[Federal Register: December 2, 2005 (Volume 70, Number 231)]
[Proposed Rules]               
[Page 72257-72260]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]



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.


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outdated regulations without diminishing public health protection.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, 

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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.regulations.gov. 

Follow the instructions for submitting comments.
     Agency Web site: http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&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.


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 

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 

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 

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, 
    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:


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

    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, 

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]