(379 days)
The Actim PROM test is a visually interpreted, qualitative immunoassay rapid test for the detection of amniotic fluid in cervicovaginal secretions during pregnancy. The Actim PROM test detects IGFBP-1, a major protein in amniotic fluid and a marker of the presence of amniotic fluid in a vaginal sample. The test is intended for prescription use in point of care and clinical laboratory settings to help diagnose the rupture of fetal membranes (ROM) in pregnant women ≥29 weeks gestation who present with signs, symptoms or complaints suggestive of ROM.
The Actim PROM test is a rapid test to aid in diagnosis of premature rupture of fetal membranes in pregnant women who present with signs, symptoms or complaints suggestive of RQM. The test is based on lateral flow immunoassay. It utilizes two monoclonal antibodies to human IGFBP-1. One of the two antibodies is bound to blue latex particles (detecting antibody). The other antibody is immobilized as a test line on the membrane (catching antibody). The test strip (dipstick) is composed of the sample/conjugate pad, the membrane with test and control lines, and the absorbent pad assembled between plastic films. The upper film contains a test window. When the sample area of the dipstick is placed in an extracted sample, the dipstick absorbs liquid, which starts to flow up the dipstick. If the sample contains IGFBP-1 it binds to the antibody labeled with latex particles. The particles are carried by the liquid flow, and if IGFBP-1 is bound to them, they bind to the catching antibody. A blue line (test line) will appear in the result area if the concentration of IGFBP-1 in the sample exceeds the detection limit of the test. A second blue line, the control line, confirms correct operator performance of the test.
The provided text describes a 510(k) submission for the Actim PROM test, which is a rapid diagnostic test to aid in the diagnosis of premature rupture of fetal membranes (PROM).
Here's an analysis of the acceptance criteria and the study that proves the device meets them:
1. Table of Acceptance Criteria and Reported Device Performance
The submission does not explicitly state pre-defined acceptance criteria in terms of specific sensitivity and specificity thresholds. However, the clinical study's results are presented, and the FDA's clearance implies that these results were deemed acceptable for the expanded intended use. For the purpose of this analysis, we can infer that the reported performance in Table 1 represents the "met" criteria.
| Metric (for ≥ 29 weeks Gestational Age) | Acceptance Criteria (Inferred) | Reported Device Performance (Without Speculum) | Reported Device Performance (With Speculum) |
|---|---|---|---|
| Sensitivity | High (to diagnose ROM) | 90.1% (95% CI: 83.1-94.4%) | 95.5% (95% CI: 89.8-98.0%) |
| Specificity | High (to rule out ROM) | 91.0% (95% CI: 84.2-95.0%) | 86.4% (95% CI: 78.7-91.6%) |
2. Sample Size Used for the Test Set and Data Provenance
- Sample Size for Test Set: 222 pregnant women for the overall study (≥ 29 weeks gestational age).
- For samples collected without a speculum: 222 (used in the overall analysis).
- For samples collected with a speculum: 220 (2 invalid results excluded).
- Data Provenance:
- Country of Origin: Multi-center study conducted at six US clinical sites.
- Retrospective or Prospective: Prospective clinical study.
3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of those Experts
The text does not specify the number of experts who established the ground truth. It states that the ground truth was determined by "clinical diagnosis as determined by the conventional clinical criteria identified above." These criteria include:
- Amniotic fluid seen leaking from the cervical os upon diagnostic speculum examination.
- Two of the three following clinical signs being positive: visual pooling of fluid in the posterior fornix, positive nitrazine test, or microscopic evidence of ferning.
The qualifications of the individuals making this clinical diagnosis (e.g., attending physicians, gynecologists, obstetricians) are not explicitly mentioned, but it is implied to be experienced medical professionals involved in patient care.
4. Adjudication Method for the Test Set
The adjudication method for establishing the ground truth was based on a combination of clinical observations and tests:
- Primary criterion: Amniotic fluid seen leaking from the cervical os upon diagnostic speculum examination.
- Secondary criteria (if the primary was not met): Fulfillment of at least two out of three conventional clinical signs (visual pooling, positive nitrazine test, or microscopic ferning).
This effectively acts as a consensus/hierarchical adjudication for clinical diagnosis, where direct observation is definitive, and a combination of other signs confirm in its absence.
5. 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, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not conducted, nor is the device an AI. The Actim PROM test is a visually interpreted, qualitative immunoassay rapid test. The study compared the device's performance against conventional clinical diagnosis, not against human readers with or without AI assistance.
6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done
The Actim PROM test is a standalone test in the sense that its result (the appearance of a blue line) is interpreted visually by a human operator. However, it's not an "algorithm only" device; it's a diagnostic kit. The study evaluates the performance of this standalone kit. The stated intended use is "visually interpreted." The "standalone" performance shown in the tables is the performance of the device without further human interpretation beyond reading the test line.
7. The Type of Ground Truth Used
The ground truth used in the clinical study was expert clinical diagnosis based on a set of conventional clinical criteria for PROM. These criteria included:
- Amniotic fluid seen leaking from the cervical os upon diagnostic speculum examination.
- Two of the three following clinical signs being positive: visual pooling of fluid in the posterior fornix, positive nitrazine test, or microscopic evidence of ferning.
8. The Sample Size for the Training Set
The text does not explicitly mention a separate "training set" for the Actim PROM device itself, as it is a lateral flow immunoassay device rather than a machine learning algorithm that requires a training phase. The clinical study described is a performance validation study on a test set.
9. How the Ground Truth for the Training Set Was Established
As there's no mention of a traditional "training set" in the context of an algorithm, this question is not directly applicable. If an older version of the device was "trained" or developed, the information is not provided in this specific submission summary. The current submission focuses on expanding the intended use for an existing device.
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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: K123986
The primary purpose of this 510(k) submission is to expand the intended use claims to support use of the Actim PROM test in pregnant women greater than or equal to (≥) 29 weeks gestational age and use of vaginal swab samples collected without the use of a speculum in addition to the current sample type, swabs collected with the use of a speculum.
To establish substantial equivalence to the predicate, the Actim PROM test was compared to the previously cleared version of the Actim PROM test (510(k) K061886).
SUBMITTER
Alere Scarborough, Inc. 10 Southgate Road Scarborough, Maine 04074 Establishment Registration Number: 1221359
CONTACT PERSON .
Angela Drysdale, VP Regulatory & Clinical Affairs - Infectious Disease Phone: (207)-730-5737 Fax: (207)-730-5717 Angela.drysdale@alere.com
DATE PREPARED
January 7, 2014
TRADE NAME
Actim PROM
COMMON NAME
Rupture of Fetal Membranes (ROM) Rapid Diagnostic Test
CLASSIFICATION NAME
Urinary pH (non-quantitative) Test System (per 21 CFR 862.1550)
CLASSIFICATION Class I
PRODUCT CODE OAM
PANEL Clinical Chemistry
PREDICATE DEVICE Actim PROM (510(k) K061886)
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DEVICE DESCRIPTION
The Actim PROM test is a rapid test to aid in diagnosis of premature rupture of fetal membranes in pregnant women who present with signs, symptoms or complaints suggestive of RQM. The test is based on lateral flow immunoassav. It utilizes two monoclonal antibodies to human IGFBP-1. One of the two antibodies is bound to blue latex particles (detecting antibody). The other antibody is immobilized as a test line on the membrane (catching antibody). The test strip (dipstick) is composed of the sample/conjugate pad, the membrane with test and control lines, and the absorbent pad assembled between plastic films. The upper film contains a test window. When the sample area of the dipstick is placed in an extracted sample, the dipstick absorbs liquid, which starts to flow up the dipstick. If the sample contains IGFBP-1 it binds to the antibody labeled with latex particles. The particles are carried by the liquid flow, and if IGFBP-1 is bound to them, they bind to the catching antibody. A blue line (test line) will appear in the result area if the concentration of IGFBP-1 in the sample exceeds the detection limit of the test. A second blue line, the control line, confirms correct operator performance of the test.
INTENDED USE
The Actim PROM test is a visually interpreted, qualitative immunoassay rapid test for the detection of amniotic fluid in cervicovaginal secretions during pregnancy. The Actim PROM test detects IGFBP-1, a major protein in amniotic fluid and a marker of the presence of ammiotic fluid in a vaginal sample. The test is intended for prescription use in point of care and clinical laboratory settings to help diagnose the rupture of fetal membranes (ROM) in pregnant women ≥29 weeks gestation who present with signs, symptoms or complaints suggestive of ROM.
TECHNOLOGICAL CHARACTERISTICS
The Actim PROM test is a qualitative, lateral flow immunoassay intended to aid in the detection of ruptured fetal membranes in pregnant women. Detection of results is by visual inspection. The Actim PROM test is intended for use in the point-of-care and clinical laboratory setting.
There have been no changes made to the Actim PROM test. The device is physically the same as the current, 510/k) cleared Actim PROM test. The purpose of this submission is to expand the indication for use claims to include use of the device in pregnant women ≥29 weeks gestational age and to allow use of the device with vaginal swabs collected without use of a speculum.
PERFORMANCE SUMMARY
CLINICAL STUDY
The clinical performance of the Actim PROM test was established in a multi-center, prospective clinical study conducted at six US clinical sites over an 18 month period. A total of 222 pregnant women presenting with signs/symptoms suggestive of ROM were evaluated using the Actim PROM test and compared to results obtained from conventional criteria. Subjects were considered clinically positive for PROM if amniotic fluid was seen leaking from the cervical os upon diagnostic speculum examination, or if two of the three following clinical signs were positive: visual pooling of fluid in the posterior fornix, positive nitrazine test or microscopic evidence of ferning. Actim PROM test performance was established relative to clinical diagnosis as determined by the conventional clinical criteria identified above.
Actim PROM test performance by sample type and gestational age versus clinical diagnosis, including 95% Confidence Intervals (CI), is presented below.
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Table 1: Actim PROM Test Performance vs. Clinical Diagnosis - Overall Results - ≥ 29 Weeks Gestational Age
| N | Sensitivity(95% Confidence Intervals) | Specificity(95% Confidence Intervals) | |
|---|---|---|---|
| ≥ 29 weeks(Without Speculum) | 222 | 90.1% (100/111)(95% CI: 83.1-94.4%) | 91.0% (101/111)(95% CI: 84.2-95.0%) |
| ≥ 29 weeks(With Speculum) | 220* | 95.5% (105/110)(95% CI: 89.8-98.0%) | 86.4% (95/110)(95% Cl: 78.7-91.6%) |
*2 invalid test results (control lines were not visible) were not included in the analysis for sample collected with speculum.
Performance of the Actim PROM test was analyzed based on a patient's gestational age at the time of sample collection.
Table 2: Actim PROM Test Performance vs. Clinical Diagnosis – ≥ 29 to 34 Weeks Gestational Age
| N | Sensitivity | Specificity | |
|---|---|---|---|
| (95% Confidence Intervals) | (95% Confidence Intervals) | ||
| ≥ 29 to 34 weeks(Without Speculum) | 97 | 95.7% (44/46) | 96.1% (49/51) |
| (95% CI: 85.5-98.8%) | (95% CI: 86.8-98.9%) | ||
| ≥ 29 to 34 weeks(With Speculum) | 96* | 95.7% (44/46) | 90.0% (45/50) |
| (95% CI: 85.8-98.8%) | (95% CI: 78.6-95.7%) |
*1 invalid test result (control line was not visible) was not included in the analysis for sample collected with speculum.
ANALYTICAL STUDIES
REPEATABILITY
A panel of specimens consisting of samples of different IGFBP-1 concentration levels was evaluated for intra-assay precision. The samples were tested with 10 replicates during the same day using three different lots of the Actim PROM test. Repeatable results were obtained.
REPRODUCIBILITY
A study of the Actim PROM test was conducted at three separate sites using panels of blind coded specimens containing negative (0ug/) of IGFBP-1), high negative (5ug/l of IGFBP-1), moderate negative (12.5ug/l of IGFBP-1), low positive (20ug/l of IGFBP-1), moderate positive (25ug/l of IGFBP-1), and high positive (30, 50, and 100ug/l of IGFBP-1) specimens. Test operators (n=9) tested each level multiple times over a period of five days. A total of 360 tests were performed (120 per site) with a total of 45 tests per sample. The overall reproducibility of the Actim PROM test is 97% (350/360) with no significant differences within runs (replicates tested by one operator), between runs (five different days), between sites (three sites) or between operators (nine operators).
ANALYTICAL SENSITIVITY
The analytical sensitivity (detection limit) of the Actim PROM test was identified by evaluating different concentrations of IGFBP-1 in extracted sample on three different lots of the Actim PROM test. Two different operators each interpreted ten devices run at each concentration under various lighting conditions for a total of 60 determinations per level. The Actim PROM test limit of detection (100% positive) is approximately 25 ug/L of IGFBP-1 in extracted sample. The measuring range of the Actim PROM test is approximately 25-500,000 ug/L in extracted sample. It should be noted that positive results could be observed for extracted samples with IGFBP-1 at <25 ug/L.
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ANALYTICAL SPECIFICITY
Analytical specificity (cross-reactivity) was tested with human IGFBP proteins at concentrations ranging from 10-5,000 µg/L of each protein in extracted sample were tested. No cross-reactivity was seen using human IGFBP-2, -3, -4, -5 and -6 proteins. The Actim PROM test is specific to human IGFBP-1.
INTERFERING SUBSTANCES
The following drugs, shower and bath products, odor control products, and vaginal pathogens were tested with Actim PROM test and were found not to affect Actim PROM test performance.
| Interfering Substance | Concentration Tested |
|---|---|
| Pevaryl (active ingredient: econatzol.nitras) | 30 mg/ml |
| Gyno-Trosyd (tioconazol) | 20 mg/ml |
| Flagyl (metronidazole) | 100 mg/ml |
| Canesten (clotrimazol) | 40 mg/ml |
| Personal Lubricant | 50% |
| Baby Oil | 50% |
| Baby Powder | 50% |
| Feminine Deodorant Suppositories | 50% |
| RepHresh Vaginal Gel | 50% |
| Feminine Deodorant Film | 50% |
| Candida albicans | 11.2 x 108 CFU/ml |
| Gardnerella vaginalis | 8.6 x 108 CFU/ml |
| Neisseria gonorrhea | 10.6 x 108 CFU/ml |
| Chlamydia trachomatis | * |
| HSV-1 | * |
| HSV-2 | * |
d as high concentration from the University of Turku, Finland
Semen and pregnancy urine were tested with the Actim PROM test. No interference of these substances was observed with the performance of the Actim PROM test. Whole blood with concentrations corresponding to typical pregnancy levels of IGFBP-1 was tested and did not affect Actim PROM test performance.
Samples with different pH levels from 3.5-8.5) were tested with the Actim PROM test and were found not to affect Actim PROM test performance.
Signed Angela Drysdale Date 1/7/2014
VP, Regulatory & Clinical Affairs - Infectious Disease Alere Scarborough, Inc.
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DEPARTMENT OF HEALTH & HUMAN SERVICES
Image /page/4/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo consists of a stylized eagle with three tail feathers. The eagle is facing to the right. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular fashion around the eagle.
Public Health Service
Food and Drug Administration 10903 New Hamnshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002
January 9, 2014
ALERE SCARBOROUGH, INC ANGELA DRYSDALE VP, REG/CLINICAL AFFAIRS - INFECTIOUS DISEASE 10 SOUTHGATE ROAD SCARBOROUGH ME 04074
Re: K123986
Trade/Device Name: Actim Prom, Actim Prom Controls Regulation Number: 21 CFR 862.1550 Regulation Name: Urinary pH (nonquantitative) test system Regulatory Class: I, meets limitations to exemption in 21 CFR 862.9(c)(9) Product Code: OAM Dated: December 23, 2013 Received: December 24, 2013
Dear Ms. Drysdale:
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. 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 Parts 801 and 809); medical device reporting (reporting of medical device-related adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.
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Page 2-Ms. Drysdale
If you desire specific advice for your device on our labeling regulations (2) CFR Parts 801 and 809), please contact the Division of Small Manufacturers, International and Consumer Assistance at its toll-free number (800) 638 2041 or (30.1) 796-7100 or at its Internet address http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803). please go to
http://www.fda.gov/MedicalDevices/Safety/ReportalProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.
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) 796-7100 or at its Internet address
http://www.fda.gov/MedicalDevices/ResourcesforYou/Industrv/default.htm.
Sincerely yours,
Courtney DHA.Lias-S
Courtney H. Lias, Ph.D. Director Division of Chemistry and Toxicology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health
Enclosure
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Indications for Use
510(k) Number (if known): K123986
Device Name: Actim® PROM
Indications for Use:
The Actim PROM test is a visually interpreted, qualitative immunoassay rapid test for the detection of amniotic fluid in cervicovaginal secretions during pregnancy. The Actim PROM test detects IGFBP-1, a major protein in amniotic fluid and a marker of the presence of amniotic fluid in a vaginal sample. The test is intended for prescription use in point of care and clinical laboratory settings to help diagnose the rupture of fetal membranes (ROM) in pregnant women > 29 weeks gestation who present with signs, symptoms or complaints suggestive of ROM.
Prescription Use X (21 CFR Part 801 Subpart D)
And/Or
Over the Counter Use (21 CFR Part 801 Subpart C)
(PLEASE DO NOT WRITE BELOW THIS LINE; CONTINUE ON ANOTHER PAGE IF NEEDED)
Concurrence of CDRH, Office of In Vitro Diagnostics and Radiological Health (OIR)
Denise Johnson-lyles -S
Division Sign-Off Office of In Vitro Diagnostics and Radiological Health
510(k) K123986
Page I of 1
§ 862.1550 Urinary pH (nonquantitative) test system.
(a)
Identification. A urinary pH (nonquantitative) test system is a device intended to estimate the pH of urine. Estimations of pH are used to evaluate the acidity or alkalinity of urine as it relates to numerous renal and metabolic disorders and in the monitoring of patients with certain diets.(b)
Classification. Class I (general controls). The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to § 862.9.