Clinical Trials - 1st Edition - ISBN: 9780123919113, 9780123919137

Clinical Trials

1st Edition

Study Design, Endpoints and Biomarkers, Drug Safety, and FDA and ICH Guidelines

Authors: Tom Brody
eBook ISBN: 9780123919137
Hardcover ISBN: 9780123919113
Imprint: Academic Press
Published Date: 11th November 2011
Page Count: 638
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Clinical Trials: Study Design, Endpoints and Biomarkers, Drug Safety, and FDA and ICH Guidelines is a practical guidebook for those engaged in clinical trial design. This book details the organizations and content of clinical trials, including trial design, safety, endpoints, subgroups, HRQoL, consent forms and package inserts. It provides extensive information on both US and international regulatory guidelines and features concrete examples of study design from the medical literature. This book is intended to orient those new to clinical trial design and provide them with a better understanding of how to conduct clinical trials. It will also act as a guide for the more experienced by detailing endpoint selection and illustrating how to avoid unnecessary pitfalls. This book is a straightforward and valuable reference for all those involved in clinical trial design.

Key Features

  • Provides extensive coverage of the "study schema" and related features of study design
  • Offers a "hands-on" reference that contains an overview of the process, but more importantly details a step-by-step account of clinical trial design
  • Features examples from the medical literature to highlight how investigators choose the most suitable endpoint(s) for clinical trial and includes graphs from real clinical trials to help explain each concept in study design
  • Integrates clinical trial design, pharmacology, biochemistry, cell biology and legal aspects to provide readers with a comprehensive look at all aspects of clinical trials
  • Includes chapters on core material and important ancillary topics, such as package inserts, consent forms, and safety reporting forms used in the United States, England and Europe
  • For complimentary access to our sample chapter (chapter 24), please copy and paste this link into your browser:


Pharmaceutical scientists and pharmacologists, medical writers and physicians, nurses and pharmacists who plan and conduct clinical trials.

Table of Contents





Abbreviations and Definitions


Chapter 1. The Origins of Drugs

I. Introduction

II. Structures of drugs

III. The 20 classical amino acids

IV. Animal models

Chapter 2. Introduction to Regulated Clinical Trials

I. Introduction

II. Study design

III. The study schema

IV. Further concepts in study design

V. Summary

VI. Amendments to the clinical study protocol

Chapter 3. Run-in Period

I. Introduction

II. Concluding remarks

Chapter 4. Inclusion/Exclusion Criteria, Stratification, and Subgroups – Part I

I. The clinical study protocol is a manual that provides the study design

II. Biology of drug resistance

III. More information on subgroups

IV. Concluding remarks

Chapter 5. Inclusion and Stratification Criteria – Part II

I. Introduction

II. Staging

III. Staging systems for various cancers

IV. Summary

V. The will rogers phenomenon

VI. Other sources of artifacts in data from clinical trials

VII. Concluding remarks

Chapter 6. Randomization, Allocation, and Blinding

I. Introduction

II. Manual technique for allocation

III. Information on randomization, blinding, and unblinding may be included in the clinical study protocol

IV. Summary

V. Subjects are enrolled into clinical trials, one by one, over the course of many months

VI. Blocked randomization

VII. Blinding

VIII. Interactive voice response systems

IX. Concluding remarks

Chapter 7. Placebo Arm as Part of Clinical Study Design

I. Introduction

II. Hawthorne effect

III. The no-treatment arm

IV. Physical aspects of the placebo

V. Active placebo

VI. Subjects in the placebo arm may receive best supportive care or palliative care

VII. Clash between best supportive care and the endpoint of HRQoL

VIII. Ethics of placebos

Chapter 8. Intent to Treat Analysis vs. Per Protocol Analysis

I. Introduction

II. ITT analysis contrasted with PP analysis

III. Disadvantages of ITT analysis

IV. Run-in period, as part of the study design, is relevant to ITT analysis and PP analysis

V. Summary

VI. Hypothetical example where study drug and control drug have same efficacy

VII. Modified ITT analysis

VIII. Start date for endpoints in clinical studies

IX. Summary and conclusions

Chapter 9. Biostatistics

I. Introduction

II. Definitions and formulas

III. Data from the study of machin and gardner

IV. Data used for constructing the kaplan-meier plot are from subjects enrolling at different times

V. Sample versus population

VI. What can be Compared

VII. One-tailed test versus two-tailed test

VIII. P value

IX. Calculating the P value – a working example

X. Summary

XI. Theory behind the Z value and the table of areas in the tail of the standard normal distribution

XII. Statistical analysis by superiority analysis versus by non-inferiority analysis

Chapter 10. Introduction to Endpoints for Clinical Trials in Pharmacology

I. Introduction

Chapter 11. Endpoints in Clinical Trials on Solid Tumors – Objective Response

I. Introduction

II. Studies characterizing an association between objective response and survival

III. Avoiding confusion when using objective response as an endpoint

Chapter 12. Oncology Endpoints

I. Introduction

II. Comparing contexts of use and advantages of various endpoints

III. Data on overall survival and PFS from clinical trials

IV. Summary

Chapter 13. Oncology Endpoints

I. Introduction

II. Agreement of results from objective response, time to progression, and overall survival – the paccagnella study

III. Can the value for PFS be less than the value for TTP?

IV. Time to progression may be the preferred endpoint where, once the trial is concluded, patients receive additional chemotherapy – the park study

V. The endpoint of TTP may be preferred over survival endpoints, where deaths result from causes other than cancer – the llovet study

VI. The endpoint of overall survival may be preferred over objective response or over TTP, where the drug is classed as a cytostatic drug – the llovet study

VII. Time to progression may show efficacy, where the endpoint of overall survival fails to show efficacy, where the number of subjects is small – the mcdermott study

VIII. Time to progression may show efficacy, where the endpoint of overall survival failed to show efficacy, where the duration of the trial was too short – the cappuzzo study

IX. Methodology TIP – advantage of using an endpoint that incorporates a “median” time

X. Summary

XI. Thymidine phosphorylase as a biomarker for survival – the meropol study

XII. Drug combinations that include capecitabine

XIII. Methodology TIP – do changes in mRNA expression result in corresponding changes in expression of polypeptide?

XIV. Conclusions

Chapter 14. Oncology Endpoint

I. Introduction

II. Difference between disease-free survival and progression-free survival

III. Ambiguity in the name of the endpoint, “disease-free survival”

IV. Disease-free survival provides earlier results on efficacy than overall survival – the add-on breast cancer study of romond

V. Disease-free survival as an endpoint in the analysis of subgroups – the add-on breast cancer study of hayes

VI. Neoadjuvant therapy versus adjuvant therapy for rectal cancer – the roh study

VII. Where efficacy of two different treatments is the same, choice of treatment shifts to the treatment that improves quality of life – the ring study

VIII. Disease-free survival and overall survival are useful tools for testing and validating prognostic biomarkers – the bepler study

IX. Summary

Chapter 15. Oncology Endpoint

I. Introduction

II. Time to distant metastasis data are acquired before overall survival data are acquired – the wee study

III. Time to distant metastasis data can reveal a dramatic advantage of the study drug, in a situation where overall survival fails to show any advantage – the roach study

IV. Use of a gene array as a prognostic factor for breast cancer patients, using the endpoint of time to distant metastasis – the loi study

V. Use of micro-RNA expression data as a prognostic factor for breast cancer patients – the foekens study

VI. Biology of micro-RNA

VII. Conclusions

Chapter 16. Neoadjuvant Therapy versus Adjuvant Therapy

I. Introduction

II. Advantages of neoadjuvant therapy

III. Advantages of adjuvant therapy

IV. Two meanings of the term adjuvant

V. Concluding remarks

Chapter 17. Hematological Cancers

I. Introduction

II. Myelodysplastic syndromes

III. Summary

IV. Cytogenetics and the hematological cancers

V. Chromosomal abnormalities in solid tumors

VI. Clinical endpoints and examples from clinical trials

VII. Cytogenetics as a prognostic marker – the grever study of CLL

VIII. Minimal residual disease

IX. Confluence of cytogenetics and gene expression

X. Conclusions

Chapter 18. Biomarkers and Personalized Medicine

I. Introduction

II. Microarrays

III. C-reactive protein

IV. Concluding remarks

Chapter 19. Endpoints in Immune Diseases

I. Introduction

II. Multiple sclerosis

III. Concluding remarks

Chapter 20. Endpoints in Clinical Trials on Infections

I. Introduction

II. Clinical and immunological features of hepatitis C virus infections

III. Acute HCV versus chronic HCV

IV. Drugs against hepatitis C virus

V. Immune responses against hepatitis C virus

VI. Kinetics of hepatitis C virus infections

VII. Responders versus non-responders

VIII. Endpoints in clinical trials against hepatitis C virus

IX. Biomarkers and Hepatitis C Virus

X. Concluding remarks

Chapter 21. Health-Related Quality of Life

I. Introduction

II. Summary

III. HRQoL instruments take on increased importance, when capturing data on adverse events, or in trials on palliative treatments

IV. Scheduling the administration of HRQoL instruments

V. HRQoL instruments in oncology

VI. Decisions on counseling; decisions on chemotherapy versus surgery

VII. Conclusions

Chapter 22. Health-Related Quality of Life Instruments for Immune Disorders

I. Introduction

II. Short form SF-36 questionnaire

III. HRQoL instruments specific for multiple sclerosis

IV. Conclusions

Chapter 23. Health-Related Quality of Life Instruments and Infections

I. Introduction

II. Health-related quality of life instruments with chronic hepatitis C virus

Chapter 24. Drug Safety

I. Introduction

II. Safety definitions

III. Paradoxical adverse drug reactions

IV. Monitoring and evaluating adverse events

V. Adverse events – capturing, transmitting, and evaluating data on adverse events

VI. Post-marketing report of adverse events

VII. Risk minimization tools

VIII. Patient-reported outcomes

IX. Summary of reporting systems suitable for capturing adverse events

X. Data and safety monitoring committee

XI. Concluding remarks

Chapter 25. Mechanism of Action, Part I

I. Introduction

II. MOA and the package insert

III. MOA and surrogate endpoints

IV. MOA and expected adverse drug reactions

V. MOA and drug combinations

VI. Mechanism of action of diseases with an immune component

VII. Immunology can be organized as pairs of concepts

VIII. Conclusions

Chapter 26. Mechanisms of Action, Part II – Cancer

I. Immune response against cancer

Chapter 27. Mechanisms of Action, Part III – Immune Disorders

I. Introduction

II. Detailed example of multiple sclerosis mechanism of action

III. Concluding remarks

Chapter 28. Mechanisms of Action, Part IV – Infections

I. Introduction

II. Hepatitis C virus infections

III. Concluding remarks

Chapter 29. Consent Forms

I. Introduction

II. Sources of the law in the united states

III. Guidance for industry

IV. Ethical doctrines

V. The case law

VI. Basis for consent forms in the code of federal regulations

VII. Summary

VIII. Examples of contemporary consent forms

IX. Ethical issues specific to Phase I clinical trials in oncology

X. Decision aids

XI. Distinction between stopping treatment and withdrawing from the study

XII. Concluding remarks

Chapter 30. Package Inserts

I. Introduction

II. Potential ambiguity of writing in package inserts

III. Package insert may protect manufacturer from liability

IV. Package insert compared with consent form

V. Relation between package inserts to the standard of care, and to off-label uses

VI. Conclusions

Chapter 31. Regulatory Approval

I. Introduction

II. History of the european medicines agency

III. International conference on harmonisation

IV. History of the medicines and healthcare products regulatory agency

V. Outline of regulatory approval in the united states

VI. Process of administering clinical trials

VII. Process of medical writing

VIII. Meetings with the U.S. food and drug administration

Chapter 32. Patents

I. Introduction

II. Types of patent documents

III. Structure of patents

IV. Timeline for patenting

V. Sources of the law for patenting

VI. Intersections between the FDA review process and patents



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About the Author

Tom Brody

Tom Brody

Dr. Tom Brody received his PhD from the University of California at Berkeley in 1980, and conducted postdoctoral research at University of Wisconsin-Madison and also at U.C. Berkeley. His 20 research publications concern the metabolism and pharmacology of folates, cloning an anti-cancer gene (XPE gene), and the structure of an antibody (natalizumab) used for treating multiple sclerosis. The author has 15 years of pharmaceutical industry experience, acquired at Schering-Plough, Cerus Corporation, and Elan Pharmaceuticals, and has contributed to FDA submissions for the indications of multiple sclerosis, melanoma, head and neck cancer, liver cancer, pancreatic cancer, and hepatitis C. At an earlier time, he wrote two editions of Clinical Trials, published by Elsevier, Inc. The author has 16 years of training and experience in the Code of Federal regulations, as it applies to pharmaceuticals and clinical trial design.

Affiliations and Expertise

Consultant for Second Genome, Inc. (Crohn's disease), Rigel Pharmaceuticals (platelet disorder), PrimeGen Biotech (stem cell therapy), Regeneron Pharmaceuticals (broadly neutralizing antibodies for HIV), and Biogen IDEC (multiple sclerosis)


"A solid guide to designing clinical trials for medical scientists, especially those working in oncology, immune disease, and infectious disease…Three chapters address quality-of-life topics."  -Selected for The First Clinical Research Bookshelf, "Essential Reading for Clinical Research Professionals," Journal of Clinical Research Best Practices, September 2012, Vol. 8, No. 9

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