Document ID: FDA-2017-N-6643-0001
Agency: fda
Document Type: Rule
Title: Medical Devices; Hematology and Pathology Devices; Classification of
the Flow Cytometric Test System for Hematopoietic Neoplasms
Posted Date: 2017-12-27T05:00Z

[Federal Register Volume 82, Number 247 (Wednesday, December 27, 2017)]
[Rules and Regulations]
[Pages 61163-61166]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-27855]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 864

[Docket No. FDA-2017-N-6643]

Medical Devices; Hematology and Pathology Devices; Classification 
of the Flow Cytometric Test System for Hematopoietic Neoplasms

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 flow cytometric test system for hematopoietic neoplasms 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 flow cytometric test system for hematopoietic 
neoplasms' 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 December 27, 2017. The classification 
was applicable on June 29, 2017.

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 flow cytometric test system 
for hematopoietic neoplasms as class II (special controls), which we 
have

[[Page 61164]]

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 (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. 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 shall 
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 October 3, 2016, Beckman Coulter submitted a request for De Novo 
classification of the ClearLLab Reagents (T1, T2, B1, B2, M). 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 the 
general controls, will provide reasonable assurance of the safety and 
effectiveness of the device.
    Therefore, on June 29, 2017, FDA issued an order to the requester 
classifying the device into class II. FDA is codifying the 
classification of the device by adding 21 CFR 864.7010. We have named 
the generic type of device flow cytometric test system for 
hematopoietic neoplasms, and it is identified as a device that consists 
of reagents for immunophenotyping of human cells in relation to the 
level of expression, antigen density, and distribution of specific 
cellular markers. These reagents are used as an aid in the differential 
diagnosis or monitoring of hematologically abnormal patients having or 
suspected of having hematopoietic neoplasms. The results should be 
interpreted by a pathologist or equivalent professional in conjunction 
with other clinical and laboratory findings.
    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--Flow Cytometric Test for Hematopoietic Neoplasms Risks and
                           Mitigation Measures
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                                            Mitigation measures/21 CFR
            Identified risks                         section
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Incorrect test results (false negatives  General Controls and Special
 or false positives).                     Controls (1) and (2) (21 CFR
                                          864.7010(b)(1) and (2)).
Incorrect interpretation of device       General Controls and Special
 results by the end user.                 Controls (1), (2), and (3) (21
                                          CFR 864.7010(b)(1), (2), and
                                          (3)).
Patient harm from specimen(s)            General Controls and Special
 collection.                              Control (1) (21 CFR
                                          864.7010(b)(1)).
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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. 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

[[Page 61165]]

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 21 CFR 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; the collections of 
information in 21 CFR part 820 have been approved under OMB control 
number 0910-0073; 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 part 864 is revised to read as follows:

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

0
2. Add Sec.  864.7010 to subpart H to read as follows:

Sec.  864.7010  Flow cytometric test system for hematopoietic 
neoplasms.

    (a) Identification. A flow cytometric test for hematopoietic 
neoplasms is a device that consists of reagents for immunophenotyping 
of human cells in relation to the level of expression, antigen density, 
and distribution of specific cellular markers. These reagents are used 
as an aid in the differential diagnosis or monitoring of 
hematologically abnormal patients having or suspected of having 
hematopoietic neoplasms. The results should be interpreted by a 
pathologist or equivalent professional in conjunction with other 
clinical and laboratory findings.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) Premarket notification submissions must include the following 
information:
    (i) The indications for use must indicate the clinical 
hematopoietic neoplasms for which the assay was designed and validated, 
for example, chronic leukemia or lymphoma.
    (ii) A detailed device description including the following:
    (A) A detailed description of all test components, all required 
reagents, and all instrumentation and equipment, including 
illustrations or photographs of nonstandard 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) A detailed description of methodology and assay procedure.
    (D) A description of appropriate internal and external quality 
control materials that are recommended or provided. The description 
must identify those control elements that are incorporated into the 
testing procedure, if applicable.
    (E) Detailed specifications for sample collection, processing, and 
storage.
    (F) Detailed specification of the criteria for test results 
interpretation and reporting including pre-established templates.
    (G) If applicable, based on the output of the results, a 
description of the specific number of events to collect, result 
outputs, and analytical sensitivity of the assay that will be reported.
    (iii) Information that demonstrates the performance characteristics 
of the test, including:
    (A) Device performance data from either a method comparison study 
comparing the specific lymphocyte cell markers to a predicate device or 
data collected through a clinical study demonstrating clinical validity 
using well-characterized clinical specimens. Samples must be 
representative of the intended use population of the device including 
hematologic neoplasms and the specific sample types for which the test 
is indicated for use.
    (B) If applicable, device performance data from a clinical study 
demonstrating clinical validity for parameters not established in a 
predicate device of this generic type using well-characterized 
prospectively obtained clinical specimens including all hematologic 
neoplasms and the specific sample types for which the device is 
indicated for use.
    (C) Device precision data using clinical samples to evaluate the 
within-lot, between-lot, within-run, between run, site-to-site and 
total variation using a minimum of three sites, of which at least two 
sites must be external sites. Results shall be reported as the standard 
deviation and percentage coefficient of variation for each level 
tested.
    (D) Reproducibility data generated using a minimum of three lots of 
reagents to evaluate mean fluorescence intensity and variability of the 
recovery of the different markers and/or cell populations.
    (E) Data from specimen and reagent carryover testing performed 
using well-established methods (e.g., CLSI H26-A2).
    (F) Specimen and prepared sample stability data established for 
each specimen matrix in the anticoagulant combinations and storage/use 
conditions that will be indicated.
    (G) A study testing anticoagulant equivalency in all claimed 
specimen type/anticoagulant combinations using clinical specimens that 
are representative of the intended use population of the device.
    (H) Analytic sensitivity data using a dilution panel created from 
clinical samples.
    (I) Analytical specificity data, including interference and cross-
contamination.
    (J) Device stability data, including real-time stability of 
reagents under various storage times and temperatures.
    (K) For devices that include polyclonal antibodies, Fluorescence 
Minus One (FMO) studies to evaluate non-specific binding for all 
polyclonal antibodies. Each FMO tube is compared to reagent reference 
to demonstrate that no additional population appears when one marker is 
absent. Pre-specified acceptance criteria must be provided and 
followed.
    (L) For devices indicated for use as a semi-quantitative test, 
linearity data using a dilution panel created from clinical samples.
    (M) For devices indicated for use as a semi-quantitative test, 
clinically relevant analytical sensitivity data,

[[Page 61166]]

including limit of blank, limit of detection, and limit of 
quantification.
    (iv) Identification of risk mitigation elements used by the device, 
including a detailed description of all additional procedures, methods, 
and practices incorporated into the instructions for use that mitigate 
risks associated with testing the device.
    (2) The 21 CFR 809.10 compliant labeling must include the 
following:
    (i) The intended use statement in the 21 CFR 809.10(a)(2) and 
(b)(2) compliant labeling must include a statement that the results 
should be interpreted by a pathologist or equivalent professional in 
conjunction with other clinical and laboratory findings. The intended 
use statement must also include information on what the device detects 
and measures, whether the device is qualitative, semi-quantitative, 
and/or quantitative, the clinical indications for which the device is 
to be used, and the specific population(s) for which the device is 
intended.
    (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) As part of the risk management activities performed under 21 
CFR 820.30 design controls, product labeling and instruction manuals 
must include clear examples of all expected phenotypic patterns and 
gating strategies using well-defined clinical samples representative of 
both abnormal and normal cellular populations. These samples must be 
selected based upon the indications described in paragraph (b)(1)(i) of 
this section.

    Dated: December 20, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-27855 Filed 12-26-17; 8:45 am]
 BILLING CODE 4164-01-P