
[Federal Register Volume 84, Number 44 (Wednesday, March 6, 2019)]
[Proposed Rules]
[Pages 8047-8050]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-03967]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 864

[Docket No. FDA-2018-N-4394]


Medical Devices; Exemption From Premarket Notification: Class II 
Devices; Flow Cytometer Instruments; Request for Comments

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order; request for comments.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
its intention to exempt certain flow cytometer instruments from 
premarket notification requirements, subject to conditions and 
limitations. The Agency has determined based on established factors 
that these devices, which are currently regulated by FDA under product 
code OYE, no longer require premarket notification to provide 
reasonable assurance of safety and effectiveness. All other class II 
devices classified under FDA's automated differential cell counter 
regulation would continue to be subject to premarket notification 
requirements. FDA is publishing this proposed order to obtain comments 
regarding this proposed exemption, in accordance with the Federal Food, 
Drug, and Cosmetic Act (FD&C Act).

DATES: Submit either electronic or written comments on the notice by 
May 6, 2019.

ADDRESSES: You may submit comments as follows. Please note that late, 
untimely filed comments will not be considered. Electronic comments 
must be submitted on or before May 6, 2019. The https://www.regulations.gov electronic filing system will accept comments until 
midnight Eastern Time at the end of May 6, 2019. Comments received by 
mail/hand delivery/courier (for written/paper submissions) will be 
considered timely if they are postmarked or the delivery service 
acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov. 
Follow the instructions for submitting comments. Comments submitted 
electronically, including attachments, to https://www.regulations.gov 
will be posted to the docket unchanged. Because your comment will be 
made public, you are solely responsible for ensuring that your comment 
does not include any confidential information that you or a third party 
may not wish to be posted, such as medical information, your or anyone 
else's Social Security number, or confidential business information, 
such as a manufacturing process. Please note that if you include your 
name, contact information, or other information that identifies you in 
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential 
information that you do not wish to be made available to the public, 
submit the comment as a written/paper submission and in the manner 
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper 
submissions): Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets 
Management Staff, FDA will post your comment, as well as any 
attachments, except for information submitted, marked and identified, 
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No. 
FDA-2018-N-4394 for ``Medical Devices; Exemptions from Premarket 
Notification: Class II Devices; Flow Cytometer Instruments; Request for 
Comments.'' Received comments, those filed in a timely manner (see 
ADDRESSES), will be placed in the docket and, except for those 
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m. 
and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with 
confidential information that you do not wish to be made publicly 
available, submit your comments only as a written/paper submission. You 
should submit two copies total. One copy will include the information 
you claim to be confidential with a heading or cover note that states 
``THIS DOCUMENT CONTAINS

[[Page 8048]]

CONFIDENTIAL INFORMATION.'' The Agency will review this copy, including 
the claimed confidential information, in its consideration of comments. 
The second copy, which will have the claimed confidential information 
redacted/blacked out, will be available for public viewing and posted 
on https://www.regulations.gov. Submit both copies to the Dockets 
Management Staff. If you do not wish your name and contact information 
to be made publicly available, you can provide this information on the 
cover sheet and not in the body of your comments and you must identify 
this information as ``confidential.'' Any information marked as 
``confidential'' will not be disclosed except in accordance with 21 CFR 
10.20 and other applicable disclosure law. For more information about 
FDA's posting of comments to public dockets, see 80 FR 56469, September 
18, 2015, or access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or 
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in 
the heading of this document, into the ``Search'' box and follow the 
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.

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, 240-402-6357, email: 
Ryan.Lubert@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Statutory Background

    Section 510(k) of the FD&C Act (21 U.S.C. 360(k)) and the 
implementing regulations, 21 CFR part 807 subpart E, require persons 
who intend to market a new device to submit and obtain clearance of a 
premarket notification (510(k)) containing information that allows FDA 
to determine whether the new device is ''substantially equivalent'' 
within the meaning of section 513(i) of the FD&C (21 U.S.C. 360c(i)) to 
a legally marketed device that does not require premarket approval.
    The 21st Century Cures Act (Pub. L. 114-255) (Cures Act) was signed 
into law on December 13, 2016. Section 3054 of the Cures Act amended 
section 510(m) of the FD&C Act. As amended, section 510(m)(2) of the 
FD&C Act provides that, 1 calendar day after the date of publication of 
the final list under paragraph (1)(B), FDA may exempt a class II device 
from the requirement to submit a report under section 510(k) of the 
FD&C Act upon its own initiative or a petition of an interested person, 
if FDA determines that a report under section 510(k) is not necessary 
to assure the safety and effectiveness of the device. To do so, FDA 
must publish in the Federal Register notice of its intent to exempt the 
device, or the petition, and provide a 60-calendar day period for 
public comment. Within 120 days after the issuance of this notice, FDA 
must publish an order in the Federal Register that sets forth its final 
determination regarding the exemption of the device that was the 
subject of the notice.

II. Factors FDA May Consider for Exemption

    There are a number of factors FDA may consider to determine whether 
a report under section 510(k) is necessary to provide reasonable 
assurance of the safety and effectiveness of a class II device. These 
factors are discussed in the January 21, 1998, Federal Register notice 
(63 FR 3142) and subsequently in the guidance the Agency issued on 
February 19, 1998, entitled ``Procedures for Class II Device Exemptions 
from Premarket Notification, Guidance for Industry and CDRH Staff'' 
(Class II 510(k) Exemption Guidance) (Ref. 1). As discussed in these 
documents, FDA generally considers the following factors to determine 
whether a report under section 510(k) is necessary for class II 
devices: (1) The device does not have a significant history of false or 
misleading claims or of risks associated with inherent characteristics 
of the device; (2) characteristics of the device necessary for its safe 
and effective performance are well established; (3) changes in the 
device that could affect safety and effectiveness will either (a) be 
readily detectable by users by visual examination or other means such 
as routine testing, before causing harm or (b) not materially increase 
the risk of injury, incorrect diagnosis, or ineffective treatment; and 
(4) any changes to the device would not be likely to result in a change 
in the device's classification. FDA may also consider that, even when 
exempting devices, these devices would still be subject to the general 
limitations on exemptions.

III. Proposed Class II Device Exemption

    FDA, on its own initiative, is proposing to exempt flow cytometer 
instruments from 510(k) review, subject to the conditions and 
limitations described in this section. These devices are currently 
class II devices under Sec.  864.5220 (21 CFR 864.5220) Automated 
differential cell counter and assigned the product code OYE. A flow 
cytometer instrument is used to count or characterize human cells in 
suspension by flowing single cells through one or more lasers and 
collecting signals using one or more fluorescence or light-scatter 
detection channels and are intended for use with FDA cleared or FDA 
approved in vitro diagnostic (IVD) reagents that employ fluorescent 
antibodies or ligands that are indicated for use with the instrument.
    We are now announcing our intent to exempt a subset of flow 
cytometer instruments currently regulated under product code OYE from 
510(k) review. FDA has assessed the need for 510(k) review against the 
criteria laid out in the Class II 510(k) Exemption Guidance and 
determined that these devices no longer require a report under section 
510(k) to provide reasonable assurance of safety and effectiveness. 
This determination is based, in part, on the Agency's knowledge of the 
device, including experience reviewing these devices over the past 34 
years, the ability to review the relevant functionality of these 
devices when they are used clinically with an IVD reagent that is 
subject to review, and relevant reports or studies on device 
performance and the Agency's ability to limit an exemption. In 
addition, FDA believes that, for these devices, the identified risks in 
the FDA document entitled ``Class II Special Controls Guidance 
Document: Premarket Notifications for Automated Differential Cell 
Counters for Immature or Abnormal Blood Cells'' can be mitigated using 
an alternative approach that provides equivalent assurance of safety 
and effectiveness in which a manufacturer's design verification and 
validation includes documenting the appropriate performance of each of 
the performance aspect mitigations identified in that document in 
sections 7 through 15 to address the risks of the device and 
documenting such performance in the design history file rather than 
providing that information in a report under section 510(k). This 
exemption is limited in scope and FDA's determination for the proposed 
exemption only applies to those flow cytometer instruments under the 
conditions listed below.

IV. Proposed Conditions and Limitations of Exemption

    FDA's proposal to grant an exemption from the 510(k) requirements 
for certain flow cytometer instruments applies under the following 
conditions: (1) The instrument must not include an indication for 
sorting and collecting

[[Page 8049]]

cells for IVD use or other clinical purposes; (2) the instrument must 
not be or include an automated hematology analyzer or include an 
indication for performing an automated differential cell count; (3) 
design verification and validation for the instrument must include 
documenting the appropriate performance of each of the performance 
aspect mitigations identified in sections 7 through 15 of the FDA 
document entitled ``Class II Special Controls Guidance Document: 
Premarket Notifications for Automated Differential Cell Counters for 
Immature or Abnormal Blood Cells''; and (4) design verification and 
validation for the instrument must include documentation of analysis 
and non-clinical testing that appropriately demonstrates: (i) The 
linearity of all fluorescent detectors covers at least four orders of 
magnitude with less than 10 percent deviation from expected values 
across the linear range. Performance must be demonstrated with either 
fluorescent beads that have been FDA-cleared, -approved, or exempted 
from the 510(k) requirements, or with fluorescent detection reagents 
that have been FDA-cleared, approved, or exempted from the 510(k) 
requirements, coupled with fresh, fixed, or stabilized cells, or some 
combination of such cells. Manufacturers may consult FDA-recognized 
consensus standards for information on how such study design and data 
analysis may be performed; and (ii) the total imprecision of the 
measured fluorescence intensity for each detection channel is less than 
10 percent Coefficient of Variation across the linear range of the 
detectors. Performance must be demonstrated with either fluorescent 
beads that have been FDA-cleared, -approved, or exempted from the 
510(k) requirements, or with fluorescent detection reagents that have 
been FDA-cleared, approved, or exempted from the 510(k) requirements, 
coupled with fresh, fixed, or stabilized cells, or some combination of 
such cells. Manufacturers may consult FDA-recognized consensus 
standards for information on how such study design and data analysis 
may be performed.
    FDA believes that flow cytometer instruments must meet these 
conditions for the device to be exempt from 510(k) requirements. FDA 
may partially limit the exemption from 510(k) requirements to specific 
devices within a listed device type. As such, this proposed exemption 
would only apply to flow cytometer instruments eligible for 
classification by FDA under product code OYE. If finalized, this 
exemption would not affect any other subset of flow cytometers or 
automated differential cell counters classified under Sec.  864.5220. 
In addition to being subject to the general limitations to the 
exemptions found in 21 CFR 864.9 and the conditions of exemption 
identified in this document, these devices will also remain subject to 
current good manufacturing practices and other general controls under 
the statute. An exemption from the requirements of 510(k) does not mean 
that the device type is exempt from any other statutory or regulatory 
requirements, unless such exemption is explicitly provided by order or 
regulation.
    Upon issuance of a final order exempting flow cytometry instruments 
from the requirements of 510(k), firms will need to either comply with 
the conditions for exemption from 510(k) requirements or submit and 
receive 510(k) clearance prior to marketing a flow cytometer 
instrument. This exemption, if finalized, will decrease regulatory 
burdens on the medical device industry and will eliminate private costs 
and expenditures required to comply with Federal regulations. 
Specifically, regulated industry will no longer have to invest time and 
resources in complying with 510(k) requirements, including preparation 
of documents and data for submission to FDA, payment of user fees 
associated with 510(k) submissions, and responding to questions and 
requests for additional information from FDA during 510(k) review for 
devices in the proposed exempted device type, subject to the conditions 
and limitations of the exemption.

V. Paperwork Reduction Act of 1995

    This proposed order refers to previously approved collections of 
information found in 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 21 CFR part 807, subpart E, regarding 
premarket notification, have been approved under OMB control number 
0910-0120 and the collections of information in 21 CFR part 820 
(Quality System Regulation), regarding the design history file, have 
been approved under OMB control number 0910-0073.

VI. References

    The following references are on display in the Dockets Management 
Staff (see ADDRESSES) and are available for viewing by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also 
available electronically at https://www.regulations.gov. FDA has 
verified the website addresses, as of the date this document publishes 
in the Federal Register, but websites are subject to change over time.

1. FDA Guidance, ``Procedures for Class II Device Exemptions from 
Premarket Notification, Guidance for Industry and CDRH Staff,'' 
February 19, 1998, available at https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080199.pdf.
2. FDA Special Controls Guidance Document, ``Class II Special 
Controls Guidance Document: Premarket Notifications for Automated 
Differential Cell Counters for Immature or Abnormal Blood Cells--
Final Guidance for Industry and FDA'' December 4, 2001, available at 
https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm092780.htm.

List of Subjects in 21 CFR Part 864

    Blood, Medical Devices, Packaging and containers.

    Therefore, under the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 321 et seq., as amended) and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR part 864 is proposed to be 
amended as follows:

PART 864--HEMATOLOGY AND PATHOLOGY DEVICES

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

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

0
2. In Sec.  864.5220, revise paragraph (b) to read as follows:


Sec.  864.5220  Automated differential cell counter.

* * * * *
    (b) Classification. Class II (Special Controls). The special 
control for this device is the Food and Drug Administration (FDA) 
document entitled ``Class II Special Controls Guidance Document: 
Premarket Notifications for Automated Differential Cell Counters for 
Immature or Abnormal Blood Cells; Final Guidance for Industry and 
FDA.'' A flow cytometer instrument that is used to count or 
characterize human cells in suspension by flowing single cells through 
one or more lasers and collecting signals using one or more 
fluorescence or light-scatter detection channels and intended for use 
with FDA-cleared or FDA-approved IVD reagents that employ fluorescent 
antibodies or ligands that are indicated for use with the instrument is 
exempt from the premarket notification procedures in subpart E of part 
807 of

[[Page 8050]]

this chapter subject to Sec.  864.9, and the following conditions for 
exemption:
    (i) The instrument must not include an indication for sorting and 
collecting cells for IVD use or other clinical purposes;
    (ii) The instrument must not be or include an automated hematology 
analyzer or include an indication for performing an automated 
differential cell count;
    (iii) Design verification and validation for the instrument must 
include documenting the appropriate performance of each of the 
performance aspect mitigations identified in sections 7 through 15 of 
the FDA document entitled ``Class II Special Controls Guidance 
Document: Premarket Notifications for Automated Differential Cell 
Counters for Immature or Abnormal Blood Cells,'' and
    (iv) Design verification and validation must include documentation 
of analysis and non-clinical testing demonstrating performance with 
either fluorescent beads that have been FDA-cleared, approved, or 
exempted from the premarket notification requirement, or with 
fluorescent detection reagents that have been FDA-cleared, approved, or 
exempted from the premarket notification requirement, coupled with 
fresh, fixed, or stabilized cells, or some combination of such cells. 
Documentation shall appropriately demonstrate:
    (A) The linearity of all fluorescent detectors covers at least four 
orders of magnitude with less than 10 percent deviation from expected 
values across the linear range; and
    (B) The total imprecision of the measured fluorescence intensity 
for each detection channel is less than 10 percent Coefficient of 
Variation across the linear range of the detectors.

    Dated: February 28, 2019.
Lowell J. Schiller,
Acting Associate Commissioner for Policy.
[FR Doc. 2019-03967 Filed 3-5-19; 8:45 am]
 BILLING CODE 4164-01-P


