Federal Register / Vol. 70, No. 231 / Friday, December 2, 2005 / Rules and Regulations 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industry and to revise outdated 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 email. 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 

§ 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 

72198 Federal Register / Vol. 70, No. 231 / Friday, December 2, 2005 / Rules and Regulations 

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 

§ 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 § 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 § 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 

Federal Register / Vol. 70, No. 231 / Friday, December 2, 2005 / Rules and Regulations 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. 

■ 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 

■ 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. 

§ 610.19 [Removed] 

■ 2. Remove § 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 

DEPARTMENT OF JUSTICE 

Federal Bureau of Investigation 

28 CFR Part 16 

[AAG/A Order No. 010–2005] 

Privacy Act of 1974; Implementation 

AGENCY: Federal Bureau of 

Investigation, DOJ. 

ACTION: Final rule.