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Translational Research in Biophotonics: Four National Cancer Institute Case Studies
Editor(s): Robert J. Nordstrom
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Book Description

Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce cancer incidence, morbidity, and mortality. Optical imaging in medicine is a rapidly growing field, showing promise for delivering new low-cost, point-of-care capabilities with dramatic increases in measurement sensitivity. Unfortunately, despite all of the promises offered by optical imaging, few concepts are making it through the translational pipeline from laboratory demonstration to commercialization for clinical use.

The National Cancer Institute of the National Institutes of Health focused a research program on the study of optical imaging for translational advancement into clinical applications for reduction of cancer morbidity and mortality. This book highlights the translational activities of four research groups created for this program, called the Network for Translational Research (NTR). The research leads were Lihong Wang, Eva Sevick-Muraca, Thomas D. Wang, and Christopher Contag. While detailed insight into the nature of the research accomplished at each of these centers is provided, the purpose of this text is to demonstrate that the NTR centers with their industrial partners created significant pathways along the direction of translational research, and that these pathways can now be followed by other researchers seeking to bring these ideas closer to commercial reality. This book will be useful for academic researchers interested in taking concepts and devices beyond the usual “proof-of-principle” barrier into areas concerned with good laboratory practices and good manufacturing practices in order to prepare for the translation to FDA discussions.


Book Details

Date Published: 1 May 2014
Pages: 362
ISBN: 9781628410686
Volume: PM246

Table of Contents
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Table of Contents

Preface
List of Contributors
List of Acronyms and Abbreviations

1. Introduction to Translational Research
Robert J. Nordstrom
1.1 Introduction
1.2 Translational Research in Biomedicine
1.3 Obstacles Facing Translational Research
     1.3.1 Academic infrastructure
     1.3.2 Industrial research efforts
     1.3.3 Regulatory impediments
1.4 The Network for Translational Research (NTR)
1.5 Conclusions
References

2. The NTR: A Format for Translation
Pushpa Tandon
2.1 Introduction
2.2 Initiation of NTR: Optical Imaging (NTROI) and Lessons Learned
2.3 NTR—Widening the Net: Optical Imaging in Multimodal Platforms
2.4 The Four Teams of NTR and the NTR Structure
     2.4.1 The cross-cutting cores
     2.4.2 Network governance
2.5 Regulatory Approvals: A Critical Step
2.6 Lessons Learned
2.7 Conclusions
References

3. Team Sciences and Core Resources within the NTR
Melissa B. Aldrich, John C. Rasmussen, Ali Azhdarinia, Bishnu P. Joshi, Md. Jashim Uddin, Walter J. Akers, Joseph P. Culver, Anne M. Smith, Jean-Pierre Bouchard, and Katsuo Kurabayashi
3.1 Introduction
3.2 Validation/Clinical Studies Core
3.3 Instrumentation and Industrial Relations Core
     3.3.1 V&V process during device design
     3.3.2 Phantoms
3.4 Chemistry Probes and Guided Therapies Core
3.5 Center 1: Washington University
3.6 Center 2: The University of Texas Health Science Center at Houston
3.7 Center 3: University of Michigan
3.8 Center 4: Stanford University
3.9 Information Technologies Core
3.10 Summary
3.11 Glossary of Terms
Acknowledgments
References

4. Bringing an Imaging Product into the Clinic
Paula M. Jacobs and Dwaine Rieves
4.1 Introduction
4.2 Drugs, Devices, and Combinations
     4.2.1 Drugs
     4.2.2 Devices
     4.2.3 Combination products
4.3 Clinical Trials
4.4 Good Manufacturing Practices and Quality System Regulations
     4.4.1 Manufacturing PET for clinical investigation
     4.4.2 Basic principles of manufacturing
4.5 Preclinical Safety Studies
4.6 Summary
References

5. Superlinear Clinical Translation of Photoacoustic Tomography
Todd N. Erpelding, Konstantin Maslov, Catherine Appleton, Julie A. Margenthaler, Michael D. Pashley, Jun Zou, Joseph P. Culver, Walter J. Akers, Samuel Achilefu, Dipanjan Pan, Gregory M. Lanza, and Lihong V. Wang
5.1 Clinical Problem: Invasiveness of Breast Cancer Staging
5.2 Primary Technological Solution
     5.2.1 Minimally invasive technology
     5.2.2 Safe and low-cost technology
5.3 Clinical Resources Needed and Patient Recruiting
     5.3.1 First-rate research hospitals and administrative commitment
     5.3.2 Compatibility with clinical workflow
5.4 Clinical Translation
     5.4.1 PAT-US system
     5.4.2 Preclinical SLN mapping using PAT-US
     5.4.3 Clinical SLN mapping using PAT-US
     5.4.4 Clinical challenges and system improvements
5.5 Emerging Technological Solutions
     5.5.1 3D PAT SLN mapping
     5.5.2 Parallel acoustic delay lines
     5.5.3 Molecular imaging
     5.5.4 Nanoparticle contrast agents
5.6 Conclusions
References

6. Acceleration of Translational Research: Enabling Discovery
Eva M. Sevick-Muraca
6.1 Introduction
6.2 The Connections between Fluorescence and Nuclear Imaging Techniques: The Physics, and Regulatory and Translational Pathways
     6.2.1 Nuclear imaging agents
     6.2.2 NIRF imaging agents
     6.2.3 Limiting factors: NIRF agent validation
     6.2.4 Limiting factors: NIR versus far-red and visibly excited fluorophores
     6.2.5 Limiting factors: efficient collection of fluorescent light
     6.2.6 The regulatory pathways for nuclear imaging and NIRF imaging
6.3 Discovery in Translational Research
     6.3.1 The lymphatic vasculature
6.4 Standards and Validation in Translational Research
     6.4.1 Standardization and validation of imaging devices
     6.4.2 Validated studies of imaging agent
6.5 Translating New Technologies to Meet Unmet Clinical Needs
Acknowledgments
References

7. Imaging and Biomarkers for Early Detection of Colorectal Cancer
D. Kim Turgeon, Bishnu P. Joshi, Bill R. Reisdorph, and Thomas D. Wang
7.1 Introduction
7.2 Describing the Unmet Clinical Need
     7.2.1 Identifying the clinical problem
     7.2.2 Explaining the need for new methods
     7.2.3 Defining the role for imaging
7.3 Proposing the Solution
     7.3.1 Identifying promising imaging targets
     7.3.2 Matching targets with molecular probe platform
     7.3.3 Choosing the appropriate imaging modalities
     7.3.4 Defining the multimodality imaging platforms
7.4 Recruiting the Study Team
     7.4.1 Clinical studies team
     7.4.2 Regulatory support
     7.4.3 Industrial partners
7.5 Planning to Commercialize the Technology
     7.5.1 Protecting the intellectual property
     7.5.2 Managing potential conflicts of interest
     7.5.3 Centers for Medicare & Medicaid Services
7.6 Performing the Preclinical Studies
     7.6.1 Macroscopic imaging
     7.6.2 Mesoscopic imaging
     7.6.3 Microscopic imaging
7.7 Developing the Regulatory Strategy
     7.7.1 Combining the imaging agent with the instrument
     7.7.2 GMP synthesis of the fluorescent-labeled peptide
     7.7.3 Performing the pharmacology/toxicology study
     7.7.4 Obtaining Chemistry, Manufacturing, and Controls (CMC) documentation
     7.7.5 Phase I clinical study
     7.7.6 Submitting the IND application
     7.7.7 Regulatory approval of the confocal imaging instrument
7.8 Performing the Clinical Study
     7.8.1 Peptide safety in human subjects
     7.8.2 Data Safety Monitoring Board
     7.8.3 Retention of clinical records
7.9 Commercializing the Product
     7.9.1 Articulating the technological innovation
     7.9.2 Envisioning the commercialized product
     7.9.3 Explaining the clinical value proposition
     7.9.4 Identifying competing products
     7.9.5 What are the likely markets?
     7.9.6 What are the perceived barriers to commercialization?
7.10 Conclusions and Future Directions
Acknowledgments
References

8. Using Optics to Reduce the Time and Distance between the Patient and the Diagnostic Event
Stephan Rogalla, Steven Sensarn, Bonnie L. King, Tobi L. Schmidt, Hyejun Ra, Ellis Garai, David Rimm, David Ostrov, Md. Jashim Uddin, Lawrence J. Marnett, Cristina Zavaleta, Sanjiv S. Gambhir, James M. Crawford, Jacques Van Dam, Shai Friedland, Olav Solgaard, Michael Mandella, and Christopher H. Contag
8.1 Introduction
8.2 Clinical Problems to be Solved
8.3 Technology Developed to Address Clinical Needs
     8.3.1 DAC microscope
     8.3.2 3.8-mm multispectral DAC and MEMS scanning mirrors
     8.3.3 DAC and wide-field fluorescent system: macro- and microscopic detection of fluorescent probes
8.4 Clinical Translation
     8.4.1 Instrumentation
     8.4.2 Dyes and probes
     8.4.3 Releasable probes and therapeutics
     8.4.4 Clinical applications in the GI tract
     8.4.5 Esophageal cancer
     8.4.6 Gastric cancer
     8.4.7 Colon cancer
8.5 Other Organ Systems
     8.5.1 Nonmelanoma skin cancer
     8.5.2 Brain cancers
     8.5.3 Breast cancer
8.6 Changing the Diagnostic Paradigm
     8.6.1 Emerging alternative optical tools
8.7 Conclusions: Clinical Results that Inform Development
     8.7.1 Improved work flow
     8.7.2 Ease of use versus disruptive technologies
     8.7.3 The patient, the doctor—benefits to both
References

9. Industrial Perspective of Academic Prototypes
Anne M. Smith and Sven Zuehlsdorff
9.1 Introduction
9.2 Academic–Industrial Collaboration: Opportunities for Academic Prototypes
     9.2.1 Defining prototypes
     9.2.2 Shared mission of academics and industry
     9.2.3 Contrasting academic and industrial prototypes
     9.2.4 Role of academic prototypes for industry: past and future
9.3 Overview of Industrial Commercialization Process
     9.3.1 The big picture
     9.3.2 Mitigation of risk in industry: the stage-gate approach
9.4 Establishing Academic–Industrial Collaborations
     9.4.1 Collaboration agreements
     9.4.2 Academic–industrial partnership grants
9.5 Summary and Conclusions
References

Appendix: Bringing a Product to Market
A.1 Introduction
A.2 Validation
     A.2.1 Introduction
     A.2.2 Crucial definitions
     A.2.3 General procedure for validation
     A.2.4 Specific validation needs for NTR researchers
     A.2.5 Validation resources
References
A.3 GLP Testing (21 CFR Part 58)
     A.3.1 Personnel
     A.3.2 Facilities
     A.3.3 Equipment
     A.3.4 Test facility operation
     A.3.5 Test and control articles
     A.3.6 Protocol and study conduct
     A.3.7 Records and reports
     A.3.8 Disqualification of test facilities
     A.3.9 Resources
A.4 Good Manufacturing Practices (21CFR Part 211 or 21 CFR Part 820)
A.5 Manufacturing (21 CFR Part 212 for PET Radiopharmaceuticals)
A.6 Basic Principles of Manufacturing
A.7 Clinical Studies
     A.7.1 Pre-IND or Pre-IDE meeting
     A.7.2 IND or IDE submission
     A.7.3 CRFs and SOPs
     A.7.4 IRB approval
     A.7.5 Clinical trial registration
References

Index

Preface

While the purpose of this book is to present translational research, this cannot be accomplished without providing a context in which to define and describe the process. The term translational research can mean different things to different people. Therefore, the first order of business is to adopt a working definition that will carry through this presentation. In 2005, the Translational Research Working Group of the National Cancer Institute (NCI) defined translational research using these words:

"Translational research transforms scientific discoveries arising from laboratory, clinical, or population studies into clinical applications to reduce cancer incidence, morbidity, and mortality."

By adopting this definition, we are limiting the nature of the translational research that will be discussed herein. This definition restricts translational research to the biomedical arena. Without a doubt, other areas of technology development face daunting translational research challenges, and while some of them will be unique to those technology areas, many of them overlap with the challenges seen in biomedical translation. What makes translational research of biomedical technologies unique is the fact that it must face the issues found in Title 21 CFR (Code of Federal Regulations) at almost every step. These regulations, written over the years, have been established to protect consumers from unsafe and ineffective medical designs and practices. They make the translation of drugs or medical devices significantly different from the translation that occurs in other technology sectors.

The second context placed on our discussion of translational research is the focus on biomedical optical imaging technologies. Optical imaging in medicine is a rapidly growing field, showing promise for delivering new, lowcost, point-of-care capabilities with dramatic increases in measurement sensitivity. Unfortunately, despite all of the promises offered by optical imaging, few concepts are making it through the translational pipeline from laboratory demonstration to commercialization for clinical use. There are a number of reasons for this sluggishness, not the least of which is the fact that this has not been the mission of academic research, and consequently, academic environments are not well equipped for carrying technologies through the maze of regulations imposed by 21 CFR. Most biomedical optical imaging concepts originate in academic laboratories, where there is a convergence of scientific knowledge concerning the biology of tissue and disease along with an understanding of the physics and engineering of optical interactions with tissue. Together, these skills are combined to create a wide range of innovative imaging devices based on a number of different physical principles. Such innovation serves as the "product" of the academic environment (i.e., publications) very well, but, without follow through, these discoveries remain in the academic realm. Academic studies may lead to an eventual demonstration of success in preclinical and limited clinical studies, but this still leaves the technology far from the commercial doorstep, and much farther from the eventual goal of routine medical practice. Although appreciated as a significant problem because technologies become abandoned after the feasibility demonstration and peer-reviewed publication, there has not been a mechanism available to toss promising technologies over the transom into commercialization.

Industrial research laboratories, on the other hand, are familiar with the efforts that must be taken to navigate the 21 CFR landscape and bring products to market. Not only must the industrial researcher be familiar with concepts of good laboratory practice (GLP) and good manufacturing practice (GMP) along with the many other guidelines imposed by the regulations, but they must also yield to constantly changing pressures of projected profitability from corporate forecasting. The product for these laboratories is, first and foremost, revenue-generating technologies and not, specifically, publications. In fact, publication could lead to a loss of a competitive edge and jeopardize trade secrets. Thus, the motivating stimuli are fundamentally different for the industrial researcher and the academic scientist—this lies at the heart of our failure to translate promising technologies.

The final consideration placed on our examination of translational research is to limit the biomedical optical imaging to problems in human cancers. This is a disease that presents itself in many different ways and in many different host organ sites, demonstrating change and evolution in functional as well as anatomic appearance. This is not much of a restriction, but it should be noted that imaging of cancer is very different from other biomedical imaging activities such as cardiac imaging or neuroimaging.

In the spirit of this definition of translational research, the National Cancer Institute (NCI) of the National Institutes of Health (NIH) focused a research program on the study of optical imaging for translational advancement into clinical applications for reduction of cancer morbidity and mortality. The program was called the Network for Translational Research: Optical Imaging in Multimodal Platforms. In it, researchers were challenged to combine optical imaging modalities with other clinically viable imaging methods to demonstrate either synergy with the two or more imaging methods, or equivalence of the optical method alone using the clinical imaging approach as a standard. Researchers were also required to join forces with an industrial research team(s) of their choice in order to strengthen communication between academic and industrial groups and promote translational activities in the academic environment and integration of corporate partners into the academic environment.

So, this is the context in which four academic teams studied the issues of translational research as members of a network called the Network for Translational Research, or NTR. Their scientific research was the vehicle for them to uncover and solve translational challenges. Combining separate research teams with a broad range of expertise to create a functional research collaborative network is challenging. To facilitate this collaborative effort, the NTR operated through a Steering Committee consisting of the research centers' principal investigators and selected staff from NCI. Meeting monthly by teleconference, the purpose of the Steering Committee was to uncover translational issues as they developed and to create consensus regarding solutions. In addition, working groups called Cores were created that focused on translational issues faced by the entire network, rather than on the technology issues of the individual research centers. The Cores drew their membership from each of the network centers but were independent from any control by the centers. The centers decided on five Cores at the beginning of the program. These Cores focused on:

- Standards and Compliance: Introduce the academic sites to the rigors of 21 CFR compliance.

- Validation and Clinical Studies: Guide the process of validating optical imaging technologies through clinical trials.

- Instrumentation and Industrial Relations: Serve as a liaison between academic and industrial laboratories to facilitate translational progress.

- Chemistry Probes and Guided Therapies: Focus on the translation of drugs, in the form of imaging agents, as supplemental to device translation.

- Information Technologies: Provide informatics tools to the network to facilitate the translation of imaging technologies.

As time progressed, the activities of the Standards and Compliance Core were merged into the Validation and Clinical Studies Core. The milestone accomplishment of the Standards and Compliance Core was the creation of a Handbook (see appendix) that can be used by research groups interested in approaching the FDA as a part of translational progress. With that task completed in year three, the members of that Core joined the Validation and Clinical Studies Core to continue solving translational challenges in that area.

While this book is intended to highlight the translational activities of the four NTR centers, auxiliary information helps to put those activities into perspective. After introductory remarks of Chapter 1, the second chapter provides a brief history of the NTR and introduces the four teams in the network. Chapter 3 goes into the details of the Research Support Cores, explaining how each helped to promote translational progress. Interactions with the FDA are a necessary part of translational activities in biomedical technologies, so Chapter 4 offers insight into those activities.

With the first four chapters as background material, Chapters 5 to 8 highlight each NTR center individually. Each investigator is given the opportunity to discuss translational research from the perspective of the center. Two teams were focused on gastrointestinal cancers, while the other two studied identification of sentinel lymph nodes in breast cancer and melanoma. Technical progress of the four centers has been well established in the numbers of publications and presentations produced by the centers. However, the purpose of this text is to demonstrate that the centers with their industrial partners also managed to create significant pathways along the direction of translational research, and that these pathways can now be followed by other researchers seeking to carry ideas further toward commercial reality.

Finally, the book concludes with a perspective from the industrial research laboratory. Translation can only occur when the skills of the industrial researchers are brought together with the creativity of academic scientists.

At the beginning of the NTR program, the four centers were told that their contribution to the biomedical imaging community would be judged not only by the direction and quality each team took in its scientific research, but also by the wake that they left behind as they progressed through the translational research environment. This wake contains the hundreds of peer-reviewed articles and conference proceedings that they have generated, but it also includes valuable mileposts through the translational research landscape. This book is a collection of those milestones and the saga of lessons learned.

Robert J. Nordstrom
Cancer Imaging Program, National Cancer Institute
National Institutes of Health
April 2014


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