[Federal Register Volume 82, Number 210 (Wednesday, November 1, 2017)]
[Rules and Regulations]
[Pages 50530-50532]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-23742]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2017-N-5995]


Medical Devices; Immunology and Microbiology Devices; 
Classification of the BCR-ABL Quantitation Test

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA or we) is classifying 
the BCR-ABL quantitation test into class II (special controls). The 
special controls that apply to the device type are identified in this 
order and will be part of the codified language for the BCR-ABL 
quantitation test's classification. We are taking this action because 
we have determined that classifying the device into class II (special 
controls) will provide a reasonable assurance of safety and 
effectiveness of the device. We believe this action will also enhance 
patients' access to beneficial innovative devices, in part by reducing 
regulatory burdens.

DATES: This order is effective November 1, 2017. The classification was 
applicable on July 22, 2016.

FOR FURTHER INFORMATION CONTACT: Ryan Lubert, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 4545, Silver Spring, MD 20993-0002, 240-402-6357, 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    Upon request, FDA has classified the BCR-ABL quantitation test as 
class II (special controls), which we have determined will provide a 
reasonable assurance of safety and effectiveness. In addition, we 
believe this action will enhance patients' access to beneficial 
innovation, in part by reducing regulatory burdens by placing the 
device into a lower device class than the automatic class III 
assignment.
    The automatic assignment of class III occurs by operation of law 
and without any action by FDA, regardless of the level of risk posed by 
the new device. Any device that was not in commercial distribution 
before May 28, 1976, is automatically classified as, and remains 
within, class III and requires premarket approval unless and until FDA 
takes an action to classify or reclassify the device (see 21 U.S.C. 
360c(f)(1)). We refer to these devices as ``postamendments devices'' 
because they were not in commercial distribution prior to the date of 
enactment of the Medical Device Amendments of 1976, which amended the 
Federal Food, Drug, and Cosmetic Act (the FD&C Act).
    FDA may take a variety of actions in appropriate circumstances to 
classify or reclassify a device into class I or II. We may issue an 
order finding a new device to be substantially equivalent under section 
513(i) of the FD&C Act (21 U.S.C. 360c(i)) to a predicate device that 
does not require premarket approval.

[[Page 50531]]

We determine whether a new device is substantially equivalent to a 
predicate by means of the procedures for premarket notification under 
section 510(k) of the FD&C Act and part 807 (21 U.S.C. 360(k) and 21 
CFR part 807, respectively).
    FDA may also classify a device through ``De Novo'' classification, 
a common name for the process authorized under section 513(f)(2) of the 
FD&C Act. Section 207 of the Food and Drug Administration Modernization 
Act of 1997 established the first procedure for De Novo classification 
(Pub. L. 105-115). Section 607 of the Food and Drug Administration 
Safety and Innovation Act modified the De Novo application process by 
adding a second procedure (Pub. L. 112-144). A device sponsor may 
utilize either procedure for De Novo classification.
    Under the first procedure, the person submits a 510(k) for a device 
that has not previously been classified. After receiving an order from 
FDA classifying the device into class III under section 513(f)(1) of 
the FD&C Act, the person then requests a classification under section 
513(f)(2).
    Under the second procedure, rather than first submitting a 510(k) 
and then a request for classification, if the person determines that 
there is no legally marketed device upon which to base a determination 
of substantial equivalence, that person requests a classification under 
section 513(f)(2) of the FD&C Act.
    Under either procedure for De Novo classification, FDA is required 
to classify the device by written order within 120 days. The 
classification will be according to the criteria under section 
513(a)(1) of the FD&C Act. Although the device was automatically placed 
within class III, the De Novo classification is considered to be the 
initial classification of the device.
    We believe this De Novo classification will enhance patients' 
access to beneficial innovation, in part by reducing regulatory 
burdens. When FDA classifies a device into class I or II via the De 
Novo process, the device can serve as a predicate for future devices of 
that type, including for 510(k)s (see 21 U.S.C. 360c(f)(2)(B)(i)). As a 
result, other device sponsors do not have to submit a De Novo request 
or premarket approval application in order to market a substantially 
equivalent device (see 21 U.S.C. 360c(i), defining ``substantial 
equivalence''). Instead, sponsors can use the less-burdensome 510(k) 
process, when necessary, to market their device.

II. De Novo Classification

    On January 19, 2016, Asuragen, Inc., submitted a request for De 
Novo classification of the QuantideX qPCR BCR-ABL IS Kit. FDA reviewed 
the request in order to classify the device under the criteria for 
classification set forth in section 513(a)(1) of the FD&C Act.
    We classify devices into class II if general controls by themselves 
are insufficient to provide reasonable assurance of safety and 
effectiveness, but there is sufficient information to establish special 
controls that, in combination with the general controls, provide 
reasonable assurance of the safety and effectiveness of the device for 
its intended use (see 21 U.S.C. 360c(a)(1)(B)). After review of the 
information submitted in the request, we determined that the device can 
be classified into class II with the establishment of special controls. 
FDA has determined that these special controls, in addition to general 
controls, will provide reasonable assurance of the safety and 
effectiveness of the device.
    Therefore, on July 22, 2016, FDA issued an order to the requestor 
classifying the device into class II. FDA is codifying the 
classification of the device by adding 21 CFR 866.6060. We have named 
the generic type of device BCR-ABL quantitation test, and it is 
identified as a reverse transcription-quantitative polymerase chain 
reaction (RT-qPCR) test for the quantitation of BCR-ABL1 expressed on 
the International Scale (IS) and control transcripts in total RNA from 
whole blood of diagnosed t(9;22) positive chronic myeloid leukemia 
(CML) patients during monitoring of treatment with tyrosine kinase 
inhibitors. This test is not intended for the diagnosis of CML.
    FDA has identified the following risks to health associated 
specifically with this type of device and the measures required to 
mitigate these risks in table 1.

    Table 1--BCR-ABL Quantitation Test Risks and Mitigation Measures
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                                            Mitigation measures/21 CFR
            Identified risks                         section
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False negative results.................  Special Controls (1) and (2)
                                          (21 CFR 866.6060(b)(1) and
                                          (2)).
False positive results.................  Special Controls (1) and (2)
                                          (21 CFR 866.6060(b)(1) and
                                          (2)).
Lack of traceability of results........  Special Control (3) (21 CFR
                                          866.6060(b)(3)).
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    FDA has determined that special controls, in combination with the 
general controls, address these risks to health and provide reasonable 
assurance of safety and effectiveness. In order for a device to fall 
within this classification, and thus avoid automatic classification in 
class III, it would have to comply with the special controls named in 
this final order. The necessary special controls appear in the 
regulation codified by this order. This device is subject to premarket 
notification requirements under section 510(k) of the FD&C Act.

III. Analysis of Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IV. Paperwork Reduction Act of 1995

    This final order establishes special controls that refer to 
previously approved collections of information found in other FDA 
regulations. These collections of information are subject to review by 
the Office of Management and Budget (OMB) under the Paperwork Reduction 
Act of 1995 (44 U.S.C. 3501-3520). The collections of information in 
the guidance document ``De Novo Classification Process (Evaluation of 
Automatic Class III Designation)'' have been approved under OMB control 
number 0910-0844; the collections of information in part 814, subparts 
A through E, regarding premarket approval, have been approved under OMB 
control number 0910-0231; the collections of information in part 807, 
subpart E, regarding premarket notification submissions, have been 
approved under OMB control number 0910-0120; and the collections of 
information in 21 CFR parts 801 and 809, regarding labeling have been 
approved under OMB control number 0910-0485.

[[Page 50532]]

List of Subjects in 21 CFR Part 866

    Biologics, Laboratories, Medical devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
866 is amended as follows:

PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES

0
1. The authority citation for part 866 continues to read as follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.

0
2. Add Sec.  866.6060 to subpart G to read as follows:


Sec.  866.6060  BCR-ABL quantitation test.

    (a) Identification. A BCR-ABL quantitation test is identified as a 
reverse transcription-quantitative polymerase chain reaction (RT-qPCR) 
test for the quantitation of BCR-ABL1 expressed on the International 
Scale (IS) and control transcripts in total RNA from whole blood of 
diagnosed t(9;22) positive chronic myeloid leukemia (CML) patients 
during monitoring of treatment with tyrosine kinase inhibitors. This 
test is not intended for the diagnosis of CML.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) Premarket notification submissions must include the following 
information:
    (i) The indication for use must indicate the variant(s) for which 
the assay was designed and validated, for example BCR-ABL e13a2 and/or 
e14a2.
    (ii) A detailed description of all components in the test, 
including the following:
    (A) A detailed description of the test components, all required 
reagents, instrumentation and equipment, including illustrations or 
photographs of non-standard equipment or methods;
    (B) Detailed documentation of the device software including, but 
not limited to, standalone software applications and hardware-based 
devices that incorporate software;
    (C) Methodology and protocols for control procedures for the assay 
to allow reporting on the International Scale;
    (D) A description of the result outputs, analytical sensitivity of 
the assay, and the range of values that will be reported; and
    (E) A description of appropriate internal and external controls 
that are recommended or provided. The description must identify those 
control elements that are incorporated into the testing procedure.
    (iii) Information that demonstrates the performance characteristics 
of the test, including:
    (A) For indications for use based on a threshold established in a 
predicate device of this generic type, device performance data from 
either a method comparison study to the predicate device or through a 
clinical study demonstrating clinical validity using well-characterized 
prospectively or retrospectively obtained clinical specimens, as 
appropriate, representative of the intended use population;
    (B) For indications for use based on a threshold not established in 
a predicate device of this generic type, device performance data from a 
clinical study demonstrating clinical validity using well-characterized 
prospectively or retrospectively obtained clinical specimens, as 
appropriate, representative of the intended use population;
    (C) Device reproducibility data generated, using a minimum of three 
sites, of which at least two sites must be external sites, with two 
operators at each site. Each site must conduct a minimum of three runs 
per operator over non-consecutive days evaluating a minimum of five 
different BCR-ABL concentrations that span and are well distributed 
over the measuring range and include MR3 (0.1 percent IS). Results 
shall be reported as the standard deviation and percentage coefficient 
of variation for each level tested. Prespecified acceptance criteria 
must be provided and followed;
    (D) Device precision data using clinical samples to evaluate the 
within-lot, between-lot, within-run, between run, and total variation;
    (E) Device linearity data using a dilution panel created from 
clinical samples;
    (F) Device analytic sensitivity data, including limit of blank, 
limit of detection, and limit of quantification;
    (G) Device specificity data, including interference and cross-
contamination; and
    (H) Device stability data, including real-time stability of samples 
under various storage times, temperatures, and freeze-thaw conditions.
    (iv) Identification of risk mitigation elements used by your 
device, including a detailed description of all additional procedures, 
methods, and practices incorporated into the instructions for use that 
mitigate risks associated with testing using your device.
    (2) Your 21 CFR 809.10 compliant labeling must include the 
following:
    (i) The intended use in your 21 CFR 809.10(a)(2) and (b)(2) 
complaint labeling must include an indication for use statement that 
reads ``This test is not intended for the diagnosis of CML''; and
    (ii) A detailed description of the performance studies conducted to 
comply with paragraph (b)(1)(iii) of this section and a summary of the 
results.
    (3) Your device output must include results on the International 
Scale (IS) and your assay must include multipoint calibration controls 
traceable to a relevant international reference panel (e.g., the World 
Health Organization International Genetic Reference Panel for 
quantitation of BCR-ABL mRNA).

    Dated: October 26, 2017.
Lauren Silvis,
Chief of Staff.
[FR Doc. 2017-23742 Filed 10-31-17; 8:45 am]
BILLING CODE 4164-01-P


