(372 days)
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Yes
The device description explicitly states that "Rho is a machine learning-based software-as-a-medical device" and "Rho uses the xray DICOM and DICOM tags of age and sex as inputs into a locked machine learning algorithm."
No.
This device is for identifying patients with possible low bone mineral density to prompt a clinical assessment; it does not directly treat or alleviate a medical condition.
Yes
The device aids radiologists in identifying patients with possible low bone mineral density (BMD) to prompt a clinical assessment of bone health, which is a diagnostic purpose.
Yes
The device is explicitly described as "machine learning-based software-as-a-medical device" and its function is to process existing medical images (x-rays) and patient data (age and sex) to generate a report. There is no mention of any hardware component being part of the device itself.
Based on the provided text, this device is not an IVD (In Vitro Diagnostic).
Here's why:
- IVD definition: In vitro diagnostics are tests performed on samples taken from the human body, such as blood, urine, or tissue, to detect diseases, conditions, or infections.
- Device function: Rho is a software application that analyzes medical images (radiographs) to identify potential low bone mineral density. It does not analyze samples taken from the body.
- Intended Use: The intended use clearly states it works with "standard frontal radiographs" and provides a "notification in the form of a report" to aid in identifying patients. This is image analysis, not in vitro testing.
Therefore, Rho falls under the category of a medical device, specifically a software-as-a-medical device (SaMD), but not an In Vitro Diagnostic.
No
The letter does not explicitly state that the FDA has reviewed, approved, or cleared a PCCP for this specific device.
Intended Use / Indications for Use
Rho is a software application intended for use opportunistically with standard frontal radiographs of the lumbar spine, thoracic spine, chest, pelvis, knee, or hand/wrist performed in patients aged 50 years and older. Rho provides a notification in the form of a report to aid radiologists and/or physician interpreters in identifying patients with possible low bone mineral density (BMD) at L1-L4 or the femoral neck to prompt a clinical assessment of bone health. Rho should not be used to rule out low BMD. Radiologists and referring clinicians should follow recommended practices for screening and assessment, regardless of the absence of Rho report.
Product codes (comma separated list FDA assigned to the subject device)
SAO
Device Description
Rho is a machine learning-based software-as-a-medical device that interfaces with institutional Picture Archiving and Communications Systems (PACS) to identify patients 50 years and older undergoing x-ray with possible low bone mineral density (BMD). Eligible x-rays are frontal projections of the lumbar spine, thoracic spine, chest, pelvis, knee or hand/wrist. Rho uses the xray DICOM and DICOM tags of age and sex as inputs into a locked machine learning algorithm. The locked machine learning algorithm is trained on a patient-based dataset (True North Imaging. TNI13). The algorithm presents a binary output to indicate whether or not the patient likely has low BMD at either the femoral neck or L1-L4. A Rho Report is generated for positive cases that can be sent back to the PACS for physician interpretation or viewed through a browser-based interface.
Radiologists can choose to include this finding in their report to the referring physician. Inclusion may trigger a referring physician to conduct a clinical fracture risk assessment related to bone health.
For cases where Rho algorithm outputs a negative result, no Rho Report will be sent, and neither the radiologist nor the referring physician will receive any device output.
Mentions image processing
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Mentions AI, DNN, or ML
Rho is a machine learning-based software-as-a-medical device
Input Imaging Modality
standard frontal radiographs of the lumbar spine, thoracic spine, chest, pelvis, knee, or hand/wrist
Anatomical Site
lumbar spine, thoracic spine, chest, pelvis, knee, or hand/wrist
Indicated Patient Age Range
50 years and older
Intended User / Care Setting
radiologists and/or physician interpreters
Description of the training set, sample size, data source, and annotation protocol
The locked machine learning algorithm is trained on a patient-based dataset (True North Imaging. TNI13).
Description of the test set, sample size, data source, and annotation protocol
The validation datasets consisted of previously acquired x-rays that include paired DXA T-scores. The performance of the device was demonstrated on three independent datasets, True North Imaging (TNI), Osteoarthritis Initiative (OAI) and OneMedNet (OMN).
The TNI6 study population consisted of patients with a lumbar spine, thoracic spine, chest, pelvis, knee, or hand x-ray within 1 year of a DXA. The validation datasets included 3729 cases from six True North Imaging centers (TNI6) from Canada, 522 US cases from OneMedNet, and 591 US cases from Osteoarthritis Initiative, a multicenter, longitudinal, prospective observational study of knee osteoarthritis. Ground truth low BMD is defined as at least one of the femoral necks or L 1-L4 vertebrae having a T-Score
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DE NOVO CLASSIFICATION REQUEST FOR RHO
REGULATORY INFORMATION
FDA identifies this generic type of device as:
Radiology software for opportunistic evaluation of low bone mineral density. This device is software which opportunistically assesses radiological images to estimate bone mineral density (BMD) intended to assist in a healthcare professional's decision to evaluate patients for possible low BMD within a bone health screening program. The software employs an algorithm that estimates BMD using eligible radiological image data obtained for other clinical purposes.
NEW REGULATION NUMBER: 21 CFR 892.1171
CLASSIFICATION: Class II
PRODUCT CODE: SAO
BACKGROUND
DEVICE NAME: Rho
SUBMISSION NUMBER: DEN230023
DATE DE NOVO RECEIVED: April 3, 2023
SPONSOR INFORMATION:
16 Bit Inc 20 Bay Street, 11th Floor, Toronto. Ontario M5J2N8 Canada
INDICATIONS FOR USE
Rho is a software application intended for use opportunistically with standard frontal radiographs of the lumbar spine, thoracic spine, chest, pelvis, knee, or hand/wrist performed in patients aged 50 years and older. Rho provides a notification in the form of a report to aid radiologists and/or physician interpreters in identifying patients with possible low bone mineral density (BMD) at L1-L4 or the femoral neck to prompt a clinical assessment of bone health. Rho should not be used to rule out low BMD. Radiologists and referring clinicians should follow recommended practices for screening and assessment, regardless of the absence of Rho report.
LIMITATIONS
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- . The sale, distribution, and use of Rho are restricted to prescription use in accordance with 21 CFR 801.109.
- . Rho cannot be used to rule out low BMD.
- . Absence of Rho report should not be considered as a negative finding.
- This device cannot replace DXA screening program: radiologists and referring clinicians . should follow recommended practices for screening and assessment.
PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.
DEVICE DESCRIPTION
Rho is a machine learning-based software-as-a-medical device that interfaces with institutional Picture Archiving and Communications Systems (PACS) to identify patients 50 years and older undergoing x-ray with possible low bone mineral density (BMD). Eligible x-rays are frontal projections of the lumbar spine, thoracic spine, chest, pelvis, knee or hand/wrist. Rho uses the xray DICOM and DICOM tags of age and sex as inputs into a locked machine learning algorithm. The locked machine learning algorithm is trained on a patient-based dataset (True North Imaging. TNI13). The algorithm presents a binary output to indicate whether or not the patient likely has low BMD at either the femoral neck or L1-L4. A Rho Report is generated for positive cases that can be sent back to the PACS for physician interpretation or viewed through a browser-based interface.
Radiologists can choose to include this finding in their report to the referring physician. Inclusion may trigger a referring physician to conduct a clinical fracture risk assessment related to bone health.
For cases where Rho algorithm outputs a negative result, no Rho Report will be sent, and neither the radiologist nor the referring physician will receive any device output.
SUMMARY OF NONCLINICAL/BENCH STUDIES
SOFTWARE
Rho software documentation and software verification and validation testing provided demonstrate that the device meets all requirements for basic documentation level as outlined in the FDA guidance document, "Content of Premarket Submissions for Device Software Functions".
SUMMARY OF CLINICAL INFORMATION
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Performance Testing
Clinical performance of the device was provided in the form of a retrospective, multi-center study to compare sensitivity and specificity of the device with the gold standard. Dual Energy Xray Absorptiometry (DXA) with pre-specified performance goals. The primary objective of the study is to demonstrate the ability of Rho to separate two groups (yes/no low BMD by DXA) with a high specificity. Ground truth low BMD is defined as at least one of the femoral necks or L 1-L4 vertebrae having a T-Score 0.775 and lower end of the two-sided 95% confidence interval of sensitivity >0.5 for the TN16 and OMN cohorts. However, the final device performance across all analysis groups did not meet those goals. The device met its performance goals of specificity and AUC in all three datasets. More specifically, device sensitivity is lower than 30% for the following subgroups: knee subgroup in both US datasets (OMN and OAL), hand/wrist subgroup in OAI, male subgroup in OAI dataset. There is uncertainty associated with the lower sensitivity in the US datasets and certain subgroups that will be addressed by indicating on the device report that negative results do not necessarily indicate absence of low BMD. A link to the study results will be provided on the device report provided to the radiologist, and performance in all subgroups will be provided in the device labeling. Although the device's low sensitivity suggests that there is a small probable benefit, the risk of false negatives is no different from current standard of care. Uncertainties associated with the device's generalizability across different datasets and different subgroups will also be addressed by postmarket monitoring described in the special controls.
Image /page/6/Figure/2 description: The image is a ROC curve, which plots sensitivity against 1-specificity. There are three curves plotted on the graph, representing the subgroups OAI, OMN, and TNI. The curves show the trade-off between the true positive rate (sensitivity) and the false positive rate (1-specificity) for each subgroup. The ROC curve is a useful tool for evaluating the performance of a binary classification model.
Figure 1: ROC curve for the three clinical datasets, TNI6, OAI and OMN
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Reproducibility of Rho Results between x-rays acquired on different days
Rho demonstrated moderate agreement when analyzing x-rays of the same body part that were acquired on the same or different days.
| x-rays on same day, same time (bilateral images) | x-rays on same day with ≥ 1 minute between | x-rays on same day with ≥ 2 minutes between | x-rays on different day, within 2 years | |
|---|---|---|---|---|
| subjects | 414 | 87 | 32 | 269 |
| % low BMD | 83 | 83 | 88 | 89 |
| % agreement | 85 | 88.5 | 84.4 | 86.2 |
| Kappa | 0.686 | 0.759 | 0.69 | 0.681 |
| z | 14 | 7.11 | 3.97 | 11.2 |
| p | 0 | 1.1E-12 | 7.1E-05 | 0 |
| Table 3. Agreement of Rho Result between 2 x-rays of the same body part | ||||
|---|---|---|---|---|
Pediatric Extrapolation
In this De Novo request, existing clinical data were not leveraged to support the use of the device in a pediatric patient population.
LABELING
The labeling meets the requirements of 21 CFR 801.109 for prescription devices and includes information on device inputs and outputs, instructions for use, intended patient population and intended users of the device, adequate warnings and precautions as well as detailed performance testing summaries. Application of the device as an evaluation tool for referral to bone health assessment is clearly stated, and there are warnings that clinical decisions should not be based solely upon the device's output and that the device cannot be used to rule out low BMD. Postmarket data collection and its purpose is acknowledged in labeling.
POSTMARKET MONITORING PLAN
The De Novo request included specifics of a post-market performance management plan to ensure regular assessment of the generalizability and device performance of Rho in the intended patient population in real-world use. The plan includes collection and review of data on the clinical use of Rho from various sources including healthcare professionals, clinical sites, and
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patient registries, analyze collected data to identify any patterns, trends, or adverse events associated with the use of Rho and assess the impact of the frequency and severity of any reported incidents on the risk profile of the device. Through automatic monitoring of the percentage of Rho positive cases at each site, and across sites, the sponsor will initiate root cause investigations in the case of performance drift. In the case of significant performance drift. including significant performance drift of a predefined subgroup, the sponsor will inform customers through a predefined communication plan; this can include adding or modifying. warnings or contraindications in the labeling, or modifying indications for use.
RISKS TO HEALTH
The table below identifies the risks to health that may be associated with use of radiology software for opportunistic evaluation of low bone mineral density and the measures necessary to mitigate these risks.
| Identified Risks to Health | Mitigation Measures |
|---|---|
| Incorrect patient management due to misinterpretation | |
| of device output or overreliance on device output for | |
| radiological image interpretation | Clinical performance testing |
| Labeling | |
| Postmarket monitoring plan | |
| False positive findings leading to unnecessary radiation | |
| exposure to the patient and clinical work-up | Clinical performance testing |
| Postmarket monitoring plan | |
| Labeling | |
| False negative findings leading to missing or delayed | |
| patient assessment | Labeling |
| Device failure leading to the absence or delay of results, | |
| leading to missing, inaccurate, or delayed patient | |
| assessment | Software verification, validation, |
| and hazard analysis |
SPECIAL CONTROLS
In combination with the general controls of the FD&C Act, radiology software for opportunistic evaluation of low bone mineral density is subject to the following special controls:
- (1) Clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. Testing must fulfill the following:
- The dataset used for training and development of the advanced algorithm must be (i) distinct from the dataset used for testing to support generalizability of the algorithm.
- (ii) Results from clinical performance testing must characterize the performance of the device compared to a clinically justified ground truth (reference method or clinical comparator).
- (iii) The test dataset must be representative of the intended patient population(s) to support a supplement to a screening program. Test datasets must have adequate representation of cases with clinically relevant confounders. The performance
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estimates and confidence intervals of the device for each individual confounding factor must be characterized in the performance testing.
- Clinical performance must characterize the dependence of software output on the (iv) hardware specifications of the acquisition system.
- (v) Clinical performance must characterize the device's reproducibility from repeated measurements on the same patients.
- (vi) The testing report must include a detailed description of pre-specified performance testing protocols (including the study objectives, primary and secondary endpoints, statistical hypotheses, performance goals, sample size calculation, statistical analyses) and dataset(s) used.
- (2) Software verification, validation, and hazard analysis must be performed.
- (3) Labeling must include:
- A description of the intended patient population, the intended user, clinical (i) environment, and context of use, including information on interpretation of outputs within the intended clinical workflow:
- (ii) A summary of the performance testing for each device output, including test methods, dataset characteristics, testing environment, results (with confidence intervals), and a summary of clinical performance for all demographic subgroups from testing dataset(s);
- (iii) A description of measurement reproducibility:
- A description of situations in which the device may fail and clinical (iv) subpopulations or acquisition system characteristics in which device was not evaluated. if any:
- A statement that the device output should not be used to replace a screening (v) program.
- (4) The device manufacturer must develop and implement a post-market performance management plan that ensures regular assessment of the generalizability and device performance in the intended patient population in real-world use. The plan must include:
- (i) Data collection, analysis methods, and procedures for:
- Monitoring relevant performance characteristics and detecting changes in (A) performance:
- (B) Identifying sources of performance changes between validation and realworld environment over time; and
- (C) Assessing the results from the performance monitoring on safety and effectiveness.
- (ii) Procedures for communicating the device's current performance to users.
- (i) Data collection, analysis methods, and procedures for:
BENEFIT-RISK DETERMINATION
The risks of the device are based on clinical studies described above. A false positive result could lead to a clinical assessment of risk, which in turn could lead to unnecessary medical imaging (including DXA). However, a patient undergoing a DXA scan is exposed to a very
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small amount of radiation, equivalent to a few days of background radiation. The high specificity of device performance demonstrated across demographic subgroups, implying that a high rate of the positive findings of low BMD from the device are real cases of low patient BMD. further mitigates the risk. In the case of a false negative result the patient continues to receive current standard of care, in that the initiation of a clinical assessment of risk depends on the health care provider.
The probable benefit of the device is that by opportunistically identifying individuals with possibly low BMD, the device facilitates the identification of patients who could benefit from possible subsequent clinical risk assessment of bone health, and DXA screening for the assessment of fracture risk.
The device operates in an opportunistic fashion, analyzing images obtained for other clinical purposes, and the follow-up to being flagged (whether a true positive or false positive) is a clinical risk assessment (questionnaire) that is already recommended in the intended population but often overlooked in the current standard of care. The implication of a negative finding (whether a true negative or false negative) is that the initiation of the clinical risk assessment will not be triggered by the device. As the device is intended to assist in a healthcare professional's decision to refer a patient for subsequent clinical assessment of bone health a false negative outcome is no different than for an individual who had an x-ray that was not analyzed by Rho.
The performance data provided support that the probable benefits outweigh the probable risks, when used as intended.
Patient Perspectives
This submission did not include specific information on patient perspectives for this device.
Benefit/Risk Conclusion
In conclusion, given the available information above, for the following indication statement:
Rho is a software application intended for use opportunistically with standard frontal radiographs of the lumbar spine, thoracic spine, chest, pelvis, knee, or hand/wrist performed in patients aged 50 years and older. Rho provides a notification in the form of a report to aid radiologists and/or physician interpreters in identifying patients with possible low bone mineral density (BMD) at L1-L4 or the femoral neck to prompt a clinical assessment of bone health. Rho should not be used to rule out low BMD. Radiologists and referring clinicians should follow recommended practices for screening and assessment, regardless of the absence of Rho report.
The input to Rho is a standard frontal radiograph of the lumbar spine, thoracic spine, chest, pelvis, knee, or hand/wrist.
The probable benefits outweigh the probable risks for Rho device. The device provides benefits, and the risks can be mitigated by the use of general controls and the identified special controls.
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CONCLUSION
The De Novo request for Rho is granted and the device is classified as follows:
Product Code: SAO Device Type: Radiology software for opportunistic evaluation of low bone mineral density Regulation Number: 21 CFR 892.1171 Class: II