Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 78281

1The Panel was convened on July 12, 1973, in an 

organizational meeting, followed by multiple 

working meetings until February 2, 1979. The Final 

Report of the Panel was completed in August 1979.

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 201 and 610

[Docket No. 1980N–0208]

Biological Products; Bacterial 

Vaccines and Toxoids; Implementation 

of Efficacy Review

AGENCY: Food and Drug Administration, 

HHS.

ACTION: Proposed rule and proposed 

order.

SUMMARY: The Food and Drug 

Administration (FDA) is proposing to 

amend the biologics regulations in 

response to the report and 

recommendations of the Panel on 

Review of Bacterial Vaccines and 

Toxoids (the Panel). The Panel reviewed 

the safety, efficacy, and labeling of 

bacterial vaccines and toxoids with 

standards of potency, bacterial 

antitoxins, and immune globulins. On 

the basis of the Panel’s findings and 

recommendations, FDA is proposing to 

classify these products as Category I 

(safe, effective, and not misbranded), 

Category II (unsafe, ineffective, or 

misbranded), or Category IIIB (off the 

market pending completion of studies 

permitting a determination of 

effectiveness). On December 13, 1985, 

FDA proposed to amend the biologics 

regulations and proposed to classify the 

bacterial vaccines and toxoids. After 

reviewing the Panel’s report and 

comments on the proposal, FDA 

published a final rule and final order on 

January 5, 2004. The court vacated the 

January 5, 2004 (69 FR 255) final rule. 

Therefore, elsewhere in this issue of the 

Federal Register, FDA is withdrawing 

the January 5, 2004, final rule. FDA is 

issuing this proposed rule and proposed 

order again to provide notice and to give 

interested persons an opportunity to 

comment.

DATES: Submit written or electronic 

comments on the proposed rule and 

proposed order by March 29, 2005.

ADDRESSES: You may submit comments, 

identified by Docket No. 1980N–0208, 

by any of the following methods:

• 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.

• E-mail: fdadockets@oc.fda.gov. 

Include Docket No. in the subject line of 

your e-mail message.

• FAX: 301–827–6870.

• Mail/Hand delivery/Courier [For 

paper, disk, or CD-ROM submissions]: 

Division of Dockets Management, 5630 

Fishers Lane, rm. 1061, Rockville, MD 

20852.

Instructions: All submissions received 

must include the agency name and 

Docket No. for this proposal. All 

comments received will be posted 

without change to http://www.fda.gov/

ohrms/dockets/default.htm, including 

any personal information provided. For 

detailed instructions on submitting 

comments and additional information 

on the process, 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:

Astrid Szeto, 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. Introduction

In this document, FDA is issuing a 

proposed rule and proposed order to:

1. Categorize those bacterial vaccines and 

toxoids licensed before July 1972 according 

to the evidence of their safety and 

effectiveness, thereby determining whether 

they may remain licensed and on the market;

2. Issue a proposed response to 

recommendations made in the Panel’s 

report.1 These recommendations concern 

conditions relating to active components, 

labeling, tests required before release of 

product lots, product standards, or other 

conditions considered by the Panel to be 

necessary or appropriate for assuring the 

safety and effectiveness of the reviewed 

products;

3. Revise the standard for potency of 

Tetanus Immune Globulin in § 610.21 (21 

CFR 610.21); and

4. Apply the labeling requirements in 

§§ 201.56 and 201.57 (21 CFR 201.56 and 

201.57) to bacterial vaccines and toxoids by 

amending the implementation dates in 

§ 201.59 (21 CFR 201.59).

II. Background

A. History of the Review

In the Federal Register of February 

13, 1973 (38 FR 4319), FDA issued 

procedures for the review by 

independent advisory review panels of 

the safety, effectiveness, and labeling of 

biological products licensed before July 

1, 1972. This process was eventually 

codified in § 601.25 (21 CFR 601.25) (38 

FR 32048 at 32052, November 20, 1973). 

Under the panel assignments published 

in the Federal Register of June 19, 1974 

(39 FR 21176), FDA assigned the 

biological product review to one of the 

following groups: (1) Bacterial vaccines 

and bacterial antigens with ‘‘no U.S. 

standard of potency,’’ (2) bacterial 

vaccines and toxoids with standards of 

potency, (3) viral vaccines and 

rickettsial vaccines, (4) allergenic 

extracts, (5) skin test antigens, and (6) 

blood and blood derivatives.

Under § 601.25, FDA assigned 

responsibility for the initial review of 

each of the biological product categories 

to a separate independent advisory 

panel consisting of qualified experts to 

ensure objectivity of the review and 

public confidence in the use of these 

products. Each panel was charged with 

preparing an advisory report to the 

Commissioner of Food and Drugs which 

was to: (1) Evaluate the safety and 

effectiveness of the biological products 

for which a license had been issued, (2) 

review their labeling, and (3) identify 

the biological products that are safe, 

effective, and not misbranded. Each 

advisory panel report was also to 

include recommendations classifying 

the products reviewed into one of three 

categories.

• Category I designating those 

biological products determined by the 

panel to be safe, effective, and not 

misbranded.

• Category II designating those 

biological products determined by the 

panel to be unsafe, ineffective, or 

misbranded.

• Category III designating those 

biological products determined by the 

panel not to fall within either Category 

I or Category II on the basis of the 

panel’s conclusion that the available 

data were insufficient to classify such 

biological products, and for which 

further testing was therefore required. 

Category III products were assigned to 

one of two subcategories. Category IIIA 

products were those that would be 

permitted to remain on the market 

pending the completion of further 

studies. Category IIIB products were 

those for which the panel recommended 

license revocation on the basis of the 

78282 Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 

2 In addition to publication in the Federal 

Register of December 13, 1985 (50 FR 51002), FDA 

is making the full Panel report available on FDA’s 

Website at http://www.fda.gov/ohrms/dockets/

default.htm. A copy of the Panel report is also 

available at the Division of Dockets Management, 

5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

3See the Federal Register of May 15, 2000 (65 FR 

31003), containing the proposed order to reclassify 

Category IIIA products into Category I and Category 

II based on the review and recommendation of the 

Vaccines and Related Biological Products Advisory 

Committee.

panel’s assessment of potential risks and 

benefits.

In its report, the panel could also 

include recommendations concerning 

any condition relating to active 

components, labeling, tests appropriate 

before release of products, product 

standards, or other conditions necessary 

or appropriate for a biological product’s 

safety and effectiveness.

In accordance with § 601.25, after 

reviewing the conclusions and 

recommendations of the review panels, 

FDA would publish in the Federal 

Register a proposed order containing: 

(1) A statement designating the 

biological products reviewed into 

Categories I, II, IIIA, or IIIB, (2) a 

description of the testing necessary for 

Category IIIA biological products, and 

(3) the complete panel report. Under the 

proposed order, FDA would propose to 

revoke the licenses of those products 

designated into Category II and Category 

IIIB. After reviewing public comments, 

FDA would publish a final order on the 

matters covered in the proposed order.

In the Federal Register of November 

21, 1980 (45 FR 77135), FDA issued a 

notice of availability of the Panel’s final 

report. In the Federal Register of 

December 13, 1985 (50 FR 51002), FDA 

issued a proposed rule that contained 

the full Panel report2 and FDA’s 

response to the recommendations of the 

Panel (the December 1985 proposal) 

(Ref. 1). In the December 1985 proposal, 

FDA proposed regulatory categories 

(Category I, Category II, or Category IIIB 

as defined previously in this document) 

for each bacterial vaccine and toxoid 

reviewed by the Panel, and responded 

to other recommendations made by the 

Panel. The public was offered 90 days 

to submit comments in response to the 

December 1985 proposal.

The definition of Category IIIA as 

described previously in this document, 

was applied at the time of the Panel’s 

review and served as the basis for the 

Panel’s recommendations. In the 

Federal Register of October 5, 1982 (47 

FR 44062), FDA revised § 601.25 and 

codified § 601.26, which established 

procedures to reclassify those products 

in Category IIIA into either Category I or 

Category II based on available evidence 

of effectiveness. The Panel 

recommended that a number of 

biological products be placed into 

Category IIIA. FDA assigned the review 

of those products previously classified 

into Category IIIA to the Vaccines and 

Related Biological Products Advisory 

Committee. FDA has addressed the 

review and reclassification of bacterial 

vaccines and toxoids classified into 

Category IIIA through a separate 

administrative procedure (see the 

Federal Register of May 15, 2000 (65 FR 

31003), and May 29, 2001 (66 FR 

29148)). Therefore, FDA does not 

further identify or discuss in this 

document any bacterial vaccines and 

toxoids classified into Category IIIA.

B. Comments on the December 1985 

Proposal

FDA received four letters of 

comments in response to the December 

1985 proposal. One letter from a 

licensed manufacturer of bacterial 

vaccine and toxoid products concerned 

the confidentiality of information it had 

submitted for the Panel’s review. As 

provided in § 601.25(b)(2), FDA 

considered the extent to which the 

information fell within the 

confidentiality provisions of 18 U.S.C. 

1905, 5 U.S.C. 552(b), or 21 U.S.C. 

331(j), before placing the information in 

the public docket for the December 1985 

proposal. Another comment from a 

member of the Panel provided an 

update of important scientific 

information related to bacterial vaccines 

and toxoids that had accrued since the 

time of the Panel’s review. The letter 

did not comment on the December 1985 

proposal nor did it contend that the 

newly available information should 

result in modification of the Panel’s 

recommendations or FDA’s proposed 

actions. FDA’s responses to the 

comments contained in the remaining 

two letters follow.

(Comment 1) One comment from a 

licensed manufacturer of bacterial 

vaccines and toxoids objected to the 

proposed classification into Category 

IIIA of several of its products for use in 

primary immunization.

As described previously in this 

document, FDA is considering those 

products proposed for Category IIIA in 

a separate rulemaking process.3 This 

proposal does not propose any action 

regarding the further classification of 

those products proposed for Category 

IIIA, including those proposed for 

Category IIIA for primary immunization. 

All manufacturers and others in the 

general public have been offered 

additional opportunity to comment on 

the final categorization of specific 

Category IIIA products in the abovenoted process.

(Comment 2) In response to FDA’s 

proposal that Pertussis Immune 

Globulin (Human) be placed into 

Category IIIA because of insufficient 

evidence of efficacy, one comment 

stated that FDA should permit 

manufacture of Pertussis Immune 

Globulin (Human) for export only. The 

comment noted that medical practices 

in other countries may differ from those 

in the United States and that in some 

countries Pertussis Immune Globulin 

(Human) plays an important role in the 

augmentation of therapy with 

antibiotics in young, very ill infants 

with pertussis.

Since that time, FDA has revoked all 

licenses for Pertussis Immune Globulin 

(Human) at the requests of the 

individual manufacturers. The FDA 

Export Reform and Enhancement Act of 

1996 (Public Law 104–134, as amended 

by Public Law 104–180) amended 

provisions of the Federal Food, Drug, 

and Cosmetic Act (the act) pertaining to 

the export of certain unapproved 

products. Section 802 of the act contains 

requirements for the export of products 

not approved in the United States. 

Under these provisions, products such 

as Pertussis Immune Globulin (Human) 

can be exported to other countries, if the 

requirements of section 802 are met.

(Comment 3) One comment 

concerned the generic order and 

wording for product labeling 

recommended by the Panel and which 

FDA proposed to adopt in its response 

to the Panel recommendation. The 

comment recommended that a labeling 

section concerning ‘‘Overdose’’ be 

included only when circumstances 

dictate. The comment stated that 

because all biological products are 

prescription products administered by 

health care providers, the risk of 

overdose should be greatly reduced.

FDA agrees that, in many cases, a 

labeling section in part 201 (21 CFR part 

201) entitled ‘‘Overdosage’’ is not 

necessary. Section 201.56(d)(3) (21 CFR 

201.56(d)(3)) of the labeling regulations 

provides that the labeling may omit any 

section or subsection of the labeling 

format (outlined in § 201.56) if clearly 

inapplicable. The ‘‘Overdosage’’ section, 

provided for in § 201.57(i) of the 

regulations, is omitted for many 

bacterial vaccine and toxoid products.

(Comment 4) One letter of comment 

objected to several statements made by 

the Panel and provided in the written 

report, but did not object to or comment 

on FDA’s proposed responses to the 

Panel’s recommendations.

FDA is not considering comments on 

the Panel’s report in this proposed rule 

Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 78283

and proposed order. The Panel’s 

recommendations are not binding but 

represent the scientific opinions of a 

panel of experts. FDA believes that the 

agency should not modify the 

statements and recommendations of the 

Panel as provided in its report, 

including through public comment. The 

purpose of the opportunity for comment 

is to allow comment on FDA’s responses 

to the Panel’s report and not on the 

Panel’s report directly.

In this proposal, FDA is again 

providing the opportunity for comment 

on FDA’s proposals.

III. Proposed Categorization of 

Products—Proposed Order

Category I. Licensed biological 

products determined to be safe and 

effective and not misbranded. Table 1 of 

this document is a list of those products 

proposed in December 1985 by FDA for 

Category I. Under the ‘‘Comments’’

column, FDA notes those products for 

which FDA’s proposed category differs 

from that recommended by the Panel. 

Products for which the licenses were 

revoked before the December 1985 

proposal and that were already 

identified in the December 1985 

proposal are not listed in the tables 

below. Products for which the licenses 

were revoked after the December 1985 

proposal are identified in the 

‘‘Comments’’ column. FDA proposes to 

adopt Category I as the final category for 

the following products.

TABLE 1.—CATEGORY I

Manufacturer/License No. Products Comments 

Alpha Therapeutic Corp., License No. 

744

Tetanus Immune Globulin (Human) Although the Panel recommended that Tetanus Immune Globulin (Human), manufactured by Alpha 

Therapeutic Corp., be placed in Category IIIB, 

FDA proposed that it be placed in Category I1

Advance Biofactures Corp., License No. 

383

Collagenase 

Armour Pharmaceutical Co., License No. 

149

Tetanus Immune Globulin (Human) Manufacturer’s licensed name is now Centeon L. L. 

C. On July 26, 1999, FDA revoked the license for 

Tetanus Immune Globulin (Human) at the request 

of the manufacturer

Connaught Laboratories, Inc., License 

No. 711

Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed, and Diphtheria 

Antitoxin 

On December 9, 1999, a name change to Aventis 

Pasteur, Inc. with an accompanying license number change to 1277 was granted to Connaught 

Laboratories, Inc. FDA revoked the licenses for 

these products at the request of the manufacturer 

on July 6, 2001, and August 2, 2001, respectively

Connaught Laboratories, Ltd., License 

No. 73

BCG Vaccine, Botulism Antitoxin (Types A, 

B, and E), Botulism Antitoxin (Type E), 

Tetanus Toxoid 

On February 24, 2000, a name change to Aventis 

Pasteur, Ltd. with an accompanying license number change to 1280 was granted. On December 

21, 2000, FDA revoked the license for Tetanus 

Toxoid at the request of the manufacturer

Cutter Laboratories, Inc., License No. 8 Plague Vaccine, Tetanus Immune Globulin 

(Human) 

On October 5, 1994, the manufacturing facilities and 

process for Plague Vaccine were transferred to 

Greer Laboratories, Inc., License No. 308. On 

May 24, 1995, FDA revoked Cutter’s license for 

Plague Vaccine at the request of Cutter, the previous manufacturer; the license for Greer Labs, 

Inc. remains in effect. Bayer Corporation now 

holds the license for Tetanus Immune Globulin 

(Human) under License No. 8

Eli Lilly & Co., License No. 56 Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed On December 2, 1985, FDA revoked the license for 

Diphtheria and Tetanus Toxoids and Pertussis 

Vaccine Adsorbed at the request of the manufacturer 

Glaxo Laboratories, Ltd., License No. 

337

BCG Vaccine On July 17, 1990, FDA revoked the license for BCG 

Vaccine at the request of the manufacturer 

Istituto Sieroterapico Vaccinogeno 

Toscano Sclavo, License No. 238

Diphtheria Antitoxin, Diphtheria Toxoid Adsorbed, Tetanus Toxoid Adsorbed On July 17, 1990, FDA revoked the license for Diphtheria Antitoxin at the request of the manufacturer. 

On July 27, 1993, FDA revoked the licenses for 

Diphtheria Toxoid Adsorbed and Tetanus Toxoid 

Adsorbed at the request of the manufacturer

Lederle Laboratories, Division American 

Cyanamid Co., License No. 17

Cholera Vaccine, Tetanus Immune Globulin 

(Human) 

On December 23, 1992, FDA revoked the license 

for Tetanus Immune Globulin (Human) at the request of the manufacturer. On October 23, 1996, 

FDA revoked the license for Cholera Vaccine at 

the request of the manufacturer

78284 Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 

TABLE 1.—CATEGORY I—Continued

Manufacturer/License No. Products Comments 

Massachusetts Public Health Biologic 

Laboratories, License No. 64

Diphtheria and Tetanus Toxoids Adsorbed, 

Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed, Tetanus and 

Diphtheria Toxoids Adsorbed (For Adult 

Use), Tetanus Antitoxin, Tetanus Immune 

Globulin (Human), Tetanus Toxoid Adsorbed, Typhoid Vaccine 

Although the Panel recommended that Tetanus Antitoxin be placed in Category IIIB, FDA proposed in 

the December 1985 proposal that it be placed in 

Category I. On October 26, 1988, FDA revoked 

the license for Typhoid Vaccine at the request of 

the manufacturer. On January 10, 1994, FDA revoked the license for Tetanus Antitoxin at the request of the manufacturer. On December 22, 

1998, FDA revoked the license for Diphtheria and 

Tetanus Toxoids and Pertussis Vaccine Adsorbed 

at the request of the manufacturer. On August 3, 

2000, FDA revoked the license for Diphtheria and 

Tetanus Toxoids Adsorbed at the request of the 

manufacturer 

Merck Sharp & Dohme, Division of 

Merck & Co., Inc, License No. 2

Tetanus Immune Globulin (Human) The manufacturer is now known as Merck & Co., 

Inc. On January 31, 1986, FDA revoked the license for Tetanus Immune Globulin (Human) at 

the request of the manufacturer 

Michigan Department of Public Health, 

License No. 99

Anthrax Vaccine Adsorbed, Diphtheria and 

Tetanus Toxoids and Pertussis Vaccine 

Adsorbed, Pertussis Vaccine Adsorbed, 

Typhoid Vaccine 

On November 11, 1998, a name change to BioPort 

Corporation (BioPort) with an accompanying license number change to 1260 was granted. The 

license for Typhoid Vaccine was revoked on June 

25, 1985, at the request of the manufacturer. The 

license for Diphtheria and Tetanus Toxoids and 

Pertussis Vaccine Adsorbed was revoked at the 

request of the manufacturer (BioPort) on November 20, 2000. The license for Pertussis Vaccine 

Adsorbed was revoked at the request of the manufacturer (BioPort) on April 22, 2003

Parke-Davis, Division of Warner-Lambert 

Co., License No. 1

Tetanus Immune Globulin (Human) On November 19, 1983, FDA revoked the license 

for Tetanus Immune Globulin (Human) at the request of the manufacturer 

Swiss Serum and Vaccine Institute 

Berne, License No. 21

Tetanus Antitoxin Although the Panel recommended that Tetanus Antitoxin be placed in Category IIIB, FDA proposes 

that it be placed in Category I. On March 13, 

1980, FDA revoked the license for Tetanus Antitoxin at the request of the manufacturer

Travenol Laboratories, Inc., Hyland 

Therapeutics Division, License No. 

140

Tetanus Immune Globulin (Human) The manufacturer is now known as Baxter 

Healthcare Corporation. On July 27, 1995, FDA 

revoked the license for Tetanus Immune Globulin 

(Human) at the request of the manufacturer

University of Illinois, License No. 188 BCG Vaccine On May 29, 1987, FDA revoked the license for BCG 

Vaccine at the request of the manufacturer 

Wyeth Laboratories, Inc, License No. 3 Cholera Vaccine, Tetanus Immune Globulin 

(Human), Typhoid Vaccine (acetone inactivated), Typhoid Vaccine (heat-phenol inactivated) 

On December 23, 1992, FDA revoked the license 

for Tetanus Immune Globulin (Human) at the request of the manufacturer. On September 11, 

2001, FDA revoked the licenses for Cholera Vaccine and Typhoid Vaccine (both forms) at the request of the manufacturer 

1The Panel recommended that Tetanus Immune Globulin (Human) manufactured by Alpha Therapeutic Corporation be placed in Category 

IIIB, products for which available data are insufficient to classify their safety and effectiveness and which should not continue in interstate commerce. In the December 1985 proposal, the agency disagreed with the Panel’s recommendation as the product was manufactured only as a partially processed biological product and was intended for export and further manufacture (50 FR 51002 at 51007). The agency continues to agree 

with this approach inasmuch as the manufacturer continues to export the product as a partially processed biological. The product is not available 

as a finished product in the United States.

Category II. Licensed biological 

products determined to be unsafe or 

ineffective or to be misbranded and 

which should not continue in interstate 

commerce. FDA does not propose that 

any products be placed in Category II.

Category IIIB. Biological products for 

which available data are insufficient to 

classify their safety and effectiveness 

and should not continue in interstate 

commerce. Table 2 of this document is 

a list of those products proposed by 

FDA for Category IIIB. We have not 

listed products for which FDA revoked 

the licenses before the December 1985 

proposal but we identified them in the 

proposal. Products for which FDA 

revoked the licenses after the December 

1985 proposal are identified in the 

‘‘Comments’’ column.

Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 78285

4 In October 2000, the Institute of Medicine (IOM) 

convened the Committee to Assess the Safety and 

Efficacy of the Anthrax Vaccine. In March 2002, the 

Committee issued its report: The Anthrax Vaccine: 

Is It Safe? Does It Work? (Ref. 2). The report 

concluded that the vaccine is acceptably safe and 

effective in protecting humans against anthrax.

FDA has revoked the licenses of all 

products proposed by FDA for Category 

IIIB. FDA proposes Category IIIB as the 

final category for the listed products.

TABLE 2.—CATEGORY IIIB

Manufacturer/License No. Products Comments 

Istituto Sieroterapico Vaccinogeno 

Toscano Sclavo, License No. 238

Diphtheria Toxoid On July 27, 1993, FDA revoked the license for Diphtheria Toxoid at the request of the manufacturer

Connaught Laboratories, Inc., License 

No. 711

Diphtheria Toxoid, Pertussis Vaccine On June 21, 1994, FDA revoked the license for 

Diphtheria Toxoid and on December 19, 1997, 

FDA revoked the license for Pertussis Vaccine, in 

both cases at the request of the manufacturer

Massachusetts Public Health Biologic 

Laboratories, License No. 64

Tetanus Toxoid On October 11, 1989, FDA revoked the license for 

Tetanus Toxoid at the request of the manufacturer

Merck Sharpe & Dohme, Division of 

Merke & Co., Inc., License No. 2

Cholera Vaccine, Diphtheria and Tetanus 

Toxoids and Pertussis Vaccine Adsorbed, 

Tetanus and Diphtheria Toxoids Adsorbed 

(For Adult Use), Tetanus Toxoid, Typhoid 

Vaccine 

The manufacturer is now known as Merck & Co., 

Inc. On January 31, 1986, FDA revoked the licenses for all the listed products at the request of 

the manufacturer

Michigan Department of Public Health, 

License No. 99

Diphtheria Toxoid Adsorbed On November 12, 1998, the name of the manufacturer was changed to BioPort, and the license 

number was changed to 1260. On November 20, 

2000, FDA revoked the license for Diphtheria Toxoid Adsorbed at the request of the manufacturer

Wyeth Laboratories, Inc., License No.3 Diphtheria Toxoid, Diphtheria Toxoid Adsorbed, Pertussis VaccineOn May 19, 1987, FDA revoked the licenses for all 

listed products at the request of the manufacturer

IV. Anthrax Vaccine Adsorbed—

Proposed Order

A. The Panel Recommendation that 

Anthrax Vaccine Adsorbed be Placed in 

Category I (Safe, Effective, and Not 

Misbranded)

In its report, the Panel found that 

Anthrax Vaccine Adsorbed (AVA), 

manufactured by Michigan Department 

of Public Health (MDPH, now BioPort) 

was safe and effective for its intended 

use and recommended that the vaccine 

be placed in Category I. In the December 

1985 proposal, FDA agreed with the 

Panel’s recommendation. During the 

comment period for the December 1985 

proposal, FDA received no comments 

opposing the placement of AVA into 

Category I.

The Panel based its evaluation of the 

safety and efficacy of AVA on two 

studies: A well-controlled field study 

conducted in the 1950s, ‘‘the Brachman 

study’’ (Ref. 1a) and an open-label safety 

study conducted by the National Center 

for Disease Control (CDC, now the 

Centers for Disease Control and 

Prevention) (50 FR 51002 at 51058). The 

Panel also considered surveillance data 

on the occurrence of anthrax disease in 

the United States in at-risk industrial 

settings as supportive of the 

effectiveness of the vaccine (50 FR 

51002 at 51059). In its proposed 

determination that the data support the 

safety and efficacy of AVA, FDA has 

identified points of disagreement with 

statements in the Panel report. However, 

FDA proposes that the data do support 

the safety and efficacy of the vaccine 

and, thus, FDA continues to accept the 

Panel’s recommendation and proposes 

to place AVA in Category I.4

On October 12, 2001, a group of 

individuals filed a citizen petition 

requesting that FDA find AVA, as 

currently manufactured by BioPort, 

ineffective for its intended use, classify 

the product as Category II, and revoke 

the license for the vaccine. The 

petitioners complained that the 

December 1985 proposal that placed 

AVA in Category I had not been 

finalized. FDA responded separately in 

a written response to the petitioners on 

August 28, 2002 (Docket No. 2001P–

0471), and FDA will not further address 

those issues in this proposal.

In March 2003, six plaintiffs, known 

as John and Jane Doe ι1 through ι6, filed 

suit in the United States District Court 

for the District of Columbia (the Court) 

seeking the Court to enjoin the Anthrax 

Vaccination Immunization Program 

(AVIP) of the Department of Defense 

(DoD), and to declare AVA an 

investigational drug when used for 

protection against inhalation anthrax. 

On December 22, 2003, the Court issued 

a preliminary injunction enjoining 

inoculations under the AVIP in the 

absence of informed consent or a 

Presidential waiver.

In the Federal Register of January 5, 

2004 (69 FR 255), FDA published a final 

rule and final order amending the 

biologics regulations in response to the 

report and recommendations of the 

Panel. The final order placed AVA into 

Category I. Following FDA’s issuance of 

the final rule and final order, the Court 

lifted the preliminary injunction on 

January 7, 2004, except as it applied to 

the six Doe plaintiffs.

On October 27, 2004, the Court issued 

a memorandum opinion vacating and 

remanding the January 2004 final rule 

and final order to FDA for 

reconsideration, following an 

appropriate notice and comment period. 

FDA is reopening the comment period 

on the entire Bacterial Vaccine and 

Toxoids efficacy review document for 

90 days.

B. Efficacy of Anthrax Vaccine 

Adsorbed

The Brachman study included 1,249 

workers in four textile mills in the 

northeastern United States that 

processed imported goat hair. Of these 

1,249 workers, 379 received anthrax 

vaccine, 414 received placebo, 116 

received incomplete inoculations of 

78286 Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 

5The Panel noted that it would be very difficult, 

if not impossible, to clinically study the efficacy of 

any anthrax vaccine (50 FR 51058). Further study 

raises ethical considerations, and the low incidence 

and sporadic occurrence of anthrax disease also 

makes further adequate and well-controlled clinical 

studies of effectiveness not possible.

6For example: The Brachman study (Ref. 1a); the 

CDC epidemiological data described in the 

December 1985 proposal; Fellows (2001) (Ref. 3); 

Ivins (1996) (Ref. 4); Ivins (1998) (Ref. 5).

either vaccine or placebo, and 340 

received no treatment but were 

monitored for the occurrence of anthrax 

disease as an observational group. The 

Brachman study used an earlier version 

of the protective antigen-based anthrax 

vaccine administered subcutaneously at 

0, 2, and 4 weeks and 6, 12, and 18 

months. During the trial, 26 cases of 

anthrax were reported across the four 

mills: 5 inhalation and 21 cutaneous 

anthrax cases. Prior to vaccination, the 

yearly average number of human 

anthrax cases was 1.2 cases per 100 

employees in these mills. Of the five 

inhalation anthrax cases (four of which 

were fatal), two received placebo and 

three were in the observational group. 

Of the 21 cutaneous anthrax cases, 15 

received placebo, 3 were in the 

observational group, and 3 received 

anthrax vaccine. Of the three cases in 

the vaccine group, one case occurred 

just prior to administration of the third 

dose, one case occurred 13 months after 

the individual received the third of the 

six doses (but no subsequent doses), and 

one case occurred prior to receiving the 

fourth dose of vaccine.

In its report, the Panel stated that the 

Brachman study results demonstrate ‘‘a 

93 percent (lower 95 percent confidence 

limit = 65 percent) protection against 

cutaneous anthrax’’ and that ‘‘inhalation 

anthrax occurred too infrequently to 

assess the protective effect of vaccine 

against this form of the disease.’’ (50 FR 

51002 at 51058). On the latter point, 

FDA does not agree with the Panel 

report. Because the Brachman 

comparison of anthrax cases between 

the placebo and vaccine groups 

included both inhalation and cutaneous 

cases, FDA has determined that the 

calculated efficacy of the vaccine to 

prevent all types of anthrax disease 

combined was, in fact, 92.5 percent 

(lower 95 percent confidence interval = 

65 percent). The efficacy analysis in the 

Brachman study includes all cases of 

anthrax disease regardless of the route 

of exposure or manifestation of disease. 

FDA agrees that the five cases of 

inhalation anthrax reported in the 

course of the Brachman study are too 

few to support an independent 

statistical analysis. However, of these 

cases, two occurred in the placebo 

group, three occurred in the 

observational group, and no cases 

occurred in the vaccine group. 

Therefore, we propose the indication 

section of the labeling for AVA not 

specify the route of exposure, and the 

vaccine be indicated for active 

immunization against Bacillus 

anthracis, independent of the route of 

exposure.5

As stated previously in this 

document, the Panel also considered 

epidemiological data—sometimes called 

surveillance data—on the occurrence of 

anthrax disease in at-risk industrial 

settings collected by the CDC and 

summarized for the years 1962-1974 as 

supportive of the effectiveness of AVA. 

In that time period, individuals received 

either vaccine produced by MDPH, now 

BioPort, or an earlier version of anthrax 

vaccine. Twenty-seven cases of anthrax 

disease were identified. Three cases 

were not mill employees but people 

who worked in or near mills; none of 

these cases had been vaccinated. 

Twenty-four cases were mill employees; 

three were partially immunized (one 

with one dose, two with two doses); the 

remainder (89 percent) were 

unvaccinated (50 FR 51002 at 51058). 

These data provide confirmation that 

the risk of disease still existed for those 

persons who were not vaccinated and 

that those persons who had not received 

the full vaccination series (six doses) 

were susceptible to anthrax infection, 

while no cases occurred in those who 

had received the full vaccination series.

In 1998, the DoD initiated the Anthrax 

Vaccination Program, calling for 

mandatory vaccination of service 

members. Thereafter, concerns about the 

vaccine caused the U.S. Congress to 

direct DoD to support an independent 

examination of AVA by the IOM. The 

IOM committee reviewed all available 

data, both published and unpublished, 

heard from Federal agencies, the 

manufacturer, and researchers. The 

committee in its published report 

concluded that AVA, as licensed, is an 

effective vaccine to protect humans 

against anthrax, including inhalation 

anthrax (Ref. 2). FDA agrees with the 

report’s finding that certain studies in 

humans and animal models support the 

conclusion that AVA is effective against 

B. anthracis strains that are dependent 

upon the anthrax toxin as a mechanism 

of virulence, regardless of the route of 

exposure.6

C. Safety of Anthrax Vaccine Adsorbed

CDC conducted an open-label study 

under an investigational new drug 

application (IND) between 1967 and 

1971 in which approximately 7,000 

persons, including textile employees, 

laboratory workers, and other at-risk 

individuals, were vaccinated with 

anthrax vaccine and monitored for 

adverse reactions to vaccination. The 

vaccine was administered in 0.5-mL 

doses according to a 0-, 2-, and 4-week 

initial dose schedule followed by 

additional doses at 6, 12, and 18 months 

with annual boosters thereafter. Several 

lots, approximately 15,000 doses, of 

AVA manufactured by MDPH were used 

in this study period. In its report, the 

Panel found that the CDC data ‘‘suggests 

that this product is fairly well tolerated 

with the majority of reactions consisting 

of local erythema and edema. Severe 

local reactions and systemic reactions 

are relatively rare’’ (50 FR 51002 at 

51059).

Subsequent to the publication of the 

Panel’s recommendations, DoD 

conducted a small, randomized clinical 

study of the safety and immunogenicity 

of AVA. (See summary in product label. 

(Ref. 6)) These more recent DoD data as 

well as post licensure adverse event 

surveillance data available from the 

Vaccine Adverse Event Reporting 

System (VAERS) further support the 

safety of AVA (Ref. 7). These data are 

regularly reviewed by FDA, and 

provided the basis for a description of 

the types and severities of adverse 

events associated with administration of 

AVA included in labeling revisions 

approved by FDA in January 2002 (Ref. 

6).

D. The Panel’s General Statement: 

Anthrax Vaccine, Adsorbed, Description 

of Product

The Panel report states:

‘‘Anthrax vaccine is an aluminum 

hydroxide adsorbed, protective, 

proteinaceous, antigenic fraction prepared 

from a nonproteolytic, nonencapsulated 

mutant of the Vollum strain of Bacillus 

anthracis’’ (50 FR 51002 at 51058).

FDA would like to clarify that while 

the B. anthracis strain used in the 

manufacture of BioPort’s AVA is the 

nonproteolytic, nonencapsulated strain 

identified in the Panel report, it is not 

a mutant of the Vollum strain but was 

derived from a B. anthracis culture 

originally isolated from a case of bovine 

anthrax in Florida.

E. The Panel’s Specific Product Review: 

Anthrax Vaccine Adsorbed: Efficacy

The Panel report states:

3. Analysis—a. Efficacy—(2) Human. The 

vaccine manufactured by the Michigan 

Department of Public Health has not been 

employed in a controlled field trial. A similar 

vaccine prepared by Merck Sharp & Dohme 

for Fort Detrick was employed by Brachman 

* * * in a placebo-controlled field trial in 

Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 78287

mills processing imported goat hair * * *. 

The Michigan Department of Public Health 

vaccine is patterned after that of Merck Sharp 

& Dohme with various minor production 

changes.

(50 FR 51002 at 51059).

FDA has found that contrary to the 

Panel’s statement, the vaccine used in 

the Brachman study was not 

manufactured by Merck Sharp & 

Dohme, but instead this initial version 

was provided to Dr. Brachman by Dr. G. 

Wright of Fort Detrick, U.S. Army, DoD 

(Ref. 1a). The DoD version of the 

anthrax vaccine used in the Brachman 

study was manufactured using an 

aerobic culture method (Ref. 8). 

Subsequent to the Brachman trial, DoD 

modified the vaccine’s manufacturing 

process to, among other things, optimize 

production of a stable and immunogenic 

formulation of vaccine antigen and to 

increase the scale of manufacture. In the 

early 1960s, DoD entered into a contract 

with Merck Sharp & Dohme to 

standardize the manufacturing process 

for large-scale production of the anthrax 

vaccine and to produce anthrax vaccine 

using an anaerobic method. Thereafter, 

in the 1960s, DoD entered into a similar 

contract with MDPH to further 

standardize the manufacturing process 

and to scale up production for further 

clinical testing and immunization of 

persons at risk of exposure to anthrax 

spores. This DoD-MDPH contract 

resulted in the production of the 

anthrax vaccine that CDC used in the 

open-label safety study and that was 

licensed in 1970.

While the Panel attributes the 

manufacture of the vaccine used in the 

Brachman study to Merck Sharp & 

Dohme, FDA has reviewed the historical 

development of AVA and concluded 

that DoD’s continuous involvement 

with, and intimate knowledge of, the 

formulation and manufacturing 

processes of all of these versions of the 

anthrax vaccine provide a foundation 

for a determination that the MDPH 

anthrax vaccine is comparable to the 

original DoD vaccine. See Berlex 

Laboratories, Inc. v. FDA, 942 F. Supp. 

19 (D.D.C. 1996). The comparability of 

the MDPH anthrax vaccine to the DoD 

vaccine has been verified through 

potency data that demonstrate the 

ability of all three versions of the 

vaccine to protect guinea pigs and 

rabbits against challenge with virulent 

B. anthracis. In addition, there are data 

comparing the safety and 

immunogenicity of the MDPH vaccine 

with the DoD vaccine. These data, while 

limited in the number of vaccines and 

samples evaluated, reveal that the 

serological responses to the MDPH 

vaccine and the DoD vaccine were 

similar with respect to peak antibody 

response and seroconversion.

F. The Panel’s Specific Product Review: 

Anthrax Vaccine Adsorbed: Labeling

The Panel report states:

3. Analysis—d. Labeling: The labeling 

seems generally adequate. There is a conflict, 

however, with additional standards for 

anthrax vaccine. Section 620.24 (a) (21 CFR 

620.24(a)) defines a total primary 

immunizing dose as 3 single doses of 0.5 mL. 

The labeling defines primary immunization 

as 6 doses (0, 2, and 4 weeks plus 6, 12, and 

18 months).

(50 FR 51002 at 51059).

The dosing schedule for AVA has 

always consisted of six doses, a 0.5-mL 

dose at 0, 2, and 4 weeks, and then at 

6, 12, and 18 months, followed by a 

subsequent 0.5-mL dose at 1 year 

intervals to maintain immunity. 

Prelicensure labels described the 

vaccination schedule as three initial 

doses, followed by three additional 

doses, and yearly subsequent doses, 

which is consistent with the additional 

standards of AVA that were originally 

published in October 1970, immediately 

before the licensure of AVA. The 1979 

labeling referred to ‘‘primary 

immunization’’ as consisting of six 

injections, with recommended yearly 

subsequent injections. The 1987 

labeling of AVA, subsequent to the 

Panel’s report, described the vaccination 

schedule as ‘‘primary immunization’’

consisting of three doses followed by 

three additional doses for a total of six 

doses followed by annual injections. 

The labeling is not inconsistent with 

§ 620.24(a) (21 CFR 620.24(a)) before it 

was revoked by FDA in 1996 as part of 

a final rule that revoked 21 CFR part 620 

and other biologics regulations because 

they were obsolete or no longer 

necessary (Ref. 9). Thus while use of the 

term ‘‘primary’’ has varied over time in 

reference to the AVA vaccination 

schedule, the licensed schedule itself 

has always consisted of six doses of 0.5 

mL administered at 0, 2, and 4 weeks 

and 6, 12, and 18 months, followed by 

additional doses on an annual basis to 

maintain immunity.

V. FDA’s Responses to Additional Panel 

Recommendations

In the December 1985 proposal, FDA 

responded to the Panel’s general 

recommendations regarding the 

products under review and to the 

procedures involved in their 

manufacture and regulation. Below, 

FDA responds again with its proposal to 

the general recommendations.

A. Generic Order and Wording of 

Labeling; Amendment of § 201.59

The Panel recommended changes to 

the labeling of the biological products 

under review. The Panel also 

recommended a generic order and 

wording for information in the labeling 

of bacterial vaccines. In the December 

1985 proposal, FDA agreed with the 

labeling changes recommended by the 

Panel.

In the December 1985 proposal, FDA 

proposed that 6 months after 

publication of a final rule, 

manufacturers of products subject to 

this Panel review submit, for FDA’s 

review and approval, draft labeling 

revised in conformance with the Panel’s 

report and with the regulations. FDA 

proposed to require that the revised 

labeling accompany all products 

initially introduced or initially 

delivered for introduction into interstate 

commerce 30 months after the date of 

publication of the final rule. The 

proposed labeling review schedule was 

consistent with the scheduling provided 

in § 201.59 of the regulations.

Since the time of the Panel’s 

recommendation, FDA has made a 

number of changes to the labeling 

regulations and related regulatory 

policies. FDA has added or revised the 

requirements in § 201.57 for including 

in the labeling, in standardized 

language, the information concerning 

use during pregnancy, pediatric use, 

and geriatric use. Section 201.57 

requires a specific order and content for 

drug product labeling. A number of 

labeling sections included in § 201.57 

were not included in the Panel’s 

recommended ordering and wording of 

the labeling but are now required to 

help ensure clarity in the labeling. FDA 

has also provided guidance regarding 

the wording of sections in which the 

agency believes complete and consistent 

language is important. Because FDA 

regularly monitors labeling for the 

products subject to this Panel review to 

determine if the labeling is consistent 

with applicable labeling requirements, 

FDA does not believe that a labeling 

review is necessary at this time. 

Accordingly, FDA proposes to amend 

the table in § 201.59 by providing that 

the labeling requirements in §§ 201.56, 

201.57, and 201.100(d)(3) (21 CFR 

201.100(d)(3)) become effective on the 

date 30 months after the date of 

publication of the final rule. Because 

FDA regularly monitors the labeling of 

all products on an ad hoc basis, FDA 

also proposes to explain in a footnote to 

the table in § 201.59(a)(3) that 

specification of a date for submission of 

78288 Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 

revised product labeling under § 201.59 

is unnecessary.

Section 314 of the National Childhood 

Vaccine Injury Act (NCVIA) of 1986 

required FDA to review the warnings, 

use instructions, and precautionary 

information that are distributed with 

each vaccine listed in section 2114 of 

the Public Health Service Act and to 

determine whether this information was 

adequate to warn health care providers 

of the nature and extent of the dangers 

posed by such vaccine. Since the 

December 1985 proposal, FDA has 

completed this review and labeling has 

been revised accordingly. FDA is also 

taking this opportunity to propose 

updating the table in § 201.59(a)(3) to 

include the current mail codes for the 

review of labeling for various biological 

products.

B. Periodic Review of Product Labeling

In its report, the Panel noted a 

number of labeling deficiencies. To 

improve the labeling, the Panel 

recommended that labeling be reviewed 

and revised as necessary at intervals of 

no more than every 2 years.

As discussed in the December 1985 

proposal, FDA believes the current 

system of labeling review will 

adequately assure accurate labeling. 

Periodic review of labeling on a set 

schedule is unnecessary. Section 

601.12(f) prescribes when revised 

labeling must be submitted, either as a 

supplement for FDA’s review or, if 

changes are minor, in an annual report. 

In addition, the agency may request 

revision of labeling when indicated by 

current scientific knowledge. FDA 

believes that, by these mechanisms, 

product labeling is kept up to date, and 

proposes that a scheduled, routine 

review of labeling is unnecessary and 

burdensome for both the agency and 

manufacturers.

C. Improvement in the Reporting of 

Adverse Reactions

The Panel recommended that actions 

be taken to improve the reporting and 

documentation of adverse reactions to 

biological products. The Panel 

particularly noted the need to improve 

the surveillance systems to identify 

adverse reactions to pertussis vaccine.

Since publication of the Panel’s 

report, the Vaccine Adverse Event 

Reporting System (VAERS) was created 

as an outgrowth of the National 

Childhood Vaccine Injury Act (NCVIA) 

and is administered by FDA and Centers 

for Disease Control and Prevention 

(CDC). VAERS accepts from health care 

providers, manufacturers, and the 

public, reports of adverse events that 

may be associated with U.S.-licensed 

vaccines. Health care providers must 

report certain adverse events included 

in a Reportable Events Table (Ref. 10) 

and any event listed in the vaccine’s 

package insert as a contraindication to 

subsequent doses of the vaccine. Health 

care providers also may report other 

clinically significant adverse events. 

FDA and CDC receive an average of 800 

to 1,000 reports each month under the 

VAERS program. A guidance document 

is available which explains how to 

complete the VAERS form (Ref. 11).

D. Periodic Review of Product Licenses

The Panel recommended that all 

licensed vaccines be periodically 

reviewed to assure that data concerning 

the safety and effectiveness of these 

products are kept current and that 

licenses be revoked for products which 

have not been marketed for years or 

which have never been marketed in the 

licensed form. The Panel noted that, by 

limiting the period for which specific 

vaccines may be licensed, older 

products would be assured periodic 

review, and new products for which 

additional efficacy data are required 

could be provisionally licensed for a 

limited time period during which 

additional data can be generated.

In its proposed response, FDA noted 

that licensing policies in effect at the 

time of the review resulted in licenses 

being held for some products which 

were never intended to be marketed as 

individual products or which were no 

longer being marketed as individual 

products. FDA had required that 

manufacturers licensed for a 

combination vaccine also hold a license 

for each individual vaccine contained in 

the combination. For example, a 

manufacturer of diphtheria, tetanus, and 

pertussis (DTP) vaccine would also be 

required to have a license for Diphtheria 

Toxoid, Tetanus Toxoid, and Pertussis 

Vaccines. Because this policy is no 

longer in effect, most licenses are for 

currently marketed products. In a few 

cases, there may be no current demand 

for a product but, for public health 

reasons, a license continues to be held 

for the product. There are some vaccines 

for which there is little current demand 

but continued licensure could expedite 

the manufacture and availability of the 

product in the event an outbreak of the 

targeted disease should occur. FDA 

believes that the routine inspection of 

licensed facilities adequately assures 

that the information held in product 

licenses is current and that a routine 

review of safety and efficacy data is 

unnecessary and burdensome. The 

Panel’s recommendation that some new 

vaccines be provisionally licensed for 

only limited periods of time while 

additional data are generated is 

inconsistent with the law that requires 

a determination that a biologic product 

is safe, pure, and potent before it is 

licensed.

E. Compensation for Individuals 

Suffering Injury From Vaccination

The Panel recommended that 

compensation from public funds be 

provided to individuals suffering injury 

from vaccinations that were 

recommended by competent authorities, 

carried out with approved vaccines, and 

where the injury was not a consequence 

of defective or inappropriate 

manufacture or administration of the 

vaccines.

A compensation program has been 

implemented consistent with the 

Panel’s recommendation. The NCVIA 

established the National Vaccine Injury 

Compensation Program (NVICP) 

designed to compensate individuals, or 

families of individuals, who have been 

injured by childhood vaccines, whether 

administered in the private or public 

sector. The NVICP, administered by the 

Health Resources and Services 

Administration, Department of Health 

and Human Services (HHS), is a no-fault 

alternative to the tort system for 

resolving claims resulting from adverse 

reactions to routinely recommended 

childhood vaccines. The specific 

vaccines and injuries covered by NVICP 

are identified in a Vaccine Injury Table 

that may periodically be revised as new 

vaccines come into use or new types of 

potential injuries are identified. The 

NVICP has resulted in a reduction in the 

amount of litigation related to injury 

from childhood vaccines while assuring 

adequate liability coverage and 

protection. The NVICP applies only to 

vaccines routinely recommended for 

infants and children. Vaccines 

recommended for adults are not covered 

unless they are routinely recommended 

for children as well, e.g., Hepatitis B 

Vaccine.

F. Public Support for Immunization 

Programs

The Panel recommended that both 

FDA and the public support widespread 

immunization programs for tetanus, 

diphtheria, and pertussis.

The National Immunization Program 

is part of CDC and was established to 

provide leadership to health agencies in 

planning and implementing 

immunization programs, to identify 

unvaccinated populations in the United 

States, to assess vaccination levels in 

state and local areas, and to generally 

promote immunization programs for 

children, including vaccination against 

diphtheria, tetanus, and pertussis. A 

Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 78289

recent survey shows that nearly 95 

percent of children 19 to 35 months of 

age have received three or more doses 

of any vaccine that contained diphtheria 

and tetanus toxoids (i.e., diphtheria and 

tetanus toxoids and pertussis vaccines 

(DTP), diphtheria and tetanus toxoids 

and acellular pertussis vaccines (DTaP) 

or diphtheria and tetanus toxoids 

vaccines (DT)) (Ref. 12).

G. Assuring Adequate Supplies of 

Bacterial Vaccines and Toxoids; 

Establishment of a National Vaccine 

Commission

The Panel recommended that FDA 

work closely with CDC and other groups 

to assure that adequate supplies of 

vaccines and passive immunization 

products continue to be available. The 

Panel recommended establishment of a 

national vaccine commission to address 

such issues.

Since the publication of the December 

1985 proposal, the National Vaccine 

Program was created by Congress 

(Public Law 99–660) with the National 

Vaccine Program Office (NVPO) within 

HHS designated to provide leadership 

and coordination among Federal 

agencies as they work together to carry 

out the goals of the National Vaccine 

Plan. The National Vaccine Plan 

provides a framework, including goals, 

objectives, and strategies, for pursuing 

the prevention of infectious diseases 

through immunizations. The National 

Vaccine Program brings together all of 

the groups that have key roles in 

immunizations, and coordinates the 

vaccine-related activities, including 

addressing adequate production and 

supply issues. Despite efforts to assure 

vaccine availability, shortages may 

occur (Ref. 13) for a variety of reasons. 

FDA proposes to continue to work with 

the NVPO, the National Institutes of 

Health, CDC, and vaccine manufacturers 

to help facilitate continued vaccine 

availability making the establishment of 

a national vaccine commission 

unnecessary.

H. Consistency of Efficacy Protocols

The Panel recommended that the 

protocols for efficacy studies be 

reasonably consistent throughout the 

industry for any generic product. To 

achieve this goal, the Panel 

recommended the development of 

industry guidelines that provide 

standardized methodology for adducing 

required information.

FDA believes that the standardization 

of clinical testing methodology for a 

group of vaccines is often not practical 

or useful. Because of the variety of 

possible vaccine types, e.g., live 

vaccines, killed vaccines, toxoids, 

bioengineered vaccines, acellular 

vaccines, and the diversity of 

populations in which the vaccine may 

be studied, it is difficult to develop 

guidance that would apply to more than 

one or two studies. FDA routinely meets 

with manufacturers before the initiation 

of clinical studies to discuss the study 

and will comment on proposed 

protocols for efficacy studies. FDA 

proposes to continue to allow flexibility 

in selecting appropriate tests, 

procedures, and study populations for a 

clinical study while assuring that the 

necessary data are generated to fulfill 

the intended objectives of the study.

I. The Effect of Regulations Protecting 

and Informing Human Study Subjects 

on the Ability to Conduct Clinical Trials

The Panel expressed concern that the 

regulations governing informed consent 

and the protection of human subjects 

involved in clinical investigations 

should not establish unnecessary 

impediments to the goal of obtaining 

adequate evidence for the safety and 

effectiveness of a product.

FDA believes that the regulations and 

policies applying to informed consent 

and the protection of human subjects do 

not inhibit the adequate clinical study 

of a product. FDA notes that whenever 

the regulations or guidance documents 

related to these subjects are modified or 

amended, FDA offers an opportunity for 

public comment on the revisions. FDA 

particularly welcomes comments on 

how appropriate informed consent and 

protection of human subjects can be 

maintained while assuring that the 

development and study of useful 

products is not inhibited.

J. Standards for Determining the Purity 

of Diphtheria and Tetanus Toxoids 

(DTs)

The Panel recommended that 

standards should be established for 

purity of both DTs in terms of limits of 

flocculation (Lf) content per milligram 

(mg) of nitrogen.

In the December 1985 proposal, FDA 

agreed that standards should be set. 

FDA has since determined that this 

approach is overly restrictive; does not 

allow FDA to keep pace with advances 

in manufacturing and technology; and, 

proposes that standards for determining 

the purity of DTs not be established. 

The Center for Biologics Evaluation and 

Research (CBER) establishes the release 

specifications for the purity of DTs 

during the review of a Biologics License 

Application (BLA). The purity of 

diphtheria toxoids in currently licensed 

vaccines is usually at least 1,500 Lf/mg 

nondialyzable nitrogen. While there are 

no general standards for tetanus toxoid 

purity in the United States, CBER has 

generally required a purity specification 

of at least 1,000 Lf/mg of nondialyzable 

nitrogen for tetanus toxoids.

K. Immunogenic Superiority of 

Adsorbed Toxoids Over Fluid Toxoids

The Panel recommended that the 

immunogenic superiority of the 

adsorbed DTs over the fluid (plain) 

preparations be strongly emphasized in 

product labeling, especially with regard 

to the duration of protection.

Tetanus Toxoid fluid, manufactured 

by Aventis Pasteur, Inc., is the only 

fluid toxoid product that remains 

licensed in the United States in 2004. 

This product is licensed for booster use 

only in persons over 7 years of age. The 

current package insert for this product 

states that, although the rates of 

seroconversion are essentially 

equivalent with either type of tetanus 

toxoid, the adsorbed toxoids induce 

more persistent antitoxin titers than 

fluid products.

L. Laboratory Testing Systems for 

Determining Potency of Tetanus and 

Diphtheria Toxoids

The Panel noted a need for further 

studies with tetanus toxoids in a World 

Health Organization (WHO) sponsored 

quantitative potency test in animals to 

establish the conditions under which 

the test results are reproducible, and to 

relate these results more closely to those 

obtained in the immunization of 

humans. The Panel also recommended 

the development of an animal or 

laboratory testing system for diphtheria 

toxoid that correlates consistently, and 

with acceptable precision, with primary 

immunogenicity in humans.

DT-containing vaccines are tested 

during the licensing process for their 

ability to induce acceptable levels of 

protective antibodies in clinical trials in 

the target populations. Properties of 

vaccines used in these clinical trials, 

including potency, also are determined 

during licensing. The acceptance 

criteria for commercial lots of these 

vaccines are set at licensing on the basis 

of the properties of the vaccines that 

induced acceptable quantitative/

qualitative levels of antibodies. The 

establishment of a correlation between a 

specific antibody response and a given 

assay would require an efficacy trial 

designed specifically to establish this 

correlation. This may call for 

vaccination of humans with sub-optimal 

doses of vaccine. Such an efficacy study 

is not feasible for ethical reasons.

The animal potency tests currently 

required by the WHO, the European 

Pharmacopoeia (EP), and FDA differ. 

Despite these differences, the potency 

78290 Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 

tests have been adequate to ensure 

sufficient immunogenic activity of the 

vaccines to induce protective immunity 

in target populations. However, 

international efforts to harmonize the 

diphtheria and tetanus potency tests 

under development are based on 

immunogenicity in animals. CBER is 

currently participating in these 

international harmonization efforts.

M. Potency Testing of DTs for Pediatric 

Use

The Panel recommended that the 

agency require potency testing after 

combination of the individual toxoid 

components in DTs for pediatric use.

FDA agrees with the recommendation. 

All manufacturers and the FDA testing 

laboratory follow this procedure on 

products submitted to the agency for 

release.

N. Potency Requirements for Pertussis 

Vaccine

The Panel recommended that the 

regulations concerning the maximum 

pertussis vaccine dose should be 

updated to reflect current 

recommendations and practices. At the 

time of the Panel review, whole cell 

pertussis vaccines were in use. 

Specifically, the Panel recommended 

that pertussis vaccine have a potency of 

four protective units per single human 

dose with the upper estimate of a single 

human dose not to exceed eight 

protective units. The Panel also 

recommended that the total immunizing 

dose be defined as four doses of four 

units each, compared to the three doses 

of four units each defined at the time of 

the recommendation in the regulations.

FDA has removed the additional 

standard regulations applicable to 

pertussis vaccine (Ref. 9). As whole cell 

pertussis vaccines are no longer 

licensed for human use in the United 

States, this recommendation no longer 

applies to products available in the 

United States.

O. Weight-Gain Test in Mice for 

Pertussis Vaccine

The Panel recommended that the 

weight-gain test in mice used to 

determine toxicity of pertussis vaccines 

be revised to include a reference 

standard and specifications regarding 

mouse strains to be used.

At the time of the Panel’s 

deliberations, only DTP vaccines 

containing a whole-cell pertussis 

component were licensed in the United 

States. The mouse weight-gain test was 

a toxicity test used for whole-cell 

pertussis vaccines. Whole-cell pertussis 

vaccines are no longer licensed in the 

United States for human use, thus the 

mouse weight-gain test is no longer in 

use. Currently, only DTP vaccines 

containing an acellular pertussis 

component (DTaP) are licensed in the 

United States. These vaccines are tested 

specifically for residual pertussis toxin 

activity.

Although not currently licensed in the 

United States, vaccines containing a 

whole-cell pertussis component are still 

in use in other countries. CBER 

continues to participate in international 

efforts to improve the tests used to 

assess toxicity of whole-cell pertussis 

vaccines, including the mouse weightgain test. CBER is represented on WHO 

committees and working groups with 

the goal of improving regulation and 

testing of whole-cell pertussis vaccines.

P. Agglutination Test to Determine 

Pertussis Vaccine Response in Humans

The Panel recommended that the 

agglutination test used to determine 

pertussis vaccine response in humans 

be standardized and that a reference 

serum be used for comparison. It also 

recommended that a reference 

laboratory be available at FDA.

As stated previously in this 

document, at the time of the Panel’s 

deliberations, only whole-cell pertussis 

vaccines were licensed in the United 

States. The agglutination test was used 

for the clinical evaluation of DTP 

vaccines. Under the Panel’s 

recommendations, FDA (CBER) 

developed and distributed reference 

materials for the agglutination assay and 

served as a reference laboratory. 

Currently, only DTaP vaccines are 

licensed in the United States. For the 

clinical evaluation of DTaP vaccines, 

the agglutination test was replaced by 

antigen-specific immunoassays, 

specifically enzyme-linked 

immunosorbent assays (ELISAs). As had 

been done with the agglutination assay, 

CBER took an active role in 

standardization of the ELISAs used to 

measure the specific antibody to the 

pertussis components of DTaP vaccines. 

Specifically, CBER distributes reference 

and control materials for the antigenspecific pertussis ELISA and has served 

as a reference laboratory.

Q. Warnings in Labeling for Pertussis 

Vaccine

The Panel recommended that the 

pertussis vaccine label warn that if 

shock, encephalopathic symptoms, 

convulsions, or thrombocytopenia 

follow a vaccine injection, no additional 

injections with pertussis vaccine should 

be given. The Panel also recommended 

that the label include a cautionary 

statement about fever, excessive 

screaming, and somnolence.

FDA agrees with the recommendation 

except that such information should be 

included in product labeling, i.e., the 

package insert, rather than the product 

label. Labeling applicable to the wholecell pertussis vaccine conformed to this 

recommendation. Because the acellular 

form of pertussis vaccine has a different 

profile of potential adverse events and 

contraindications, the product labeling 

is worded consistent with available 

data.

R. Field Testing of Fractionated 

Pertussis Vaccines

The Panel recommended that any 

fractionated pertussis vaccine that 

differs from the original whole cell 

vaccine be field tested until better 

laboratory methods for evaluating 

immunogenicity are developed. The 

Panel recommended that the fieldtesting include agglutination testing 

and, if possible, evaluation of clinical 

effectiveness.

The currently approved vaccines 

containing an acellular pertussis 

component were studied in the United 

States and abroad in human populations 

with the antibody response being 

measured and clinical effectiveness 

evaluated.

S. Use of Same Seed Lot Strain in 

Manufacturing Bacillus Calmette-Guerin 

(BCG) Vaccine

The Panel recommended that all BCG 

vaccines be prepared from the same 

seed lot strain with demonstrated 

efficacy, if available data justify such 

action.

BCG vaccines are not recommended 

for routine immunization in the United 

States. The two currently U.S.-licensed 

BCG vaccines are produced using 

different seed strains. Most BCG 

vaccines produced globally are 

manufactured using seed strains with a 

unique history. Recent evidence 

suggests that these different BCG strains 

do differ genetically and have slightly 

varying phenotypes. However, a meta 

analysis of the current human BCG 

vaccination data performed in 1994 by 

Harvard University concluded that no 

strain-to-strain differences in protection 

could be detected. Although there have 

been differences in immunogencity 

among strains demonstrated in animal 

models, no significant differences have 

been seen in human clinical trials (Ref. 

14). Thus, FDA does not find that 

available human data justify 

requirement of a single BCG vaccine 

strain.

Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 78291

T. Development of an Improved Cholera 

Vaccine

The Panel recommended public 

support for development of an improved 

cholera vaccine because unsatisfactory 

sanitary conditions in many countries 

make it clear that control of the disease 

by sanitation alone cannot be realized in 

the foreseeable future.

Cholera is not an endemic disease in 

the United States. However, there is risk 

to U.S. travelers to certain countries 

where the disease is endemic. FDA 

continues to cooperate with 

international health agencies in efforts 

to evaluate new types of vaccines and to 

study the pathogenesis of the disease. 

CBER personnel have chaired and 

participated in the WHO Cholera 

Vaccine Standardization Committee and 

have participated in drafting new WHO 

guidelines for immune measurement of 

protection from cholera.

U. Plague Vaccine Immunization 

Schedule

The Panel recommended that the 

following plague vaccine immunization 

schedule be considered:

1. A primary series of 3 intramuscular (IM) 

injections (1 mL, 0.2 mL, and 0.2 mL), 1 and 

6 months apart, respectively;

2. Booster IM injections of 0.2 mL at 12, 

18, and 24 months; and,

3. For persons achieving a titer of 1:128 

after the third and fifth inoculations, booster 

doses when the passive agglutination titer 

falls below 1:32 and empirically every 2 

years when the patient cannot be tested 

serologically.

FDA agrees with the recommendation, 

and the currently licensed vaccine is 

labeled consistent with the 

recommendation.

VI. FDA’s Response to General 

Research Recommendations

In its report, the Panel identified 

many areas in which there should be 

further investigation to improve existing 

products, develop new products, 

develop new testing methodologies, and 

monitor the population for its immune 

status against bacterial disease. In the 

December 1985 proposal, FDA 

responded to these recommendations in 

the responses identified as items 11, 17 

(in part), 21, 25, and 27. As discussed 

in the December 1985 proposal, FDA 

considered the Panel’s 

recommendations in defining its 

research priorities at the time the 

recommendations were made. Because a 

considerable amount of time has 

elapsed since these recommendations 

were made and FDA initially responded 

to the recommendations, FDA is not 

providing specific responses to each 

recommendation. As in any area of 

scientific research, new discoveries and 

new concerns require a continual 

reevaluation of research priorities and 

objectives to assure their relevance to 

current concerns.

FDA recognizes the Panel’s desire to 

have FDA’s research program evolve 

with the significant issues and findings 

of medical science. In order to assure 

the continued relevance of its research 

program, CBER’s research program for 

vaccines, including bacterial vaccines 

and related biological products, is 

subject to peer review by the Panel’s 

successor, the Vaccines and Related 

Biological Products Advisory 

Committee (see, for example, the 

transcripts from the meetings of June 11 

(Ref. 15) and November 29, 2001 (Refs. 

16 and 17), and March 6, 2002 (Ref. 18)). 

In addition, CBER has defined as part of 

its mission statement a strategic goal of 

assuring a high quality research program 

that contributes directly to its regulatory 

mission. This goal includes a plan to 

assure that CBER’s research program 

continues to support the regulatory 

review of products and timely 

development of regulatory policy, and 

to have a significant impact on the 

evaluation of biological products for 

safety and efficacy.

Because of limited resources, FDA 

also supports the leveraging of resources 

to create effective collaborations in the 

advancement of science. FDA has issued 

a ‘‘Guidance for FDA Staff: The 

Leveraging Handbook, an Agency 

Resource for Effective Collaborations.’’

(Ref. 19). Through cooperation with 

international, other Federal, and State 

health care agencies and the industry 

and academia, the agency intends that 

its research resources will reap the 

benefits of a wide range of experience, 

expertise, and energy from the greater 

scientific community while the agency 

maintains its legal and regulatory 

obligations. FDA invites comment at 

any time on ways it may improve its 

research program and set its objectives.

VII. Proposed Amendment to the 

Regulations

In the December 1985 proposal, FDA 

proposed to amend § 610.21 (21 CFR 

610.21), limits of potency, by revising 

the potency requirements for Tetanus 

Immune Globulin (Human) (TIG). FDA 

proposed to amend the regulations to 

require a minimum potency of 250 units 

of tetanus antitoxin per container for 

TIG. FDA advises that in this discussion 

and in the proposed regulation, ‘‘per 

container’’ means that amount of the 

contents of the container deliverable to 

the patient in normal use. The current 

regulation provides for a minimum 

potency of 50 units of tetanus antitoxin 

per milliliter of fluid. FDA proposes the 

change because the concentration of 

antitoxin per milliliter has varied 

widely in the past without any apparent 

effect on the performance of the 

product. TIG is routinely manufactured 

consistently at a concentration of 170 

units per milliliter. However, there was 

no evidence upon which to establish a 

revised minimum potency on a per 

milliliter basis. Because the evidence of 

efficacy for TIG was based on use of 

product administered consistently at 

doses of 250 units or larger and the 

varying concentration of the product 

without any apparent adverse effect, 

FDA proposes that it is more 

appropriate to regulate the potency on a 

per vial basis, rather than by units per 

milliliter. The current licensed product 

continues to be marketed at a potency 

no less than the minimum dose (250 

units), which historically has been 

shown to be clinically effective.

FDA received no comments opposing 

the proposed revision to § 610.21 and 

therefore proposes to amend the 

regulations to require a minimum 

potency of 250 units of tetanus antitoxin 

per container for TIG.

VIII. 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 this 

proposed rule under Executive Order 

12866, 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 Regulatory 

Flexibility Act requires agencies to 

analyze whether a rule may have a 

significant economic impact on a 

substantial number of small entities 

and, if it does, to analyze regulatory 

options that would minimize the impact 

on small entities. The Unfunded 

Mandates Reform Act requires that 

agencies prepare a written statement 

under section 202(a) of anticipated costs 

and benefits before proposing any rule 

that may result in an expenditure by 

State, local, or tribal governments, in the 

aggregate, or by the private sector, of 

$100 million (adjusted annually for 

inflation) in any one year.

The agency believes that this 

proposed rule is consistent with the 

78292 Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 

regulatory philosophy and principles 

identified in the Executive Order. In 

addition, this proposed rule is not a 

significant regulatory action as defined 

by the Executive Order and so is not 

subject to review under the Executive 

Order. Because this proposed rule does 

not impose new requirements on any 

entity it has no associated compliance 

costs, and the agency certifies that the 

proposed rule will not have a significant 

economic impact on a substantial 

number of small entities. Therefore, 

under the Regulatory Flexibility Act, no 

further analysis is required. Because this 

proposed rule does not impose 

mandates on State, local, or tribal 

governments, in the aggregate, or the 

private sector, that will result in an 

expenditure in any one year of $100 

million or more, FDA is not required to 

perform a cost benefit analysis under 

the Unfunded Mandates Reform Act. 

The current inflation adjusted statutory 

threshold is approximately $110 

million.

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. 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 is not required.

D. 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 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.

IX. 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.

X. References

The following references have been 

placed on display in the Division of 

Dockets Management (HFA–305), Food 

and Drug Administration, 5630 Fishers 

Lane, rm.1061, Rockville, MD 20852, 

and may be seen by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday.

1. The full Panel Report was incorporated 

into the ‘‘Biological Products; Bacterial 

Vaccines and Toxoids; Implementation of 

Efficacy Review,’’ proposed rule, published 

in the Federal Register of December 13, 1985 

(50 FR 51002).

1a. Brachman, P. S.; H. Gold; S. Plotkin; F. 

R. Fekety; M. Werrin; and N. R. Ingraham, 

‘‘Field Evaluation of a Human Anthrax 

Vaccine,’’ American Journal of Public Health, 

52:632–645, 1962.

2. Joellenbeck, Lois M.; Lee L. Zwanziger; 

Zane S. Durch; and Brian L. Strom; Editors, 

Committee to Assess the Safety and Efficacy 

of the Anthrax Vaccine, Medical Follow-Up 

Agency, The National Academies Press, 

Washington, DC, April 2002, http://

www.nap.edu/catalog/10310.html (FDA has 

verified the Web site address, but we are not 

responsible for subsequent changes to the 

Web site after this document publishes in the 

Federal Register).

3. Fellows, P. F.; M. K. Linscott; B. E. Ivins; 

M. L. M. Pitt; C. A. Rossi; P. H. Gibbs and 

A. M. Friedlander, ‘‘Efficacy of a Human 

Anthrax Vaccine in Guinea Pigs, Rabbits, and 

Rhesus Macaques Against Challenge by 

Bacillus Anthracis Isolates of Diverse 

Geographical Origin,’’ Vaccine 19(23/

24):3241–3247, 2001.

4. Ivins, B. E.; P. F. Fellows; M. L. M. Pitt; 

J. E. Estep; S. L. Welkos; P. L.Worsham and 

A. M. Friedlander, ‘‘Efficacy of a Standard 

Human Anthrax Vaccine Against Bacillus 

Anthracis Aerosol Spore Challenge in Rhesus 

Monkeys,’’ Salisbury Medical Bulletin

87(Suppl.):125–126, 1996.

5. Ivins, B. E.; M. L. M. Pitt; P. F. Fellows; 

J. W. Farchaus; G. E. Benner; D. M. Waag; S. 

F. Little; G. W. Anderson, Jr.; P. H. Gibbs; and 

A. M. Friedlander, ‘‘Comparative Efficacy of 

Experimental Anthrax Vaccine Candidates 

Against Inhalation Anthrax in Rhesus 

Macaques,’’ Vaccine, 16(11/12):1141–1148, 

1998.

6. Anthrax Vaccine Adsorbed (BIOTHRAX) 

Package Insert (January 31, 2002).

7. Reports and evaluation of reports of 

adverse events following administration of 

anthrax vaccine received by the Federal 

Vaccine Adverse Event Reporting System 

(VAERS) through November 2004.

8. Wright, G. G.; T. W. Green; and R. G. 

Kanode, Jr., ‘‘Studies on Immunity in 

Anthrax: V. Immunizing Activity of AlumPrecipitated Protective Antigen,’’ Journal of 

Immunology, 73:387–391, 1954.

9. 61 FR 40153, August 1, 1996.

10. ‘‘Table of Reportable Events Following 

Vaccination,’’ http://www.vaers.org/

reportable.htm. (FDA has verified the Web 

site address, but we are not responsible for 

subsequent changes to the Web site after this 

document publishes in the Federal Register).

11. ‘‘Guidance for Industry: How to 

Complete the Vaccine Adverse Event 

Reporting System Form (VAERS–1),’’

September 1998, http://www.fda.gov/cber/

gdlns/vaers–1.pdf. (FDA has verified the Web 

site address, but we are not responsible for 

subsequent changes to the Web site after this 

document publishes in the Federal Register).

12. ‘‘Estimated Vaccination Coverage With 

3+DTP Among Children 19–35 Months of 

Age by Race/Ethnicity, and by State and 

Immunization Action Plan Area—U.S., 

National Immunization Survey, Q3/2000 - 

Q2/2001’’, http://www.cdc.gov/nip/coverage/

NIS/00–01/tab19–3dptlraceliap.htm. (FDA 

has verified the Web site address, but we are 

not responsible for subsequent changes to the 

Web site after this document publishes in the 

Federal Register).

13. Protecting Our Kids: What Is Causing 

the Current Shortage in Childhood 

Vaccines?—Testimony Before the Committee 

on Governmental Affairs, United States 

Senate, June 12, 2002, http://www.cdc.gov/

nip/news/testimonies/vac-shortages-walt–6–

12–2002.htm. (FDA has verified the Web site 

address, but we are not responsible for 

subsequent changes to the Web site after this 

document publishes in the Federal Register).

14. Colditz, et al., ‘‘Efficacy of BCG Vaccine 

in the Prevention of Tuberculosis: Meta 

Analysis of the Published Literature’’, 

Journal of the American Medical Association, 

271:698–702, 1994.

15.http://www.fda.gov/ohrms/dockets/ac/

01/transcripts/3755t1.pdf

16.http://www.fda.gov/ohrms/dockets/ac/

01/transcripts/3805t2l01.pdf

17.http://www.fda.gov/ohrms/dockets/ac/

01/transcripts/3805t2l02.pdf

18.http://www.fda.gov/ohrms//dockets/ac/

02/transcripts/3842t1.pdf

19.http://www.fda.gov/cber/gdlns/

leverhnbk.pdf

List of Subjects

21 CFR Part 201

Drugs, Labeling, Reporting and 

recordkeeping requirements.

21 CFR Part 610

Biologics, Labeling, Reporting and 

recordkeeping requirements.

Therefore, under the Federal Food, 

Drug, and Cosmetic Act, the Public 

Health Service Act, and under authority 

delegated by the Commissioner of Food 

and Drugs, it is proposed that 21 CFR 

parts 201 and 610 be amended as 

follows:

PART 201—LABELING

1. The authority citation for 21 CFR 

part 201 continues to read as follows:

Federal Register / Vol. 29, No. 249 / Wednesday, December 29, 2004 / Proposed Rules 78293

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 358, 360, 360b, 360gg–360ss, 371, 

374, 379e; 42 U.S.C 216, 241, 262, 264.

2. Section 201.59 is amended in the 

table in paragraph (a)(3) by:

a. Removing ‘‘HFB–240’’ everywhere 

it appears and adding in its place 

‘‘HFM–99’’ in the BIOLOGICS section of 

the table, under ‘‘Mail Routing Code’’;

b. Revising the entries for the drug 

classes ‘‘Bacterial vaccines and toxoids 

with standards of potency’’ and ‘‘Viral 

and rickettsial vaccines’’ in the 

BIOLOGICS section of the table to read 

as follows.

§ 201.59 Effective date of §§ 201.56, 201.57, 

201.100(d)(3), and 201.100(e).

(a) * * *

(3) * * *

Effective Revised labeling due Drug class Mail routing code 

Biologics

[Insert date 30 months after date 

of publication in the Federal 

Register] 

See footnote3 Bacterial vaccines and toxoids with standards of potency HFM–99

* * * ** * *

Nov. 1, 19821 Nov 1, 19802 Viral and rickettsial vaccines HFM–99

* * * ** * *

1Except the effective date for all biological products reviewed generically by the advisory panel is 30 months after a final order is published 

under § 601.25(g) of this chapter. 2Except the due date for all biological products reviewed generically by the advisory panel is 6 months after a final order is published under 

§ 601.25(g) of this chapter.

3FDA has determined that a review of product labeling under this section is unnecessary.

* * * * *

PART 610—GENERAL BIOLOGICAL 

PRODUCTS STANDARDS

3. 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.

4. Section 610.21 is amended by 

revising the entry ‘‘Tetanus Immune 

Globulin (Human), 50 units of tetanus 

antitoxin per milliliter’’ under the 

heading ‘‘ANTIBODIES’’ to read as 

follows:

§ 610.21 Limits of potency.

* * * * *

ANTIBODIES

* * * * *

Tetanus Immune Globulin (Human), 

250 units of tetanus antitoxin per 

container.

* * * * *

Dated: December 21, 2004.

Jeffrey Shuren,

Assistant Commissioner for Policy.

[FR Doc. 04–28322 Filed 12–23–04; 11:16 

am]

BILLING CODE 4160–01–S