[Federal Register Volume 60, Number 144 (Thursday, July 27, 1995)]
[Rules and Regulations]
[Pages 38480-38482]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-18446]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Part 866

[Docket No. 91N-0063]


Immunology and Microbiology Devices; Revocation of the Exemption 
From Premarket Notification; Blood Culturing System Devices

AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is revising the 
microbial growth monitor classification regulation by revoking the 
exemption from the premarket notification requirements for automated 
blood culturing system devices used in testing blood and other normally 
sterile body fluids for bacteria, fungi, and other microorganisms. 
Revocation of the exemption is necessary because of the importance of 
these devices in providing rapid diagnosis of potentially life-
threatening conditions. Devices using traditional manual methods 
employing turbidity measurements or direct counts, included under this 
classification regulation, will continue to be exempt from the 
requirement of premarket notification.

DATES: The final rule is effective October 25, 1995. A premarket 
notification submission is required for any automated blood culturing 
system intended to be introduced or delivered for introduction into 
commerce on or after October 25, 1995, under section 510(k) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k)), and the 
procedures in subpart E of 21 CFR part 

[[Page 38481]]
807. A manufacturer or an initial distributor of an imported blood 
culturing device that has already begun commercial distribution under 
the existing exemption from premarket notification is required to 
submit a premarket notification on or before October 25, 1995 and must 
have a premarket notification cleared by FDA by April 22, 1996.
FOR FURTHER INFORMATION CONTACT: Joseph M. Sheehan, Center for Devices 
and Radiological Health (HFZ-84), Food and Drug Administration, 2094 
Gaither Rd., Rockville, MD 20850, 301-594-4765, Ext. 157.

SUPPLEMENTARY INFORMATION:

I. Background

    Blood culturing system devices are diagnostic devices used in 
clinical settings to detect the presence or growth of bacteria, fungi, 
or other microorganisms from blood samples or from samples of other 
body fluids that are normally sterile. The process involves testing for 
these microorganisms by inoculating the patient's sample directly into 
broth media or by inoculating a processed sample concentrate onto agar 
media. Microbial growth is monitored either by traditional manual 
methods (visual inspection, microscopic evaluation, and/or 
subculturing) or by instrument-assisted (automated) monitoring of 
microbial metabolic activities, such as the detection of increased 
presence of carbon dioxide or changes in fluorescence, bioluminescence, 
or ATPase activities.
    In the Federal Register of November 9, 1982 (47 FR 50814 at 50826), 
FDA classified blood culturing system devices into class I (21 CFR 
866.2560). In the Federal Register of June 12, 1989 (54 FR 25042 at 
25046), FDA published a final rule exempting microbial growth monitors, 
subject to certain limitations, from the requirement of premarket 
notification. In the Federal Register of April 26, 1991 (56 FR 19333), 
FDA proposed to revoke this exemption for blood culturing system 
devices because of safety and effectiveness considerations. FDA 
determined, on reconsideration, that blood culturing system devices do 
not meet the criteria for exemption identified in the regulation 
published in the Federal Register of June 12, 1989.
    Although current efforts have been directed toward streamlining the 
regulation of in vitro diagnostic devices, FDA's revocation of the 
blood culturing system devices exemption is necessary because it is 
based on significant safety and effectiveness considerations.
    Subsequent to June 12, 1989, through the medical/scientific 
literature, FDA became aware of a significant number of problems 
related to these devices. These problems include: (1) Failure of media 
to support growth of certain organisms; (2) false negative and false 
positive results; and (3) cross contamination of cultures. Also, in the 
early 1990's, the use of instrument assisted microbial growth monitors, 
originally intended for blood culturing, started to be commonly used to 
detect, recover, and provide a complete panel of susceptibility results 
for Mycobacterium tuberculosis.
    Since these devices are relied upon for rapid diagnosis of 
bacterial or fungal infection, and are commonly used to detect, 
recover, and determine susceptibility of Mycobacterium tuberculosis, 
the reported failure of these devices raises significant questions of 
safety and effectiveness. Bacterial or fungal infections of the 
bloodstream may be life-threatening. Tuberculosis is a disease of 
serious health consequences for the patient and its potential for quick 
dissemination is a very significant public health concern. Malfunction 
of these devices, therefore, could result in misdiagnosis and 
mistreatment, thus endangering patients, health care professionals, and 
the public at large.
    Because of safety and effectiveness concerns presented by the 
device, FDA believes it is necessary to revoke the exemption from the 
premarket notification procedures to enable FDA to monitor the 
introduction into commerce, by manufacturers and importers, of 
automated blood culturing system devices, and to determine whether the 
devices are as safe and effective as legally marketed devices. Devices 
using traditional manual methods employing visual turbidity measurement 
or direct counts are not affected by this final regulation.
    FDA provided interested persons 60 days to submit written comments 
on the proposal. FDA received two comments. A summary of these comments 
and FDA's responses follows:
     1. One comment requested clarification of the continued exemption 
for traditional culture media used with manual blood culture methods. 
The comment suggested that the amended section contain language that 
makes it clear that traditional manual blood culture bottles in which 
microbial growth is detected by visual reading and conventional 
subculturing techniques are not affected by the revocation of the 
exemption.
    FDA agrees with this suggestion. Conventional media dispensed in 
blood culture bottles (20 to 100 milliliter volume) with limited entry 
seals that are used only with conventional manual blood culture 
procedures (visual observation for signs of microbial growth and 
routine subcultures and/or microscopic screening for presence of 
bacteria and fungi) are not dependent on instrument-based monitoring 
for detection of signs of microbial growth. However, media bottles used 
with the automated system are an integral part of the system; 
therefore, any new or modified media to be used with an automated blood 
culturing system are also subject to the revocation.
    2. A second comment objected to the continued exemption for blood 
culture systems not using automated instrumentation.
    FDA disagrees with the comment. Current traditional manual blood 
culturing methods use media formulations and techniques that have been 
in use for many years. The types of media used are often commercialized 
for blood culturing by manual procedures developed and controlled by 
individual laboratories. In contrast, devices or systems that specify 
incubation and observation procedures based on a combination of 
different media or for use with a monitoring component (other than 
visual inspection for evidence of microbial growth and routine 
subculture to solid media and microscopic examination) are not exempt 
from premarket notification.
    Closed systems that exclude routine microscopic examination and 
subcultures would also be considered a microbial growth monitor and 
would be subject to the revocation. Similarly, any media bottle 
designed to be used with a microbial growth monitor (blood culture 
instrument or detection mechanism other than direct observation/
subculture/microscopic inspection) for detection of microorganisms from 
patient specimens would be considered a component of the microbial 
growth monitor and also subject to the revocation.

II. References

    The following information has been placed on display in the Dockets 
management Branch (HFA-350), Food and Drug Administration, rm. 1-24, 
12420 Parklawn Dr., Rockville, MD 20857, and may be seen by interested 
persons between 9 a.m. and 4 p.m., Monday through Friday.
     1. Aronson, M. D., and D. H. Bor, ``Blood Cultures,'' Annals of 
Internal Medicine, 106:246-253, 1987.
    2. Thorpe, T. C., et al., ``BacT/Alert: An Automated Calorimetric 
Microbial Detection System,'' Journal of Clinical Microbiology, 
28:1608-1612, 1990.

[[Page 38482]]

    3. Wallis, C., and J. L. Melnick, ``Rapid, Calorimetric Method for 
the Detection of Microorganisms in Blood Culture,'' Journal of Clinical 
Microbiology, 21:505-508, 1985.
    4. Washington, II, J. A., and D. M. Ilstrue, ``Blood Cultures: 
Issues and Controversies,'' Reviews of Infectious Diseases, 8:792-802, 
1986.
    5. Welch, W. D., et al., ``Variability in CO2, O2, and pH 
levels in Blood Culture Bottles from Five Different Manufacturers,'' 
Journal of Clinical Microbiology, 20:881-883, 1984.

III. Environmental Impact

     The agency has determined under 21 CFR 25.24(a)(8) and (a)(10) 
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. Analysis of Impacts

    FDA has examined the impact of the final rule under Executive Order 
12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 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 final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule 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. Because this final rule revokes an exemption and 
places manufacturers of these devices on a level with manufacturers of 
other devices, the agency certifies that the final rule will not have a 
significant economic impact on a substantial number of small entities. 
Therefore, under the Regulatory Flexibility Act, no further analysis is 
required on small entities.

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

    1. The authority citation for 21 CFR part 866 continues to read as 
follows:
    Authority: Secs. 501, 510, 513, 515, 520, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 351, 360, 360c, 360e, 360j, 
371).

    2. Section 866.2560 is amended by revising paragraph (b) to read as 
follows:


Sec. 866.2560 Microbial growth monitor.

 * * * * *
    (b) Classification. Class I. With the exception of automated blood 
culturing system devices that are used in testing for bacteria, fungi, 
and other microorganisms in blood and other normally sterile body 
fluids, this device is exempt from the premarket notification 
procedures in subpart E of part 807 of this chapter.

    Dated: July 18, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-18446 Filed 7-26-95; 8:45 am]
BILLING CODE 4160-01-F