Clinical Pharmacology Current Topics and Case Studies 2nd Edition by Markus Müller 3319273450 9783319273457

Part I: Introduction

1: The Discipline of Clinical Pharmacology

References

2: Current Issues in Drug Development

2.1 Historical Success

2.2 The Dawn of the Molecular Era, the ‘Druggable Genome’ and the Market Fragmentation

2.3 Innovation and Stagnation

2.4 The Development of EBM Methodology

2.5 Issues in Preclinical and Clinical Drug Development

2.6 The Role of Academic Medicine

2.7 Confidence Crisis and Public Opinion

Conclusion

References

Further Reading

3: Current Issues in Drug Regulation

3.1 The Drug Regulators’ Decision-Making

3.2 Authorising a Medicinal Product in the EU

3.2.1 The Centralised Authorisation

3.2.2 The Mutual Recognition Procedure (MRP) and the Decentralised Procedure (DCP) [14]

3.2.3 The National Procedure

3.3 Regulatory Life Cycle Management of Medicinal Products

3.3.1 From Efficacy to Post-marketing Relative Effectiveness Assessment

3.3.2 Pharmacovigilance and Signal Detection

3.3.3 Risk Management Plans (RMPs)

3.3.4 When Should a Medicinal Product Be Authorised?

References

4: Current Topics in Drug Reimbursement

4.1 Introduction

4.2 Marketing Authorisation Versus Reimbursement

4.3 Relative Effectiveness and Health Technology Assessment in Europe: The Role of EUnetHTA

4.3.1 HTA: Definition

4.3.2 Relative Effectiveness Within the Context of HTA

4.3.3 Rapid Assessment

4.4 Austrian Case Study: Vive La Différence?

4.4.1 Interpretation

4.5 Thinking About Reimbursement During Drug Development

4.6 Tying It All Together: Electronic Health Records, Registries and Outcome-Based Pricing

4.6.1 Managed Entry Agreements

4.7 Summary and Conclusions

References

Part II: Clinical Trials

5: Ethics in Clinical Research

5.1 Development of Worldwide Standards in Clinical Research Ethics

5.2 Research Ethics Committees Today: Function and Composition

5.3 Research Ethics Committees: Issues of Debate

5.3.1 Increasing Workload

5.4 Compensation for Committee Members

References

6: Good Clinical Practice (GCP) and Scientific Misconduct

6.1 Good Clinical Practice

6.1.1 Historic Background

6.1.1.1 The Prussian Directive and the Case of Neisser

The Neisser Case

6.1.1.2 Federal Food and Drugs Act of 1906

6.1.1.3 The Sulphanilamide Disaster and the ‘Food, Drug and Cosmetic Act’, 1938

6.1.1.4 Second World War Crimes

Unit 731

Nazi Experiments

6.1.1.5 Nuremberg Trial and Nuremberg Code

6.1.1.6 Thalidomide (Contergan) Tragedy

6.1.1.7 Declaration of Helsinki [8]

6.1.2 Development of Good Clinical Practice Guidelines

6.1.2.1 International Conference of Harmonisation (ICH [16])

ICH Parties

ICH Observers

ICH Steering Committee

6.1.3 ICH Topics [17]

6.1.3.1 ICH TOPIC E6, Note of Guidance for Good Clinical Practice (CPMP/ICH/135/95): The Princip

6.1.3.2 Institutional Review Board/Independent Ethics Committee (IRB/IEC)

6.1.3.3 Investigator

Investigator’s Qualifications and Agreements

Should Study Participants Receive Payment?

Should There Be a Different Standard for Paying Healthy Subjects as Opposed to Patient Subjects

Patient Information

The Informed Consent Process

Records and Reports

Source Data

Case Record Form (CRF)

Archiving

Progress Reports

Safety Reporting

Serious Adverse Event

Suspected Unexpected Serious Adverse Event (SUSAR)

Causality Assessment

Final Reports

6.1.3.4 Sponsor

Quality Assurance and Quality Control

Additional Responsibilities of the Sponsor

6.1.4 Discussion

6.1.4.1 Is ICH–GCP Just a ‘Bronze Standard’? [20]

6.1.4.2 The E6(R2) Integrated Addendum [34]

6.1.4.3 ICH–GCP and Academic Research

6.1.5 Summary

6.2 Research Misconduct

6.2.1 What Is Research Misconduct?

6.2.2 Forms of Research Misconduct

6.2.3 How Common Is Research Misconduct or Fraud?

6.2.4 Conclusion

References

7: Phase I Studies and First-In-Human Trials

7.1 Introduction

7.2 Definition Phase I

7.3 General Considerations for Phase I Studies, Trial Design and Study Protocol

7.4 Preclinical Development

7.5 Choice of Subjects, Study Population

7.6 Dose Finding

7.7 Route and Rate of Administration

7.8 Clinical Environment

7.9 Specificities of First-in-Man Trials with Monoclonal Antibodies

References

Further Reading

8: Clinical Trials: Interventional Studies

8.1 Introduction

8.2 Types of Clinical Trials

8.2.1 Purpose

8.2.2 Definition

8.3 Randomization

8.3.1 The Basic Idea, Like Most Good Things Is Very Simple [2]

8.3.2 Simple Randomization

8.3.3 Permuted Block Randomization

8.3.4 Stratified Randomization

8.3.5 Pseudo-randomization

8.3.6 Allocation Concealment

8.4 Blinding

8.4.1 Human Behavior Is Influenced by What We Know or Believe

8.5 Different Study Designs

8.5.1 Parallel Group Design

8.5.2 Crossover Design

8.5.3 Factorial Design

8.6 Study Endpoint

8.7 Interim Analyses

References

9: Observational Studies

9.1 Introduction

9.2 Methodological Principles

9.2.1 Study Population

9.2.2 Data Sources

9.2.2.1 Exposure

9.2.2.2 Outcome

9.2.3 Measurement Issues

9.2.4 Measures of Association and Impact

9.2.5 Interpreting an Effect: Bias, Confounding, and Sampling Error

9.2.5.1 Bias

9.2.5.2 Confounding

9.2.5.3 Sampling Variation

9.3 Overview of Study Design Types

9.3.1 Descriptive Studies

9.3.2 Analytical Study Designs

9.3.2.1 Cross-Sectional Study

9.3.2.2 Cohort Study: Principles and Practical Example

9.3.2.3 Case-Control Study: Principles and a Practical Example

The Cases

The Controls and the Source Population

Measurement of the Main Exposure Factor

Handling Potential Confounders

Analysis and Results

Summary of Case-Control Studies

9.3.2.4 Case-Crossover Studies

9.3.3 Meta-analysis of Observational Studies

References

Further Reading

Part III: Tools in Clinical Pharmacology

10: Tools in Clinical Pharmacology: Imaging Techniques

10.1 Introduction

10.2 Positron Emission Tomography (PET)

10.3 Single-Photon Emission Computed Tomography (SPECT)

10.4 Optical Imaging

10.5 Magnetic Resonance Imaging (MRI)

10.6 Computed Tomography (CT)

10.7 Ultrasound Imaging

10.8 Example for Using PET in Drug Development: Aprepitant

References

11: Pharmacokinetics II: 14C-Labelled Microdosing in Assessing Drug Pharmacokinetics at Phase 0

11.1 Origins of 14C-Labelled Tracers

11.2 Administration of 14C-Drugs to Humans

11.3 Accelerator Mass Spectrometry

11.3.1 The Emergence of Microdosing

11.3.2 Application of Microdosing

11.4 Pharmacokinetic Linearity

11.5 Microdosing and Metabolism

Conclusions

References

12: Current Concepts of Pharmacogenetics, Pharmacogenomics, and the “Druggable” Genome

12.1 Genetic Variation in the Human Genome: Biological Basis of Pharmacogenetics

12.2 The Promise of Pharmacogenetics, Pharmacogenomics, and Genomic Medicine

12.3 Genetic Variants Affecting Pharmacokinetics

12.4 Pharmacogenetic Testing for Optimizing Drug Dose

12.5 Pharmacogenetic Testing to Prevent Adverse Drug Reactions

12.6 Genetics of Pharmacodynamics

12.7 The Predictive Power of Pharmacogenomics

12.8 The “Druggable” Genome

12.9 Challenges that Lie Ahead

References

13: Pharmacokinetics I: PK-PD Approach, the Case of Antibiotic Drug Development

13.1 Pharmacokinetics and Pharmacodynamics Concepts in Antimicrobials

13.1.1 Principles in Antimicrobial Pharmacokinetic and Pharmacodynamic

13.1.2 Free Unbound Drug Concentrations

13.1.3 Model-Based Drug Development

13.2 Designing Antimicrobial Experiments

13.2.1 Microdialysis for Determination of Time-Course of Free Drug Concentrations

13.2.2 Defining In Vitro Antimicrobial Action

13.2.3 In Vitro Time-Kill Kinetic Models

13.2.4 Animal Infection Models

13.3 Special Populations

13.3.1 Critically Ill Patients

13.3.2 Renal Impairment

13.3.3 Obesity

13.3.4 Geriatric Populations

13.3.5 Pediatric Populations

Conclusion

References

14: Epidemiology and Biostatistics

14.1 Introduction

14.2 Measures of the Disease Frequency

14.2.1 Prevalence

14.2.2 Incidence

14.2.3 Mortality

14.3 Relationship Between Prevalence, Incidence, and Mortality

14.4 Survival Analysis

14.5 Censured Data

14.6 Case Fatality Rate

14.7 Risk, Relative Risk, and Attributable Risk

14.8 Epidemiologic Study Designs

14.9 Statistical Measures

14.9.1 Why Use Statistics?

14.9.2 Variables

14.9.3 Presentation of Variables

14.10 Population and Sample

14.10.1 Hypothesis Testing and the p Value

14.10.2 Post Hoc Analysis or “Fishing for Results”

14.10.3 Multiple Testing

14.10.4 Correlation Analysis

14.10.5 Association and Causation

14.10.5.1 Association Strength

14.10.5.2 Temporal Relationship

14.10.5.3 Dose-Response Relationship

14.10.5.4 Constancy

14.10.5.5 Plausibility

14.10.5.6 Experiment

14.10.5.7 Specificity

References

15: Placebo Effects and Placebo Control in Clinical Trials

15.1 The Recent Debate About Research Ethics in Placebo-­Controlled Trials (PCTs)

15.2 Placebo vs. Active Control

15.3 The Issue of “Assay Sensitivity”

15.4 Placebo-Controlled Trial: Ethical or Not?

15.4.1 The Concept of Non-inferiority to Placebo

15.5 Criteria for Justification of Placebo

References

Part IV: Topics in Clinical Pharmacology

16: Pharmaceutical Drug Safety

16.1 Introduction

16.2 Thalidomide: A Disaster as Starting Point for the Methodical Assessment of Drug Safety

16.3 During Drug Development Only Frequent ADRs Can Be Detected

16.4 ADR Reporting and Worldwide Pharmacovigilance

16.5 Spontaneous Reporting Systems

16.6 Drug Safety Issues After Lipobay and Vioxx

16.7 Recent and Future Developments in Pharmacovigilance

Conclusions

References

17: Drug Interactions

17.1 Definition

17.2 Relevance of Interactions

17.3 Categories of Interaction

17.4 Factors Promoting Interactions and Their Clinical Relevance

17.5 Most Important Mechanisms of Interactions According to the ADME Schemata

17.5.1 ADME: Interactions Based on Drug Absorption

17.6 ADME: Interactions Based on Drug Distribution

17.6.1 ADME: Interactions Based on Drug Metabolism

17.6.2 Examples for Clinically Relevant Interactions Based on CYP3A4

17.6.3 ADME: Interactions Based on Drug Excretion

17.7 Management of Potential Drug Interactions

References

18: Development of Advanced Therapy Medicinal Products: A Case for Early Scientific Advice

18.1 Introduction

18.2 Cell-Based Medicinal Products (CBMPs)

18.3 Efficacy and Safety Challenges

18.3.1 Patient Integration

18.3.2 Characterization

18.4 Gene Therapy Medicinal Products (GTMP)

18.5 Development Challenges and Strategies to Address Them

18.5.1 Vector Manufacture

18.5.2 Achieving Stable Gene Expression

18.5.3 Clinical Efficacy and Safety

18.6 Combined ATMPs

18.7 Involvement of CAT in ATMP Development

References

19: Biologics

19.1 Introduction

19.2 Specificity Versus Pleiotropy

19.3 Preclinical Development of Biologics

19.4 Specific Safety Consideration

19.5 Pharmacokinetic–Pharmacodynamic Properties

19.6 New Advances

References

20: Generics, Biosimilars, Enantiomers, and Me-Toos

20.1 Generics

20.1.1 Regulatory Background

20.1.2 Patent Protection, Data Protection, and Marketing Protection for New Products

20.1.3 Salts and Esters

20.1.4 Bioequivalence

20.1.5 Bioequivalence: Some Special Issues

20.1.5.1 Narrow Therapeutic Index Drugs (NTIDs)

20.1.5.2 Highly Variable Drug Products (HVDPs)

20.1.5.3 Chiral Drugs and Enantiomers

20.1.5.4 tmax

20.1.5.5 Drugs Which Are Not Orally Absorbed

20.1.5.6 Inhaled Drugs

20.1.5.7 Bioequivalence of Intravenous Products? Complex Parenterals

20.2 Biosimilars

20.2.1 Complexity

20.2.2 Biosimilars: General Issues

20.2.3 Regulatory Experience

20.3 Enantiomers

20.3.1 Sophisticated Nonsense?

20.3.2 Rationale for the Development of Chirally Pure Drugs

20.3.3 Pharmacodynamic and Kinetic Differences Between Enantiomers

20.3.4 Recent Regulatory Experience of the Chiral Switch: A Word of Caution

20.4 Me-Toos

20.4.1 Background

20.4.2 What Are “Me-Too” Drugs?

20.4.3 Is First-in-Class Also Best-in-Class?

20.4.4 What Is a Drug Class?

20.4.5 Is There a “Class Effect”?

References

21: Orphan Drugs for Rare Diseases

21.1 What Are Rare Diseases?

21.2 What Are Orphan Drugs?

21.3 The Orphan Drug Legislation

21.4 The Committee for Orphan Medicinal Products (COMP)

21.5 Orphan Incentives [1]

21.6 What Are the Criteria for Orphan Designation?

21.7 General Requirements for a Valid Condition for Orphan Designation [13]

21.8 What Data Are Necessary at the Time of Orphan Drug Designation?

21.8.1 Some Examples for a Positive Opinion for Orphan Designation

21.8.2 Reason for Negative Opinions: Subsetting, No Significant Benefit

21.8.2.1 Subsetting/Valid Condition

21.8.2.2 Significant Benefit

21.8.2.3 All Negative Opinions [21]

21.9 Scientific Advice: Protocol Assistance [22]

21.10 Confirmation of Orphan Status at the Time of Marketing Authorisation [24]

21.11 Challenging Marketing Exclusivity for Orphan Medicinal Products

21.12 Success of the Orphan Programme

21.12.1 Designated Orphan Medicinal Products

21.12.2 Marketing Authorisations for Orphan Medicinal Products

21.13 Discussion

21.14 Useful Links

References

22: Special Situations, Market Fragmentation II: Sex Differences

22.1 Expanding Scope of Gender and Sex Differences

22.2 Sex Versus Gender

22.3 Sex Matters

22.3.1 Physiological Variability

22.3.2 Pharmacokinetics: Sex Differences

22.3.3 Pharmacodynamic: Sex Differences

22.3.4 Female-Specific Aspects

22.3.5 Adverse Drug Reactions

22.3.6 Clinical Trials: Women’s Representation

22.3.6.1 History

22.3.6.2 Barriers of Participation in Clinical Trials

22.4 Regulatory Changes to Include Women in Clinical Trials

22.5 Pregnancy

22.6 From Sex Differences to Individual Differences: Where the Science Is Taking Us

References

23: Special Situations III: Medicines for Children

23.1 Children as Therapeutic Orphans

23.2 Hurdles to Drug Development for Children

23.2.1 Ethical and Legal Aspects

23.2.2 Lack of Public Acceptance

23.2.3 Methodological Challenges of Clinical Studies in Children

23.2.4 Lack of Research Infrastructures and Paediatric Research Networks

23.2.5 Low Economic Potential of Paediatric Indications for Pharmaceutical Industry

23.3 Regulatory Initiatives to Improve Paediatric Drug Development

23.3.1 Paediatric Initiatives in the USA

23.3.2 EU Paediatric Regulation

23.3.2.1 Requirements and Rewards

23.3.2.2 Paediatric Investigation Plan

23.3.2.3 Paediatric Committee

23.3.2.4 Collateral Measures

23.3.2.5 Achievements of the Paediatric Regulation

23.4 Points to Consider for a Paediatric Investigation Plan

23.4.1 Paediatric Indications

23.4.2 Child-Appropriate Formulations

23.4.3 Juvenile Animal Studies

23.4.4 Clinical Pharmacology Studies in Children

23.4.5 Clinical Efficacy and Safety Studies

23.4.6 Extrapolation