Profile: CT Lung Nodule Volume Measurement for Primary/Regional Nodes and Metastatic Sites

QIBA v-CT Chest

Section 1: Title Page

The Radiological Society of North America (RSNA) Quantitative Imaging Biomarker Alliance (QIBA) Volumetric Computed Tomography (v-CT) Technical Committee: Proffered Protocol for Quantifying the Volumes of Solid Tumors of the Chest in Patients with Cancer

Running Title: "QIBA v-CT Chest"

Version 1.0 of 25 May 2009

Proffered by the Volumetric CT Technical Committee (in alphabetical order)

Avila R Kitware, Inc.
Buckler A (Chair) Buckler Biomedical LLC
Dorfman G (UPICT liaison) Cornell
Fenimore C (WG 1C leader) Nat Inst Standards & Technology
Ford R RadPharm, Inc.
Gottlieb R Roswell Park Cancer Center
Hayes W Bristol Myers Squibb
Hillman B Metrix, Inc.
McNitt-Gray M University California Los Angeles
Mozley PD (pharma industry co-chair) Merck & Co Inc/PhRMA
Mulshine JL Rush
Nicholson D Definiens, Inc.
O'Donnell K (IHE liaison) Toshiba
Petrick N (WG 1A leader) US Food and Drug Administration
Schwartz LH (academic co-chair)
Sullivan DC (RSNA Executive Sponsor) Duke University
Zhao B Memorial Sloan Kettering Cancer Center
Zyzwutslast affiliation of the last name on list

Acknowledgement: The v_CT Committee is deeply grateful for the remarkable support and technical assistance provided by the staff of the Radiological Society of North America, including Susan Anderson, Linda Bresolin, Joseph Koudelik, and Fiona Miller.

Suggestion for attribution: Everybody who ever made a call and/or wants to go on record as endorsing the work should be included. A list of 1,000 names doesn't seem as though it would be too long. This is going to be published on the web. If preferred, then we can list the "regulars" as "core members" or some other euphemism.

Table of Contents Page

Section 2: Executive Summary, Introduction and Background Information

The v-CT technical committee is composed of scientists representing the imaging device manufacturers, image analysis software developers, image analysis laboratories, biopharmaceutical industry, academia, government research organizations, professional societies, and regulatory agencies, among others. All work is classified as pre-competitive. A more detailed description of the v-CT group and its work can be found at the following web link: http://qibawiki.rsna.org/index.php?title=Volumetric_CT

The long-term goal of the v-CT committee is to qualify the quantification of anatomical structures with x-ray computed tomography (CT) as biomarkers. The v-CT group selected solid tumors of the chest in patients with lung cancer as its first case-in-point. The rationale for selecting lung cancer as a prototype is that the systems engineering analysis, the groundwork, profile claims documents, and roadmaps for biomarker qualification in this specific setting can serve as a general paradigm for eventually quantifying volumes in other structures and other diseases.

The specific aim of this image acquisition and processing protocol is to describe procedures that seem sufficient for quantifying the volumes of neoplastic masses in the chest that have relatively simple geometric shapes and are adequately demarcated from surrounding non-neoplastic tissues. This particular image acquisition and processing protocol is limited to masses that have measurable diameters of 10 mm or more. The profile claims document on which this protocol is based asserts that following these image acquisition and processing procedures will produce volume measures with less than 18% test-retest variability.

The protocol describes, in predominantly chronological order, procedures that are required to achieve this level of precision. At each step in the process, key terms include procedures that are (1) "acceptable", by which it is meant that anything less rigorous will likely fail to meet minimum criteria for precision and accuracy; (2) "targets", by which it is meant parameters that are most likely to meet or exceed specifications; and (3) "ideal", by which it is meant parameters that are probably the best fit-for-purpose currently available, regardless of the effort required to implement them.

The protocol describes procedures that should be universally followed in this setting, regardless of the instrument that is used to acquire the data. It also provides links to tables that list specific settings on various makes-and-models of CT scanners.

This protocol should be considered for use in the care of individual patients in conventional medical settings, as well as in clinical trials of new therapies for lung cancer. Some of these clinical settings are described in Table 1. Separate profile claims documents describe processes and procedures for quantifying the volumes of small lung nodules and other anatomical structures in different clinical settings.

Table 1: Summary of Image Processing Issues Relative to Stage of Lung Cancer

Stage	% of Cases	5-year Survival %	Imaging Focus / Therapy Focus	Imaging Tool	Issues	Thoracic Segmentation	Hi-Res
I	16	49	Primary tumor / Neo and adjuvant RX	sCT	Small cancers surrounded by air	Can be straightforward	Needed
II/III	35	15.2	Primary, hilar and mediastinal lymph nodes / Combined modality	sCT, PET	Larger tumors and nodes abut other structures	Often challenging	Optional
IV	41	3	Primary/regional nodes and metastatic sites / Chemotherapy	sCT, PET, Bone, Brain scans	Tumor response often determined outside of the chest	Often challenging	Optional

Table 1; Summary of how staging relates to lung cancer drug therapy approaches, the imaging approaches used in those stages and issues relative to the image requirements. >br />

Profile Claims (what users will be able to achieve)

Claim #1: Can create, store, retrieve images of lung tumors

Precursor: None; proven DICOM (CT Storage)

Claim #2: Can create, store, retrieve linear, area and volume measurements made on lung tumor images

Precursor: None; proven DICOM (SR Storage w Templates, e.g. Chest CAD)

Claim #3: Can create, store, and retrieve mark ups of lung tumors, i.e., region of interest (ROI) boundaries

Precursor: Need Sample Implementation
- Chest CAD polylines or New DICOM Segmentation objects (by pixel) are likely sufficient, but should try out a sample implementation to confirm (and identify key Details to require in the Profile). Possibilities for data storage include polylines, voxels, and polygons/triangles. See also Segmentation and Markup Formats

Claim #4: Can measure lung tumor volume with repeatability of 18% for tumors greater than 10mm in Longest Diameter

Rationale: For uniformly expanding cubes and solid spheres, an increase in the RECIST defined uni-dimensional Longest Diameter of a Measurable Lesion corresponds to an increase in volume of about 72%. To diagnose Progressive Disease at a change of about one half that volume, 36%, the noise needs to be less than about 18%. The claim is thus set to be "twice as sensitive as RECIST".

<What do we mean by reproducibility>

How should the repeatability be expressed? It's easier to meet % targets for larger tumors. Should we use mm3 instead? Or should we state % for a certain sized tumor? There is a description in Jim Mulshine's work that we can copy here?

Precursor: Demonstrate this accuracy and repeatability is easily achievable

Groundwork: Test-Retest measurements of FDA phantoms, i.e. very-best-case-scenario, with variability one order of magnitude less than variability in "real-life", i.e. algorithm returns variability of less than 1.5%

<Relevant Groundwork Link 2:> Test-Retest measurements of small sample of NIST cases, i.e. nearly-best-case-clinical-scenario, with variability for measurement of isolated, simple lung tumors of less than 3% (up to 4 times the noise in phantoms and less than one fifth the noise expected in real life scenarios).

<Relevant Groundwork Link 3:> Test-Retest measurements of a few well behaved masses in the MSKCC coffee break study of less than 10% between Image Set 1 and Image Set 2 of each patient studied twice in succession. This 10% threshold is somewhat capriciously based on the assumption that the precision of measurement in selected MSKCC coffee break tumors will be twice as good as that which can be achieved in most clinical trial scenarios.

Precursor: Should thought be given to revising the RECIST definitions?

Claim #5: Can retrieve and/or contribute images, measurements and markups from/to caBIG

Are we and caBIG ready to get into this now or is it OK to leave this until our next profile, e.g. volume change, when our ideas and caBIGs infrastructure are more mature/stable?

Section 3: Imaging Protocol: Overview

3.1. Utilities and Endpoints of the Imaging Protocol within the Clinical Trial

Claim: This image acquisition and processing protocol should be sufficient to quantify the volume of a solid tumor of the lung, and its longitudinal changes in volume within subjects. The protocol is otherwise agnostic to the clinical settings in which the measurements are made and the way the measurements will be used to make decisions about individual patients with cancer or new treatments for patients with cancer.

3.2. Management of Pre-enrollment Imaging Tests

The history of prior medical imaging procedures that might, or might not, be used as part of the selection criteria for enrolling patients in a clinical trial that uses this protocol is outside the scope of the QIBA v-CT committee. However, only image acquisition and processing protocols that conform to, or exceed, the minimum design specifications described in this protocol are sufficient for quantifying volumes with the precision of measurement specified in the profile claims document. In practice, this will often require "baseline" scans to be repeated according to these guidelines when the objective is to quantify longitudinal changes within subjects.

3.3. Timing of Imaging Tests within the Clinical Trial Calendar

The v-CT committee agrees with the authors of RECIST 1.1., who wrote " all baseline evaluations should be performed as close as possible to the treatment start". Otherwise, these imaging procedures are not time-sensitive. The interval between follow up scans within patients may be determined by current standards for good clinical practice (cGCP) or the rationale driving a clinical trial of a new treatment.

3.4. Management of On-protocol Imaging Performed Off-schedule

"On Protocol, Off Schedule" CT scans should be acquired, processed, and analyzed exactly like on protocol, on schedule CT scans.

3.5. Management of Off-protocol Imaging

The v-CT committee notes that other sources of information, including Off-Protocol imaging procedures, can add valuable information about the management of individual patients or the conduct of a clinical trial. However, their use is outside the scope of this image acquisition and processing protocol.

3.6. Subject Selection Criteria Related to Imaging (mainly exclusionary in nature)

There are few, if any, absolute contra-indications to the CT image acquisition and processing procedures described in this protocol.
The v-CT committee recognizes that there may be relative contra-indications to radiation exposure, e.g., in young children or pregnant women. Methods for quantifying and classifying relative risks are referenced. Otherwise, explications of radiation risks are predominantly outside the scope of work conducted by the v-CT technical committee.
The v-CT committee acknowledges that there are potential risks associated with the use of contrast material. The default recommendations for intravenous and oral contrast that follow assume there are no known contra-indications in a particular patient. The committee assumes that local standards for good clinical practice (cGCP) will be substituted for the default in cases where there are known risks, e.g., patients with chronic renal failure.

Section 4: Subject Preparation

4.1. Interval Timing (e.g., oral and/or IV intake, vigorous physical activity, timing relative to non-protocol-related medical interventions, etc.)

There are no specific patient preparation procedures for the CT scans of the chest described in this protocol. The v-CT committee acknowledges that there are specifications for other procedures that might be acquired contemporaneously, such as requirements for fasting prior to FDG PET scans or the administration of oral contrast for abdominal CT. Those timing procedures may be followed as indicated without adverse impact on these guidelines.

4.2. Specific Pre-imaging Instructions

4.2.1. Prior to Arrival

The local standard of care for acquiring CT scans may be followed. For example, patients may be advised to wear comfortable clothing, leave jewelry at home, etc.

4.2.2. Upon Arrival (including ancillary testing associated with the imaging and downstream actions relative to such testing)

Detail: Staff shall prepare the patient according to the local standard of care.
- Patients should be assessed for any removable metal objects on their bodily surfaces that will be in the field of view.
- Patient should be "comfortably positioned", in "comfortable clothes to minimize patient motion and stress (which might affect the imaging results) and any unnecessary patient discomfort.
Detail: Bladder State
- Ideal: micturation immediately prior to being placed in the gantry
- Target: empty bladder
- Acceptable: any
- The target here is purely for patient comfort.
Note: Factors that adversely influence patient positioning or limit their ability to cooperate should be recorded in the corresponding DICOM tags and case report forms, e.g., agitation in patients with decreased levels of consciousness, patients with chronic pain syndromes that limit their ability to cooperate with requirements for breath holding or remaining motionless, etc.

Section 5: Imaging Procedures: General

5.1. Imaging Agent Preparation and Specification (Contrast agent or radiopharmaceutical) The v-CT committee acknowledges that the use of intravenous contrast material is often medically indicated for the diagnosis and staging of lung cancer in many clinical settings. However, the use of contrast is not an absolute requirement for quantifying the volumes of many tumors in the chest or achieving the specific aims associated with this protocol.

5.1.1. Contrast administration: (agent, dose, route)

Ideal: Arterial phase intravenous contrast administered by power injector with measurements made under the exact same conditions every time for every patient. The same contrast agent (brand, type and concentration) should be used for every patient in a trial each time they are scanned.
Target: Same method of administration, and exact same start time of scans relative to contrast administration. Sites should use the same contrast agent (brand, type and concentration) each time they scan a particular patient.
Acceptable: Manual administration or no administration. Regardless, exactly the same contrast agents and administration procedures must be used in each examination, even if that means no intravenous contrast is ever given.

5.1.2. Contrast Dose Reduction Based On Creatinine Clearance: (renal function) Site-specific sliding scales that have been approved by local medical staffs and regulatory authorities should be used for patients with impaired renal function.

5.2. Imaging Data Acquisition

5.2.1. Subject Positioning

Detail: The following details shall be recorded, manually by the staff if necessary.

Patient Positioning

Ideal: Patients should be positioned in the exact same way for every scan, with careful attention paid to details such as the position of their upper extremities, the anterior-to-posterior curvature of their spines as determined by pillows under their backs or knees, and the lateral straightness of their spines. For patients placed in a prone position, the head should be tilted in the same direction each time.
Target: Supine/Arms Up/Head First (Mike McNitt-Gray: we actually perform thoracic scans feet first - head does not go through gantry and neither do any intravenous lines)

• Note: Target is provided as a default to drive some consistency when details of prior scans are not available.

Acceptable: any position that is consistent with prior scan, e.g., in patients who are physically unable to have their arms placed above their heads, every effort should be made to insure that the upper extremities lie on the table in the same position each time.

• Consistency is required to avoid unnecessary variance in attenuation, changes in gravity induced shape, or changes in anatomical shape due to posture, contortion, etc. When changes in position are medically unavoidable due to a change in clinical status, details should be provided.

5.2.2. Instructions to Subject During Acquisition (e.g., breathing)

Breath Hold

Ideal: Single breath hold at full inspiration
Target: Single breath hold at full inspiration
Acceptable: suspended respiration near high % of end inspiration

Rationale:

• Breath hold reduces motion, which degrades the image.

• Full inspiration inflates lungs which is necessary to separate structures and make lesion more conspicuous.

5.2.3. Timing (e.g., relative to previously administered imaging agents / enhancers; inter-time point standardization)

The time-interval between the administration of intravenous contrast and the start of the image acquisition should be determined in advance, and then maintained as precisely as possible during all subsequent examinations.

Section 6: Universal Parameters (independent of vendor, platform, and version)

6.1 Devices

In clinical settings, the v-CT committee expects that the protocol will be implemented on scanners that conform to the expectations of the Medical Device Directive Quality System and the Essential Requirements of the Medical Device Directive. These instruments should have been designed and tested for safety in accordance with IEC 601-1, as well as for ElectroMagnetic Compatibility (EMC) in accordance with the European Union’s EMC Directive, 89/336/EEC. Labeling for these requirements, as well as ISO 9001 and Class II Laser Product,should appear at appropriate locations on the product and in its literature. The scanners should be CSA compliant.

6.2 # of channels

Ideal: 64 or greater
Target: 16 or greater
Acceptable: 1 or greater

6.3 Detail: Protocol retrieval

The acquisition system shall support saving and easily calling up saved acquisition protocols.

• The running title of this image acquisition and processing protocol will be "QIBA vCT chest".

6.4 Detail: Anatomical Coverage

Scout/topogram/planning view should be acquired to insure the field of view will cover the entire lung, from above the thoracic inlet to a level just below the diaphragm.

The acquisition system shall produce images with the following characteristics:

6.5 Detail: Slice Width

Ideal: <= 1 mm
Target: 1-2.5 mm
Acceptable: <= 5 mm

• Direct component of voxel size; determines resolution along patient (z) axis

6.6 Detail: Slice interval

Ideal: contiguous or 20% overlap
Target: contiguous or 20% overlap
Acceptable: contiguous

• Gaps are not acceptable, as they may "truncate" the spatial extent of the tumor, degrade the identification of tumor boundaries, etc.

6.7 Detail: Isotropic Voxels

Ideal: yes
Target: yes
Acceptable: attempts should be made to maximize in-plane resolution and keep the reconstruction interval constant, and in no case, more than 5 mm.

• Isotropic voxels reduce the volume measurement error effect of tumor orientation (which is difficult to control)

• Requiring isotropic voxels means requiring that the same value be selected for both slice width and voxel size.

6.8 Detail: Field of View:Voxel Size

Ideal: Rib-to-rib: 0.55mm - 0.75mm
Target: Outer Thorax: 0.7mm - 0.8mm
Acceptable: Complete Thorax: 0.8 - 1.0mm

• Smaller voxels reduce partial volume effects and (likely) provide higher precision (i.e. higher spatial resolution)

• But larger voxels increase field of view and thus encompass more anatomy

6.9 Detail: Scan Plane

Ideal: 0 azimuth
Target: 0 azimuth
Acceptable: constant, so that patients with physical deformities or external hardware can be repositioned the same way during each scanning procedure.

6.10 Detail: Motion Artifact

Ideal: no artifact
Target: no artifact
Acceptable: "minimal" to the extent that motion does not degrade the ability of image analysts to detect the boundaries of target lesions

• Motion artifacts may produce false targets and distort the size of existing targets

Mike McNitt-Gray: As much as I would love to have sections 6.11 through 6.13 remain in here, I think we should remove them and save them for version 2 of this protocol; the terms "minimal" or "low" noise are vague and not helpful. I also think that specifying spatial resolution and noise targets in phantoms may be beyond what we can actually support right now, but should come out of 1C efforts.Please keep placeholders but I think we should remove for protocols we would recommend tomorrow

6.11 Detail: Noise Level

Ideal: "minimal"
Target: "low"
Acceptable: "predictable"

• Greater levels of noise may degrade segmentation by image analysis operators or automatic edge detection algorithms

6.12 Detail: Noise

Ideal: std. deviation in 20 cm water phantom < 40 HU
Target: std. deviation in 20 cm water phantom < 40 HU
Acceptable: std. deviation in 20 cm water phantom < 40 HU

• Thinner slices have much higher noise than thicker slices for a given mAs (or effective mAs) setting.

• Constant noise might be accomplished by increasing mAs for thinner slices and reducing for thicker slices.

6.13 Detail: Spatial Resolution

Ideal: 7-8 lp/cm
Target: 6-8 lp/cm
Acceptable: 6-8 lp/cm

• Resolution is the number of resolvable line-pairs per cm in a scan of an ACR resolution phantom (or equivalent)

• Higher spatial resolution is necessary to distinguish borders of tumors

• Spatial resolution is determined by scanner geometry (not under user control) and reconstruction algorithm (which is under user control.

6.14 Detail: KVP

Ideal: 120
Target: 110-130
Acceptable: 110-140, adjusted as medically necessary or medically indicated, depending on the body habitus of individual patients.

• kVp should be consistent for all scans of a patient

• kVP determines contrast between tissues and also influences noise and radiation dose

6.15 effective mAs (medium patient)

Ideal: 80 to 160 depending on body habitus
Target: 60 to 200 depending on body habitus
Acceptable: 40 to 350

• mAs should be sonsistent for all scans of a patient • effective mAs = (mA*time/pitch) • higher mAs lowers noise but increases radiation dose

6.16 Detail: Rotation Speed

Ideal: As fast as technically feasible
Target: Manufacturer's default
Acceptable: Manufacturer's default

• Faster rotation reduces the breath hold requirements and reduces the likelihood of motion artifacts

6.17 Detail: Collimation width (total nominal beam width - often not specified on scanner interface)

Ideal: 20 to 40 mm
Target: 10 to 80 mm
Acceptable: 5 to 160 mm

• Wider collimation widths can increase coverage and shorten acquisition, but can introduce cone beam artifacts which may degreade image quality

6.18 Detail: Mode (Mike McNitt-Gray: Not really sure what this refers to and is probably not consistent between scanners; suggest removal)

Ideal: best available
Target: "High Speed" and "Helical Mode"
Acceptable: Manufacturer's default

6.19 Detail: Table speed

Ideal: Table speed to yield IEC pitch value of approximately 1 and still complete thoracic scan within 10 seconds to insure a single breathold by nearly all subjects
Target: Table speed to yield IEC pitch value of approximately 1 and still complete thoracic scan within 15 seconds to insure a single breathold by vast majority of subjects
Acceptable: Table speed necessary to complete thoracic scan within 30 seconds to insure a single breathold by most subjects

Section 7: Specific Parameters (vendor, platform, and/or version-dependent-- may be contained in associated tables)

7.1. Hardware and Set-up

The tables in Appendix 1 describe the image acquisition and processing settings for a variety of scanners. These settings are recommended as targets, but it should be noted that the v-CT committee has not yet completed the process of vetting them as fit-for-purpose.

7.2. Software (if appropriate, provide as electronic file for direct implementation on to the imaging platform if appropriate)

At this time, no image analysis software packages have been submitted to the v-CT committee for vetting. The committee has briefly reviewed several packages that seem likely to eventually meet minimum standards for precision of measurement, but has not yet conducted any formal analyses. Proceedings of evaluation processes and procedures may be found on the v-CT website as they become available.

Section 8: Inherent Image Data Reconstruction / Processing (e.g., data correction, smoothing)

The acquisition system shall be able to perform reconstruction with the following parameters:

8.1 Recononstruction Kernel Characteristics

Ideal: slightly enhancing
Target: standard to enhancing
Acceptable: soft to overenhancing

8.2 Reconstruction Interval

Ideal: <=1 mm
Target: <3 mm
Acceptable: <=5 mm

8.3 Reconstruction Interval Overlap

Ideal: slightly overlapping (interval is less than or equal to reconstructed slice thickness; e.g. 5 mm thick slices, spaced 4 mm apart or 1.25 mm spaced 1 mm apart)
Target: slightly overlapping to contiguous (interval is equal to reconstructed slice thickness; e.g., 5 mm thick slices, spaced 5 mm apart or 1.25 mm spaced 1.25 mm apart)
Acceptable: contiguous reconstructions (interval equal to reconstructed slice thickness)

• Reconstructing datasets with overlap will increase the number of images and may slow down throughput, increase reading time and increase storage requirements. It should be noted that for multidetector row CT (MDCT) scanners, creating overlapping image data sets has **NO** effect on radiation exposure; this is true because multiple reconstructions having different kernel, slice thickness and intervals can be reconstructed from the same acquisition (raw projection data) and therefore no additional radiation exposure is needed.

• Decisions about overlap should consider the technical requirements of the clinical trial, including effects on measurement, throughput, image analysis time, and storage requirements.

Decisions about kernel should consider impacts on both noise and spatial resolution requirements

Section 9: Archival Requirements for Primary Source Imaging Data

9.1 Detail: Data should be archived in DICOM 3.0 format or the current version of DICOM recommended by XXX WG YY of the XXX.

9.2 De-identification / Anonymization Schema(s) to Be Used

Ideal: Imaging data for analysis at central laboratories should be de-identified prior to transfer. The de-identification software should be certified as fit-for-purpose by regulatory authorities at both the site of origin and site of receipt. All personal patient information that is not needed for achieving the specific aims of the trial should be removed. Pre-specified data, such as height, weight, and in some cases, sex, race, or age, may be retained if it has been approved for use by regulatory authorities. Quality assurance procedures must be performed by the recipient to verify that the images that will be submitted for analysis have been properly de-identified.
Target: Same as ideal
Acceptable: Data should be transferred to the "quarantine area" of a "safe harbor" for de-identification by professional research organizations or trained operators using procedures that have been certified by regulatory authorities at both the site of origin and the site of receipt. Quality assurance procedures performed by the recipient should verify that the images that will be submitted for analysis have been properly de-identified. Images that were not properly de-identified prior to receipt by the central archiving facility should be obliterated after assuring that copies conform to quality standards for patient privacy.

9.3. Archival and Transmission of Image Data 11.1. Transmission of Imaging Data from Sites to Central Archive

Ideal: electronic transmission of encrypted data over a secure network
Target: electronic transmission with a secure file transfer protocol
Acceptable: courier shipment of physical media containing electronic copies of the data

Note: The submission of films for digitization is not acceptable

9.4. Requirements for Local Retention of Imaging Data

Retention should conform to local law governing patient care or the requirements of the clinical trial, whichever is stricter in terms of retention times and retention format

9.5. Requirements for Central Management of Imaging Data and Imaging Metadata (e.g., the results of image analysis)

Get Merck Clinical Computer Validation and Quality Assurance to propose a passage that can be vetted by other pharma compaies

Section 10: Post-processing (i.e., anything not done on an acquisition platform that affects DICOM image data and/or pixel / voxel values)

None prior to importation into free standing image analysis software package

Appendices

Appendix 1. Definitions of Terms and Abbreviations
Appendix 2: Acquisition Parameters and Settings for Specific Makes & Models
Appendix 3. Imaging-associated Risks and Risk Management
Appendix 4. Reader Training
Appendix 5. Site Selection, Qualification and Protocol-specific Training

Appendix 1: Definitions of Terms and Abbreviations

Appendix 2: Acquisition Parameters and Settings for Specific Makes & Models

Acquisition Parameters and Settings for Specific Makes & Models

Appendix 3. Imaging-associated Risks and Risk Management

12.1. Radiation Dose and Safety Considerations

It is recognized that X-ray CT uses ionizing radiation and this poses some small, but non-zero risk to the patients in any clinical trial. The radiation dose to the subjects in any trial should consider the age and disease status (e.g. known disease or screening populations) of these subjects as well as the goals of the clinical trial. These should inform the tradeoffs between desired image quality and radiation dose necessary to achieve the goals of the clinical trial.

12.2. Imaging Agent Dose and Safety Considerations

12.3. Imaging Hardware-specific Safety Considerations

Appendix 4. Reader Training

Appendix 5. Site Selection, Qualification and Protocol-specific Training:

A4.1. Necessary Site Characteristics: (e.g., support infrastructure, internet capability, image de-identification and transmission capability)

A4.2. Personnel

A4.2.1. Qualifications
- 13.2.1.1. Technical
- 13.2.1.2. Physics
- 13.2.1.3. Physician
A4.2.2. Protocol-specific Training
- 13.2.2.1. Technical
- 13.2.2.2. Physics
- 13.2.2.3. Physician

A4.3. Availability of Relevant Imaging Equipment

A4.4. Baseline Quality Control Metrics and Capability for Quality Control Procedures (Pertinent to the Clinical Trial)

Section 14: Quality Control

14.1. Quality Control Associated with Individual Subject Imaging

Activity: Acquisition System Calibration

Ideal: A protocol specific calibration and QA program shall be designed consistent with the goals of the clinical trial.

This program shall include (a) elements to verify that sites are performing the specified protocol correctly, and (b) elements to verify that sites’ CT scanner(s) is (are) performing within specified calibration values. These may involve additional phantom testing that address issues relating to both radiation dose and image quality (which may include issues relating to water calibration, uniformity, noise, spatial resolution -in the axial plane-, reconstructed slice thickness z-axis resolution, contrast scale, CT number calibration and others). This phantom testing may be done in additional to the QA program defined by the device manufacturer as it evaluates performance that is specific to the goals of the clinical trial.

Target: A protocol specific calibration and QA program shall be designed consistent with the goals of the clinical trial.

This program may include (a) elements to verify that sites are performing the specified protocol correctly, and (b) elements to verify that sites’ CT scanner(s) is (are) performing within specified calibration values. These may involve additional phantom testing that address a limited set of issues primarily relating dose and image quality (such as water calibration and uniformity). This phantom testing may be done in additional to the QA program defined by the device manufacturer as it evaluates performance that is specific to the goals of the clinical trial.

Acceptable: Site staff shall conform to the QA program defined by the device manufacturer.
- 14.1.1. Phantom Imaging and/or Calibration (Performed in Association with Subject Imaging and/or per routine during the trial for QC Purposes)
- 14.1.2. Quality Control of the Subject Image and Image Data
- 14.1.3. Documentation of Phantom Imaging and Calibration

14.2. Quality Control Associated with Imaging Agent Administration

14.3. Management and Reporting of Adverse Events Associated with Imaging Agent and Enhancer Administration

14.4. Management and Reporting of Adverse Events Associated with Image Data Acquisition

14.5. Quality Control of Inherent Image Data Reconstruction / Processing

14.5.1. Universal
14.5.2. Vendor-, Platform- and/or Version-specific

14.6. Quality Control of Image Analysis and Interpretation

14.7. Site-Related Quality Control

14.7.1. Mandatory for Site-Selection (e.g., routine and periodic QC measures and documentation)
14.7.2. Mandatory to Submit Prior to Patient Accrual
14.7.3. Mandatory to Submit Periodically During the Trial

Section 15: Required Documentation

15.1. Subject preparation

15.2. Imaging agent dose calculation

15.3. Imaging agent-related

15.4. Image data acquisition-related

15.5. Inherent image data reconstruction / processing

15.6. Image analysis and interpretation

15.7. Site selection and Quality Control