Drug Safety Evaluation E-Book

Shayne Cox Gad

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: Pharmaceutical Development
• Sprache: Englisch

Seitenzahl: 2812

Veröffentlichungsjahr: 2016

Beschreibung

This practical guide presents a road map for safety assessment as an integral part of the development of new drugs and therapeutics. * Helps readers solve scientific, technical, and regulatory issues in preclinical safety assessment and early clinical drug development * Explains scientific and philosophical bases for evaluation of specific concerns - including local tissue tolerance, target organ toxicity and carcinogenicity, developmental toxicity, immunogenicity, and immunotoxicity * Covers the development of new small and large molecules, generics, 505(b)(2) route NDAs, and biosimilars * Revises material to reflect new drug products (small synthetic, large proteins and cells, and tissues), harmonized global and national regulations, and new technologies for safety evaluation * Adds almost 20% new and thoroughly updates existing content from the last edition

Leseprobe

Table of Contents

Cover

Title Page

ACKNOWLEDGEMENT

PREFACE

ABOUT THE AUTHOR

1 THE DRUG DEVELOPMENT PROCESS AND THE GLOBAL PHARMACEUTICAL MARKETPLACE

1.1 INTRODUCTION

1.2 THE MARKETPLACE

1.3 HISTORY OF MODERN THERAPEUTICS

1.4 THE DRUG DEVELOPMENT PROCESS

1.5 STRATEGIES FOR DEVELOPMENT: LARGE VERSUS SMALL COMPANY OR THE SHORT VERSUS LONG GAME

1.6 SAFETY ASSESSMENT AND THE EVOLUTION OF DRUG SAFETY

1.7 THE THREE STAGES OF DRUG SAFETY EVALUATION IN THE GENERAL CASE

REFERENCES

2 REGULATION OF HUMAN PHARMACEUTICAL SAFETY

2.1 INTRODUCTION

2.2 BRIEF HISTORY OF US PHARMACEUTICAL LAW

2.3 FDAMA SUMMARY: CONSEQUENCES AND OTHER REGULATIONS

2.4 OVERVIEW OF US REGULATIONS

2.5 ORGANIZATIONS REGULATING DRUG AND DEVICE SAFETY IN THE UNITED STATES

2.6 PROCESS OF PHARMACEUTICAL PRODUCT DEVELOPMENT AND APPROVAL

2.7 TESTING GUIDELINES

2.8 TOXICITY/SAFETY TESTING: CELLULAR AND GENE THERAPY PRODUCTS

2.9 TOXICITY TESTING: SPECIAL CASES

2.10 INTERNATIONAL PHARMACEUTICAL REGULATION AND REGISTRATION

2.11 COMBINATION PRODUCTS

2.12 CONCLUSIONS

REFERENCES

FURTHER READING

3 DATA MINING

3.1 INTRODUCTION

3.2 PC‐BASED INFORMATION PRODUCTS: LASER DISC

3.3 CONCLUSIONS

REFERENCES

4 SCREENS IN SAFETY AND HAZARD ASSESSMENT

4.1 INTRODUCTION

4.2 CHARACTERISTICS OF SCREENS

4.3 USES OF SCREENS

4.4 TYPES OF SCREENS

4.5 CRITERION: DEVELOPMENT AND USE

4.6 ANALYSIS OF SCREENING DATA

4.7 UNIVARIATE DATA

REFERENCES

5 FORMULATIONS, ROUTES, AND DOSAGE REGIMENS

5.1 MECHANISMS

5.2 COMMON ROUTES

5.3 FORMULATION OF TEST MATERIALS

5.4 DOSING CALCULATIONS

5.5 CALCULATING MATERIAL REQUIREMENTS

5.6 EXCIPIENTS

REFERENCES

6 NONCLINICAL MANIFESTATIONS, MECHANISMS, AND END POINTS OF DRUG TOXICITY

6.1 MANIFESTATIONS

6.2 MECHANISMS OF TOXICITY

6.3 END POINTS MEASURED IN GENERAL TOXICITY STUDIES

6.4 COMPLICATIONS

REFERENCES

7 PILOT TOXICITY TESTING IN DRUG SAFETY EVALUATION

7.1 INTRODUCTION

7.2 RANGE‐FINDING STUDIES

7.3 ACUTE SYSTEMIC TOXICITY CHARACTERIZATION

7.4 SCREENS

7.5 PILOT AND DRF STUDIES

REFERENCES

8 REPEAT‐DOSE TOXICITY STUDIES

8.1 OBJECTIVES

8.2 REGULATORY CONSIDERATIONS

8.3 STUDY DESIGN AND CONDUCT

8.4 STUDY INTERPRETATION AND REPORTING

REFERENCES

9 GENOTOXICITY

9.1 ICH TEST PROFILE

9.2 DNA STRUCTURE

9.3 CYTOGENETICS

9.4

IN VITRO

CYTOGENETIC ASSAYS

9.5

IN VIVO

CYTOGENETIC ASSAYS

9.6 SISTER CHROMATID EXCHANGE ASSAYS

REFERENCES

10 QSAR TOOLS FOR DRUG SAFETY

10.1 STRUCTURE–ACTIVITY RELATIONSHIPS

10.2 SAR MODELING METHODS

10.3 APPLICATIONS IN TOXICOLOGY

10.4 GENOTOXICITY

10.5 COMPARISON OF AVAILABLE MODELS/APPLICATIONS

REFERENCES

11 IMMUNOTOXICOLOGY IN DRUG DEVELOPMENT

11.1 INTRODUCTION

11.2 OVERVIEW OF THE IMMUNE SYSTEM

11.3 IMMUNOTOXIC EFFECTS

11.4 IMMUNOSUPPRESSION

11.5 IMMUNOSTIMULATION

11.6 REGULATORY POSITIONS

11.7 EVALUATION OF THE IMMUNE SYSTEM

11.8 NONSPECIFIC IMMUNITY FUNCTION ASSAY

11.9 T‐CELL‐DEPENDENT ANTIBODY RESPONSE (TDAR)

11.10 APPROACHES TO COMPOUND EVALUATION

11.11 PROBLEMS AND FUTURE DIRECTIONS

REFERENCES

12 NONRODENT ANIMAL STUDIES

12.1 INTRODUCTION

12.2 COMPARISON BETWEEN RODENT AND NONRODENT EXPERIMENTAL DESIGN

12.3 DIFFERENCES IN STUDY ACTIVITIES

12.4 NONRODENT MODELS

12.5 DOG

12.6 THE FERRET

12.7 THE PIG

12.8 NONHUMAN PRIMATES

12.9 STATISTICS IN LARGE ANIMAL STUDIES

12.10 SUMMARY

REFERENCES

13 DEVELOPMENTAL AND REPRODUCTIVE TOXICITY TESTING

13.1 INTRODUCTION

13.2 ICH STUDY DESIGNS

13.3 METHODOLOGICAL ISSUES

13.4 DEVELOPMENTAL STUDIES IN PRIMATES

13.5 DATA INTERPRETATION

13.6 JUVENILE AND PEDIATRIC TOXICOLOGY

13.7

IN VITRO

TESTS FOR DEVELOPMENTAL TOXICITY

13.8 APPRAISAL OF CURRENT APPROACHES FOR DETERMINING DEVELOPMENTAL AND REPRODUCTIVE HAZARDS

REFERENCES

14 CARCINOGENICITY STUDIES

14.1 INTRODUCTION

14.2 MECHANISMS AND CLASSES OF CARCINOGENS

14.3 GENOTOXIC CARCINOGENS

14.4 EPIGENETIC CARCINOGENS

14.5 REGULATORY REQUIREMENTS AND TIMING

14.6 SPECIES AND STRAIN

14.7 ANIMAL HUSBANDRY

14.8 DOSE SELECTION

14.9 GROUP SIZE

14.10 ROUTE OF ADMINISTRATION

14.11 STUDY DURATION

14.12 SURVIVAL

14.13 END POINTS MEASURED

14.14 TRANSGENIC MOUSE MODELS

14.15 INTERPRETATION OF RESULTS: CRITERIA FOR A POSITIVE RESULT

14.16 STATISTICAL ANALYSIS

14.17 WEIGHT‐OF‐EVIDENCE FACTORS FOR CONSIDERATION IN A CARCINOGENICITY ASSESSMENT DOCUMENT (CAD)

14.18 CONCLUSIONS

REFERENCES

15 HISTOPATHOLOGY IN NONCLINICAL PHARMACEUTICAL SAFETY ASSESSMENT

15.1 INTRODUCTION

15.2 CLINICAL PATHOLOGY

REFERENCES

16 IRRITATION AND LOCAL TISSUE TOLERANCE IN PHARMACEUTICAL SAFETY ASSESSMENT

16.1 INTRODUCTION

16.2 FACTORS AFFECTING IRRITATION RESPONSES AND TEST OUTCOME

16.3 PRIMARY DERMAL IRRITATION (PDI) TEST

16.4 OTHER NONPARENTERAL ROUTE IRRITATION TESTS

16.5 OCULAR IRRITATION TESTING

16.6 VAGINAL IRRITATION

16.7 ACUTE PRIMARY VAGINAL IRRITATION STUDY IN THE FEMALE RABBIT

16.8 PARENTERAL IRRITATION/TOLERANCE

16.9 PROBLEMS IN TESTING (AND THEIR RESOLUTIONS)

16.10 PHOTOTOXICITY

16.11 HEMOCOMPATIBILITY

REFERENCES

17 PHARMACOKINETICS AND TOXICOKINETICS IN DRUG SAFETY EVALUATION

17.1 INTRODUCTION

17.2 REGULATIONS

17.3 PRINCIPLES

17.4 PHARMACOKINETICS

17.5 LABORATORY METHODS

17.6 SAMPLING METHODS AND INTERVALS

17.7 STUDY TYPES

17.8 ANALYSIS OF DATA

17.9 PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING

17.10 POINTS TO CONSIDER

17.11 BIOLOGICALLY DERIVED MATERIALS

17.12 POINTS TO CONSIDER

REFERENCES

18 SAFETY PHARMACOLOGY

18.1 REGULATORY REQUIREMENTS

18.2 STUDY DESIGNS AND PRINCIPLES

18.3 ORGAN SYSTEM‐SPECIFIC TESTS

18.4 CARDIOVASCULAR

18.5 CENTRAL NERVOUS SYSTEM

18.6 RESPIRATORY/PULMONARY SYSTEM

18.7 SECONDARY ORGAN SYSTEM

18.8 RENAL FUNCTION TESTS

18.9 SUMMARY

REFERENCES

19 SPECIAL CONCERNS FOR THE PRECLINICAL EVALUATION OF BIOTECHNOLOGY PRODUCTS

19.1 REGULATION

19.2 PRECLINICAL SAFETY ASSESSMENT

19.3 RECOMBINANT DNA TECHNOLOGY

19.4 IMMUNOGENICITY/ALLERGENICITY

19.5 MONOCLONAL ANTIBODY TECHNOLOGY

19.6 BIOPROCESS TECHNOLOGY

19.7 GENE THERAPY PRODUCTS

19.8 VACCINES

19.9 SPECIAL CHALLENGES

19.10 PLANNING A SAFETY EVALUATION PROGRAM

19.11 CHALLENGES: BIOSIMILARS

REFERENCES

20 SAFETY ASSESSMENT OF INHALANT DRUGS AND DERMAL ROUTE DRUGS

20.1 INHALED THERAPEUTICS

20.2 THE PULMONARY SYSTEM

20.3 PENETRATION AND ABSORPTION OF INHALED GASES AND VAPORS

20.4 DEPOSITION OF INHALED AEROSOLS

20.5 ABSORPTION AND CLEARANCE OF INHALED AEROSOLS

20.6 PHARMACOKINETICS AND PHARMACODYNAMICS OF INHALED AEROSOLS

20.7 METHODS FOR SAFETY ASSESSMENT OF INHALED THERAPEUTICS

20.8 PARAMETERS OF TOXICITY EVALUATION

20.9 INHALATION EXPOSURE TECHNIQUES

20.10 THE UTILITY OF TOXICITY DATA

20.11 FORMULATION AND POTENTIAL MUCOSAL DAMAGE

20.12 THERAPEUTIC DRUG DELIVERY BY THE DERMAL ROUTE

REFERENCES

21 SPECIAL CASE PRODUCTS

21.1 INTRODUCTION

21.2 IMAGING AGENTS

REFERENCES

22 SPECIAL CASE PRODUCTS

22.1 INTRODUCTION

REFERENCES

23 PEDIATRIC PRODUCT SAFETY ASSESSMENT (2006 GUIDANCE, INCLUDING JUVENILE TOXICOLOGY)

23.1 INTRODUCTION

23.2 ISSUES TO CONSIDER REGARDING JUVENILE ANIMAL STUDIES

23.3 GENERAL CONSIDERATIONS IN DESIGNING TOXICITY STUDIES IN JUVENILE ANIMALS

23.4 STUDY DESIGNS AND CONSIDERATIONS

REFERENCES

24 USE OF IMAGING, IMAGING AGENTS, AND RADIOPHARMACEUTICALS IN NONCLINICAL TOXICOLOGY

24.1 INTRODUCTION

24.2 X‐ray

24.3 POSITRON EMISSION TOMOGRAPHY (PET)

24.4 SINGLE‐PHOTON EMISSION COMPUTED TOMOGRAPHY (SPECT)

24.5 COMPUTED TOMOGRAPHY (CT)

24.6 MAGNETIC RESONANCE IMAGING (MRI)

24.7 OPTICAL IMAGING

24.8 ULTRASOUND

24.9 NANOPARTICLE CONTRAST AGENTS

24.10 RADIOPHARMACEUTICALS

24.11 APPLICATIONS OF PRECLINICAL IMAGING IN LABORATORY ANIMALS

24.12 NONCLINICAL SAFETY ASSESSMENT FOR IMAGING AGENTS

24.13 RADIOPHARMACEUTICALS

24.14 NONCLINICAL LATE RADIATION TOXICITY STUDIES

24.15 STUDY DESIGN

REFERENCES

25 OCCUPATIONAL TOXICOLOGY IN THE PHARMACEUTICAL INDUSTRY

25.1 INTRODUCTION

25.2 OCCUPATIONAL TOXICOLOGY VERSUS DRUG SAFETY EVALUATION

25.3 REGULATORY PRESSURES IN THE UNITED STATES AND THE EUROPEAN COMMUNITY

25.4 ORGANIZATIONAL STRUCTURE

25.5 ACTIVITIES

25.6 CONCLUSION

REFERENCES

26 STRATEGY AND PHASING FOR NONCLINICAL DRUG SAFETY EVALUATION IN THE DISCOVERY AND DEVELOPMENT OF PHARMACEUTICALS

26.1 INTRODUCTION

26.2 REGULATORY REQUIREMENTS

26.3 ESSENTIAL ELEMENTS OF PROJECT MANAGEMENT

26.4 SCREENS: THEIR USE AND INTERPRETATION IN SAFETY ASSESSMENT

26.5 STRATEGY AND PHASING

26.6 CRITICAL CONSIDERATIONS

26.7 SPECIAL CASES IN SAFETY ASSESSMENT

26.8 SUMMARY

REFERENCES

27 THE APPLICATION OF

IN VITRO

TECHNIQUES IN DRUG SAFETY ASSESSMENT

27.1 INTRODUCTION

27.2

IN VITRO

TESTING IN PHARMACEUTICAL SAFETY ASSESSMENT

27.3 DEFINING TESTING OBJECTIVE

27.4 TEST SYSTEMS: CHARACTERISTICS, DEVELOPMENT, AND SELECTION

27.5

IN VITRO

MODELS

27.6 LETHALITY

27.7

IN SILICO

METHODS

27.8 THE FINAL FRONTIER AND BARRIER: REGULATORY ACCEPTANCE

27.9 SUMMARY

REFERENCES

Further Reading

28 EVALUATION OF HUMAN TOLERANCE AND SAFETY IN CLINICAL TRIALS

28.1 THE PHARMACEUTICAL CLINICAL DEVELOPMENT PROCESS AND SAFETY

28.2 LIMITATIONS ON/OF CLINICAL TRIALS

28.3 THE CLINICAL TRIAL PROCESS

28.4 INSTITUTIONAL REVIEW BOARDS (IRBS)/ETHICS COMMITTEES IN THE CLINICAL TRIAL PROCESS

28.5 DRUG FORMULATIONS AND EXCIPIENTS

28.6 PHASE I DESIGNS

28.7 CLINICAL TRIAL SAFETY INDICATORS

28.8 ASSESSMENT OF UNWANTED DRUG EFFECTS

REFERENCES

29 POSTMARKETING SAFETY EVALUATION

29.1 CAUSES OF SAFETY WITHDRAWALS

29.2 REGULATORY REQUIREMENTS

29.3 MANAGEMENT OF ADR AND ADE DATA

29.4 CAUSALITY ASSESSMENT

29.5 COURSES OF CORRECTIVE ACTION

29.6 LEGAL CONSEQUENCES OF SAFETY WITHDRAWAL

REFERENCES

30 STATISTICS IN PHARMACEUTICAL SAFETY ASSESSMENT

30.1 INTRODUCTION

30.2 EXPERIMENTAL DESIGN

30.3 DATA RECORDING

30.4 GENERALIZED METHODOLOGY SELECTION

30.5 STATISTICAL ANALYSIS: GENERAL CONSIDERATIONS

30.6 HYPOTHESIS TESTING OF CATEGORICAL AND RANKED DATA

30.7 HYPOTHESIS TESTING: UNIVARIATE PARAMETRIC TESTS

30.8 METHODS FOR THE REDUCTION OF DIMENSIONALITY

30.9 META‐ANALYSIS

30.10 BAYESIAN INFERENCE

30.11 DATA ANALYSIS APPLICATIONS IN SAFETY ASSESSMENT STUDIES

REFERENCES

31 COMBINATION PRODUCTS

31.1 COMBINATION PRODUCTS

REFERENCES

32 QUALIFICATION OF IMPURITIES, DEGRADANTS, RESIDUAL SOLVENTS, METALS, AND LEACHABLES IN PHARMACEUTICALS

32.1 IMPURITIES

32.2 RESIDUAL SOLVENTS

32.3 EXTRACTABLES AND LEACHABLES

32.4 RESIDUAL METALS AND ELEMENTS

REFERENCES

33 TISSUE, CELL, AND GENE THERAPY

33.1 SAFETY ASSESSMENT OF CELL THERAPY (CT) PRODUCTS

33.2 NONCLINICAL SAFETY ASSESSMENT OF GENE THERAPY PRODUCTS (GTPS)

33.3 DEFINITIONS

REFERENCES

APPENDIX A: SELECTED REGULATORY AND TOXICOLOGICAL ACRONYMS

APPENDIX B: DEFINITION OF TERMS AND LEXICON OF “CLINICAL” OBSERVATIONS IN NONCLINICAL (ANIMAL) STUDIES

APPENDIX C: NOTABLE REGULATORY INTERNET ADDRESSES

APPENDIX D: GLOSSARY OF TERMS USED IN THE CLINICAL EVALUATION OF THERAPEUTIC AGENTS

APPENDIX E: COMMON VEHICLES FOR THE NONCLINICAL EVALUATION OF THERAPEUTIC AGENTS

REFERENCES

APPENDIX F: GLOBAL DIRECTORY OF CONTRACT PHARMACEUTICAL TOXICOLOGY LABS

Index

End User License Agreement

List of Tables

Chapter 05

TABLE E.1

Index of Vehicles and Excipients: Codex and Details

TABLE E.2

Acacia

TABLE E.3

Acetic Acid

TABLE E.4

Acetone

TABLE E.5

Acetylmethylamide

TABLE E.6

Alginic Acid

TABLE E.7

Anecortave Acetate

TABLE E.8

Avicel CL‐611

TABLE E.9

Balanced Salt Saline

TABLE E.10

Basal Salt Solution

TABLE E.11

Benzoic Acid

TABLE E.12

β‐Cyclodextrin

TABLE E.13

Bicarbonate Buffer, pH 9.5

TABLE E.14

Calcium Chloride

TABLE E.15

Canola Oil

TABLE E.16

Capryol 90

TM

TABLE E.17

Captisol

TM

TABLE E.18

Carboxymethylcellulose (CMC)

TABLE E.19

Carboxymethylcellulose Calcium (Calcium CMC)

TABLE E.20

Carboxymethylcellulose Sodium (Sodium CMC)

TABLE E.21

Cetyl Alcohol

TABLE E.22

Citrate Buffer

TABLE E.23

Citric Acid Buffer

TABLE E.24

Collagen Matrix

TABLE E.25

Corn Oil

TABLE E.26

Cottonseed Oil

TABLE E.27

Cyclohexane

TABLE E.28

Dextrose

TABLE E.29

Dichlorvos

TABLE E.30

Diethylacetamide

TABLE E.31

Diethylene Glycol Monoethyl Ether (DEGEE)

TABLE E.32

Dimethylacetamide (DMA)

TABLE E.33

Dimethyl Sulfoxide (DMSO)

TABLE E.34

Dulbecco’s Modified Phosphate‐Buffered Saline (PBS)

TABLE E.35

Dulbecco’s Phosphate‐Buffered Saline (PBS)

TABLE E.36

Ethanol (EtOH)

TABLE E.37

Gelatin Capsules

TABLE E.38

Gelatin Phosphate Buffer

TABLE E.39

Gelucire 44/14

TM

TABLE E.40

Gelucire 50/13

TM

TABLE E.41

Gluconic Acid

TABLE E.42

Glycerol

TABLE E.43

Glycofurol

TABLE E.44

Gum Tragacanth

TABLE E.45

Gum Xanthan

TABLE E.46

Hydrochloric Acid (HCl)

TABLE E.47

Hydroxyethylcellulose

TABLE E.48

Hydroxypropyl‐β‐Cyclodextrin (HPβCD)

TABLE E.49

Hydroxypropyl Cellulose

TABLE E.50

Hydroxypropyl Methylcellulose (HPMC)

TABLE E.51

Hypotonic Phosphate‐Buffered Saline (PBS)

TABLE E.52

Isopropyl Alcohol

TABLE E.53

Isopropyl Myristate

TABLE E.54

Kolliphor EL

TM

TABLE E.55

Kolliphor ELP

TM

TABLE E.56

Kolliphor RH40

TM

TABLE E.57

Labrafil M1944

TM

TABLE E.58

Labrasol

TM

TABLE E.59

Lactose

TABLE E.60

Lanolin

TABLE E.61

Lauroglycol 90

TM

TABLE E.62

Maltitol Solution

TABLE E.63

Maltol

TABLE E.64

Mannitol

TABLE E.65

Methylcellulose

TABLE E.66

Methylpyrrolidone

TABLE E.67

Mineral Oil

TABLE E.68

Olive Oil

TABLE E.69

Peanut Oil

TABLE E.70

PEG 200

TABLE E.71

PEG 300

TABLE E.72

PEG 400

TABLE E.73

PEG 600

TABLE E.74

PEG 810

TABLE E.75

PEG 1000

TABLE E.76

PEG 1500

TABLE E.77

PEG 1540

TABLE E.78

PEG 4000

TABLE E.79

PEG 6000

TABLE E.80

PEG 10 000

TABLE E.81

PEG 4 000 000

TABLE E.82

Petrolatum

TABLE E.83

Phosphate‐Buffered Saline (PBS)

TABLE E.84

Poloxamer 188

TM

TABLE E.85

Poly(glycolide‐

co

‐

DL

‐Lactide) Microspheres

TABLE E.86

Polyglyceryl Oleate

TABLE E.87

Polyvinylpyrrolidone (PVP)

TABLE E.88

Propylene Glycol

TABLE E.89

Randomly Methylated β‐Cyclodextrins (RAMEB)

TABLE E.90

Safflower Oil

TABLE E.91

Saline (pH Adj.)

TABLE E.92

Sesame Oil

TABLE E.93

Sodium Acetate Trihydrate Buffer

TABLE E.94

Sodium Chloride

TABLE E.95

Sodium Dihydrogen Phosphate Dihydrate (SDPD)

TABLE E.96

Sodium Metabisulfite

TABLE E.97

Sodium Phosphate Buffer

TABLE E.98

Sodium Sulfite

TABLE E.99

Solutol HS15

TM

TABLE E.100

Soybean Oil

TABLE E.101

Sulfobutyl Ether β‐Cyclodextrin (SBECD)

TABLE E.102

Tartaric Acid

TABLE E.103

Terbinafine HCl

TM

Placebo Nail Lacquer

TABLE E.104

Transcutol

TM

TABLE E.105

Trisodium Citrate Dihydrate

TABLE E.106

Tween 20

TM

TABLE E.107

Tween 80

TM

TABLE E.108

Vitamin E TPGS

TABLE E.109

Water

TABLE E.110

Xylitol

TABLE E.111

Combination Formulations

Chapter 01

TABLE 1.1

Top 20 Selling Pharmaceuticals (2013)

TABLE 1.2

Top 25 Drug Companies by sales (2014)

TABLE 1.3

Examples of Drugs from Different Sources

TABLE 1.4

Potential New Drugs in US Clinical Trials by Primary Disease/Medical Use, 2005–2006

TABLE 1.5

2006 Status of Drugs in Development

TABLE 1.6

INDs Received and Active at CDER

Chapter 02

TABLE 2.1

Important Dates in US Federal Drug Law

TABLE 2.2

Summary of the Contents of the 1997 Food and Drug Administration Modernization Act

TABLE 2.3

Composition of Standard Investigational New Drug Application (Traditional Format)

TABLE 2.4

Product Class Review Responsibilities

TABLE 2.5

Congressional Committees Responsible for FDA Oversight

TABLE 2.6

Synopsis of General Guidelines for Animal Toxicity Studies for Drugs

TABLE 2.7

Duration of Repeated‐Dose Toxicity Studies to Support Clinical Trials and Marketing

a

TABLE 2.8

Numbers of Animals per Dosage Group in Systemic Toxicity Studies (OECD Guidances)

TABLE 2.9

Comparison of Postnatal Development Stages

TABLE 2.10

Comparison of FDA’s Expedited Programs for Serious Conditions (CDER and CBER,

2014

)

TABLE 2.11

ICH Representation

TABLE 2.12

Steps in ICH Guideline Development and Implementation

TABLE 2.13

International Conference on Harmonization Guidelines

TABLE 2.14

ICH Current Guidelines Governing Nonclinical Safety Evaluation

TABLE 2.15

Comparison of Traditional and ICH Guidelines for Reproductive and Developmental Toxicology

TABLE 2.16

Required Duration of Dosing in Nonclinical Study to Support Clinical Dosing

TABLE 2.17

Composition of the Common Technical Document (ICH Format)

Chapter 03

TABLE 3.1

Sources of Prior Art

TABLE 3.2

Key Safety Assessment Reference Texts

Chapter 04

TABLE 4.1

Pharmacologic Receptor Screen Panel

TABLE 4.2

Discovery and Discrimination of Toxicants

Chapter 05

TABLE 5.1

Potential Routes of Administration

TABLE 5.2

Normal pH Range for Human Physiologic Fluids

TABLE 5.3

Selected Factors That May Affect Chemical Distribution to Various Tissues

TABLE 5.4

Test Subject Characteristics That Can Influence GI Tract Absorption

a

TABLE 5.5

Chemical Characteristics of a Drug That May Influence Absorption

TABLE 5.6

Volume Guidelines for Administration of Compounds by Route of Administration to Laboratory Animals

TABLE 5.7

Examples of Excipients in Drug Formulation (Other than Vehicles)

TABLE 5.8

Basic Principles to Be Observed in Developing and Preparing Test Material Formulations

TABLE 5.9

Standardized Total Compound Requirements for Rodent Diet Studies

a,b

TABLE 5.10

US Code of Federal Register References to Excipients

TABLE 5.11

Summary of Toxicological Studies Recommended for New Pharmaceutical Excipients Based on Route of Exposure

TABLE 5.12

Limit Doses for Toxicological Studies

TABLE 5.13

Base Set Studies for a Single Dose up to 2‐Week Exposure in Humans

TABLE 5.14

Appendix 3 Studies for Repeated Chronic Exposure in Humans

Chapter 06

TABLE 6.1

Manifestations of Toxicity

TABLE 6.2

Mechanisms of Toxicity

TABLE 6.3

Common Evaluation Parameters for Toxicity Studies

TABLE 6.4

Correlation of Clinical Signs and Target Organs

TABLE 6.5

Clinical Pathology Measures

TABLE 6.6

Association of Changes in Biochemical Parameters with Actions at Particular Target Organs

TABLE 6.7

Some Probable Conditions Affecting Hematological Changes

TABLE 6.8

Clinical Chemistry Measures that are Considered Useful in Identifying Liver Toxicity

TABLE 6.9

Tissues for Histopathology

TABLE 6.10

FDA Criteria for a Neurotoxicity Screen as a Component of Acute, Pilot, and Subchronic Studies

TABLE 6.11

FDA Draft Recommendation for Type I Immunotoxicity Test That Can Be Included in Repeated Dose Toxicity Studies

Chapter 07

TABLE 7.1

Dosage Selection for the Two‐Step Dose‐Probing Protocol Design

TABLE 7.2

Comparison of Toxicity Classification Based on LD

50

versus Fixed‐Dose Procedure

TABLE 7.3

Information, Including Lethality, which Can Be Gained in Acute Toxicity Testing

TABLE 7.4

Clinical Observation in Acute Toxicity Tests

TABLE 7.5

Summary of Clinical Observations from Actual Acute Toxicity Tests

TABLE 7.6

Example of Clinical Observations Broken Down by Dosage Group and Sex in an Acute Toxicity Study of the Drug SC‐37407

a

TABLE 7.7

Minimal Acute Toxicity Study Summary of the Drug SC‐34871

TABLE 7.8

Examples of Body Weight Changes in Rats from Minimal Acute Toxicity Studies

TABLE 7.9

Examples of Gross Necropsy Findings from Acute Toxicity Studies

TABLE 7.10

Neuromuscular Screen Observations

TABLE 7.11

Sample Data Sets: LD

50

Calculations Using Fewer Dosages

a

TABLE 7.12

Sample Data Sets: Homogeneous versus Heterogeneous Data

TABLE 7.13

Seven‐Day Nonrodent Pilot Toxicology Study

TABLE 7.14

Seven‐Day Rodent Pilot Toxicology Study

TABLE 7.15

Correlation of Clinical Signs and Target Organs

Chapter 08

TABLE 8.1

Key Concepts in Understanding Toxicity

TABLE 8.2

Recommended Duration of Repeated‐Dose Toxicity Studies to Support the Conduct of Clinical Trials

TABLE 8.3

Numbers of Animals for Chronic and Subchronic Study per Test Group

TABLE 8.4

The Three Dimensions of Dose–Response

TABLE 8.5

Guidance on Volumes of Administration

TABLE 8.6

Total Blood Volumes and Recommended Maximum Blood Sample Volumes for Species of Given Bodyweight

TABLE 8.7

Summary Integrative Assessment of Study Results

TABLE 8.8

Troubleshooting in General Toxicology

Chapter 09

TABLE 9.1

Genotoxicity Tests Recommended by ICH

TABLE 9.2

Tissues Sensitive to Genotoxic and/or Nongenotoxic Carcinogens

TABLE 9.3

Fifteen Common Assays Described by OECD

TABLE 9.4

Composition of Standard S9 Mix

TABLE 9.5

Genotype of Commonly Used Strains of

Salmonella typhimurium

LT2 and Their Reversion Events

TABLE 9.6

Positive Controls for Use in Plate Incorporation Assays

TABLE 9.7

Alternative Test under ICH

Chapter 10

TABLE 10.1

Molecular Parameters of Interest

TABLE 10.2

Existing SAR Models for Toxicology End Points

TABLE 10.3

Comparison of Commercial Software Features

TABLE 10.4

Statistical External Validation for Oral LD

50

Prediction Using Data Set

TABLE 10.5

ICH M7 Classification of Genotoxic/Mutagenic Risk of Impurity

TABLE 10.6

Available QSAR Predictive Modeling Systems

TABLE 10.7

Terminology Used in the Outputs Provided by Derek for Each End Point

TABLE 10.8

Prediction Results for Ames Mutagenicity Characteristics

TABLE 10.9

Comparison of MCASE versus Derek versus Leadscope versus TOPKAT—Current State of Predictive Toxicology FDA Purchased LEADSCOPE in 2001

Chapter 11

TABLE 11.1

Drugs Withdrawn from the Market Due to Dose‐ and Time‐Unrelated Toxicity Not Identified in Animal Experiments

TABLE 11.2

Cellular Components of the Immune System and Their Functions

TABLE 11.3

Antibodies Involved in the Humoral Immune Response

TABLE 11.4

Growth and Differentiation Factors of the Immune System

TABLE 11.5

Cells and Mechanisms Involved in Cell‐Mediated Cytotoxicity

TABLE 11.6

Immunosuppressive Drugs and Their Effects

TABLE 11.7

Drugs That Produce Immunostimulation

TABLE 11.8

Types of Hypersensitivity Responses

TABLE 11.9

Proteins and Soluble Mediators Involved in Hypersensitivity

TABLE 11.10

Comparison of Current ICH and Former European Union (EU) and US Immunotoxicity

TABLE 11.11

Typical Indicators of Immunotoxicity, Which May Be Observed during Regulatory Repeat‐Dose Toxicity Studies

TABLE 11.12

Evaluation of Clinical Pathology

TABLE 11.13

Examples of Antemortem and Postmortem Findings That May Include Potential Immunotoxicity if Treatment Related

TABLE 11.14

Immune System Components in Organ Sites

Chapter 12

TABLE 12.1

Comparison of Rodent and Nonrodent Experimental Design

TABLE 12.2

Four‐Week Dog or Primate Toxicity Study

TABLE 12.3

Thirteen‐Week Dog Toxicity Study

TABLE 12.4

Use of the Beagle in Safety Assessment Studies

TABLE 12.5

Four‐Week Ferret Toxicity Study

TABLE 12.6

Use of the Ferret in Safety Assessment Studies

TABLE 12.7

The Minipig in Toxicity Testing

TABLE 12.8

Main Advantages of the Minipig

TABLE 12.9

Minipig Clinical Chemistry Parameters in Different Strains

TABLE 12.10

Minipig Hematologic Parameters in Different Strains

TABLE 12.11

Comparison of Xenobiotic Metabolism Systems in Rat and Pig

TABLE 12.12

Permissible Dosing Volumes for Nonhuman Primates

TABLE 12.13

Use of the Nonhuman Primate in Safety Assessment Studies

TABLE 12.14

Example 1

TABLE 12.15

Two‐Factor Analysis of Variance for the Covariate

TABLE 12.16

One‐Way Analysis of Variance of the Variable of Sex

TABLE 12.17

One‐Way Analysis of Variance for Combined Sexes

TABLE 12.18

Two‐Factor Analysis of Variance with Sex as a Factor

TABLE 12.19

Analysis of Covariance of the Factorial Model

Chapter 13

TABLE 13.1

Teratological Classification in Animal Species of Groups of Substances Universally Recognized as Human Teratogens: Summary of Classifications by Animal Species

TABLE 13.2

Current Regulatory Guidelines—ICH and FDA

TABLE 13.3

Comparison of ICH Stages and Study Types with Similar Observations Made

TABLE 13.4

Recommendations for Acceptable Group Size (Litters)

TABLE 13.5

General Nonclinical Findings to Consider in Male Fertility Risk Assessment

TABLE 13.6

Examples of Litter Effects in Control Litters

TABLE 13.7

Pregnancy Categories

a

TABLE 13.8

Pregnancy Categories

TABLE 13.9

Cross‐Species Postnatal Maturation

TABLE 13.10

Nervous System

TABLE 13.11

Reproductive System

TABLE 13.12

Skeletal System

TABLE 13.13

Pulmonary System

a

TABLE 13.14

Immune System

TABLE 13.15

Renal—Functional

TABLE 13.16

Renal—Anatomical

TABLE 13.17

Metabolism

TABLE 13.18

Cardiac

a

Chapter 14

TABLE 14.1

Historical Identification of Chemically Induced Cancer

TABLE 14.2

Standard Tissue List

TABLE 14.3

Tumor‐Bearing Animals in Control Groups from Rodent Studies

TABLE 14.4

Interpretation of the Analysis of Tumor Incidence and Survival Analysis (Life Table)

TABLE 14.5

Trend versus Heterogeneity

TABLE 14.6

Comparative Percent Incidence of Pertinent Neoplasia in Different Strains of Rats and Mice (104 Weeks Old)

TABLE 14.7

Examples of Neoplastic Effects in Rodents with Limited Significance for Human Safety

Chapter 15

TABLE 15.1

Tissues for Histopathology

TABLE 15.2

Principles of Drug Testing Before Trials in Humans as Defined in 1938 by Geiling and Cannon

TABLE 15.3

Discriminating Factors for Assessing Cause–Effect Relationships and Adversity of Pathology Findings

TABLE 15.4

Examples of Basic Tests Applicable to Most Rat, Dog, and Monkey Studies

Chapter 16

TABLE 16.1

Evaluation of Local Tissue Reactions in Tissue Irritation Studies

TABLE 16.2

Scale of Weighted Scores for Grading the Severity of Ocular Lesions

a

TABLE 16.3

Scoring Criteria for Vaginal Irritation

TABLE 16.4

Microscopic Scoring Procedure for Vaginal Sections

TABLE 16.5

Known Phototoxic Agents

Chapter 17

TABLE 17.1

Fundamental Terms Used in PK Studies

TABLE 17.2

Receptors Slowing Gastric Emptying

TABLE 17.3

Volume and Half‐Life of Body Water in Selected Species

TABLE 17.4

Typical Organ Weights in Adult Laboratory Animals

TABLE 17.5

Summary of Prominent Phase I Biotransformation Reactions

TABLE 17.6

Examples of Xenobiotics Metabolized by Human P450

TABLE 17.7

A Comparison of the Key

In Vitro

Drug‐Metabolizing Experimental Systems (Liver Microsomes), Liver Postmitochondrial Supernatant (S9), Liver Cytosol, and Hepatocytes and Their Contents of Major Drug‐Metabolizing Enzymes

TABLE 17.8

Examples of Xenobiotics Activated by Human Cytochrome P450 Isoenzymes

TABLE 17.9

Differences in the Disposition of 2,4‐Dichlorophenoxyacetic Acid

TABLE 17.10

“General Rules” on Interspecies Differences in DMPK

TABLE 17.11

Total Liver Content of CYP Enzymes in Humans, Monkeys, Pigs, and Dogs

TABLE 17.12

Properties of Primary Radioisotopes Employed in PKs

TABLE 17.13

Selected Factors that May Affect Chemical Distribution to Various Tissues

TABLE 17.14

Approximate Volumes of Pertinent Biological Fluids in Adult Laboratory Animals

TABLE 17.15

Blood Samples Required so that Certain TK Parameters Can Be Obtained and Calculated

TABLE 17.16

Examples of Stereoselective Differences in Metabolism (

R

) versus (

S

) Ifosfamide

TABLE 17.17

Advantages and Disadvantages of Monoclonal Antibodies Compared with Polyclonal Antisera

TABLE 17.18

Selected Human Transporters Compared to Monkeys, Pigs, and Dogs

Chapter 18

TABLE 18.1

Cardiovascular System Safety Pharmacology Evaluations

TABLE 18.2

Respiratory System Safety Pharmacology Evaluation

TABLE 18.3

Central Nervous System (CNS) Safety Pharmacology Evaluation

TABLE 18.4

Secondary Organ System Safety Pharmacology Evaluation

TABLE 18.5

Noncardiac Drugs Known to Induce or Worsen Heart Failure according to the Suggested Mechanism(s) Implicated

TABLE 18.6

Isolated Tissue Pharmacologic Assays

TABLE 18.7

Drugs Known to Cause Pulmonary Disease

TABLE 18.8

Drugs Known to Adversely Affect Respiratory Function

TABLE 18.9

Drugs Known to Influence Ventilatory Control

TABLE 18.10

Required Respiratory System Safety Pharmacology Evaluation

TABLE 18.11

Regulatory Documents Recommending Respiratory Function Testing in Safety Pharmacology Studies

TABLE 18.12

Functional Respiratory Responses to Standard Pharmacologic Agents

Chapter 19

TABLE 19.1

Blockbuster Biotech Approvals (2007)

TABLE 19.2

Comparison of Protein Therapeutic Agents with Small‐Molecule Drugs

TABLE 19.3

Differences between Chronic Use Nonclinical Safety Assessment Plans for Large and Small Molecules

TABLE 19.4

Classification of Bioengineered Products on Practical Grounds

TABLE 19.5

Historical Perspectives of Biologic Therapeutics Regulation

TABLE 19.6

Points to Consider in the Preclinical Safety Assessment of Biologics

TABLE 19.7

Biotechnology‐Derived Drug Test Matrix

TABLE 19.8

Vaccine Test Matrix

TABLE 19.9

Biologics Test Matrix

TABLE 19.10

Factors to Consider in Species Selection for Protein Therapeutic Development

TABLE 19.11

Consequences of Immunogenicity

TABLE 19.12

Immunogenicity Bioanalytical Strategy for Animal Studies

TABLE 19.13

Side Effects of Licensed Monoclonal Antibodies

TABLE 19.14

Relative Merits of Live versus Killed Vaccines

TABLE 19.15

Vaccines Approved by US FDA Since 1986

TABLE 19.16

Issues in the Safety Evaluation of Species‐Specific rDNA Products

TABLE 19.17

Alternative Models for Toxicity Assessment

TABLE 19.18

Nonclinical Studies with Marketed Biosimilars

Chapter 20

TABLE 20.1

Respiratory Parameters for Common Experimental Species and Man

TABLE 20.2

Advantages, Disadvantages, and Considerations Associated with Patterns of Inhalation Exposure

TABLE 20.3

Test Requirement Matrix for Topical Agents

Chapter 21

TABLE 21.1

Timing of Nonclinical Studies for Nonbiological Imaging Agents Submitted to an IND

TABLE 21.2

Factors Used for Milligram per Kilogram to Milligram per Square Meter Conversions

Chapter 22

TABLE 22.1

New Drug and Biologic Agents Approved to Treat Cancer, 2004–2010

TABLE 22.2

Examples of Treatment Schedules for Anticancer Pharmaceuticals to Support Initial Clinical Trials

TABLE 22.3

Special Case: Oncology Agents (Cytotoxic)

TABLE 22.4

Special Case: Oncology Agents (Protein‐Targeted Molecules)

TABLE 22.5

Pre‐IND Nonclinical Safety

Chapter 23

TABLE 23.1

Drugs that Exhibit Differences in Toxicity between Adult and Pediatric Patients

TABLE 23.2

Enzymatic Metabolism Development (Humans, Rats, and Rabbits)

TABLE 23.3

Earliest Starting Day Based on Dosing Routes

TABLE 23.4

Litter Composition Study Design Options

TABLE 23.5

Juvenile Nonhuman Primate Model

TABLE 23.6

Juvenile Dog Model

TABLE 23.7

Juvenile Minipig Model

Chapter 24

TABLE 24.1

Classification of X‐Ray Contrast Media for Small‐Animal CT Imaging

TABLE 24.2

Glossary of Echocardiographic Terms and Changes Associated with a Decreased Cardiac Function

TABLE 24.3

Timing of Nonclinical Studies for Nonbiological Products Submitted to an IND

Chapter 25

TABLE 25.1

Comparison of Occupational and Preclinical Toxicology

TABLE 25.2

Toxicological Testing Requirements under EC Seventh Amendment (Directive 92/32/EC‐Notification of New Substances)

TABLE 25.3

Comparison of Occupational Toxicology in Pharmaceutical and Chemical Industries

TABLE 25.4

Summary of Protocols Used for Current Test Methods

TABLE 25.5

Methods for Setting Occupational Exposure Limits (OELs)

TABLE 25.6

Banding Decision Matrix

Chapter 26

TABLE 26.1

Postapproval Adverse Side Effects and Related Drug Withdrawals Since 1990

TABLE 26.2

Synopsis of General Guidelines for Animal Toxicity Studies (US FDA,

Total Drug Quality

)

TABLE 26.3

Glossary of Project Management Terms

Chapter 27

TABLE 27.1

The Usual Way of Characterizing the Toxicity of a Compound or Product Is to Develop Information in a Tier Approach Manner

TABLE 27.2

Levels of Models for Safety Assessment and Toxicological Research

TABLE 27.3

Rationale for Using

In Vivo

Test Systems

TABLE 27.4

Limitations of

In Vivo

Testing Systems Which Serve as a Basis for Seeking

In Vivo

Alternatives for Toxicity Tests

TABLE 27.5

Multistage Scheme for the Development, Validation, and Transfer of

In Vitro

Test System Technology in Toxicology

TABLE 27.6

Possible Interpretations When

In Vitro

Data Do Not Predict Results of

In Vivo

Studies

TABLE 27.7

Earthworm 48 h Contact Test: Acute Lethality

TABLE 27.8

Earthworm Toxicity—Toxicity Rating

TABLE 27.9

Earthworm Acute Lethality: Comparative Values

TABLE 27.10

Rationales for Seeking

In Vitro

Alternatives for Eye Irritancy Tests

TABLE 27.11

In Vitro

Alternatives for Eye Irritation Tests

TABLE 27.12

In Vitro

Dermal Irritation Test Systems

TABLE 27.13

Requested Reference Compounds for Skin Sensitization Studies (US Consumer Product Safety Commission)

TABLE 27.14

Alternative Developmental Toxicity Test Systems

TABLE 27.15

Developmental Toxicity Test System Considerations

TABLE 27.16

Representative

In Vitro

Test Systems for Respiratory System Toxicity

TABLE 27.17

Representative

In Vitro

Test Systems for Neurotoxicity

TABLE 27.18

Representative

In Vitro

Test Systems for Renal Toxicity

TABLE 27.19

Representative

In Vitro

Test Systems for Cardiovascular Toxicity

TABLE 27.20

Representative

In Vitro

Test Systems for Hepatic Toxicity

TABLE 27.21

Representative

In Vitro

Test Systems for Other Target Organ Studies

TABLE 27.22

Status of Nonanimal Methods That Have Regulatory Standing (Acceptance)

Chapter 28

TABLE 28.1

Sources of Variability in Drug Response That May Cause Toxicity or Lack of Efficacy

TABLE 28.2

Number of New Phase 2, 2/3, and 3 Clinical Trials within ClinicalTrials.gov by Year,

n

(%)

TABLE 28.3

Challenges in Pharmacogenomic Profiling in Drug Discovery

TABLE 28.4

Major Proposed Changes in the Common Rule Notice of Proposed Rulemaking (NPRM)

a

TABLE 28.5

Key Features of Clinical Trial Design

TABLE 28.6

Exploratory Clinical Study Approaches

TABLE 28.7

Selected Reports of Genetic Associations with Drug‐Induced Liver Injury

TABLE 28.8

Educational Internet Sources on Pharmacogenetics and Drug Development

TABLE 28.9

Key Terms

TABLE 28.10

Hill Criteria for Evaluation Causation

TABLE 28.11

An Approach to Classifying Clinical Studies according to Objective

TABLE 28.12

Phase I Study—Type A

TABLE 28.13

Phase I Study—Type B

TABLE 28.14

Phase I Study—Type C

TABLE 28.15

Phase I Study—Type D

TABLE 28.16

Phase I Study—Type E

TABLE 28.17

Comparisons of Study Types

TABLE 28.18

Design and Dosing Schedule for a First Repeat‐Dose Phase I Study

TABLE 28.19

Selected List of Examinations and Tests Used to Evaluate Safety

TABLE 28.20

Selected Examples of Safety Measurements and Tests for a Specialized Dermatological Examination

TABLE 28.21

Procedures and Tests Performed in Ophthalmological Examination

TABLE 28.22

Selected Considerations Pertaining to Laboratory Data

TABLE 28.23

Hematology, Clinical Chemistry, and Urinalysis Parameters Usually Evaluated during the Development of a New Therapeutic Agent

TABLE 28.24

Adult Behavioral Rating Scales

a

TABLE 28.25

Pediatric Behavioral Rating and Diagnostic Scales

TABLE 28.26

Psychometric and Performance Tests

a

TABLE 28.27

Biomarkers in Heart Failure

TABLE 28.28

Deleterious Effects of Biomarkers of Inflammation in Heart Failure

TABLE 28.29

Major Causes of Acute Functional Adverse Drug Reactions

Chapter 29

TABLE 29.1

Therapeutic Products Withdrawn from the Marketplace Due to Safety Reasons in the United Kingdom and/or the United States 1961–2001

TABLE 29.2

List of Drugs Withdrawn Since 1990

TABLE 29.3

A Special Case of the General Risk Assessment Model in a Regulated Environment

TABLE 29.4

Characteristics of Drug Safety Withdrawals (1960–August 2001)

TABLE 29.5

Factors That Increase Patient Risk for Adverse Drug Interactions

TABLE 29.6

Limitations of the FDA’s Current Clinical Trials

TABLE 29.7

How a Spontaneous Drug Case is First Submitted to the Food and Drug Administration

TABLE 29.8

MedDRA Structure

TABLE 29.9

Criteria for Negligence—D + L + F + C = N

TABLE 29.10

Criteria for Strict Liability—D + D + C = SL

Chapter 30

TABLE 30.1

Sample Size Required to Obtain a Specified Sensitivity at

p

 < 0.05

TABLE 30.2

Some Frequently Used Terms and Their General Meanings (Marriott, 1991)

TABLE 30.3

Types of Variables (Data) and Examples of Each Type

TABLE 30.4

Rules for Form Design and Preparation

TABLE 30.5

The Three Dimensions of Dose Response

TABLE 30.6

Common Data Transformations

a

TABLE 30.7

Forms of Statistical Graphics (by Function)

TABLE 30.8

Average Number of Animals Needed to Detect a Significant Increase in the Incidence of an Event (Tumors, Anomalies, etc.) Over the Background Incidence (Control) at Several Expected Incidence Levels Using Fisher’s Exact Probability Test (

p

 = 0.05)

Chapter 31

TABLE 31.1

Examples of Existing Device/Drug Combination Products

TABLE 31.2

Likelihood New Combination Device Drug Technologies

TABLE 31.3

Classification Examples of Products

TABLE 31.4

Product Class Review Responsibilities

Chapter 32

TABLE 32.1

Thresholds for Action on Impurities in a Drug Product

TABLE 32.2

Tests to Investigate the

In Vivo

Relevance of

In Vitro

Mutagens (Positive Bacterial Mutagenicity)

TABLE 32.3

Threshold for Degradation Products in New Drug Products

TABLE 32.4

Illustration of Reporting Degradation Product Results for Identification and Qualification in an Application

TABLE 32.5

Class Exposure and Concentration Limits for Individual Metal Catalysts and Metal Reagents

Chapter 33

TABLE 33.1

Pharmacokinetic Considerations for Gene Therapy

List of Illustrations

Chapter 01

FIGURE 1.1 General case oral drug: lead through Phase I (do only what you must).

FIGURE 1.2 General case oral drug: lead through Phase I (minimize risk).

Chapter 02

FIGURE 2.1 Center for Drug Evaluation and Research (CDER).

FIGURE 2.2 Center for Biologics Evaluation and Research (CBER).

Chapter 03

FIGURE 3.1 Prior art in assessing pharmaceutical developability.

Chapter 04

FIGURE 4.1 Decision making for pharmaceutical candidates based on outcome of screening tests. (a) A 100% probability of efficacy means that every compound that has the observed performance in the model(s) used has the desired activity in man. (b) A 0% probability of efficacy means that every compound that has the observed performance in the model(s) used does not have the desired activity in man. (c) A 100% probability of a safety finding means that such a compound would definitely cause this toxicity in man. (d) A 0% probability means this will never cause such a problem in man. Note: these four cases (a, b, c, and d) are almost never found. The height of the “impact” column refers to the relative importance (“human risk”) of a safety finding. Compound A has a high probability of efficacy but also a high probability of having some adverse effect in man. But if that adverse effect is of low impact—say, transitory muscle irritation for a life‐saving antibiotic—A should go forward. Likewise, B, which has a low probability of efficacy and a high probability of having an adverse effect with moderate impact, should not be pursued. Compound C is at a place where the high end of the impact scale should be considered. Though there is only a 5% probability of this finding (say, neurotoxicity or carcinogenicity) being predictive in man, the adverse effect is not an acceptable one. Here a more definitive test is called for or the compound should be dropped.

FIGURE 4.2 Setting thresholds using historical control data. The figure shows a Gaussian (“normal”) distribution of screen parameters; 99.7% of the observations in the population are within three standard deviations (SD) of the historic mean. Here the threshold (i.e., the point at which a datum is outside of normal) was set at

X

c

 = mean + 3 SD. Note that such a screen is one sided.

FIGURE 4.3 Example of a control chart used to “prescreen” data (actually, explore and identify influential variables) from a portion of a functional observational battery.

FIGURE 4.4 Plotting central tendency. Possible individual scores for righting reflexes may range from 0 to 8 (Gad, 1982a). Group total scores would thus range from 0 to 40. (Shown are the number of groups that contain individual scores in the individual categories.)

FIGURE 4.5 Analog plot for dose–response contrasts. One of many possible approaches to graphically presenting multidimensional data. In this case, various effects—day of dosing, dose–response, and magnitude of response—are simultaneously portrayed, with the size of each circle being proportional to the magnitude of the measured value.

Chapter 05

FIGURE 5.1 The magic bullet concept.

FIGURE 5.2 Evolution of formulations through phase I.

FIGURE 5.3 Three different systemic absorption curves.

FIGURE 5.4 Path of drugs through the body after absorption by one of three routes of administration.

FIGURE 5.5 Course of moisture absorption of skin.

Chapter 07

FIGURE 7.1 Example of typical dosage probe protocol.

FIGURE 7.2 Example of dose probe method with delayed deaths.

FIGURE 7.3 Example of typical up/down acute lethality protocol.

FIGURE 7.4 Example of typical pyramiding dose protocol.

FIGURE 7.5 Example of typical “leapfrog” dosing protocol.

FIGURE 7.6 Example of typical limit test protocol.

FIGURE 7.7 British Toxicology Society fixed‐dose procedure.

FIGURE 7.8 Examples of probit–log dosage response curves illustrating differences in slope curves and the relationship between the slope, LD

50

, and LD

01

.

FIGURE 7.9 Example of minimum lethal dose (MLD) pyramiding dose design.

FIGURE 7.10 Example of minimal acute toxicity protocol.

FIGURE 7.11 Example of a form for recording clinical observations in acute systemic toxicity studies.

FIGURE 7.12 Example of complete acute toxicity protocol.

FIGURE 7.13 Exploratory IND enabling acute study.

FIGURE 7.14 The design and conduct of a supplemented (or “heavy”) acute systemic toxicity study. The figure illustrates the approach to such a study when it is to serve as the definitive systemic toxicity study for some period of time.

FIGURE 7.15 Example of pyramiding dose study for acute toxicity testing in a nonrodent species.

FIGURE 7.16 Example of use of screens in selecting drug candidates for development.

FIGURE 7.17 Example of general toxicity screen.

FIGURE 7.18 Example of rat toxicity screen for drugs.

FIGURE 7.19 Example of rising dose tolerance test (no pharmacokinetic (PK) groups).

Chapter 09

FIGURE 9.1 Schematic representation of events leading to neoplasia.

Chapter 11

FIGURE 11.1 Simplified schematic of immunoregulatory circuit that regulates activation of T cells and B cells involved in humoral (T‐cell‐dependent) and cell‐mediated immunity. (1) Antigen (Ag) is processed by the APCs expressing class II MHC molecules. (2) Antigen plus class II MHC is then presented to antigen‐specific T helper cells (CD4

+

), which stimulates secretion of IL‐2. (3) IL‐2 in turn stimulates proliferation (clonal expansion) of T cells and differentiation into T suppressor (T

s

), T killer (T

k

), and T helper (T

h

) effector cells. The expanded clone has a higher likelihood of finding the appropriate B cell that has the same antigen and class II molecules on its surface. (4) Next, the antigen binds to an antibody (Ab) on the surface of a specific B cell. (5) The B cell in turn processes the antigen and presents it (plus class II MHC) to the specific T

h

cell. The T

h

cell is then stimulated to secrete additional ILs that stimulate clonal expansion and differentiation of the antigen‐specific B cell.

FIGURE 11.2 CDER flowchart for determining when to conduct specific immunotoxicity testing. Annotations in right margin indicate location of text describing specific advice. GPMT, guinea pig maximization test; BA, Buehler assay (Buehler patch test); LLNA, local lymph node assay; MIGET; mouse IgE test. (There is only a relatively small database available for assessing the usefulness of the MIGET for drug regulatory purposes.)

FIGURE 11.3 Follow‐up studies to consider for exploring mechanisms of immunotoxicity. Annotations in right margin indicate location of text describing specific advice. (1) Examples include myelosuppression, histopathology in immune‐associated tissues, increased infection, tumors, decreased serum Ig, and phenotypic changes in immune cells. (2) Other acceptable assays include drug effect on NK‐cell function

in vitro

blastogenesis, cytotoxic T‐cell function cytokine production, DTH, and host resistance to infections or implanted tumors. (3) Examples include anemia, leukopenia, thrombocytopenia, pneumonitis, vasculitis, lupus‐like reactions, and glomerulonephritis. (4) Examples include cardiopulmonary distress, rashes, flushed skin, and swelling of face or limbs. (5) Examples include vasculitis, lupus‐like reactions, glomerulonephritis, and hemolytic anemia. (6) There are no established assays that reliably assess potential for autoimmunity and acute systemic hypersensitivity. (7) The popliteal lymph node assay (PLNA) has only a relatively small database available for assessing its usefulness for drug regulatory purposes.

FIGURE 11.4 Line chart for modified Buehler test for delayed contact dermal sensitization in guinea pig.

FIGURE 11.5 Line chart for guinea pig maximization test for dermal sensitization.

FIGURE 11.6 Illustrative figures for injection and patching of animals in GPMT.

FIGURE 11.7 Mouse LLNA.

FIGURE 11.8 Mouse local lymph node assay (LLNA) (ICVAM protocol). Modification using flow cytometry instead of radiolabeling is preferable.

Chapter 13

FIGURE 13.1 ICH line charts of nonclinical reproductive and developmental toxicology studies. A, B, C, D, and E here refer to ICH stages as explained in Table 13.3.

FIGURE 13.2 Relationship of maternal body weight and gravid uterine weight in rats. Relationship between gravid uterine weight and maternal body weight change in control rats between days 0 and 20 of gestation. One hundred and twenty pregnant Sprague–Dawley (Crl : CD(SD)BR) rats were dosed orally with 0.5% aqueous methylcellulose on days 6–17 of gestation and cesarean sectioned on day 20 of gestation. The gravid uterus from each animal was removed and weighed.

FIGURE 13.3 Body weight changes versus gravid uterine weight changes in rabbits. Relationship between gravid uterine weight and maternal body weight change in untreated rabbits between days 0 and 28 of gestation. Fifty‐three pregnant New Zealand white rabbits that had not been treated with control article or test agent were cesarean sectioned on day 28 of gestation. The gravid uterus from each animal was removed and weighed.

FIGURE 13.4 Embryo–fetal development (EFD) study in nonhuman primates.

FIGURE 13.5 Percentage preimplantation losses versus corpora lutea in rats. Effect of litter size on mean percentage preimplantation loss in 1035 control rat litters. Between 1970 and 1988, 1035 control rats were cesarean sectioned on day 20 of gestation, and the numbers of resorptions and implants were counted. Numbers within the bars indicate the number of litters.

FIGURE 13.6 Resorption rate versus number of implants in rats. Effect of litter size on mean percentage resorption rate in 2258 control rat litters. Between 1970 and 1988, 2258 control rats were cesarean sectioned on day 20 of gestation and the numbers of resorptions and implants were counted. Numbers within the bars indicate the number of litters.

FIGURE 13.7 Effect of litter size (live fetuses per litter) on incidence of supernumerary rib in 1379 control rat litters. Between 1978 and 1988, fetal skeletons from 1379 L of control rats were stained with alizarin red and examined for supernumerary rib.

FIGURE 13.8 Litter effect with supernumerary rib in 1379 control litters. Between 1978 and 1988, fetal skeletons from 1379 litters of control rats were stained with alizarin red and examined for supernumerary rib in addition to other anomalies. The calculation of the expected number of fetuses with supernumerary rib in each litter was based on the assumption that each fetus had an equally likely chance of having supernumerary rib independent of the incidence among littermates (K. Soper, personal communication, 1990).

FIGURE 13.9 Maternal weight change versus fetal weight changes. Correlation between drug‐induced effects on maternal body weight change and fetal weight in rabbits. The data were collected from the high‐dosage group of a developmental toxicity study of a prospective drug candidate. The rabbits were dosed orally with the test agent from days 6 to 18 of gestation. On day 28 of gestation, the rabbits were cesarean sectioned and the live fetuses weighed.

FIGURE 13.10 Integrative evaluation of potential reproductive risk. Flowchart A. Overall decision tree for evaluation on reproduction/developmental toxicity risk.

FIGURE 13.11 Flowchart for reproductive risk assessment of a drug. Flowchart B. Decision tree for end points with no signal.

FIGURE 13.12 Scheme for integrative assessment of reproductive/developmental risk of a drug. Flowchart C. Integration of positive reproduction/ancillary study results.

FIGURE 13.13 Comparative stages of development for neonatal and juvenile toxicity studies.

Chapter 16

FIGURE 16.1 Schematic portraying penetration of light of varying wavelengths into skin.

FIGURE 16.2 Line chart for design and conduct of phototoxicity assay using rabbits.

FIGURE 16.3 (a) Guinea pig and (b) mouse for phototoxicity testing.

Chapter 17

FIGURE 17.1 Passage of chemical moieties from GI tract into bloodstream.

Chapter 20

FIGURE 20.1 The distribution of cell types in the respiratory tract and lungs.

FIGURE 20.2 Dose–response plot in terms of probit of cumulative percentage response to logarithm of exposure duration. A, B, and C indicate three exemplary curves.

FIGURE 20.3 Dose–response plot in terms of logarithms of exposure concentration and durations. A and B indicate nonspecific example compounds A and B.

Chapter 23

FIGURE 23.1 Comparative stages of development for neonatal and juvenile toxicity studies.

Chapter 24

FIGURE 24.1 Multimodality imaging instrumentations. The modern molecular imaging equipment includes magnetic field/radiofrequency (magnetic resonance imaging (MRI)), X‐ray (computed tomography (CT)), high‐frequency sound waves (ultrasound (US)), optical (bioluminescence/fluorescence), gamma rays (single‐photon emission computed tomography (SPECT)), and annihilation twin photons from beta emission (positron emission tomography (PET)).

Chapter 26

FIGURE 26.1 Attrition during development of new molecules with promise of therapeutic potential. Over the course of taking a new molecular entity through scale‐up, safety and efficacy testing, and, finally, to market, typically only one out of every 9 000–10 000 will go to the marketplace.

FIGURE 26.2 An example of program evaluation and review technique (PERT) chart of the development of a new pharmaceutical through to the filing of an new drug application (NDA). Circles are “nodes” indicating completion of activities. Diamonds are initiation points for tasks that have starting points independent of others. This “network” serves to illustrate the relationships between different activities and to evaluate effects of changes on project timing.

FIGURE 26.3 Gantt, or bar, chart showing scheduling of major safety assessment activities (studies) involved in pharmaceutical development project.

FIGURE 26.4 Hybrid project Gantt chart which identifies work of each development function (“line operation”) in development of new compound and how it matches phase of development.

FIGURE 26.5 Three different approaches to matching preclinical safety efforts to support clinical development of new drug. Which is the best one for any specific case depends on the considerations of resource availability and organizational tolerance of “risk.” In plan 1, little effort will be “wasted” on projects that fail during early (phase I) clinical trials, but if phase I trials are successful, there will be major delays. In plan 3, clinical development will never be held up waiting for more safety work, but a lot of effort will go into projects that never get past phase I. Plan 2 is a compromise. Delays are to allow additional preclinical (animal safety) studies to support longer clinical trials in accordance with FDA or other applicable guidelines.

Chapter 27

FIGURE 27.1 Development of a hazard assessment profile.

FIGURE 27.2 Graph showing a comparison of the lethality of a group of 18 drugs of diverse structure in

in vivo

(mouse) and

in vitro

(cultured mouse lymphoma cells) test systems. Correlation of these LD

50

/LC

50

values is very poor, though extreme high‐ and low‐scale values seem to be more closely associated in the two systems.

Chapter 28

FIGURE 28.1 Pharmaceutical development process viewed as four stages (discovery, preclinical development, clinical development, and NDA review) as well as important postmarket surveillance phase.

FIGURE 28.2 Traditional view based on administered dose or plasma concentration metric (AUC or

C

max

).

FIGURE 28.3 FDA form 3674.

FIGURE 28.4 Matrix illustrating relationship between phases of development and types of study by objective that may be conducted during each clinical development of new medicinal product. The shaded circles show the types of the study most usually conducted in a certain phase of development; the open circles show certain types of study that may be conducted in that phase of development but are less usual. Each circle represents an individual study. To illustrate the development of a single study, one circle is joined by a dotted line to an inset column that depicts the elements and sequence of an individual study.

FIGURE 28.5 Adverse drug reaction (curve

Q

) plotted against time (abscissa

T

). Dashed lines show three courses an ADR can take: increasing severity to death, leveling off to chronicity, or return to abscissa, indicating recovery. Four criteria that must be met before drug is eligible to be empiric correlate of

Q

(adverse drug reaction) are listed.

FIGURE 28.6 Six methods of linking drug with adverse drug reaction.

Chapter 29

FIGURE 29.1 Global drug safety reports.

FIGURE 29.2 FDA form 3500A.

Chapter 30

FIGURE 30.1 Overall decision tree for selecting statistical procedures.

FIGURE 30.2 Decision tree for selecting hypothesis‐testing procedures.

FIGURE 30.3 Decision tree for selecting modeling procedures.

FIGURE 30.4 Decision tree for selection of reduction of dimensionality procedures.

FIGURE 30.5 EDA.

FIGURE 30.6 Variance inflation: points are means minus error bars plus one SD.

FIGURE 30.7 Common curvilinear curves: (a) exponential growth law, log

Y

 = 

A

(

B

x

); (b) exponential decay law, log

Y

 = 

A

(

B

−

x

); (c) asymptotic regression, log

Y

 = 

A

 − 

B

(Ψ

x

); and (d) logistic growth law, log

Y

 = 

A

/(1 + 

B

Ψ

x

).

FIGURE 30.8 Acquisitions of postnatal development landmarks in rats.

Chapter 32

FIGURE 32.1 Hierarchical approach to qualification (Q3B)*.

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