Clinical Trials: Study Design, Endpoints and Biomarkers, Drug Safety, and FDA and ICH Guidelines

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Clinical Trials

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

Second Edition

Tom Brody, Ph.D.

Table of Contents

Cover image

Title page

Copyright

Dedication

Acknowledgments

Preface

The Study Schema and Study Design

Intent-to-Treat Analysis and Placebos

How to Choose Endpoints

Diagnostic Tests

Mechanism of Action

Standards

FDA’s Warning Letters

ClinicalTrials.gov and Other Registries for Clinical Trials

Introduction

I Good Clinical Practice

II FDA’s Decision-Making Process in Granting Approval to a Drug

III Disclaimer

Abbreviations and Definitions

Biographies

Chapter 1. Origins of Drugs

Abstract

I Introduction

II Structures of Drugs

III The 20 Classical Amino Acids

IV Animal Models

V Estimating Human Dose From Animal Studies

VI Origin of Drugs That are Biosimilars

VII Origin of Drugs That are Orphan Drugs

VIII Summary

Chapter 2. Clinical Trial Design

Abstract

I Introduction to Regulated Clinical Trials

II Study Design

III The Study Schema

IV Further Concepts in Clinical Trial Design

V FDA’s Decision-Making Processes Regarding Dose Modification and Discontinuation

VI Amendments to the Clinical Study Protocol

VII Concluding Remarks

Chapter 3. Run-In Period

Abstract

I Introduction

II FDA’s Decision-Making Processes in Evaluating Run-In Period

III Concluding Remarks

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

Abstract

I The Clinical Study Protocol is a Manual that Provides the Study Design

II Biochemistry of Drug Resistance

III FDA’s Warning Letters and Inclusion/Exclusion Criteria

IV Subgroups and Subgroup Analysis

V FDA’s Decision-Making Processes in Evaluating Stratification and Subgroups

VI Concluding Remarks

Chapter 5. Inclusion/Exclusion Criteria, Stratification, and Subgroups—Part II

Abstract

I Introduction

II Staging

III Staging Systems for Various Cancers

IV The Will Rogers Phenomenon

V Other Sources of Artifacts in Data from Clinical Trials

VI Concluding Remarks

Chapter 6. Blinding, Randomization, and Allocation

Abstract

I Introduction

II Logistics of Keeping Track of Study Subjects

III Blocked Randomization

IV Clinical Study Protocol Randomization Instructions

V Instructions for Unblinding

VI Summary of Unblinding

VII FDA Warning Letters

VIII Interactive Voice Response Systems

IX Concluding Remarks

Chapter 7. Placebo Arm as Part of Clinical Trial Design

Abstract

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 BSC and the Endpoint of HRQoL

VIII Ethics of Placebos

IX FDA’s Decision-Making Process in Evaluating the Placebo Arm

X Standard of Care

Chapter 8. Intent-to-Treat Analysis Versus Per Protocol Analysis

Abstract

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 the Same Efficacy

VII Modified ITT Analysis

VIII Start Date for Endpoints in Clinical Trials

IX FDA’s Decision-Making Processes, Relating to ITT Analysis and PP Analysis

X Concluding Remarks

Chapter 9. Biostatistics—Part I

Abstract

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 Tail of the Standard Normal Distribution

XII Statistical Analysis by Superiority Analysis Versus by Noninferiority Analysis

Chapter 10. Biostatistics—Part II

Abstract

I Introduction

II Discussions that Impact Sample Size Determination

III Statistical Terms Commonly Used in Sample Size Calculations

IV Null and Alternative Hypotheses

V Degree of Certainty: Alpha (α) and Beta (β)

VI Statistical Methods for Determining Trial Size

VII Continuous Variables: Testing the Difference Between Two Means

VIII Changes in Sample Size Assumptions can Yield Dramatic Changes to Sample Size

IX Changing Assumptions About Alpha (α) or Beta (β)

X Changing Assumptions About Theta (θ)

XI Binary Variables: Testing the Difference Between Two Proportions

XII Time to Event Variables: Testing for Differences Between Two Groups Using the Logrank Test

XIII Binary Variable: Testing for Equivalence of Two Proportions

XIV Other Helpful Considerations

XV Writing a Sample Size Section of a Clinical Study Protocol

Chapter 11. Introduction to Endpoints

Abstract

I FDA’s Guidance for Industry

Chapter 12. Oncology Endpoint—Objective Response

Abstract

I Introduction to Endpoints in Oncology Clinical Trials

II Studies Characterizing an Association Between Objective Response and Survival

III Avoiding Confusion When Using Objective Response as an Endpoint

IV FDA’s Decision-Making Process in Evaluating Objective Response

V Concluding Remarks

Chapter 13. Oncology Endpoints: Overall Survival and Progression-Free Survival

Abstract

I Introduction

II Advantages of PFS Over Overall Survival

III Advantages of Overall Survival Over PFS

IV Guidance From Clinical Trials on Using Endpoints

V Concluding Remarks

Chapter 14. Oncology Endpoints: Time to Progression

Abstract

I Introduction

II Agreement of Results from Objective Response, TTP, and Overall Survival—The Paccagnella Study

III Can the Value for PFS be Less Than the Value for TTP?

IV Data on the Endpoint of TTP can be Used to Gain FDA-Approval

V TTP may be the Preferred Endpoint Where, Once the Trial is Concluded, Patients Receive Additional Chemotherapy—The Park Study

VI The Endpoint of TTP may be Preferred Over Survival Endpoints, Where Deaths Result from Causes Other Than Cancer—The Llovet Study

VII 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

VIII TTP may Show Efficacy, Where the Endpoint of Overall Survival Fails to Show Efficacy, Where the Number of Subjects is Small—The McDermott Study

IX TTP 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

X Methodology Tip—Advantage of Using an Endpoint that Incorporates a Median Time

XI Summary

XII Thymidine Phosphorylase as a Biomarker for Survival—The Meropol Study

XIII Drug Combinations that Include Capecitabine

XIV Methodology Tip—Do Changes in mRNA Expression Result in Corresponding Changes in Expression of Polypeptide?

XV Concluding Remarks

Chapter 15. Oncology Endpoint: Disease-Free Survival

Abstract

I Introduction

II Difference Between DFS and PFS

III Ambiguity in the Name of the Endpoint, DFS

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 DFS and Overall Survival are Useful Tools for Testing and Validating Prognostic Biomarkers—The Bepler Study

IX FDA’s Decision-Making Process in Evaluating the Endpoint of DFS

X Summary

Chapter 16. Oncology Endpoint: Time to Distant Metastasis

Abstract

I Introduction

II TDM 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 TDM—The Loi Study

V Use of Micro-RNA Expression Data as a Prognostic Factor for Breast Cancer Patients—The Foekens Study

VI Biology of miRNA

VII Concluding Remarks

Chapter 17. Neoadjuvant Therapy Versus Adjuvant Therapy

Abstract

I Advantages of Neoadjuvant Therapy

II Advantages of Adjuvant Therapy

III Two Meanings of the Word Adjuvant

IV Summary of Neoadjuvant Versus Adjuvant Therapy in Cancer

V Induction Therapy Versus Maintenance Therapy in Autoimmune Diseases

VI Conclusions

Chapter 18. Hematological Cancers

Abstract

I Introduction

II Myelodysplastic Syndromes

III Summary

IV Cytogenetics of Hematological Cancers

V Chromosomal Abnormalities in Solid Tumors

VI Endpoints in Hematological Cancers

VII Cytogenetics as a Prognostic Marker—The Grever Study of CLL

VIII Minimal Residual Disease

IX Confluence of Cytogenetics and Gene Expression

X Concluding Remarks

Chapter 19. Biomarkers

Abstract

I Introduction

II Methodology Tip—Microarrays

III C-Reactive Protein

IV Biomarkers—Specialized Topics

V Exploring New Types of Biomarkers

VI Single Nucleotide Polymorphisms

VII Validating Biomarkers

VIII Biomarker Validation from FDA Submissions for In Vitro Diagnostics Tests

IX Concluding Remarks

Chapter 20. Endpoints for Immune Diseases

Abstract

I Introduction

II Subsets of Multiple Sclerosis

III FDA’s Decision-Making Process in Evaluating Endpoints for Multiple Sclerosis

IV Concluding Remarks

Chapter 21. Endpoints for Infections

Abstract

I Introduction

II Clinical and Immunological Features of HCV Infections

III Acute HCV Versus Chronic HCV

IV Drugs Against HCV

V Immune Responses Against HCV

VI Kinetics of HCV Infections

VII Responders Versus Nonresponders

VIII Endpoints in Clinical Trials Against HCV

IX Concluding Remarks

Chapter 22. Health-Related Quality of Life Tools—Oncology

Abstract

I Introduction

II Summary

III HRQoL Tools Take on Increased Importance When Capturing Data on Adverse Events, or in Trials on Palliative Treatments

IV Scheduling the Administration of HRQoL Tools

V HRQoL Tools in Oncology

VI Decisions on Counseling; Decisions on Chemotherapy Versus Surgery

VII Concluding Remarks

Chapter 23. Health-Related Quality-of-Life Tools—Immune Disorders

Abstract

I Introduction

II Short Form SF-36 Questionnaire

III HRQoL Instruments Specific for Multiple Sclerosis

IV Concluding Remarks

Chapter 24. Health-Related Quality-of-Life Tools—Infections

Abstract

I Introduction

II HRQoL Tools With Chronic HCV

Chapter 25. Drug Safety

Abstract

I Introduction

II Safety Definitions

III QT Interval Prolongation

IV Stevens–Johnson Syndrome

V Idiosyncratic Drug Reactions

VI FDA’s Decision-Making Process in Evaluating Adverse Events

VII Drug-Induced Liver Injury

VIII Assessing Causality

IX Paradoxical Adverse Drug Reactions

X Capturing Adverse Events

XI FDA’s Warning Letters About Failure to Report SAEs

XII Drugs that Create Risk for Infections

XIII FDA’s Decision-Making Process on Adverse Events that Appear Irrelevant to the Study Drug

XIV Postmarketing Reporting of Adverse Events

XV Risk Minimization Tools

XVI FDA’s Decision-Making Process in Evaluating Risk Minimization Tools

XVII European Union’s Risk Management Tools

XVIII Summary

XIX Patient-Reported Outcome

XX Summary of Reporting Systems

XXI Data and Safety Monitoring Committee

Data Safety Monitoring Board Charter

Introduction

Role of the Board

Board Membership

Term

Conflict of Interest and Financial Disclosure

Compensation

Board Meetings and Reports

Organizational Meeting

Interim Review Meetings

Format

Participants

Review Materials

Periodic Reports to the DMC

Unscheduled Meetings

DMC Recommendations

Outside Experts

Access to Interim Results

Stopping Rules

Communications

Other Communications

Sponsor’s Decisions and Announcements

Timetable

Contact Information

XXII Concluding Remarks

Chapter 26. Mechanism of Action of Diseases and Drugs—Part I

Abstract

I Introduction

II MOA and the Package Insert

III MOA and Surrogate Endpoints

IV MOA and Expected Adverse Drug Reactions

V FDA’s Warning Letter Regarding Assessing Safety of the Study Drug, According to Its Membership in a Particular Class of Drugs

VI MOA and Drug Combinations

VII MOA of Diseases With an Immune Component

VIII Immune System Pathology in Inflammatory Disorders

IX Cells of the Immune System

X Drugs that Modulate the Immune System

XI Immunology can be Organized as Pairs of Concepts

XII Concluding Remarks

Chapter 27. Mechanism of Action—Part II (Cancer)

Abstract

I Introduction

II Immune Evasion

III Concluding Remarks

Chapter 28. Mechanism of Action—Part III (Immune Disorders)

Abstract

I Introduction

II Detailed Mechanism of Action of Multiple Sclerosis

III Animal Models of Multiple Sclerosis

IV Etiology and Mechanisms of Multiple Sclerosis

V Diagram of Multiple Sclerosis Mechanism

VI Additional Mechanisms of Action in Multiple Sclerosis

VII Concluding Remarks

Chapter 29. Mechanisms of Action—Part IV (Infections)

Abstract

I Introduction

II HCV Infections

III Life Cycle of HCV

IV Initiating Biosynthesis of the HCV Polypeptide

V Membranous Web and Lipid Droplet

VI NS3/4A Protease

VII NS5A—HCV’s Recruiting and Assembly Protein

VIII NS5B—HCV’s RNA Polymerase

IX E1 and E2—HCV’s Envelope Proteins

X Core Protein of HCV

XI Innate Immune Response Against HCV

XII Chronic Inflammation

XIII Oncogenes and Growth Factors

XIV Acquired Immune Response Against HCV

XV Concluding Remarks

Chapter 30. Consent Forms

Abstract

I Introduction

II Sources of the Law in the United States

III Guidance for Industry

IV Distinction Between Stopping Treatment and Withdrawing From the Study

V Ethical Doctrines

VI The Case Law

VII Basis for Consent Forms in the CFR

VIII Summary

IX Examples of Contemporary Consent Forms

X Ethical Issues Specific to Phase I Clinical Trials in Oncology

XI FDA’s Warning Letters

XII Decision Aids

XIII Concluding Remarks

Chapter 31. Package Inserts

Abstract

I Introduction

II Drug–Drug Interactions

III FDA’s Decision-Making Process in Evaluating Drug–Drug Interactions

IV Summary of Drug–Drug Interactions

V Animal Toxicity Data and the Package Insert

VI Summary

VII Brand Names, Chemical Names, Packaging

VIII Ambiguous Writing on Package Inserts

IX Package Insert May Protect Manufacturer From Liability

X Package Insert Compared With Consent Form

XI Relation Between Package Inserts to the Standard of Care, and to Off-Label Uses

XII Concluding Remarks

Chapter 32. Warning Letters

Abstract

I Introduction

II List of Topics

III Warning Letter Describing Authority of FDA Inspectors

IV Anecdotal Description of an FDA Inspection, FDA’s Requirements for Record Keeping During Drug Manufacture, and Guidance for Responding to FDA’s Complaints

V FDA’s Warning Letter Distinguished from FDA’s Form 483 Notice

VI Warning Letter on Corrective Responses, by Sponsor, for a Tumor Clinical Trial

VII Definitions

VIII Failure of Sponsor to have an FDA-approved IND

IX Institutional Review Board

X Consent Forms

XI Data Monitoring Committee (DMC)

XII Protocol Deviations

XIII Clinical Hold

XIV Concomitant Medications

XV Inclusion/Exclusion Criteria

XVI Drug Accountability, Drug Storage, Drug Dispensing, and Record Keeping

XVII Withdrawal of Subjects From the Clinical Trial

XVIII Contract Research Organizations

XIX Case Report Forms

XX Investigator’s Brochure

XXI Off-Label Uses

XXII Conclusion

Chapter 33. Regulatory Approval

Abstract

I Origins of the Federal Food, Drug and Cosmetic Act and Its Amendments

II Federal Food, Drug and Cosmetic Act of 1938

III Drug Amendments Act of 1962

IV FDA Modernization Act of 1997 and Phase IV Clinical Trials

V History of European Medicines Agency

VI International Conference on Harmonisation

VII History of the Medicines and Healthcare Products Regulatory Agency

VIII Outline of Regulatory Approval in the United States

IX Investigational New Drug

X IND and the Common Technical Document

XI Institutional Review Board

XII Timeline of FDA Approval

XIII Special Protocol Assessment

XIV Target Product Profile

XV Company Core Data Sheet

XVI Accelerated Approval

XVII Refuse to File

XVIII Clinical Hold

XIX Exemplary Account of FDA Timeline, After Submission of NDA or BLA

XX FDA Approval Letter

XXI FDA Feedback at Time of Issue of the FDA Approval Letter

XXII Processes of Administring Clinical Trials

Chapter 34. Patents

Abstract

I Introduction

II Services Provided by the Patent Attorney or Agent

III History of Patenting

IV Outline of the Patenting Process

V Types of Patent Documents

VI Organization of Information in a Patent

VII Time-line for Patenting

VIII Provisional Patent Applications

IX Sources of the Law for Patenting

X Intersections Between the FDA Review Process and Patents

Index

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Dedication

To Shideh and Dawnia

Acknowledgments

I thank Julia Haynes, Molly McLaughlin, Kristine Jones, and April Graham of Elsevier, Inc., for their devotion and expertise in the editing and production phases of this book.

I am indebted to Dr Waihei A. Chu, PharmD, for his guidance in the field of regulatory writing. In his own words: I thank the following people for answering specific questions during the course of this project. Nearly all of these persons are physicians and principal investigators in clinical trials in oncology, multiple sclerosis, and infectious diseases. Many of these persons are thought-leaders in the field of study design or are tenured professors in medical schools. I thank Masha Hareli, Amit Bar-Or, and Olaf Steve, for authoritative guidance on multiple sclerosis. I thank Christina Slover for guidance on drug–drug interactions. I am grateful to Patrick Archdeacon, Patricia Harley, Michelle Eby, and Joette M. Meyer, all of the FDA, for information on various aspects of the FDA approval process. I am grateful to Peter C. Raich for granting permission to reproduce his consent forms, and I thank David Cella for sending me these forms. I thank Marc Buyse, Tomasz Burzykowski, Daniel J. Sargent, Gerold Bepler, Sally Stenning, John Hainsworth, Sanjiv S. Agarwala, Clifford A. Hudis, Axel Grothey, Wen-Jen Hwu, Keith Wheatley, Joseph A. Sparano, Elizabeth A. Eisenhauer, Miguel Martin, and Linda Colangelo, for their expert guidance on endpoints. I am deeply grateful to Frank Worden and Bruce E. Johnson for guidance on run-in periods. I am most grateful to David Cella, Barbara Vickrey, Andrea (Andy) Trotti, and Jinny Tavee, for help on health-related quality-of-life (HRQoL) instruments. I thank Jeffrey A. Cohen for his detailed responses to my questions on multiple sclerosis. Also, I am grateful to Ching-Hon Pui, James B. Nachman, Eric E. Hedrick, Stacey L. Berg, and Tanja Hartmann for their insights regarding the leukemias. I acknowledge Margaret von Mehren for information on gastrointestinal stromal tumors. I thank Bruce A. Roe for modifying my diagram of the Philadelphia chromosome, and I thank Adele K. Fielding for further guidance on this chromosome. I am also grateful to Jake Liang and Robert E. Lanford for explaining relations between IFN-alpha and IFN-gamma, as they apply to hepatitis C virus.

I thank Martin E. Stryjewski, Jonathan S. Berek, James Cassidy, Olivier Leroy, and Michael E. Pichichero, for help on per protocol analysis and intent-to-treat analysis. I thank Lawrence Rubinstein, Thomas G. Roberts Jr, Thomas J. Lynch, Murray D. Norris, Bradley R. Prestidge, and Igor Sherman, for information on subgroups or on inclusion/exclusion criteria.

I am grateful to Peter J. Barrett-Lee for information on drug safety. I thank Anthony Viera for information on randomization. I thank Syed Y. Zafar and Richard L. Schilsky for their expertise on best supportive care and palliative care. I acknowledge Karen Mosher for her expertise on decision aids, as it relates to consent forms. I am grateful to Elizabeth B. Andrews, Balall Naeem, Michael Klepper, and Barry D.C. Arnold, for their knowledge regarding the CIOMS I form. I thank Patricia Mozzicato for her time answering questions about the MedDRA terminology. Moreover, I thank Tiiamari Pennanen for information on the history of the European Medicines Agency, and Dominic Stevenson and Sarah Heffer for advice on the Yellow Card. For the first edition of this book, I thank Jenna Elder and Harvey Motulsky for reviewing the draft chapter on biostatistics.

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Preface

This book is a pharmacology textbook. It can serve a handbook for all personnel involved in regulated clinical trials, including employees at the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The book quotes extensively from comments by FDA reviewers, which are published on the FDA’s website at the time that the FDA grants approval to a drug. In other words, along with the FDA’s approval letter, the FDA also publishes its Medical Reviews, Clinical Reviews, Pharmacology Reviews, and other documents, each of which includes comments from various FDA personnel.

The content of these reviews closely tracks the Sponsor’s Integrated Summary of Safety (ISS), submitted as part of an NDA or BLA. It is therefore the case that this book provides an accurate representation of what the FDA looks for (and complains against), during its review of submissions from a Sponsor’s phase II and phase III clinical trials. In all, the author made use of the Medical Reviews and Clinical Reviews that accompanied about 75 of the FDA’s approval letters.

In this book, the words Sponsor and investigator are sometimes used interchangeably, though it should be noted that the Sponsor is the party that initiates a clinical trial, while an investigator is the party that actually does the work, such as the work of writing the Clinical Study Protocol and other FDA-submissions, enrolling study subjects, administering the study drug, and collecting data on efficacy and safety (1).

Also, to ensure that the book is a lively and compelling textbook and handbook, the text provides the history of consent forms using the example of Walter Reed’s yellow fever study, the history of the FDA and the EMA, background information on assay methods in biochemistry and immunology, and quotations from published courtroom opinions relating to clinical trials.

This book fulfills various unmet needs, as detailed below.

The Study Schema and Study Design

The best way to communicate trial design is with a flow chart or table called the schema.

The author observed that the schema is rarely detailed in any explicit way by books or journal articles. Unfortunately, books on clinical trials generally refrain from disclosing much on trial design, for example, regarding the various goals of the run-in period, or regarding decision trees that may modify drug dosing during the course of an ongoing trial. This book provides a thorough introduction to study design, includes many representative diagrams of the study schema, and details several distinct reasons for including a run-in period.

Intent-to-Treat Analysis and Placebos

Second, the authors observed that other aspects of clinical trials are inadequately described in textbooks, for example, they were covered only by a short paragraph. These aspects include intent-to-treat (ITT) analysis, modified ITT (mITT) analysis, and per protocol (PP) analysis. ITT analysis is a term that is almost universally used in clinical trials, but the available textbooks on clinical trial design typically fail to describe ITT analysis, mITT analysis, or PP analysis, and how to choose between these three types of data analysis. This book contains an entire chapter on ITT, mITT, and PP analyses. It is also the case that most or all books on clinical trials fail to include any organized account of placebos. This book has an entire chapter on placebos.

How to Choose Endpoints

Third, definitions of endpoints used in oncology clinical trials are frequently disclosed in the available textbooks, but unfortunately, textbooks generally fail to state the advantages of any given endpoint over another, and fail to state situations where a particular endpoint gives ambiguous information or where an endpoint cannot be used. These oncology endpoints include objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), time to distant metastasis (TDM), disease-free survival (DFS), 6-month PFS, and health-related quality of life (HRQoL). The FDA’s Guidance for Industry (2) provides a fine introduction to these endpoints, but refrains from detailing, for example, situations where any given endpoint is likely to be unreliable or unusable. This book fulfills an unmet need by providing a more detailed account on how to choose the most appropriate oncology endpoint, and on when to refrain from using a given endpoint.

Diagnostic Tests

Fourth, this book takes care to integrate diagnostic tests with each disease. What are described are disability status questionnaires, HRQoL questionnaires, blood counts, flow cytometry, immunoassays, polymerase chain reaction (PCR), microarrays, and magnetic resonance imaging (MRI). Moreover, this book provides an introduction to the process of FDA approval for diagnostics tests.

Mechanism of Action

Fifth, the book describes the mechanisms of various diseases and the mechanisms of action of various drugs. These mechanisms are integrated into the context of clinical trials, in commentary demonstrating how the mechanism of action can influence the inclusion/exclusion criteria, warnings on consent forms, and information on package inserts. This book also describes how the mechanism of action can influence study design, that is, the particular combination and timing of administered drugs. The book reveals that a knowledge of the mechanism of action can encourage regulatory agencies to allow a clinical trial to be initiated.

Standards

Sixth, the text emphasizes the role of various standards that apply to clinical trials. These standards include criteria for measuring physical fitness, such as the Eastern Cooperative Oncology Group (ECOG) score, Karnofsky score, and the Kurtzke Expanded Disability Status Scale (EDSS) score, criteria for measuring tumor size and number (Response Evaluation Criteria in Solid Tumors, RECIST criteria), and criteria for staging tumors [Tumor Node Metastasis (TNM) staging; Dukes’ staging]. The text provides a warning about potential confusion that can arise, when two different sets of standards are applied to one disease. This warning takes the form of a narrative on the Will Rogers Phenomenon.

The administrative law, and guidance documents from regulatory agencies, constitute another type of standard. These standards are also revised from time to time. The ICH Guidelines and the FDA’s Guidance for Industry documents constitute a recurring theme in this textbook.

FDA’s Warning Letters

This textbook uses the FDA’s Warning Letters as a source material. The FDA issues Warning Letters to manufacturers of drugs, medical devices, foods, and dietary supplements. Generally, these letters include complaints about a company’s failure to comply with one or more sections of Title 21 of the Code of Federal regulations. The FDA uses two different instruments for complaining about failures to follow various sections of Title 21 of the Code of Federal Regulations, for the situation where the failures are detected during an FDA inspection of the Sponsor’s clinical facilities or manufacturing facilities. These two instruments are the FDA’s Form 483 notices and the FDA’s Warning Letters. Quotations from the FDA’s Warning Letters are included at various points in this book. A sustained account of the FDA’s Warning Letters, as well as a description of their relation to the FDA’s Form 483, appears in one of the last chapters in this book.

ClinicalTrials.gov and Other Registries for Clinical Trials

ClinicalTrials.gov is a registry of clinical trials, developed by the FDA and NIH, and first operational in 2000 (3). In 2007, the Food and Drug Administration Amendments Act (FDAAA) imposed the requirement that sponsors of clinical trials register and report summary results at www.ClinicalTrials.gov (4). As of Jan. 2009, ClinicalTrials.gov had more than 67,000 registered trials (5). About one-quarter of these trials are sponsored by pharmaceutical companies. Zarin et al. (6) describe the content of this website.

The European Union provides the EU Clinical Trials Registry, which contains information on clinical trials that were conducted in the European Union, starting after May 1, 2004. This Registry contains information that was entered by Sponsors of clinical trials. The information, which appears in the EudraCT database, can be searched by the public, and the information includes the trial design, Sponsor, medicine, therapeutic area, summary of results, and whether the trial is merely authorized, or is ongoing or complete. EudraCT is provided in 24 different languages. The step at which the user can select the language, is provided on the world wide web at: www.eudrapharm.eu/eudrapharm/. Any member of the public can input query terms such as the trade name or the chemical name of the drug.

Registries that are not affiliated with any governmental agency include, for example, the TYSABRI Pregnancy Exposure Registry. This registry is identified on the package insert for Tysabri, which states that, [i]f a woman becomes pregnant while taking TYSABRI, consider enrolling her in the TYSABRI Pregnancy Exposure Registry by calling 1-800-456-2255 (7).

Each study has a unique registration number. Another registry used for clinical trials is the International Standard Randomised Controlled Trial Number (ISRCTN) (8). Where a clinical trial is conducted in only one country, study information should be entered only in one register, to avoid duplication and confusion. However, companies that perform international clinical studies may be required to register their trial in a national clinical study register, as well as in an international clinical study register (9). The WHO International Clinical Trials Registry Platform (ICTRP) provides a search portal to locate trials from many primary registries worldwide (http://www.who.int/ictrp/en/). This registry began operating in 2005 (10). A similar service for ongoing and completed studies is available from the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) (http://www.ifpma.org/ clinicaltrials) (11).

The FDA Amendments Act, enacted in Sep. 2007. Congress expanded the requirements for sponsors and investigators to post information about clinical trials, including selected aspects of trial results, on ClinicalTrials.gov (12). Requirements relevant to registration are set forth in Section 801 of this Act. Section 801 mandates registration on ClinicalTrials.gov of all new controlled clinical investigations (other than phase I) of drugs, biologics, and devices subject to regulations by the FDA. This applies to research for any condition, regardless of sponsor type, for example, industry, government, or academic (13). New clinical studies must be registered within 21 days after the first patient is enrolled, where updates of the registry information must occur at least every 12 months. Recruitment status should be updated within 30 days of any change. Dec. 2007 was the due date to start registering new studies or updating all required information fields for ongoing studies (14,15). One of the FDA’s Guidance for Industry documents, Providing Regulatory Submissions in Electronic Format, provides guidance for registering your clinical trial (16).

Although Public Law No. 110-85 contains a section named, Section 801, the law only has 88 sections. Section 801 is reproduced, in part, below (17):

(i) SEARCHABLE CATEGORIES.—The Director of NIH shall ensure that the public may, in addition to keyword searching, search the entries in the registry data bank by 1 or more of the following criteria:

(I) The disease or condition being studied in the clinical trial, using Medical Subject Headers (MeSH) descriptors.

(II) The name of the intervention, including any drug or device being studied in the clinical trial.

(III) The location of the clinical trial.

(IV) The age group studied in the clinical trial, including pediatric subpopulations.

(V) The study phase of the clinical trial.

(VI) The sponsor of the clinical trial, which may be the National Institutes of Health or another Federal agency, a private industry source, or a university or other organization.

(VII) The recruitment status of the clinical trial.

(VIII) The National Clinical Trial number or other study identification for the clinical trial.

The International Committee of Medical Journal Editors (ICMJE) adopted the policy that clinical trials be registered at the onset of patient enrollment, as a condition for publication (18). In observing that trial registration is largely voluntary, and that registries contain only a small proportion of trials, the ICMJE proposed that trial registration be a solution to the problem of selective awareness, and set forth the goal that ICMJE member journals require (as a condition of consideration for publication) registration in a public trials registry (19,20). Trials must register at or before the onset of patient enrollment. Hirsch (21) and others (22,23) provide comments on this policy. In a survey of editorial policies of 165 medical journals, Hopewell et al. (24), found that 44 specially require that the clinical trial be registered before submitting the manuscript to the journal.

According to the FDA’s Guidance for Industry document on good pharmacovigilance practices, a sponsor may establish or create a new registry, for example, for the goals of evaluating safety signals identified from spontaneous case reports or from literature reports, and for evaluating factors that affect the risk of adverse outcomes, such as dose, timing of exposure, or patient characteristics (25).

This book emphasizes cancer for a number of reasons. Therapy for cancer involves more variables, more drug candidates, and more drug combinations, than therapy for other diseases. Hence, there is a greater need to provide a harmonious description of trial design and endpoints, as it applies to cancer. Also, the number of cancer clinical trials is greater than for other diseases. In Jan. 2011, about 27,000 cancer trials, 4190 trials on immunological diseases (sum of arthritis, multiple sclerosis, lupus, psoriasis, Crohn’s disease, and ulcerative colitis), 5180 trials on diabetes, and 690 trials on atherosclerosis, were identified on www.ClinicalTrials.gov.

¹American Academy or Pediatrics Policy Statement. Off-label use of drugs in children. Pediatrics 2014;133:563–7.

²U.S. Department of Health and Human Services. Food and Drug Administration. Guidance for industry. Clinical trial endpoints for the approval of cancer drugs and biologicals; 2007 (19 pp.).

³Steinbrook R. Public registration of clinical trials. New Engl. J. Med. 2004;351:315–7.

⁴Anderson ML, et al. Compliance with results reporting at ClinicalTrials.gov. New Engl. J. Med. 2015;372:1031–9.

⁵Wood AJ. Progress and deficiencies in the registration of clinical trials. New Engl. J. Med. 2009;360:824–30.

⁶Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov results database—update and key issues. New Engl. J. Med. 2011;364:852–60.

⁷TYSABRI (natalizumab) Injection Full Prescribing Information. Biogen IDEC, Inc.; January 1, 2012 (32 pp.).

⁸Thomas KB, Tesch C. Clinical trial disclosure-focusing on results. The Write Stuff. 2008;17:70–3.

⁹Thomas KB, Tesch C. Clinical trial disclosure-focusing on results. The Write Stuff. 2008;17:70–3.

¹⁰Sim I. Trial registration for public trust: making the case for medical devices. J. Gen. Intern. Med. 2008;23(Suppl. 1):64–8.

¹¹Thomas KB, Tesch C. Clinical trial disclosure-focusing on results. The Write Stuff. 2008;17:70–3.

¹²Wood AJ. Progress and deficiencies in the registration of clinical trials. New Engl. J. Med. 2009;360:824–30.

¹³Thomas KB, Tesch C. Clinical trial disclosure-focusing on results. The Write Stuff. 2008;17:70–3.

¹⁴Thomas KB, Tesch C. Clinical trial disclosure-focusing on results. The Write Stuff. 2008;17:70–3.

¹⁵Wood AJJ. Progress and deficiencies in the registration of clinical trials. New Engl. J. Med. 2009;360:824–30.

¹⁶U.S. Department of Health and Human Services. Food and Drug Administration. Providing regulatory submissions in electronic format—drug establishment registration and drug listing; May 2009 (13 pp.).

¹⁷Public Law 110-85. 110th Congress. September 27, 2007. Food and Drug Administration Amendments of 2007.

¹⁸Foote M. Clinical trial registries and publication of results—a primer. In: Foote M, editor. Clinical trial registries a practical guide for sponsors and researchers of medicinal products. Basel, Switzerland: Birkhäuser Verlag; 2006. pp. 1–12.

¹⁹De Angelis CD, Drazen JM, Frizelle FA, et al. Is this clinical trial fully registered?—A statement from the International Committee of Medical Journal Editors. New Engl. J. Med. 2005;352:2436–8.

²⁰De Angelis CD, Drazen JM, Frizelle FA, et al. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. J. Am. Med. Assoc. 2004;292:1363–4.

²¹Hirsch L. Trial registration and results disclosure:impact of US legislation on sponsors, investigators, and medical journal editors. Curr. Med. Res. Opin. 2008;24:1683–9.

²²Bonati M, Pandolfini C. Trial registration, the ICMJE statement, and paediatric journals. Arch. Dis. Child 2006;91:93.

²³Sekeres M, Gold JL, Chan AW, et al. Poor reporting of scientific leadership information in clinical trial registers. PLoS One 2008;3:e1610.

²⁴Hopewell S, Altman DG, Moher D, Schulz KF. Endorsement of the CONSORT Statement by high impact factor medical journals: a survey of journal editors and journal ‘Instructions to Authors’. Trials 2008;9:20.

²⁵U.S. Department of Health and Human Services. Food and Drug Administration. Guidance for industry. Good pharmacovigilance practices and pharmacoepidemiologic assessment; March 2005 (20 pp.).

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Introduction

Where a drug or medical device is tested on human subjects, the test may be called a clinical trial. Clinical trials may be conducted in an academic setting, where the goals are to obtain knowledge on the mechanism of action, efficacy, and pharmacokinetics of the drug. Clinical trials are also conducted by the pharmaceutical industry, where the goals are to obtain knowledge on safety, efficacy, pharmacokinetics, and mechanism of action, and to obtain regulatory approval.

The structure of clinical trials is set forth in a document called the Clinical Study Protocol. Clinical Study Protocols contain a number of common elements, or concepts, despite the variety of drugs being tested, and the variety of diseases. These common elements include inclusion and exclusion criteria for the study subjects, subgroups of the study population, methods for stratifying the study subjects, techniques for recruitment, obtaining consent, randomization, and allocation, and statistical methods for data presentation and analysis. The Clinical Study Protocol includes a summary called the synopsis and a flow chart called the study schema. The schema provides the study design, the identity of the study drug and control, and an identification of some of the endpoints.

Endpoints in any given clinical trial may relate, for example, to tumor size, the number of lesions in an organ or tissue, the concentration of bacteria or viruses in the bloodstream, or to a metabolite or hormone in the bloodstream. Endpoints can take the form of relatively subjective data from questionnaires filled out by study subjects, or of relatively objective data, such as laboratory values in chemistry and hematology, or images from computed tomography and magnetic resonance imaging (MRI).

In clinical trials, the main goals are capturing and analyzing data on safety and efficacy. It is usually not the goal to ensure that study subjects recover from their disorder.

Trials intended for regulatory approval by the US Food and Drug Administration (FDA), as well as monitoring activities in the postapproval context, are regulated by the United States Code (USC) and by the administrative law, that is, the Code of Federal Regulations (CFR). The term administrative law refers to the rules in the CFR. The USC contains statutes, whilst the CFR contains rules. The relevant statutes are found in Title 21 of the USC (21 USC §355).

The relevant administrative law (or rules) is found in Title 21 and Title 45 of the CFR, as indicated below:

• Investigational New Drug (IND) (21 CFR §312)

• New Drug Application (NDA) (21 CFR §314)

• Investigator's Brochures (IB) (21 CFR §312)

• Integrated Summary of Safety (ISS) (21 CFR §314.50 (d)(5))

• Integrated Summary of Efficacy (ISE) (21 CFR §314.50 (d)(5))

• Consent form (21 CFR §50 and 45 §CFR 46)

• Package insert (21 CFR §201.10 and 21 CFR §201.56)

• Data Monitoring Committee Charter (DMC Charter) (21 CFR §312.50 and 45 CFR §46).

I Good Clinical Practice

Clinical trials intended for regulatory approval should conform to a set of guidelines known as, Good Clinical Practice (GCP). According to the ICH Guidelines:

Good Clinical Practice is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible 1.

GCP encompasses the requirement that the clinical study be approved by an independent ethics board, such as an Institutional Review Board (IRB), prior to initiating the clinical study. GCP also encompasses the requirements that study subjects give informed consent prior to entering the study, that records of study subjects be kept confidential, that investigators be properly qualified by education and training, that adequate medical care be given to any study subjects who suffer from study-related adverse events, that serious adverse events be immediately reported to the sponsor, and that study drugs and placebo (if any) be manufactured according to Good Manufacturing Practices (GMP).

The ICH Guideline for Good Clinical Practice also provides the organization and content of the Clinical Study Protocol. The Clinical Study Protocol is, in essence, the instruction manual used by persons involved in conducting the trial. Additionally, the ICH Guideline for Good Clinical Practice details the organization and content of the Investigator's Brochure (IB), a document that compiles relevant clinical data and non-clinical data. These data include those arising apart from the study, for example, from reports from animal studies and from clinical trials conducted by other investigators, as well as data from human subjects arising from the study itself. Most of the information set forth in this textbook can be viewed in the context of Good Clinical Practice.

The ICH Good Clinical Practice Guidelines sets forth international standards for the quality, safety, and efficacy of developmental-stage pharmaceutical products. The ICH Good Clinical Practice Guidelines were made binding by the EU Clinical Trials Directive in 2004.2 They require the sponsor to verify the qualifications of the investigators, obtain informed consent before each subject's participation in the trial, ensure the trials are adequately monitored, and that the institutional review board (IRB) reviews and approves the Clinical Study Protocol, and oversee the trial.

This textbook frequently refers to the ICH Guidelines and the FDA's Guidance for Industry documents, and uses these documents as anchor points for the various narratives.

II FDA’s Decision-Making Process in Granting Approval to a Drug

This textbook is unique in its extensive use of documents published by the FDA at the time the FDA grants approval to a drug. These document are published by the FDA, in its response to an NDA or BLA submitted by a Sponsor. The decision-making processes leading to regulatory approval of various drugs are available, in part, on the website of the FDA. The available documents, which are published at the time that the FDA grants approval to a drug, include:

• Approval Letter

• Package Insert

• Medical Review or Clinical Review

• Pharmacology Review

• Statistical Review

• Package Insert

• Administrative Documents and Correspondence.

For the Reviews, it is the case that FDA reviewers reproduce some of the data that had been submitted by the Sponsor, re-analyze the results, and come to their own conclusions. The Reviews include clearly labeled comments from the reviewers. These comments provide invaluable guidance from the ultimate authority on the types of study design and data that are needed to influence the FDA to grant approval. These comments sometimes take the form of complaints, however, since the Reviews are published at the time of FDA approval, it is generally not the case that the complaints are harsh enough to bring a halt to the drug-approval process. On occasion, parts of the FDA's Reviews that correspond to an earlier phase of the drug-approval process will reveal harsh complaints, such as those involving a Clinical Hold or a Refuse to File notice, and where these complaints were eventually overcome by the Sponsor. Moreover, because the Reviews are published at the time of FDA approval, it is the case that these Reviews often emphasize postmarketing requirements that were imposed by the FDA, for example, the requirement to conduct confirmatory clinical trials, in the case of a trial that had received an accelerated approval, or the requirement to include an REMS in the postmarketing situation.

III Disclaimer

The following is a disclaimer. The present writing does not constitute legal advice, and it does not establish any relationship between the reader and the authors. A goal of the present writing is to facilitate communication between investigators in pharmaceutical companies and their attorneys, in matters limited to consent forms, package inserts, and patents. The opinions set forth herein do not necessarily reflect the opinions of the authors’ past, present, or future employers.

¹ICH Harmonised Tripartite Guidelines. Guideline for Good Clinical Practice E6 (R1). Step 4 version, June 1996.

²Hathaway CR, Manthei JR, Haas JB, Scherer CA. Looking abroad: clinical drug trials. Food and Drug Law Journal. 2008; 63:673–681.

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Abbreviations and Definitions

ADCC antibody-dependent cell cytotoxicity

ADME absorption, distribution, metabolism, and excretion

ADR adverse drug reaction

AE adverse event

ALL acute lymphocytic leukemia; acute lymphoblastic leukemia

AML acute myeloid leukemia; acute myelogenous leukemia

APC antigen presenting cell. APCs include cells of the immune system, for example, dendritic cells and macrophages. Antigens, which take the form of peptides and oligopeptides, are noncovalently bound to MHC, and are presented to T cells by way of the MHC, where presentation occurs in an immune synapse that involves the APC and a T cell

ASCO American Society of Clinical Oncology

AUC area under the curve of concentration, in serum or plasma, over time. The AUC represents the overall impact of a drug, over the course of time, to organs, tissues, and cells, in the physiological milieu

bid bid in die, which is Latin for twice a day

Cmax maximum concentration in plasma or serum. Plasma refers to blood containing an anticoagulant, with blood cells removed. Serum prepared by allowing blood naturally to clot, followed by discarding the clot and the blood cells

Cmin minimum concentration in plasma or serum

CBER Center for Biologics Evaluation and Research

CD cluster of differentiation. The CD nomenclature refers to cell-surface proteins of immune cells, and is used to identify immune cells

CDER Center for Drug Evaluation and Research

CFR; C.F.R. Code of Federal Regulations

CI confidence interval

CIOMS Council for International Organizations of Medical Sciences

CLL chronic lymphocytic leukemia; chronic lymphoblastic leukemia

CMI Consumer Medication Information

CML chronic myeloid leukemia; chronic myelogenous leukemia

CONSORT Consolidated Statement of Reporting Trials

COPD chronic obstructive pulmonary disease

CR complete response. Complete response is a type of objective response. Objective response means assessing tumor size and number, as described by the RECIST criteria. CR is also used to refer to a totally different parameter, complete remission

CRF Case Report Form

CRP C-reactive protein

CTCAE Common Terminology Criteria for Adverse Events

DC dendritic cell

DFS disease-free survival

DMC Data Monitoring Committee

DNA deoxyribonucleic acid

DSMC Data and Safety Monitoring Committee

ECG electrocardiogram

ECOG Eastern Cooperative Oncology Group

ECRIN European Clinical Infrastructure Network

EGF epidermal growth factor

EMA; EMEA European Medicines Agency. EMEA was the formerly used abbreviation, but in Dec. 2009 the abbreviation was changed to EMA

FDA US Food and Drug Administration

FDA Form 356h the form used to submit an NDA or BLA

FDA Form 483 Form 483 is sometimes issued during the time of an FDA inspection of a clinical or manufacturing facility. If the problems are not corrected in due course, FDA may follow-up by issuing a Warning Letter

FDA Form 1571 the form used to submit an IND

FOLFIRI anticancer therapy using folinic acid, fluorouracil, and irinotecan. Folinic acid, also known as leucovorin, is a trivial name for 5-formyl-tetrahydrofolic acid

FPI Full Prescribing Information. FPI is the US Food and Drug Administration’s name for part of the package insert

5-FU 5-fluorouracil

GCP Good Clinical Practices

GLP Good Laboratory Practices

Gy Gray (1 gray=1 J/kg and also equals 100 rad). The gray is a unit of absorbed energy per mass of tissue

HCV hepatitis C virus

HERG gene human ether-related a-go-go gene

HIPAA Health Insurance Portability and Accountability Act

HR hazard ratio

HRQoL health-related quality of life, or simply, QoL.

IB Investigator’s Brochure

ICH International Conference Harmonization

ICMJE International Committee of Medical Journal Editors

ICSR Individual Case Safety Reports

IM intramuscular

IND Investigational New Drug application

IP intraperitoneal or intraperitoneally

ITT intent to treat, as in, intent-to-treat analysis

IV intravenous or intravenously

IVRS interactive voice response systems

LDH lactic dehydrogenase

LLOQ lower limit of quantification

M molarity; moles per liter

MABEL minimum anticipated biological effect level

MDS myelodysplastic syndromes (MDS is a genus of related diseases)

MedDRA Medical Dictionary for Regulatory Activities Terminology

MHC major histocompatibility complex. The MHC is a complex of membrane-bound proteins, expressed by a dendritic cell, that is used to hold antigenic peptides. The MCH presents the antigenic peptides to a T cell, that is, to the T cell receptor of a T cell. In response, the T cell is activated. The complex of MHC (residing on a dendritic cell) and the T cell receptor (residing on a T cell) is called the immune synapse

MHRA Medicines and Healthcare products Regulatory Agency

miRNA micro-RNA; micro-ribonucleic acid

mL milliliter

MOG myelin oligodendrocyte glycoprotein

MRD minimal residual disease. MRD refers to the amount of leukemic blood cells following therapy against leukemia. For MRD analysis, the blood cells can be acquired from the bone marrow or from peripheral blood, and then identified. Identification employs the polymerase chain reaction, a technique that can detect mRNA specific to leukemic cells

MTX methotrexate. Methotrexate, a drug used for treating cancer and arthritis. MTX is a chemical analog of folic acid

NK cell natural killer cell. NK cells can kill target cells by way of ADCC. In ADCC, an antibody binds to the NK cell by way of the constant region of the antibody and an Fc receptor. Also, the same antibody binds to a target cell by way of its variable region, and a specific antibody on the target cell. In ADCC, various ligand and receptors, expressed on the surface of the NK cell and the target cell must be compatible with each other. When the above conditions are met, the NK cell kills the target cell

NOAEL no-observed adverse effect level. This term is used in toxicology, in the context of using animal studies to arrive at a human dose

NS2 nonstructural protein 2 of hepatitis C virus

NS5A nonstructural protein 5A of hepatitis C virus

OR objective response

OS overall survival

P value assuming that there is no actual difference in the means between two groups of data, the P value is the probability of finding a difference (a difference arising by chance alone) between the means of the two groups that is as large, or larger, than the experimentally observed difference

PBMCs peripheral blood mononuclear cells. The term PBMCs refers to a preparation of bulk leukocytes. PBMCs include T cells, B cells, NK cells, and monocytes, and they may include circulating tumor cells. PBMCs do not include red blood cells and polymorphonuclear leukocytes (neutrophils)

PCR polymerase chain reaction. PCR is a technique for reproducing, in a reiterative and exponential manner, a region of double-stranded DNA

PD progressive disease

PDR Physician’s Desk Reference. The PDR contains reproductions of package inserts, including the black box warnings of the inserts

PFS progression-free survival

pH negative log of hydrogen ion concentration

PK pharmacokinetics. PK refers to drug concentrations, over the course of time, during absorption, distribution, metabolism, and excretion, of any administered drug. Pharmacodynamics, in contrast, refers to the physiological responses of organs, tissues, cells, and genes, to an administered drug

PP per protocol, as in per protocol analysis

PPI Patient Package Insert

PR partial response

PSUR Periodic Safety Update Reports

QT interval Time (ms) between Q wave and T wave

QTc interval corrected QT interval

RCT randomized controlled trial; randomised controlled trial (British spelling)

RECIST Response Evaluation Criteria In Solid Tumors

REMS Risk Evaluation and Mitigation Strategy

RTF Refuse to File

RFS relapse-free survival

RNA ribonucleic acid

RTOG Radiation Therapy Oncology Group

SAE serious adverse event

SC subcutaneous

SNP single nucleotide polymorphism

SPA request for Special Protocol Assessment

SVR sustained virological response

SWOG Southwest Oncology Group

T cells thymus-derived cells

TDM time to distant metastasis

TdP Torsade de pointes

Th1 Th1 refers to Th1-type helper T cells. Th1 also refers to any Th1-type cytokine, for example, IFN-gamma, without regard to the cell origin

Th2 Th2 refers to Th2-type helper T cells. Th2 also refers to any Th2-type cytokine, for example, IL-4, IL-5, IL-10, and IL-13, without regard to the cell origin

tid ter in die, which is Latin for three times a day

q3w every three weeks

USC; U.S.C. United States Code

USPTO United States Patent and Trademark Office

WHO World Health Organization

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Biographies

The author 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. Most of his 20 research publications concern the enzymology, metabolism, and pharmacokinetics of folates and related amino acids (1,2,3,4). Also, he cloned, sequenced, and expressed an oncogene (XPE gene) (5,6,7). Later, he performed research on the structure of an antibody (natalizumab) used for treating multiple sclerosis (8). The author has 15 years of pharmaceutical industry experience, acquired at Schering-Plough, Cerus Corporation, and Athena Neurosciences (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 Nutritional Biochemistry, published by Elsevier, Inc. (9). Nutritional Biochemistry describes the clinical features, diagnosis, treatment, and mechanisms of action of 40 drugs, relating to the metabolic diseases. More recently, the author acquired 3 years of experience in FDA regulations, as applied to package inserts, as well as further experience in medical writing in oncology, immune disorders, and infections, at Baker Hostetler, LLP, Costa Mesa, CA. The author has 16 years of training and experience in the Code of Federal regulations, as it applies to pharmaceuticals and clinical trial design.

Dr Jennifer A. Elder, PhD, author of Chapter 10, Biostatistics: Part II, is Chief Scientific Officer at PharPoint Research, Inc., in Durham, NC. Dr Elder has performed statistical analyses for clinical trials for 15 years, with 11 of those years being in the CRO industry. Dr Elder served as the lead statistician on pivotal studies for various compounds, and has participated in the completion of several NDA, MAA, sNDA, and IND applications, and provided strategic consulting, and statistical analysis oversight for over 75 projects.

¹Brody T, Stokstad ELR. Folate oligoglutamate:amino acid transpeptidase. J. Biol. Chem. 1982;257:14271–9.

²Brody T, Watson JE, Stokstad ELR. Folate pentaglutamate and folate hexaglutamate mediated one-carbon metabolism. Biochemistry 1982;21:276–82.

³Brody T, Stokstad ELR. Nitrous oxide provokes changes in folylpenta- and hexaglutamates. J. Nutr. 1990;120:71–80.

⁴Brody T, Stokstad ELR. Incorporation of the 2-ring carbon of histidine into folylpolyglutamate coenzymes. J. Nutr. Biochem. 1991;2:492–8.

⁵Brody T, Keeney S, Linn S. Human damage-specific DNA binding protein p48 subunit mRNA, GenBank, Accession # U18299; 1995.

⁶Keeney S, Eker AP, Brody T, et al. Correction of the DNA repair defect in xeroderma pigmentosum group E by injection of a DNA damage-binding protein. Proc. Natl Acad. Sci. 1994;91:4053–6.

⁷Dualan R, Brody T, Keeney S, et al. Chromosomal localization and cDNA cloning of the genes (DDB1 and DDB2) for the p127 and p48 subunits of a human damage-specific DNA binding protein. Genomics 1995;29:62–9.

⁸Brody T. Multistep denaturation and hierarchy of disulfide bond cleavage of a monoclonal antibody. Analytical Biochem. 1997;247:247–56.

⁹Brody T. Nutritional biochemistry. 2nd ed. San Diego, CA: Academic Press; 1999.

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Chapter 1

Origins of Drugs

Abstract

A brief history of the discovery and invention of a selection of drugs is provided, as an introduction to this textbook on clinical trials. Examples were chosen from drugs that are classified as natural products, analogs of naturally occurring metabolites, antibodies, and drugs identified by screening libraries of chemicals. Also, as an introduction to clinical trials, information is given on scaling-up a drug dose suitable for animals, to that suitable for humans.

Keywords

Drug discovery; recombinant antibodies; animal models

I Introduction

Drugs have a number of origins, as outlined:

• Natural products, for example, chemicals from plants and microorganisms.

• Analogs of naturally occurring chemicals that reside in various biosynthetic pathways of mammals.

• Antibodies that bind to naturally occurring targets in the body.

• Discovery that an existing drug, established as effective for a first disease, is also effective for treating an unrelated second disease.

• Drugs identified by screening libraries of chemicals.

Some drugs are based on natural products, where the natural products were known to have pharmacological effects. The term natural products is a term of the art that generally refers to chemicals derived from plants, fungi, or microorganisms. Drugs that are derived from natural products, or that actually are natural products, include warfarin (1), penicillin (2,3), cyclosporine (4), aspirin (5,6), paclitaxel (7), fingolimod (8), and reserpine (9). Many other drugs have structures based on chemicals that occur naturally in the human body, that is, where the drugs are analogs of these chemicals. These include analogs of intermediates or final products of biosynthetic pathways. Drugs that are analogs of chemicals in biosynthetic pathways include methotrexate, cladribine, and ribavirin.

Still other drugs originated by first identifying a target cell, or target protein, and then by preparing antibodies that bind to that target. Vaccines have a similar origin. Once a target protein is identified, this target protein (or a derivative of it) can be formulated as a vaccine. Typically, vaccines take the form of the target protein derivative, called an antigen, in combination with a second compound that is an immune adjuvant.

Drugs are also derived using a screening assay and by testing hundreds or thousands of purified candidate compounds using that assay. Where the screening method is automated, the method is called high-throughput screening. The screening assay may consist of tumor cells that are cultured in vitro, where a robot determines if the candidate drug inhibits a particular enzyme in the tumor cell or if the candidate drug kills the tumor cell.

II Structures of Drugs

A knowledge of the structure of a drug to be used in a clinical trial is needed for the following reasons. First, the issue of whether a drug is hydrophobic or hydrophilic will dictate the nature of the excipient. If a drug is not water-soluble, then the excipient might need to include a solubilizing agent, such as a solvent. Second, the structure can also provide an idea of stability during long-term