[Federal Register Volume 70, Number 231 (Friday, December 2, 2005)]
[Proposed Rules]
[Pages 72257-72260]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-23545]
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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;
Companion Document to Direct Final Rule
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to remove
the regulation applicable to the status of specific products; Group A
streptococcus. FDA is proposing to remove 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outdated regulations without diminishing public health protection. This
proposed rule is a companion to the direct final rule published
elsewhere in this issue of the Federal Register. We are taking this
[[Page 72258]]
action because the proposed change is noncontroversial, and we do not
anticipate any significant adverse comments. 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: Submit written or electronic comments on or before February 15,
2006.
ADDRESSES: You may submit comments, identified by Docket No. 2005N-0335
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
This proposed rule is a companion to the direct final rule
published elsewhere in this issue of the Federal Register. This
companion proposed rule provides the procedural framework to finalize
the rule in the event that the direct final rule receives any
significant adverse comments and is withdrawn. The comment period for
this companion proposed rule runs concurrently with the comment period
for the direct final rule. Any comments received under this companion
rule will also be considered as comments regarding the direct final
rule. We are publishing the direct final rule because the rule is
noncontroversial, and we do not anticipate that it will receive any
significant adverse comments.
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 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
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 subjects of a
significant adverse comment.
If no significant adverse comment is received in response to the
direct final rule, no further action will be taken related to this
proposed rule. Instead, we will publish a confirmation document, before
the effective date of the direct final rule, confirming that the direct
final rule will go into effect on June 2, 2006. Additional information
about direct rulemaking procedures is set forth in a guidance published
in the Federal Register of November 21, 1997 (62 FR 62466).
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 to 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
[[Page 72259]]
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 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.
II. Highlights of the Proposed Rule
We are proposing to remove 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. 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 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 (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 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 the proposed rule is removing a regulation,
it would not result in any increased burden or costs on small entities.
Therefore, the agency certifies that the proposed 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,
[[Page 72260]]
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 proposed 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 proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed 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 proposed 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.
IV. Paperwork Reduction Act of 1995
This proposed 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.
V. 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.
VI. 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.
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, it is proposed that 21 CFR part 610 be
amended as follows:
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
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]
2. Remove Sec. 610.19.
Dated: November 21, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-23545 Filed 12-1-05; 8:45 am]
BILLING CODE 4160-01-S