The RAMP CK-MB Assay is a quantitative immunochromatographic test indicated for use as an in vitro diagnostic product used with the RAMP Clinical Reader to measure CK-MB levels in EDTA whole blood. Measurement of CK-MB aids in the rapid diagnosis of acute myocardial infarction (AMI). The RAMP CK-MB Assay is not intended to monitor reperfusion patients. The RAMP CK-MB Assay is intended to be used only to prioritize patient management for those suspected of AMI.

Device Description

The RAMP CK-MB Assay is a quantitative immunochromatographic test for the determination of CK-MB levels in EDTA whole blood. Diluted EDTA whole blood is added to the sample well of the Test Cartridge which houses the immunochromatographic test strip. The red blood cells are retained in the sample pad, and the separated plasma migrates along the strip. Fluorescent-dyed latex particles coated with anti-CK-MB antibodies bind to CK-MB, if present in the sample. As the sample migrates along the strip, CK-MB bound particles are immobilized at the detection zone, and additional particles are immobilized at the internal control zone. The RAMP Reader then measures the amount of fluorescence emitted by the complexes bound at the detection zone and at the internal control zone. Using a ratio between the two fluorescence values, a quantitative reading is calculated.

AI/ML Overview

Here's an analysis of the acceptance criteria and study proving device performance for the Response Biomedical Corp. RAMP CK-MB Premarket Notification (K033747) based on the provided text:

Important Note: The provided text is a 510(k) summary, which is a regulatory document. It describes the studies performed to demonstrate substantial equivalence to a predicate device, not necessarily pre-defined "acceptance criteria" in the rigorous sense of a clinical trial primary endpoint. Therefore, I will interpret "acceptance criteria" as the performance characteristics and comparative metrics targeted to establish substantial equivalence.

Acceptance Criteria and Reported Device Performance

Acceptance Criteria (Interpreted)	Reported Device Performance (RAMP CK-MB Assay)
Precision (Intra-assay & Inter-assay)	Intra-assay Precision (Within-run %CV): - 7.7% at 7.19 ng/mL - 7.8% at 14.29 ng/mL - 4.8% at 25.06 ng/mL Total Precision (%CV): - 8.6% at 7.19 ng/mL - 8.5% at 14.29 ng/mL - 6.9% at 25.06 ng/mL
Linearity (R-value & Slope)	R = 0.999 for actual vs. expected CK-MB concentration Slope = 1.05 Offset = 0.098
Percent Recovery	Ranged from 99% to 111% (average 106%) for spiked CK-MB antigen (at 2.5, 5.0, 10.0, 20.0, 40.0, and 60.0 ng/mL concentrations)
Hook Effect	No high dose hook effect up to 1000 ng/mL CK-MB
Analytical Sensitivity (Lower Limit of Detection - LLD)	LLD = 0.32 ng/mL CK-MB
Analytical Specificity (Cross-reactivity)	CK-MM and CK-BB: No significant cross-reactivity HAMA, HAGA, HARA, RhF: Limited cross-reactivity
Interference	No evidence of cross-reactivity or interference observed for hemoglobin (up to 2000 mg/dL), triglyceride (up to 3000 mg/dL), bilirubin (up to 80 mg/dL), cholesterol, or heparin (up to 104 IU/mL). No trend observed with increasing interferent concentration.
Normal Range	0.00 to 3.74 ng/mL in a study of 180 healthy individuals (5th to 95th percentile). (Compared favorably to Triage: 0.80-4.94 ng/mL and Dimension: 0.10-3.11 ng/mL, and their package inserts).
Precision (Replicate Correlation)	Combined Populations: R=0.993, R²=0.988 (n=183) Suspect AMI Patients: R=0.993, R²=0.986 (n=128) Normal Individuals: R=0.959, R²=0.920 (n=55)
Method Comparison (Correlation with Predicate Device - Dimension CK-MB Assay)	RAMP CK-MB vs. Dimension: - Combined Normal and Suspect AMI: R=0.986, R²=0.972 (n=363) - Suspect AMI: R=0.984, R²=0.967 (n=183) - Normal: R=0.882, R²=0.779 (n=180)
Method Comparison (Correlation with Predicate Device - Triage CK-MB Assay)	Triage CK-MB vs. Dimension (for context/comparison): - Combined Populations: R=0.981, R²=0.962 (n=363) - Suspect AMI: R=0.981, R²=0.963 (n=183) - Normal: R=0.457, R²=0.209 (n=180)

Study Details:

Sample sizes used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)
- Precision Study: 184 subjects (55 normal, 129 suspected AMI). Data provenance is from "individual hospital criteria," suggesting it might be from sites within Canada or the US, but the specific country is not explicitly stated. The samples were taken and stored refrigerated for up to one day between analyses, implying a prospective or recently collected retrospective setup.
- Method Comparison Study: 365 subjects (180 normal, 185 suspected AMI). Data provenance similar to the precision study, from "individual hospital criteria." Normal subjects were consented, and waste samples were used for suspected AMI subjects. Samples were processed for rapid tests (RAMP and Triage) within one day, and heparin samples were frozen and sent to a reference lab for Dimension testing. This suggests a mixed prospective/retrospective approach.
- Expected Values (Normal Range Study): 180 healthy individuals (84 males, 96 females). Data provenance is not specified beyond "normal population studied."
Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)
- This device is an in vitro diagnostic (IVD) for measuring a biomarker (CK-MB). The ground truth for such devices is typically the quantitative value obtained from a reference method or predicate device, not expert interpretation of images or clinical diagnoses based on subjective input.
- For the "Method Comparison Study," the Dimension® RxL Mass Creatine Kinase MB Isoenzyme Flex® assay was used as the reference method (predicate device) against which both RAMP CK-MB and Triage CK-MB were compared. The "ground truth" (or reference standard) in this context is the quantitative CK-MB concentration determined by the Dimension assay.
- No human experts were used to establish the "ground truth" in the way one might for an imaging AI device; instead, an established laboratory method served as the reference. Clinical criteria for "suspected AMI" were mentioned as selection criteria for patients but not as the ground truth for an individual CK-MB value.
Adjudication method (e.g., 2+1, 3+1, none) for the test set
- No adjudication method, as typically described for subjective assessments like clinical diagnoses or imaging interpretations, was mentioned. The comparison was statistical (correlation, slope, intercept) between quantitative measurements from different assays.
- Outliers were removed from the dataset: "one outlier was removed from the population with suspect AMI" in the Precision Study, and "two outliers were removed from the suspect AMI samples from both the RAMP and Triage analyses" in the Method Comparison Study. This isn't an "adjudication" in the traditional sense but rather a data cleaning step.
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 reader study was mentioned. This device is an in vitro diagnostic assay, not an AI for image interpretation or a decision support tool for human readers. Its performance is measured directly against predicate assays and analytical specifications.
If a standalone (i.e. algorithm only without human-in-the-loop performance) was done
- Yes, the performance characteristics (precision, linearity, sensitivity, specificity, interference) and the method comparison studies represent the standalone performance of the RAMP CK-MB Assay and RAMP Reader system. It's essentially an "algorithm only" in the sense that the device outputs a quantitative value automatically, though it's an assay system rather than an AI algorithm as typically understood for imaging.
The type of ground truth used (expert consensus, pathology, outcomes data, etc.)
- Analytical Performance (Precision, Linearity, etc.): Ground truth was established by controlled laboratory experiments using known concentrations of CK-MB and analysis of samples without known interferents.
- Clinical Performance (Normal Range, Method Comparison): The "ground truth" or reference was the Dimension® RxL Mass Creatine Kinase MB Isoenzyme Flex® assay. For the normal range study, the normality of individuals was likely based on clinical screening (healthy individuals).
The sample size for the training set
- The document does not explicitly describe a "training set" in the context of machine learning or AI. This is a traditional IVD device (immunochromatographic assay). The development of such an assay involves extensive laboratory work to optimize reagents, antibodies, and detection protocols. This optimization phase isn't typically referred to as "training" in the same way an AI model is trained.
How the ground truth for the training set was established
- As there's no explicitly defined "training set" for an AI model, this question is not directly applicable. The development process would have involved establishing the ground truth for various analytical parameters through experiments with known samples and concentrations, guiding the assay's design and calibration.

Summary

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K033747

Response Biomedical Corp. RAMP CK-MB Premarket Notification

MAY 1 7 2004

510(k) Summary of Safety and Effectiveness 4.0

This summary of 510(k) safety and effectiveness information is being submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

The assigned 510(k) number is: K033747

1. Establishment

Response Biomedical Corp. 8081 Lougheed Highway Burnaby, British Columbia Canada, V5A 1W9

Tel: (604) 681-4101 Fax: (604) 412-9830

William J. Radvak Contact: President and CEO

November 27, 2003 Prepared:

2. Regulatory Information

Trade Name:	Response Biomedical Corp. RAMP® CK-MB Assay
Common Name:	CK-MB immunological test system
Classification Name:	CK-MB immunological test system
Regulation Number:	862.1215
Product Code:	JHX
Panel:	Clinical Chemistry

3. Predicate Device

Immunoassay:	Triage Cardiac Panel®; CK-MB Assay (K973126) which iscurrently being marketed by Biosite Diagnostics, Inc.
Immunoassay:	Dimension® RxL Mass Creatine Kinase MB IsoenzymeFlex®, (K970343) which is currently being marketed by DadeBehring Inc.

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Description of the Device 4.

The RAMP CK-MB Assay is a quantitative immunochromatographic test for the determination of CK-MB levels in EDTA whole blood. Diluted EDTA whole blood is to the sample well of the Test Cartridge which houses the added immunochromatographic test strip. The red blood cells are retained in the sample pad, and the separated plasma migrates along the strip. Fluorescent-dyed latex particles coated with anti-CK-MB antibodies bind to CK-MB, if present in the sample. As the sample migrates along the strip, CK-MB bound particles are immobilized at the detection zone, and additional particles are immobilized at the internal control zone.

The RAMP Reader then measures the amount of fluorescence emitted by the complexes bound at the detection zone and at the internal control zone. Using a ratio between the two fluorescence values, a quantitative reading is calculated.

5. Indication for Use

6. Comparison of Technological Characteristics

The RAMP CK-MB Assay, Triage Cardiac Panel (Triage) - CK-MB; and Dade Dimension RxL (Dimension) Creatine Kinase MB Isoenzyme (CK-MB) Flex Assays are for the quantitative measurement of CK-MB in human whole blood (RAMP and Triage) or plasma (Triage and Dimension). All three immunoassays utilize the binding of CK-MB to specific antibodies and utilize light in their respective detection systems. Both the RAMP and Triage assays measure light production from a fluorescence reaction using a fluorometer while the Dimension measures the amount of colored produced which is directly proportional to the concentration of CK-MB present in the patient sample. Both the RAMP CK-MB and the Triage CK-MB are quantitative immunochromatographic tests, whereas the Dimension CK-MB test is a sandwich enzyme immunoassay.

7. Summary of Studies

PERFORMANCE CHARACTERISTICS

PRECISION: The intra-assay and the inter-assay precision of the RAMP CK-MB Assay were determined by one operator assaying duplicates of three standards (7.19, 14.29 and 25.06 ng/mL CK-MB) twice each day over 10 days. The mean, standard deviation and %CV were calculated for the predicted CK-MB at each concentration. Within run precision was 7.7%, 7.8% and 4.8% respectively. Total precision was 8.6%, 8.5% and 6.9% respectively.

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LINEARITY and PERCENT RECOVERY: CK-MB antigen concentrations of 2.5, 5.0, 10.0, 20.0, 40.0 and 60.0 ng/mL were prepared in normal donor EDTA blood. The linearity and percent recovery were determined by assaying five replicates of each concentration and baseline. The mean, standard deviation and %CV were calculated for the predicted CK-MB at each concentration. Linear regression analysis of actual CK-MB concentration versus expected CK-MB concentration resulted with an R = 0.999 and a slope of 1.05 with an offset of 0.098. The recovery of spiked CK-MB antigen at the six concentrations ranged from 99 to 111% with an average of 106%.

HOOK EFFECT: There is no high dose hook effect in the RAMP CK-MB Assay up to the highest level tested (1000 ng/mL CK-MB).

ANALYTICAL SENSITIVITY: The lower limit of detection (LLD) is defined as the analyte concentration corresponding to the mean (n=20) plus 2 standard deviations of the zero. The LLD is 0.32 ng/mL CK-MB. CK-MB levels in excess of 80 ng/mL are reported as greater than (>) 80 ng/mL.

ANALYTICAL SPECIFICITY: Potentially cross-reactive substances were evaluated by spiking different concentrations into blood. CK-MM and CK-BB appear to have no significant cross-reactivity with the RAMP CK-MB Assay. HAMA, HAGA, HARA and RhF appear to have limited cross-reactivity with the RAMP CK-MB Assay.

INTERFERENCE: Potentially interfering substances were evaluated by spiking different concentrations of potential interferents in blood with CK-MB added. Different blood samples were used for each potential interference was evaluated by calculating the CK-MB concentration of potential interferent-spiked blood, expressed as a percentage of the CK-MB concentration of the unspiked (no potential interferent) blood sample. No evidence of cross-reactivity or interference was observed for hemoglobin, triglyceride, bilirubin, cholesterol, or heparin at levels of very high physiological concentrations, up to 2000 mg/dL, 3000mg/dL, 80 mg/dL, and 104 IU/mL, respectively. No trend was observed in the CK-MB predictions as the concentration of potential interferent was increased.

CLINICAL PERFORMANCE

EXPECTED VALUES

Whole blood samples from 180 healthy individuals (84 males and 96 females) were assayed for Troponin I by the three methods, RAMP, Triage, and Dimension. The lower assisted on the point on of the ormal range were defined as the 5" and 95" percentile values and are presented in Table 4-1. The RAMP CK-MB normal range distribution is presented in Figure 4-1.

The normal range of the RAMP CK-MB Assay was found to be 0.00 to 3.74 ng/mL in the normal population studied. The Triage system reports values less than 0.8 as "< 0.8" and because of this the normal range of the Triage Troponin I Assay was found to be 0.80 to 4.94 ng/mL in the normal population studied. This is very similar to the normal range described in the Triage CK-MB package insert of < 4.3 ng/mL [1]. Finally, the Dimension normal range was found to be 0.10 to 3.11 ng/mL in the normal population studied. This is very similar to the normal range described in the Dimension CK-MB package insert of 0.00 to 3.6 ng/mL [2]. The data is presented in Table 4-1.

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Percentile	RAMPng/mL	Triageng/mL	Dimensionng/mL
5th (LLN)	0.00	0.80	0.10
50th	0.78	1.30	0.70
90th	2.87	3.83	2.21
95th (ULN)	3.74	4.94	3.11
97.5th	4.99	8.38	4.88

Table 4-1: Percentile Ranking of Normal Individuals

Figure 4-1: RAMP Normal Range Distribution

Image /page/3/Figure/4 description: The image is a combination of a bar graph and a line graph. The bar graph, labeled as 'Frequency', shows the frequency of different values of 'RAMP CK-MB' on the x-axis, ranging from 0.00 to >10.5. The line graph, labeled as 'Cumulative %', shows the cumulative percentage on the right y-axis, ranging from 0% to 100%.

PRECISION STUDY

One hundred and eighty-four (184) subjects were enrolled in the Precision Study. Of these, 55 were normal individuals (28 males and 27 females) and 129 were suspected of acute myocardial infarct (AMI) based on the individual hospital criteria (76 males and 53 females). The samples were selected from those obtained during the Method Comparison Study. The samples were stored refrigerated for up to one day between analyses. The data were reviewed and one outlier was removed from the population with suspect AMI, Correlation for CK-MB replicate Result 2 vs Result 1 is presented in Tatler with 3

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Population	n	Slopey =	Intercept	R2	R
Combined Populations,	183	0.989	0.021	0.988	0.993
Patients with suspect AMI	128	0.989	0.051	0.986	0.993
Normal Individuals	55	0.926	0.056	0.920	0.959

Table 4-2: Precision of RAMP CK-MB Assay, Result 1 vs Result 2

METHOD COMPARISON

Three hundred and sixty-five (365) subjects were enrolled in the Method Comparison Study. Of these subjects 180 were normal individuals (84 males and 96 females) and 185 were patients suspected of AMI based on the individual hospital criteria (115 males and 70 females). EDTA and heparin whole blood samples were obtained for each of these subjects. All normal subjects were consented. Waste samples were used for the subjects suspected of AMI. An aliquot of whole blood was taken for the RAMP CK-MB Assay and heparinized plasma was prepared for the Triage CK-MB Assay and the Dimension CK-MB assay. The samples were stored refrigerated for up to one day between analysis for the rapid tests. Heparin samples were frozen and sent to a reference lab for the Dimension testing.

Results were compared between the RAMP CK-MB and the Triage CK-MB each to the Dimension CK-MB Assay. The data were winsorized to account for the differing reportable ranges and two outliers were removed from the suspect AMI samples from both the RAMP and Triage analyses. The correlation data is presented for both the RAMP and Triage CK-MB Assays versus the Dimension CK-MB Assay in Table 4-3.

Population	n	Slopey=	Intercept	R2	R
RAMP CK-MB Assay
Combined Normal andSuspect AMI Subjects	363	0.966	0.600	0.972	0.986
Suspect AMI Subjects	183	0.955	1.207	0.967	0.984
Normal Subjects	180	0.978	0.162	0.779	0.882
Triage CK-MB Assay
Combined Populations	363	1.036	2.204	0.962	0.981
Patients with suspect AMI	183	1.017	3.783	0.963	0.981
Normal Individuals	180	1.124	0.911	0.209	0.457

Table 4-3: Correlation of RAMP and Triage vs. Dimension

8. Conclusion

The RAMP CK-MB Assay when utilized with the RAMP Reader is substantially equivalent to other assays currently in commercial distribution for the measurement of CK-MB.

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Image /page/5/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle or bird-like symbol with three curved lines representing its body and wings. The symbol is enclosed within a circular border, and the text "DEPARTMENT OF HEALTH & HUMAN SERVICES • USA" is arranged around the upper half of the circle.

Food and Drug Administration 2098 Gaither Road Rockville MD 20850

MAY 1 7 2004

Mr. William J. Radvak President and CEO Response Biomedical Corp. 8081 Lougheed Hwy. Burnaby, British Columbia, Canada V5A 1W9

K033747 Re:

Trade/Device Name: RAMP CK-MB Assay Regulation Number: 21 CFR 862.1215 Regulation Name: Creatine phosphokinasc/creatine kinase or isoenzymes test system Regulatory Class: Class II Product Code: JHX Dated: March 15, 2004 Reccived: March 15, 2004

Dear Mr. Radvak:

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 prodicate 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. 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.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to such additional controls. Existing major regulations affecting your device can be found in Title 21, Code of Federal Regulations (CFR), Parts 800 to 895. 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 CHR Part 807); labeling (21 CFR Parts 801 and 809); and good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820).

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Page 2

This letter will allow you to begin marketing your device as described in your Section 510(k) premarket notification. The FDA finding of substantial equivalence of your device to a legally marketed predicate device results in a classification for your device and thus, permits your device to proceed to the market.

If you desire specific information about the application of labeling requirements to your device, or questions on the promotion and advertising of your device, please contact the Office of In Vitro Diagnostic Device Evaluation and Safety at (301) 594-3084. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). You may obtain other general information on your responsibilities under the Act from the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638-2041 or (301) 443-6597 or at its Internet address http://www.fda.gov/cdrh/dsma/dsmamain.html.

Sincerely vours.

Jean M. Cooper, US, DVM.

Jean M. Cooper, MS, D.V.M. Director Division of Chemistry and Toxicology Office of In Vitro Diagnostic Device Evaluation and Safety Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known): K033747

RAMP CK-MB Assay Device Name:

The RAMP CK-MB Assay is a quantitative Indications For Use: immunochromatographic test indicated for use as an in vitro diagnostic product used with the RAMP Clinical Reader to measure CK-MB levels in EDTA whole blood. Measurement of CK-MB aids in the rapid diagnosis of acute myocardial infarction (AMI). The RAMP CK-MB Assay is not intended to monitor reperfusion patients. The RAMP CK-MB Assay is intended to be used only to prioritize patient management for those suspected of AMI.

Prescription Use X (IVD) (Part 21 CFR 801 Subpart D)

AND/OR Over-The-Counter Use N/A (21 CFR 807 Subpart C)

(PLEASE DO NOT WRITE BELOW THIS LINE-CONTINUE ON ANOTHER PAGE IF NEEDED)

Concurrence of CDRH, Office of In Vitro Diagnostic Devices (OIVD)

ivision Sig

Office of In Vitro Diagnostic Device Evaluation an

Page 1 of 1

510(k) K035747

Regulation Number and Section

§ 862.1215 Creatine phosphokinase/creatine kinase or isoenzymes test system.

(a)
Identification. A creatine phosphokinase/creatine kinase or isoenzymes test system is a device intended to measure the activity of the enzyme creatine phosphokinase or its isoenzymes (a group of enzymes with similar biological activity) in plasma and serum. Measurements of creatine phosphokinase and its isoenzymes are used in the diagnosis and treatment of myocardial infarction and muscle diseases such as progressive, Duchenne-type muscular dystrophy.(b)
Classification. Class II.