ICH E8- General Considerations for Studies Flashcards
1
Q
What are examples of a Human Pharmacology study?
A
- Dose-tolerance studies
- Drug interaction studies
- Single and multiple dose PK and/or PD studies
- Early Measurement of Drug Activity
2
Q
Dose response exploration studies are examples of what kind of trial?
A
Therapeutic Exploratory
3
Q
The following studies describe what kind of trial?
- Comparative effectiveness studies
- Pharmacoeconomic studies
A
Therapeutic Use
4
Q
What are characteristics of a human pharmacological study?
A
- Usually have non-therapeutic objectives
- Initial administration to humans
- Estimate initial safety and tolerance
- Toxicity in Humans
- Early Measurement of drug activity
- Pharmacokinetics: Body’s effect on the drug
-Pharmacodynamics: Drug’s effect on the body
5
Q
What phase are Human Pharmacology studies?
A
Phase 1
6
Q
What are characteristics of a Initial Safety and Tolerability study?
A
- Usually intended to determine the tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected.
- Typically include both single and multiple dose administration
7
Q
What phase are Initial Safety and Tolerability studies?
A
Phase 1
7
Q
What is pharmacokinetics?
A
- Body’s effect on the drug
- The absorption, distribution, metabolism and excretion of the drug in the human body
8
Q
What phase are Pharmacokinetics studies?
A
Phase 1
9
Q
What phase are Pharmacodynamics
studies?
A
Phase 1
9
Q
What phase are Early Measurement of Drug Activity studies?
A
Phase 1
10
Q
What are characteristics of a Therapeutic Exploratory study?
A
- Primary objective is to explore therapeutic efficacy in patients
- Determine dose
- Determine regimen
- Assessment of drug safety
- Evaluation of different target populations
- Effectiveness of drug
- Drug to drug interactions
10
Q
What phase are Therapeutic Exploratory studies?
A
Phase 2
11
Q
What are characteristics of a Therapeutic Confirmatory study?
A
- Primary objective is to demonstrate, or confirm therapeutic benefit
- Confirm preliminary evidence from Phase II
- Basis for marketing approval
- Dose/Response Relationship
- Monitor side effects
- Explore the drug’s use in wider populations, in different stages of disease
- Interactions with other drugs/food
- Confirm safety and effectiveness for use in recipient population
- Development of Instructions for Use or Product Label
12
Q
What phase are Therapeutic Confirmatory studies?
A
Phase 3
13
Q
What are characteristics of a Therapeutic Use study?
A
- Begins after drug approval
- Optimization of drug
- Drug effectiveness and safety in other/new patient populations
- Monitor long term adverse events
- Contraindicative drugs or diseases
- Drug to drug interactions
- Dose-response and Safety Profile
- Epidemiology
- Morbidity or Mortality
14
Q
What phase are Therapeutic Use studies?
A
Phase 4
15
Q
What are some design techniques to avoid bias?
A
- Blinding (single and double blind)
- Randomization
- Compliance
16
Q
Describe Parallel Group Design
A
- most common clinical trial design for confirmatory trials
- subjects are randomized to one of two or more arms and each arm is allocated a different treatment
17
Q
Describe Crossover Design
A
each subject is randomized to a sequence of two or more treatments and subject acts as his own control for treatment comparisons
18
Q
What is the benefit of a Crossover Design?
A
reduces the number of subjects and usually the number of assessments needed to achieve a specific power
19
Q
What is carry over and in what type of trial is it a concern?
A
Carryover is the residual influence of treatments in subsequent treatment periods
Crossover Design
20
Q
Describe Factorial Design
A
Two or more treatments are evaluated simultaneously through the use of varying combinations of the treatments
21
Q
Explain Factorial Design formats
A
Simplest example is the 2×2 factorial design in which subjects are randomly allocated to one of the four possible combinations of two treatments
A alone
B alone
both A and B
neither A nor B
22
What trials show equivalence or non-inferiority?
Placebo controlled trial; comparison to an active comparator
23
What do Group sequential designs facilitate?
The conduct of interim analysis
24
Why are Group sequential designs applied?
Its more practicable to assess grouped subject outcomes at periodic intervals during the trial than on a continuous basis as data from each subject become available
25
What is the checking and assessment of data during the period of time between trial completion (the last observation on the last subject) and the breaking of the blind, for the purpose of finalizing the planned analysis?
Blind review
26
What is the extent to which a variable (e.g. a rating scale) measures what it is supposed to measure?
Content Validity
27
Describe a Double-Dummy
A technique for retaining the blind when administering supplies in a clinical trial, when the two treatments cannot be made.
Supplies are prepared for Treatment A (active and indistinguishable placebo) and for Treatment B (active and indistinguishable placebo). Subjects then take two sets of treatment; either A (active) and B (placebo), or A (placebo) and B (active).
28
What type of trial has the primary objective of showing that the response to two or more treatments differs by an amount which is clinically unimportant?
Equivalence Trial
29
Define Interim Analysis
Any analysis intended to compare treatment arms with respect to efficacy or safety at any time prior to the formal completion of a trial.
30
What is the formal evaluation of the quantitative evidence from two or more trials bearing on the same question?
Meta-Analysis
31
Define a Non-Inferiority Trial
A trial with the primary objective of showing that the response to the investigational product is not clinically inferior to a comparative agent (active or placebo control)
32
Define a Superiority Trial
A trial with the primary objective of showing that the response to the investigational product is superior to a comparative agent (active or placebo control)
33
Define Treatment Emergent
An event that emerges during treatment having been absent pre-treatment, or worsens relative to the pre-treatment state
34
The following studies describe what kind of trial?
- Comparative studies
- Randomized parallel dose response studies
- Clinical safety studies
- Studies of mortality/ morbidity outcomes
Phase III: Therapeutic Confirmatory
35
Which trial phase's objectives include dose tolerance assessments?
Phase I - human pharmacology
36
Which trial phase's objectives include dose-response explorations?
Phase II - Therapeutic Exploratory
37
Which trial phase's objectives include confirming/establishing the dose-response relationships?
Phase III - Therapeutic Confirmatory
38
Which trial phase's objectives include mortality/morbidity outcomes and comparative effectiveness studies?
Phase IV - Therapeutic Use
39
What are some important considerations for determining the nature of non-clinical studies and their timing with respect to clinical trials?
1) Duration and total exposure proposed in individual patients
2) Drug Characteristics
3) Disease/condition targeted for treatment
4) Use in special populations
5) Route of administration
40
Which phase starts with the initial administration of an IP into humans?
Phase I
41
What type of patients are used in Phase I trials?
Healthy volunteers or certain types of patients such as mild hypertension.
Sometimes seriously ill patient with no other options or when drug is toxic to healthy volunteers (cytotoxic chemo agents)
42
What is the most typical kind of Phase I study?
Human pharmacology
43
What is the most typical kind of Phase II study?
Therapeutic Exploratory
44
What is the primary objective of Phase II studies?
Explore therapeutic efficacy
45
What type of patients are typically used in Phase II studies?
- Narrow criteria
- Homogenous
- Closely Monitored
46
What is an important goal of Phase II studies?
Determine the dose(s) and regimen for Phase III trials
47
What is the most typical kind of Phase III study?
Therapeutic Confirmatory
48
What is the primary objective of Phase III studies?
- Confirm and establish dose-response relationships
- Confirm therapeutic benefit
49
Phase III studies provide an adequate basis for what?
Marketing approval
50
When do Phase IV studies begin?
After marketing approval
51
Which trial design includes groups of patients where each group only receives one type of treatment for the entire study participation period?
Parallel group design
52
Which trial design includes sequences of treatments where patients may start off on one treatment and then switch to another at a certain point in the trial?
Cross-over design
53
Which trial design involves testing the effect of two or more treatments simultaneously?
Factorial design
Subject 1 - Treatments A and B
Subject 2 - Treatment A not B
Subject 3 - Treatment B not A
Subject 4 - Neither A or B
54
What type of study increases the dose of treatment over trial participation period?
Dose escalation study
55
What type of study keeps the dose constant over trial participation period?
Fixed dose-dose response
56
What should happen for patients who stop treatment prematurely?
Protocol must specify procedures for follow-up of these specific patients
57
What is an endpoint that is intended to relate to a clinically important outcome but does not directly measure a clinical benefit?
Surrogate endpoint
58
What is it called when the investigator, sponsor and staff involved in the treatment or clinical evaluation of the subjects and data analysis are unaware of the treatment assignments?
Double Blinding
59
What is it called when the treatment assignment is unknown to the trial participant?
Single blinding
60
How should AEs be classified when compiling safety data in trials?
According to their seriousness and their likely causal relationship to the IP
61
62
What is pharmcodynamics?
The drug's effect on the human body
63
What is safety and tolerability as it relates to IP?
The safe dose range of the drug for future trials
64
How many subjects are enrolled in Phase I studies?
6-20 subjects
65
What types of designs are implemented in Phase I trials?
- Blinded
- Randomized
- Dose escalation
- Open Label
- Single Center
66
What is the typical duration of Phase I trials?
9-18 months
67
Are healthy volunteers used in Phase II trials?
No, typically only subjects with the condition under study
68
How many subjects are typically enrolled in Phase II studies?
50-200 subjects with the condition under study
69
What types of designs are used in Phase II studies?
- Blinded
- Randomized
- Controlled
- Strict Inclusion/Exclusion
- Concurrent controls and comparisons
70
What is the typical duration of Phase II studies?
1-3 years
71
Are healthy volunteers used in Phase III trials?
No, typically only subjects with the condition under study
72
How many subjects are enrolled in phase III trials?
200-1,000 subjects
73
What types of designs are implemented in phase III trials?
- Blinded
- Randomized
- Controlled
- General population
74
What is the typical duration of Phase III trials?
2-5 years
75
Are healthy volunteers enrolled in Phase IV trials?
No, typically only subjects with the condition under study
76
How many patients are typically enrolled in Phase IV studies?
100s of patients
Subjects may be users of the drug or individuals belonging to new populations that need further investigation, such as children, elderly, other diseases etc.
77
What are typical design elements of Phase IV trials?
- Blinded
- Randomized
- Controlled
78
What is the typical duration of Phase IV trials?
1-3 years; may be longer if required by the regulatory authority
