Overview
Clinical trial sponsors face many challenges when medical imaging is used to evaluate the safety and efficacy of new medical treatments. These challenges are even more significant when the treatment is being developed for rare diseases. Medical imaging plays an important role in these trials as it provides a non-invasive way to assess treatment response.
As a requirement, most rare disease clinical trials are multicentre, and often multinational for sufficient patient recruitment, even in phase I and II trials. This can challenge clinical study protocol harmonization, the selection of appropriate biomarkers, ethical review, site IRB approval, indemnity, organization of clinical services, standards of care, and cultural diversity.
And, most diagnoses classified as rare diseases affect numerous body systems. It’s not unusual for a patient with a rare disorder to have symptoms and/or underlying disease that affects their cardiovascular, neurological, and respiratory systems, among others. As a result, the sponsor’s selected imaging partner should possess broad expertise across all therapeutic areas and a thorough understanding of the imaging modalities typically used across each rare disease and body system.
Additionally, as there are not many people living with the diagnosis, finding patients and keeping them engaged in clinical trials is critical. Trial sponsors can’t risk a patient dropping out of a study because imaging processes were not performed correctly (i.e, requiring the patient to repeat scans, etc.) or the imaging analysis is unreliable.
Significant progress has been made in our understanding of the biological basis of disease mechanism for rare diseases. This has been possible with the use of novel laboratory, analytical, and imaging techniques combined with the expertise and hard work of scientists and physicians taking care of these patients.
Leveraging the expertise of these scientists and physicians is important while designing and executing rare disease clinical trials.
For these and many other reasons, trial sponsors need an imaging provider with a combination of robust, proven processes, extensive experience, and far-reaching scientific expertise for medical imaging to be used effectively and reliably during the clinical development of rare disease treatments.
CASE STUDY – HOCM
Background
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease in the US, with an estimated prevalence of 1 in 500. HCM is a chronic, progressive disease which over time results in tissue remodeling characterized histologically by myocyte hypertrophy and disarray, microvascular remodeling, and fibrosis. Two HCM types are obstructive HCM (oHCM or HOCM) and non-obstructive HCM that are recognized based on the presence or absence of obstruction of the left ventricular outflow tract (LVOT).
Imaging in HOCM
Various imaging modalities can be used to assess cardiac structure and function, the presence and severity of LVOT obstruction and tissue characteristics. Transthoracic echocardiography and cardiac MRI (CMR) remain the imaging modalities of choice in the diagnosis and clinical management of HOCM. In clinical trials, echocardiography and CMR can support eligibility criteria and efficacy endpoints.
Echocardiography
Echocardiography is a non-invasive imaging modality that has high diagnostic accuracy and is considered one of the most commonly performed imaging tests to provide valuable information on the key features of HOCM. Echo is widely available and relatively inexpensive, making it attractive for collection of imaging data across multiple investigator sites participating in clinical trials. It can provide great insight on cardiac structure and function in patients with HOCM such as Left Ventricular (LV) myocardial thickness, changes in LV ejection fraction (LVEF), and LVOT peak pressure gradients.
Cardiac MRI
CMR is valuable in evaluating the disease severity and characterizing the morphological and functional pathology of HOCM.
Standard CMR images in cine mode can reliably assess cardiac structure and function, e.g., LV or left atrial (LA) volumes, LV wall thickness. Advanced CMR techniques can provide quantitative assessment in pathological changes due to HOCM at a cellular level. Late gadolinium (Gd) enhancement (LGE) imaging is used to quantify myocardial fibrosis mass. CMR methods such as T1 and T2 mapping can show myocardial injuries related to HOCM without using a contrast agent. T1 mapping with Gd-based contrast is utilized to measure the extracellular volume fraction which is elevated due to cellular hypertrophy.
Study Implementation
Calyx Medical Imaging supported a Phase III clinical trial in which the sponsor was evaluating a new treatment for symptomatic HOCM. The clinical trial included 15 sites with over 130 screened and 81 enrolled subjects. Both echocardiography and CMR were included to support eligibility and efficacy assessments in the HOCM clinical trials.
Echocardiography was the modality of choice to screen patients, meet study primary and secondary endpoints, and support dose titration. The imaging protocol consisted of echo images obtained at rest and with Valsalva maneuvers which made the image acquisition complex. To ensure harmonization of all incoming imaging data, the Calyx Medical Imaging team worked with sites to train the sonographers on all aspects of image acquisition and patient preparation.
All echo images were analyzed by independent reviewers (cardiologists) who were trained on the study-specific image analysis protocol. To maintain independent reads in a standardized manner, the Calyx study team monitored reviewer performance throughout the study, making sure that all readers adhered to the review assessment criteria and maintained reader-to-reader variability at an acceptable level. All resulting data was checked by the Calyx team for accuracy and completeness prior to reporting.
CMR supported the trial’s secondary and exploratory endpoints, having been used to assess cardiac structure and function, myocardial fibrosis, and extracellular volume fraction. These CMR assessments required a complex CMR acquisition protocol with both standardized and novel CMR imaging sequences. Calyx developed a customized image acquisition protocol for this study. Because of the highly complex nature of the acquisition protocol and to maximize the consistency and quality of CMR images across all participating sites, Calyx’s Scientific and Medical team worked closely with each site to optimize the CMR protocol specific to the site’s scanner and reviewed the quality of each CMR sequence in detail.
As the clinical trial included different types of CMR assessments and all assessments required contour placement, we streamlined a workflow to optimize the usage of the reviewers’ time and minimize reader variability. To ensure the accuracy of CMR data review, Calyx identified and recruited reviewers/cardiologists who are experts in the field, conducted thorough reviewer training on the assessment criteria, and continued monitoring reviewer performance.
Results
Site qualification and all baseline imaging were successfully completed for echocardiography and CMR. The success of the site initiation/qualification process resulted from rigorous image quality checks of test transfer from participating investigator sites, site communication, and query management.
Calyx Medical Imaging successfully supported all subject enrollments, providing independent verification of specific imaging-based inclusion/exclusion criteria using echocardiography with a short turn-around-time. At the time of this writing, the sponsor had concluded patient enrollment and recognized Calyx’s expertise and diligence in delivering timely independent analysis results. The sponsor continues to rely on Calyx Medical Imaging for the image acquisition and review that will support the study’s primary efficacy endpoint.
Calyx Experience in Rare Disease
Overview
Clinical trial sponsors face many challenges when medical imaging is used to evaluate the safety and efficacy of new medical treatments. These challenges are even more significant when the treatment is being developed for rare diseases. Medical imaging plays an important role in these trials as it provides a non-invasive way to assess treatment response.
As a requirement, most rare disease clinical trials are multicentre, and often multinational for sufficient patient recruitment, even in phase I and II trials. This can challenge clinical study protocol harmonization, the selection of appropriate biomarkers, ethical review, site IRB approval, indemnity, organization of clinical services, standards of care, and cultural diversity.
And, most diagnoses classified as rare diseases affect numerous body systems. It’s not unusual for a patient with a rare disorder to have symptoms and/or underlying disease that affects their cardiovascular, neurological, and respiratory systems, among others. As a result, the sponsor’s selected imaging partner should possess broad expertise across all therapeutic areas and a thorough understanding of the imaging modalities typically used across each rare disease and body system.
Additionally, as there are not many people living with the diagnosis, finding patients and keeping them engaged in clinical trials is critical. Trial sponsors can’t risk a patient dropping out of a study because imaging processes were not performed correctly (i.e, requiring the patient to repeat scans, etc.) or the imaging analysis were unreliable.
Significant progress has been made in our understanding of the biological basis of disease mechanism for rare diseases. This has been possible with the use of novel laboratory, analytical, and imaging techniques combined with the expertise and hard work of scientists and physicians taking care of these patients. Leveraging the expertise of these scientists and physicians is important while designing and executing rare disease clinical trials.
For these and many other reasons, trial sponsors need an imaging provider with a combination of robust, proven processes, extensive experience, and far-reaching scientific expertise for medical imaging to be used effectively and reliably during the clinical development of rare disease treatments.
Case Study – EoE
Background
Eosinophilic esophagitis (EoE) is a chronic, allergic inflammatory disease of the esophagus that occurs when eosinophil (a type of white blood cell) accumulates in the esophagus. The elevated number of eosinophils cause injury and inflammation to the esophagus, causing difficulties with eating or swallowing. Long-term consequences potentially result in poor growth and/or chronic pain. Both genetic and environmental factors are thought to play a role in the disease pathogenesis that impacts as much as 22.7 per 100,000 people worldwide, primarily adolescents and adults younger than 50 years.
Imaging in EOE
In EoE clinical trials, medical imaging is one of the key diagnostic tests used to screen subjects. Endoscopy video is the imaging modality of choice for the diagnosis of EoE, which makes EOE clinical trials uniquely complex. The video review of endoscopy in EoE studies requires special training of gastroenterologists, consensus agreement, and significant clinical experience in reading endoscopy videos, specifically for the assessment criteria EREFS (Edema, Rings, Exudate, Furrows, Stricture). Additionally, maintaining high quality video acquisition across global investigative sites is a unique challenge of EoE trials, as the endoscopy procedure is largely dependent on the endoscopist’s expertise and experience.
The EREFS guidelines aim to standardize a dependable way to quantify a diagnosis of EoE. While reproducibility is the goal of these guidelines for EoE in clinical trials and the clinic, there still exist challenges associated with getting experts to agree on the analysis in some cases.
Minimizing reader discordance and central-site reader discordance is one of the challenges in imaging clinical studies. At Calyx, we have developed a comprehensive reader selection and training program to harmonize the central review process for EoE studies and other rare disease indications. This program is enhanced periodically based on lessons learned from current studies as well as integrating feedback from expert readers.
Study Implementation
Calyx Medical Imaging played a vital role in multiple phase 2/3 EoE studies being conducted by a clinical trial sponsor seeking regulatory approval for an EoE treatment. The imaging data was critical to the sponsor’s success as it supported the studies’ key goal to enrich the EoE patient population in the study. To ensure the accuracy of the imaging reads, Calyx identified and recruited world-class gastroenterologists to participate as independent reviewers as part of the central read model.
Calyx established standardized guidelines for trial sites to utilize and follow, specifically regarding subject preparation, esophagus insufflation, and insertion/withdrawal rates. Furthermore, through collaborative efforts of peer-to-peer communications from the central reader to site investigator and facilitated by the Calyx Scientific and Medical team, we further enhanced overall study quality to minimize central-site discordance and improve longitudinal endoscopy acquisitions for the global trial.
Calyx Medical Imaging was also responsible for supporting assessment of all proximal and distal esophageal features and providing overall scores according to EREFS criteria by implementing a double read with adjudication read model. Continuous monitoring of reader performance through intra- and inter-reader agreement rates ensured the highest possibility of reproducibility throughout the study. Moreover, if there was discordance in the scoring of EoE cases, independent reviewer consensus meetings facilitated discussions between the readers and ensured the scoring criteria was applied consistently. These sessions emulated clinical practice in a trial setting by culminating in a final decision based on consensus agreement between all independent reviewers, leaving the sponsor highly satisfied
Results
Calyx’s Medical Imaging management of a comprehensive EoE training program for internal stakeholders and partners, led by internal scientific expertise and strong collaboration with KOLs delivered reliable imaging data demonstrating the efficacy of the sponsor’s compound. Calyx’s expertise was integral to the study’s success and subsequent regulatory approvals.
Calyx Experience in Rare Disease
Overview
Clinical trial sponsors face many challenges when medical imaging is used to evaluate the safety and efficacy of new medical treatments. These challenges are even more significant when the treatment is being developed for rare diseases. Medical imaging plays an important role in these trials as it provides a non-invasive way to assess treatment response.
As a requirement, most rare disease clinical trials are multicentre, and often multinational for sufficient patient recruitment, even in phase I and II trials. This can challenge clinical study protocol harmonization, the selection of appropriate biomarkers, ethical review, site IRB approval, indemnity, organization of clinical services, standards of care, and cultural diversity.
And, most diagnoses classified as rare diseases affect numerous body systems. It’s not unusual for a patient with a rare disorder to have symptoms and/or underlying disease that affects their cardiovascular, neurological, and respiratory systems, among others. As a result, the sponsor’s selected imaging partner should possess broad expertise across all therapeutic areas and a thorough understanding of the imaging modalities typically used
across each rare disease and body system.
Additionally, as there are not many people living with the diagnosis, finding patients and keeping them engaged in clinical trials is critical. Trial sponsors can’t risk a patient dropping out of a study because imaging processes were not performed correctly (i.e, requiring the patient to repeat scans, etc.) or the imaging analysis were unreliable.
Significant progress has been made in our understanding of the biological basis of disease mechanism for rare diseases. This has been possible with the use of novel laboratory, analytical, and imaging techniques combined with the expertise and hard work of scientists and physicians taking care of these patients. Leveraging the expertise of these scientists and physicians is important while designing and executing rare disease clinical trials.
For these and many other reasons, trial sponsors need an imaging provider with a combination of robust, proven processes, extensive experience, and far-reaching scientific expertise for medical imaging to be used effectively and reliably during the clinical development of rare disease treatments.
Background
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease characterized by scarring (fibrosis) of lung tissue, resulting in reduced intake of oxygen. It is a rare disease of unknown cause that affects 13 to 20 out of every other 100,000 people, primarily adults.
In IPF clinical trials, medical imaging is one of the key diagnostic tests used to screen subjects. High-resolution CT (HRCT) is the imaging modality of choice for the diagnosis of IPF. In some cases, when HRCT diagnosis is not conclusive, a review of lung biopsy tissue by a pathologist may be required to confirm the diagnosis of IPF. This requirement makes IPF clinical trials uniquely complex. The imaging review of chest HRCT in IPF studies requires special training of radiologists and significant clinical experience in reading lung HRCT scans.
The same is true for pathology.
Additionally, there are published guidelines by scientific experts and societies that are used by radiologists and pathologists for the review of images and biopsy specimens. These guidelines allow a harmonized and standardized way to confirm a diagnosis of IPF. While these guidelines are aimed at standardizing the diagnosis of IPF in clinical trials and the clinic, there still exist challenges associated with getting experts to agree on the diagnosis in some cases.
Minimizing reader discordance and central-site reader discordance is one of the challenges in imaging clinical studies. At Calyx, we have developed a comprehensive reader selection and training program to harmonize the central review process for IPF studies and other rare disease indications. This program is enhanced periodically based on lessons learned from current studies.
Study Implementation
Calyx Medical Imaging played a vital role in multiple phase 2/3 IPF studies being conducted by a clinical trial sponsor seeking regulatory approval for the first-ever treatment of IPF. The imaging data was critical to the sponsor’s success as it supported the studies’ key goal to enrich the IPF patient population in the study. To ensure the accuracy of the imaging reads, Calyx identified and recruited world-class radiologists and pathologists to participate as independent reviewers as part of the central read model.
Calyx Medical Imaging was responsible for supporting two data streams during these studies, i.e. radiology and pathology, which required a unique set of scientific and operational expertise. The two data streams required logistics expertise since the data came in through two different workflows and were routed to different sets of readers. While the data streams were unique, the final decision reported to the sites required a combination of
assessments from both data streams.
Moreover, if there was discordance in the diagnosis of IPF between radiologists and pathologists, a hospitalstyle multi-disciplinary discussion (MDD) session was arranged virtually (vMDD), to facilitate discussion between the readers and an independent clinician. The goal of this session was to make a final decision based on consensus between all the parties. The latter was very well received by the investigators since it emulated clinical practice in a trial setting.
Results
Calyx’s management of multiple data streams, comprehensive IPF training program for internal stakeholders and partners, and reporting of unified results, combined with internal scientific expertise and strong collaboration with KOLs led to the delivery of reliable imaging data that demonstrated the efficacy of the compound and was key to the success of these studies and their subsequent regulatory approvals.
Calyx Experience in Rare Disease Studies
Calyx Medical Imaging’s experience is drawn from managing over 2,600 trials to date which include more than 4.4 million images from roughly 155,000 sites globally. Within this experience is our management of over 170 rare disease trials, which have led to the approval of over 20 indications classified as rare diseases.
Calyx Medical Imaging is a leading imaging core lab with the experience and ability to provide a wide range of services involving neuroimaging in clinical trials. Calyx Imaging’s CNS group understands the unique and custom requirements of neurooncology trials and has the flexibility, creativity, bandwidth, and understanding in place to effectively manage and support these clinical trials.
White Paper
Overview
Calyx Medical Imaging is a leading imaging core lab with the experience and ability to provide a wide range of services involving neuroimaging in clinical trials. Calyx Medical Imaging’s CNS group understands the unique and custom requirements required of Multiple Sclerosis trials and have the flexibility, creativity, bandwidth, and understanding already in place to effectively manage and support these clinical trials.
Case Study
A significant portion of our CNS experience is in Multiple Sclerosis (MS). For MS studies, we recommend conventional MRI sequences (T1, T1 post gadolinium, FLAIR and T2) for MS lesion evaluation (lesion counts and lesion volume). From the T1 sequence brain volume assessments such as total brain volume/brain volume change, grey matter volume, white matter volume, and CSF (cerebrospinal fluid) volume can be derived. Calyx can support further exploratory measures analyzed on Magnetization Transfer Imaging, Diffusion Tensor Imaging and Double Inversion Recovery. As a basis of a robust independent review assessment, standardized image acquisition is key. Thus, site training and imaging acquisition guidelines are critical for consistent and high-quality MRI images.
Case Study
Calyx Medical Imaging played a vital role in a phase 3, double blind, randomized, multicenter trial in patients with relapsing-remitting multiple sclerosis. Based on the centrally assessed imaging data it was shown that the investigational drug significantly reduces MS lesion activity. The superiority of the investigational drug against interferon treatment was also demonstrated on clinical grounds (relapse rate reduction of 52%). The trial was the largest phase 3 clinical trial program ever submitted to the FDA for a new MS drug at the time.
Example of MS lesion count and volume assessment.
FLAIR image with lesion count and volume of new (green ROI) and enlarging (blue ROI) T2 hyperintense lesions.
T1 Gadolinium enhanced sequence with lesion count and volume of T1 hyperintense lesions (yellow ROI).
Experience
Calyx Medical Imaging’s experience is drawn from managing over 2600 trials to date which include more than 4.4 million images from roughly 155,000 sites globally. Within this experience is our management of nearly 180 CNS protocols and over 30 MS studies.
Overview
Calyx Medical Imaging is a leading imaging core lab with the experience and ability to provide a wide range of services involving neuroimaging in clinical trials. Calyx Medical Imaging’s CNS group understands the unique and custom requirements required of Multiple Sclerosis trials and have the flexibility, creativity, bandwidth, and understanding already in place to effectively manage and support these clinical trials.
A significant portion of our CNS experience is in Multiple Sclerosis (MS). Apart from standard MS assessments such as lesion counts (including lesion evolution), lesion and brain volumes Calyx also supports advanced MS analyses:
MAGNETIZATION TRANSFER IMAGING (MTI)
Magnetization Transfer Imaging is a method that has been found to correlate with clinical disability in MS patients. This method is sensitive to the extent of myelination and provides a quantitative assessment of myelin integrity. The MT ratio, a parameter derived from MT imaging data, is a useful imaging biomarker for assessing extent of demyelination and remyelination in MS clinical studies.
DIFFUSION TENSOR IMAGING (DTI)
DTI has been found to provide information about tissue microstructure and architecture including size, shape and organization and as a result represents an effective tool for evaluating white matter tissue integrity. The DTI tool can be used to obtain useful information in many ways – evaluation of Gadolinium-enhancing lesions by DTI provides information about tissue changes in active lesions; analysis of normal appearing white matter (NAWM) using the DTI tool may provide some insight into the early changes in the WM in MS. Parameters such as mean diffusivity (MD), fractional anisotropy (FA) and volume ratio (VR) are some of the most important quantitative indices that are extracted from DTI data.
FUNCTIONAL MAGNETIC RESONANCE IMAGING (FMRI)
fMRI can be used to measure brain activity at rest or while performing a task by detecting the changes associated with blood flow. The underlying understanding is that cerebral blood flow and brain activity are directly correlated. Similarly, functional brain connectivity can be deduced using fMRI data. Activation and/or functional connectivity maps and analysis can provide insight into the brain activity and hence possible abnormalities and response to therapeutics.
DOUBLE INVERSION RECOVERY (DIR)
The Double Inversion Recovery sequence (DIR) has been advocated for detecting gray matter (GM) lesions due to its ability to enhance soft tissue contrast in the brain. It combines two inversion pulses in order to simultaneously suppress signals from tissues with different longitudinal relaxation times. In the brain, DIR allows to selectively image grey matter (GM) by nulling the signal from white matter (WM) and cerebrospinal fluid (CSF) at the time of the excitation pulse.
OPHTHALMIC IMAGING
Within Multiple Sclerosis, it is possible to see structural changes in the retina, specifically within the Ganglion Cell Arteritis (GCA) and Nerve Fiber Layer (NFL). A combination of OCT, FP, and FAF could be appropriate for your trial to evaluate the retinal changes. The combination of Calyx’s operational bench strength and global site/image processing capabilities with
the expertise of Calyx’s medical advisor make for an ideal study management structure.
Ophthalmology imaging endpoints have historically been serviced by academic core labs and though they offer the relevant expertise in the modality and indication, they lack the infrastructure, validated quality systems and SOPs to manage a late phase study. Leveraging expertise across each lab, including Calyx’s systems and export capability will reduce the added workarounds by the sponsor.
Case Study
Calyx Medical Imaging played a vital role in a phase 2, double blind, randomized, multicenter trial in patients with relapsing-remitting multiple sclerosis including MTI analysis. During site standardization Calyx supported the installation of the MTI specific software on the MRI scanners. 110 timepoint MTI datasets of 12 patients have been acquired, collected and processed. Structural MR image processing encompassed image pre-processing, linear spatial normalization, and voxel classification. Lesion-based mean Magnetization Transfer Ratios (MTR) and voxel-based gray matter and white matter MTR histograms were derived for the MTR analysis.
Experience
Calyx Medical Imaging’s experience is drawn from managing over 2600 trials to date which include more than 4.4 million images from roughly 155,000 sites globally. Within this experience is our management of nearly 180 CNS protocols and over 30 MS studies, of which 4 included advanced MRI.
Calyx experience in implementing advanced MRI techniques in Multiple Sclerosis studies:
