Document ID: FDA-2014-N-1176-0001
Agency: fda
Document Type: Rule
Title: Medical Devices; Hematology and Pathology Devices; Classification of
Early Growth Response 1 Gene Fluorescence In-Situ Hybridization
Test System for Specimen Characterization
Posted Date: 2014-09-03T04:00Z

[Federal Register Volume 79, Number 170 (Wednesday, September 3, 2014)]
[Rules and Regulations]
[Pages 52195-52197]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-20882]

[[Page 52195]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 864

[Docket No. FDA-2014-N-1176]

Medical Devices; Hematology and Pathology Devices; Classification 
of Early Growth Response 1 Gene Fluorescence In-Situ Hybridization Test 
System for Specimen Characterization

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA) is classifying early 
growth response 1 (EGR1) gene fluorescence in-situ hybridization (FISH) 
test system for specimen characterization into class II (special 
controls). The special controls that will apply to this device are 
identified in this order and will be part of the codified language for 
the early growth response 1 (EGR1) gene fluorescence in-site 
hybridization (FISH) test system for specimen characterization 
classification. The Agency is classifying the device into class II 
(special controls) in order to provide a reasonable assurance of safety 
and effectiveness of the device.

DATES: This order is effective October 3, 2014. The classification was 
applicable July 29, 2013.

FOR FURTHER INFORMATION CONTACT: Shyam Kalavar, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 5568, Silver Spring, MD 20993-0002, 301-796-6807.

SUPPLEMENTARY INFORMATION: 

I. Background

    In accordance with section 513(f)(1) of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act) (21 U.S.C. 360c(f)(1)), devices that were 
not in commercial distribution before May 28, 1976 (the date of 
enactment of the Medical Device Amendments of 1976), generally referred 
to as postamendments devices, are classified automatically by statute 
into class III without any FDA rulemaking process. These devices remain 
in class III and require premarket approval, unless and until the 
device is classified or reclassified into class I or II, or FDA issues 
an order finding the device to be substantially equivalent, in 
accordance with section 513(i) of the FD&C Act, to a predicate device 
that does not require premarket approval. The Agency determines whether 
new devices are substantially equivalent to predicate devices by means 
of premarket notification procedures in section 510(k) of the FD&C Act 
(21 U.S.C. 360(k)) and part 807 (21 CFR part 807) of the regulations.
    Section 513(f)(2) of the FD&C Act, as amended by section 607 of the 
Food and Drug Administration Safety and Innovation Act (Public Law 112-
144), provides two procedures by which a person may request FDA to 
classify a device under the criteria set forth in section 513(a)(1). 
Under the first procedure, the person submits a premarket notification 
under section 510(k) of the FD&C Act for a device that has not 
previously been classified and, within 30 days of receiving an order 
classifying the device into class III under section 513(f)(1) of the 
FD&C Act, the person requests a classification under section 513(f)(2). 
Under the second procedure, rather than first submitting a premarket 
notification under section 510(k) of the FD&C Act and then a request 
for classification under the first procedure, the person determines 
that there is no legally marketed device upon which to base a 
determination of substantial equivalence and requests a classification 
under section 513(f)(2) of the FD&C Act. If the person submits a 
request to classify the device under this second procedure, FDA may 
decline to undertake the classification request if FDA identifies a 
legally marketed device that could provide a reasonable basis for 
review of substantial equivalence with the device or if FDA determines 
that the device submitted is not of ``low-moderate risk'' or that 
general controls would be inadequate to control the risks and special 
controls to mitigate the risks cannot be developed.
    In response to a request to classify a device under either 
procedure provided by section 513(f)(2) of the FD&C Act, FDA will 
classify the device by written order within 120 days. This 
classification will be the initial classification of the device.
    In accordance with section 513(f)(1) of the FD&C Act, FDA issued an 
order on March 20, 2013, classifying the Vysis EGR1 FISH Probe Kit--SC 
into class III, because it was not substantially equivalent to a device 
that was introduced or delivered for introduction into interstate 
commerce for commercial distribution before May 28, 1976, or a device 
that was subsequently reclassified into class I or class II. On April 
9, 2013, Abbott Molecular, Inc., submitted a request for classification 
of Vysis EGR1 FISH Probe Kit--SC under section 513(f)(2) of the FD&C 
Act. The manufacturer recommended that the device be classified into 
class II.
    In accordance with section 513(f)(2) of the FD&C Act, 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. FDA 
classifies 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 to provide reasonable assurance of the safety and 
effectiveness of the device for its intended use. After review of the 
information submitted in the de novo request, FDA determined that the 
device can be classified into class II with the establishment of 
special controls. FDA believes these special controls, in addition to 
general controls, will provide reasonable assurance of the safety and 
effectiveness of the device.
    Therefore, on July 29, 2013, FDA issued an order to the requestor 
classifying the device into class II. FDA is codifying the 
classification of the device by adding Sec.  864.1870.
    Following the effective date of this final classification 
administrative order, any firm submitting a premarket notification 
(510(k)) for an early growth response 1 (EGR1) gene fluorescence in-
situ hybridization (FISH) test system for specimen characterization 
will need to comply with the special controls named in the final 
administrative order.
    The device is assigned the generic name early growth response 1 
(EGR1) gene fluorescence in-situ hybridization (FISH) test system for 
specimen characterization, and it is identified as a device intended to 
detect the EGR1 probe target on chromosome 5q in bone marrow specimens 
from patients with acute myeloid leukemia (AML) or myelodysplastic 
syndrome (MDS). The assay results are intended to be interpreted only 
by a qualified pathologist or cytogeneticist. These devices do not 
include automated systems that directly report results without review 
and interpretation by a qualified pathologist or cytogeneticist. These 
devices also do not include any device intended for use to select 
patient therapy, predict patient response to therapy, or to screen for 
disease as well as any device with a claim for a particular diagnosis, 
prognosis, monitoring, or risk assessment.
    FDA has identified the following risks to health associated with 
this type of device and the measures required to mitigate these risks 
in table 1:

[[Page 52196]]

           Table 1--Identified Risks and Required Mitigations
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             Identified risks                   Required mitigations
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False negative result.....................  Special controls (1), (2),
                                             and (3).
False positive result.....................  Special controls (1), (2),
                                             and (3).
------------------------------------------------------------------------

    FDA believes that the following special controls, in addition to 
the general controls, address these risks to health and provide 
reasonable assurance of safety and effectiveness:
    1. Premarket notification submissions must also include the 
following information:
    a. A detailed description of all probes included in the kit;
    b. Purpose of each probe;
    c. Probe molecular specificity;
    d. Probe specificity;
    e. Probe limits;
    f. Probe sensitivity;
    g. Specification of required ancillary reagents, instrumentation, 
and equipment;
    h. Specification of the specimen collection, processing, storage, 
and slide preparation methods;
    i. Specification of the assay procedure;
    j. Specification of control elements that are incorporated into the 
recommended testing procedures;
    k. Specification of risk mitigation elements: Description of all 
additional procedures, methods, and practices incorporated into the 
directions for use that mitigate risks associated with testing;
    l. Specification of the criteria for test result interpretation and 
reporting;
    m. Device analytical sensitivity data;
    n. Device analytical specificity data;
    o. Device reference limit data;
    p. Device precision/reproducibility data;
    q. Device stability data to include:
    i. Real-time stability;
    ii. Freeze-thaw stability;
    iii. Transport and temperature stability;
    iv. Post-hybridization signal stability;
    v. Photostability of probe; and
    r. Documentation that demonstrates the clinical validity of the 
device. The documentation must include data from clinical studies, a 
minimum of two peer-reviewed published literature references using the 
specific device seeking marketing clearance, or both. Documentation for 
the clinical studies and peer-reviewed published literature references 
cited must include the following elements:
    i. Documentation that the sponsor's probe was used in the 
literature reference,
    ii. Number and type of specimens,
    iii. Target population studied,
    iv. Upper reference limit, and
    v. Range of positive probe results.
    2. Your Sec.  809.10(b)(12) (21 CFR 809.10(b)(12)) compliant 
labeling must include a statement summarizing the data identified in 
Sec.  864.1870(b)(1)(xiii) through (b)(1)(xviii) and a description of 
the studies supporting the information, including the pre-specified 
acceptance criteria for these performance studies, justification for 
the pre-specified acceptance criteria, and whether the pre-specified 
acceptance criteria were met.
    3. Your Sec.  809.10 compliant labeling must include:
    a. A warning that reads ``The assay results are intended to be 
interpreted only by a qualified pathologist or cytogeneticist.''
    b. A warning that reads ``This device is not for high-risk uses 
such as selecting therapy, predicting therapeutic response or disease 
screening.''
    c. A warning that reads ``The use of this device for diagnosis, 
monitoring or risk assessment has not been established.''
    Early growth response 1 (EGR1) gene fluorescence in-situ 
hybridization (FISH) test system for specimen characterization are 
prescription devices restricted to patient use only upon the 
authorization of a practitioner licensed by law to administer or use 
the device. (See section 520(e) of the FD&C Act (21 U.S.C. 360j(e)) and 
21 CFR 801.109 (Prescription devices).). Prescription-use restrictions 
are a type of general control as defined in section 513(a)(1)(A)(i) of 
the FD&C Act.
    Section 510(m) of the FD&C Act provides that FDA may exempt a class 
II device from the premarket notification requirements under section 
510(k) of the FD&C Act if FDA determines that premarket notification is 
not necessary to provide reasonable assurance of the safety and 
effectiveness of the device. For this type of device, FDA has 
determined that premarket notification is necessary to provide 
reasonable assurance of the safety and effectiveness of the device. 
Therefore, this device type is not exempt from premarket notification 
requirements. Persons who intend to market this type of device must 
submit to FDA a premarket notification, prior to marketing the device, 
which contains information about the early growth response 1 (EGR1) 
gene fluorescence in-situ hybridization (FISH) test system for specimen 
characterization they intend to market.

II. 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.

III. Paperwork Reduction Act of 1995

    This final administrative 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 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.

List of Subjects in 21 CFR Part 864

    Blood, Medical devices, Packaging and containers.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
864 is amended as follows:

PART 864--HEMATOLOGY AND PATHOLOGY DEVICES

0
1. The authority citation for 21 CFR part 864 continues to read as 
follows:

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

0
2. Add Sec.  864.1870 to subpart B to read as follows:

Sec.  864.1870  Early growth response 1 (EGR1) gene fluorescence in-
situ hybridization (FISH) test system for specimen characterization.

    (a) Identification. An early growth response 1 (EGR1) gene 
fluorescence in-situ hybridization (FISH) test system for specimen 
characterization is a device intended to detect the EGR1 probe target 
on chromosome 5q in bone marrow specimens from patients with acute 
myeloid leukemia (AML) or myelodysplastic syndrome (MDS). The assay 
results are intended to be interpreted only by a qualified pathologist 
or cytogeneticist. These devices do not include automated systems that 
directly report results without review and interpretation by a 
qualified pathologist or cytogeneticist.

[[Page 52197]]

These devices also do not include any device intended for use to select 
patient therapy, predict patient response to therapy, or to screen for 
disease as well as any device with a claim for a particular diagnosis, 
prognosis, monitoring, or risk assessment.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) Premarket notification submissions must also include the 
following information:
    (i) A detailed description of all probes included in the kit;
    (ii) Purpose of each probe;
    (iii) Probe molecular specificity;
    (iv) Probe specificity;
    (v) Probe limits;
    (vi) Probe sensitivity;
    (vii) Specification of required ancillary reagents, 
instrumentation, and equipment;
    (viii) Specification of the specimen collection, processing, 
storage and slide preparation methods;
    (ix) Specification of the assay procedure;
    (x) Specification of control elements that are incorporated into 
the recommended testing procedures;
    (xi) Specification of risk mitigation elements: Description of all 
additional procedures, methods, and practices incorporated into the 
directions for use that mitigate risks associated with testing;
    (xii) Specification of the criteria for test result interpretation 
and reporting;
    (xiii) Device analytical sensitivity data;
    (xiv) Device analytical specificity data;
    (xv) Device reference limit data;
    (xvi) Device precision/reproducibility data;
    (xvii) Device stability data to include:
    (A) Real-time stability,
    (B) Freeze-thaw stability,
    (C) Transport and temperature stability,
    (D) Post-hybridization signal stability,
    (E) Photostability of probe, and
    (xviii) Documentation that demonstrates the clinical validity of 
the device. The documentation must include data from clinical studies, 
a minimum of two peer-reviewed published literature references using 
the specific device seeking marketing clearance, or both. Documentation 
for the clinical studies and peer-reviewed published literature 
references cited must include the following elements:
    (A) Documentation that the sponsor's probe was used in the 
literature reference,
    (B) Number and type of specimens,
    (C) Target population studied,
    (D) Upper reference limit, and
    (E) Range of positive probe results.
    (2) Your Sec.  809.10(b)(12) of this chapter compliant labeling 
must include a statement summarizing the data identified in paragraphs 
(b)(1)(xiii) through (xviii) of this section and a description of the 
studies supporting the information, including the pre-specified 
acceptance criteria for these performance studies, justification for 
the pre-specified acceptance criteria, and whether the pre-specified 
acceptance criteria were met.
    (3) Your Sec.  809.10 of this chapter compliant labeling must 
include:
    (i) A warning that reads ``The assay results are intended to be 
interpreted only by a qualified pathologist or cytogeneticist.''
    (ii) A warning that reads ``This device is not for high-risk uses 
such as selecting therapy, predicting therapeutic response or disease 
screening.''
    (iii) A warning that reads ``The use of this device for diagnosis, 
monitoring or risk assessment has not been established.''

    Dated: August 27, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-20882 Filed 9-2-14; 8:45 am]
BILLING CODE 4164-01-P