secondly, that subjects should be included in the analysis as ______________. A third consequence is that subjects should be ___________&_____________ regardless of adherence to the planned course of treatment and that those assessments should be used in the analysis.

all; randomized; followed-up and assessed

Firstly, the ______ addendum distinguishes discontinuation of randomised treatment from study withdrawal. The former represents an intercurrent event, to be addressed in the precise specification of the trial objective through the estimand. The latter gives rise to missing data to be addressed in the statistical analysis.

ICH E9 (R1)

Secondly, the _______ addendum highlights the distinct consequences of different intercurrent events. Events such as discontinuation of treatment, switching between treatments, or use of an additional medication may render the later measurements of the variable irrelevant or difficult to interpret even when they can be collected. Measurements after a subject dies do not exist.

ICH E9 (R1)

Thirdly, issues related to the concept of analysis sets are considered in the framework of addendum ________. Section 5.2. strongly recommends that analysis of superiority trials be based on the full analysis set, defined to be as close as possible to including all randomised subjects. However, trials often include repeated measurements on the same subject. Clarity is introduced by carefully defining the treatment effect of interest in a way that determines both the population of subjects to be included in the estimation of that treatment effect and the observations from each subject to be included in the analysis considering the occurrence of intercurrent events.

ICH E9 (R1)

The meaning and role of an analysis of the _________ set is also re-visited in the ICH E9 (R1) addendum; in particular whether the need to explore the impact of protocol violations and deviations can be addressed in a way that is less biased and more interpretable than naïve analysis of the __________ set.

per protocol

Finally, the concept of _____________ (see 1.2.) is given expanded discussion under the heading of sensitivity analysis within addendum ICH E9 (R1). A distinction is made between the sensitivity of inference to the assumptions of a chosen method of analysis and the sensitivity to the choice of analytic approach more broadly.

robustness

The _______ is a systematic description of the treatment effect to be quantified in order to answer the trial's research objective. The _________ consists of the following five attributes: Treatment, Population, Variable, Population-Level Summary, and Handling of Intercurrent Events (ICEs).

estimand

The estimand framework enables proper trial planning that clearly distinguishes between the target of estimation (___________________), the method of estimation (_________), the numerical result (“__________”, see Glossary), and a sensitivity analysis. This will assist sponsors in planning trials, regulators in their reviews, and will enhance the interactions between these parties when discussing the suitability of clinical trial designs, and the interpretation of clinical trial results. The specification of appropriate estimands (see A.3.) will usually be the main determinant for aspects of trial design, conduct (see A.4.) and analysis (see A.5.).

trial objective, estimand estimator estimate

An __________ is a precise description of the treatment effect reflecting the clinical question posed by a given clinical trial objective. It summarises at a population level what the outcomes would be in the same patients under different treatment conditions being compared.

estimand

Unlike missing data, ____________ events are not to be thought of as a drawback to be avoided in clinical trials. Discontinuation of prescribed treatment, use of additional medication, and other such events may occur in clinical practice as they do in clinical trials, and their occurrence needs to be considered explicitly when defining the clinical question of interest.

intercurrent

In a clinical trial, _______________________ treatments are often identified as e.g. background treatment, rescue medication, prohibited medication, distinguishing their different roles and allowing them to be considered separately.

additional or alternative

The occurrence of the intercurrent event is considered irrelevant in defining the treatment effect of interest: the value for the variable of interest is used regardless of whether or not the intercurrent event occurs. For example, when specifying how to address use of additional medication as an intercurrent event, the values of the variable of interest are used whether or not the patient takes additional medication. If applied in relation to whether or not a patient continues treatment, and whether or not a patient experiences changes in other treatments (e.g. background or concomitant treatments), the intercurrent event is considered to be part of the treatments being compared. In that case, this reflects the comparison described in the ICH E9 Glossary (under ITT Principle) as the effect of a treatment policy.

Treatment policy strategy

A scenario is envisaged in which the intercurrent event would not occur: the value of the variable to reflect the clinical question of interest is the value which the variable would have taken in the hypothetical scenario defined. If a ____________________ is proposed, it should be made clear what hypothetical scenario is envisaged. For example, wording such as “if the patient does not take additional medication” might lead to confusion as to whether the patient hypothetically does not take additional medication because it is not available or because the particular patient is supposed not to require it.

hypothetical strategy(ies)

This relates to the variable of interest (see A.3.3.). An intercurrent event is considered in itself to be informative about the patient’s outcome and is therefore incorporated into the definition of the variable.

Composite variable strategies

For this strategy, response to treatment prior to the occurrence of the intercurrent event is of interest. Terminology for this strategy will depend on the intercurrent event of interest; e.g. “while alive”, when considering death as an intercurrent event. Like the composite variable strategy, the ___________________ can hence be thought of as impacting the definition of the variable, in this case by restricting the observation time of interest to the time before the intercurrent event.

While on treatment strategies

The target population might be taken to be the _____________ in which an intercurrent event would occur. Alternatively, the target population might be taken to be the _______________ in which an intercurrent event would not occur. The clinical question of interest relates to the treatment effect only within the _________________.

principal stratum

The validity of statistical analyses may rest upon untestable assumptions and, depending on the proportion of missing data, this may undermine the ____________ of the results (see A.5.).

robustness

To reduce ____________, measures can be implemented to retain subjects in the trial. However, measures to reduce or avoid ___________ events that would normally occur in clinical practice risk reducing the external validity of the trial.

missing data intercurrent

An _________ for the effect of treatment relative to a control will be estimated by comparing the outcomes in a group of subjects on the treatment to those in a similar group of subjects on the control.

estimand

For a given estimand, an _____________________, or estimator, should be implemented that is able to provide an estimate on which reliable interpretation can be based.

aligned method of analysis

Inferences based on a particular estimand should be robust to limitations in the data and deviations from the assumptions used in the statistical model for the main estimator. This robustness is evaluated through a __________________.

sensitivity analysis

Distinct from sensitivity analysis, where investigations are conducted with the intent of exploring robustness of departures from assumptions, other analyses that are conducted in order to more fully investigate and understand the trial data can be termed _________________________ (see Glossary; A.5.3.).

supplementary analysis

Supplementary analyses for an estimand can be conducted in addition to the main and sensitivity analysis to provide additional insights into the understanding of the ___________.

treatment effect

Section 5.2.3. indicates that it is usually appropriate to plan for analyses based on both the ____________________ and the __________________ so that differences between them can be the subject of explicit discussion and interpretation. Consistent results from analyses based on the ____ and the ____ is indicated as increasing confidence in the trial results.

Full Analysis Set (FAS) Per Protocol Set (PPS)

Analysis of the ________________ does not achieve the goal of estimating the effect in any principal stratum, for example, in those subjects able to tolerate and continue to take the test treatment, because it may not compare similar subjects on different treatments.

Per protocol set (PPS)

A trial __________ should define and specify explicitly a primary estimand that corresponds to the primary trial objective. The ___________ and the analysis plan should pre-specify the main estimator that is aligned with the primary estimand and leads to the primary analysis, together with a suitable sensitivity analysis to explore the robustness under deviations from its assumptions. Estimands for secondary trial objectives (e.g. related to secondary variables) that are likely to support regulatory decisions should also be defined and specified explicitly, each with a corresponding main estimator and a suitable sensitivity analysis. Additional exploratory trial objectives may be considered for exploratory purposes, leading to additional estimands.

Protocol

Results from the main, sensitivity and supplementary analyses should be reported systematically in the ___________________, specifying whether each analysis was pre-specified, introduced while the trial was still blinded, or performed post hoc. Summaries of the number and timings of each intercurrent event in each treatment group should be reported.

clinical trial report

Changes to the _________ during the trial can be problematic and can reduce the credibility of the trial. Addressing intercurrent events that were not foreseen at the design stage, and are identified during the conduct of the trial, should discuss not only the choices made for the analysis, but the effect on the _________, i.e. on the description of the treatment effect that is being estimated, and the interpretation of the trial results. A change to the _________ should usually be reflected through amendment to the protocol.

estimand

________________________ is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the ______________________, and that the clinical trial data are credible.

Good Clinical Practice (GCP) Declaration of Helsinki

The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the United States to facilitate the __________________ of clinical data by the regulatory authorities in these jurisdictions.

mutual acceptance

all noxious and unintended responses to a medicinal product related to any dose should be considered:

adverse drug reactions

all noxious and unintended responses to a medicinal product related to any dose should be considered:

adverse drug reactions

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An _________________ can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

adverse event (AE)

Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.

Applicable regulatory requirements

The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and the applicable regulatory requirements.

Approval (related to IRB)

A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

Audit

A declaration of confirmation by the auditor that an audit has taken place.

Audit certificate

A written evaluation by the sponsor's auditor of the results of the audit.

Audit report

Documentation that allows reconstruction of the course of events.

Audit trail

A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s)._______-blinding usually refers to the subject(s) being unaware, and _______- blinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment assignment(s).

Blinding/masking Single Double

A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.

Case report forms (CRF)

A printed, optical, or electronic document designed to record all of the protocol required information to be reported to the sponsor on each trial subject.

Case report forms (CRF)

Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. These terms are synonymous.

clinical trial and clinical study

A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports).

Clinical trial/study report

An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial.

Comparator (product)

Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable regulatory requirements.

Compliance (in relation to clinical trials)

Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of a subject's identity.

Confidentiality

A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol may serve as the basis of a contract.

Contract

A committee that a sponsor may organize to coordinate the conduct of a multicentre trial

Coordinating committee

An investigator assigned the responsibility for the coordination of investigators at different centres participating in a multicentre trial.

Coordinating investigator

A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions.

Contract Research Organization (CRO)

Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors) with __________________ should take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s proprietary information.

Direct access

All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken.

Documentation

Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced

Essential documents

A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.

Good Clinical Practice (GCP)

Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee, Data Monitoring Committee)

A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read, and who reads the informed consent form and any other written information supplied to the subject.

Impartial witness

An independent body (a review board or a committee, institutional, regional, national, or supranational), constituted of medical professionals and non-medical members, whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, reviewing and approving/providing favourable opinion on, the trial protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

Independent Ethics Committee (IEC)

A process by which a subject voluntarily confirms his or her willingness to participate in a particular trial, after having been informed of all aspects of the trial that are relevant to the subject's decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.

Informed consent

The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located at the site of the trial, at the sponsor's and/or contract research organization’s (CRO’s) facilities, or at other establishments deemed appropriate by the regulatory authority(ies).

Inspection

Any public or private entity or agency or medical or dental facility where clinical trials are conducted.

Institution (medical)

An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the methods and material to be used in obtaining and documenting informed consent of the trial subjects.

IRB

A report of intermediate results and their evaluation based on analyses performed during the course of a trial.

Interim clinical trial/study report

A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Investigational product

A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal investigator. See also Subinvestigator.

Investigator

A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to the study of the investigational product(s) in human subjects.

Investigator’s brochure

An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective subject, to the subject's participation in the clinical trial.

Legally Acceptable Representative

The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

Monitoring

A written report from the monitor to the sponsor after each site visit and/or other trial-related communication according to the sponsor’s SOPs.

Monitoring report

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

Multi center trial

Biomedical studies not performed on human subjects.

Nonclinical study

The judgement and/or the advice provided by an Independent Ethics Committee (IEC).

Opinion (in relation to Independent Ethics Committee)

Original medical record

Source documents

A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol amendments.

Protocol

A written description of a change(s) to or formal clarification of a protocol.

Protocol amendment

A written description of a change(s) to or formal clarification of a protocol.

Protocol amendment

All those planned and systematic actions that are established to ensure that the trial is performed and the data are generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the applicable regulatory requirement(s).

Quality assurance

The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled.

Quality Control (QC)

The process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias.

Randomization

Bodies having the power to regulate. In the ICH GCP Guideline the expression _________________ includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29). These bodies are sometimes referred to as competent authorities.

Regulatory Authorities

Any untoward medical occurrence that at any dose: - results in death, - is life-threatening, - requires inpatient hospitalization or prolongation of existing hospitalization, - results in persistent or significant disability/incapacity,

Serious Adverse Event (SAE)

Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)

All information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents (original records or certified copies).

Source data

Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial).

Source documents

An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.

Sponsor

An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate direction the investigational product is administered to, dispensed to, or used by a subject. The term does not include any person other than an individual (e.g., it does not include a corporation or an agency). The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.

Sponsor-investigator

Detailed, written instructions to achieve uniformity of the performance of a specific function.

Standard Operating Procedures (SOPs)

Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates, residents, research fellows). See also Investigator.

Sub investigator

An individual who participates in a clinical trial, either as a recipient of the investigational product(s) or as a control.

Subject/Trial Subject

A unique identifier assigned by the investigator to each trial subject to protect the subject's identity and used in lieu of the subject's name when the investigator reports adverse events and/or other trial related data.

Subject Identification Code

The location(s) where trial-related activities are actually conducted.

Trial Site

An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting).

Unanticipated adverse drug reaction

Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

Vulnerable subjects

The physical and mental integrity of the subjects participating in a clinical trial.

Well being of trial subjects

A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated signature or by generation through a validated process) to have the same information, including data that describe the context, content, and structure, as the original.

Certified copy

A document that describes the strategy, methods, responsibilities, and requirements for monitoring the trial.

Monitoring plan

A process of establishing and documenting that the specified requirements of a computerized system can be consistently fulfilled from design until decommissioning of the system or transition to a new system. The approach to validation should be based on a risk assessment that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results.

Validation of computerized systems

Clinical trials should be conducted in accordance with the ethical principles that have their origin in the ___________________________, and that are consistent with GCP and the applicable regulatory requirement(s).

Declaration of Helsinki

A trial should be conducted in compliance with the protocol that has received prior _________________________ approval/favourable opinion.

institutional review board (IRB)/independent ethics committee (IEC)

Investigational products should be manufactured, handled, and stored in accordance with applicable _____________________. They should be used in accordance with the approved protocol.

good manufacturing practice (GMP)

Investigational products should be manufactured, handled, and stored in accordance with applicable _____________________. They should be used in accordance with the approved protocol.

good manufacturing practice (GMP)

The _______ should obtain the following documents: trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator proposes for use in the trial, subject recruitment procedures (e.g., advertisements), written information to be provided to subjects, Investigator's Brochure (IB), available safety information, information about payments and compensation available to subjects, the investigator’s current curriculum vitae and/or other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to fulfil its responsibilities. The _______ should review a proposed clinical trial within a reasonable time and document its views in writing, clearly identifying the trial, the documents reviewed and the dates for the following: - approval/favourable opinion; - modifications required prior to its approval/favourable opinion; - disapproval / negative opinion; and - termination/suspension of any prior approval/favourable opinion.

IRB/IEC

The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the degree of risk to human subjects, but at least ______ per year.

Continuing review occurs once per year

The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended that the IRB/IEC should include: (a) At least _____ members. (b) At least one member whose primary area of interest is in a ___________ area. (c) At least one member who is _____________ of the institution/trial site. Only those IRB/IEC members who are ______________ of the investigator and the sponsor of the trial should vote/provide opinion on a trial-related matter. A list of IRB/IEC members and their qualifications should be maintained.

Five nonscientific independent

Specifying that the investigator should promptly report to the IRB/IEC: (4)

(a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7, 4.5.2, 4.5.4). (b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2). (c) All adverse drug reactions (ADRs) that are both serious and unexpected. (d) New information that may affect adversely the safety of the subjects or the conduct of the trial.

The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for a period of at least __________ after completion of the trial and make them available upon request from the regulatory authority(ies).

3-years

The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as described in the _________, ____________________, in the product information and in other information sources provided by the sponsor.

protocol, in the current Investigator's Brochure

The ____________ should maintain a list of appropriately qualified persons to whom the investigator has delegated significant trial-related duties.

investigator

The ______________ should ensure that all persons assisting with the trial are adequately informed about the protocol, the investigational product(s), and their trial-related duties and functions.

investigator

The _____________ is responsible for supervising any individual or party to whom the investigator delegates trial-related duties and functions conducted at the trial site. If the _______________________ retains the services of any individual or party to perform trial-related duties and functions, the _______________________ should ensure this individual or party is qualified to perform those trial-related duties and functions and should implement procedures to ensure the integrity of the trial-related duties and functions performed and any data generated.

investigator investigator/institution

Before initiating a trial, the investigator/institution should have written and dated approval/favourable opinion from the IRB/IEC for the trial:

protocol written informed consent form consent form updates subject recruitment procedures (e.g., advertisements) and any other written information to be provided to subjects

As part of the investigator's/institution’s written application to the IRB/IEC, the investigator/institution should provide the IRB/IEC with a current copy of the _____________________. If the _____________________. is updated during the trial, the investigator/institution should supply an updated copy to the IRB/IEC.

Investigator's Brochure

The investigator/institution should conduct the trial in compliance with the protocol agreed to by the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by the IRB/IEC. The ________________ and _____________ should sign the protocol, or an alternative contract, to confirm agreement.

investigator/institution the sponsor

The investigator should not implement any deviation from, or changes of the protocol without agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an amendment, except:

where necessary to eliminate an immediate hazard(s) to trial subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of telephone number(s)).

The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be submitted:

IRB Sponsor Regulatory Authorities

IRB/IEC for favorable opinion/approval Sponsor for agreement Regulatory Authorities (if necessary)

Responsibility for investigational product(s) accountability at the trial site(s) rests with the _______________________. Includes storage delegation to pharmacist, record keeping (delivery, inventory, use, by subject and return to sponsor), and ensuring product is used per protocol.

investigator/institution

Any revised written informed consent form, and written information should receive the _______ approval/favourable opinion in advance of use.

IRB/IEC's

In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the _______________. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written approval/favourable opinion of the written informed consent form and any other written information to be provided to subjects.

Declaration of Helsinki

Prior to a subject’s participation in the trial, the written informed consent form should be signed and personally dated by the subject or by _______________________ and by ______________________.

the subject or by the subject's legally acceptable representative the person who conducted the informed consent discussion.

If a subject is unable to read or if a legally acceptable representative is unable to read, a ___________ should be present during the entire informed consent discussion. After the written informed consent form and any other written information to be provided to subjects, is read and explained to the subject or the subject’s legally acceptable representative, and after the subject or the subject’s legally acceptable representative has ______ consented to the subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed consent form, the ______ should sign and personally date the consent form.

impartial witness orally Witness

The ICF should explain the following:

Purpose of the study, what’s experimental about it, risk/benefits of participation, compensation, randomization, confidentiality of records, voluntary participation, trial contacts in even of trial related injury, possible reasons for trial participation termination, expected duration of trial and how many patients to be recruited

Except as described in 4.8.14, a _______________________ (i.e., a trial in which there is no anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and date the written informed consent form.

non-therapeutic trial

4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative provided the following conditions are fulfilled:

(a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent personally. (b) The foreseeable risks to the subjects are low. (c) The negative impact on the subject’s well-being is minimized and low. (d) The trial is not prohibited by law. (e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the written approval/ favourable opinion covers this aspect. So if there’s no other patient populations to test, risk and negative impact are low, it’s not unlawful, and if IRB/IEC approve

When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the trial with the consent of the subject’s legally acceptable representative (e.g., minors, or patients with severe dementia), the subject should be:

informed about the trial to the extent compatible with the subject’s understanding and, if capable, the subject should sign and personally date the written informed consent.

In emergency situations, when prior consent of the subject is not possible, the consent of the subject's ____________________, if present, should be requested. If __________________ isn’t present, follow procedure in protocol approved by IRB/IEC

legally acceptable representative

Prior to participation in the trial, the subject or the subject's legally acceptable representative should receive:

a copy of the signed and dated written informed consent form and any other written information provided to the subjects.

The _________________ should maintain adequate and accurate source documents and trial records that include all pertinent observations on each of the site’s trial subjects.

investigator/institution

Any change or correction to a CRF should be ______________________ and should not obscure the original entry

dated, initialed, and explained (if necessary)

The investigator/institution should maintain the trial documents as specified in _____________________________________ and as required by the applicable regulatory requirement(s). The investigator/institution should take measures to prevent accidental or premature destruction of these documents.

Essential Documents for the Conduct of a Clinical Trial (see 8.)

Essential documents should be retained until at least _____-years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least_____-years have elapsed since the formal discontinuation of clinical development of the investigational product.

The investigator should submit written summaries of the trial status to the IRB/IEC __________, or more frequently, if requested by the IRB/IEC.

annually Progress reports to be submitted by investigator once per year unless required more often by IRB

All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that the _________ or other document (e.g.,__________________) identifies as not needing immediate reporting.

protocol Investigator's Brochure

If the ____________ terminates or suspends a trial without prior agreement of the sponsor, the ____________ should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the termination or suspension. If the ____________ terminates or suspends a trial (see 5.21), the investigator should promptly inform the institution where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of the termination or suspension. If the ____________ terminates or suspends its approval/favourable opinion of a trial (see 3.1.2 and 3.3.9), the investigator should inform the institution where applicable and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.

Investigator Sponsor IRB/IEC

Upon completion of the trial, the _____________, where applicable, should inform the institution; the investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(ies) with any reports required.

Investigator

The _______ should implement a system to manage quality throughout all stages of the trial process.

sponsor

The ________ is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

sponsor

The _________ is responsible for securing agreement from all involved parties to ensure direct access (see 1.21) to all trial related sites, source data/documents , and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.

sponsor

A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the ________. The CRO should implement quality assurance and quality control.

sponsor

Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the __________.

sponsor

The sponsor may consider establishing an _________________ to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The _______ should have written operating procedures and maintain written records of all its meetings.

independent data-monitoring committee (IDMC)

The ____________ should utilize qualified individuals (e.g., biostatisticians, clinical pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.

sponsor

The sponsor should base their approach to validation of such systems (electronic trial data handling and/or remote electronic trial data systems) on a _______________ that takes into consideration the intended use of the system and the potential of the system to affect human subject protection and reliability of trial results.

risk assessment

The ________, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical Trial).

sponsor

If the sponsor discontinues the clinical development of an investigational product (i.e., for any or all indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential documents for at least ____-years after formal discontinuation or in conformance with the applicable regulatory requirement(s).

Before entering an agreement with an investigator/institution to conduct a trial, the sponsor should provide the investigator(s)/institution(s) with the _________ and an up-to- date ______________, and should provide sufficient time for the investigator/institution to review the protocol and the information provided.

protocol Investigator's Brochure

The sponsor should obtain the investigator's/institution's agreement:

- comply with GCP during trial - ensure data reporting/handling - permit monitoring, auditing, and inspection - store essential documents

The _______ should determine, for the investigational product(s), acceptable storage temperatures, storage conditions (e.g., protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.

sponsor

The _________ should ensure that it is specified in the protocol or other written agreement that the investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory inspection.

sponsor

The _______ is responsible for the ongoing safety evaluation of the investigational product(s). The________ should promptly notify all concerned investigator(s)/institution(s) and the regulatory authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.

sponsor

The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both ________ and ___________.

serious unexpected

The purposes of trial ______________ are to verify that: (a) The rights and well-being of human subjects are protected. (b) The reported trial data are accurate, complete, and verifiable from source documents. (c) The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).

monitoring

___________ monitoring is performed at the sites at which the clinical trial is being conducted. ____________ monitoring is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately qualified and trained persons (e.g., data managers, biostatisticians).

On-site Centralized

Review, that may include ____________________, of accumulating data from centralized monitoring can be used to: (a) identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations. (b) examine data trends such as the range, consistency, and variability of data within and across sites. (c) evaluate for systematic or significant errors in data collection and reporting at a site or across sites; or potential data manipulation or data integrity problems. (d) analyze site characteristics and performance metrics. (e) select sites and/or processes for targeted on-site monitoring.

statistical analyses

The __________ ensures that the investigator and the investigator's trial staff are adequately informed about the trial.

monitor

The ___________ in accordance with the sponsor’s requirements should ensure that the trial is conducted and documented properly

monitor(s)

Main line of communication between sponsor and investigator

Monitor

Monitors verify:

That the investigator and site are compliant, all is stored and documented correctly especially essential documents, check for accurate completion of CRF entries, determine whether all adverse events (AEs) are appropriately reported within the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the applicable regulatory requirement(s), and communicate deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.

The monitor should submit a written report to the sponsor after: Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or actions recommended to secure compliance.

each trial-site visit or trial-related communication

The sponsor should develop a __________________ that is tailored to the specific human subject protection and data integrity risks of the trial. The plan should describe the monitoring strategy, the monitoring responsibilities of all the parties involved, the various monitoring methods to be used, and the rationale for their use. The plan should also emphasize the monitoring of critical data and processes.

monitoring plan

The purpose of a sponsor's _____, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.

audit

The sponsor should appoint individuals, who are _______________ of the clinical trials/systems, to conduct audits.

independent

To preserve the independence and value of the audit function, the regulatory authority(ies) should not routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case basis when evidence of serious __________________ exists, or in the course of legal proceedings.

GCP non-compliance

If a trial is prematurely terminated or suspended, the sponsor should ________ inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The IRB/IEC should also be informed _________ and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s).

promptly

Whether the trial is completed or prematurely terminated, the sponsor should ensure that the ______________ are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory requirement(s). The sponsor should also ensure that the ______________ in marketing applications meet the standards of the ICH Guideline for Structure and Content of Clinical Study Reports.

clinical trial reports

Clinical trial protocol includes:

- general information - background information - trial objectives and purpose - trial design - selection and withdrawal of subjects - treatment of subjects - assessment of efficacy (specify efficacy parameters and how these will be analyzed) - assessment of safety - statistics - direct access to source data/documents (monitoring permissions) - ethics - data handling and record keeping - financing and insurance - publication policy -supplements

The following are required components of what? - general information - background information - trial objectives and purpose - trial design - selection and withdrawal of subjects - treatment of subjects - assessment of efficacy (specify efficacy parameters and how these will be analyzed) - assessment of safety - statistics - direct access to source data/documents (monitoring permissions) - ethics - data handling and record keeping - financing and insurance - publication policy -supplements

Protocol

The _____________________ is a compilation of the clinical and nonclinical data on the investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to provide the investigators and others involved in the trial with the information to facilitate their understanding of the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose frequency/interval, methods of administration: and safety monitoring procedures. The _____________________ also provides insight to support the clinical management of the study subjects during the course of the clinical trial.

Investigator's Brochure (IB)

The IB should be reviewed at least _________ and revised as necessary in compliance with a sponsor's written procedures.

annually

Generally, the _________ is responsible for ensuring that an up-to-date IB is made available to the investigator(s) and the _________________ are responsible for providing the up-to-date IB to the responsible IRBs/IECs.

sponsor investigators

The IB should include:

Title Page Confidentiality Statement Table of Contents Summary Introduction Physical, Chemical, and Pharmaceutical Properties and Formulation Nonclinical Studies Nonclinical Pharmacology Pharmacokinetics and Product Metabolism in Animals Toxicology Effects in Humans Pharmacokinetics and Product Metabolism in Humans Safety and efficacy Marketing Experience (where is it approved) Summary of Data and Guidance for the Investigator

The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical trial. This understanding should be based on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and clinical information on the investigational product(s). Guidance should also be provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions that is based on previous human experience and on the pharmacology of the investigational product.

The following are components of? Title Page Confidentiality Statement Table of Contents Summary Introduction Physical, Chemical, and Pharmaceutical Properties and Formulation Nonclinical Studies Nonclinical Pharmacology Pharmacokinetics and Product Metabolism in Animals Toxicology Effects in Humans Pharmacokinetics and Product Metabolism in Humans Safety and efficacy Marketing Experience (where

Investigator Brochure (IB)

The ______________________ are an integrated set of guidance covering the planning, design, conduct, safety, analysis, and reporting of clinical studies. ICH E8 provides an overall introduction to clinical development, designing quality into clinical studies and focusing on those factors critical to the quality of the studies. The guidelines should be considered and used in an integrated, holistic way rather than focusing on only one guideline or subsection.

ICH Efficacy guidelines

Quality of a clinical study is also considered in this document as _____________________. The purpose of a clinical study is to generate reliable information to answer the research questions and support decision making while protecting study participants.

fitness for purpose

After initial clinical studies provide sufficient information on safety, clinical pharmacology and dose, __________ and __________ studies (usually referred to as phases 2 and 3, respectively) are conducted to further evaluate both the safety and efficacy of the drug.

exploratory and confirmatory

Phase 1 study looks to:

Establish dosage, methods of pharmacokinetics (metabolism/absorption/maybe drug level to response testing in healthy subjects)

The initial administration of an investigational product to humans (usually referred to as:

phase 1

After initial clinical studies provide sufficient information on safety, clinical pharmacology and dose, __________________________ studies (usually referred to as phases 2 and 3, respectively) are conducted to further evaluate both the safety and efficacy of the drug.

exploratory and confirmatory

_______________ studies are designed to investigate safety and efficacy in a selected population of patients for whom the drug is intended. Additionally, these studies aim to refine the effective dose(s) and regimen, refine the definition of the targeted population, provide a more robust safety profile for the drug, and include evaluation of potential study endpoints for subsequent studies.

Exploratory

________________ studies are designed to confirm the preliminary evidence accumulated in earlier clinical studies that a drug is safe and effective for use for the intended indication and recipient population. These studies are often intended to provide an adequate basis for marketing approval, and to support adequate instructions for use of the drug and official product information.

Confirmatory

This (study design) may include investigating subgroups of patients with frequently occurring or potentially relevant co- morbidities (e.g., cardiovascular disease, diabetes, hepatic and renal impairment) to characterise the safe and effective use of the drug in patients with these conditions.

Confirmatory study

________ provides an outline of critical issues in paediatric drug development and approaches to the safe, efficient, and ethical study of drugs in paediatric populations.

ICH E11

A key aspect of a ______ approach to study design is to ask whether the objectives being addressed by the study are clearly articulated; whether the study is designed to meet the research question it sets out to address; whether these questions are meaningful to patients; and whether the study hypotheses are specific and scientifically valid.

quality

Clinical study design is best informed by input from a broad range of _______________, including patients and healthcare providers. It should be open to challenge by subject matter experts and stakeholders from outside, as well as within, the sponsor organisation.

stakeholders

Ensuring adequate quality and characterisation of _______________________ properties of investigational medicinal product is an important element in planning a drug development programme and is addressed in ICH and regional quality guidelines.

physicochemical

Age-appropriate formulation development may be a consideration when clinical studies are planned in ___________ populations.

pediatric (ICH E11- E11A Clinical Trials in Pediatric Population)

Guidance on non-clinical safety studies is provided in ______ Nonclinical Safety Studies, ICH Safety (S) Guidelines and related Q&A documents, as well as in regional guidance

ICH M3

_________________ support clinical studies (and may encompass evidence generated in in vivo and in vitro models, and by modelling and simulation)

Non clinical studies

The scope of ____________ studies, and their timing with respect to clinical studies, depend on a variety of factors that inform further development, such as - drug’s chemical or molecular properties - mechanism of action - route(s) of administration; absorption, distribution, metabolism, and excretion (ADME) - physiological effects on organ systems - dose/concentration-response relationships - metabolites - and duration of action and use

Non clinical

Guidance for non-clinical safety studies to support human clinical studies in special populations should be reviewed (see, e.g., _______ Reproductive Toxicology, ______ Nonclinical Paediatric Safety, and ____).

ICH S5 S11 M3

The use of biomarkers has the potential to facilitate the availability of safer and more effective drugs, to guide dose selection, and to enhance a drug’s benefit-risk profile (see _______ Qualification of Genomic Biomarkers) and may be considered throughout drug development.

ICH E16

Phase __ studies may be conducted in healthy volunteer participants or in a selected population of patients who have the condition or the disease, depending on drug properties and the objectives of the development programme.

Phase 1

The initial and subsequent administration of a drug to humans is usually intended to determine the _______________________

tolerability of the dose range

Phase __ studies often intended to provide an adequate basis for marketing approval, and to support adequate instructions for use of the drug and official product information. They aim to evaluate the drug in participants with or at risk of the condition or disease who represent those who will receive the drug once approved. This may include investigating subgroups of patients with frequently occurring or potentially relevant co- morbidities (e.g., cardiovascular disease, diabetes, hepatic and renal impairment) to characterise the safe and effective use of the drug in patients with these conditions.

3/confirmatory

If the intent is to administer a drug for a long period of time, then studies involving extended exposure to the drug should be conducted (_______Clinical Safety for Drugs used in Long-Term Treatment).

ICH E1

_________ provides an outline of critical issues in paediatric drug development and approaches to the safe, efficient, and ethical study of drugs in paediatric populations.

ICH E11

_______ provides an outline of critical issues in developing drugs for use in geriatric populations and approaches to their safe, efficient, and ethical study.

ICH E7

After the approval of a drug, additional studies may be conducted to further understand the safety and efficacy of the drug in its approved indication (usually referred to as phase ___).

__________ design studies allow prospectively planned modifications to the study, such as changes in the population studied or changes in doses of the drug studied over the course of the study, based on accumulating data.

adaptive

_________________ studies allow for the investigation of multiple drugs or multiple conditions under a shared framework.

Master protocol

___________ studies allow for multiple drugs to be investigated in a continuous manner, with different drugs entering the study at different times and leaving the study based on pre-specified decision rules.

Platform

The designs of randomised studies range from simple parallel group designs to more complex variants. Name the complex examples:

Adaptive Master protocol Platform

The number of participants (sample size) in a study should be large enough to provide a reliable answer to the questions addressed (see ICH E9). This number is usually determined by the ______________ of the study.

primary objective

Study population determined by _______

Inclusion and exclusion criteria

The major purpose of a ________________ is to separate the effect of the treatment(s) from the effects of other factors such as natural course of the disease, other medical care received, or observer or patient expectations

control group (E10 Choice of Control Group in Clinical Trials)

The definition of _____________ should align with the objectives of the study (ICH E9(R1)).

treatments

The source of control group data may be internal or external to the study. The intent of using an _______ control group is to help ensure that the only differences between treatment groups are due to the treatment they receive and not due to differences in the selection of participants, the timing and measurement of study outcomes, or other differences. With use of an ________ control group, individuals are selected from an external source, and the individuals may have been treated at an earlier time (historical control group) or during the same time but in another setting than participants in the study.

internal external

Important limitations of the use of external controls are discussed in ICH E10. Particular care is needed to minimise the likelihood of _____________________.

erroneous inference (false conclusions)

A ____________ variable is an attribute of interest that may be affected by the drug. The response variable may relate to pharmacokinetics, pharmacodynamics, efficacy, or safety of the drug, or to the use of the drug including, for example, in adherence to risk minimisation measures post- approval. Study endpoints are the ____________ variables that are chosen to assess drug effects.

response

The _________ endpoint should be capable of providing clinically relevant and convincing evidence related to the primary objective of the study (ICH E9).

primary

______________ endpoints are either supportive measurements related to the primary objective or measurements of effects related to the secondary objectives.

Secondary

____________ endpoints are used to further explain or to support study findings or to explore new hypotheses for later research.

Exploratory

_________ discusses principles for controlling and reducing bias mainly in the context of interventional studies.

ICH E9

In studies with _________ control groups, randomisation is used to ensure comparability of treatment groups, thereby minimising the possibility of bias in treatment assignment.

internal

Events after randomisation (particularly _________________ (ICH E9(R1)) may affect the validity and interpretation of comparisons between treatment groups.

intercurrent events

It is important when defining the treatment effect (____________) to account for the occurrence of intercurrent events.

estimand

A ____________ is defined as a quantity that is a target of estimation in a statistical analysis. It is used to describe the treatment effect that a study aims to quantify. It is used to describe the treatment effect that a study aims to quantify.

Estimand

Concealing the treatment assignments (___________) limits the occurrence of conscious or unconscious bias in the conduct and interpretation of a clinical study that may affect the course of treatment, monitoring, endpoint ascertainment, and participants’ responses

blinding

The principal features of the statistical analysis should be planned during the design of the study and should be clearly specified in a protocol written before the study begins (__________). The protocol should define the estimand(s) following the framework established in ___________.

ICH E9 ICH E9(R1)

Study _______ comprise all information generated, collected, or used in the context of the study ranging from existing source data to study-specific assessments.

data

Study data can be broadly classified into two types: (1) data generated specifically for the present study (_____________________) and (2) data obtained from sources external to the present study (___________________).

primary data collection secondary data use

The following are examples of what kind of data: collected via case report forms, laboratory measurements, electronic patient reported outcomes, or mobile health tools

Primary data collection

The following are examples of what kind of data: historical clinical studies, national death databases, disease and drug registries, claims data, and medical and administrative records from routine medical practice

External data sources

Data quality attributes include:

- consistency (uniformity of ascertainment over time) - accuracy (correctness of collection, transmission, and processing) - completeness (lack of missing information).

There are several additional considerations with ____________ data use. For example, methods to conceal the treatment should be considered when selecting and prior to analysing data from external sources. As another example, absence of affirmative information on a condition or event does not necessarily mean the condition or event is not present. There may also be a delay between the occurrence of events and their appearance in existing data sources.

secondary

During clinical development, the timing of ___________ studies will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of alternative treatments.

pediatric

In the case of medicinal products for diseases predominantly or exclusively affecting pediatric patients, the entire development program will be conducted in the pediatric population except for ____________________________, which will usually be obtained in adults. Some products may reasonably be studied only in the pediatric population even in the initial phases, e.g., when studies in adults would yield little useful information or expose them to inappropriate risk.

initial safety and tolerability data

The presence of a __________________________ disease for which the product represents a potentially important advance in therapy suggests the need for relatively urgent and early initiation of pediatric studies. In this case, medicinal product development should begin early in the pediatric population, following assessment of initial safety data and reasonable evidence of potential benefit. Pediatric study results should be part of the marketing application database. In circumstances where this has not been possible, lack of data should be justified in detail.

serious or life-threatening

Testing of medicinal products in the pediatric population would usually begin in Phase __ or __.

2 or 3

In most cases, only _________ pediatric data would be available at the time of submission of the application, but more would be expected after marketing.

limited

The development of many new chemical entities is discontinued during or following Phase __ and __ studies in adults for lack of efficacy or an unacceptable side effect profile.

1 and 2

Even for a nonserious disease, if the medicinal product represents a major therapeutic advance for the pediatric population, studies should begin ________ in development, and the submission of pediatric data would be expected in the application. Lack of data should be justified in detail. Thus, it is important to carefully weigh benefit/risk and therapeutic need in deciding when to start pediatric studies.

early

When a medicinal product is studied in pediatric patients in one region, the __________ (e.g., pharmacogenetic) and __________ (e.g., diet) factors1 that could impact on the extrapolation of data to other regions should be considered.

intrinsic extrinsic

Pharmacokinetic studies generally should be performed to support formulation development and determine pharmacokinetic parameters in different age groups to support __________ recommendations.

dosing

Relative bioavailability comparisons of pediatric formulations with the adult oral formulation typically should be done in ________. Definitive pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the medicinal product is likely to be used should be conducted in the _____________ population.

adults pediatric

Pharmacokinetic studies in the pediatric population are generally conducted in patients with _____________. This may lead to higher intersubject variability than studies in normal volunteers, but the data better reflect clinical use.

the disease

For medicinal products that exhibit linear pharmacokinetics in adults, ______________ pharmacokinetic studies in the pediatric population may provide sufficient information for dosage selection.

single-dose

Any nonlinearity in absorption, distribution, and elimination in adults and any difference in duration of effect between single and repeated dosing in adults would suggest the need for __________________ studies in the pediatric population.

steady state

Dosing recommendations for most medicinal products used in the pediatric population are usually based on milligram (mg)/kilogram (kg) _______________ up to a maximum adult dose.

body weight

The volume of blood withdrawn should be _____________ in pediatric studies. Institutional Review Boards/Independent Ethics Committees (IRB’s/IEC’s) review and may define the maximum amount of blood (usually on a milliliters (mL)/kg or percentage of total blood volume basis) that may be taken for investigational purposes.

minimized

Because developing systems may respond differently from matured adult organs, some ___________________ and drug interactions that occur in pediatric patients may not be identified in adult studies. In addition, the dynamic processes of growth and development may not manifest ____________________ acutely, but at a later stage of growth and maturation. Long-term studies or surveillance data, either while patients are on chronic therapy or during the posttherapy period, may be needed to determine possible effects on skeletal, behavioral, cognitive, sexual, and immune maturation and development.

adverse events

Where __________ studies are needed, it may be necessary to develop, validate, and employ different endpoints for specific age and developmental subgroups.

efficacy

When a medicinal product is to be used in the pediatric population for the same indication(s) as those studied and approved in adults, the disease process is similar in adults and pediatric patients, and the outcome of therapy is likely to be comparable, ________________ from adult efficacy data may be appropriate. In such cases, pharmacokinetic studies in all the age ranges of pediatric patients likely to receive the medicinal product, together with safety studies, may provide adequate information for use by allowing selection of pediatric doses that will produce blood levels similar to those observed in adults.

extrapolation

When a medicinal product is to be used in younger pediatric patients for the same indication(s) as those studied in older pediatric patients, the disease process is similar, and the outcome of therapy is likely to be comparable, ______________ of efficacy from older to younger pediatric patients may be possible. In such cases, pharmacokinetic studies in the relevant age groups of pediatric patients likely to receive the medicinal product, together with safety studies, may be sufficient to provide adequate information for pediatric use.

extrapolation

An approach based on pharmacokinetics is likely to be insufficient for medicinal products where blood levels are known or expected not to correspond with efficacy or where there is concern that the concentration-response relationship may differ between the adult and pediatric populations. In such cases, studies of the ________________________________ effect of the medicinal product would usually be expected.

clinical or the pharmacological

Normally the pediatric database is limited at the time of approval. Therefore, _______________ surveillance is particularly important.

postmarketing

If the clearance pathways of a medicinal product are well established and the ontogeny of the pathways understood, age categories for pharmacokinetic evaluation might be chosen based on any “_____________” where clearance is likely to change significantly.

break point

The following is one possible categorization of pediatric ages. There is, however, considerable overlap in developmental (e.g., physical, cognitive, and psychosocial) issues across the age categories. Ages are defined in completed days, months, or years.

• Preterm newborn infants • Term newborn infants (0 to 27 days) • Infants and toddlers (28 days to 23 months) • Children (2 to 11 years) • Adolescents (12 to 16-18 years (dependent on region))

Most pathways of drug clearance (hepatic and renal) are mature at what pediatric ages, with clearance often exceeding adult values? Changes in clearance of a drug may be dependent on maturation of specific metabolic pathways.

Children (2-11)

The category of preterm newborn infants is not a _________________ group of patients.

homogeneous

While term newborn infants are developmentally more mature than preterm newborn infants, many of the physiologic and pharmacologic principles discussed above also apply to term infants. Volumes of distribution of medicinal products may be different from those in older pediatric patients because of different body water and fat content and high body-surface-area-to-weight ratio.

Term newborn infants (0 to 27 days)

This is a period of rapid CNS maturation, immune system development and total body growth. Oral absorption becomes more reliable. Hepatic and renal clearance pathways continue to mature rapidly. By this age, clearance of many drugs on a mg/kg basis may exceed adult values. The developmental pattern of maturation is dependent on specific pathways of clearance. There is often considerable inter-individual variability in maturation.

Toddlers (28 days- 23 months)

This is a period of sexual maturation; medicinal products may interfere with the actions of sex hormones and impede development. In certain studies, pregnancy testing and review of sexual activity and contraceptive use may be appropriate. This is also a period of rapid growth and continued neurocognitive development. Within this age group, adolescents are assuming responsibility for their own health and medication. Noncompliance is a special problem, particularly when medicinal products (for example, steroids) affect appearance. In clinical studies compliance checks are important. Recreational use of unprescribed drugs, alcohol and tobacco should be specifically considered.

Adolescents (12 to 16-18 years (dependent on region))

The pediatric population represents a ____________ subgroup.

vulnerable

When protocols involving the pediatric population are reviewed, there should be ________ members or experts consulted by the ________ who are knowledgeable in pediatric ethical, clinical, and psychosocial issues.

IRB/IEC

As a rule, a pediatric subject is legally unable to provide informed consent. Fully _____________ should be obtained from the legal guardian in accordance with regional laws or regulations. Where appropriate, participants should ______ to enroll in a study (age of assent to be determined by IRB's/IEC's or be consistent with local legal requirements). Participants of appropriate intellectual maturity should personally sign and date either a separately designed, written assent form or the written informed consent.

informed consent assent

Refusal to assent or withdrawal of assent by a child should be respected. Although a participant’s wish to withdraw from a study must be respected, there may be circumstances in therapeutic studies for serious or life-threatening diseases in which, in the opinion of the investigator and parent(s)/legal guardian, the welfare of a pediatric patient would be jeopardized by his or her failing to participate in the study. In this situation, continued ______________________________________ should be sufficient to allow participation in the study.

parental (legal guardian) consent

It is important to minimize ___________________ in pediatric trials. This can be minimized if studies are designed and conducted by investigators experienced in the treatment of pediatric patients.

distress/discomfort

Over the course of a clinical study, it may be necessary to reassess the _______ of a child in recognition of their advancing age, evolving maturity and competency, especially for long-term studies or studies that may require sample retention. During clinical studies there is a requirement for obtaining adequate informed consent for continued participation from pediatric participants once a child reaches the age of legal consent.

assent

A rationale for the selection of the pediatric population to be included in clinical studies should be provided. ____________________ alone may not serve as an adequate categorical determinant to define developmental subgroups in pediatric studies. Physiological development and maturity of organs, pathophysiology and natural history of the disease or condition, available treatment options, and the pharmacology of the investigational product are factors to be considered in determining the subgroups in pediatric studies.

Chronological age

___________ include term, post-term and preterm newborn infants. This population represents a broad maturational range, the conditions that affect this population can vary considerably; therefore, it is important to carefully consider the rationale for the selection of a neonatal population or subpopulation to be studied.

Neonates Pre term: 0 PostTerm infants: 0-27

The concept of “______________” is used in different ways in drug development. “Pediatric ______________” is defined as an approach to providing evidence in support of effective and safe use of drugs in the pediatric population when it can be assumed that the course of the disease and the expected response to a medicinal product would be sufficiently similar in the pediatric and reference (adult or other pediatric) population.

extrapolation

Advancement in clinical pharmacology and quantitative ___________________________ techniques has enabled progress in utilizing model-informed approaches (e.g., mathematical/statistical models and simulations based on physiology, pathology and pharmacology) in drug development. ______ can help quantify available information and assist in defining the design of pediatric clinical studies and/or the dosing strategy. This tool that can help avoid unnecessary pediatric studies and help ensure appropriate data are generated from the smallest number of pediatric patients

Modeling and simulation (M&S)

Emerging knowledge is incorporated into the model in an iterative approach to revisit and improve the model. A series of “__________________” cycles should be used for model building and simulation/prediction, and be confirmed as soon as new information is generated.

learn and confirm

Before deciding which types of methodological approaches are to be used in clinical trial design and execution, one should consider several practical factors that influence the design and execution of pediatric clinical trials. Three key practical factors to consider are:

- feasibility (limited pediatric potential patients) - outcome assessments (different endpoints for specific age and developmental subgroups) - long-term clinical aspects, including safety (rare events may not be identifiable in pre- registration development, and that pediatric-specific adverse events are unlikely to be detected in development programs that are limited in size and duration)

_______-term effects of drug treatment in children can include impacts on development, growth, and/or maturation of organ/system function. Therefore, adequate baseline assessments of growth/development and organ function, and regular follow-up measurements should be planned and discussed with regulatory authorities, as appropriate.

Long

Expression of understanding and agreement by fully informed parent(s) or legal guardian to permit the investigator/sponsor of a clinical study to enroll a child in a clinical investigation. The choice of the terms parental consent or parental permission in different regions may reflect local legal/regulatory and ethical considerations.

Parental (legal guardian) consent/permission:

The affirmative agreement of a child to participate in research or to undergo a medical intervention. Lack or absence of expression of agreement or disagreement must not be interpreted as assent.

Child asssent

A range of quantitative approaches, including pharmacometrics/systems pharmacology and other mathematical/statistical approaches based on physiology, pathology and pharmacology to quantitatively characterize the interactions between a drug and an organ system which could predict quantitative outcomes of the drug and/or system’s behavior in future experiments. In modelling and simulation, existing knowledge is often referred to as “prior” knowledge.

Modelling and Simulation (M&S)

______________ may lead to adverse reactions in children that are not observed (or not to the same extent) in adults. Thus, the use of ______________ in pediatric medicines should take into account factors such as age, weight, maturity (e.g., term and preterm newborns related to their physiologic development), frequency of dosing, intended duration of treatment, and potential for additional ______________ exposure from commonly co-administered medicines. The use of ______________ and their quantity in a formulation should minimize risk and ensure product performance, stability, palatability, microbial control, and dose uniformity. Alternatives to ______________ that pose a significant risk to children should always be considered, and the risk posed by the ______________ weighed against the severity of the disease and availability of alternative treatments. When selecting excipients, one should always consider the potential impact on absorption and bioavailability of the API.

Excipient (inactive substance that serves as the vehicle or medium for a drug or other active substance)

Orally administered pediatric medicines must be ____________ to ensure dose acceptance and regimen adherence. A formulation strategy for developing palatable drug preparations includes minimizing/eliminating aversive attributes of the API and considering favorable flavor attributes.

palatable

Formulation requirements for ____________ warrant special attention, such as its effects on electrolyte, fluid or nutritional balance. Intramuscular preparations should be avoided where possible due to pain, risk of over-penetration (e.g., bone, vasculature), and unpredictable drug absorption. Likewise, the tolerability of subcutaneous and intravenous preparations should be evaluated. For ____________, environmental conditions (e.g., temperature, light) and equipment used for drug administration (e.g., enteral feeding tubes) may have an effect on drug delivery and bioavailability.

neonates

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. It can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Adverse Event (or Adverse Experience)

In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal product related to any dose should be considered ______________________.

adverse drug reactions

Regarding marketed medicinal products, a well-accepted definition of an ___________________ in the post-marketing setting is found in WHO Technical Report 498 [1972] and reads as follows: A response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function.

adverse drug reaction

Unexpected adverse drug reaction

The term "________" is often used to describe the intensity () of a specific event (as in mild, moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor medical significance (such as severe headache). This is not the same as "________," which is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient's life or functioning.

severe serious Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.

A _____________________ (experience) or reaction is any untoward medical occurrence that at any dose: * results in death, * is life-threatening, * requires inpatient hospitalisation or prolongation of existing hospitalisation, * results in persistent or significant disability/incapacity, or * is a congenital anomaly/birth defect. NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe.

serious adverse event

Examples of ___________________ are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalisation; or development of drug dependency or drug abuse.

Serious adverse events Medical and scientific judgement should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalisation but may jeopardise the patient or may require intervention to prevent one of the other outcomes listed in the definition above. These should also usually be considered serious.

As stated in the definition (II.A.3.), an "____________" adverse reaction is one, the nature or severity of which is not consistent with information in the relevant source document(s). Until source documents are amended, expedited reporting is required for additional occurrences of the reaction.

unexpected

The following documents or circumstances will be used to determine whether an adverse event/reaction is expected: 1. For a medicinal product not yet approved for marketing in a country, a company's ______________________ will serve as the source document in that country. (See section III.F. and ICH Guideline for the ______________________.) 2. Reports which add significant information on specificity or severity of a known, already documented serious ADR constitute unexpected events. For example, an event more specific or more severe than described in the ______________________ would be considered "unexpected". Specific examples would be (a) acute renal failure as a labeled ADR with a subsequent new report of interstitial nephritis and (b) hepatitis with a first report of fulminant hepatitis.

Investigator's Brochure

What document would specify if an adverse event/reaction is expected or not?

Investigators Brochure

All adverse drug reactions (ADRs) that are both serious and unexpected are subject to ___________________.

expedited reporting

All adverse drug reactions (ADRs) that are both _________ and ___________ are subject to expedited reporting.

serious and unexpected

Expedited reporting of reactions which are serious but expected will ordinarily be ________________. Expedited reporting is also ________________ for serious events from clinical investigations that are considered not related to study product, whether the event is expected or not.

inappropriate

Information obtained by a sponsor or manufacturer on serious, unexpected reports from any source should be submitted on an ___________ basis to appropriate regulatory authorities if the minimum criteria for expedited reporting can be met. See section III.B.

expedited

All cases judged by either the reporting health care professional or the sponsor as having a reasonable suspected causal relationship to the medicinal product qualify as _____.

ADRs

There are situations in addition to single case reports of "serious" adverse events or reactions that may necessitate rapid communication to regulatory authorities; appropriate medical and scientific judgement should be applied for each situation. a. For an "expected," serious ADR, an increase in the rate of occurrence which is judged to be clinically important. b. A significant hazard to the patient population, such as lack of efficacy with a medicinal product used in treating life-threatening disease. c. A major safety finding from a newly completed animal study (such as carcinogenicity).

Rapid reporting to regulatory authorities mainly based on safety, aside from serious and unexpected

Fatal or life-threatening, unexpected ADRs occurring in clinical investigations qualify for very rapid reporting. Regulatory agencies should be notified (e.g., by telephone, facsimile transmission, or in writing) as soon as possible but no later than __ calendar days after first knowledge by the sponsor that a case qualifies, followed by as complete a report as possible within __ additional calendar days. This report must include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar medicinal products.

7 8

Serious, unexpected reactions (ADRs) that are not fatal or life-threatening must be filed as soon as possible but no later than ___ calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting.

Fatal/life threatening ADRs should be reported by sponsor by day __ of event knowledge, report should be submitted by __ days after. For non fatal/life threatening ADRs should be reported by day ___ of sponsor knowledge.

7, 8 15

When a serious adverse reaction is judged reportable on an expedited basis, it is recommended that the blind be broken only for that specific patient by the sponsor even if the investigator has not broken the blind. It is also recommended that, when possible and appropriate, the blind be maintained for those persons, such as biometrics personnel, responsible for analysis and interpretation of results at the study's conclusion.

Retain blind when possible, event during event reporting

It is recommended that any adverse drug reactions that qualify for expedited reporting observed with one product dosage form or use be cross referenced to regulatory records for ___________ dosage forms and uses for that product.

all other

Although such information is not routinely sought or collected by the sponsor, serious adverse events that occurred after the patient had completed a clinical study (including any protocol-required post-treatment follow-up) will possibly be reported by an investigator to the sponsor.

Report after study completion if necessary

In general, the sponsor of a study should amend the __________________________ as needed, and in accord with any local regulatory requirements, so as to keep the description of safety information updated.

Investigator's Brochure

The minimum information required for ___________________ purposes is: an identifiable patient, the name of a suspect medicinal product, an identifiable reporting source, and an event or outcome that can be identified as serious and unexpected and for which, in clinical investigation cases, there is a reasonable suspected causal relationship.

expedited reporting

ACRP-CP Exam Flashcards

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