Biomarkers in Drug Discovery and Development E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
This book continues the legacy of a well-established reference within the pharmaceutical industry - providing perspective, covering recent developments in technologies that have enabled the expanded use of biomarkers, and discussing biomarker characterization and validation and applications throughout drug discovery and development. * Explains where proper use of biomarkers can substantively impact drug development timelines and costs, enable selection of better compounds and reduce late stage attrition, and facilitate personalized medicine * Helps readers get a better understanding of biomarkers and how to use them, for example which are accepted by regulators and which still non-validated and exploratory * Updates developments in genomic sequencing, and application of large data sets into pre-clinical and clinical testing; and adds new material on data mining, economics, and decision making, personal genetic tools, and wearable monitoring * Includes case studies of biomarkers that have helped and hindered decision making * Reviews of the first edition: "If you are interested in biomarkers, and it is difficult to imagine anyone reading this who wouldn't be, then this book is for you." (ISSX) and "...provides a good introduction for those new to the area, and yet it can also serve as a detailed reference manual for those practically involved in biomarker implementation." (ChemMedChem)
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Table of Contents
Cover
List of Contributors
Preface
Part I: Biomarkers and Their Role in Drug Development
1 Biomarkers Are Not New
Introduction
Uroscopy
Blood Pressure
Imaging
Electrocardiography
Hematology
Blood and Urine Chemistry
Fashionable “Omics”
The Future
2 Biomarkers: Facing the Challenges at the Crossroads of Research and Health Care
Introduction
Brief History of Biomarker Research, 1998–2008: The First Decade
Science and Technology Advances in Biomarker Research
Policies and Partnerships
Challenges and Setbacks
Looking Forward
References
3 Enabling Go/No Go Decisions
Understanding Risk
Decision Gates
Role of Biomarkers in Decision-Making
Efficacy Biomarkers
Safety Biomarkers
Biomarkers and Patient Selection
The Regulatory Side of Biomarkers – Validation and Qualification
Future Roles of Biomarkers in Decision-Making
References
4 Developing a Clinical Biomarker Method with External Resources: A Case Study
References
Part II: Identifying New Biomarkers: Technology Approaches
5 Imaging as a Localized Biomarker: Opportunities and Challenges
Introduction
Anatomy of an Imaging Biomarker
Quantitative Imaging Biomarkers Alliance (QIBA)
Conclusions – Challenges and Future Opportunities
References
6 Imaging for Early Clinical Drug Development: Integrating Imaging Science with Drug Research
Introduction
An Overview of Early Clinical Development
How Imaging Can Inform Early Development?
Guiding an Imaging Solution Toward Application
Conclusions and Future Directions
References
7 Circulating MicroRNAs as Biomarkers in Cardiovascular and Pulmonary Vascular Disease: Promises and Challenges
Introduction
MicroRNA Biogenesis
Detection of Extracellular miRNAs
Utility of c-miRNAs as Biomarkers in Cardiovascular Disease
Utility of c-miRNAs as Biomarkers in Pulmonary Vascular Disease
Challenges of Using c-miRNAs as Biomarkers
Conclusions and Future Perspectives
Acknowledgments
Disclosures
References
Part III: Characterization, Validation, and Utilization
8 Characterization and Validation of Biomarkers in Drug Development: Regulatory Perspective
Introduction
Regulatory Paths in Biomarker Evaluation and Qualification
Evidentiary Recommendations
Harmonization
Summary
References
9 Fit-for-Purpose Method Validation and Assays for Biomarker Characterization to Support Drug Development
Introduction
General Processes
Method Validation and Assay Application in Drug Development
Conclusions and Perspectives
Acknowledgments
References
10 Applying Statistics Appropriately for Your Biomarker Application
Introduction
Fundamentals
Practi(sti)cal Magic: Which Witch is Which?
Miscellaneous Data
Issues Specific to Specialized Fields
Summary: Quick Do's and Don'ts
References
Part IV: Biomarkers in Discovery and Preclinical Safety
11 Qualification of Safety Biomarkers for Application to Early Drug Development
Historical Background to Preclinical Safety Assessment
Limitations Faced in Preclinical Safety Assessment
Why Qualify Biomarkers?
Collaboration in Biomarker Qualification
References
12 A Pathologist's View of Drug and Biomarker Development
Suggestions for Improving Drug and Biomarker Development
Conclusions
References
13 Development of Serum Calcium and Phosphorus as Safety Biomarkers for Drug-Induced Systemic Mineralization: Case Study with the MEK Inhibitor PD0325901
Introduction
Toxicology Studies
Discussion
Safety Biomarkers
Clinical Doses and Responses
Conclusions
Acknowledgments
References
Note
14 New Markers of Kidney Injury
Introduction
New Preclinical Biomarkers of Nephrotoxiciy
Summary
References
Part V: Translating from Preclinical to Clinical and Back
15 Biomarkers from Bench to Bedside and Back – Back-Translation of Clinical Studies to Preclinical Models
Introduction
Current Immuno-Oncology Approaches – One Size Fits All? The Case of PD-L1
Cardiovascular Diseases – Heart Failure
Role of Biomarkers in Heart Failure Drug Development
The Role of Medical Devices as Tools to Back-Translate the Human Situation into Preclinical Disease Models
Metabolic Liver Diseases
Discussion
References
16 Translational Medicine – A Paradigm Shift in Modern Drug Discovery and Development: The Role of Biomarkers
Drug Targets: Historical Perspectives
Biomarkers: Utilitarian Classification
Principles of Target Selection
Summary
References
17 Clinical Validation and Biomarker Translation
Introduction
Conclusion
Acknowledgment
References
18 Predicting and Assessing an Inflammatory Disease and Its Complications: Example from Rheumatoid Arthritis
Introduction
Rheumatoid Arthritis Disease Process
Studies on Etiology and Pathogenesis as a Basis for Development of Biomarkers for Diagnosis and Prognosis in RA
Better Diagnosis by Means of Biomarkers and Genetics
Better Prognostic Tools with the Help of Biomarkers and Genetics
Biomarkers Proving Leads Concerning Effects of Treatment of Rheumatoid Arthritis
Concluding Remarks
Further Reading
Reference
19 Validating
In Vitro
Toxicity Biomarkers Against Clinical Endpoints
Introduction
In Vitro
Toxicity Biomarkers
Conclusions
Reference
Part VI: Biomarkers in Clinical Trials
20 Opportunities and Pitfalls Associated with Early Utilization of Biomarkers: A Case Study in Anticoagulant Development
Introduction
A Case Study Data with an Experimental FXa Inhibitor
Pursuing Biomarkers Beyond PT, INR, and aPTT
Conclusions
References
21 Integrating Molecular Testing into Clinical Applications
Introduction
Clinical Laboratory Regulation
Genetic Testing and Patient Privacy
Testing in Research Laboratories
Molecular Testing from Research to Clinical Application
The Role of the FDA in Molecular Testing
Reimbursement for Molecular Testing
Summary
References
Part VII: Big Data, Data Mining, and Biomarkers
22 IT Supporting Biomarker-Enabled Drug Development
A Paradigm Shift in Bio-pharmaceutical R&D
Data Integration and Management
Imaging Biomarker Data, Regulatory Compliance, and SOA
Biomarkers and Cognitive Computing
Chemical and Biomedical Literature, Patents, and Drug Safety
Genes and Proteins
Biochemical Pathways, Protein Interactions, and Drug Targets
Conclusions
Acknowledgments
References
Notes
23 Identifying Biomarker Profiles Through the Epidemiologic Analysis of Big Health Care Data – Implications for Clinical Management and Clinical Trial Design: A Case Study in Anemia of Chronic Kidney Disease
Introduction
Considerations on Epidemiologic Design and the Analysis of Big Health Care Data
Clinical Background of Anemia of CKD and Study Premises
Study Concept, Biological Rationale, and Study Design
The Biomarker Profile: Implications for Clinical Management
The Biomarker Profile: Implications for Clinical Trial Design
References
24 Computational Biology Approaches to Support Biomarker Discovery and Development
Introduction
Mapping Pathways of Diseases and Drugs Through Text Mining
Identification of Biomarkers for Patient Stratification Through Predictive Modeling
Building Translational Research Platforms Integrating Clinical, Phenotypic, and Genomic Data to Support Predictive Modeling
A Case Study Identifying Cell Line–Derived Translational Biomarkers for Predicting the Treatment Outcome to Erlotinib or Sorafenib, and Selecting Drug-Sensitive Cancer Indications
Conclusions
References
Part VIII: Lessons Learned: Practical Aspects of Biomarker Implementation
25 Biomarkers in Pharmaceutical Development: The Essential Role of Project Management and Teamwork
Introduction: Pharmaceutical Project Teams
Team Dynamics: Pharmaceutical Project Teams
Consequences of Biomarkers in Pharmaceutical Development Strategies
Project Management
Challenges Associated with Different Types of Biomarkers
Management of Logistics, Processes, and Expectations
Summary
References
26 Novel and Traditional Nonclinical Biomarker Utilization in the Estimation of Pharmaceutical Therapeutic Indices
Introduction
In Vitro Therapeutic Indices
Novel Metabonomic Biomarkers of Toxicity
Novel Transcriptomic Biomarkers
Conclusions
References
Part IX: Where Are We Heading and What Do We Really Need?
27 Ethics of Biomarkers: The Borders of Investigative Research, Informed Consent, and Patient Protection
Introduction
Biomarkers, Ethics, and Investigative Research
Population Biobanks and the Challenge of Harmonization
Informed Consent: Centrality and Inadequacy of the Ideal
Other Areas that Warrant Consideration: Commercialization of Biobanks
Science, Ethics, and the Changing Role of the Public
Public Consultation and Deliberative Democracy
Conclusions
Acknowledgments
References
Note
28 Anti-Unicorn Principle: Appropriate Biomarkers Don't Need to Be Rare or Hard to Find
Introduction
Unicorn Biomarkers
Horse Biomarkers
Mule Biomarkers
Conclusions
References
29 Translational Biomarker Imaging: Applications, Trends, and Successes Today and Tomorrow
Introduction
Yesterday's Imaging Biomarkers: Prototypes for Tomorrow
Today's Imaging Biomarkers: Successes and Failures to Leverage Future Needs
The Future Imaging Biomarker
Summary
References
Index
End User License Agreement
List of Tables
Chapter 2
Table 2.1 Major scientific contributions and research infrastructure supporti...
Table 2.2 Major international policy issues related to biomarker research.
Table 2.3 Looking ahead: implementing biomarkers in clinical care.
Chapter 3
Table 3.1 Go/no go decision gate in drug development.
Table 3.2 Example of a target product profile defining criteria required to m...
Table 3.3 Examples of safety biomarkers used in preclinical and clinical deve...
Chapter 5
Table 5.1 Comparison of strengths and limitations of clinical imaging modalit...
Table 5.2 Examples of image-based measures of biological processes that have ...
Table 5.3 Key formal definitions of terms adopted by the quantitative imaging...
Table 5.4 QIBA criteria for evaluating proposed imaging biomarker opportuniti...
Table 5.5 Definition of the stages of QIBA profile development.
Table 5.6 Current QIBA biomarker committees that are developing formal QIBA p...
Chapter 7
Table 7.1 Circulating miRNAs in cardiovascular disease.
Table 7.2 Circulating miRNAs in pulmonary vascular disease.
Chapter 10
Table 10.1 Common data transformations.
Table 10.2 Nonparametric equivalents of parametric tests.
Chapter 12
Table 12.1 The role of morphology in the diagnosis of major autoimmune diseas...
Table 12.2 FDA-approved cancer biomarkers, 2011–2016.
Table 12.3 Analysis of major autoimmune diseases by gene expression studies.
Chapter 13
Table 13.1 Summary of toxicology studies conducted with PD0325901.
Table 13.2 Mean clinical chemistry changes in male rats administered PD032590...
Table 13.3 Mean serum phosphorus and plasma 1,25-dihydroxyvitamin D in male r...
Table 13.4 Mean serum calcium and albumin in male rats administered PD0325901...
Table 13.5 Toxicity to skin and gastrointestinal tract are associated with ME...
Table 13.6 Primary target organ toxicities observed in preclinical studies.
Chapter 14
Table 14.1 Common medications associated with acute renal injury.
Table 14.2 Biomarkers of renal injury by region of specificity, onset, platfo...
Chapter 15
Table 15.1 PD-L1 assays used for patient selection.
Table 15.2 Most commonly used experimental mouse model systems in cancer immu...
Chapter 17
Table 17.1 Examples of companion diagnostics and qualified biomarkers approve...
Chapter 18
Table 18.1 Classification criteria for rheumatoid arthritis.
Table 18.2 Contribution of genetic risk factors in rheumatoid arthritis.
Chapter 20
Table 20.1
In vitro
effect of an experimental factor Xa inhibitor on absolute pr...
Table 20.2 Comparison of human recombinant thromboplastin and rabbit brain th...
Table 20.3
In vitro
effect of an experimental factor Xa inhibitor on prothrombin...
Table 20.4
In vitro
effect of an experimental factor Xa inhibitor on internation...
Table 20.5 Comparison of PT/control ratio and international normalization rat...
Table 20.6 Factor X activity and percent inhibition in plasma samples contain...
Chapter 22
Table 22.1 Mapping of DICOM imaging metadata tags into SDTM Imaging (IM) doma...
Table 22.2 Five levels of SOA maturity.
Chapter 25
Table 25.1 Success factors of a Drug Development Project Team.
Table 25.2 Biomarkers in the pharmaceutical development cycle.
Chapter 26
Table 26.1 Tiers of biomarkers.
Table 26.2 Efficacy endpoints of traditional and novel pharmacodynamic biomar...
Table 26.3 Genes commonly changed by diverse oncologic agents in rat liver.
Chapter 29
Table 29.1 Commonly employed contrast moieties or “labels” by imaging modalit...
Table 29.2 Major categories of imaging agents, common examples, and correspon...
List of Illustrations
Chapter 5
Figure 5.1 Three interrelated stages of biomarker development. For a given b...
Figure 5.2 Quantitative imaging biomarkers can provide important information...
Chapter 6
Figure 6.1 Imaging technologies need to be carefully selected in order to in...
Figure 6.2 PET examples of a drug with high brain uptake (a) and one with li...
Figure 6.3 Illustration of a radiolabeled small organic molecule (a) and an ...
Figure 6.4 Illustration of a neuroreceptor ligand (a) with high binding to s...
Figure 6.5 FDG-PET may supply results on three parameters: maximum FDG uptak...
Figure 6.6 Options are available to develop imaging methods before integrati...
Chapter 7
Figure 7.1 Biogenesis of miRNA. miRNAs are transcribed in the nucleus by RNA...
Figure 7.2 Transport of extracellular miRNA. For intracellular miRNA, one st...
Figure 7.3 Techniques for miRNA quantification. Technologies for the measure...
Figure 7.4 Challenges in defining c-miRNA biomarkers for human disease. Firs...
Chapter 9
Figure 9.1 Path from putative to confirmed mechanism of a novel biomarker th...
Figure 9.2 On- and off-target biomarkers of a specific mechanism of drug int...
Figure 9.3 Parallelism of three individual matrix lots. Each lot is represen...
Figure 9.4 Use of sample controls for trend analysis on variability. Low, mi...
Figure 9.5 Method validation specificity tests of a target biomarker (a) and...
Figure 9.6 Levey Jennings plots of (a) low and (b) high sample controls of s...
Figure 9.7 Baseline concentration distribution of TRACP5b in various patient...
Figure 9.8 Selectivity test of CTx in sera from healthy and patient populati...
Chapter 12
Figure 12.1 A comparison of the number of FDA-approved biomarkers between 20...
Figure 12.2 Graphing the relationship between the cost of drug development a...
Figure 12.3 A comparison of a battlefield with a disease (idiopathic pulmona...
Chapter 13
Figure 13.1 Chemical structure of PD0325901.
Figure 13.2 Mineralization of the aorta in a male rat administered PD0325901...
Figure 13.3 Hypothesis for the mechanism for systemic mineralization in the ...
Figure 13.4 Relationships between dose and exposure with the primary toxicit...
Chapter 17
Figure 17.1 Biomarker development pipeline. Source: Adapted from Sin et al. ...
Chapter 18
Figure 18.1 Inflamed RA joint. In healthy joints, a thin synovial membrane l...
Figure 18.2 Inflammatory cells in the RA joint. A number of immune cells hav...
Figure 18.3 Rheumatoid arthritis is a multifactorial disease. A number of pr...
Figure 18.4 Inflammatory burden. With increased accumulated inflammatory bur...
Chapter 19
Figure 19.1 Biomarkers in clinical medicine. Biomarkers of safety and effica...
Figure 19.2 Technical aspects of biomarker utility. Biomarkers must be suffi...
Chapter 20
Figure 20.1 Intrinsic and extrinsic coagulation pathways.
Chapter 21
Figure 21.1 Distribution of CLIA certificates by type in non-CLIA-exempt sta...
Chapter 22
Figure 22.1 Sequential R&D process.
Figure 22.2 Decision gates (milestones) to manage sequential R&D processes....
Figure 22.3 Parallel biomarker-enabled processes up to preclinical developme...
Figure 22.4 Healthcare & Life Sciences Standards Organizations.
Figure 22.5 Proposed IT architecture for biomarker-based clinical developmen...
Figure 22.6 Partial sample of pharmacogenomics (PG) SDTM domain.
Chapter 23
Figure 23.1 Randomized clinical trial concept – high vs. low.
Figure 23.2 Concept for this case study – fast vs. slow.
Figure 23.3 Identifying the “slow” trajectory based upon WBV hypothesis.
Figure 23.4 Incidence rates per 1000 person-years (
y-
axis) of various hemogl...
Figure 23.5 Graphical representation of the comparisons of hazard ratios bet...
Figure 23.6 Graphical representation of risk for each trajectory within each...
Figure 23.7 Mimicking the clinical trial designs (a graphical representation...
Figure 23.8 Mimicking the epidemiologic designs – incidence rates by Hgb mil...
Figure 23.9 Effects of dose escalations and right censoring (a graphical rep...
Chapter 24
Figure 24.1 Diseases and/or drug maps for drug purposing and repurposing. (a...
Figure 24.2 Method and data source evaluation using NCI-DREAM drug sensitivi...
Figure 24.3 A case study on computational supports of translational biomarke...
Chapter 25
Figure 25.1 Translational research (TMed) organizational models.
Figure 25.2 Sample Gantt chart of a drug development plan incorporating biom...
Figure 25.3 Oncology biomarker map.
Figure 25.4 Sample logistics. LC–MS/MS, liquid chromatography–mass s...
Chapter 29
Figure 29.1 Proportion (as %) of pharmaceutical and cell therapy scientific ...
Figure 29.2 Imaging prevalence (as % of total number of clinical trials) in ...
Guide
Cover
Table of Contents
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Biomarkers in Drug Discovery and Development
A Handbook of Practice, Application, and Strategy
Edited by
Ramin Rahbari, MS, MBA
Innovative Scientific Management
New York, New York
Jonathan Van Niewaal, MBA
Innovative Scientific Management
Woodbury, Minnesota
Michael R. Bleavins, PhD, DABT
White Crow Innovation
Dexter, Michigan
Second Edition
This edition first published 2020
© 2020 John Wiley & Sons Inc.
Edition History
John Wiley & Sons Inc. (1e, 2010)
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List of Contributors
Salvatore Alesci
Takeda Pharmaceuticals
Cambridge, MA
USA
Sara Assadian
PROOF Centre of Excellence
Vancouver, BC
Canada
and
University of British Columbia
Vancouver, British Columbia
Canada
Robert Balshaw
PROOF Centre of Excellence and Biomarkers in Transplantation Team
Vancouver, BC
Canada
Mats Bergstrom
Independent Consultant
Uppsala
Sweden
Sven A. Beushausen
Zoetic Pharmaceuticals
Amherst
New York, NY
USA
Michael R. Bleavins
White Crow Innovation
Dexter, MI
USA
Alan P. Brown
Novartis Institutes for Biomedical Research
Cambridge, MA
USA
Michael Burgess
University of British Columbia
Vancouver, BC
Canada
Bruce D. Car
Bristol-Myers Squibb Co.
Princeton, NJ
USA
Stephen Y. Chan
University of Pittsburgh Medical Center
Pittsburgh, PA
USA
Kay A. Criswell
Westbrook Biomarker & Pharmaceutical Consulting, LLC
Westbrook, CT
USA
Breanne Crouch
PROOF Centre of Excellence
Vancouver, BC
Canada
and
University of British Columbia
Vancouver, British Columbia
Canada
Miranda K. Culley
Center for Pulmonary Vascular Biology and Medicine, Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute
University of Pittsburgh School of Medicine
Pittsburgh, PA
USA
Ian Dews
Envestia Ltd.
Thame, Oxfordshire
UK
Andrew Dorner
Takeda Pharmaceuticals International Co.
Cambridge, MA
USA
Gregory J. Downing
Innovation Horizons, LLC
Washington, DC
USA
Robert W. Dunstan
Abbvie
Worcester, MA
USA
Giora Z. Feuerstein
United States Department of Defense
Defense Threat Reduction Agency
Fort Belvoir, VA
USA
Edward P. Ficaro
INVIA Medical Imaging Solutions
Ann Arbor, MI
USA
William R. Foster
Bristol-Myers Squibb Co.
Princeton, NJ
USA
Ross A. Fredenburg
Amathus Therapeutics, Inc.
Cambridge, MA
USA
Gregory P. Fusco
Epividian, Inc.
Chicago, IL
USA
Brian Gemzik
Bristol-Myers Squibb Co.
Princeton, NJ
USA
Federico Goodsaid
Regulatory Pathfinders
San Juan
PR USA
Michael Hehenberger
HM NanoMed
Westport, CT
USA
Nita Ichhpurani
Innovative Scientific Management
Toronto, ON
Canada
Malle Jurima-Romet
Celerion
Montreal, QC
Canada
Paul Keown
PROOF Centre of Excellence and Biomarkers in Transplantation Team
Vancouver, BC
Canada
Anthony A. Killeen
University of Minnesota
Minneapolis, MN
USA
Ji-Young V. Kim
PROOF Centre of Excellence and Biomarkers in Transplantation Team
Vancouver, BC
Canada
Lena King
Innovative Scientific Management
Guelph, ON
Canada
Lars Klareskog
Karolinska Institute
Stockholm
Sweden
Frank Kramer
Bayer AG
Wuppertal
Germany
Karen Lam
PROOF Centre of Excellence
Vancouver, BC
Canada
and
University of British Columbia
Vancouver, British Columbia
Canada
Jean W. Lee
BioQualQuan
Camarillo, CA
USA
Deanne Lister
Invicro, a KonicaMinolta Company, San Diego, CA and Department of Radiology
University of California, San Diego, Molecular Imaging Center, Sanford Consortium for Regenerative Medicine
Bin Li
Takeda Pharmaceuticals International Co.
Cambridge, MA
USA
Xiaowu Liang
ImmPORT Therapeutics
Irvine
California
Calvert Louden
Johnson & Johnson Pharmaceuticals
Raritan, NJ
USA
William B. Mattes
National Center for Toxicological Research
US FDA
Jefferson, AR
USA
Patrick McConville
Invicro, a KonicaMinolta Company, San Diego, CA and Department of Radiology
University of California, San Diego, Molecular Imaging Center, Sanford Consortium for Regenerative Medicine
Bruce McManus
PROOF Centre of Excellence
Vancouver, BC
Canada
and
University of British Columbia
Vancouver, British Columbia
Canada
Robert McMaster
PROOF Centre of Excellence and Biomarkers in Transplantation Team
Vancouver, BC
Canada
Jonathan B. Moody
INVIA Medical Imaging Solutions
Ann Arbor, MI
USA
Philip S. Murphy
GlaxoSmithKline Research and Development
Stevenage
UK
Raymond T. Ng
PROOF Centre of Excellence and Biomarkers in Transplantation Team
Vancouver, BC
Canada
Matthias Ocker
Bayer AG
Germany
Berlin
and
Charite University Medicine
Berlin
Germany
Damian O'Connell
Experimental Drug Development Centre A*STAR
Singapore
J. Fred Pritchard
Celerion
Lincoln Nebraska, NE
USA
M. Lynn Pritchard
Branta Bioscience, LLC
Littleton, NC
USA
Ramin Rahbari
Innovative Scientific Management
New York, NY
USA
Ruth A. Roberts
Apconix
Alderley Edge, Cheshire
UK
Robert R. Ruffolo
Ruffolo Consulting
Spring City, PA
USA
J. Lynn Rutkowski
Ossianix
Philadelphia, PA
USA
David Adler
Bayer AG
Germany
Berlin
Hyunjin Shin
Takeda Pharmaceuticals International Co.
Cambridge, MA
USA
Frank D. Sistare
Merck Research Laboratories
West Point, PA
USA
Scott J. Tebbutt
PROOF Centre of Excellence and Biomarkers in Transplantation Team
Vancouver, BC
Canada
William L. Trepicchio
Takeda Pharmaceuticals International Co.
Cambridge, MA
USA
Christina Trollmo
Roche Pharmaceuticals
Stockholm
Sweden
Jin Wang
Amgen, Inc.
Thousand Oaks, CA
USA
Frank L. Walsh
Wyeth Research
Collegeville, PA
USA
Yuling Wu
MedImmune
Gaithersburg, MD
USA
Mary Zacour
BioZac Consulting
Montreal, QC
Canada
Preface
Since the first edition of Biomarkers in Drug Development: A Handbook of Practice, Application, and Strategy was published in 2010, biomarkers have become even more significant, valuable, and important in the decision-making multiple criteria for the development of new drugs. In particular, previously novel biomarkers in nonclinical studies have transitioned into clinical trials. Companies and regulatory agencies have become more comfortable with the inclusion of biomarkers in ex vivo experiments with human tissues/biofluids or Phase I trials, with many early clinical trials now including patients after an additional single ascending dose study in human volunteers.
The use of biomarker technologies and strategies in pharmaceutical development remains the basis for translational medicine, improved patient stratification, and identification of underlying causes of diseases once lumped together based primarily on symptomatology. The approval rates for new drugs have also increased relative to 2010, at least partially due to judicious use of biomarkers to identify the best compounds, as well as answering the regulators' questions more specifically. Patients, regulatory reviewers, and the pharmaceutical industry are seeing safer, more efficacious, and better understood drugs to treat complex diseases. The challenges of escalating drug development costs, increasing duration of clinical development times, high rates of compound failure in Phase II and III clinical trials, blockbuster drugs coming off patent, and novel but unproven targets emerging from discovery all continue to modify the arena. These factors have pressured pharmaceutical research divisions to look for ways to reduce development costs, make better and more informed decisions earlier, reassess traditional testing strategies, and implement new technologies to improve the drug discovery and development processes. Biomarkers remain an important tool for getting new medicines to patients and helping identify molecules with unacceptable liabilities earlier in the process.
Biomarkers have proven to be valuable drug development tools that enhance target validation, thereby helping better understand mechanisms of action and enabling earlier identification of compounds with the highest potential for efficacy in humans. In gene therapy, use of animal models of disease in toxicology studies frequently allows very early monitoring of disease-related biomarkers that are known to be important in disease cause and progression, with the same biomarkers measured in the clinical trials. The biomarker endpoints can be essential for eliminating compounds with unacceptable safety risks or lack of target engagement, enabling the concept of “fail fast, fail early,” and providing more accurate or complete information regarding drug performance and disease progression. At the same time that pharmaceutical scientists are focusing on biomarkers in drug discovery and development, and clinical investigators and health care practitioners are using biomarkers increasingly in medical decision-making and diagnosis. Similarly, regulatory agencies have recognized and embraced the value of biomarkers to guide regulatory decision-making about targeting, drug safety, and efficacy. Regulatory agencies in the United States, Europe, Great Britain, Japan, and China have taken leadership roles in encouraging biomarker innovation in the industry and collaboration to identify, evaluate, and qualify novel biomarkers. Moreover, a biomarker strategy facilitates the choice of a critical path to differentiate products in a competitive marketplace.
Biomarkers continue to be a significant focus of specialized scientific meetings and extensive media coverage. The targeted use of biomarkers also is more prominent in scientific society meeting presentations to highlight new therapeutic targets, upstream and downstream applications relevant to a given disease, and as case studies describing how decision-making and compound selection were influenced. We, the coeditors, felt that updating the first edition of Biomarkers in Drug Development: A Handbook of Practice, Application, and Strategy was timely, as was the continued emphasis on practical aspects of biomarker identification and use, as well as their strategic implementation, and essential application in improving drug development approaches. We each have experience working with biomarkers in drug development, but we recognized that the specialized knowledge of a diverse group of experts was necessary to create the type of comprehensive book that is needed. Therefore, contributions were invited from authors writing chapters in the first edition, and others who are equally renowned experts in their respective fields. The contributors include scientists from academia, research hospitals, biotechnology and pharmaceutical companies, contract research organizations, and consulting firms and those from the FDA. This second edition also has included more coverage on information technology and computational influences in biomarker development and application. The result is a book that we believe will appeal broadly to pharmaceutical research scientists, clinical and academic investigators, regulatory scientists, managers, students, and all other professionals engaged in drug development who are interested in furthering their knowledge of biomarkers.
As discussed early in the book, biomarkers are not new, yet they also are continuously evolving. They have been used for hundreds of years to help physicians diagnose and treat disease. What is new is an expansion from outcome biomarkers to target and mechanistic biomarkers; the availability of “omics,” imaging, and other technologies that allow collection of large amounts of data at the molecular, tissue, and whole-organism levels; and the use of data-rich biomarker information for “translational research,” from the laboratory bench to the clinic and back. The potential and value from the clinical observations back to the bench should not be taken lightly. Improvements in data storage, computational tools, and modeling abilities provide us with the insight through the process and the ability to reverse mine even very large data sets. Later chapters are dedicated to highlighting several important technologies that affect drug discovery and development, the conduct of clinical trials, and the treatment of patients.
The book continues with invited leaders from industry and regulatory agencies to discuss the qualification of biomarker assays in the fit-for-purpose process, including perspectives on the development of diagnostics. The importance of statistics cannot be overlooked, and this topic is also profiled with a practical overview of concepts, common mistakes, and helpful tips to ensure credible biomarkers that can address their intended uses. Specific case studies are used to present information on concepts and examples of utilizing biomarkers in discovery, preclinical safety assessment, clinical trials, and translational medicine. Examples are drawn from a wide range of target-organ toxicities, therapeutic areas, and product types. It is hoped that by presenting a wide range of biomarker applications, discussed by knowledgeable and experienced scientists, readers will develop an appreciation of the scope and breadth of biomarker knowledge and find examples that will help them in their own work.
Lessons learned and the practical aspects of implementing biomarkers in drug development programs are perhaps the most critical message to convey. Many pharmaceutical companies have created translational research divisions, and increasingly, external partners, including academic and government institutions, contract research organizations, and specialty laboratories, are providing technologies and services to support biomarker programs. This is changing the traditional organizational models within industry and paving the way toward greater collaboration across sectors and even among companies within a competitive industry. Perspectives from contributing authors representing several of these different sectors are presented.
The book concludes with a perspective on future trends and outlooks on development, including increasing capabilities in data integration, privacy concerns, the reality of personalized medicine, and the addressing of ethical concerns. The field of biomarkers in drug development is evolving rapidly, and this book presents a snapshot of some exciting new approaches. By utilizing the book as a source of new knowledge, or to reinforce or integrate existing knowledge, we hope that readers will gain a greater understanding and appreciation of the strategy and application of biomarkers in drug development and become more effective decision-makers and contributors in their own organizations.
We also note with regret the passing of Dr. Mallé Jurima-Romet, our coeditor for the first edition. Although Mallé was not able to be part of the second edition of the book, her spirit and commitment to the field of biomarkers resides throughout the book. She was a champion of biomarkers and influenced many during her career.
As he has for many years, Dr. Felix de la Iglesia also directed us with advice, commentary, and mentorship. His coaching to always work with sound science, pay attention to the literature, not being afraid to go somewhere just because no one else has ventured into that territory, and to push boundaries all resonate in work. The value of his experience and critical commentary have enhanced this book.
July 2019
Ramin Rahbari
Jon Van Niewaal
Michael R. Bleavins
Part IBiomarkers and Their Role in Drug Development
1Biomarkers Are Not New
Ian Dews
Envestia Ltd., Thame, Oxfordshire, UK
Introduction
The word biomarker in its medical context is a little over 40 years old. The first ever usage of this term was by Karpetsky, Humphrey, and Levy in the April 1977 edition of the Journal of the National Cancer Institute, where they reported that the “serum RNase level … was not a biomarker either for the presence or extent of the plasma cell tumor.” Few new words have proved so popular – a recent PubMed search lists more than 810, 676 publications that use it! Part of this success can undoubtedly be attributed to the fact that the word gave a long-overdue name to a phenomenon that has been around at least since the seventh century BC, when Sushustra, the “father of Ayurvedic surgery,” recorded that the urine of patients with diabetes attracted ants because of its sweetness. However, although the origins of biomarkers are indeed ancient, it is fair to point out that the pace of progress over the first 2500 years was somewhat less than frenetic.
Uroscopy
Because of its easy availability for inspection, urine was for many centuries the focus of attention. The foundation of the “science” of uroscopy is generally attributed to Hippocrates (460–355 BC) who hypothesized that urine was a filtrate of the “humors,” taken from the blood and filtered through the kidneys, a reasonably accurate description. One of his more astute observations was that bubbles on the surface of the urine (now known to be due to proteinuria) were a sign of long-term kidney disease. Galen (AD 129–200), the most influential of the ancient Greco-Roman physicians, sought to make uroscopy more specific but, in reality, added little to the subject beyond the weight of his reputation, which served to hinder further progress in this as in many other areas of medicine.
Five hundred years later, Theophilus Protospatharius, another Greek writer, took an important step towards the modern world when he investigated the effects of heating urine, thus developing the world's first medical laboratory test. He discovered that heating urine of patients with symptoms of kidney disease caused cloudiness (in fact, the precipitation of proteins). In the sixteenth century, Paracelsus (1493–1541) in Switzerland used vinegar to bring out the same cloudiness (acid, like heat, will precipitate proteins).
Events continued to move both farther north and closer to modernity when in 1695 Frederick Deckers of Leiden in the Netherlands identified this cloudiness as resulting from the presence of albumin. The loop was finally closed when Richard Bright (1789–1858), a physician at Guy's Hospital in London, made the association between proteinuria and autopsy findings of abnormal kidneys.
The progress from Hippocrates's bubbles to Bright's disease represents the successful side of uroscopy, but other aspects of the subject now strike us as a mixture of common sense and bizarre superstition. The technique of collecting urine was thought to be of paramount importance for accurate interpretation. In the eleventh century, Ismail of Jurjani insisted on a full 24-hour collection of urine in a vessel that was large and clean (very sensible) and shaped like a bladder, so that the urine would not lose its “form” (not at all sensible). His advice to keep the sample out of the sun and away from heat continues, however, to be wise counsel even today.
Gilles de Corbeil (1165–1213), physician to King Philip Augustus of France, recorded differences in sediment and color of urine which he related to 20 different bodily conditions. He also invented the matula, or jorden, a glass vessel through which the color, consistency, and clarity of the sample could be assessed. Shaped like a bladder rounded at the bottom and made of thin clear glass, the matula was to be held up in the right (not the left) hand for careful inspection against the light. De Corbeil taught that different areas of the body were represented by the urine in different parts of the matula. These connections, which became ever more complex, were recorded on uroscopy charts that were published only in Latin, thus ensuring that the knowledge and its well-rewarded use in treating wealthy patients were confined only to appropriately educated men. To further this education, de Corbeil, in his role as a professor at the Medical School of Salerno, set out his own ideas and those of the ancient Greek and Persian writers in a work called Poem on the Judgment of Urines, which was set to music such that medical students could memorize it more easily. It remained popular for several centuries.
Blood Pressure
One of the first deviations from the usage of urine in the search for markers of function and disease came in 1555 with the publication of a book called Sphygmicae artis iam mille ducentos annos perditae & desideratae Libri V by a physician named Józef Struś (better known by his Latinized name, Iosephus Struthius) from Poznán, Poland. In this 366-page work, Struthius described placing increasing weights on the skin over an artery until the pulse was no longer able to lift the load. The weight needed to achieve this gave a crude measure of what he called “the strength of the pulse” or, as we would call it today, blood pressure.
Early attempts at quantitative measurement of blood pressure had to be made on animals rather than on human subjects because of the invasiveness of the technique. The first recorded success with these techniques dates from 1733, when the Reverend Stephen Hales, a British veterinary surgeon, inserted a brass pipe into a horse's artery and connected the pipe to a glass tube. Hales observed the blood rising in the tube and concluded not only that the rise was due to the pressure of the blood in the artery but also that the height of the rise was a measure of that pressure.
By 1847, experimental technique had progressed to the point where it was feasible to measure blood pressure in humans, albeit still invasively. Carl Ludwig inserted brass cannulas directly into an artery and connected them via further brass pipework to a U-shaped manometer. An ivory float on the water in the manometer was arranged to move a quill against a rotating drum, and the instrument was known as a kymograph (“wave-writer” in Greek).
Meanwhile, in 1834, Jules Hérisson had described his sphygmomètre, which consisted of a steel cup containing mercury, covered by a thin membrane, with a calibrated glass tube projecting from it. The membrane was placed over the skin covering an artery, and the pressure in the artery could be gauged from the movements of the mercury into the glass tube.
Although minor improvements were suggested by a number of authors over the next few years, credit for the invention of the true sphygmomanometer goes to Samuel Siegfried Karl Ritter von Basch, whose original 1881 model used water in both the cuff and the manometer tube. Five years later, Scipione Riva-Rocci introduced an improved version in which an inflatable bag in the cuff was connected to a mercury manometer, but neither of these early machines attracted widespread interest. Only in 1901, when the famous American surgeon Harvey Cushing brought back one of Riva-Rocci's machines on his return from a trip to Italy did noninvasive blood pressure measurement really take off.
Sphygmomanometers of the late nineteenth century relied on palpation of the pulse and so could only be used to determine systolic blood pressure. Measurement of diastolic pressure only became possible when Nikolai Korotkoff observed in 1905 that characteristic sounds were made by the constriction of the artery at certain points in the inflation and deflation of the cuff. The greater accuracy allowed by auscultation of these Korotkoff sounds opened the way for the massive expansion in research works on blood pressure that characterized the twentieth century.
Imaging
To physicians keen to understand the hidden secrets of the human body, few ideas have been more appealing than the dream of looking through the skin to examine the tissues beneath. The means for achieving this did not appear until a little over a century ago and then very much by accident. On the evening of 8 November 1895, Wilhem Roentgen, a German physicist working at the University of Würzburg, noticed that light was coming from fluorescent material in his laboratory and worked out that this was the result of radiation escaping from a shielded gas discharge tube with which he was working. He was fascinated by the ability of this radiation to pass through apparently opaque materials and promptly set about investigating its properties in more detail. While conducting experiments with different thicknesses of tinfoil, he noticed that if the rays passed through his hand, they cast a shadow of the bones.
Having seen the potential medical uses for his new discovery, Roentgen immediately wrote a paper entitled “On a new kind of ray: a preliminary communication” for the Würzburg Physical Medical Society, reprints of which he sent to a number of eminent scientists with whom he was friendly. One of these, Franz Exner of Vienna, was the son of the editor of the Vienna Presse, and hence the news was published quickly, first in that paper and then across Europe. Whereas we are inclined to believe that rapid publication is a feature of the Internet age, the Victorians were no slouches in this matter, and by 24 January 1896, a reprint of the Würzburg paper had appeared in the London Electrician, a major journal able to bring details of the invention to a much wider technical audience.
The speed of the response was remarkable. Many physics laboratories already had gas discharge tubes, and, within a month, physicists in a dozen countries were reproducing Roentgen's findings. Edwin Frost produced an X-ray image of a patient's fractured wrist for his physician brother, Gilmon Frost, at Dartmouth College in the United States, while at McGill University in Montreal, John Cox used the new rays to locate a bullet in a gunshot victim's leg. Similar results were obtained in cities as far apart as Copenhagen, Prague, and Rijeka in Croatia. Inevitably, not everyone was initially quite so impressed; The Lancet of 1 February 1896, expressed considerable surprise that the Belgians had decided to bring X-rays into practical use in hospitals throughout the country! Nevertheless, it was soon clear that a major new diagnostic tool had been presented to the medical world, and there was little surprise when Roentgen received a Nobel Prize in Physics in 1901.
Meanwhile, in March 1896, Henri Becquerel, Professor of Physics at the Muséum National d'Histoire Naturelle in Paris, while investigating Roentgen's work, wrapped a fluorescent mineral, potassium uranyl sulfate, in photographic plates and black material in preparation for an experiment requiring bright sunlight. However, a period of dull weather intervened, and, prior to performing the experiment, Becquerel found that the photographic plates were fully exposed. This led him to write this: “One must conclude from these experiments that the phosphorescent substance in question emits rays which pass through the opaque paper and reduce silver salts.” Becquerel received a Nobel Prize, which he shared with Marie and Pierre Curie, in 1903, but it was to be many years before the use of spontaneous radioactivity reached maturity in medical investigation in such applications as isotope scanning and radioimmunoassay.
The use of a fluoroscopic screen on which X-ray pictures are to be viewed was implicit in Roentgen's original discovery and soon became part of the routine equipment not only of hospitals but even of shoe shops, where large numbers of children's shoe fittings were carried out in the days before the true dangers of radiation were appreciated. However, the greatest value of the real-time viewing approach emerged only following the introduction of electronic image intensifiers by Philips in 1955.
Within months of the introduction of planar X-rays, physicians were asking for a technique that would demonstrate the body in three dimensions. This challenge was taken up by several scientists in different countries, but because of the deeply ingrained habit of reviewing only the national, not the international, literature, they remained ignorant of each other's progress for many years.
Carl Mayer, a Polish physician, first suggested the idea of tomography in 1914. André-Edmund-Marie Bocage in France, Gustav Grossmann in Germany, and Allesandro Vallebona in Italy all developed the idea further and built their own equipment. George Ziedses des Plantes in the Netherlands pulled all these strands together in the 1930s and is generally considered the founder of conventional tomography.
Further progress had to wait for the development of powerful computers, and it was not until 1972 that Godfrey Hounsfield, an engineer at EMI (EMI Records Ltd., a British Transnational conglomerate), designed the first computer-assisted tomographic device, the EMI scanner, installed at Atkinson Morley Hospital, London, an achievement for which he received both a Nobel Prize and a knighthood.
Parallel with these advances in X-ray imaging were ongoing attempts to make similar use of the spontaneous radioactivity discovered by Becquerel. In 1925, Herrman Blumgart and Otto Yens made the first use of radioactivity as a biomarker when they used bismuth-214 to determine the arm-to-arm circulation time in patients. Sodium-24, the first artificially created biomarker radioisotope, was used by Joseph Hamilton to investigate electrolyte metabolism in 1937.
Unlike X-rays, however, radiation from isotopes weak enough to be safe was not powerful enough to create an image merely by letting it fall on a photographic plate. This problem was solved when Hal Anger of the University of California, building on the efficient γ-ray capture system using large flat crystals of sodium iodide doped with thallium developed by Robert Hofstadter in 1948, constructed the first gamma camera in 1957.
The desire for three-dimensional images that led to tomography with X-rays also influenced radioisotope imaging and drove the development of single-photon-emission computed tomography (SPECT) by David Kuhl and Roy Edwards in 1968. Positron-emission tomography (PET) also builds images by detecting energy given off by decaying radioactive isotopes in the form of positrons that collide with electrons and produce γ-rays that shoot off in nearly opposite directions. The collisions can be located in space by interpreting the paths of the γ-rays, and this information is then converted into a three-dimensional image slice. The first PET camera for human studies was built by Edward Hoffman, Michael Ter-Pogossian, and Michael Phelps in 1973 at Washington University. The first whole-body PET scanner appeared in 1977.
Radiation, whether from X-ray tubes or from radioisotopes, came to be recognized as having dangers both for the patient and for personnel operating the equipment, and efforts were made to discover media that would produce images without these dangers. In the late 1940s, George Ludwig, a junior lieutenant at the Naval Medical Research Institute in Bethseda, Maryland, undertook experiments using industrial ultrasonic flaw detection equipment to determine the acoustic impedance of various tissues, including human gallstones surgically implanted into the gallbladders of dogs. His observations were detailed in a 30-page project report to the Naval Medical Research Institute dated 16 June 1949, now considered the first report of its kind on the diagnostic use of ultrasound. However, a substantial portion of Ludwig's work was considered classified information by the Navy and was not published in medical journals.
Civilian research into what became the two biggest areas of early ultrasonic diagnosis – cardiology and obstetrics – began in Sweden and Scotland, respectively, both making use of gadgetry initially designed for shipbuilding. In 1953, Inge Edler, a cardiologist at Lund University, collaborated with Carl Hellmuth Hertz, a graduate student in the department of nuclear physics who was familiar with using ultrasonic reflectoscopes for nondestructive materials testing, and together they developed the idea of using this method in the field of medicine. They made the first successful measurement of heart activity on 29 October 1953, using a device borrowed from Kockums, a Malmö shipyard. On 16 December of the same year, the method was used to generate an echo encephalogram. Edler and Hertz published their findings in 1954.
At around the same time, Ian Donald of the Glasgow Royal Maternity Hospital struck up a relationship with boilermakers Babcock & Wilcox in Renfrew, where he used their industrial ultrasound equipment to conduct experiments assessing the ultrasonic characteristics of various in vitro preparations. With fellow obstetrician John MacVicar and medical physicist Tom Brown, Donald refined the equipment to the point where it could be used successfully on live volunteer patients. These findings were reported in The Lancet on 7 June 1958, as “Investigation of abdominal masses by pulsed ultrasound.”
Nuclear magnetic resonance (NMR) in molecules was first described by Isidor Rabi in 1938. His work was followed up eight years later by Felix Bloch and Edward Mills Purcell, who, working independently, noticed that magnetic nuclei such as hydrogen and phosphorus, when placed in a magnetic field of a specific strength, absorb radio-frequency energy, a situation described as being “in resonance.”
For the next 20 years, NMR found purely physical applications in chemistry and physics, and it was not until 1971 that Raymond Damadian showed that the nuclear magnetic relaxation times of different tissues, especially tumors, differed, thus raising the possibility of using the technique to detect disease. Magnetic resonance imaging (MRI) was first demonstrated on small test tube samples in 1973 by Paul Lauterbur, and in 1975 Richard Ernst proposed using phase and frequency encoding and the Fourier transform, the technique that still forms the basis of MRI.
The first commercial nuclear magnetic imaging scanner allowing imaging of the body appeared in 1980 using Ernst's technique, which allowed a single image to be acquired in approximately five minutes. By 1986, the imaging time was reduced to about five seconds without compromising on image quality. In the same year, the NMR microscope was developed, which allowed approximately 10-mm resolution on approximately 1-cm samples. In 1993, functional magnetic resonance imaging (fMRI) was developed, thus permitting the mapping of function in various regions of the brain.
Electrocardiography
Roentgen's discovery of X-rays grew out of the detailed investigation of electricity that was a core scientific concern of the nineteenth century, and it is little surprise that investigators also took a keen interest in the electricity generated by the human body itself. Foremost among these was Willem Einthoven. Before his days, although it was known that the body produced electrical currents, the technology was inadequate to measure or record them with any sort of accuracy. Starting in 1901, Einthoven, a professor at the University of Leiden, conducted a series of experiments using a string galvanometer. In his device, electric currents picked up from electrodes on the patient's skin passed through a thin filament running between very strong electromagnets. The interaction of the electric and magnetic fields caused the filament or “string” to move, and this was detected by using a light to cast a shadow of the moving string onto a moving roll of photographic paper.
It was not, at first, an easy technique. The apparatus weighed 600 lb, including the water circulation system essential for cooling the electromagnets, and was operated by a team of five technicians. Over the next two decades, Einthoven gradually refined his machine and used it to establish the electro-cardiographic (ECG) features of many different heart conditions, work that was eventually recognized with a Nobel Prize in 1924.
