ACRP CPI® > ICH E8 Clinical Development > Flashcards

ICH E8 Clinical Development Flashcards

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1
Q

General Considerations for Clinical Trials, Intention of Guidelines (4)

Describe, Facilitate, Present, and Provide

A
  1. Describe: international principal and practices in clinical trial and drug development
  2. Facilitate: evaluation and acceptance of foreign clinical trial data by promoting standardization
  3. Present: overview of ICH safety and efficacy documents.
  4. Provide: glossary terms used in ICH safety and efficacy related documents
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2
Q

Drug, Synonymous

A

Investigational (medicinal) product

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3
Q

General Principles, Protection of Clinical Trial Subjects (2)

Before and During Drug Development

A

Before Clinical Trial:

Existing non-clinical and clinical investigations should be sufficient to indicate the drug is acceptably safe for the propose investigation in humans.

During Clinical Trial:

Emerging non-clinical and clinical investigations should be reviewed and evaluated to assess implications for the safety of the trial subjects.

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4
Q

General Principles, Scientific Approach in Design and Analysis, Clinical Study Classifications (4)

A
  1. Human Pharmacology
  2. Therapeutic Exploratory
  3. Therapeutic Confirmatory
  4. Therapeutic Use
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5
Q

Clinical Study, Human Pharmacology, Study Objectives (6)

A
  1. Assess tolerance and safety
  2. Define pharmacokinetics (PK) and pharmacodynamics (PD)
  3. Explore drug metabolism and drug interactions
  4. Evaluate activity, assess immunogenicity
  5. Assess renal/hepatic tolerance
  6. Assess cardiac toxicity
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6
Q

Clinical Study, Human Pharmacology, Study Examples (3)

A
  1. BA/BE studies under fasted/fed conditions
  2. Dose-tolerance studies
  3. Single and multiple dose PK/PD studies
  4. Drug interaction studies
  5. QTc prolongation study
  6. Human factor studies for drug devliery devices
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7
Q

Clinical Study, Therapeutic Exploratory, Study Objectives (4)

A
  1. Explore use for the targeted indication
  2. Estimate dose and dosing regimen for subsequent studies
  3. Explore dose-response/exposure-response relationship
  4. Provide basis for confirmatory study design, endpoints, methodologies
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8
Q

Clinical Study, Therapeutic Exploratory, Study Examples (2)

A
  1. Randomized controlled clinical trials of relatively short duration in well-defined populations (using surrogate/pharmacological/clinical measures as endpoint)
  2. Dose finding studies
  3. Biomarker exploration studies
  4. Studies to validate patient reported outcomes
  5. Adaptive designs that may combine exploratory and confirmatory
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9
Q

Clinical Study, Therapeutic Confirmatory, Study Objectives (4)

A
  1. Demonstrate/confirm efficacy
  2. Establish safety profile in larger, more representative patient populations
  3. Provide an adequate basis for assessing the risk/benefit relationship to support licensing
  4. Establish dose-response relationship
  5. Establish safety profile and confirm efficacy in specific populations
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10
Q

Clinical Study, Therapeutic Confirmatory, Study Examples (6)

A
  1. Randomized controlled clinical trials to establish efficacyin larger more representative patient populations
  2. Dose-repsonse Studies
  3. Clinical safety studies
  4. Studies of mortality/morbidity outcomes
  5. Studies in special populations
  6. Studies that seek to demonstrate efficacy for multiple drugs in a single protocol
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11
Q

Clinical Study, Therapeutic Use, Study Objectives (3)

A
  1. Extend understanding of risk/benefit relationship in general or special populations and environments
  2. Identify less comm adverse reactions
  3. Refine dosing recommendation
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12
Q

Clinical Study, Therapeutic Use, Study Examples (8)

A
  1. Comparative effectiveness studies
  2. Long-term follow-up studies
  3. Studies of mortality/morbidity or other additional endpoints
  4. Large, simple randomized trials
  5. Pharmacoeconomic studies
  6. Pharmacoepidemiology studies
  7. Observational studies of the use of the drug in clinical practice
  8. Disease or drug registries
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13
Q

Clinical Development, General Considerations, Non-clinical Studies for Overall Aspects of Trial, Aspects (5+1)

A
  1. Duration and total exposure proposed in individual patients
  2. characteristics of the drug (e.g., long vs short half-life)
  3. Disease or condition targeted for treatment
  4. Use in special population (e.g., expecting mothers)
  5. Route of administration
  6. Effects (toxicology, pharmacology, and pharmacokinetics)
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14
Q

Clinical Development, General Consideration, Nonclinical Studies for Safety Aspects of Trial, Focused Goals (3)

A

Non-clinical pharmacokinetics, pharmacological and toxicological evaluations should support defining the:

  1. Initial human dose
  2. safe duration of exposure
  3. physiological and toxicological effects
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15
Q

Clinical Development, Nonclinical Studies, General Consideration for Pharmacological and Pharmacokinetic Aspects of Trial (5)

A

Non-clinical pharmacokinetics and pharmacology profile support defining the:

  1. pharmacological basis of principal effects (mechanism of action)
  2. Dose-response/concentration-response relationship and duration of action
  3. Study of the potential clinical routes of administration
  4. Systemic general pharmacology (ie., effects on major organ systems and physiological responses)
  5. Studies on absorption, distribution, metabolism and excretion (ADME)
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16
Q

Clinical Development, Investigational Products, Formulation Requirement (4)

A

Formulations used in clinical trials should be:

  1. well characterized (e.g., bioavailability)
  2. appropriate for the trial stage
  3. adequately supplied (for wide duration and dosing range)
  4. supporting alternative formulation and bioequivalence studies
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17
Q

Clinical Development, Strategic Planning

A

While drug development is ideally a logical and step-wise procedure, it is essential to identify characteristics of the drug in early stages and strategically plan the clinical development

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18
Q

Phases of Clinical Development, Dose-response Studies (3)

A

Dose-response information should be obtained at all stages of development:

  1. early tolerance studies
  2. short-term pharmacodynamic effect studies
  3. large efficacy studies
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19
Q

Primarily Human Pharmacology Studies (Phase I), Subjects Characteristics,
Healthy Subjects vs Patients

A

Studies in Phase I usually have non-therapeutic objectives, and may be conducted in both healthy subjects or predefined patients (i.e., mild conditions).

However, drugs with significant potential toxicity, are usually studied in patients (not justified to be studied in healthy subjects).

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20
Q

Primarily Human Pharmacology Studies (Phase I), Estimation of Initial Safety and Tolerability, Purpose (2)

A

Administration of drug (typically both single and multiple dose) to determine:

  1. nature of ADR that can be expected
  2. tolerability of the dose range expected for efficacy
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21
Q

Primarily Human Pharmacology Studies (Phase I),
Pharmacokinetics, Significance of ADME (3)

A

Characterization of ADME, which is important to:

  1. assess drug clearance
  2. anticipate possible accumulation of drug or metabolites
  3. anticipate drug-drug interactions
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22
Q

Primarily Human Pharmacology Studies (Phase I),
Pharmacokinetics, Special Consideration

Examples:
Orally Administered
Sub-populations
Concomitant Treatment

A

Assessment of pharmacokinetics

Orally administered drugs: effect of food on bioavailability of drugs, especially modified release products

Sup-populations: elderly, children, women, ethnic subgroups, and patients with impaired elimination (renal or hepatic failure)

Concomitant treatment: drug-drug interactions

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23
Q

Primarily Human Pharmacology Studies (Phase I),
Assessment of Pharmacodynamics, Focuses (2)

A

Pharmacodynamics at this stages focuses on:

  1. Drug blood level - dosage relationship (in healthy subjects and patients)
  2. Early estimates of activity and potential efficacy (in patients with target disease)
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24
Q

Primarily Human Pharmacology Studies (Phase I), Early Measurement of Drug Activity, Feasibility Criteria

A

Assessment may be appropriate when:

drug activity is readily measurable with a short duration of drug exposure in patients at this early stage.

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25
Primarily Therapeutic Exploratory Studies (Phase II), Primary Objective
Explore therapeutic efficacy in patients
26
Primarily Therapeutic Exploratory Studies (Phase II), Study Designs Examples (2) Initial Studies Subsequent Studies
Initial Studies: 1. comparison with concurrent controls 2. comparison with baseline status Subsequent Studies: randomized concurrent controls
27
Primarily Therapeutic Exploratory Studies (Phase II), Patient Characteristics
Selected by relatively narrow criteria, leading to a relatively homogeneous population.
28
Primarily Therapeutic Exploratory Studies (Phase II), Dose Escalation Design, Method
Provide an early estimate of dose response (to be confirmed by later stage III studies) by using a parallel dose-response design.
29
Primarily Therapeutic Exploratory Studies (Phase II), Secondary Objectives (4)
1. determine the doses and regimen for phase III trials 2. evaluate potential study endpoints 3. evaluate therapeutic regimens (including concomitant medications) 4. determine target populations (mild vs severe disease)
30
Primarily Human Pharmacological Studies (Phase I), Primary Objective
Non-therapeutic objective: Estimation of initial safety and tolerability, and assessment of pharmacokinetics and pharmacodynamics
31
Primarily Human Pharmacological Studies (Phase I), Secondary Objective
Preliminary assessment on drug activity or potential therapeutics benefit
32
Primarily Therapeutic Confirmatory Studies (Phase III), Primary Objective
Demonstrate or confirm: therapeutic benefit (safety and efficacy) for the intended indication and recipient population (as basis for market approval)
33
Primarily Therapeutic Confirmatory Studies (Phase III), Secondary Objectives (4)
1. Explore dose-response relationship 2. Explore drug's use in wider population 3. Explore drug combination 4. Evaluate extended exposure (continued from II)
34
Primarily Therapeutic Use Studies (Phase IV), Main Objectives
Optimization of drug's use beyond prior demonstration of drug's safety, efficacy and dose definition.
35
Primarily Therapeutic Use Studies (Phase IV), Categorization Criteria (2)
Phase IV studies are: 1. All studies performed after drug approval, and 2. Related to (but not required for) the approved indication
36
Primarily Therapeutic Use Studies (Phase IV), Common Examples (4)
1. additional drug-drug interaction studies 2. additional dose-response studies safety studies 3. mortality/morbidity studies (supportive) 4. epidemiological studies (supportive)
37
Clinical Development, Development of an Application Unrelated to Original Approved Use, Scenarios (4)
New development plan includes the following examples: 1. New or modified indications 2. New dosage regimens (including combined treatment) 3. New routes of administration 4. Additional patient populations which may be fast-tracked with obviated studies by the availability of existing data.
38
Clinical Development, Special Considerations, Aspects (3)
1. Studies of drug metabolites 2. Drug-drug interactions 3. Special populations
39
Clinical Development, Special Considerations, Studies of Drug Metabolites, Steps (2)
Studies should focus on: 1. Identification of metabolites 2. Detailed pharmacokinetics of major active metabolites
40
Clinical Development, Special Considerations, Drug-drug Interactions, Focused Study Target sources (3)
Potential drug-drug interactions should focus on targets indicated by: 1. results of non-clinical studies 2. information on similar drugs 3. frequently co-administration
41
Clinical Development, Special Considerations, Drug-drug Interactions, Focused Study Aspects (3)
alteration of or altered by: 1. Absorption 2. Metabolism 3. Excretion
42
Clinical Development, Special Considerations on Special Populations, Examples (3)
1. Pregnant women 2. Nursing women 3. Children
43
Clinical Development, Special Considerations on Special Populations, Rationales Aspects (3)
Special populations requires special considerations as they have unique: 1. risk/benefit 2. modification of use (dose or schedule) 3. pharmacokinetic and pharmacodynamic
44
Clinical Development, Special Considerations on Investigations in Pregnant Women, Aspects (3)
Unless the trial is intended for use during pregnancy, clinical trials should: 1. exclude pregnant women from enrollment 2. discontinue enrollment women become pregnant 3. follow-up mother, fetus and child.
45
Clinical Development, Special Considerations on Investigations in Nursing Women, Focused Aspects (2)
Studies on nursing women should focus on: 1. examining excretion of drug or metabolites into milk 2. monitoring the babies for effect of the drug
46
Clinical Development, Special Considerations on Investigations in Children, General Steps (3)
1. Extrapolate information on results from adult trials 2. Evaluate effect in trials with older children 3. Extending the evaluation into younger children and infants
47
Clinical Trial, Protocol, General Objectives (3)
Objectives should include study goals (exploratory or confirmatory) that focuses: 1. characterization of safety and efficacy 2. assessment of pharmacokinetic parameters (PK) 3. assessment of pharmacological, physiological, and biochemical effects (PD).
48
Clinical Trial, Protocol, Design Type Examples (5)
1. parallel group 2. cross-over 3. factorial 4. dose escalation 5. dose response to fixed dose
49
Clinical Trial, Protocol, Design General Considerations (6)
1. study type 2. study controls (comparators) 3. study size 4. endpoint analysis 5. AE monitoring 6. follow-up (completed or pre-mature termination)
50
Clinical Trial, Study Design, Selection of Subject, Factors to Consider for Inclusion and Exclusion Criteria (4)
Inclusion and exclusion criteria are defined by: 1. development stage and studied indication 2. enrollment in other or previous trials (carry-over effects) 3. prior non-clinical and clinical knowledge 4. variability of patients or healthy subjects
51
Clinical Trial, Study Design, Selection of Subject, Special Consideration for Contraception (2)
Contraception provision should be considered when enrolling: 1. Female with childbearing potential 2. Male with sexual partners who have childbearing potential for trials involving mutagenic or reproductive toxic drugs.
52
Clinical Trial, Study Design, Selection of Control Group, Types (4)
1. Placebo 2. no treatment 3. active controls 4. different dosing external controls may be justified but should be cautioned for erroneous inferences.
53
Clinical Trial, Study Design, Number of Subjects (3+2)
Sample size is determined by: 1. the expected magnitude of the treatment effect 2. variability of data 3. specified probability of error 4. requirement for additional information (population subsets or secondary endpoints) 5. type of effect (e.g., safety assessment requires more than efficacy assessment)
54
Clinical Trial, Study Design, Response Variables, Primary, Secondary vs Surrogate Endpoints
Primary endpoints: reflect clinically relevant effects based on the principal objective of the study. Secondary endpint: assess other drug effects other than the primary endpoints (may or may not be related to primary endpoints) Surrogate endpoint: intended to relate to a clinically important outcome but does not in itself measure a clinical benefit (can serve as primary endpoint when appropriate)
55
Clinical Trial, Study Design, Response Variables, Standards for Response Variables Measurement (3)
The measurement should be: 1. validated and and testable 2. accurate and precise 3. reproducible and reliable
56
Clinical Trial, Study Design, Methods to Minimize or Assess Bias (2+1)
1. Randomization: minimizes selection bias 2. Blinding: minimizes subjective bias 3. Compliance: asses deviation (document actual patient usage of the drug in addition to the prescribed dosage)
57
Clinical Trial, Conduct Guidelines, Safety (2, 3)
E1: Extend of Population Exposure to Assess Clinical Safety (for drug intended long-term treatment of Non-life-threatening conditions) E2: Clinical Safety Data Management E2A: Definition and Standards for Expedited Reporting E2B: Data Elements for Transmission of Individual Case Safety Reports E2C: Periodic Safety Update Reports for Marketed Drugs
58
Clinical Trial, Conduct Guidelines Specialty Report and Registration (3)
E3: Structure and Content of Clinical Study Reports E4: Dose-response Information to Support Drug Registration E5: Ethnic Factors in the Acceptability of Foreign Clinical Data
59
Clinical Trial, Conduct Guidelines Consolidated Guidelines
E6: Good Clinical Practice: Consolidated Guidelines
60
Clinical Trial, Conduct Guidelines Clinical Trial Designs (5)
E7: Studies in support of Special Populations: Geriatrics E8: General Consideration for Clinical Trials E9: Statistical Considerations in the Design of Clinical Trials E10: Choice of Control Group in Clinical Trials E11: Studies in support of Special Populations: Pediatrics
61
Clinical Trial, Conduct Guidelines Non-clinical (2)
M3: Non-clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals S6: Safety Studies for Biotechnology-derived Products
62
Clinical Trial, Analysis Plan, General Considerations (4)
1. subject allocation method 2. response variable measurement 3. specific hypothesis to be tested 4. approaches to common problems (i.e., early withdrawn and protocol violation)
63
Clinical Trial, Analysis, Statistical Adjustment Early Termination Studies
Reduced statistical power requires review and adjustment for the overall levels of statistical significance and estimates of the effect size.
64
Clinical Trial Analysis, Summary for Safety Report, Procedure (3)
1. safety data collection 2. data tabulation 3. adverse events classification (by seriousness and causality)
65
Clinical Tria Reporing, Guidelines
Clinical Trials Report as per E3 and E6
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