(62 days)
First Sign® Drug of Abuse Buprenorphine Cup Test
First Sign® Drug of Abuse Buprenorphine Dip Card Test
First Sign™ Drug of Abuse Buprenorphine Tests are immunochromatographic assays for the qualitative determination of Buprenorphine, in human urine at cut-off concentration of 10 ng/mL. The tests are available in a Cup format and a Din Card format.
The tests may yield preliminary positive results even when prescription drug Buprenorphine is ingescribed doses; it is not intended to distinguish between prescription use or abuse of this drug. There is no uniformly recognized cutoff concentration level for Buprenorphine in urine. The tests provide only preliminary test results. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. Gas Chromatography/Mass Spectrometry is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive.
For in vitro diagnostic use only. The tests are intended for over-the-counter and for prescription use.
First Sign® Drug of Abuse Butalbital Cup Test
First Sign® Drug of Abuse Butalbital Dip Card Test
First Sign™ Drug of Abuse Butalbital Tests are immunochromatographic assays for the qualitative determination of Butalbital in human urine at cut-off concentration of 300 ng/mL. The tests are available in a Cup format and a Dip Card format.
The tests may yield preliminary positive results even when prescription drug Butalbital is ingested, at prescribed doses; it is not intended to distinguish between prescription use or abuse of this drug. There is no uniformly recognized cutoff concentration level for Butalbital in urine. The tests provide only preliminary test results. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. Gas Chromatography/Mass Spectrometry is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive.
For in vitro diagnostic use only. The tests are intended for over-the-counter and for prescription use.
First Sign® Drug of Abuse Morphine Cup Test
First Sign® Drug of Abuse Morphine Dip Card Test
First Sign™ Drug of Abuse Morphine Tests are immunochromatographic assays for the qualitative determination of Morphine in human urine at cut-off concentration of 300 ng/mL. The tests are available in a Cup format and a Dip Card format.
The tests provide only preliminary test results. A more specific alternative chemical method must be used in order to obtain a confirmed analytical result. Gas Chromatography/Mass Spectrometry is the preferred confirmatory method. Clinical consideration and professional judgment should be exercised with any drug of abuse test result, particularly when the preliminary result is positive.
For in vitro diagnostic use only. The tests are intended for over-the-counter and for prescription use.
First Sign™ Drug of Abuse Buprenorphine Test, First Sign™ Drug of Abuse Butalbital Test and First Sign™ Drug of Abuse Morphine Test are immunochromatographic assays. Each assay test is a lateral flow system for the qualitative detection of Buprenorphine, or Butalbital or Morphine in human urine. The products are single-use in vitro diagnostic devices, which come in the formats of Dip Cards or Cups. Each test kit contains a Test Device (in one of the two formats), a package insert and a urine cup for sample collection. Each test device is sealed with a desiccant in an aluminum pouch.
Here's a breakdown of the acceptance criteria and study information for the First Sign® Drug of Abuse Buprenorphine, Butalbital, and Morphine tests, based on the provided text:
Acceptance Criteria and Device Performance for Buprenorphine Test
| Acceptance Criteria Category | Specific Criteria/Test | Device Performance (Buprenorphine Dip Card) | Device Performance (Buprenorphine Cup) |
|---|---|---|---|
| Precision | Agreement at Cut-Off (10 ng/mL) | 3-/47+ (Lot 1, 2, 3) | 3-/47+ (Lot 4), 2-/48+ (Lot 5), 3-/47+ (Lot 6) |
| Agreement for -100% to -25% Cut-Off (Negative) | 50-/0+ for all concentrations | 50-/0+ for all concentrations | |
| Agreement for +25% to +100% Cut-Off (Positive) | 50+/0- for all concentrations | 50+/0- for all concentrations | |
| Cut-off Verification | Positive at and above +25% cut-off | All positive | All positive |
| Negative at and below -25% cut-off | All negative | All negative | |
| Interference | No interference at 100ug/mL for listed compounds | No differences observed for different formats; compounds listed showed no interference | No differences observed for different formats; compounds listed showed no interference |
| Specificity | Cross-reactivity for related substances | Buprenorphine (100% at 10 ng/mL), Buprenorphine-3-D-Glucuronide (67% at 15 ng/mL), Norbuprenorphine (25% at 40 ng/mL), Norbuprenorphine-3-D-Glucuronide (2% at 500 ng/mL). Morphine, Oxymorphone, Hydromorphone not detected at 100,000 ng/mL. | Same as Dip Card |
| Effect of Urine Specific Gravity & pH | All positive at and above +25% Cut-Off | All positive | All positive |
| All negative at and below -25% Cut-Off | All negative | All negative | |
| Method Comparison (Clinical Samples) | Agreement with GC/MS | (Details in Discordant Results Table) | (Details in Discordant Results Table) |
| Lay-User Study - Correct Results | -100% to -25% Cut-off (Negative) | 100% for all negative concentrations except +25% which was 95% (1 false negative) | 100% for all negative concentrations |
| +25% to +75% Cut-off (Positive) | 95% (1 false negative) for +25% Cutoff, 100% for +50% and +75% Cutoff | 95% (1 false negative) for +25% Cutoff, 100% for +50% and +75% Cutoff | |
| Lay-User Study - Ease of Use | Instructions easily followed | All lay users indicated instructions can be easily followed | All lay users indicated instructions can be easily followed |
Acceptance Criteria and Device Performance for Butalbital Test
| Acceptance Criteria Category | Specific Criteria/Test | Device Performance (Butalbital Dip Card) | Device Performance (Butalbital Cup) |
|---|---|---|---|
| Precision | Agreement at Cut-Off (300 ng/mL) | 3-/47+ (Lot 1, 3), 4-/46+ (Lot 2) | 3-/47+ (Lot 4, 5, 6) |
| Agreement for -100% to -25% Cut-Off (Negative) | 50-/0+ for all concentrations | 50-/0+ for all concentrations | |
| Agreement for +25% to +100% Cut-Off (Positive) | 50+/0- for all concentrations | 50+/0- for all concentrations | |
| Cut-off Verification | Positive at and above +25% cut-off | All positive | All positive |
| Negative at and below -25% cut-off | All negative | All negative | |
| Interference | No interference at 100µg/mL for listed compounds | No differences observed for different formats; compounds listed showed no interference | No differences observed for different formats; compounds listed showed no interference |
| Specificity | Cross-reactivity for related substances | Butalbital (100% at 300 ng/mL), Secobarbital (100% at 300 ng/mL), Amobarbital (10% at 3000 ng/mL), Alphenal (120% at 250 ng/mL), Aprobarbital (150% at 200 ng/mL), Allobarbital (60% at 500 ng/mL), Butabarbital (30% at 1000 ng/mL), Cyclopentobarbital (100% at 300 ng/mL), Pentobarbital (23% at 1300 ng/mL), Phenobarbital (16% at 1900 ng/mL). | Same as Dip Card |
| Effect of Urine Specific Gravity & pH | All positive at and above +25% Cut-Off | All positive | All positive |
| All negative at and below -25% Cut-Off | All negative | All negative | |
| Method Comparison (Clinical Samples) | Agreement with GC/MS | (Details in Discordant Results Table) | (Details in Discordant Results Table) |
| Lay-User Study - Correct Results | -100% to -25% Cut-off (Negative) | 100% for -100% to -50% Cutoff. 95% for -25% Cutoff (1 false positive). | 100% for -100% to -50% Cutoff. 95% for -25% Cutoff (1 false positive). |
| +25% to +75% Cut-off (Positive) | 95% for +25% Cutoff (1 false negative), 100% for +50% and +75% Cutoff. | 100% for +25% to +75% Cutoff. | |
| Lay-User Study - Ease of Use | Instructions easily followed | All lay users indicated instructions can be easily followed | All lay users indicated instructions can be easily followed |
Acceptance Criteria and Device Performance for Morphine Test
| Acceptance Criteria Category | Specific Criteria/Test | Device Performance (Morphine Dip Card) | Device Performance (Morphine Cup) |
|---|---|---|---|
| Precision | Agreement at Cut-Off (300 ng/mL) | 2-/48+ (Lot 1, 3), 1-/49+ (Lot 2) | 2-/48+ (Lot 4, 6), 3-/47+ (Lot 5) |
| Agreement for -100% to -25% Cut-Off (Negative) | 50-/0+ for all concentrations | 50-/0+ for all concentrations | |
| Agreement for +25% to +100% Cut-Off (Positive) | 50+/0- for all concentrations | 50+/0- for all concentrations | |
| Cut-off Verification | Positive at and above +25% cut-off | All positive | All positive |
| Negative at and below -25% cut-off | All negative | All negative | |
| Interference | No interference at 100μg/mL for listed compounds | No differences observed for different formats; compounds listed showed no interference | No differences observed for different formats; compounds listed showed no interference |
| Specificity | Cross-reactivity for related substances | Morphine (100% at 300 ng/mL), 6-Acetylmorphine (40% at 750 ng/mL), Codeine (100% at 300 ng/mL), Morphine-3-B-glucuronide (67% at 450 ng/mL), EthylMorphine (150% at 200 ng/mL), Heroin (43% at 700 ng/mL), Hydromorphone (8% at 4000 ng/mL), Hydrocodone (15% at 2000 ng/mL), Levorphanol (3% at 12000 ng/mL), Thebaine (0.3% at 90000 ng/mL). Oxycodone, Procaine not detected at 100,000 ng/mL. | Same as Dip Card |
| Effect of Urine Specific Gravity & pH | All positive at and above +25% Cut-Off | All positive | All positive |
| All negative at and below -25% Cut-Off | All negative | All negative | |
| Method Comparison (Clinical Samples) | Agreement with GC/MS | (Details in Discordant Results Table) | (Details in Discordant Results Table) |
| Lay-User Study - Correct Results | -100% to -25% Cut-off (Negative) | 100% for -100% to -50% Cutoff. 95% for -25% Cutoff (1 false positive). | 100% for -100% to -25% Cutoff. |
| +25% to +75% Cut-off (Positive) | 100% for +25% to +75% Cutoff. | 95% for +25% Cutoff (1 false negative), 100% for +50% and +75% Cutoff. | |
| Lay-User Study - Ease of Use | Instructions easily followed | All lay users indicated instructions can be easily followed | All lay users indicated instructions can be easily followed |
Study Details Proving Device Meets Acceptance Criteria:
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Sample sizes used for the test set and the data provenance:
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Precision Studies:
- For each drug (Buprenorphine, Butalbital, Morphine) and each format (Cup, Dip Card), 3 different lots of devices were tested.
- Each lot was tested with 9 concentrations (e.g., -100% cut-off to +100% cut-off).
- At each concentration, tests were performed two runs per day for 25 days, by three different operators.
- This totals to: 3 lots * 9 concentrations * 2 runs/day * 25 days = 1350 tests per operator * 3 operators = 4050 tests per lot. This figure appears to be incorrect considering the "50-/0+" or "3-/47+" reported results which suggest 50 tests per concentration per lot.
- Given the "50-/0+" format in the tables, it implies 50 tests per concentration per lot. So, for 9 concentrations and 3 lots, this would be 9 * 50 * 3 = 1350 tests for each format (Dip Card/Cup) within the precision study section.
- Data Provenance: The samples were prepared by "spiking drug in negative urine samples." These were likely laboratory-prepared samples. "Each drug concentration was confirmed by GC/MS."
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Cut-off Verification:
- A total of 150 samples (equally distributed at -50%, -25%, cut-off, +25%, +50% concentrations) were tested.
- Performed using three different lots of each device by three different operators.
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Interference & Specificity:
- Samples were prepared by adding potential interfering substances to drug-free urine and to urine containing target drugs at +/- 25% cut-off levels.
- These urine samples were tested using three lots of each device for all formats. The number of individual samples is not explicitly stated but implies sufficient testing to cover all listed interfering substances and cross-reactants at specified concentrations.
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Effect of Urine Specific Gravity & pH:
- Urine samples with varying specific gravity (1.000 to 1.035) and pH (4 to 9) were spiked with target drugs at +/- 25% cut-off levels.
- These samples were tested using three lots of each device for all formats. The number of individual samples is not explicitly stated.
-
Method Comparison Studies (Clinical Samples):
- 80 unaltered clinical samples (40 negative and 40 positive) were run for each drug (Buprenorphine, Butalbital, Morphine) and each format (Cup, Dip Card).
- Data Provenance: "unaltered clinical samples." The country of origin is not specified but implicitly US as this is an FDA submission. These are retrospective given they are "clinical samples" compared to a reference method from what is implied a clinical laboratory setting.
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Lay-User Study:
- 280 lay persons tested the devices for each drug (Buprenorphine, Butalbital, Morphine).
- Urine samples were prepared at negative, +/-75%, +/-50%, +/-25% of the cutoff by spiking drugs into drug-free pooled urine specimens. 7 concentrations were tested, with 20 samples per concentration.
- This means 7 concentrations * 20 samples = 140 samples were used per drug/format in the lay-user study.
- Each participant was provided with 1 blind-labeled sample.
- Data Provenance: Laboratory-prepared spiked urine samples.
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Number of experts used to establish the ground truth for the test set and the qualifications of those experts:
- For the Method Comparison Studies, the ground truth was established by Gas Chromatography/Mass Spectrometry (GC/MS) results. This is an analytical method, not human expert interpretation. Therefore, no human experts were used to establish ground truth for this portion in the traditional sense.
- For Lay-User studies, the "ground truth" for the samples was the known concentration of the spiked drug, confirmed by GC/MS.
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Adjudication method (e.g. 2+1, 3+1, none) for the test set:
- Precision, Cut-off, Interference, Specificity, Specific Gravity/pH studies: It's not explicitly stated that an adjudication method was used between readers/operators. For precision, three operators participated, and results were summarized, but no formal adjudication process between them is described.
- Method Comparison Studies: Three different laboratory assistants ran the tests, and their results were compared to GC/MS. No adjudication method between the assistants is explicitly mentioned.
- Lay-User Study: Each lay person tested one blind-labeled sample. No adjudication is applicable here as each person provided a single result for their assigned sample.
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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 comparative effectiveness study was mentioned. The studies focus on the performance of the device itself (standalone) and its interpretation by users (lay-user study), which is a single-reader, single-case scenario in the context of the device's output. There is no AI component mentioned in the document, so no improvement due to AI assistance can be reported.
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If a standalone (i.e. algorithm only without human-in-the loop performance) was done:
- The "First Sign® Drug of Abuse" tests are described as "immunochromatographic assays" and "lateral flow systems," which means they are physical test strips/cups that display visual results (lines). The performance studies (precision, specificity, interference, etc.) directly reflect the standalone analytical performance of these devices, as their reactivity with known concentrations and substances is measured. The "Method Comparison Studies" with laboratory assistants and the "Lay-user studies" do involve human interpretation of these visual results, but the core analytical reaction is standalone.
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The type of ground truth used (expert consensus, pathology, outcomes data, etc):
- The primary ground truth used across all analytical performance studies (precision, cut-off, interference, specificity, specific gravity/pH) and method comparison studies was Gas Chromatography/Mass Spectrometry (GC/MS) results for drug concentrations in urine samples. This is considered a gold standard analytical method.
- For the lay-user study, the "ground truth" was the known spiked concentration in the urine samples, which itself was confirmed by GC/MS.
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The sample size for the training set:
- The document does not describe a computational algorithm or AI model that requires a training set. The devices are immunochromatographic assays. Therefore, the concept of a "training set" in the context of machine learning is not applicable here.
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How the ground truth for the training set was established:
- As there is no AI/algorithm and thus no "training set," this question is not applicable.
§ 862.3650 Opiate test system.
(a)
Identification. An opiate test system is a device intended to measure any of the addictive narcotic pain-relieving opiate drugs in blood, serum, urine, gastric contents, and saliva. An opiate is any natural or synthetic drug that has morphine-like pharmocological actions. The opiates include drugs such as morphine, morphine glucoronide, heroin, codeine, nalorphine, and meperedine. Measurements obtained by this device are used in the diagnosis and treatment of opiate use or overdose and in monitoring the levels of opiate administration to ensure appropriate therapy.(b)
Classification. Class II (special controls). An opiate test system is not exempt if it is intended for any use other than employment or insurance testing or is intended for Federal drug testing programs. The device is exempt from the premarket notification procedures in subpart E of part 807 of this chapter subject to the limitations in § 862.9, provided the test system is intended for employment and insurance testing and includes a statement in the labeling that the device is intended solely for use in employment and insurance testing, and does not include devices intended for Federal drug testing programs (e.g., programs run by the Substance Abuse and Mental Health Services Administration (SAMHSA), the Department of Transportation (DOT), and the U.S. military).