[Federal Register Volume 66, Number 90 (Wednesday, May 9, 2001)]
[Proposed Rules]
[Pages 23634-23636]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 01-11580]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 864

[Docket No. 95P-0351]


Hematology and Pathology Devices; Reclassification of Automated 
Differential Cell Counters

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
reclassify from class III (premarket approval) to class II (special 
controls) the automated differential cell counter (ADCC). The ADCC is a 
device intended to identify and classify one or more of the formed 
elements of the blood, or to flag, count, or classify immature or 
abnormal hematopoietic cells of the blood, bone marrow, or other body 
fluids. FDA is basing this reclassification on new information 
submitted in a reclassification petition from the International Society 
for Laboratory Hematology (ISLH). The agency is taking this action 
under the Federal Food, Drug, and Cosmetic Act (the act), as amended by 
the Medical Device Amendments of 1976 (the 1976 amendments), the Safe 
Medical Devices Act of 1990 (the SMDA), and the Food and Drug 
Administration Modernization Act of 1997 (FDAMA).

DATES:  Submit written comments by August 7, 2001.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Larry J. Brindza, Center for Devices 
and Radiological Health (HFZ-440), Food and Drug Administration, 2098 
Gaither Rd., Rockville, MD 20850, 301-594-1293.

SUPPLEMENTARY INFORMATION:

I. Background (Regulatory Authorities)

    The act, as amended by the 1976 amendments (Public Law 94-295), the 
SMDA (Public Law 101-629), and FDAMA (Public Law 105-115), established 
a comprehensive system for the regulation of medical devices intended 
for human use. Section 513 of the act (21 U.S.C. 360c) established 
three categories (classes) of devices, depending on the regulatory 
controls needed to provide reasonable assurance of their safety and 
effectiveness. The three categories of devices are class I (general 
controls), class II (special controls), and class III (premarket 
approval).
    Under section 513 of the act, devices that were in commercial 
distribution before May 28, 1976 (the date of enactment of the 1976 
amendments), generally referred to as preamendments devices, are 
classified after FDA has: (1) Received a recommendation from a device 
classification panel (an FDA advisory committee); (2) published the 
panel's recommendation for comment, along with a proposed regulation 
classifying the device; and (3) published a final regulation 
classifying the device. FDA has classified most preamendments devices 
under these procedures.
    Devices that were not in commercial distribution prior to May 28, 
1976, generally referred to as postamendments devices, are classified 
automatically by statute (section 513(f) of the act) into class III 
without any FDA rulemaking process. Those devices remain in class III 
and require premarket approval, unless and until: (1) The device is 
reclassified into class I or II; (2) FDA issues an order classifying 
the device into class I or II in accordance with section 513(f)(2) of 
the act, as amended by FDAMA; or (3) FDA issues an order finding the 
device to be substantially equivalent, under section 513(i) of the act, 
to a predicate device that does not require premarket approval. The 
agency determines whether new devices are substantially equivalent to 
previously offered devices by means of premarket notification 
procedures in section 510(k) of the act (21 U.S.C. 360(k)) and part 807 
of the regulations (21 CFR part 807).
    A preamendments device that has been classified into class III may 
be marketed, by means of premarket notification procedures, without 
submission of a premarket approval application (PMA) until FDA issues a 
final regulation under section 515(b) of the act (21 U.S.C. 360e(b)) 
requiring premarket approval.
    Reclassification of classified preamendments devices is governed by 
section 513(e) of the act. This section provides that FDA may, by 
rulemaking, reclassify a device (in a proceeding that parallels the 
initial classification proceeding) based upon ``new information.'' The 
reclassification can be initiated by FDA or by the petition of an 
interested person. The term ``new information,'' as used in section 
513(e) of the act, includes information developed as a result of a 
reevaluation of the data before the agency when the device was 
originally classified, as well as information not presented, not

[[Page 23635]]

available, or not developed at that time. (See, e.g., Holland Rantos v. 
United States Department of Health, Education, and Welfare, 587 F.2d 
1173, 1174 n.1 (D.C. Cir. 1978); Upjohn v. Finch, 422 F.2d 944 (6th 
Cir. 1970); and Bell v. Goddard, 366 F.2d 177 (7th Cir. 1966).)
    Reevaluation of the data previously before the agency is an 
appropriate basis for subsequent regulatory action where the 
reevaluation is made in light of newly available regulatory authority 
(see Bell v. Goddard, supra, 366 F.2d at 181; Ethicon, Inc. v. FDA, 762 
F.Supp. 382, 389-91 (D.D.C. 1991)), or in light of changes in ``medical 
science.'' (See Upjohn v. Finch, supra, 422 F.2d at 951.) Regardless of 
whether data before the agency are past or new data, ``new 
information'' to support reclassification under section 513(e) of the 
act must be ``valid scientific evidence,'' as defined in section 
513(a)(3) of the act and 21 CFR 860.7(c)(2). (See, e.g., General 
Medical Co. v. FDA, 770 F.2d 214 (D.C. Cir. 1985); Contact Lens Assoc. 
v. FDA, 766 F.2d 592 (D.C. Cir.), cert. denied, 474 U.S. 1062 (1985).) 
FDA relies upon ``valid scientific evidence'' in the classification 
process to determine the level of regulation for devices. For the 
purpose of reclassification, the valid scientific evidence upon which 
the agency relies must be publicly available. Publicly available 
information excludes trade secret and/or confidential commercial 
information, e.g., nonpublic information in a pending PMA. (See section 
520(c) of the act (21 U.S.C. 360j(c).)

II. Regulatory History of the Device

    In the Federal Register of June 8, 1990 (55 FR 23510), FDA issued a 
final rule that amended 21 CFR 864.5220 to reclassify the ADCC intended 
to flag or identify specimens containing abnormal blood cells from 
class III into class II. The rule continued to classify the ADCC 
intended for all other uses into class III. FDA based the rule on new 
information in a petition from the Health Industry Manufacturers 
Association.
    On September 22, 1995, Abbott Laboratories, Santa Clara, CA 95054, 
submitted a petition under sections 513(e) and 515(b) of the act to 
reclassify the ADCC from class III to class II for its general uses in 
identifying and counting blood elements and cells. On September 4, 
1997, FDA received a letter from ISLH announcing that ISLH was 
replacing Abbott Laboratories as the petitioner. Consistent with the 
act and the regulations, FDA referred the petition to the Hematology 
and Pathology Device Panel (the Panel) for its recommendation on the 
change in classification requested by the petitioner. The Panel based 
its recommendation to reclassify the ADCC from class III to class II on 
the belief that special controls, including voluntary standards and 
guidance documents, as well as published references, and the clinical 
experience of the Panel, are sufficient to provide reasonable assurance 
of the safety and effectiveness of the ADCC. Accordingly, FDA is now 
proposing to reclassify the ADCC from class III (premarket approval) to 
class II (special controls) when the device is intended to be used to 
identify and classify one or more of the formed elements of the blood, 
or to flag, count, or classify immature or abnormal hematopoietic cells 
of the blood, bone marrow, or other body fluids.

III. Proposed Dates

    FDA proposes that any final regulation based on this proposal 
become effective 30 days after its date of publication in the Federal 
Register.

IV. Device Description

    An ADCC is a device used to identify one or more of the formed 
elements of the blood. These devices may also have the capability to 
flag, count, or classify immature or abnormal hematopoietic cells of 
the blood, bone marrow, or other body fluids. These devices may combine 
an electronic particle counting method, optical method, or a flow 
cytometric method utilizing monoclonal CD (cluster designation) 
markers. The device may include accessory CD markers.

V. Recommendation of the Panel

    On January 20, 1999, the Panel recommended that the ADCC be 
reclassified from class III to class II. The Panel believed that 
classification in class II with the special control ``Guidance for 
Premarket Notification for Automated Differential Cell Counters for 
Immature or Abnormal Blood Cells'' would provide reasonable assurance 
of the safety and effectiveness of the device.

VI. Risks to Health

    Failure of the device to perform satisfactorily may lead to an 
error in the diagnosis of a blood cell disorder. Inappropriate therapy 
based on inaccurate diagnostic data may place the patient at risk.

VII. Summary of Reasons for Recommendation

    The Panel believes that the ADCC should be reclassified into class 
II because special controls, in addition to general controls, provide 
reasonable assurance of the safety and effectiveness of the device, and 
there is sufficient information to establish special controls to 
provide such assurance. Adherence to ``Guidance for Premarket 
Notification for Automated Differential Cell Counters for Immature or 
Abnormal Blood Cells'' can control the risk of misdiagnosis and 
inappropriate therapy by having the manufacturer provide appropriate 
data to support all claims for substantial equivalence and performance 
of ADCC.

VIII. Summary of Data Upon Which the Recommendation Is Based

    The performance characteristics of the technology used in ADCCs 
over many years of experience plus the proven safety and effectiveness 
of the device are well documented in the medical literature (Ref. 1). 
FDA can evaluate performance characteristics for abnormal cell types 
such as nucleated red blood cells and immature reticulocyte fraction in 
510(k) submissions (Refs. 2, 3, and 4). Based on the available 
information, FDA believes that the special control discussed below is 
capable of providing reasonable assurance of the safety and 
effectiveness of the automated differential cell counter for the 
identified risks to health of this device.

IX. Special Controls

    In addition to general controls, FDA believes that the ``Guidance 
for Premarket Notification for Automated Differential Cell Counters for 
Immature or Abnormal Blood Cells'' is an adequate special control to 
address the risks to health described above.
    In order to receive ``Guidance for Premarket Notification for 
Automated Differential Cell Counters for Immature or Abnormal Blood 
Cells'' via your fax machine, call the CDRH Facts-On-Demand system at 
800-899-0381 or 301-827-0111 from a touch-tone telephone. Press 1 to 
enter the system. At second voice prompt press 1 to order a document. 
Enter the document number (1184) followed by the pound sign (#). Follow 
the remaining voice prompts to complete your request. Persons 
interested in obtaining a copy of the guidance may also do so using the 
Internet. CDRH maintains an entry on the Internet for easy access to 
information including text, graphics, and files that may be downloaded 
to a personal computer with access to the Internet. Updated on a 
regular basis, the CDRH home page includes ``Guidance for Premarket 
Notification for Automated Differential Cell Counters for Immature or 
Abnormal Blood Cells,'' device safety alerts, Federal Register 
reprints, information on premarket submissions (including lists of 
approved

[[Page 23636]]

applications and manufacturers' addresses), small manufacturers' 
assistance, information on video conferencing and electronic 
submissions, mammography matters, and other device-oriented 
information. The CDRH home page may be accessed at http://www.fda.gov/cdrh.

X. FDA's Tentative Findings

    FDA agrees with the recommendation of the Panel and believes ADCCs 
should be classified into class II because special controls, in 
addition to general controls, provide reasonable assurance of the 
safety and effectiveness of the device, and there is sufficient 
information to establish special controls to provide such assurance.

XI. 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.

XII. Analysis of Impacts

    FDA has examined the impacts of this proposed rule under Executive 
Order 12866, and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121)), and the Unfunded Mandates Reform Act of 
1995 (Public Law 104-4). Executive Order 12866 directs agencies to 
assess all costs and benefits of available regulatory alternatives and, 
when regulation is necessary, to select regulatory approaches that 
maximize net benefits (including potential economic, environmental, 
public health and safety, and other advantages; distributive impacts; 
and equity). The agency believes that this reclassification action is 
consistent with the regulatory philosophy and principles identified in 
the Executive order. In addition, the reclassification action is not a 
significant regulatory action as defined by the Executive order and so 
is not subject to review under the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Reclassification of this device from class III to 
class II will relieve all manufacturers of the device of the cost of 
complying with the premarket approval requirements in section 515 of 
the act. Because reclassification will reduce regulatory costs with 
respect to this device, it will impose no significant economic impact 
on any small entities, and it may permit small potential competitors to 
enter the marketplace by lowering their costs. The agency therefore 
certifies that this reclassification action, if finalized, will not 
have a significant economic impact on a substantial number of small 
entities. In addition, this reclassification action will not impose 
costs of $100 million or more on either the private sector or State, 
local, and tribal governments in the aggregate, and therefore a summary 
statement or analysis under section 202(a) of the Unfunded Mandates 
Reform Act of 1995 is not required.

XIII. Paperwork Reduction Act of 1995

    The proposed rule does not contain information collection 
provisions that are subject to review by the Office of Management and 
Budget under the Paperwork Reduction Act of 1995 (44 U.S.C 3501-3520).

XIV. Request for Comments

    Interested persons may submit to the Dockets Management Branch 
(address above) written comments regarding this proposal by August 7, 
2001. Two copies of any comments are to be submitted, except that 
individuals may submit one copy. Comments are to be identified with the 
docket number found in brackets in the heading of this document. 
Received comments may be seen in the Dockets Management Branch between 
9 a.m. and 4 p.m., Monday through Friday.

XV. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 am. and 4 p.m., Monday through Friday:
    1. Various authors, ``The White Blood Cell Differential,'' Parts 
I & II, Blood Cells 11:1-314, 1985.
    2. Dutcher, T. F., ``Leukocyte Differentials, Are They Worth The 
Effort?'' Clinics in Laboratory Medicine 4 (1): 71-87, 1984.
    3. Rumke, C. L., ``The Statistically Expected Variability in 
Differential Leukocyte Counting,'' In: Differential Leukocyte 
Counting,'' edited by J. A. Koepke, College of American 
Pathologists, Skokie, IL, pp. 39-45, 1977.
    4. Rumke, C. L., ``Statistical Reflections in Finding Atypical 
Cells,'' Blood Cells 11: 141-144, 1985.

List of Subjects in 21 CFR Part 864

    Biologics, Blood, Laboratories, 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, FDA proposes 
that 21 CFR part 864 be amended as follows:

PART 864--HEMATOLOGY AND PATHOLOGY DEVICES

    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.

    2. Section 864.5220 is revised to read as follows:


Sec. 864.5220  Automated differential cell counter.

    (a) Identification. An automated differential cell counter is a 
device used to identify one or more of the formed elements of the 
blood. The device may also have the capability to flag, count, or 
classify immature or abnormal hematopoietic cells of the blood, bone 
marrow, or other body fluids. These devices may combine an electronic 
particle counting method, optical method, or a flow cytometric method 
utilizing monoclonal CD (cluster designation) markers. The device 
includes accessory CD markers.
    (b) Classification. Class II (special controls). The special 
control for this device is the FDA guidance document entitled 
``Guidance for Premarket Notification for Automated Differential Cell 
Counters for Immature or Abnormal Blood Cells.''

    Dated: April 28, 2001.
Linda S. Kahan,
Deputy Director for Regulations Policy, Center for Devices and 
Radiological Health.
[FR Doc. 01-11580 Filed 5-8-01; 8:45 am]
BILLING CODE 4160-01-S