The intended use of Voxel Dosimetry™ is to provide estimates (deterministic) of absorbed radiation dose at voxel as a result of administering one of the supported radionuclides and to provide a dose map. This is dependent on input data regarding bio distribution being supplied to the application.

Voxel Dosimetry™ only allows voxel-based dose calculations for patients who have been administered with radioisotopes.

Warning! The Voxel Dosimetry™ is only intended for calculating dose for FDA approved radiopharmaceuticals for any clinical purpose, and calculation of unapproved drugs can only be used for research purpose.

Device Description

Voxel Dosimetry™ is a tool for voxel level absorbed dose calculation resulting from radiotracer injection. Voxel Dosimetry™ workflow consists of the following steps:

SPECT/CT or PET/CT DICOM data loading from the data manager GOLD or PACS
Registration of different time-points to a common reference study
Generation and integration of voxel-level time-activity curves
Voxel-level absorbed dose calculation using a Monte Carlo-method
Saving of the absorbed dose-map back to GOLD or PACS in DICOM format

AI/ML Overview

Here's a breakdown of the acceptance criteria and the study proving the device meets them, based on the provided text:

Acceptance Criteria and Device Performance

Acceptance Criteria (Implicit)	Reported Device Performance
Cumulated Activity Accuracy
Difference in cumulated activity between Voxel Dosimetry™ and true cumulated activity (XCAT phantom with mono-exponential model). - For Ga68 (Kidney, Tumor, Spleen) - For I123 (Kidney, Tumor, Spleen) - For I131 (Kidney, Tumor, Spleen) - For In111 (Kidney, Tumor, Spleen) - For Lu177 (Kidney, Tumor, Spleen) - For Tc99m (Kidney, Tumor, Spleen) - For Y90 (Kidney, Tumor, Spleen)	- Ga68: 6%, 6%, 7% - I123: 3%, 1%, 2% - I131: 7%, 2%, 3% - In111: 11%, 7%, 7% - Lu177: 7%, 3%, 3% - Tc99m: 8%, 7%, 6% - Y90: 12%, 8%, 8%
Dose Calculation Accuracy
Difference in Voxel Dosimetry™ dose compared to PENELOPE dose. - For I123 (Kidney, Tumor, Spleen) - For I131 (Kidney, Tumor, Spleen) - For Ga68 (Kidney, Tumor, Spleen) - For In111 (Kidney, Tumor, Spleen) - For Lu177 (Kidney, Tumor, Spleen) - For Tc99m (Kidney, Tumor, Spleen) - For Y90 (Kidney, Tumor, Spleen)	- I123: 2%, 3%, 3% - I131: 3%, 3%, 3% - Ga68: 12%, 12%, 12% - In111: 2%, 2%, 3% - Lu177: 1%, 1%, 1% - Tc99m: 2%, 3%, 3% - Y90: 5%, 6%, 4%
Correlation with Predicate Device (OLINDA/EXM® v2.0) - Pearson's r for left kidney doses - Pearson's r for right kidney doses	- r_left = 0.97 - r_right = 0.98
Relative Difference from Predicate Device (OLINDA/EXM® v2.0) - Average relative difference in kidney doses	- -2%
Safety and Effectiveness	The stated differences in cumulated activities and doses in phantom studies are considered small, with the exception of Ga68, which has high positron energy. The differences between SMC and OLINDA/EXM® v2.0 in kidney dosimetry (2%) are less than the known uncertainty in Lu177 kidney dosimetry, indicating no impact on safety or effectiveness.
Compliance with Software Specifications	"The testing results support that all the software specifications have met the acceptance criteria."

Study Details

Sample size used for the test set and the data provenance:
- Phantom Testing:
  - The exact "sample size" in terms of number of different XCAT phantoms generated is not explicitly stated. However, it involved generating an XCAT phantom for each isotope tested (Ga68, I123, I131, In111, Lu177, Tc99m, Y90), with four time points for each isotope.
  - Provenance: Synthetic/simulated data (XCAT phantom).
- Clinical Data Comparison:
  - Patient Sample Size: Six patients, twelve treatment cycles.
  - Provenance: This appears to be retrospective clinical data, as patients underwent Lu177-DOTATE treatments and were scanned at specific time points. The publication (Hippeläinen et al., 2017) suggests it was a real-world study. The specific country of origin is not mentioned.
Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- Phantom Testing: Ground truth was established by analytical or established Monte Carlo methods (PENELOPE, mono-exponential model). No human experts were directly involved in establishing this ground truth.
- Clinical Data Comparison: The comparison was against the predicate device OLINDA/EXM® v2.0, which itself is a calculation tool. While presumably experts would have performed the initial OLINDA/EXM® calculations, the text doesn't specify experts for this comparison's ground truth beyond the output of the predicate.
Adjudication method for the test set:
- No adjudication method (like 2+1 or 3+1) is mentioned, as the ground truth for both test sets (phantom and clinical comparison) was established via computational models or comparison with another software, not human consensus.
If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:
- No MRMC or human-in-the-loop study with human readers/AI assistance was conducted or reported. This device is a dose calculation software, not an AI-assisted diagnostic tool for human interpretation.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:
- Yes, the performance evaluation was entirely a standalone assessment of the algorithm. Its calculations were compared against analytical results (phantom studies) or another standalone algorithm (OLINDA/EXM® v2.0).
The type of ground truth used (expert consensus, pathology, outcomes data, etc.):
- Phantom Testing:
  - For cumulated activity: Analytical integration of a mono-exponential model.
  - For dose calculations: Monte Carlo simulation results from PENELOPE code.
- Clinical Data Comparison: Reference standard was the output of the legally marketed predicate device, OLINDA/EXM® v2.0.
The sample size for the training set:
- The document does not explicitly mention a "training set" in the context of machine learning model development. This device appears to be based on a Semi-Monte Carlo (SMC) method for dose calculation, which is a physics-based model rather than a data-driven machine learning model requiring a specific training set. Therefore, this question is not directly applicable in the typical sense. The underlying physics models and S-values might be "trained" or derived from theoretical physics and extensive pre-computed data, but not in the sense of a deep learning model.
How the ground truth for the training set was established:
- As explained above, there's no mention of a traditional machine learning "training set" or its ground truth establishment in the provided text. The SMC method is a computational technique based on physical principles, not a model learned from labeled data in the usual machine learning context.

Summary

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October 17, 2019

Image /page/0/Picture/1 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the FDA acronym with the full name of the agency on the right. The symbol on the left is a stylized representation of a human figure, while the FDA acronym is in a blue square. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

Hermes Medical Solutions AB % Joakim Arwidson VP Quality and Regulatory Affairs Strandbergsgatan 16 112 51 Stockholm SWEDEN

Re: K191216

Trade/Device Name: Voxel Dosimetry™ v1.0 Regulation Number: 21 CFR 892.2050 Regulation Name: Picture archiving and communications system Regulatory Class: Class II Product Code: LLZ Dated: September 4, 2019 Received: September 18, 2019

Dear Joakim Arwidson:

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR 803) for

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devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely.

For

Thalia T. Mills, Ph.D. Director Division of Radiological Health OHT7: Office of In Vitro Diagnostics and Radiological Health Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K191216

Device Name Voxel Dosimetry v1.0

Voxel Dosimetry™ only allows voxel-based dose calculations for patients who have been administered with radioisotopes.

Type of Use (Select one or both, as applicable)

Prescription Use (Part 21 CFR 801 Subpart D)

Over-The-Counter Use (21 CFR 801 Subpart C)

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510 (k) SUMMARY

A. Submitted by:

Submitters name and address: Hermes Medical Solutions AB Strandbergsgatan 16 112 51 Stockholm Sweden

. Submitters telephone number

Phone:	+46 8 19 03 25
Cell:	+46 708 19 03 08
E-mail:	ioakim.arwidson@hermesmedical.com

● Contact person

Joakim Arwidson VP Quality & Regulatory Hermes Medical Solutions AB Strandbergsgatan 16 112 51 Stockholm Sweden

Registration number . 9710645

B. Preparation date:

2019-03-12

C. Proprietary/Trade name, Common name, Classification name:

Proprietary/Trade name ● Voxel Dosimetry™ v1.0
. Common name System, Image Processing, Radiological
. Classification name Picture archiving and communications system, Class II, 21CFR892.2050.

D. Legally marketed device (predicate device):

Following legally marketed device has been used for comparison.

MIM-MRT Dosimetry (K182624) ●
. OLINDA/EXM® v2.0 (K163687)

E. Description of the device that is subject of this premarket notification:

Voxel Dosimetry™ is a tool for voxel level absorbed dose calculation resulting from radiotracer injection. Voxel Dosimetry™ workflow consists of the following steps:

SPECT/CT or PET/CT DICOM data loading from the data manager GOLD or ● PACS
. Registration of different time-points to a common reference study
. Generation and integration of voxel-level time-activity curves

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. Voxel-level absorbed dose calculation using a Monte Carlo-method
. Saving of the absorbed dose-map back to GOLD or PACS in DICOM format

F. Intended use:

The intended use of Voxel Dosimetry™ is to provide estimates (deterministic) of absorbed radiation dose at voxel level as a result of administering one of the supported radionuclides and to provide a dose map. This is dependent on input data regarding bio distribution being supplied to the application.

Voxel Dosimetry™ only allows voxel-based dose calculations for patients who have been administered with radioisotopes.

G. Technological characteristics:

MIM – MRT Dosimetry is based on voxel S-values (VSV), which is a voxel-based schema published in MIRD Pamphlet No. 17 (MIRD pamphlet No. 17: The dosimetry of nonuniform activity distributions-radionuclide S values at the voxel level. MIRD, J Nucl Med. 1999 Jan;40(1):115-36S), in which sources and targets are defined at the voxel level and voxel S-values calculated in a 3D matrix. The VSV approach is limited to lesions located in a homogeneous medium. As mentioned below, the Semi-Monte Carlo (SMC) method used in Voxel Dosimetry™ operates on a voxel level and performs dose calculation for photons and electrons based on patient specific CT scans. Voxel Dosimetry refers to the same patient population as MIM - MRT Dosimetry, support of the same isotopes (Lu-177, I-131) and has equivalent intended use.

The output from Voxel Dosimetry and MIM – MRT Dosimetry are dose maps containing voxel level doses to be used for dose volume histograms and curve analysis.

OLINDA/EXM® v2.0 is based on the use of S-factors, which are calculated on patient-like phantoms using a Monte Carlo method. The S-factors are equal to the average absorbed dose to a target organ generated by a unit of activity in a source organ. OLINDA/EXM® v2.0 dose calculations can thus be performed by multiplying the source organ time-activity curve integral by the S-factor. The SMC method used in Voxel Dosimetry™, on the other hand, operates on a voxel level and performs dose calculations for photons and electrons based on patient specific CT scans. Therefore, Voxel Dosimetry™ is patient-specific and produces voxel-level dose-maps instead of average organ-level dose estimates as OLINDA/EXM® v2.0 provides. Voxel Dosimetry ™ can also perform accurate lesion dosimetry because doses are calculated on a voxel-level and the same method can be used for lesions as for organs. This is not possible with OLINDA/EXM® v2.0, with which only a rough estimate of lesion doses is possible.

The output from Voxel Dosimetry v1.0 is a dose map containing voxel level doses in comparison to the predicate device OLINDA/EXM® v2.0, where the output is a CSV file including estimated dose for the organs.

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H. Testing:

The tests for verification and validation followed Hermes Medical Solutions AB design-controlled procedures. The Risk analysis was completed, and risk control implemented to mitigate identified hazards.

Voxel Dosimetry and OLINDA/EXM® v2.0 Lu177-DOTATATE kidney doses were compared, because this is one of the most common situations in internal radionuclide dosimetry today. The average of the relative differences between SMC and OLINDA/EXM® v2.0 was found to be 2% (Hippeläinen ET, Tenhunen MJ, Mäenpää HO, Heikkonen JJ, Sohlberg AO. Dosimetry software Hermes Internal Radiation Dosimetry: from quantitative image reconstruction to voxel-level absorbed dose distribution. Nuclear Medicine Communications 2017;38:5:357-365.), which is less than the uncertainty in Lu177 kidney dosimetry (Gustafsson J, Brolin G, Cox M, Ljungberg M, Johansson L, Gleisner KS. Uncertainty propagation for SPECT/CT-based renal dosimetry in Lu-177 peptide receptor radionuclide therapy. Phys Med Biol. 2015;60(21):8329–8346.) and thus the difference will not affect safety or effectiveness.

The validation (see TAB 5 - CL92.01 P55V1.0 Clinical Validation in the original 510k application), was performed by generating an XCAT phantom for each isotope, with four time points dependent on the isotope. The XCAT phantom code also generated cumulated activities for each voxel using a mono-exponential model with the effective half-lives of the isotopes. The phantom data was processed in Voxel Dosimetry™ which generated cumulated activities for each voxel based on the trapezoidal integration. The Voxel Dosimetry cumulated activities were compared to the true cumulated activities calculated with the mono-exponential model and the mentioned effective half-lives. The true cumulated activity was obtained by analytically integrating the monoexponential model. The true cumulated activity phantom data was also used to compare the Voxel Dosimetry™ dose calculations to the dose calculations made with the Monte Carlo code PENELOPE.

Isotope	Kidney	Tumor	Spleen
Ga68	6	6	7
I123	3	1	2
I131	7	2	3
In111	11	7	7
Lu177	7	3	3
Tc99m	8	7	6
Y90	12	8	8

Difference (100% x (Voxel Dosimetry -true)/true) between Voxel Dosimetry™ cumulated activity and the true cumulated activity.

Difference (100% x (Voxel Dosimetry -PENELOPE) between Voxel Dosimetry™ dose and PENELOPE dose

	Difference [%]
Isotope	Kidney	Tumor	Spleen
I123	2	3	3
I131	3	3	3
Ga68	12	12	12
In111	2	2	3
Lu177	1	1	1
Tc99m	2	3	3
Y90	5	6	4

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The cumulated activities and doses obtained with Voxel Dosimetry™ match the reference values well. The differences in cumulated activities are due to differences in time-activity curve shapes. The piecewise linear model used in Voxel Dosimetry™ did not always perfectly match the simulated mono-exponential kinetics. Differences in doses were small. The only larger difference is seen with the Ga68 isotope, which has high positron energy.

In addition to phantom testing, Voxel Dosimetry™ was also validated against the predicate device OLINDA/EXM® v2.0. Twelve treatment cycles of six patients who underwent Lu177-DOTATE treatments were compared. The patients were scanned with a Siemens Symbia T2 SPECT/CTscanner 1, 24, 72 and 168 hours after the treatment. The SPECT/CT scans were reconstructed and left and right kidney doses obtained with Voxel Dosimetry™ and OLINDA/EXM® were compared. Voxel Dosimetry and OLINDA/EXM® v2.0 left and right kidney doses were found to be highly correlated (Pearson's rleft=0.97 and rleft=0.98). The average of the relative difference was -2% when compared to OLINDA/EXM® v2.0. These results are presented in more detail in the publication (Hippeläinen E, Tenhunen M, Mäenpää H, Heikkonen J, Sohlberg A. Dosimetry software Hermes Internal Radiation Dosimetry: from quantitative image reconstruction to voxellevel absorbed dose distribution. Nucl Med Commun 2017; 38:357-365).

The testing results support that all the software specifications have met the acceptance criteria.

I. Substantially Equivalent/Conclusions:

MIM – MRT Dosimetry is based on voxel S-values (VSV), which is a voxel-based schema published in MIRD Pamphlet No. 17 (MIRD pamphlet No. 17: The dosimetry of nonuniform activity distributions--radionuclide S values at the voxel level. MIRD, J Nucl Med. 1999 Jan;40(1):115-36S), in which sources and targets are defined at the voxel level and voxel S-values calculated in a 3D matrix. The VSV approach is limited to lesions located in a homogeneous medium. As mentioned below, the Semi-Monte Carlo (SMC) method used in Voxel Dosimetry™ operates on a voxel level and performs dose calculation for photons and electrons based on patient specific CT scans. Voxel Dosimetry refers to the same patient population as MIM – MRT Dosimetry, support of the same isotopes (Lu-177, I-131) and has equivalent intended use.

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In summary, the Voxel Dosimetry™ v1.0, described in this submission has equivalent intended use and is, in our opinion, substantially equivalent to a combination of the predicate devices MIM-MRT Dosimetry (K182624) and OLINDA/EXM® v2.0 (K163687) and supports its clinical effectiveness, safety and intended use.

Regulation Number and Section

§ 892.2050 Medical image management and processing system.

(a)
Identification. A medical image management and processing system is a device that provides one or more capabilities relating to the review and digital processing of medical images for the purposes of interpretation by a trained practitioner of disease detection, diagnosis, or patient management. The software components may provide advanced or complex image processing functions for image manipulation, enhancement, or quantification that are intended for use in the interpretation and analysis of medical images. Advanced image manipulation functions may include image segmentation, multimodality image registration, or 3D visualization. Complex quantitative functions may include semi-automated measurements or time-series measurements.(b)
Classification. Class II (special controls; voluntary standards—Digital Imaging and Communications in Medicine (DICOM) Std., Joint Photographic Experts Group (JPEG) Std., Society of Motion Picture and Television Engineers (SMPTE) Test Pattern).