K Number

Device Name

POMC/PCSK1/LEPR CDx Panel

Manufacturer

PreventionGenetics, LLC

Date Cleared

2022-01-21

(490 days)

Product Code

QRV

Regulation Number

862.1164

Intended Use

The POMC/PCSK1/LEPR CDx Panel is a next generation sequencing (NGS)-based in vitro diagnostic test that analyzes genomic DNA isolated from blood or saliva. Specimens used with the test are K-EDTA blood collected using certain indicated K-EDTA blood collection devices and saliva collected using ORAcollect-Dx™ OCD-100 devices. The test detects germline nucleotide substitutions, short insertions and deletions, and copy number variants (CNVs) within the following 3 genes: - Pro-opiomelanocortin (POMC) . - Proprotein Convertase Subtilisin/Kexin type 1 (PCSKI) . - Leptin Receptor (LEPR) . The test is a companion diagnostic device intended to select adult and pediatric patients 6 years of age and older who have obesity and certain variants in POMC, PCSKI or LEPR genes for treatment with IMCIVREE® (setmelanotide) in accordance with the approved therapeutic product labeling. The POMC/PCSK1/LEPR CDx Panel is a single-site assay performed at PreventionGenetics, LLC (Marshfield, WI).

Device Description

The POMC/PCSK1/LEPR CDx Panel is a next generation sequencing (NGS) assay for the detection of germline variants in three genes (pro-opiomelanocortin (POMC), leptin receptor (LEPR), and convertase subtilisin/kexin type 1 (PCSK1)). The POMC/PCSK1/LEPR CDx Panel is performed in a single laboratory (PreventionGenetics, LLC in Marshfield, WI).

More Information

Contact

Type

Center

Panel

Date Received

Product Code

Subsequent Product Codes

Applicant Name (Manufacturer)

Device Name

Decision

Street 1

Street 2

City

State

Country Code

ZIP

Postal Code

Class Advise Committee

SSP Indicator

Third Party Reviewed

Expedited Review

Predicate Devices

K152464

Reference Devices

K152464

AI/ML (Artificial Intelligence / Machine Learning)

No
The summary describes a standard NGS-based in vitro diagnostic test for detecting genetic variants. There is no mention of AI or ML in the device description, intended use, or performance studies. The analysis is based on detecting specific genetic variants, not on learning patterns or making predictions using AI/ML algorithms.

Therapeutic

No.
The device is an in vitro diagnostic test used to identify specific genetic variants that help select patients for treatment; it does not directly treat or prevent a medical condition.

Diagnostic

Yes

The 'Intended Use / Indications for Use' section explicitly states that the device is an "in vitro diagnostic test" and a "companion diagnostic device."

SaMD (Software as a Medical Device)

The device is an in vitro diagnostic test that analyzes genomic DNA from blood or saliva using next generation sequencing (NGS). This involves physical components for sample collection, processing, and sequencing, which are hardware. While software is undoubtedly used for data analysis, the device as a whole is not software-only.

IVD (In Vitro Diagnostic)

Yes, this device is an IVD (In Vitro Diagnostic).

Here's why:

Explicitly stated in the Intended Use: The very first sentence of the "Intended Use / Indications for Use" section clearly states: "The POMC/PCSK1/LEPR CDx Panel is a next generation sequencing (NGS)-based in vitro diagnostic test..."
Analyzes specimens outside the body: The test analyzes genomic DNA isolated from blood or saliva, which are specimens collected from the patient and tested in vitro (outside the living organism).
Provides information for diagnosis or treatment: The test is a "companion diagnostic device intended to select adult and pediatric patients... for treatment with IMCIVREE® (setmelanotide) in accordance with the approved therapeutic product labeling." This directly links the test results to guiding treatment decisions, a key characteristic of an IVD.

Therefore, based on the provided information, the POMC/PCSK1/LEPR CDx Panel is definitively an In Vitro Diagnostic device.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

Pro-opiomelanocortin (POMC) .
Proprotein Convertase Subtilisin/Kexin type 1 (PCSKI) .
Leptin Receptor (LEPR) .

The test is a companion diagnostic device intended to select adult and pediatric patients 6 years of age and older who have obesity and certain variants in POMC, PCSKI or LEPR genes for treatment with IMCIVREE® (setmelanotide) in accordance with the approved therapeutic product labeling. The POMC/PCSK1/LEPR CDx Panel is a single-site assay performed at PreventionGenetics, LLC (Marshfield, WI).

Product codes (comma separated list FDA assigned to the subject device)

QRV

Device Description

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

Not Found

Indicated Patient Age Range

adult and pediatric patients 6 years of age and older

Intended User / Care Setting

The POMC/PCSK1/LEPR CDx Panel is a single-site assay performed at PreventionGenetics, LLC (Marshfield, WI).

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Precision/Reproducibility Study:
A precision study was performed to assess precision of the POMC/PCSK I/LEPR CDx Panel across different sources of variability over five sequencing runs. The study used " saliva samples collected into DNA Genotek ORAcollect Dx OCD-100 (K152464) and PIK-EDTA whole blood samples from patients within the intended use population. The samples were tested over DMA days using inputs of 200 ng DNA (one run), 300 ng DNA (1010) runs), and 400 ng DNA (one run) and reagent lots, multiple operators, and memonstruments. Samples included representative SNVs and insertions and deletions

Regulation Number and Section

N/A

Summary

Image /page/0/Picture/0 description: The image shows the logo of the U.S. Food and Drug Administration (FDA). The logo consists of two parts: a symbol on the left and the text "FDA U.S. FOOD & DRUG ADMINISTRATION" on the right. The symbol is a stylized representation of a caduceus, a traditional symbol of medicine. The text is written in blue and is stacked in three lines, with "FDA" on the top line, "U.S. FOOD & DRUG" on the second line, and "ADMINISTRATION" on the third line.

EVALUATION OF AUTOMATIC CLASS III DESIGNATION FOR POMC/PCSK1/LEPR CDx Panel DECISION SUMMARY

I Background Information:

A De Novo Number

DEN200059

B Applicant

PreventionGenetics, LLC

C Proprietary and Established Names

POMC/PCSK1/LEPR CDx Panel

D Regulatory Information

| Product
Code(s) | Classification | Regulation
Section | Panel |
|--------------------|----------------|------------------------------------------------------------------------------------|----------------------------|
| QRV | Class II | 21 CFR 862.1164 -
Setmelanotide
eligibility gene variant
detection system | CH - Clinical
Chemistry |

II Submission/Device Overview:

A Purpose for Submission:

De Novo request for evaluation of automatic class III designation for POMC/PCSK1/LEPR CDx Panel

B Measurand:

Germline variants in genes in human genomic DNA

C Type of Test:

Next generation sequencing

Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002 www.fda.gov

III Indications for Use:

A Indication(s) for Use:

Pro-opiomelanocortin (POMC) .
Proprotein Convertase Subtilisin/Kexin type 1 (PCSKI) .
Leptin Receptor (LEPR) .

B Special Conditions for Use Statement(s):

. Rx - For Prescription Use Only.
. For in vitro diagnostic use.
. Therapeutic decisions must be based on the independent medical judgement of the treating physician, taking into consideration the test results and all applicable information concerning the patient's condition, clinical history, and other findings.
. This test must be ordered by a qualified medical professional in accordance with clinical laboratory regulations. The classification and interpretation of all variants identified reflects the current state of scientific understanding at the time the result report is issued.
. When NGS does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles. Occasionally, a patient may carry an allele which does not capture or amplify, due for example to a large deletion or insertion.
. Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.
. The POMC/PCSK1/LEPR CDx Panel is not intended to detect mosaic variants.
. We cannot be certain that the reference sequences are correct. Genome build hg19, GRCh37 (Feb2009) is used as reference for this assay.
. Insertions and deletions larger than 18 base pairs in the variable number tandem repeat (VNTR) region in exon 3 (NM 000939.3) of the POMC gene with coordinates chr2:25,384,457-25,384,474 (GRCh37/hg19) containing repeated sequence "AGCAGCGGC" were not validated with this device and will not be reported.
. Two runs of intronic mononucleotide repeats [e.g., (A)n or (T)n] are excluded from the analysis. The excluded regions reside in LEPR (NM 002303.5) intron 4 (chr1:66,037,998-66,038,001) and post-coding (chr1:66,096,092-66,096,098) (GRCh37/hg19).

. Balanced translocations or inversions within a targeted gene, or large unbalanced translocations or inversions that extend beyond the genomic location of a targeted gene are not detected.
. In nearly all cases, our ability to determine the exact copy number change within a targeted gene is limited. In particular, when we find copy excess within a targeted gene, we cannot be certain that the region is duplicated, triplicated, etc. In many duplication cases, we are unable to determine the genomic location or the orientation of the duplicated segment with respect to the gene. In particular, we often cannot determine if the duplicated segment is inserted in tandem within the gene or inserted elsewhere in the genome. Similarly, we may not be able to determine the orientation of the duplicated segment (direct or inverted), and whether it will disrupt the open reading frame of the given gene.
. The performance of the POMC/PCSK1/LEPR CDx Panel was assessed for single nucleotide variants (SNVs), insertions and deletions 50 base pairs reported by the device may not be accurate other than the homozygous deletion in exons 6, 7. and 8 in the LEPR gene.
. The accuracy of the POMC/PCSK 1/LEPR CDx Panel was not assessed for PCSK 1 exon 2 and LEPR exon 7.
. The POMC/PCSK1/LEPR CDx Panel is for use only with whole blood collected in K2EDTA blood collection tubes or saliva specimens collected in DNA Genotek ORAcollect DxTM OCD-100 saliva collection devices.
. The assay has been validated with the Illumina NovaSeq6000.
. By definition, there is not sufficient scientific information available to make a pathogenicity assignment to variants of uncertain significance (VUS/VOUS). All variants and these variants in particular could change classification as new scientific information becomes available, which may impact patient eligibility for IMCIVREE (setmelanotide) injection.
. The pathogenicity assignments determined with the POMC/PCSK1/LEPR CDx Panel are intended to predict response to therapy with setmelanotide and are not intended for diagnostic purposes.

C Special Instrument Requirements:

Illumina NovaSeq6000 Sequencer (qualified by PreventionGenetics, LLC)

Device/System Characteristics: IV

A Device Description:

B Principle of Operation

Saliva samples collected into DNA Genotek ORAcollect Dx OCD-100 collection devices (K152464) and K2EDTA whole blood samples collected into certain indicated K2EDTA blood collection devices (as described in the labeling) are shipped to the Prevention Genetics (PG)

laboratory (Marshfield, WI). The laboratory utilizes NGS technologies to cover the full coding regions of the genes plus ~10 bases of noncoding DNA flanking each exon. DNA is captured using an optimized set of DNA hybridization capture probes and then sequenced using Illumina's Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA). Variant interpretations are based on the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines.

C Instrument Description Information

1. Instrument Name:
  Illumina NovaSeq6000 Sequencer (qualified by PreventionGenetics, LLC)
1. Specimen Identification:
  A maximum of P | POMC/PCSK |/LEPR CDx Panel samples can be prepared on | | | |assay at a time. Al and at least of positive human controls are processed (0) 4) along with patient samples with each library preparation of the POMC/PCSK1/LEPR CDx Panel. I 15721 TOKAT
1. Specimen Sampling and Handling:
  Specimens are collected and shipped to PreventionGenetics, LLC where they are accessioned upon receipt. Specimens may be stored according to the conditions described in Specimen stability (section F below) prior to processing.
1. Calibration:
  Calibration is performed after installation and may be performed after instrument repairs are performed. Calibration checks are performed regularly.
1. Quality Control:
  See Traceability, Stability, Expected Values (Controls, Calibrators, or Methods) (section VI.A.5. below).

V Standards/Guidance Documents Referenced:

CLSI EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - 3rd Edition

CLSI, EP09c, 3rd Edition, Measurement Procedure Comparison and Bias Estimation Using Patient Samples

CLSI. EP07, 3rd Edition, Interference Testing in Clinical Chemistry

Considerations for Design. Development, and Analytical Validation of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases: April 13, 2018

Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices; May 11, 2005

Cybersecurity for Networked Medical Devices Containing Off-the-Shelf (OTS) Software: January 14, 2005

Off-the-Shelf Software Use in Medical Devices; September 9, 1999

VI Performance Characteristics:

A Analytical Performance:

1. Precision/Reproducibility:

A precision study was performed to assess precision of the POMC/PCSK I/LEPR CDx Panel across different sources of variability over five sequencing runs. The study used " saliva samples collected into DNA Genotek ORAcollect Dx OCD-100 (K152464) and PIK-EDTA whole blood samples from patients within the intended use population. The samples were tested over DMA days using inputs of 200 ng DNA (one run), 300 ng DNA (1010) runs), and 400 ng DNA (one run) and reagent lots, multiple operators, and memonstruments. Samples included representative SNVs and insertions and deletions 10% weight loss after 1 year of treatment with IMCIVREE.

| Parameter | Statistic | Study 1
(N=10) | Study 2 (N=11) |
|----------------------------------------------------------|-----------|-------------------|----------------|
| Patients Achieving at Least
10% Weight Loss at Year 1 | n (%) | 8 (80.0%) | 5 (45.5%) |
| | 95% CI1 | (44.4%, 97.5%) | (16.8%, 76.6%) |
| | P-value2 | EDTA whole blood from 8 donors and from saliva from 8 donors. Each donor's DNA was assessed fresh after collection and extraction (baseline sample), after refrigerated storage (3.8 ± 0.8°C) 3 days and 1 month, and after 3 freeze/thaw cycles (each cycle consisted of a minimum of 3 h at -38.3 ± 0.3ºC and a minimum of 3 h at 45.5 ± 0.2°C). The complete sequence across POMC. PCSK1, and LEPR genes, including variants and reference sequence, was compared between each test condition and baseline. All samples passed OC metrics and demonstrated 100% sequence agreement between each test condition and baseline for all conditions tested. Studies to assess the stability of extracted DNA stored frozen (-20℃) for 12 months and 36 months are ongoing.

Proposed Labeling: VII

The labeling supports the decision to grant the De Novo request for this device.

Identified Risks to Health	Mitigation Measures
Incorrect performance of the test leading to
false positive results (causing patients to
receive drug treatment inappropriately) or false
negative results (causing patients to miss an
opportunity for drug treatment)	· Certain design verification and validation
activities, including documentation of
certain studies.
· Certain labeling information, including
certain limiting statements and
performance information.
Incorrect interpretation of genetic data leading
to false positive results (causing patients to
receive drug treatment inappropriately) or false
negative results (causing patients to miss an
opportunity for drug treatment)	· Certain design verification and validation
activities, including documentation of
certain studies and variant interpretation
and classification procedures.
· Certain labeling information, including
certain limiting statements and
performance information.

VIII Identified Risks and Mitigations:

IX Benefit/Risk Assessment:

A Summary of the Assessment of Benefit:

The POMC/PCSK1/LEPR CDx Panel provides a companion diagnostic test to select patients who have obesity and certain variants in POMC, PCSK1, or LEPR genes for IMCIVREE (setmelanotide) treatment. IMCIVREE (setmelanotide) is currently the only approved drug treatment for this patient population.

B Summary of the Assessment of Risk:

Incorrect performance of the test and/or incorrect interpretation of genetic data could lead to false positive or false negative results. False positive results could lead to a patient not eligible

for treatment receiving drug treatment inappropriately. False negative results could lead to a missed opportunity for drug treatment.

The most common adverse reactions associated with IMCIVREE (setmelanotide) treament in clinical studies were injections, skin hyperpigmentation, nausea, headache, diarthea, abdominal pain, back pain, fatigue, vomiting, depression, upper respiratory tract infection, and spontaneous penile erection. Depression and suicidal ideation occurred in IMCIVREE (setmelanotide) clinical studies.

C Patient Perspectives:

This submission did not include specific information on patient perspectives for this device.

D Summary of the Assessment of Benefit-Risk:

The risks of erroneous results are mitigated by the requirement of certain design verification and validation, including certain studies to ensure high analytical accuracy, precision, and specificity performance, and acceptable variant classification and interpretation procedures. Certain labeling information, including limiting statements in the test reports and labeling, serve to reduce the chances of false positives or negatives as a result of incorrect performance of the test and/or incorrect interpretation of genetic data.

Additionally, the IMCIVREE (setmelanotide) drug label includes stopping criteria to limit duration of drug exposure if a patient has not lost at least 5% of baseline body weight (or 5% of baseline body mass index for patients with continued growth potential) after 12-16 weeks of treatment, as well as periodic monitoring of treatment response. The drug label also includes monitoring for serious adverse effects, including new onset or worsening depression and discontinuation of the drug if a patient experiences suicidal thoughts or behaviors.

The probable benefits of this device outweigh the probable risks of this device, in light of the listed special controls and applicable general controls.

X Conclusion:

The De Novo request is granted and the device is classified under the following and subject to the special controls identified in the letter granting the De Novo request:

Product Code(s): ORV Device Type: Setmelanotide eligibility gene variant detection system Class: II Regulation: 21 CFR 862.1164