Medical Imaging in Clinical Trials

Foreword\nPreface\n	References\nContents\nContributors\nPart I:\rOverview and Trial Management\n	Chapter 1: Medical Imaging Modalities\n		Introduction\n		Image Orientation\n		Planar Imaging: X-Ray Techniques\n			Radiography/X-Ray\n			Dual Energy X-Ray Absorptiometry\n		Computed Tomography\n		Magnetic Resonance Imaging\n			Diffusion Weighted Imaging\n			Magnetic Resonance Spectroscopy\n			Functional MRI\n			MRI Summary\n		Nuclear Medicine Imaging\n			Positron Emission Tomography\n			Single-Photon Emission Computed Tomography\n		Ultrasound Techniques\n			Grayscale Ultrasound\n			Doppler Ultrasound\n			Echocardiography\n			Bone Ultrasonometry\n		Radiation Dosages Among Imaging Modalities\n		Conclusion\n		References\n	Chapter 2: The Metrics and New Imaging Marker Qualification in Medical Imaging Modalities\n		Introduction\n		Discrimination or Sensitivity and Specificity\n		Precision and Accuracy\n		Reliability\n		Relevant\n		Accepted by Regulatory Agencies\n		Acceptable Cost\n		Acceptable to the Subject\n		Safe for the Subject and Operator\n		Development of New Biomarkers\n		Identification of Systematic and Random Errors\n		Conclusion\n		References\n	Chapter 3: Radiation Risks and Dosimetry Assessment\n		Introduction\n		How Do We Assess the Radiation Dose?\n		What Are the Risks?\n		What Do I Tell Participants?\n		What Will the IRB/REC Want to Know?\n		Training and Quality Assurance\n		Appendix 3.1: Units of Radiation Dose, Risk Estimates and Measurement of Radiation Dose\n		References\n	Chapter 4: Imaging Review Charters and Operational Considerations\n		Background\n			Historical Development and Use of Imaging Review Charters\n			Current Use of Imaging Charters\n		State-of-the-Art Imaging Review Charters\n			Standard Content\n			Defining the Response Criteria\n			Designing the Read\n				Reader Allocation for Oncology Trials\n					Purpose of the Global Session\n				The Eligibility Read\n				Reading for Confirmation of PD in Oncology\n			Selecting and Screening Readers\n			Reader Training/Mock Read\n			Reader Monitoring\n				Adjudication in Oncology\n		Use of the Imaging Charter in Adaptive Design Clinical Trials\n		Operational Considerations\n			How to Handle Specific Data Issues\n				Handling Missing Image Sets\n				Handling Unreadable Image Sets\n			Regulatory Compliance\n				HIPAA Compliance for Digital Image Data\n				Supporting Internal Database Audits: Electronic Signatures and Records\n		Future of Charters\n		Conclusion\n		Appendix 4.1: Consortiums Established to Help Standardize Imaging for Clinical Trials\n		References\n	Chapter 5: Defining the Radiological Blinded Read and Adjudication\n		Introduction\n		Categories of Central Reads\n			Eligibility Read\n			Efficacy and Safety Reads\n				Consensus Read\n				Paired Read, No Adjudication\n				Standard Paired Read, with Forced Adjudication\n				Standard Paired Read, Open Adjudication\n				Paired Read, Reread Then Adjudication\n				Pseudo-Paired Read and Adjudication\n				Multiple Paired Readers, Forced Adjudication\n			Progressive Disease Read in Oncology\n		Image Presentation\n			Basic Blinding\n			Blinding to Temporal Sequence\n		Incidental Findings\n		Pre-read Training and Reader Calibration\n		Conclusion\n		References\n	Chapter 6: Medical Imaging in Drug Development\n		Introduction\n		New Product Development\n		Imaging as a Biomarker\n		Key Elements for Product Approval\n		Earlier Decision Making\n		Opportunities for Imaging\n		Detection of Disease Progression\n		Do the Results of the Imaging Study Answer the Key Scientific Question?\n			Key Considerations for Successful Imaging Studies\n				Creating a Successful Imaging Team\n				Imaging Endpoints\n				Imaging Hardware\n				Image Acquisition\n				Precision\n				Statistical Considerations\n		Core Principles Pertinent to Imaging Studies\n		First in Man Studies: Role of Imaging\n		Phase II and Beyond: Scientific Considerations (Strategic and Technical)\n			Essential Studies\n			Supportive Studies\n			Nice to Have Studies\n			Potential for Future Development\n		Protocol Development\n		Regulatory Considerations\n			Considerations for Trial Design and Conduct\n			End of Phase II Meeting\n			Pre-submission Meetings\n			Advisory Board Hearing\n		Financial Considerations\n			Estimating Costs for Imaging Endpoints\n		Value of Imaging Partners\n		Operational Considerations\n		Compliance\n		Summary\n		References\n	Chapter 7: Evaluating and Working with an Imaging Core Laboratory\n		Introduction\n		Corporate Infrastructure\n		Study Design\n		Study Start-Up Activities\n		Investigational Site Training and Qualification\n		Study Conduct\n		Risk Mitigation Plan\n		Study Closeout, Analysis, and Communication\n		Metrics Champion Consortium (MCC)\n		Culture and Financial Strategy\n		Appendix 7.1: Checklist for Selecting an Imaging Core Lab\n		Reference\nPart II:\rTherapeutic Specifics of Medical Imaging\n	Chapter 8: Monitoring Responses to Therapy in Oncology\n		Introduction\n		Conventional Response Assessment Methods\n			WHO Criteria\n			RECIST\n			RECIST 1.1\n		Limitations of Conventional Response Assessment Methods\n		Revised and Modified RECIST and Beyond\n			Lymphoma\n			Mesothelioma\n			HCC and GIST\n				HCC: mRECIST for Locoregional Treatments\n				GIST: Choi’s Criteria for Targeted Therapies\n				HCC: Necrosis to Tumor Ratio\n				HCC: Choi’s Criteria for Targeted Therapies\n			NSCLC\n		Summary\n		References\n	Chapter 9: Cardiac Imaging in Clinical Trials\n		Introduction\n		Ischemic Heart Disease\n			Nuclear Medicine\n			Myocardial Stress Testing\n			Cardiac Positron Emission Tomography (PET)\n			Computed Tomography Angiography (CTA)\n			CT Angiography of Vascular Structures\n			Prognostic Implications of an Abnormal Coronary CT Angiogram (CCTA)\n			Coronary Artery Calcium (CAC) Score\n		Management of Coronary Artery Stenosis\n			Cardiac Catheterization\n			Quantitative Coronary Angiography (QCA)\n			Coronary Artery Stent Placement\n			Magnetic Resonance Imaging (MRI)\n			MRI Vascular Imaging\n			Two-Dimensional Echocardiography\n			Carotid Ultrasound\n		Imaging of the Vascular Anatomy: Intravascular Ultrasound (IVUS)\n			Methodology for IVUS\n			Applications for IVUS\n		Validating the Efficacy of New Treatments\n			Optical Coherence Tomography (OCT) in Cardiology\n		Summary and Conclusion\n		Future Directions\n		References\n	Chapter 10: Neuroimaging in Clinical Trials\n		Introduction\n		Structural Neuroimaging Techniques\n			Computed Tomography (CT)\n			Magnetic Resonance Imaging (MRI)\n		Neuroimaging Methods to Assess Function\n			Functional Magnetic Resonance Imaging (fMRI)\n			Positron Emission Tomography (PET)\n			Single-Photon Emission Computed Tomography (SPECT)\n			Magnetic Resonance Spectroscopic Imaging (MRSI)\n		Neuroimaging of Neuro-oncology\n			MRI Score for Tumor Grading\n			Response Assessment Criteria\n				World Health Organization (WHO) Criteria\n				RECIST 1.0\n				RECIST 1.1\n				Macdonald Criteria\n			Limitations of Response Criteria\n				Pseudoprogression\n				Enhancement as a Result of Therapy\n				Pseudoresponse/Pseudoregression\n				Failure to Measure Non-enhancing Tumor\n			Neuroimaging of High-Grade Gliomas\n			Metastatic Tumors\n			WHO Grade II Astrocytomas\n			Diffuse Infiltrative Low-Grade Astrocytomas\n			Non-infiltrative Low-Grade Astrocytomas\n				Pilocytic Astrocytoma\n				Pleomorphic Xanthoastrocytomas\n			Designing a Neuro-oncology Clinical Trial\n		Multiple Sclerosis (MS)\n			Clinical Markers for Multiple Sclerosis\n				EDSS, Expanded Disability Status Scale\n				MSFC, Multiple Sclerosis Functional Composite\n			Imaging of Multiple Sclerosis\n			Clinical Correlations and Role in Clinical Trials of MRI\n			MS Criteria Involving Neuroimaging\n				Poser Criteria\n				McDonald Criteria\n				Barkhof Criteria\n		Stroke\n		Alzheimer’s Disease (AD)\n		Medical Devices: Contraindications\n		References\n	Chapter 11: Imaging in Musculoskeletal, Metabolic, Endocrinological, and Pediatric Clinical Trials\n		Introduction\n		Osteoporosis\n		Rheumatoid Arthritis\n		Osteoarthritis (Degenerative Joint Disease)\n		Fracture Healing\n		Bone Marrow Disease\n		Pediatric Bone Disease\n		Endocrinology and Safety Studies\n		Summary\n		References\n	Chapter 12: Body Composition\n		Introduction\n		Modeling Body Composition\n			Two-Compartment Model\n			Three Compartment, Model 1\n			Three Compartment, Model 2 Using DXA\n			Four-Compartment Model\n			Tissue and Organ Compartment Models\n				Adipose Tissue\n				Subcutaneous Adipose Tissue (SAT)\n		Body Composition Compartments and Measures\n			Adipose Cross-Sectional Area (CSA)\n			Adipose or Organ Volume\n			Bone Mineral Content (BMC)\n			Fat Mass (FM)\n			Lean Soft Tissue Mass (LSTM)\n			Fat-Free Mass (FFM)\n			Soft Tissue Mass (STM)\n			Total Body Mass (TBM)\n			Percent Fat Mass (PCTFM)\n		Dual-Energy X-Ray Absorptiometry\n			Why Use DXA for Clinical Trials Instead of Other Body Composition Methods?\n			Special DXA Regions of Interest\n			DXA Body Composition Reference Data\n			Scanning Obese Patients with DXA\n			DXA Quality Control\n		Tissue Compartment Imaging Using CT and MRI\n			CT and MRI in Clinical Trials\n		Radiation Protection Regulations for the Use of DXA and CT\n			Dose\n		Summary\n		References\n	Chapter 13: Optical Coherence Tomography as a Biomarker in Clinical Trials for Ophthalmology and Neurology\n		Introduction\n		Basic Technology\n		What Is Normal?\n		The “So What” Question\n			Does Structure Predict Functional Impairment for the Macula?\n			The Thrombogenics Story\n		The Neuro-ophthalmology and Neurology Chronicles\n		Neurodegeneration\n		Summary\n		General Bibliography\n	Chapter 14: Nuclear Medicine: An Overview of Imaging Techniques, Clinical Applications and Trials\n		Introduction\n		Basics of Nuclear Physics\n		Nuclear Imaging Technique\n		Radiotracer in Human Studies\n		Cellular Mechanism of Radiotracers\n		Radiation Safety\n			Radiation Exposure to the Workers\n			Radiation Exposure to the Patient\n		Good Clinical Practice (GCP) and Good Manufacturing Practice (GMP)\n		Quality Control\n			Uniformity Calibration\n			Spatial Resolution\n			Spatial Linearity\n		Nuclear Imaging in Oncology\n			Brain Tumor\n			Lung Carcinoma\n			Colorectal Carcinomas\n			Lymphoma\n			Melanoma\n			Head and Neck Tumors\n			Breast Carcinoma\n			Gastroesophageal Carcinoma\n			Ovarian Carcinoma\n			Prostate Cancer\n		Nuclear Imaging in Central Nervous System\n			Dementia\n			Epilepsy\n		Nuclear Imaging in Cardiovascular System\n			Radiopharmaceuticals\n			Clinical Application\n		Nuclear Imaging in Genitourinary System\n		Nuclear Imaging in Infection and Inflammation\n			Gallium-67\n			Radiolabeled Leukocytes\n				Clinical Utility\n			Tc-99m Fanolesomab\n		Pediatric Nuclear Medicine\n		Future Trends and Outlook\n		References\n	Chapter 15: Contrast Agents in Radiology\n		Introduction\n		Groups of Contrast Agents\n		Iodinated Contrast Media\n			Osmolality\n			Iodine Content\n			Meglumine Versus Sodium Salts\n			Nonionic LOCMs\n		MR Contrast Media\n			Type of Contrast Media\n				Paramagnetic Contrast Media\n				Small-Molecular Contrast Media with Higher Molarity\n				Small-Molecular Contrast Media with Weak Protein Affinity\n				Small-Molecular Contrast Media with Stronger Protein Affinity\n				Superparamagnetic Contrast Media\n				SPIO\n				USPIO\n				Macromolecules\n				Ventilation Agents\n				Molecular or Cellular Imaging Agents\n				Outlook\n		US Contrast Media\n			US Contrast Agents for Liver Imaging\n			Contrast Mechanism\n			Outlook\n		Approval Status of Contrast Agents and Their Off-Label Use\n		Appendix 15.1: Overview of Available Nonionic, Low-osmolar, and Iso-osmolar Contrast Media and Their Physicochemical Properties\n		Appendix 15.2: Physicochemical Properties of Tissue-specific and Nonspecific MR Contrast Agents\n		Appendix 15.3: Overview of Approved and Selected Experimental MR Contrast Media with Approval Status, Distribution, and Physicochemical Properties\n		Appendix 15.4: Overview of Available US Contrast Media with Current Approval and Distribution Status\n		References\nPart III:\rThe Future of Imaging in Clinical Trials\n	Chapter 16: Pharmaceutical Industry Perspective Regarding Imaging Techniques\n		Introduction\n		Evolving Regulatory Standards\n		Evolution of Pharmaceutical Markets\n		Biomarkers\n		Imaging Biomarkers\n			Advantages of Imaging Biomarkers\n		Biomarkers and Qualification\n		Opportunity for Effective Implementation of Imaging Technology\n		Summary\n		References\nAppendix 1: FDA Draft Guidance Document – Guidance for Industry Standards for Clinical Trial Imaging Endpoints\nAppendix 2: Imaging Core Lab Lexicon\nAppendix 3: Quantitative Imaging Biomarkers Alliance (QIBA)\n	QIBA Mission\n	QIBA Modality Committees\nIndex