Dose Finding in Drug Development

by Ting, Naitee

• ISBN13: 9780387290744
• ISBN10: 0387290745
• Format: Hardcover
• Copyright: 2006-03-31
• Publisher: Springer Verlag

Summary

When you go to the pharmacy and fill a prescription, have you ever wondered if the dose of the medication is right for you? Can the dose be too low so that the drug will not work? Can the dose be too high that it may cause some potential problem? How do people learn about dosing information? This book answers some of these questions. Dosing information on the drug label is based on discussion and agreement between the pharmaceutical manufacturer and the drug regulatory agency. A drug label is a high level summary of results obtained from many scientific experiments. Scientists with biological, chemical, medical, or statistical background working in the pharmaceutical industry designed and executed these experiments to obtain information to help understand the dosing information. This book introduces the drug development process, the design and analysis of clinical trials. Many of the discussions are based on applications of statistical methods in the design and analysis of dose response studies. Although the book is prepared mainly for statisticians/biostatisticians, it also serves as a useful reference to a variety of professionals working for the pharmaceutical industry. The potential readers include pharmacokienticists, clinical scientists, clinical pharmacologists, pharmacists, project managers, pharmaceutical scientists, clinicians, programmers, data managers, regulatory specialists, and study report writers. This book is also a good reference for professionals working in a drug regulatory environment, for example, the FDA. Scientists and/or reviewers from both U.S. and foreign drug regulatory agencies can benefit greatly from this book. In addition, statistical and medical professionals in academia may find this book helpful in understanding the drug development process and practical concerns in selecting doses for a new drug. From the reviews: "The book will be of particular interest to statisticians with some pharmaceutical industry experience who find themselves working on phase II dose finding problems. It will also be valuable for clinicians and pharmacokineticists with some statistical background. All chapters in the book are extensively referenced as they each do not pretend to exhaust their subject." Journal of Biopharmaceutical Statistics, Issue #2, 2007

Table of Contents

Preface	v
Introduction and New Drug Development Process	1	(17)
Introduction	1	(3)
New Drug Development Process	4	(1)
Nonclinical Development	5	(3)
Pharmacology	5	(1)
Toxicology/Drug Safety	6	(1)
Drug Formulation Development	7	(1)
Premarketing Clinical Development	8	(5)
Phase I Clinical Trials	8	(2)
Phase II/III Clinical Trials	10	(2)
Clinical Development for Life-Threatening Diseases	12	(1)
New Drug Application	12	(1)
Clinical Development Plan	13	(1)
Postmarketing Clinical Development	14	(2)
Concluding Remarks	16	(2)
Dose Finding Based on Preclinical Studies	18	(12)
Introduction	18	(2)
Parallel Line Assays	20	(1)
Competitive Binding Assays	20	(5)
Anti-infective Drugs	25	(1)
Biological Substances	25	(1)
Preclinical Toxicology Studies	26	(2)
Extrapolating Dose from Animal to Human	28	(2)
Dose-Finding Studies in Phase I and Estimation of Maximally Tolerated Dose	30	(19)
Introduction	30	(1)
Basic Concepts	30	(2)
General Considerations for FIH Studies	32	(5)
Study Designs	33	(2)
Population	35	(2)
Dose Selection	37	(5)
Estimating the Starting Dose in Phase I	37	(3)
Dose Escalation	40	(2)
Assessments	42	(4)
Safety and Tolerability	42	(1)
Pharmacokinetics	43	(1)
Pharmacodynamics	43	(3)
Dose Selection for Phase II	46	(3)
Dose-Finding in Oncology---Nonparametric Methods	49	(10)
Introduction	49	(1)
Traditional or 3 + 3 Design	50	(1)
Basic Properties of Group Up-and-Down Designs	51	(1)
Designs that Use Random Sample Size: Escalation and A + B Designs	52	(1)
Escalation and A + B Designs	52	(1)
The 3 + 3 Design as an A + B Design	53	(1)
Designs that Use Fixed Sample Size	53	(2)
Group Up-and-Down Designs	54	(1)
Fully Sequential Designs for Phase I Clinical Trials	54	(1)
Estimation of the MTD After the Trial	54	(1)
More Complex Dose-Finding Trials	55	(1)
Trials with Ordered Groups	55	(1)
Trials with Multiple Agents	56	(1)
Conclusion	56	(3)
Dose Finding in Oncology---Parametric Methods	59	(14)
Introduction	59	(2)
Escalation with Overdose Control Design	61	(2)
EWOC Design	61	(1)
Example	62	(1)
Adjusting for Covariates	63	(5)
Model	63	(3)
Example	66	(2)
Choice of Prior Distributions	68	(2)
Independent Priors	69	(1)
Correlated Priors	69	(1)
Simulations	70	(1)
Concluding Remarks	70	(3)
Dose Response: Pharmacokinetic-Pharmacodynamic Approach	73	(16)
Exposure Response	73	(1)
How Dose Response and Exposure Response Differ	73	(1)
Why Exposure Response is More Informative	73	(1)
FDA Exposure Response Guidance	73	(1)
Time Course of Response	74	(1)
Action, Effect, and Response	74	(1)
Models for Describing the Time Course of Response	74	(1)
Pharmacokinetics	75	(2)
Review of Basic Elements of Pharmacokinetics	75	(1)
Why the Clearance/Volume Parameterization is Preferred	76	(1)
Pharmacodynamics	77	(1)
Review of Basic Elements of Pharmacodynamics	77	(1)
Delayed Effects and Response	77	(3)
Two Main Mechanism Classes for Delayed Effects	78	(2)
Cumulative Effects and Response	80	(2)
The Relevance of Considering Integral of Effect as the Outcome Variable	80	(1)
Why Area Under the Curve of Concentration is not a Reliable Predictor of Cumulative Response	80	(1)
Schedule Dependence	81	(1)
Predictability of Schedule Dependence	82	(1)
Disease Progress	82	(2)
The Time Course of Placebo Response and Disease Natural History	82	(1)
Two Main Classes of Drug Effect	83	(1)
Modeling Methods	84	(2)
Analysis	84	(1)
Mixed Effect Models	85	(1)
Simulation	85	(1)
Clinical Trial Simulation	85	(1)
Conclusion	86	(3)
General Considerations in Dose-Response Study Designs	89	(17)
Issues Relating to Clinical Development Plan	89	(1)
General Considerations for Designing Clinical Trials	90	(6)
Subject Population and Endpoints	91	(2)
Parallel Designs versus Crossover Designs	93	(1)
Selection of Control	93	(1)
Multiple Comparisons	94	(1)
Sample Size Considerations	95	(1)
Multiple Center Studies	96	(1)
Design Considerations for Phase II Dose-Response Studies	96	(7)
Frequency of Dosing	97	(2)
Fixed-Dose versus Dose-Titration Designs	99	(1)
Range of Doses to be Studied	100	(1)
Number of Doses to be Tested	101	(1)
Dose Allocation, Dose Spacing	102	(1)
Optimal Designs	103	(1)
Concluding Remarks	103	(3)
Clinical Trial Simulation---A Case Study Incorporating Efficacy and Tolerability Dose Response	106	(21)
Clinical Development Project Background	106	(2)
Clinical Trial Objectives	107	(1)
Uncertainties Affecting Clinical Trial Planning	107	(1)
The Clinical Trial Simulation Project	108	(12)
Clinical Trial Objectives Used for the CTS Project	109	(2)
The Simulation Project Objective	111	(1)
Simulation Project Methods 1: Data Models and Design Options	111	(6)
Simulation Project Methods 2: Analysis and Evaluation Criteria	117	(3)
Simulation Results and Design Recommendations	120	(5)
Objective 1: Power for Confirming Efficacy	120	(1)
Objective 2: Accuracy of Target Dose Estimation	121	(1)
Objective 3: Estimation of a Potentially Clinically Noninferior Dose Range	121	(3)
Trial Design Recommendations	124	(1)
Conclusions	125	(2)
Analysis of Dose-Response Studies---Emax Model	127	(19)
Introduction to the Emax Model	127	(2)
Sensitivity of the Emax Model Parameters	129	(5)
Sensitivity of the E0 and Emax Parameters	129	(1)
Sensitivity of the ED50 Parameter	130	(1)
Sensitivity of the N Parameter	131	(1)
Study Design for the Emax Model	131	(2)
Covariates in the Emax Model	133	(1)
Similar Models	134	(1)
A Mixed Effects Emax Model	134	(1)
Examples	135	(6)
Oral Artesunate Dose-Response Analysis Example	135	(2)
Estimation Methodology	137	(1)
Initial Parameter Values for the Oral Artesunate Dose-Response Analysis Example	138	(1)
Diastolic Blood Pressure Dose-Response Example	139	(2)
Conclusions	141	(5)
Analysis of Dose-Response Studies---Modeling Approaches	146	(26)
Introduction	146	(3)
Some Commonly Used Dose-Response Models	149	(4)
Emax Model	150	(1)
Linear in Log-Dose Model	151	(1)
Linear Model	151	(1)
Exponential (Power) Model	151	(1)
Quadratic Model	152	(1)
Logistic Model	152	(1)
Estimation of Target Doses	153	(3)
Estimating the MED in Dose-Finding Example	155	(1)
Model Uncertainty and Model Selection	156	(4)
Combining Modeling Techniques and Multiple Testing	160	(9)
Methodology	160	(2)
Proof-of-Activity Analysis in the Dose-Finding Example	162	(1)
Simulations	163	(6)
Conclusions	169	(3)
Multiple Comparison Procedures in Dose Response Studies	172	(12)
Introduction	172	(1)
Identifying the Minimum Effective Dose (MinED)	172	(5)
Problem Formulation	172	(2)
Review of Multiple Test Procedures	174	(2)
Simultaneous Confidence Intervals	176	(1)
Identifying the Maximum Safe Dose (MaxSD)	177	(1)
Examples	177	(3)
Extensions	180	(1)
Discussion	181	(3)
Partitioning Tests in Dose-Response Studies with Binary Outcomes	184	(16)
Motivation	184	(1)
Comparing Two Success Probabilities in a Single Hypothesis	185	(3)
Comparison of Success Probabilities in Dose-Response Studies	188	(7)
Predetermined Step-Down Method	188	(2)
Sample-Determined Step-Down Method	190	(4)
Hochberg's Step-up Procedure	194	(1)
An Example Using Partitioning Based Stepwise Methods	195	(2)
Conclusion and Discussion	197	(3)
Analysis of Dose-Response Relationship Based on Categorical Outcomes	200	(20)
Introduction	200	(1)
When the Response is Ordinal	201	(6)
Modeling Dose-Response	201	(2)
Testing for a Monotone Dose-Response Relationship	203	(4)
When the Response is Binary	207	(3)
Multiple Comparisons	210	(3)
Bonferroni Adjustment	211	(1)
Bonferroni-Holm Procedure	211	(1)
Hochberg Procedure	212	(1)
Gate-Keeping Procedure	212	(1)
A Special Application of Dunnett's Procedure for Binary Response	213	(1)
Discussion	213	(7)
Power and Sample Size for Dose Response Studies	220	(23)
Introduction	220	(1)
General Approach to Power Calculation	221	(2)
Multiple-Arm Dose Response Trial	223	(10)
Normal Response	224	(3)
Binary Response	227	(3)
Time-to-Event Endpoint	230	(3)
Phase I Oncology Dose Escalation Trial	233	(5)
The A + B Escalation without Dose De-Escalation.	234	(2)
The A + B Escalation with Dose De-Escalation	236	(2)
Concluding Remarks	238	(5)
Index	243