[Federal Register Volume 70, Number 231 (Friday, December 2, 2005)]
[Rules and Regulations]
[Pages 72197-72199]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-23546]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 610

[Docket No. 2005N-0355]
RIN 0910-AF20


Revocation of Status of Specific Products; Group A Streptococcus

AGENCY: Food and Drug Administration, HHS.

ACTION: Direct final rule.

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SUMMARY: The Food and Drug Administration (FDA) is removing the 
regulation applicable to the status of specific products; Group A 
streptococcus. FDA is removing the regulation because the existing 
requirement for Group A streptococcus organisms and derivatives is both 
obsolete and a perceived impediment to the development of Group A 
streptococcus vaccines. The regulation was written to apply to a group 
of products that are no longer on the market. We are taking this action 
as part of our continuing effort to reduce the burden of unnecessary 
regulations on industry and to revise outdated regulations without 
diminishing public health protection. We are issuing the removal 
directly as a final rule because it is noncontroversial, and there is 
little likelihood that we will receive any significant adverse 
comments. Elsewhere in this issue of the Federal Register, we are 
publishing a companion proposed rule under our usual procedures for 
notice and comment in the event that we receive any significant adverse 
comments on the direct final rule. If we receive any significant 
adverse comments that warrant terminating the direct final rule, we 
will consider such comments on the proposed rule in developing the 
final rule.

DATES: This direct final rule is effective June 2, 2006. Submit written 
or electronic comments on or before February 15, 2006. If we receive no 
significant adverse comments during the specified comment period, we 
intend to publish a confirmation document on or before the effective 
date of this direct final rule confirming that the direct final rule 
will go into effect on June 2, 2006. If we receive any significant 
adverse comments during the comment period, we intend to withdraw this 
direct final rule before its effective date by publication in the 
Federal Register.

ADDRESSES: You may submit comments, identified by Docket No. 2005N-0355 
and/or RIN number 0910-AF20, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web Site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.

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.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the 
Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and docket number or regulatory information number (RIN) for this 
rulemaking. All comments received may be posted without change to 
http://www.fda.gov/ohrms/dockets/default.htm, including any personal 
information provided. For additional information on submitting 
comments, see the ``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.fda.gov/ohrms/dockets/default.htm 
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 Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Valerie A. Butler, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background

    Section 610.19 Status of specific products; Group A streptococcus 
(21 CFR 610.19), was published in the Federal Register of January 5, 
1979 (44 FR 1544). FDA issued that regulation after reviewing and 
considering the findings of the independent advisory Panel on Review of 
Bacterial Vaccines and Bacterial Antigens with ``No U.S. Standard of 
Potency'' (the Panel). The preamble to the proposed rule for Sec.  
610.19, which was published in the Federal Register of November 8, 1977 
(42 FR 58266), contained the findings of the Panel, including the 
Panel's specific findings about then-licensed products that contained 
Group A streptococcus (42 FR 58266 at 58277 through 58278). The 
regulation was a part of the Panel's review of the safety, 
effectiveness, and labeling of biological products licensed before July 
1, 1972. In 1972, the regulatory authority of these biological products 
was transferred from the National Institutes of Health (NIH) to FDA. 
The Panel reviewed those licensed biological bacterial products that 
were labeled, ``No U.S. Standard of Potency.'' (There was a separate 
review for the ``Bacterial Vaccines and Toxoids with Standards of 
Potency.'') Products considered by the Panel included primarily 
mixtures of bacterial preparations, e.g., Mixed Vaccine Respiratory, 
which was described as containing chemically killed organisms 
consisting of Streptococcus (pyrogenes, viridans, and nonhemolytic), 
Staphylococcus (aureus and albus), Diplococcus pneumoniae, Neiserria 
catarrhalis, Klebsiella pneumoniae, and Haemophilus influenzae 
manufactured by Hollister-Stier, Division of Cutter Laboratories (42 FR 
58266 at 58268). Many of the products considered by the Panel were 
indicated as treatments for diverse ailments such as colds, asthma, 
arthritis, and uveitis (42 FR 58266 at 58270).
    The Panel report listed a number of major concerns with this group 
of products (``No U.S. Standard of Potency'') (42 FR 58266 at 58269). 
One of the major concerns was that no defined standards of potency 
existed for any of the products, so it was not possible to establish 
that the microbial factors manufacturers claimed to be present in the 
products were indeed there or in what concentration (42 FR 58266 at 
58270). Many of these products were developed years before specific 
etiologic agents were associated with the cause of specific diseases. 
Moreover, the labeled indications for these products were for diseases 
of obscure etiology (Id.). Manufacturers could provide to the Panel 
neither clinical data to support the safety or efficacy of the 
products, nor any justification for

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using the products as described other than uncontrolled and unconfirmed 
clinical impressions (Id.). Additional safety questions arose from the 
fact that the products were administered repeatedly over extended 
periods of time with no evidence of systematic followup for the types 
of adverse effects that might be associated with repeated inoculations 
(Id.). The Panel stated in their report, that in view of what was known 
from laboratory studies about potential risks associated with repeated 
inoculations of foreign substances, they had reservations about the 
long-term safety of this group of products (42 FR 58266 at 58270 
through 58271). In fact, the Panel did not classify any of these 
products into category I (those biological products determined to be 
safe, effective, and not misbranded) (42 FR 58266 at 58315).
    In the Panel report, the section specifically concerning Group A 
streptococcal vaccines describes the history, dating back to the 1930s, 
of major attempts to immunize humans with hemolytic streptococci (42 FR 
58266 at 58277). These early studies demonstrated severe systemic 
toxicities (Id.). One study (Ref. 1) described the occurrence of acute 
rheumatic fever in siblings of rheumatic fever patients following 
vaccination with a partially purified preparation (Id.). In addition, 
immunological cross-reactivity between streptococcal cell wall protein 
and mammalian myocardium was demonstrated in vitro (Id.) (Ref. 2). 
However, the Panel report differentiated between the licensed products 
under review and highly purified preparations, which were at the 
research stage. The Panel report stated that the safety profile for a 
highly purified preparation was quite different, noting that no anti-
heart reactive antibody has been observed in the post immunization sera 
of infants or adults receiving the purified preparation (Id.) (Ref. 3). 
The Panel concluded, based on demonstrated safety concerns, that the 
uncontrolled use of the Group A streptococcal antigens in bacterial 
vaccines with ``No U.S. Standard of Potency'' represented unacceptable 
risks (42 FR 58266 at 58278). In fact, the Panel stated:
    In view of the carefully conducted controlled studies currently 
under way with purified chemically defined antigenic preparations, 
one finds it difficult to justify the use of uncontrolled, poorly 
defined preparations presumed to contain antigens that have been 
demonstrated in earlier studies to produce local and systemic 
reactions. The hypothetical and theoretical objections stemming from 
laboratory studies linking mammalian and streptococcal antigens have 
been given serious consideration in the design and conduct of 
present studies treating humans with the newer purified 
streptococcal antigens.
(42 FR 58266 at 58277). In contrast to the uncontrolled, poorly defined 
preparations, the Panel made clear at the time that they were not 
condemning the use of purified or characterized streptococcal antigens 
(Id.). Further, FDA reviews each biological product and determines 
whether the risk-benefit relationship is acceptable for the stage of 
investigation and for licensure (see 21 CFR parts 312 and 601). This 
review is performed under the authority of the Federal Food, Drug, and 
Cosmetic Act and the Public Health Service Act (see 21 U.S.C. 355(i); 
42 U.S.C. 262(a)(3) and (a)(2)(A)). FDA's review is adequate to assess 
the safety, purity, and potency of products that companies seek to 
license, and to ensure that human subjects in clinical trials of 
investigational products are not exposed to unreasonable and 
significant risk of illness or injury.
    Therefore, FDA concludes that Sec.  610.19, which was codified 
following the Panel report, was meant to apply only to those bacterial 
vaccines which the Panel had under their review--licensed but poorly 
characterized products labeled ``No U.S. Standard of Potency''--and not 
to more characterized preparations under investigation then or now. 
Because there are no bacterial mixtures with ``No U.S. Standard of 
Potency'' containing Group A streptococcal antigens licensed at this 
time, and current manufacturing technology allows for characterization 
and purification of Group A streptococcal products, this regulation is 
obsolete. Although it was never intended to apply to the development of 
Group A streptococcal vaccines that had adequate testing, FDA has 
determined that it has been perceived to cover these products as well, 
and therefore should be removed in a direct final rule.

II. Highlights of the Direct Final Rule

    We are removing Sec.  610.19 because the existing requirement is 
obsolete and perceived to be impeding the development of Group A 
streptococcal vaccines using purified or characterized streptococcal 
antigens. The regulation is obsolete because it was written to apply to 
a group of products that are no longer on the market. Certain parties 
interested in developing new Group A streptococcal vaccines perceive 
the regulation as an impediment, voiced during public meetings and 
workshops, e.g., the Group A streptococcus workshop sponsored by the 
National Institute of Allergy and Infectious Diseases, NIH, held in 
Bethesda, MD on March 29 and 30, 2004. Group A streptococci are 
responsible for significant morbidity and mortality worldwide, 
including rheumatic fever and glomerulonephritis, as well as 
pharyngitis, impetigo, and other clinical manifestations. Therefore, a 
vaccine to prevent diseases caused by this organism would have a public 
health benefit. We are taking this action as part of our continuing 
effort to reduce the burden of unnecessary regulations on industry and 
to revise outdated regulations without diminishing public health 
protection.

III. Rulemaking Action

    In the Federal Register of November 21, 1997 (62 FR 62466), FDA 
described its procedures on when and how the agency will employ direct 
final rulemaking. We have determined that this rule is appropriate for 
direct final rulemaking because we believe that it is noncontroversial 
and we anticipate no significant adverse comments. Consistent with our 
procedures on direct final rulemaking, FDA is publishing elsewhere in 
this issue of the Federal Register a companion proposed rule to remove 
Sec.  610.19. FDA is removing the regulation because it is both 
obsolete and a perceived impediment to the development of Group A 
streptococcus vaccines. The companion proposed rule provides a 
procedural framework within which the rule may be finalized in the 
event that the direct final rule is withdrawn because of any 
significant adverse comment. The comment period for the direct final 
rule runs concurrently with the companion proposed rule. Any comments 
received in response to the companion proposed rule will be considered 
as comments regarding the direct final rule.
    We are providing a comment period on the direct final rule of 75 
days after the date of publication in the Federal Register. If we 
receive any significant adverse comments, we intend to withdraw this 
direct final rule before its effective date by publication of a notice 
in the Federal Register. A significant adverse comment is defined as a 
comment that explains why the rule would be inappropriate, including 
challenges to the rule's underlying premise or approach, or would be 
ineffective or unacceptable without a change. In determining whether an 
adverse comment is significant and warrants terminating a direct final 
rulemaking, we will consider whether the comment raises an issue 
serious enough to warrant a substantive response in a notice-and-
comment process in accordance with section 553 of the Administrative 
Procedure Act (5 U.S.C. 553). Comments that are

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frivolous, insubstantial, or outside the scope of the rule will not be 
considered significant or adverse under this procedure. A comment 
recommending a regulation change in addition to those in the rule would 
not be considered a significant adverse comment unless the comment 
states why the rule would be ineffective without the additional change. 
In addition, if a significant adverse comment applies to an amendment, 
paragraph, or section of this rule and that provision can be severed 
from the remainder of the rule, we may adopt as final those provisions 
of the rule that are not the subjects of a significant adverse comment.
    If any significant adverse comments are received during the comment 
period, FDA will publish, before the effective date of this direct 
final rule, a document withdrawing the direct final rule. If we 
withdraw the direct final rule, any comments received will be applied 
to the proposed rule and will be considered in developing a final rule 
using the usual notice-and-comment procedures.
    If FDA receives no significant adverse comments during the 
specified comment period, FDA intends to publish a document, before the 
effective date of the direct final rule, confirming the effective date.

IV. Analysis of Impacts

A. Review Under Executive Order 12866, the Regulatory Flexibility Act, 
and the Unfunded Mandates Act of 1995

    FDA has examined the impacts of the direct final rule under 
Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-
612), 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 direct final rule is not a significant regulatory action 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 the direct final rule is removing a 
regulation, it would not result in any increased burden or costs on 
small entities. Therefore, the agency certifies that the direct 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 $115 million, using the most current (2003) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
direct final rule to result in any 1-year expenditure that would meet 
or exceed this amount.

B. Environmental Impact

    The agency has determined, under 21 CFR 25.31(h), 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.

C. Federalism

    FDA has analyzed this direct final rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the direct final rule does not contain policies that have substantial 
direct effects on the States, on the relationship between the National 
Government and the States, or on the distribution of power and 
responsibilities among the various levels of government. Accordingly, 
the agency has concluded that the direct final rule does not contain 
policies that have federalism implications as defined in the Executive 
order and, consequently, a federalism summary impact statement is not 
required.

V. Paperwork Reduction Act of 1995

    This direct final rule contains no collections of information. 
Therefore, clearance by the Office of Management and Budget under the 
Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520) is not required.

VI. Request for Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper 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 
Division of Dockets Management between 9 a.m. and 4 p.m., Monday 
through Friday.

VII. 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.
    1. Massell, B.F., L.H. Honikman, and J. Amezcua, ``Rheumatic 
Fever Following Streptococcal Vaccination. Report of Three Cases,'' 
Journal of the American Medical Association, 207(6): 1115-1119, 
1969.
    2. Kaplan, M.H. and M. Meyeserian, ``An Immunological Cross-
Reaction Between Group A Streptococcal Cells and Human Heart 
Tissue,'' Lancet, 1:706-710, 1962.
    3. Fox, E.N., L.M. Pachman, M.K. Wittner, and A. Dorfman, 
``Primary Immunization of Infants and Children with Group A 
Streptococcal M Protein,'' Journal of Infectious Diseases, 120:598-
604, 1969.

List of Subjects in 21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under authority delegated by the 
Commissioner of Food and Drugs, 21 CFR part 610 is amended as follows:

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

0
1. The authority citation for 21 CFR part 610 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 
264.


Sec.  610.19  [Removed]

0
2. Remove Sec.  610.19.

    Dated: November 21, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-23546 Filed 12-1-05; 8:45 am]
BILLING CODE 4160-01-S