[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]
[[Page 72197]]
=======================================================================
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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regulations on industry and to revise outdated regulations without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
[[Page 72198]]
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
[[Page 72199]]
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