Rho

DEN230023 · 16 Bit, Inc. · SAO · Apr 9, 2024 · Radiology

Device Facts

• Record ID: DEN230023
• Device Name: Rho
• Applicant: 16 Bit, Inc.
• Product Code: SAO · Radiology
• Decision Date: Apr 9, 2024
• Decision: DENG
• Submission Type: Direct
• Regulation: 21 CFR 892.1171
• Device Class: Class 2
• Attributes: AI/ML, Software as a Medical Device

Intended 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.

Device Story

Software application; analyzes standard frontal radiographs (lumbar/thoracic spine, chest, pelvis, knee, hand/wrist); identifies potential low bone mineral density (BMD) at L1-L4 or femoral neck; provides notification report to radiologists/physicians; intended to prompt clinical assessment of bone health; not for ruling out low BMD; used in clinical settings; supports clinical decision-making by flagging patients for follow-up; does not replace formal screening programs.

Clinical Evidence

Retrospective, multi-center study across three datasets (TNI, OMN, OAI) totaling 4,842 cases. Ground truth established by DXA (T-score < -1.0). Primary endpoints: sensitivity, specificity, and AUC. Results showed high specificity (range 0.71-1.00) but variable sensitivity (range 0.22-0.83) across subgroups. AUC ranged from 0.73 to 0.98. Study demonstrated device met prespecified AUC and specificity goals, though sensitivity was lower in US-based datasets (OMN/OAI) compared to the Canadian dataset (TNI).

Technological Characteristics

Radiology software for opportunistic evaluation of low bone mineral density. Employs an algorithm to estimate BMD from existing radiological image data. Subject to software verification, validation, and hazard analysis. Requires performance characterization regarding hardware acquisition system dependence and measurement reproducibility.

Indications for Use

Indicated for patients aged 50+ undergoing standard frontal radiographs of lumbar spine, thoracic spine, chest, pelvis, knee, or hand/wrist to aid in identifying possible low BMD at L1-L4 or femoral neck. Not for ruling out low BMD.

Regulatory Classification

Identification

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.

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:

Submission Summary (Full Text)

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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 < - 1.0 when assessed by DXA. 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 TNI dataset was split by geographically separated imaging clinics into a training set (TNI13) and clinical validation set (TNI6). The TNI13 dataset was used exclusively for algorithm development. The TN16 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. A comparison of the clinical validation set to US reference population can be found in Table 1.

The study had prespecified coprimary endpoints of sensitivity and specificity and a secondary endpoint of an area under the receiver operating characteristic curve (AUC). Additional endpoints were specified for the following subgroups: age, gender, race, anatomy, x-ray manufacturer, x-ray tube voltage (kVp), exposure and imager pixel spacing.

| | US Reference<br>NHANES, all<br>races1 | TNI6 | Clinical Validation Set<br>OMN | OAI2 |
|-----------------------------------------------|---------------------------------------------------------|-----------------------------------------------------|------------------------------------------------|-------------------------------------------------------------------------------|
| Age (years) | 50-80+ | 50-101 | 50-90 | 50-83 |
| Study population | General population | Imaging clinic<br>patients * | Imaging clinic<br>patients * | Study participants<br>with symptomatic<br>tibiofemoral knee<br>osteoarthritis |
| BMI (kg/m²) | F: 27.4 (0.2) †<br>M: 27.1 (0.2) | F: 26.5 (5.5)<br>M: 26.8 (4.4) | F: 28.2 (5.4)<br>M: 28.0 (4.9) | F: 30.5 (5.7)<br>M: 29.8 (4.3) |
| L1-L4 BMD<br>(Hologic units,<br>g/cm²) | F: 0.95 [0.65 –<br>1.23] ††<br>M: 1.07 [0.80 –<br>1.40] | F: 0.96 [0.71-1.27]<br>M: 1.14 [0.80-<br>1.52] | F: 1.02 [0.74-1.33]<br>M: 1.18 [0.84-1.66] | N/A |
| Femoral neck<br>BMD (Hologic<br>units, g/cm²) | F: 0.72 [0.45 –<br>1.01]<br>M: 0.80 [0.55 –<br>1.06] | F: 0.66 [0.51 –<br>0.84]<br>M: 0.72 [0.54-<br>0.94] | F: 0.71 [0.52-0.96]<br>M: 0.78 [0.56-<br>0.99] | F: 0.75 [0.50-1.15]<br>M: 0.82 [0.51-1.36] |

Table 1. Comparison of the Clinical Validation Set to US reference population: ranges of bone mineral density, prevalence of low bone mineral density, and body mass index

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| Prevalence of<br>low BMD by<br>DXA (T<-1) | F: 67% †††<br>M: 40% | F: 89%<br>M: 66% | F: 69%<br>M: 52% | F:51%<br>M:28% |
|-------------------------------------------|-------------------------------------------|----------------------------------|---------------------------|----------------|
| Collection sites | 3 mobile exam<br>centers,<br>44 sites, US | n=6, Toronto,<br>Ontario, Canada | n=6, US | n=4, US |
| DXA<br>Manufacturers | Hologic (100%) | GE (100%) | GE (97%),<br>Hologic (3%) | GE (100%) |

1 https://www.cdc.gov/nchs/data/series/sr 11/sr11 251.pdf

2 DXA bone mineral density (BMD) was only measured as the femoral neck.

https://pubmed.ncbi.nlm.nih.gov/18786841/

*higher possibility of low BMD, but also likely the type of people who would be getting x-rays that Rho would analyze (e.g., knee pain)

+ estimated weighted mean (se), SD is ~4-5. Beydoun MA and Wang J. Gender-ethnic Disparity in BMI and Waist Circumference Distribution Shifts in US Adults. Obesity 2010

+ +mean [lowest 5th percentile - highest 95th percentile] from

https://www.cdc.gov/nchs/data/series/sr 11/sr11 251.pdf using weighted means for age 50+ for L1-4 (Table 1) and Femoral Neck (Table 17).

*** sum of prevalence of low bone mass and osteoporosis from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757905/ Table 1

### Device Performance by dataset:

Ground truth is established by DXA acquired from the same patient, and ground truth low BMD is defined as at least one of femoral neck or L1-L4 having a T-Score < - 1.0 when assessed by DXA. DXA data acquired from the same patient is currently used in the patient bone mineral density screening program, and it is the current standard of care and well-established in clinical practice.

Sensitivity, specificity, and AUC performance were assessed within validation datasets and in pre-defined subsets of demographic subgroups. Results are presented in Table 2.

| | Analysis<br>group | n | Sensitivity | Specificity | AUC |
|---------------------|-----------------------------------|------|------------------|------------------|------------------|
| | All data split by dataset | | | | |
| | TNI | 3729 | 0.67 (0.66-0.69) | 0.90 (0.88-0.92) | 0.88 (0.88-0.90) |
| | OMN | 513 | 0.45 (0.41-0.50) | 0.93 (0.90-0.96) | 0.85 (0.82-0.88) |
| | OAI | 591 | 0.36 (0.31-0.41) | 0.94 (0.92-0.96) | 0.82 (0.79-0.85) |
| | Sexes split by dataset | | | | |
| Females | TNI | 3111 | 0.70 (0.68-0.71) | 0.90 (0.88-0.92) | 0.89 (0.88-0.91) |
| | OMN | 274 | 0.48 (0.42-0.54) | 0.94 (0.89-0.98) | 0.87 (0.83-0.90) |
| | OAI | 293 | 0.44 (0.37-0.50) | 0.90 (0.85-0.94) | 0.81 (0.77-0.85) |
| Males | TNI | 618 | 0.49 (0.45-0.53) | 0.90 (0.86-0.93) | 0.82 (0.79-0.85) |
| | OMN | 239 | 0.41 (0.34-0.49) | 0.92 (0.88-0.96) | 0.83 (0.78-0.87) |
| | Analysis<br>group | n | Sensitivity | Specificity | AUC |
| | OAI | 298 | 0.22 (0.15-0.30) | 0.98 (0.96-0.99) | 0.79 (0.75-0.84) |
| | Age decades split by dataset | | | | |
| | TNI | 844 | 0.64 (0.61-0.68) | 0.95 (0.92-0.97) | 0.89 (0.87-0.90) |
| 50-59 | OMN | 106 | 0.43 (0.33-0.53) | 0.95 (0.88-1.00) | 0.88 (0.82-0.93) |
| | OAI | 177 | 0.26 (0.15-0.38) | 0.98 (0.96-0.99) | 0.77 (0.70-0.84) |
| | TNI | 1339 | 0.65 (0.63-0.67) | 0.94 (0.91-0.96) | 0.90 (0.89-0.92) |
| 60-69 | OMN | 181 | 0.48 (0.40-0.55) | 0.91 (0.86-0.97) | 0.83 (0.78-0.88) |
| | OAI | 202 | 0.34 (0.25-0.43) | 0.94 (0.90-0.97) | 0.82 (0.77-0.87) |
| | TNI | 1031 | 0.69 (0.66-0.71) | 0.86 (0.82-0.90) | 0.87 (0.85-0.89) |
| 70-79 | OMN | 176 | 0.48 (0.39-0.56) | 0.93 (0.88-0.97) | 0.88 (0.84-0.92) |
| | OAI | 181 | 0.38 (0.30-0.45) | 0.88 (0.81-0.94) | 0.78 (0.72-0.83) |
| | TNI | 515 | 0.74 (0.71-0.78) | 0.71 (0.62-0.80) | 0.84 (0.80-0.88) |
| 80+ | OMN | 50 | 0.35 (0.21-0.50) | 0.95 (0.85-1.00) | 0.80 (0.69-0.90) |
| | OAI | 31 | 0.56 (0.35-0.75) | 1.00 (1.00-1.00) | 0.95 (0.88-1.00) |
| | X-ray body parts split by dataset | | | | |
| | TNI | 1331 | 0.83 (0.81-0.85) | 0.80 (0.75-0.84) | 0.89 (0.88-0.91) |
| Chest | OMN | 149 | 0.51 (0.39-0.62) | 0.90 (0.80-1.00) | 0.86 (0.81-0.92) |
| | TNI | 791 | 0.57 (0.54-0.60) | 0.95 (0.93-0.98) | 0.91 (0.89-0.93) |
| Lumbar | OMN | 99 | 0.39 (0.29-0.50) | 0.93 (0.86-1.00) | 0.85 (0.79-0.91) |
| | TNI | 328 | 0.75 (0.71-0.80) | 0.92 (0.84-1.00) | 0.93 (0.89-0.95) |
| Thoracic | OMN | 44 | 0.50 (0.35-0.65) | 1.00 (1.00-1.00) | 0.86 (0.76-0.94) |
| | TNI | 457 | 0.72 (0.69-0.76) | 0.99 (0.97-1.00) | 0.96 (0.94-0.97) |
| Pelvis | OMN | 82 | 0.56 (0.44-0.68) | 0.97 (0.92-1.00) | 0.90 (0.84-0.95) |
| | OAI | 197 | 0.55 (0.45-0.64) | 0.93 (0.89-0.97) | 0.91 (0.88-0.94) |
| | TNI | 250 | 0.56 (0.50-0.61) | 0.91 (0.85-0.97) | 0.85 (0.80-0.89) |
| Hand/wrist | OMN | 54 | 0.45 (0.31-0.61) | 0.81 (0.67-0.95) | 0.73 (0.61-0.85) |
| | OAI | 174 | 0.24 (0.15-0.33) | 0.96 (0.92-0.98) | 0.77 (0.70-0.82) |
| | TNI | 572 | 0.41 (0.37-0.44) | 0.96 (0.93-0.99) | 0.87 (0.84-0.90) |
| Knee | OMN | 85 | 0.29 (0.18-0.39) | 0.97 (0.92-1.00) | 0.86 (0.79-0.92) |
| | OAI | 220 | 0.28 (0.21-0.36) | 0.94 (0.91-0.98) | 0.76 (0.71-0.81) |
| | Races split by dataset* | | | | |
| | TNI | 3292 | 0.67 (0.66-0.69) | 0.90 (0.88-0.92) | 0.89 (0.88-0.90) |
| White | OMN | 142 | 0.46 (0.38-0.55) | 0.98 (0.94-1.00) | 0.90 (0.86-0.94) |
| | OAI | 418 | 0.36 (0.30-0.42) | 0.94 (0.91-0.96) | 0.80 (0.77-0.84) |
| | TNI | 24 | 0.33 (0.10-0.60) | 1.00 (1.00-1.00) | 0.77 (0.36-0.91) |
| Black | OMN | 114 | 0.36 (0.25-0.46) | 0.95 (0.90-0.99) | 0.86 (0.80-0.91) |
| | OAI | 147 | 0.40 (0.27-0.53) | 0.95 (0.92-0.98) | 0.86 (0.80-0.91) |
| | TNI | 134 | 0.74 (0.67-0.81) | 0.96 (0.88-1.00) | 0.93 (0.89-0.96) |
| Asian | OMN | 134 | 0.47 (0.38-0.56) | 0.91 (0.84-0.98) | 0.84 (0.78-0.89) |
| | Analysis<br>group | n | Sensitivity | Specificity | AUC |
| | OAI | 5 | 0.00 (0.00-0.00) | 1.00 (1.00-1.00) | 0.83 (0.50-1.00) |
| | OMN | 123 | 0.49 (0.40-0.59) | 0.88 (0.79-0.95) | 0.80 (0.73-0.87) |
| Hispanic | OAI | 10 | 0.20 (0.00-0.50) | 1.00 (1.00-1.00) | 0.98 (0.92-1.00) |
| | BMI category split by dataset** | | | | |
| | TNI | 1584 | 0.75 (0.73-0.77) | 0.87 (0.83-0.91) | 0.90 (0.88-0.91) |
| 18.5 to <25 | OMN | 147 | 0.58 (0.51-0.66) | 0.81 (0.69-0.92) | 0.82 (0.75-0.89) |
| | OAI | 32 | 0.45 (0.27-0.64) | 0.83 (0.62-1.00) | 0.75 (0.58-0.90) |
| | TNI | 1265 | 0.63 (0.61-0.66) | 0.90 (0.87-0.93) | 0.87 (0.85-0.89) |
| 25 to <30 | OMN | 187 | 0.46 (0.38-0.54) | 0.94 (0.89-0.98) | 0.86 (0.81-0.90) |
| | OAI | 80 | 0.33 (0.21-0.45) | 0.98 (0.93-1.00) | 0.83 (0.75-0.90) |
| | TNI | 792 | 0.53 (0.50-0.57) | 0.92 (0.89-0.95) | 0.86 (0.83-0.88) |
| ≥ 30 | OMN | 156 | 0.29 (0.20-0.37) | 0.96 (0.92-0.99) | 0.83 (0.77-0.88) |
| | OAI | 106 | 0.37 (0.22-0.53) | 0.97 (0.94-1.00) | 0.92 (0.87-0.96) |
| | Manufacturer split by dataset | | | | |
| | TNI | 1094 | 0.65 (0.62-0.67) | 0.91 (0.88-0.94) | 0.90 (0.88-0.91) |
| GE | OMN | 34 | 0.77 (0.56-0.86) | 0.76 (0.61-0.82) | 0.87 (0.76-0.96) |
| | OAI | 145 | 0.60 (0.49-0.71) | 0.88 (0.82-0.93) | 0.86 (0.80-0.90) |
| | OMN | 104 | 0.39 (0.30-0.49) | 1.00 (1.00-1.00) | 0.87 (0.81-0.93) |
| FUJIFILM | OAI | 194 | 0.17 (0.11-0.24) | 0.99 (0.97-1.00) | 0.90 (0.86-0.93) |
| AGFA | OAI | 84 | 0.44 (0.29-0.60) | 0.95 (0.89-0.98) | 0.89 (0.82-0.94) |
| Swissray | OAI | 149 | 0.39 (0.28-0.50) | 0.95 (0.91-0.98) | 0.88 (0.83-0.92) |
| Imaging<br>Dynamics | TNI | 2616 | 0.68 (0.67-0.70) | 0.89 (0.87-0.91) | 0.88 (0.87-0.89) |
| Other | TNI | 19 | 0.65 (0.44-0.83) | 1.00 (1.00-1.00) | 0.88 (0.69-1.00) |
| Samsung | OMN | 125 | 0.47 (0.37-0.57) | 0.91 (0.84-0.97) | 0.85 (0.79-0.90) |
| Konica<br>Minolta | OMN | 80 | 0.38 (0.27-0.50) | 0.97 (0.90-1.00) | 0.90 (0.84-0.95) |
| Siemens | OMN | 22 | 0.50 (0.31-0.68) | 1.00 (1.00-1.00) | 0.93 (0.79-1.00) |
| Canon Inc | OMN | 106 | 0.45 (0.34-0.56) | 0.94 (0.88-1.00) | 0.85 (0.78-0.91) |
| Philips | OMN | 21 | 0.56 (0.36-0.76) | 1.00 (1.00-1.00) | 0.96 (0.88-1.00) |
| other | OMN | 21 | 0.55 (0.30-0.80) | 1.00 (1.00-1.00) | 0.95 (0.89-1.00) |

Table 2. Sensitivity and Specificity by analysis group - TNI, OMN and OAI

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*Hispanic results are not shown for TNI (n=6). ** BM<18.5 kg/m² as OMN only had 3 patients in that group. Ground truth Low BMD was defined by DXA (at least one of the femoral neck or L1-4 having a T-score <- 1).

The device demonstrated a high specificity across all three datasets and a comparatively low sensitivity; however, the device demonstrated lower sensitivity in the OMN and OAI datasets (e.g. the datasets sourced solely from US healthcare environments) as compared to the TNI6 dataset (the dataset sourced from Canada healthcare environment). A high specificity implies that a high rate of the positive findings of low BMD from the device are real cases of low patient BMD. The risk of false negatives from this device is low because the patients continue to receive

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standard of care and still undergo clinical screening assessment of bone health. The device fully met the prespecified AUC performance goal for all subgroups in all three datasets.

Study Limitation: The sponsor originally proposed co-primary endpoints of sensitivity and specificity (performance goals specified as the lower end of the two-sided 95% confidence interval of specificity >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<br>of device output or overreliance on device output for<br>radiological image interpretation | Clinical performance testing<br>Labeling<br>Postmarket monitoring plan |
| False positive findings leading to unnecessary radiation<br>exposure to the patient and clinical work-up | Clinical performance testing<br>Postmarket monitoring plan<br>Labeling |
| False negative findings leading to missing or delayed<br>patient assessment | Labeling |
| Device failure leading to the absence or delay of results,<br>leading to missing, inaccurate, or delayed patient<br>assessment | Software verification, validation,<br>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.

### 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