(11 days)
None.
Not Found
Unknown
The device description mentions a "multivariate index assay" and an "AlloMap Test algorithm" that converts gene expression levels to a score. While this suggests a computational method is used, the summary does not explicitly state whether this algorithm utilizes AI or ML techniques. The lack of mention of AI, DNN, or ML, and the absence of details about training sets for model development, make it impossible to definitively confirm the presence of AI/ML.
No
This device is an In Vitro Diagnostic (IVD) test service that aids in identifying heart transplant recipients with a low probability of moderate/severe acute cellular rejection. It does not directly treat or prevent a disease or condition.
Yes
The "Intended Use / Indications for Use" states that "AlloMap Testing is intended to aid in the identification of heart transplant recipients with stable allograft function who have a low probability of moderate/severe acute cellular rejection (ACR) at the time of testing in conjunction with standard clinical assessment." This explicitly indicates its purpose is to provide information for diagnosis or to aid in identifying a medical condition.
No
The device description clearly states that the testing involves processing blood samples, determining gene expression levels via real time PCR, and converting these to a score. This process involves physical laboratory procedures and hardware (PCR machines), not just software.
Yes, this device is an IVD (In Vitro Diagnostic).
Here's why:
- Explicitly Stated: The "Intended Use / Indications for Use" section clearly states: "AlloMap Molecular Expression Testing is an In Vitro Diagnostic Multivariate Index assay (IVDMIA) test service..."
- Definition of IVD: An IVD is a medical device used to examine specimens, such as blood, collected from the human body to provide information for diagnosis, monitoring, or screening. This description perfectly matches the AlloMap test, which analyzes RNA from peripheral blood to aid in identifying patients with a low probability of rejection.
- Testing Performed Outside the Body: The test is performed in a laboratory (XDx Laboratories) on a blood sample taken from the patient, which is the hallmark of an in vitro diagnostic.
Therefore, based on the provided information, the AlloMap Molecular Expression Testing is indeed an In Vitro Diagnostic device.
N/A
Intended Use / Indications for Use
AlloMap Molecular Expression Testing is an In Vitro Diagnostic Multivariate Index assay (IVDMIA) test service, performed in a single laboratory, assessing the gene expression profile of RNA isolated from peripheral blood mononuclear cells (PBMC). AlloMap Testing is intended to aid in the identification of heart transplant recipients with stable allograft function who have a low probability of moderate/severe acute cellular rejection (ACR) at the time of testing in conjunction with standard clinical assessment.
Indicated for use in heart transplant recipients:
- l 15 years of age or older
- I At least 2 months (>55 days) post-transplant
Product codes (comma separated list FDA assigned to the subject device)
OJC
Device Description
AlloMap Molecular Expression Testing is performed in a single laboratory (XDx Laboratories). Blood is drawn from the patient and subsequently processed, packaged and shipped frozen to the XDx Laboratory. At the XDx Laboratory, gene expression levels are determined via real time PCR for each of the test and control genes and converted to the AlloMap Test Score. The AlloMap Test Score is then reported to the physician.
A sample collection kit is sent to ordering laboratories/physicians. The collection kits contain the following components:
CPT™ Cell Preparation Tube with Sodium Citrate, 8.0 ml, 60/box
(only tubes supplied by XDx should be used)
AlloMap Sample Processing Reagents
- 10 centrifuge tubes with 5.0 mL phosphate buffered saline ●
- 10 tubes with 1.8 mL of LyseDx™ lysing reagent ●
- 10 disposable transfer pipettes
- Sample preparation instructions ●
XDx Laboratory Frozen Shipper Pack
- Aqui-Pak 6-Bay absorbent pouch .
- . 95 kPa Specimen Transport Bag
- Dry ice label ●
- List of Contents card
- Styrofoam™ cooler
- Outer shipping box
- FedEx Shipping Packets (customized airbills and labels) .
- 9 x 12 plastic zip bag
- Requisitions, 2-part NCR
- Aqui-Pak 6-Bay absorbent pouch, each ●
- 95 kPa specimen transport bags, each ●
Mentions image processing
Not Found
Mentions AI, DNN, or ML
Not Found
Input Imaging Modality
Not Found
Anatomical Site
Heart
Indicated Patient Age Range
15 years of age or older
Intended User / Care Setting
Physician / Single laboratory (XDx Laboratories)
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
A total of 300 samples, from 154 patients enrolled in CARGO not used to develop the AlloMap Test algorithm, were assayed with the AlloMap Test. These samples conformed to the following inclusion criteria:
- At least 55 days since transplantation, and
- . More than 30 days after administration of immunosuppressive therapy for treating rejection.
The study used the following definition for rejection: a local biopsy grade ≥3A that was also assigned grade ≥3A by at least one of the three panel pathologists ("confirmed rejection"). All local ≥3A biopsies were graded by the central pathologists. The no rejection class included all samples that did not qualify as rejection.
Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)
Clinical validation was performed to evaluate the performance characteristics of the AlloMap Test in cardiac transplant patients. Samples used for the study were derived from the prospective, observational multi-center Cardiac Allograft Rejection Gene Expression Observational (CARGO) study. A total of 300 samples, from 154 patients enrolled in CARGO, were assayed with the AlloMap Test. The AUC calculated from the 300 samples from 154 patients using the method of Emir et al. (1998) was 0.67 with 95% confidence interval from 0.56 to 0.78 calculated by bootstrap. The AUC for the 55-182 days post-transplant period was 0.71 with 95% confidence interval from 0.56 to 0.84. The AUC for the ≥183 days post-transplant period was 0.67 with 95% confidence interval from 0.50 to 0.88.
Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)
PPV = positive predictive value, NPV = negative predictive value
For >2 - 6 months (n=166 samples):
| AlloMap
Score | % Pts
Below | PPV
≥3A(2R) | PPV
Std. Err. | NPV
6 months (n=134 samples):
| AlloMap
Score | % Pts
Below | PPV
≥3A(2R) | PPV
Std. Err. | NPV
§ 862.1163 Cardiac allograft gene expression profiling test system.
(a)
Identification. A cardiac allograft gene expression profiling test system is a device that measures the ribonucleic acid (RNA) expression level of multiple genes and combines this information to yield a signature (pattern, classifier, index, score) to aid in the identification of a low probability of acute cellular rejection (ACR) in heart transplant recipients with stable allograft function.(b)
Classification. Class II (special controls). The special control is FDA's guidance document entitled “Class II Special Controls Guidance Document: Cardiac Allograft Gene Expression Profiling Test Systems.” See § 862.1(d) for the availability of this guidance document.
0
510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY AND INSTRUMENT COMBINATION TEMPLATE
A. 510(k) Number:
- B. Purpose for Submission: New device
- C. Measurand:
RNA expression of 20 genes
D. Type of Test:
Quantitative RT-PCR analysis of 20 genes (11 informative; 9 control); IVDMIA Test service performed in a single laboratory in XDx's Brisbane, CA facility
-
E. Applicant:
XDx -
F. Proprietary and Established Names: AlloMap® Molecular Expression Testing
G. Regulatory Information:
-
- Regulation section: 21 CFR §862.1163
-
- Classification: Class II
-
- Product code: OJC Cardiac allograft gene expression profiling test system
-
- Panel: Chemistry (75)
H. Intended Use:
-
- Intended use(s): See Indications for use below.
-
- Indication(s) for use:
AlloMap Molecular Expression Testing is an In Vitro Diagnostic Multivariate Index assay (IVDMIA) test service, performed in a single laboratory, assessing the gene expression profile of RNA isolated from peripheral blood mononuclear cells (PBMC). AlloMap Testing is intended to aid in the identification of heart transplant recipients with stable allograft function who have a low probability of moderate/severe acute cellular rejection (ACR) at the time of testing in conjunction with standard clinical assessment.
Indicated for use in heart transplant recipients:
- l 15 years of age or older
- I At least 2 months (>55 days) post-transplant
-
- Special conditions for use statement(s): For prescription use only.
-
- Special instrument requirements:
1
| System Identifying
Number | Manufacturer | Model | Serial Number |
---|---|---|---|
969050 | Beckman Coulter | Biomek FXp (8 single) | A318430104 |
504671 | Beckman Coulter | Biomek FXp (8 single) | A318430102 |
504672 | Beckman Coulter | Biomek FXp (8 single) | A318430103 |
Liquid Handler Instruments:
PCR Instruments: All RT-PCR instruments are from Applied Biosystems, Model 7900HT. The System Identifying Number and Serial Number are the same. Serial numbers of the instruments are: 200866, 279001667, 279001146, 200899, 201747, 201308, 279000980, 279000917.
Note: The liquid handling instruments and RT-PCR instruments are components of this assay and are cleared only for this assay and not for any other application. In addition, clearance is only limited to the liquid handling and PCR instruments with the serial numbers as specified above.
I. Device Description:
AlloMap Molecular Expression Testing is performed in a single laboratory (XDx Laboratories). Blood is drawn from the patient and subsequently processed, packaged and shipped frozen to the XDx Laboratory. At the XDx Laboratory, gene expression levels are determined via real time PCR for each of the test and control genes and converted to the AlloMap Test Score. The AlloMap Test Score is then reported to the physician.
A sample collection kit is sent to ordering laboratories/physicians. The collection kits contain the following components:
CPT™ Cell Preparation Tube with Sodium Citrate, 8.0 ml, 60/box
(only tubes supplied by XDx should be used)
AlloMap Sample Processing Reagents
- 10 centrifuge tubes with 5.0 mL phosphate buffered saline ●
- 10 tubes with 1.8 mL of LyseDx™ lysing reagent ●
- 10 disposable transfer pipettes
- Sample preparation instructions ●
XDx Laboratory Frozen Shipper Pack
- Aqui-Pak 6-Bay absorbent pouch .
- . 95 kPa Specimen Transport Bag
- Dry ice label ●
- List of Contents card
- Styrofoam™ cooler
- Outer shipping box
- FedEx Shipping Packets (customized airbills and labels) .
2
- 9 x 12 plastic zip bag
- Requisitions, 2-part NCR
- Aqui-Pak 6-Bay absorbent pouch, each ●
- 95 kPa specimen transport bags, each ●
J. Substantial Equivalence Information:
-
- Predicate device name(s): None.
-
- Predicate K number(s): Not applicable.
-
- Comparison with predicate: Not applicable.
K. Standard/Guidance Document Referenced (if applicable):
· Draft Guidance for Industry, Clinical Laboratories, and FDA Staff - In Vitro Diagnostic Multivariate Index Assays
• Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: Class II Special Controls Guidance Document: Gene Expression Profiling Test System for Breast Cancer Prognosis
• Interference Testing in Clinical Chemistry; Approved Guideline (EP7-A2)
L. Test Principle:
Blood specimen collection at the referring facility is initiated by a physician order. Whole blood is collected in an 8.0 mL Vacutainer CPT Cell Preparation Tube with Sodium Citrate (CPT tube). The PBMCs are separated from the whole blood sample via centrifugation of the CPT tube. The PBMCs are washed, pelleted and lysed using reagents provided to customers by XDx. This PBMC lysate material is frozen and shipped to XDx. Upon arrival at XDx, RNA from the PBMC lysate is purified and quantified using spectrophotometric methods. Upon meeting acceptance criteria, cDNA synthesis proceeds using a liquid handling instrument to dispense samples and reagents to the 96-well reaction plates.
Purified RNA is converted to cDNA. The cDNA provides the template for the qRT-PCR. cDNA synthesis steps are monitored for run to run variability by including pooled human RNA prepared using the same procedures utilized for patient testing. The cDNA is added to the AlloMap reagent plates and the plates are sealed and loaded into the qRT-PCR instruments.
The XDx-developed Analyzer software converts sample data generated from the qRT-PCR plate to an AlloMap test score using the proprietary XDx AlloMap algorithm for multivariate analysis. A report is generated that provides the physician with the AlloMap test score. Longitudinal results, negative predictive values (NPV) for two time post-transplant periods and patient demographics are also provided. The physician interprets the results along with other standard clinical assessments of cardiac allograft status to determine probability of ACR.
M. Performance Characteristics (if/when applicable):
-
- Analytical performance:
3
a. Precision/Reproducibility:
Precision was evaluated using two types of samples, XDx donor samples and patient samples. Patient samples were obtained from 6 individual cardiac transplant recipients from two CARGO centers (3 patients per center). 3 samples per patient were provided from one center, and 4 samples per patient were provided from the second center.
Patient | Sex | Race | Days Since Tx | Age at visit | ISHLT Grade |
---|---|---|---|---|---|
P1 | Male | Hispanic | 294 | 31 | Grade 1A |
P2 | Male | Asian | 653 | 32 | Grade 1B |
P3 | Male | Black | 431 | 59 | Grade 1A |
P4 | Male | Caucasian | 232 | 60 | Grade 0 |
P5 | Male | Asian | 279 | 44 | Grade 1B |
P6 | Female | Caucasian | 274 | 34 | Grade 1B |
Patient Information for Samples used in Precision Study
The AlloMap scores for healthy donors ranged from 28 to 30. The AlloMap scores for patients ranged from 24 to 34 (no biopsy information available). There are three arms for each type of sample: Arms A, B, and C. For Arms A and B, three sources of variability, run-to-run, operator-tooperator (inter-operator) and within operator (intra-operator), were estimated at different points of the process. Arm A provides variability estimates from RNA->cDNA->Assay, while Arm B provides variability estimates from cDNA->Assay. Arm C estimates variability of lot-to-lot, plate-to-plate within a lot, and section-to-section within a plate and a lot at the Assay level. Arm A: For each operator in this study, testing was conducted on four separate days. All four operators performed 4 separate runs with samples from each of the 4 donors. For each operator, each run was initiated on a separate day and included 1 sample from each of the four donors. One lot of reagents was used in testing.
Arm B: For each operator in this study, testing was conducted on two separate days. One lot of reagents was used in testing.
Arm C: All testing was performed by a single operator on a single day; run-torun precision was not a component of this arm. This arm used 3 lots of reagents for the analytical phase of testing to measure lot-to-lot, plate-to-plate and section-to-section precision.
The precision of the AlloMap Test process is summarized below. Summary of maximum CV's are:
- . Overall CV's (Tables A1, A2, A7 and A8):
- o 4 Donor Samples (Arm A): ≤6.3%
4
- 6 Patient Samples (Arm A): ≤10.4% o
- o Donor Sample (Arm C): 3.8%
- Pooled Patient Sample (Arm C): 4.4% o
- Run-to-run CV's (Tables A3, A4) ●
- o Donor Samples: ≤9.2%
- o Patient Samples: ≤11.9%
- . Operator-to-operator CV's (Tables A5, A6)
- o Donor Samples: ≤8.3%
- o Patient Samples: ≤11.7%
- Lot-to-lot CV's (Tables A9, A10) ●
- o Donor Samples: ≤4.7%
- o Patient Samples: ≤4.5%
- Plate-to-plate CV's (Tables A11, A12)
- o Donor Samples: ≤5.1%
- o Patient Samples: 15) | | Met all testing QC criteria | |
|--------------------------|-----------|----------------------------|----|------------------------------------|----|-----------------------------|----|
| | | # | % | # | % | # | % |
| 1.5 to 2.1 | 235 | 226 | 96 | 9 | 4 | 217 | 92 |
| 2.2 to 2.8 | 128 | 120 | 94 | 8 | 6 | 111 | 87 |
| 2.9 to 3.5 | 10 | 7 | 70 | 3 | 30 | 6 | 60 |
| 3.6 to
11.8 | 25 | 6 | 24 | 19 | 76 | 3 | 12 |
| 1.5 to 3.5 | 373 | 353 | 95 | 20 | 5% | 334 | 90 |
The acceptable A260/A280 ratio range for AlloMap testing is 1.5 to 3.5.
d. Analytical specificity:
Immunosuppression therapy:
Serum drug levels for cyclosporine A, tacrolimus and sirolimus, were examined in the XDx CARGO database to assess the potential of immunosuppressant interference on the AlloMap test. These drugs were chosen based on common usage and on the inclusion of more than one mechanism of action.
Drug levels were extracted for the 700 CARGO samples used in the XDx Population study. The distribution of the three immunosuppressants ranged across and above the therapeutic levels typical of cardiac transplant patients. The level of concordance between AlloMap scores and biopsy grades were compared in samples with therapeutic levels versus those samples with drug levels greater than the therapeutic range.
Serum levels of immunosuppressants (cyclosporine A, tacrolimus and sirolimus) for the samples from the Population Study data set were obtained.
10
The distribution of all samples, and samples broken down into rejection (R) and no rejection (NR) subsets are shown for below, within and above the respective therapeutic ranges. Class definitions are: R is local biopsy grades ≥3A and NR is local biopsy grade 2 - 6 months (n=166 samples) | | | | | >6 months (n=134 samples) | | | | | |
|------------------|-------------------------------|----------------|------------------|----------------|------------------|---------------------------|----------------|------------------|----------------|------------------|------------------|
| AlloMap
Score | % Pts
Below | PPV
≥3A(2R) | PPV
Std. Err. | NPV