ICH-E8

Question 1

What type of study has the following objectives:

•Assess tolerance

• Define/describe PK1and PD2

• Explore drug metabolism and drug interactions

• Estimate activity

Answer 1

Human Pharmacology

Question 2

Examples of Human Pharmacology studies?

Answer 2

• Dose-tolerance studies • Single and multiple dose PK and/or PD studies • Drug interaction studies

Question 3

What type of study has the following objectives: • Explore use for the targeted indication • Estimate dosage for subsequent studies • Provide basis for confirmatory study design, endpoints, methodologies

Answer 3

Therapeutic Exploratory

Question 4

Example of Therapeutic Exploratory studies?

Answer 4

• Earliest trials of relatively short duration in well- defined narrow patient populations, using surrogate or pharmacological endpoints or clinical measures • Dose-response exploration studies

Question 5

What type of study has the following objectives: • Demonstrate/confirm efficacy • Establish safety profile • Provide an adequate basis for assessing the benefit/risk relationship to support licensing • Establish dose-response relationship

Answer 5

Therapeutic Confirmatory

Question 6

Examples of Therapeutic Confirmatory studies?

Answer 6

• Adequate, and well controlled studies to establish efficacy • Randomised parallel dose response studies • Clinical safety studies • Studies of mortality/ morbidity outcomes • Large simple trials • Comparative studies

Question 7

What type of study has the following objectives: • Refine understanding of benefit/risk relationship in general or special populations and/or environments • Identify less common adverse reactions • Refine dosing recommendation

Answer 7

Therapeutic Use

Question 8

Examples of Therapeutic Use studies?

Answer 8

• Comparative effectiveness studies • Studies of mortality/morbidity outcomes • Studies of additional endpoints • Large simple trials • Pharmacoeconomic studies

Question 9

What does PK1 and PK2 mean?

Answer 9

1Pharmacokinetics 2Pharmacodynamics

Question 10

Important considerations for determining the nature of non-clinical studies and their timing to clinical trials: 5 of them

Answer 10

a) duration and total exposure proposed in individual patients b) characteristics of the drug (e.g. long half life, biotechnology products) c) disease or condition targeted for treatment d) use in special populations (e.g. women of childbearing potential) e) route of administration

Question 11

The basis and direction of the clinical exploration and development rests on the nonclinical pharmacokinetic and pharmacology profile, which includes information such as: 5 of them

Answer 11

a) Pharmacological basis of principal effects (mechanism of action). b) Dose-response or concentration-response relationships and duration of action c) Study of the potential clinical routes of administration d) Systemic general pharmacology, including pharmacological effects on major organ systems and physiological responses e) Studies of absorption, distribution, metabolism and excretion

Question 12

How many phases of clinical drug development are there?

Answer 12

4.

Question 13

True or False? One type of trial may not occur in several phases?

Answer 13

False

Question 14

True or False? Drug development is ideally a logical, step-wise procedure in which information from small early studies is used to support and plan later larger, more definitive studies.

Answer 14

True

Question 15

Initial trials provide an early evaluation of short-term safety and tolerability and can provide___________and____________ information needed to choose a suitable dosage range and administration schedule for initial exploratory therapeutic trials.

Answer 15

pharmacodynamic and pharmacokinetic

Question 16

Later confirmatory studies are generally larger and longer and include a more ________.

Answer 16

diverse patient population.

Question 17

_________ should be obtained at all stages of development, from early tolerance studies, to studies of short-term pharmacodynamic effect, to large efficacy studies

Answer 17

Dose-response information

Question 18

What is the most typical kind of study in Phases 1-4?

Answer 18

Phase 1-Human Pharmacology Phase 2-Therapeutic Exploratory Phase 3-Therapeutic Confirmatory Phase 4-Variety of studies-Therapeutic Use

Question 19

What does phase 1 studies start with?

Answer 19

Phase I starts with the initial administration of an investigational new drug into humans

Question 20

Phase 1 studies typically have therapeutic objectives? T/F?

Answer 20

False

Question 21

What type of subjects are in phase 1 studies, usually.

Answer 21

healthy volunteer subjects or certain types of patients, e.g. patients with mild hypertension.

Question 22

What type of drugs are studied in phase 1

Answer 22

Drugs with significant potential toxicity, e.g. cytotoxic drugs, are usually studied in patients

Question 23

T/F in Phase 1 studies they are can be open, baseline controlled or may use randomization and blinding?

Answer 23

True

Question 24

Studies in phase 1 typically involve one or a combo of the following aspects: 4 of them

Answer 24

a) Estimation of Initial Safety and Tolerability—is 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. These studies typically include both single and multiple dose administration. b) Pharmacokinetics–Characterisation of a drug’s absorption, distribution, metabolism, and excretion continues throughout the development plan. Their preliminary characterisation is an important goal of Phase I. c) Assessment of Pharmacodynamics–Depending on the drug and the endpoint studied, pharmacodynamic studies and studies relating drug blood levels to response (PK/PD studies) may be conducted in healthy volunteer subjects or in patients with the target disease. In patients, if there is an appropriate measure, pharmacodynamic data can provide early estimates of activity and potential efficacy and may guide the dosage and dose regimen in later studies. d) Early Measurement of Drug Activity–Preliminary studies of activity or potential therapeutic benefit may be conducted in Phase I as a secondary objective.

Question 25

Why are pharmacokinetic studies important in phase 1

Answer 25

Pharmacokinetic studies are particularly important to assess the clearance of the drug and to anticipate possible accumulation of parent drug or metabolites and potential drug-drug interactions. Some pharmacokinetic studies are commonly conducted in later phases to answer more specialised questions. Pharmacokinetics may be assessed via separate studies or as a part of efficacy, safety and tolerance studies

Question 26

Define Pharmacokinetics and Pharmacodynamics

Answer 26

Pharmacokinetics Definition: Pharmacokinetics defines what the body does to the drug . Pharmacokinetics is the study of a drug absorption, distribution, metabolism and elimination from the body. Pharmacodynamics describes what the drug does to the body.

Question 27

What is the primary objective for phase 2 studies?

Answer 27

Phase II is usually considered to start with the initiation of studies in which the primary objective is to explore therapeutic efficacy in patients.

Question 28

Examples of study designs in phase 2 studies?

Answer 28

Initial therapeutic exploratory studies may use a variety of study designs, including concurrent controls and comparisons with baseline status. Subsequent trials are usually randomised and concurrently controlled to evaluate the efficacy of the drug and its safety for a particular therapeutic indication

Question 29

Examples of patient population in phase 2 studies?

Answer 29

Studies in Phase II are typically conducted in a group of patients who are selected by relatively narrow criteria, leading to a relatively homogeneous population and are closely monitored.

Question 30

What is an important goal in phase 2 studies?

Answer 30

An important goal for this phase is to determine the dose(s) and regimen for Phase III trials. Early studies in this phase often utilise dose escalation designs (see ICH E4) to give an early estimate of dose response and later studies may confirm the dose response relationship for the indication in question by using recognised parallel dose response designs (could also be deferred to phase III). Confirmatory dose response studies may be conducted in Phase II or left for Phase III. Doses used in Phase II are usually but not always less than the highest doses used in Phase I

Question 31

What are some other objectives besides the main one for a phase 2 trial?

Answer 31

may include evaluation of potential study endpoints, therapeutic regimens (including concomitant medications) and target populations (e.g. mild versus severe disease) for further study in Phase II or III. These objectives may be served by exploratory analyses, examining subsets of data and by including multiple endpoints in trials.

Question 32

Primary objective of phase 3 studies?

Answer 32

Phase III usually is considered to begin with the initiation of studies in which the primary objective is to demonstrate, or confirm therapeutic benefit. Studies in Phase III are designed to confirm the preliminary evidence accumulated in Phase II that a drug is safe and effective for use in the intended indication and recipient population. These studies are intended to provide an adequate basis for marketing approval.

Question 33

Primary objective of phase IV studies?

Answer 33

Phase IV begins after drug approval. Therapeutic use studies go beyond the prior demonstration of the drug’s safety, efficacy and dose definition. Studies in Phase IV are all studies (other than routine surveillance) performed after drug approval and related to the approved indication. They are studies that were not considered necessary for approval but are often important for optimising the drug’s use. They may be of any type but should have valid scientific objectives. Commonly conducted studies include additional drug drug interaction, dose-response or safety studies and studies designed to support use under the approved indication, e.g. mortality/morbidity studies, epidemiological studies

Question 34

What are some special considerations in phased studies?

Answer 34

3.1.4.1 Studies of Drug Metabolites 3.1.4.2 Drug-Drug Interactions 3.1.4.3 Special Populations

Question 35

What are some examples of special populations that require more risk/benefit considerations: (3)

Answer 35

1. Investigations in pregnant women–generally should be excluded if not intended for use in pregnancy 2. Investigations in nursing women–Excretion of the drug or its metabolites into human milk should be examined where applicable. When nursing mothers are enrolled in clinical studies their babies should be monitored for the effects of the drug 3. Investigations in children–The extent of the studies needed depends on the current knowledge of the drug and the possibility of extrapolation from adults and children of other age groups. Some drugs may be used in children from the early stages of drug development (see ICHM3). For a drug expected to be used in children, evaluation should be made in the appropriate age group. When clinical development is to include studies in children, it is usually appropriate to begin with older children before extending the trial to younger children and then infants

Question 36

The following important principles should be followed in planning the objectives, design, conduct, analysis and reporting of a clinical trial. Each part should be defined in a written protocol before the study starts:

Answer 36

3.2.1 Objectives The objective(s) of the study should be clearly stated and may include exploratory or confirmatory characterisation of safety and/or efficacy and/or assessment of pharmacokinetic parameters and pharmacological, physiological, biochemical effects. 3.2.2 Design The appropriate study design should be chosen to provide the desired information.Examples of study design include parallel group, cross-over, factorial, dose escalation,and fixed dose-dose response. (See ICH E4, E6, E9 and E10). Appropriate comparators should be utilised and adequate numbers of subjects included to achieve the study objectives. Primary and secondary endpoints and plans for their analyses should be clearly stated (see ICH E9). The methods of monitoring adverse events by changes in clinical signs and symptoms and laboratory studies should be described (see ICH E3). The protocol should specify procedures for the follow-up of patients who stop treatment prematurely. 3.2.3 Conduct-The study should be conducted according to the principles described in this guideline and in accordance with other pertinent elements outlined in ICH E6 and other relevant ICH guidelines 3.24- Analysis The study protocol should have a specified analysis plan that is appropriate for the objectives and design of the study, taking into account the method of subject allocation, the measurement methods of response variables, specific hypotheses to be tested, and analytical approaches to common problems including early study withdrawal and protocol violations. 3.25 Reporting

Question 37

True or False? Study endpoints are the response variables that are chosen to assess drug effects that are related to pharmacokinetic parameters, pharmacodynamic measures, efficacy and safety

Answer 37

true

Question 38

A primary endpoint(s) should reflect clinically relevant effects and is typically selected based on the principal objective of the study. Secondary endpoints assess other drug effects that may or may not be related to the primary endpoint. Endpoints and the plan for their analysis should be prospectively specified in the protocol. True or False

Answer 38

true

Question 39

What is a surrogate endpoint?

Answer 39

A surrogate endpoint is an endpoint that is intended to relate to a clinically important outcome but does not in itself measure a clinical benefit. Surrogate endpoints may be used as primary endpoints when appropriate (when the surrogate is reasonably likely or well known to predict clinical outcome).

Question 40

What are some methods to minimize bias?

Answer 40

a) Randomisation In conducting a controlled trial, randomised allocation is the preferred means of assuring comparability of test groups and minimising the possibility of selection bias. b) Blinding Blinding is an important means of reducing or minimising the risk of biased study outcomes. A trial where the treatment assignment is not known by the study participant because of the use of placebo or other methods of masking the intervention, is referred to as a single blind study. When the investigator and sponsor staff who are involved in the treatment or clinical evaluation of the subjects and analysis of data are also unaware of the treatment assignments, the study is double blind. c) Compliance Methods used to evaluate patient usage of the test drug should be specified in the protocol and the actual usage documented.

Question 41

What are some design principles in a trial?

Answer 41

3.2.2.1 Selection of subjects account in selecting the subject population (e.g. normal healthy subjects, cancer patients or other special populations in early phase development) as should prior non-clinical and clinical knowledge. The variability of groups of patients or healthy volunteers studied in early trials may be limited to a narrow range by strict selection criteria, but as drug development proceeds, the populations tested should be broadened to reflect the target population 3.2.2.2 Selection of Control Group Trials should have an adequate control group. Comparisons may be made with placebo, no treatment, active controls or of different doses of the drug under investigation. The choice of the comparator depends, among other things, on the objective of the trial 3.2.2.3 Number of subjects The size of a trial is influenced by the disease to be investigated, the objective of the study and the study endpoints. Statistical assessments of sample size should be based on the expected magnitude of the treatment effect, the variability of the data, the specified (small) probability of error (see ICH E9) and the desire for information or subsets of the population or secondary endpoints.. In some circumstances a larger database may be needed to establish the safety 3.2.2.4 Response Variables Response variables should be defined prospectively, giving descriptions of methods of observation and quantification. Objective methods of observation should be used where possible and when appropriate 3.2.2.5 Methods to Minimise or Assess Bias

Question 42

FILL IN THE BLANKS

Answer 42