
[Federal Register Volume 76, Number 96 (Wednesday, May 18, 2011)]
[Proposed Rules]
[Pages 28689-28696]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-12088]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2011-N-0103]


Microbiology Devices; Classification of In Vitro Diagnostic 
Device for Bacillus Species Detection

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
classify in vitro diagnostic devices for Bacillus species (spp). 
detection into

[[Page 28690]]

class II (special controls), in accordance with the recommendation of 
the Microbiology Devices Advisory Panel (the Panel). In addition, the 
proposed rule would establish as a special control limitations on the 
distribution of this device. FDA is publishing in this document the 
recommendations of the Panel regarding the classification of this 
device. After considering public comments on the proposed 
classification, FDA will publish a final regulation classifying this 
device. Elsewhere in this issue of the Federal Register, FDA is 
announcing the availability for comment of the draft guidance document 
that FDA proposes to designate as a special control for this device.

DATES: Submit electronic or written comments by August 16, 2011. See 
section IV of this document for the proposed effective date of a final 
rule based on the proposed rule in this document.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2011-
N-0103, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier (for paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2011-N-0103 for this rulemaking. All comments 
received may be posted without change to http://www.regulations.gov, 
including any personal information provided. For additional information 
on submitting comments, see the ``Request for Comments'' heading of the 
SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number(s), found in brackets in the heading of this document, 
into the ``Search'' box and follow the prompts and/or go to the 
Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, 
MD 20852.

FOR FURTHER INFORMATION CONTACT:  Beena Puri, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, rm. 5553, Silver Spring, MD 20993-0002, 301-796-6202.

SUPPLEMENTARY INFORMATION: 

I. Background

A. Legal Authority

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 
301 et seq.), as amended by the Medical Device Amendments of 1976 (Pub. 
L. 94-295), the Safe Medical Devices Act of 1990 (SMDA) (Pub. L. 101-
629), the Food and Drug Administration Modernization Act of 1997 
(FDAMA) (Pub. L. 105-115), the Medical Device User Fee and 
Modernization Act of 2002 (MDUFMA) (Pub. L. 107-250), and the Food and 
Drug Administration Amendments Act of 2007 (FDAAA) (Pub. L. 110-85), 
establishes a comprehensive system for the regulation of medical 
devices intended for human use. Section 513 of the FD&C Act (21 U.S.C. 
360c) establishes 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 FD&C Act, FDA refers to devices that were 
in commercial distribution before May 28, 1976 (the date of enactment 
of the 1976 amendments), as ``preamendments devices.'' FDA classifies 
these devices after it: (1) Receives a recommendation from a device 
classification panel (an FDA advisory committee); (2) publishes the 
panel's recommendation for comment, along with a proposed regulation 
classifying the device; and (3) publishes a final regulation 
classifying the device. (See also section 513(d) (21 U.S.C. 360c(d)). 
FDA has classified most preamendments devices under these procedures.
    FDA refers to devices that were not in commercial distribution 
before May 28, 1976, as ``postamendments devices.'' These devices are 
classified automatically by statute (section 513(f)) of the FD&C Act 
(21 U.S.C. 360c(f)) into class III without any FDA rulemaking process. 
Those devices remain in class III and require premarket approval, 
unless and until: (1) FDA reclassifies the device into class I or II; 
(2) FDA issues an order classifying the device into class I or class II 
in accordance with section 513(f)(2) of the FD&C Act (21 U.S.C. 
360(f)(2)), as amended by FDAMA; or (3) FDA issues an order finding the 
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. The Agency determines whether a postamendments 
device is substantially equivalent to a predicate device by means of 
premarket notification procedures described in section 510(k) of the 
FD&C Act (21 U.S.C. 360(k)) and 21 CFR part 807.
    A person may market a preamendments device that has been classified 
into class III through premarket notification procedures, without 
submission of a premarket approval application (PMA) until FDA issues a 
final regulation under section 515(b) of the FD&C Act (21 U.S.C. 
360e(b)) requiring premarket approval. Consistent with the FD&C Act and 
the regulations, FDA consulted with the Panel, regarding the 
classification of this device.

B. Regulatory History of In Vitro Diagnostic Devices for Bacillus Spp. 
Detection

    After the enactment of the Medical Device Amendments of 1976, FDA 
undertook to identify and classify all preamendments devices, in 
accordance with section 513(b) of the FD&C Act (21 U.S.C. 360c(b)). 
However, in vitro diagnostic devices for Bacillus spp. detection were 
not identified and classified in this initial effort. FDA subsequently 
identified several preamendments devices for Bacillus spp. detection, 
including Bacillus spp. antisera conjugated with a fluorescent dye 
(immunofluorescent reagents) used to presumptively identify bacillus-
like organisms in clinical specimens, antigens used to identify 
antibodies to B. anthracis (anti-toxin and anti-capsular) in serum, and 
bacteriophage used for differentiating B. anthracis from other Bacillus 
spp. based on susceptibility to lysis by the phage.
    Consistent with the FD&C Act and the regulations, FDA held a Panel 
meeting on March 7, 2002, regarding the classification of the 
preamendments in vitro diagnostic devices for Bacillus spp. detection. 
After the Panel meeting, FDA found three additional in vitro diagnostic 
devices for Bacillus spp. detection to be substantially equivalent to 
another device within that type. These three devices have the same 
intended use as their predicate devices, but make use of newer nucleic 
acid amplification technology (NAAT). While they exhibit technological 
differences from the preamendments Bacillus spp. detection devices, FDA 
has determined that they are as safe and effective as, and do not raise 
different

[[Page 28691]]

questions of safety and effectiveness than, their predicates. (See 
section 513(i) of the FD&C Act (21 U.S.C. 360c(i).)

II. Panel Recommendation

    During a public meeting held on March 7, 2002, the Panel made the 
following recommendation regarding the classification of in vitro 
diagnostic devices for Bacillus spp. detection (Ref. 1).

A. Identification

    FDA is proposing the following identification based on the Panel's 
recommendation and the available information. An in vitro diagnostic 
device for Bacillus spp. detection is used to detect and differentiate 
among Bacillus spp. and presumptively identify B. anthracis (B. 
anthracis) and other Bacillus spp. from cultured isolates or clinical 
specimens as an aid in the diagnosis of anthrax and other diseases 
caused by Bacillus spp. This device may consist of Bacillus spp. 
antisera conjugated with a fluorescent dye (immunofluorescent reagents) 
used to presumptively identify bacillus-like organisms in clinical 
specimens; or bacteriophage used for differentiating B. anthracis from 
other Bacillus spp. based on susceptibility to lysis by the phage; or 
antigens used to identify antibodies to B. anthracis (anti-toxin and 
anti-capsular) in serum. Bacillus infections include anthrax 
(cutaneous, inhalational, or gastrointestinal) caused by B. anthracis, 
and gastrointestinal disease and non-gastrointestinal infections caused 
by Bacillus cereus (B. cereus).

B. Classification Recommendation

    The Panel recommended that in vitro diagnostic devices for Bacillus 
spp. Detection be classified into class II. The Panel believed that 
class II with the special controls (special controls guidance document 
and distribution limitations) would provide reasonable assurance of the 
safety and effectiveness of the device. Elsewhere in this issue of the 
Federal Register, FDA is announcing the availability of the guidance 
document that will serve as a special control for this device.

C. Summary of Reasons and Data To Support the Recommendations

    At the March 7, 2002, meeting, the Panel considered information 
from the literature presented by FDA (Refs. 2 to 5), information 
presented at the meeting by representatives from the United States Army 
Medical Research Institute for Infectious Diseases (USAMRIID) who 
shared the historical perspective on their institution's use of devices 
for the detection of B. anthracis and their personal experience using 
these devices, and the Panel's personal knowledge and experience.
    Evidence presented to the Panel addressed how the preamendments 
devices of this type work and some of their limitations. Bacteriophage 
tests are used for differentiating B. anthracis from other Bacillus 
spp. based on susceptibility to lysis by the phage. They have been 
shown to specifically lyse vegetative B. anthracis and not B. cereus 
strains, although the phage can fail to lyse rare strains of B. 
anthracis. Bacillus spp. antisera tests conjugated with a fluorescent 
dye (immunofluorescent reagents) are used to microscopically visualize 
specific binding with cultured bacteria. Gram positive rods with 
capsules that fluoresce is presumptive evidence for identification of 
B. anthracis and must be confirmed with further testing. Antigen tests 
are used to identify antibodies to B. anthracis (anti-toxin and anti-
capsular) in serum. They can be used for confirmation of anthrax if the 
patient survives the disease, because early antibiotic treatment does 
not abrogate antibody expression. However, such serological testing is 
most useful for monitoring responses to anthrax vaccines and for 
epidemiological investigations.
    The Panel recommended prescription use of the device, with the 
added restrictions that use of these devices be limited to persons with 
specific training or experience in the applicable testing methods, and 
only in facilities under the oversight of public health laboratories, 
so that the laboratories would coordinate and communicate with state 
and local public health directors and that performance of the device in 
the laboratory hands might be systematically collated for interagency 
review (including FDA).
    The Panel believes that in vitro diagnostic devices for Bacillus 
spp. should be classified into class II because special controls, in 
addition to general controls, would provide reasonable assurance of the 
safety and effectiveness of the device, and there is sufficient 
information to establish special controls to provide such assurance.

D. Risks to Health

    Based on the Panel's discussion and recommendations, and FDA's 
experience with these devices, we believe the following are risks to 
health associated with the use of the device type.
    Failure of in vitro diagnostic devices for Bacillus spp. detection 
to perform as indicated or an error in interpretation of results may 
lead to misdiagnosis and improper patient management or inaccurate 
epidemiological information that may contribute to inappropriate public 
health responses. FDA believes that this type of device presents risks 
associated with a false negative test result, and a false positive test 
result, as explained below. In addition, there may be risks to 
laboratory workers resulting from handling cultures and control 
materials.
    A false positive result may lead to a medical decision causing a 
patient to undergo unnecessary or ineffective treatment, as well as 
inaccurate epidemiological information on the presence of anthrax 
disease in a community. A false negative result may lead to delayed 
recognition by the physician of the presence or progression of disease 
and inaccurate epidemiological information to control and prevent 
additional infections. A false negative result could potentially delay 
diagnosis and treatment of infection caused by B. anthracis or other 
Bacillus spp.
    Because handling the quality control organisms and those 
potentially present in the specimen may pose a risk to laboratory 
workers, use of these products and the needed laboratory control 
materials would be restricted to laboratories with the appropriate 
biosafety facilities and training.

E . Special Controls

    The Panel suggested the following special controls: (1) That FDA 
partner with the Centers for Disease Control and Prevention (CDC), 
USAMRIID, and other appropriate Agencies involved in laboratory 
performance issues to develop practical ways to evaluate the 
performance of these devices; (2) that appropriate biosafety handling 
of the diagnostic specimens be followed; and (3) that FDA develop 
testing guidelines to include recommendations on specimen selection, 
procedures, interpretation of results, and possibly public health 
notification.
    Based on the Panel's discussion and recommendations, FDA believes 
that, in addition to general controls, the special controls discussed 
in the following paragraphs are adequate to address the risks to 
health.
    FDA believes that the draft guidance document entitled ``Class II 
Special Controls Guidance Document: ``In Vitro Diagnostic Devices for 
Bacillus spp. Detection'' and limitations on distribution of these 
devices, set forth in the proposed classification regulation, will help 
to address the issues identified previously and provide a reasonable

[[Page 28692]]

assurance of safety and effectiveness of the device. Elsewhere in this 
issue of the Federal Register, FDA is announcing the availability for 
comment of the draft of the guidance document that is proposed to serve 
as a special control for this device. The class II special controls 
guidance provides information on how to meet premarket (510(k)) 
submission requirements for the assays in the sections that discuss 
performance characteristics and labeling. The performance 
characteristics section describes studies to demonstrate appropriate 
performance and control against assays that may otherwise fail to 
perform to acceptable standards. The labeling section addresses factors 
such as directions for use, quality control and precautions for use and 
interpretation.
    In addition, FDA proposes to require as a special control in the 
proposed classification regulation that distribution of the device be 
limited to laboratories with experienced personnel who have training in 
principles and use of microbiological culture identification methods 
and infectious disease diagnostics, and with appropriate biosafety 
equipment and containment. As noted, the Panel was concerned that these 
devices be used by personnel sufficiently skilled to maximize their 
performance and to appropriately interpret and make use of test 
results. FDA believes that this proposed distribution limitation will 
appropriately help assure the safe and effective use of these devices, 
and that it is consistent with the intent of the Panel in its 
discussion of limitations on the use of the devices and on monitoring 
of test results.

                                Table 1--Risks to Health and Mitigation Measures
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               Identified risks                                        Mitigation measures
----------------------------------------------------------------------------------------------------------------
A false negative test result may lead to delay  Device description--Recommended.
 of therapy and progression of disease and      Performance Studies--Recommended.
 epidemiological failure to promptly recognize  Labeling--Recommended.
 disease in the community.                      Limited Distribution--Required.
A false positive test result may lead to        Device description--Recommended.
 unnecessary treatment and incorrect            Performance Studies--Recommended.
 epidemiological information that leads to      Labeling--Recommended.
 unnecessary prophylaxis and management of      Limited Distribution--Required.
 others.
Biosafety and risks to laboratory workers       Labeling--Recommended.
 handling test specimens and control materials. Limited Distribution--Required.
----------------------------------------------------------------------------------------------------------------

III. Proposed Classification

    FDA agrees with the Panel's recommendation that in vitro diagnostic 
devices for Bacillus spp. detection should be classified into class II 
because special controls, in addition to general controls, will provide 
reasonable assurance of the safety and effectiveness of the device, and 
there is sufficient information to establish special controls to 
provide such assurance.

IV. Proposed Effective Date

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

V. Environmental Impact

    The Agency has determined that under 21 CFR 25.34(b) this 
classification 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.

VI. Analysis of Impacts

A. Introduction

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Pub. L. 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 proposed rule is not a significant regulatory action as defined by 
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 of the minor impact expected from this 
proposed rule, the Agency proposes to certify that the final rule will 
not have a significant economic impact on a substantial number of small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $135 million, using the most current (2009) Implicit 
Price Deflator for the Gross National Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.

B. Objective

    The objective of the proposed regulation is to ensure the continued 
safety and effectiveness of in vitro diagnostic test kits for the 
identification of potential Bacillus (Bacillus spp.) infections.

C. Baseline

    Since the 1950s, diagnostic tests have been used to detect Bacillus 
spp., differentiate between species, and identify B. anthracis from 
culture isolates or clinical specimens. Over the 10-year period 1999 to 
2009, there have been approximately 8,000 such tests (using the 
estimated annual testing rate), the vast majority of which were for the 
purposes of proficiency testing and training. No accidents have been 
reported associated with these tests.
    There are currently five diagnostic test kits cleared from 
different manufacturers, as well as devices developed by CDC and 
Department of Defense. The CDC test kits have been distributed to 
approximately 114 laboratories that belong to the national LRN 
(Laboratory Response Network). Kits are able to test between 10 and 100 
samples depending on the testing capability of the different test kits. 
The alternative to using in vitro diagnostic test kits to identify 
potential exposure to

[[Page 28693]]

B. anthracis is to use blood, fluid, and tissue specimens to grow 
cultures that may be used to identify the bacillus. This method is more 
time-consuming and presents risks that the disease (if present) will 
progress and be more difficult to treat when identified. It also means 
increased patient anxiety while the culture is growing, whether the 
patient has been exposed or not. A patient that may have contracted 
inhalational anthrax would be expected to have high levels of anxiety 
while awaiting diagnosis. The diagnostic test kits offer significant 
public health benefits by providing rapid diagnosis that can both save 
lives by identifying patients with anthrax and rapidly beginning 
treatment as well as avoiding unnecessary prophylactic treatments for 
patients that are found to not have the bacillus.
    Currently most marketed diagnostic test kits have extremely high 
predictive values. Sensitivities of these devices (proportion of 
positive patients correctly identified by the test) have been tested to 
be over 99 percent and specificities (proportion of negative patients 
correctly identified by the test) approach 100 percent.
    However, after the 2001 incident of inhalational anthrax exposures, 
there was an increased public awareness of the risk of contracting 
anthrax due to the media publicity that surrounded the event. Fourteen 
manufacturers reacted to this increased public attention by submitting 
inquiries to FDA about obtaining marketing clearance for additional 
products that would diagnose the presence of the bacillus. Two of the 
14 inquiries have resulted in diagnostic products getting cleared 
through the Premarket Notification (510(k)) process and one 
manufacturer submitting an Investigational Device Exemption (IDE). The 
remaining manufacturers expressed interest but decided not to conduct 
the necessary investigations to ensure the safety and effectiveness of 
the test kits.
    The increased level of public attention and concern towards 
potential inhalational anthrax exposures that result from any incident 
(such as in 2001) is likely to have similar responses from potential 
manufacturers in the future. In the absence of this proposed rule, 
there will continue to be ambiguity as to the specific testing criteria 
for the device to be cleared for marketing. In addition, FDA resources 
will be spent responding to these inquiries for potential products that 
are not destined to be marketed.

D. The Proposed Regulation

    We are proposing to classify anthrax diagnostic test kits as Class 
II, and designate special controls. The special controls include 
limitations of distribution for all Bacillus spp. detection devices and 
the special controls guidance will include recommendations for the 
performance data, quality control information, and labeling. This 
guidance document will be unlikely to affect the number of laboratory 
tests for Bacillus spp. or the number of tests used for training 
purposes. Generally, these recommendations are already being practiced. 
The document is also not likely to result in any procedural changes in 
how laboratories handle the diagnostic test kits because we have been 
interacting with manufacturers individually to ensure safety and 
effectiveness and the guidance document is designed to clearly 
articulate the best current practices. The proposed rule will ensure 
that information provided to manufacturers and users of these 
diagnostic test kits is consistent and appropriate and limit 
distribution to laboratories that have experienced personnel and 
appropriate biosafety equipment.

E. Impact of the Proposed Regulation

    If the proposed regulation is implemented, potential marketers of 
these kits would clearly know what criteria and what evidence would be 
needed to ensure clearance of their devices. In addition, laboratory 
personnel would have assurance that they were handling the test kits 
appropriately, thus both ensuring the predictive value of the test kits 
were maximized and any potential risk of exposure to pathogens due to 
careless handling of the test kits remain minimized. That being said, 
we do not expect any change from current conditions that would result 
from the proposed regulation. The current predictive values of the test 
kits are already extremely high. Of the five products currently 
cleared, there were no reports of false positive (specificity of 100 
percent) and few reports of false negatives (estimated sensitivity of 
99.6 percent combining all products). Therefore, we do not expect any 
change in either use of the test kits by laboratories or in the 
predictive value of the test kits in patients. The proposed rule will, 
however, provide additional levels of assurance that the test kits will 
provide accurate and timely diagnosis and the proper laboratory 
procedures will maintain the safe and effective use of the test kits.

F. Costs

    The costs of the proposed rule are due to manufacturers' ensuring 
that product labeling will be consistent with the language suggested in 
the guidance document as well as likely periodic quality control 
testing to ensure that marketed test kits maintain levels of safety and 
effectiveness. The costs associated with ensuring consistent labeling 
are expected to be minor. The labeling recommendation is based on the 
labeling of the currently cleared devices and little or no change from 
current conditions is expected. Nevertheless, we have estimated that 
manufacturers may incur minor revisions to their labels in response to 
the new guidance after regulatory staff review and compare current 
labeling language and design to the language and design recommendations 
(including photographs or diagrams) proposed in the guidance document. 
To account for these reviews and any possible labeling revisions, we 
have estimated that typical label changes for typical medical devices 
or diagnostic products would cost manufacturers approximately $2,200 
per label change per brand. This estimate is based on market driven 
label revisions and was derived from estimates for a variety of devices 
similar to test kits (Cost Analysis of the Labeling and Related Testing 
Requirements for Medical Glove Manufacturers, Eastern Research Group 
(ERG), 2002) and account for only simple language and design 
alterations. We have further estimated that changes of this sort 
typically occur about every 5 years in response to market changes and 
improvements to the specific product. The manufacturers of each of the 
4 currently marketed test kits are likely to review and perhaps revise 
labels for a total cost of $8,800. Over an expected 5-year evaluation 
period (based on a typical labeling cycle), the annualized cost of 
reviewing and revising labels is only $1,900 (3-percent annual discount 
rate) or $2,100 (7-percent annual discount rate).
    In addition, the draft guidance document will include a description 
of the quality control tests recommended to ensure the safety and 
effectiveness of the diagnostics. While these tests are currently used 
to develop marketed products, it is possible that the frequency of 
testing to ensure continued quality may increase as a result of the 
proposed rule. We have estimated that additional quality control 
testing may require expenditures of as much as $100 per product per 
year for each brand. This cost is based on a sampling of typical 
laboratory control tests (including ELISHA, Lowry, and other ASTM 
(American Society for Testing of Materials) recommended tests) for

[[Page 28694]]

devices (ERG, 2002). Therefore, for the duration of a 5-year evaluation 
period, we expect the industry may incur additional quality control 
testing costs of about $400 per year.
    The proposed rule is designed to articulate current practices for 
the currently marketed test kits. However, because of this regulatory 
classification, it is possible that these additional activities will 
result in minor cost increases. We have estimated that the proposed 
rule could result in, at most, annualized costs of approximately $2,300 
(3 percent) or $2,500 (7 percent).

G. Benefits

    There are unlikely to be any direct public health benefits of the 
proposed rule, because the rule articulates current industry practice 
and does not change the expected use of the diagnostic product. 
However, the proposed regulation is designed to ensure continued 
quality of this important diagnostic tool. The Bacillus spp. test kit 
provides important public health benefits through rapid diagnosis and 
thus, rapid treatment of a fatal disease, or rapid identification that 
treatment is not necessary. The absence of this diagnostic test kit, or 
even a decrease in the performance of the kit, would increase the 
negative outcomes of any future anthrax event, including increases in 
potential mortalities. The proposed regulation will provide additional 
assurance that the current level of public health protection is 
maintained.
    In addition, it is possible that any slight label revisions or 
standardization of information in the labeling, as well as an increased 
emphasis on laboratory training, may decrease the likelihood of 
potential mishandling of either the diagnostic test kits or the test 
medium. There is currently no way to quantify this effect because there 
has been no reported exposure or risk associated with these diagnostic 
tests or the test medium in this country. We acknowledge that it is 
possible that mishandling could occur in the future and it is possible 
that clear, consistent instructions may avoid some potential future 
mishandling, but cannot quantify any benefit based on this eventuality.
    However, the response of potential marketers of Bacillus spp. test 
kits to the publicity that surrounded the 2001 anthrax event indicates 
that a potential benefit could be derived from clearly articulating the 
tests needed to provide sufficient data to ensure adequate safety and 
effectiveness of these products. By having consistent and easily 
available criteria, potential marketers will easily be able to 
ascertain whether or not to pursue market clearance. The availability 
of this information is expected to result in better, and perhaps fewer, 
potential marketing applications that may arise in response to future 
incidents of public inhalation anthrax exposure. Of course we hope that 
future events do not occur; however, there is a low level of 
probability that an incident could occur in the future. We have 
estimated the annual probability of a public inhalational anthrax 
incident to be approximately between 2 percent and 5 percent based on 
historical occurrences. We received 14 inquiries in regards to 
obtaining clearances which have resulted in 3 applications and 2 
clearances. Using the success rate of 14 percent (2 successes from 14 
inquiries), we expect a reduction of approximately 0.24 to 0.6 
unsuccessful inquiries or applications each year. (Twelve unsuccessful 
inquiries or applications multiplied by the annual probability of an 
incident). The estimated effort to potential marketers of contacting 
FDA, obtaining advice concerning the clearance process, and 
preliminarily preparing a marketing application is estimated to take 
approximately 5 days of review, market research, and internal 
decisionmaking. The mean salary for employees within NAICS 325413 (In 
Vitro Diagnostic Substance Manufacturing) is approximately $80,000 
(Census, 2007). A week of FTE (full-time employee) time would thus have 
an average cost to manufacturers of about $1,500. By avoiding 
unnecessary (and ultimately unsuccessful) inquiries for potential 
marketing applications, we expect the proposed rule to result in 
savings of between $400 and $900 per year. ($1,500 multiplied by 0.24 
and 0.6 avoided inquiries each year).
    In addition, FDA resources will not be spent responding to 
inquiries or reviewing unsuccessful applications that would not be 
submitted with the clear information that would be the result of the 
proposed rule. The average FDA full-time equivalent employee is valued 
at approximately $130,000, including salary, benefits, overhead, and 
support). Responding to inquiries concerning a potential application 
may consume a few hours of resources per inquiry while reviewing an 
application may consume as much as 2 weeks of review time. On average, 
we expect each avoided inquiry or application to save approximately 8 
hours of FDA resources. Thus, with the clear information available as a 
result of the proposed rule, FDA is expected to save between $100 and 
$300 per year ($130,000 divided by 235 days times 0.24 and 0.6 annual 
inquiries avoided).
    Thus, we estimate the proposed regulation will result in 
quantifiable benefits of avoiding unnecessary inquiries and potential 
applications to be between $500 and $1,200 per year. We believe that 
the unquantified benefits of providing an additional level of quality 
assurance, maintaining the predictive value of the marketed test kits, 
and avoiding any potential future laboratory errors cannot be 
estimated, but represent real benefits to the public health.

H. Alternatives to the Proposed Rule

    We identified four plausible alternatives to the proposed rule.
    1. Continue to regulate as an unclassified device. This alternative 
would not provide an assurance of safety and effectiveness and would 
continue the current level of inconsistent information for potential 
new marketers.
    2. Regulate this diagnostic test as a Class I device. Because 
sufficient information was available to develop special controls for 
this device, this alternative, which would require general controls 
only, was not considered sufficient for the potential risks of this 
device.
    3. Regulate this diagnostic test as a Class III device. Premarket 
approval and clinical data collection are not appropriate for the 
potential risks of this device, which are more appropriately dealt with 
using the proposed special controls. Classifying the test as Class III 
would increase the cost of marketing the devices without an increase in 
assurances of safety and effectiveness.
    4. Regulate this diagnostic test as a Class II device with 
alternative special controls. The proposed guidance document is 
sufficient to provide assurances of safety and effectiveness. Other 
potential special controls were deemed to not be cost-effective and not 
provide additional assurances of safety and effectiveness.

I. Regulatory Flexibility Analysis

    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because of the minor costs to manufacturing entities 
attributable to the proposed rule, the Agency believes the proposed 
rule will not have a significant economic impact on a substantial 
number of small manufacturing entities. In addition, the proposed rule 
will not affect testing laboratories because we do not expect any 
change in current use of the diagnostic test kit.

[[Page 28695]]

    There are currently five cleared diagnostic kits for the 
identification of Bacillus spp. marketed by five companies. These 
companies are classified in the In Vitro Diagnostic Substance 
Manufacturing Industry (NAICS 325413) by the Census of Manufacturers. 
This industry is typified by small entities. For this industry, the 
Small Business Administration classifies any establishment with 500 or 
fewer employees as small. The typical establishment in this industry 
employs only about 120 employees, so virtually every company is small. 
Value of shipments for this industry is approximately $50,000,000 per 
establishment. The expected annualized cost per affected establishment 
($800) represents less than 0.002 percent of annual shipments.
    Testing Laboratories (NAICS 541380) are considered small by the 
Small Business Administration if they generate $12,000,000 or less in 
annual revenue. There is no change in activity expected by this 
industry from the proposed rule, so we do not expect any impact on 
laboratories.

VII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. Section 4(a) of the 
Executive order requires Agencies to ``construe * * * a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
the Federal statute.'' Federal law includes an express preemption 
provision that preempts certain state requirements ``different from or 
in addition to'' certain Federal requirements applicable to devices. 21 
U.S.C. 360k; See Medtronic v. Lohr 518 U.S. 470 (1996); Riegel v. 
Medtronic, 552 U.S. 312 (2008). The special control regarding limited 
distribution set out in the proposed regulation, if finalized, would 
create a requirement. The other special controls, if finalized, would 
create ``requirements'' to address each identified risk to health 
presented by these specific medical devices under 21 U.S.C. 360k, even 
though product sponsors may have flexibility in how they meet those 
requirements. Cf. Papike v. Tambrands, Inc., 107 F.3d 737, 740-42 (9th 
Cir. 1997).

VIII. Paperwork Reduction Act of 1995

    FDA concludes that this proposed rule contains no new collections 
of information. Therefore, clearance by the Office of Management and 
Budget under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 
3501-3520) is not required.
    The proposed rule would establish as special control a draft 
guidance document that refers to previously approved collections of 
information found in other FDA regulations. These collections of 
information are subject to review by OMB under the PRA. The collections 
of information in 21 CFR part 807, subpart E, regarding premarket 
notification submissions, have been approved under OMB control no. 
0910-0120. The collections of information in 21 CFR part 801 and 21 CFR 
809.10, regarding labeling, have been approved under OMB control no. 
0910-0485.

IX. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) electronic or written comments regarding this proposed 
rule. It is only necessary to send one set of comments. It is no longer 
necessary to send two copies of mailed comments. Identify comments with 
the docket number found in brackets in the heading of this document. 
Received comments may be seen in the Division of Dockets Management 
between 9 a.m. and 4 p.m., Monday through Friday.

X. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. We 
have verified all Web site addresses, but we are not responsible for 
subsequent changes to the Web sites after this document publishes in 
the Federal Register.
    1. Transcript of the FDA Microbiology Devices Panel meeting, March 
7, 2002, at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfAdvisory/details.cfm?mtg=348.
    2. Abshire, T.G. et al., ``Validation of the use of gamma phage for 
identifying Bacillus anthracis,'' 102nd American Society for 
Microbiology Annual Meeting poster C122, 2001.
    3. Brown, Eric R. and William B. Cherry, ``Specific identification 
of Bacillus anthracis by means of a variant bacteriophage,'' vol. 96, 
Journal of Infectious Disease, p. 34, 2001.
    4. Brown, Eric R. et al., ``Differential diagnosis of Bacillus 
cereus, Bacillus anthracis and Bacillus cereus var. mycoides,'' vol. 
75, Journal of Bacteriology, p. 499, 1957.
    5. Buck C.A. et al., ``Phage isolated from lysogenic Bacillus 
anthracis,'' vol. 85, Journal of Bacteriology, p. 423, 1963.

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, it is 
proposed that 21 CFR part 866 be amended as follows:

PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES

    1. The authority citation for 21 CFR part 866 continues to read as 
follows:

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

    2. Section 866.3045 is added to subpart D to read as follows:


Sec.  866.3045  In vitro diagnostic device for Bacillus spp. detection.

    (a) Identification. An in vitro diagnostic device for Bacillus spp. 
detection is used to detect and differentiate among Bacillus spp. and 
presumptively identify Bacillus anthracis and other Bacillus spp. from 
cultured isolates or clinical specimens as an aid in the diagnosis of 
anthrax and other diseases caused by Bacillus spp. This device may 
consist of Bacillus spp. antisera conjugated with a fluorescent dye 
(immunofluorescent reagents) used to presumptively identify bacillus-
like organisms in clinical specimens; or bacteriophage used for 
differentiating B. anthracis from other Bacillus spp. based on 
susceptibility to lysis by the phage; or antigens used to identify 
antibodies to B. anthracis (anti-toxin and anti-capsular) in serum. 
Bacillus infections include anthrax (cutaneous, inhalational, or 
gastrointestinal) caused by B. anthracis, and gastrointestinal disease 
and non-gastrointestinal infections caused by B. cereus.
    (b) Classification. Class II (special controls). The special 
controls are:
    (1) FDA's guidance document entitled: ``Class II Special Controls 
Guidance Document: In Vitro Diagnostic Devices for Bacillus spp. 
Detection; Guidance for Industry and FDA.'' See Sec.  866.1(e) for 
information on obtaining this document.
    (2) The distribution of these devices is limited to laboratories 
with experienced personnel who have training in principles and use of 
microbiological culture identification methods and infectious disease 
diagnostics, and with appropriate biosafety equipment and containment.


[[Page 28696]]


    Dated: May 12, 2011.
Nancy K. Stade,
Deputy Director for Policy, Center for Devices and Radiological Health.
[FR Doc. 2011-12088 Filed 5-17-11; 8:45 am]
BILLING CODE 4160-01-P


