[Federal Register: December 19, 2005 (Volume 70, Number 242)]
[Rules and Regulations]               
[Page 75018-75028]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr19de05-10]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 610

[Docket No. 1980N-0208]

 
Biological Products; Bacterial Vaccines and Toxoids; 
Implementation of Efficacy Review

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule and final order.

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SUMMARY: The Food and Drug Administration (FDA) proposed to amend the 
biologics regulations and proposed to classify the bacterial vaccines 
and toxoids on the basis of findings and recommendations of the Panel 
on Review of Bacterial Vaccines and Toxoids (the Panel) on December 13, 
1985. The Panel reviewed the safety, efficacy, and labeling of 
bacterial vaccines and toxoids with standards of potency, bacterial 
antitoxins, and immune globulins. After the initial final rule and 
final order was vacated by the U.S. District Court for the District of 
Columbia on October 27, 2004, FDA published a new proposed rule and 
proposed order on December 29, 2004 (69 FR 78281). The purpose of this 
final rule and final order is to amend the biologics regulations, issue 
a final order in response to the report and recommendations of the 
Panel; and, respond to comments on the previously published proposed 
rule and proposed order submitted to the Division of Dockets 
Management. This final rule and final order does not address Anthrax 
Vaccine Adsorbed (AVA). The final order concerning AVA is published 
elsewhere in this issue of the Federal Register. FDA is classifying 
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).

DATES: This rule is effective December 19, 2006. The final order on 
categorization of products is effective immediately.

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:

Table of Contents

I. Introduction
II. Background
    A. History of the Review
    B. Comments on the December 1985 Proposal
III. Categorization of Products--Final Order
IV. FDA's Response to Additional Panel Recommendations
    A. Generic Order and Wording of Labeling
    B. Periodic Review of Product Labeling
    C. Improvement in the Reporting of Adverse Reactions
    D. Periodic Review of Product Licenses
    E. Compensation for Individuals Suffering Injury From Vaccination
    F. Public Support for Immunization Programs
    G. Assuring Adequate Supplies of Bacterial Vaccines and Toxoids; 
Establishment of a National Vaccine Commission
    H. Consistency of Efficacy Protocols
    I. The Effect of Regulations Protecting and Informing Human Study 
Subjects on the Ability to Conduct Clinical Trials
    J. Standards for Determining the Purity of Diphtheria and Tetanus 
Toxoids
    K. Immunogenic Superiority of Adsorbed Toxoids Over Fluid Toxoids
    L. Laboratory Testing Systems for Determining Potency of Tetanus 
and Diphtheria Toxoids
    M. Potency Testing of Diphtheria and Tetanus Toxoids for Pediatric 
Use
    N. Potency Requirements for Pertussis Vaccine
    O. Weight-Gain Test in Mice for Pertussis Vaccine
    P. Agglutination Test to Determine Pertussis Vaccine Response in 
Humans
    Q. Warnings in Labeling for Pertussis Vaccine
    R. Field Testing of Fractionated Pertussis Vaccines
    S. Use of Same Seed Lot Strain in Manufacturing Bacillus Calmette-
Guerin (BCG) Vaccine
    T. Development of an Improved Cholera Vaccine
    U. Plague Vaccine Immunization Schedule
V. FDA's Response to General Research Recommendations
VI. What Comments Did We Receive?
    A. FDA's Consideration of Comments on the Panel's Report
    B. Biological Products Review Process
    C. Plague Vaccine
    D. Miscellaneous Comments
VII. Amendment to the Regulations
VIII. Analysis of Impacts
    A. Review Under Executive Order 12866, the Regulatory Flexibility 
Act, and the Unfunded Mandates Reform Act of 1995
    B. Environmental Impact
    C. Paperwork Reduction Act of 1995
    D. Federalism
IX. References

I. Introduction

    On December 13, 1985, FDA proposed to amend the biologics 
regulations and proposed to classify the bacterial vaccines and toxoids 
on the bases of findings and recommendations of the Panel. The Panel 
reviewed the safety, efficacy, and labeling of bacterial vaccines and 
toxoids with standards of potency, bacterial antitoxins, and immune 
globulins. After reviewing the Panel's report and comments on the 
proposal, FDA published a final rule and final order on January 5, 2004 
(69 FR 255). On October 27, 2004, the U.S. District Court for the 
District of Columbia vacated the January 5, 2004, final rule and final 
order. On December 29, 2004, FDA published a withdrawal of the January 
5, 2004, final rule and final order. Concurrently with the withdrawal 
of the final rule and final order, FDA published again a proposed rule 
and proposed order (69 FR 78281) to provide notice and to give 
interested persons an opportunity to comment.
    The purpose of this document is to: (1) Categorize those bacterial 
vaccines

[[Page 75019]]

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;\1\ (2) issue a final response to 
recommendations made in the Panel's report.\2\ 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; and (3) 
revise the standard for potency of Tetanus Immune Globulin in Sec.  
610.21 (21 CFR 610.21).
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    \1\ The final order concerning AVA is published elsewhere in 
this issue of the Federal Register.
    \2\ The 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.
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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 
Sec.  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 Sec.  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 
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 Sec.  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 77134), 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 report\3\ and FDA's 
response to the recommendations of the Panel (the December 1985 
proposal). 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.
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    \3\ In addition to publication in the Federal Register of 
December 13, 1985 (50 FR 51002), the full Panel report is available 
on FDA's Website at http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm 

(Docket No. 1980N-0208). A copy of the Panel report is also 
available at the Division of Dockets Management, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852.
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    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 Sec.  601.25, and codified 
21 CFR 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 
Sec.  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.

[[Page 75020]]

    (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 has addressed those 
products proposed for Category IIIA in a separate rulemaking 
process.\4\ This final rule and final order does not take 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 above-noted 
process.
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    \4\ See the Federal Register of May 15, 2000 (65 FR 31003) and 
May 29, 2001 (66 FR 29148), 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.
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    (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 of the 
act 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 the 
biological products that would be subject to this labeling are 
prescription products administered by health care providers, the risk 
of overdose should be greatly reduced.
    We agree that, in many cases, a labeling section in part 201 (21 
CFR part 201) entitled ``Overdosage'' is not necessary. Section 
201.56(d)(3) of the labeling regulations provides that the labeling may 
omit any section or subsection of the labeling format if clearly 
inapplicable. The ``Overdosage'' section, provided for in Sec.  
201.57(i) of the regulations, is omitted for many bacterial vaccine and 
toxoid products.
    (Comment 4) One comment objected to several statements made by the 
Panel and provided in the Panel's written report, but did not object to 
or comment on FDA's proposed responses to the Panel's recommendations.
    The Panel's recommendations represent the scientific opinions of a 
panel of experts and are not binding. We believe 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 report and not on the Panel report directly. In reaching our 
conclusion, we took into account the Panel report and comments on the 
Panel report.
    In the December 1985 proposal, FDA provided the opportunity for 
comment on FDA's proposals in response to the Panel report. In the 
December 29, 2004 (69 FR 78281), proposed rule and proposed order (the 
December 2004 proposal), FDA again provided the opportunity for comment 
on FDA's proposals. The public was offered 90 days to submit comments 
in response to the December 2004 proposal.
    In response to the December 2004 proposal, most of the comments 
received pertained to AVA. A response to comments about AVA is provided 
in a document published elsewhere in this issue of the Federal 
Register. A discussion of comments to the December 2004 proposal other 
than those pertaining to AVA is provided under section VI of this 
document.

III. Categorization of Products--Final 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 2004 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 identified as such 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. After review of the comments on the December 1985 
and December 2004 proposals, and finding no additional scientific 
evidence to alter the proposed categorization, FDA adopts Category I as 
the final category for the listed products.

                          Table 1.--Category I
------------------------------------------------------------------------
   Manufacturer/
    License No.           Products*                  Comments
------------------------------------------------------------------------
Alpha Therapeutic   Tetanus Immune        Although the Panel recommended
 Corp., License      Globulin (Human)      that Tetanus Immune Globulin
 No. 744                                   (Human), manufactured by
                                           Alpha Therapeutic Corp., be
                                           placed in Category IIIB, FDA
                                           proposed that it be placed in
                                           Category I. Alpha Therapeutic
                                           Corp. no longer exists. The
                                           new owner is Grifols
                                           Biologicals, Inc. On August
                                           15, 2003, FDA revoked the
                                           license for Tetanus Immune
                                           Globulin (Human)
-------------------
Advance             Collagenase           ..............................
 Biofactures
 Corp., License
 No. 383
-------------------

[[Page 75021]]


Armour              Tetanus Immune        The manufacturer's licensed
 Pharmaceutical      Globulin (Human)      name is now ZLB Behring AG.
 Co., License No.                          On July 26, 1999, FDA revoked
 149                                       the license for Tetanus
                                           Immune Globulin (Human) at
                                           the request of the
                                           manufacturer
-------------------
Aventis Pasteur,    BCG Vaccine,          On February 24, 2000, a name
 Ltd., License No.   Botulism Antitoxin    change to Aventis Pasteur,
 1280                (Types A, B, and      Ltd. with an accompanying
                     E), Botulism          license number change to 1280
                     Antitoxin (Type E),   was granted. On December 21,
                     Tetanus Toxoid        2000, FDA revoked the license
                                           for Tetanus Toxoid at the
                                           request of the manufacturer
-------------------
Connaught           Diphtheria and        On December 9, 1999, a name
 Laboratories,       Tetanus Toxoids and   change to Aventis Pasteur,
 Inc., License No.   Pertussis Vaccine     Inc. with an accompanying
 711                 Adsorbed, and         license number change to 1277
                     Diphtheria            was granted to Connaught
                     Antitoxin             Laboratories, Inc. FDA
                                           revoked the licenses for
                                           these products at the request
                                           of the manufacturer on July
                                           6, 2001, and August 2, 2001,
                                           respectively
-------------------
Cutter              Plague Vaccine,       On October 5, 1994, the
 Laboratories,       Tetanus Immune        manufacturing facilities and
 Inc., License No.   Globulin (Human)      process for Plague Vaccine
 8                                         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 Laboratories, Inc.
                                           remains in effect. Bayer
                                           Corp. now holds the license
                                           for Tetanus Immune Globulin
                                           (Human) under License No. 8.
                                           The Bayer Corp. subsidiary
                                           that holds the license for
                                           Tetanus Immune Globulin
                                           (Human) is Talecris
                                           Biopharmaceutics, Inc. under
                                           License No. 1716
-------------------
Eli Lilly & Co.,    Diphtheria and        On December 2, 1985, FDA
 License No. 56      Tetanus Toxoids and   revoked the license for
                     Pertussis Vaccine     Diphtheria and Tetanus
                     Adsorbed              Toxoids and Pertussis Vaccine
                                           Adsorbed at the request of
                                           the manufacturer
-------------------
Glaxo               BCG Vaccine           On July 17, 1990, FDA revoked
 Laboratories,                             the license for BCG Vaccine
 Ltd., License No.                         at the request of the
 337                                       manufacturer
-------------------
Istituto            Diphtheria            On July 17, 1990, FDA revoked
 Sieroterapico       Antitoxin,            the license for Diphtheria
 Vaccinogeno         Diphtheria Toxoid     Antitoxin at the request of
 Toscano Sclavo,     Adsorbed, Tetanus     the manufacturer. On July 27,
 License No. 238     Toxoid Adsorbed       1993, FDA revoked the
                                           licenses for Diphtheria
                                           Toxoid Adsorbed and Tetanus
                                           Toxoid Adsorbed at the
                                           request of the manufacturer
-------------------
Lederle             Cholera Vaccine,      On December 23, 1992, FDA
 Laboratories,       Tetanus Immune        revoked the license for
 Division American   Globulin (Human)      Tetanus Immune Globulin
 Cyanamid Co.,                             (Human) at the request of the
 License No. 17                            manufacturer. On October 23,
                                           1996, FDA revoked the license
                                           for Cholera Vaccine at the
                                           request of the manufacturer
-------------------
Massachusetts       Diphtheria and        Although the Panel recommended
 Public Health       Tetanus Toxoids       that Tetanus Antitoxin be
 Biologic            Adsorbed,             placed in Category IIIB, FDA
 Laboratories,       Diphtheria and        proposed in the December 1985
 License No. 64      Tetanus Toxoids and   proposal that it be placed in
                     Pertussis Vaccine     Category I. On October 26,
                     Adsorbed, Tetanus     1988, FDA revoked the license
                     and Diphtheria        for Typhoid Vaccine at the
                     Toxoids Adsorbed      request of the manufacturer.
                     (For Adult Use),      On January 10, 1994, FDA
                     Tetanus Antitoxin,    revoked the license for
                     Tetanus Immune        Tetanus Antitoxin at the
                     Globulin (Human),     request of the manufacturer.
                     Tetanus Toxoid        On December 22, 1998, FDA
                     Adsorbed, Typhoid     revoked the license for
                     Vaccine               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. On July 1,
                                           2004, FDA revoked the license
                                           for Tetanus Immune Globulin
                                           (Human) at the request of the
                                           manufacturer. On August 23,
                                           2004, FDA revoked the license
                                           for Tetanus Toxoid Adsorbed
                                           at the request of the
                                           manufacturer
-------------------
Merck Sharp &       Tetanus Immune        The manufacturer is now known
 Dohme, Division     Globulin (Human)      as Merck & Co., Inc. On
 of Merck & Co.,                           January 31, 1986, FDA revoked
 Inc., License No.                         the license for Tetanus
 2                                         Immune Globulin (Human) at
                                           the request of the
                                           manufacturer
-------------------
Michigan            Diphtheria and        On November 11, 1998, a name
 Department of       Tetanus Toxoids and   change to BioPort Corp.
 Public Health,      Pertussis Vaccine     (BioPort) with an
 License No. 99      Adsorbed, Pertussis   accompanying license number
                     Vaccine Adsorbed,     change to 1260 was granted.
                     Typhoid Vaccine*      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
-------------------

[[Page 75022]]


Parke-Davis,        Tetanus Immune        On November 19, 1983, FDA
 Division of         Globulin (Human)      revoked the license for
 Warner-Lambert                            Tetanus Immune Globulin
 Co., License No.                          (Human) at the request of the
 1                                         manufacturer
-------------------
Swiss Serum and     Tetanus Antitoxin     Although the Panel recommended
 Vaccine Institute                         that Tetanus Antitoxin be
 Berne, License                            placed in Category IIIB, FDA
 No. 21                                    proposed 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            Tetanus Immune        The manufacturer is now known
 Laboratories,       Globulin (Human)      as Baxter Healthcare Corp. On
 Inc., Hyland                              July 27, 1995, FDA revoked
 Therapeutics                              the license for Tetanus
 Division, License                         Immune Globulin (Human) at
 No. 140                                   the request of the
                                           manufacturer
-------------------
University of       BCG Vaccine           On May 29, 1987, FDA revoked
 Illinois, License                         the license for BCG Vaccine
 No. 188                                   at the request of the
                                           manufacturer
-------------------
Wyeth               Cholera Vaccine,      On December 23, 1992, FDA
 Laboratories,       Tetanus Immune        revoked the license for
 Inc., License No.   Globulin (Human),     Tetanus Immune Globulin
 3                   Typhoid Vaccine       (Human) at the request of the
                     (acetone              manufacturer. On September
                     inactivated),         11, 2001, FDA revoked the
                     Typhoid Vaccine       licenses for Cholera Vaccine
                     (heat-phenol          and Typhoid Vaccine (both
                     inactivated)          forms) at the request of the
                                           manufacturer
------------------------------------------------------------------------
* The final order for Anthrax Vaccine Adsorbed is published elsewhere in
  this issue of the Federal Register.

    Category II. Licensed biological products determined to be unsafe 
or ineffective or to be misbranded and which should not continue in 
interstate commerce. FDA did not propose that any products be placed in 
Category II and in this final rule and final order does not categorize 
any products 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 in 
this document products for which FDA revoked the licenses before the 
December 1985 proposal but we identified them in the December 1985 
proposal. Products for which FDA revoked the licenses after the 
December 1985 proposal are identified in the ``Comments'' column.
    FDA has revoked the licenses of all products proposed by FDA for 
Category IIIB. After review of the comments on the December 1985 and 
December 2004 proposals, and finding no additional scientific evidence 
to alter the proposed categorization, FDA adopts Category IIIB as the 
final category for the listed products.

                         Table 2.--Category IIIB
------------------------------------------------------------------------
   Manufacturer/
    License No.           Products                   Comments
------------------------------------------------------------------------
Connaught           Diphtheria Toxoid,    On June 21, 1994, FDA revoked
 Laboratories,       Pertussis Vaccine     the license for Diphtheria
 Inc., License No.                         Toxoid and on December 19,
 711                                       1997, FDA revoked the license
                                           for Pertussis Vaccine, in
                                           both cases at the request of
                                           the manufacturer
-------------------
Istituto            Diphtheria Toxoid     On July 27, 1993, FDA revoked
 Sieroterapico                             the license for Diphtheria
 Vaccinogeno                               Toxoid at the request of the
 Toscano Sclavo,                           manufacturer
 License No. 238
-------------------
Massachusetts       Tetanus Toxoid        On October 11, 1989, FDA
 Public Health                             revoked the license for
 Biologic                                  Tetanus Toxoid at the request
 Laboratories,                             of the manufacturer
 License No. 64
-------------------
Merck Sharp &       Cholera Vaccine,      The manufacturer is now known
 Dohme, Division     Diphtheria and        as Merck & Co., Inc. On
 of Merck & Co.,     Tetanus Toxoids and   January 31, 1986, FDA revoked
 Inc., License No.   Pertussis Vaccine     the licenses for all the
 2                   Adsorbed, Tetanus     listed products at the
                     and Diphtheria        request of the manufacturer
                     Toxoids Adsorbed
                     (For Adult Use),
                     Tetanus Toxoid,
                     Typhoid Vaccine
-------------------
Michigan            Diphtheria Toxoid     On November 11, 1998, the name
 Department of       Adsorbed              of the manufacturer was
 Public Health,                            changed to BioPort, and the
 License No. 99                            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               Diphtheria Toxoid,    On May 19, 1987, FDA revoked
 Laboratories,       Diphtheria Toxoid     the licenses for all listed
 Inc., License No.   Adsorbed, Pertussis   products at the request of
 3                   Vaccine               the manufacturer
------------------------------------------------------------------------


[[Page 75023]]

IV. 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. In this 
section of the document, FDA responds in final to the general 
recommendations.

A. Generic Order and Wording of Labeling

    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 Sec.  201.59 of the 
regulations. Although proposed, we are not making this change because 
it does not appear to be necessary at this time.
    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 Sec.  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 Sec.  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, we do not believe that a labeling review is 
necessary at this time.
    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.

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 and December 2004 
proposal, we believe 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) (21 CFR 601.12(f)) 
prescribes when revised labeling must be submitted, either as a 
supplement or, if changes are minor, in an annual report. In addition, 
FDA may request revision of labeling when indicated by current 
scientific knowledge. We believe that, by these mechanisms, product 
labeling is kept up to date, and 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 NCVIA and is 
administered by FDA and the 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. 1) 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 about 
1,000 reports each month under the VAERS program. A guidance document 
is available which explains how to complete the VAERS form (Ref. 2).

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 the December 1985 proposal (50 FR 51002 at 51109), 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 and tetanus toxoids and pertussis (DTP) vaccine would also 
be required to have separate licenses 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. We believe 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

[[Page 75024]]

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 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 (DTP), diphtheria and tetanus toxoids and 
acellular pertussis (DTaP) or diphtheria and tetanus toxoids vaccines 
(DT)) (Ref. 3).

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. 4) for a variety of 
reasons. FDA will 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.
    We believe 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. We routinely meet with manufacturers before the initiation of 
clinical studies to discuss the study and will comment on proposed 
protocols for efficacy studies. We intend 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.
    We believe 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. We note 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. We particularly welcome comments on how appropriate 
informed consent and protection of human subjects can be maintained 
while assuring that the development and study of useful products are 
not inhibited.

J. Standards for Determining the Purity of Diphtheria and Tetanus 
Toxoids

    The Panel recommended that standards should be established for 
purity of both diphtheria and tetanus toxoids in terms of limits of 
flocculation (Lf) content per milligram (mg) of nitrogen.
    In the December 1985 proposal, we agreed that standards should be 
set. We have since determined that this approach is overly restrictive 
and does not allow FDA to keep pace with advances in manufacturing and 
technology. The Center for Biologics Evaluation and Research (CBER) 
approves the release specifications for the purity of diphtheria and 
tetanus toxoids during the review of a Biologics License Application 
(BLA). The purity of diphtheria toxoids in vaccines currently licensed 
in the United States is usually at least 1,500 Lf/mg nondialyzable 
nitrogen and the purity of tetanus toxoids in vaccines currently 
licensed in the United States is usually at least 1,000 Lf/mg of 
nondialyzable nitrogen. However, because the purity of tetanus and 
diphtheria toxoids in different vaccines is established during

[[Page 75025]]

the BLA review, the purity may vary between products.

K. Immunogenic Superiority of Adsorbed Toxoids Over Fluid Toxoids

    The Panel recommended that the immunogenic superiority of the 
adsorbed diphtheria and tetanus toxoids 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 
2005. 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.
    Diphtheria and tetanus toxoids 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 animal potency tests currently required by WHO, the European 
Pharmacopoeia (EP), and FDA differ. Despite these differences, the 
potency 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 Diphtheria and Tetanus Toxoids for Pediatric Use

    The Panel recommended FDA require potency testing after combination 
of the individual diphtheria and tetanus toxoid components in 
Diphtheria and Tetanus Toxoid vaccines for pediatric use.
    We agree 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.
    We have removed the additional standard regulations applicable to 
pertussis vaccine (Ref. 5). 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) vaccines are licensed in the 
United States.
    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 weight-gain 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 or DTaP combination 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 antigen-specific 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.
    We agree with the recommendation except that such information 
should be included in product labeling as described in Sec.  
201.100(d), i.e., the package insert, rather than the product label. 
Labeling applicable to whole-cell

[[Page 75026]]

pertussis vaccines was revised to include much of the information 
recommended by the Panel; whole-cell pertussis vaccines are no longer 
licensed in the United States. Because the acellular forms of pertussis 
vaccine have a different profile of potential adverse events and 
contraindications, the product labeling for these products 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 field-testing 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. 
6). Thus, FDA does not find that available human data justify 
requirement of a single BCG vaccine strain.

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. We continue 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 three intramuscular (IM) injections (1 
milliliter (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.
    We agree with the recommendation, and the currently licensed 
vaccine is labeled consistent with the recommendation. However, this 
vaccine is not currently in production or distribution.

V. 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, we 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, we 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, we are 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.
    We recognize 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 
February 17, 2005 (Ref. 7), May 6, 2004 (Ref. 8), and May 8, 2003 (Ref. 
9). In addition, CBER has defined as part of its strategic plan its 
goal of 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, we also support the leveraging of 
resources to create effective collaborations in the advancement of 
science. We have issued a Guidance for FDA Staff: The Leveraging 
Handbook, an Agency Resource for Effective Collaborations (Ref. 10). 
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. We 
invite comment at any time on ways we may improve our research program 
and set our objectives.

VI. What Comments Did We Receive?

    We received about 350 comments on the December 2004 proposal. Most 
of the comments related to AVA. A response to comments about AVA is 
provided in a document published elsewhere in this issue of the Federal 
Register. Comments on the December 2004 proposal not relating to AVA 
are discussed in this section of this document.

A. FDA's Consideration of Comments on the Panel's Report

    (Comment 1) Some comments criticized FDA for stating in the 
December 2004 proposal that we were

[[Page 75027]]

not considering comments on the Panel report.
    (Response) We wish to clarify our review of comments. We are not 
considering comments on the Panel report because the Panel's 
recommendations are not binding on the public or FDA. The Panel is 
comprised of experts offering scientific opinions for our 
consideration. We should not modify the statements and recommendations 
of the Panel as provided in their report, including through public 
comment. The purpose of the opportunity for public comment allows 
comment on FDA's responses to the Panel report and not on the Panel 
report directly. We can take action with regard to public comments on 
FDA's responses to the Panel report and therefore, we directed comments 
to our responses rather than to the report itself.

B. Biological Products Review Process

    (Comment 2) One comment submitted by the former Chief Counsel for 
FDA during the time that the proposed and final regulations on the 
Biological Products Review were issued discussed the historical 
development of the Biological Products Review. The commenter did not 
comment on the December 2004 proposal nor did he request modification 
of FDA's proposed actions.
    (Response) We offer no response to this informative general 
comment.

C. Plague Vaccine

    (Comment 3) One comment noted that the plague vaccine was licensed 
and once recommended by the CDC's Advisory Committee on Immunization 
Practices, but is no longer produced.
    (Response) As mentioned earlier in this document and consistent 
with the comment, the plague vaccine remains licensed but is not 
currently in production or distribution.

D. Miscellaneous Comments

    (Comment 4) Numerous miscellaneous comments on the December 2004 
proposal were received. Many of the comments expressed an opinion about 
the conduct of vaccination administration programs or activities 
associated with the Department of Defense. Other miscellaneous comments 
provided links to Internet sites, but did not provide a comment on the 
December 2004 proposal. Other submissions to the Docket were electronic 
mailings to other parties that copied the Docket.
    (Response) These miscellaneous comments noted above are not 
relevant or responsive to the December 2004 proposed order and 
accordingly, we are not providing any response to them.

VII. Amendment to the Regulations

    In the December 1985 proposal and December 2004 proposal, we 
proposed to amend Sec.  610.21, limits of potency, by revising the 
potency requirements for Tetanus Immune Globulin (Human) (TIG). We 
proposed to amend the regulations to require a minimum potency of 250 
units of tetanus antitoxin per container for TIG.
    The current regulation requires that the minimum potency of TIG 
must not be less than 50 units of tetanus antitoxin per mL of fluid. 
All currently licensed TIG meets this minimum potency standard, and is 
marketed with a labeled potency of 250 units per container. However the 
number of units per mL has varied (the current standard provides only a 
minimum potency per mL of fluid) and thus, the volume per 250 unit 
container has varied. Because the volume of the final products has 
varied without any apparent effect on performance of the product, FDA 
has determined that it is not appropriate to regulate the potency of 
TIG on a per mL basis. We advise that in this discussion and in the 
regulation, ``per container'' means that amount of the contents of the 
container (vial or syringe) deliverable to the patient in normal use. 
FDA believes that TIG should continue to be marketed at a potency of no 
less than 250 units per container, which is the dose routinely 
recommended for prophylaxis against tetanus. All current manufacturers 
of TIG are already conforming to the proposed requirement by labeling 
their products with a potency of 250 units per container, while also 
complying with the existing regulation. Thus, the FDA believes this 
change will better reflect modern labeling practices.
    We received no comments opposing the proposed revision to Sec.  
610.21 and therefore, we are amending 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 Reform Act of 1995

    FDA has examined the impacts of this 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 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. The agency believes that this final rule is 
consistent with the regulatory philosophy and principles identified in 
the Executive order. In addition, this final 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 final rule 
does not impose new requirements on any entity and has no associated 
compliance costs, the agency certifies that the 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 
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. Paperwork Reduction Act of 1995

    This final 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 final rule in accordance with the principles 
set forth

[[Page 75028]]

in Executive Order 13132. FDA has determined that the 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 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.

IX. 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. 
(FDA has verified the Web site addresses, but we are not responsible 
for subsequent changes to the Web sites after this document publishes 
in the Federal Register).
    1. ``Table of Reportable Events Following Vaccination,'' http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.vaers.hhs.gov/reportable.htm
.

    2. ``Guidance for Industry: How to Complete the Vaccine Adverse 
Event Reporting System Form (VAERS-1)'', September 1998, http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/gdlns/vaers-1.pdf
.

    3. ``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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.cdc.gov/nip/coverage/NIS/00-01/tab19-3dpt_race_iap.htm
.

    4. 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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.cdc.gov/nip/news/testimonies/vac-shortages-walt-6-12-2002.htm
.

    5. 61 FR 40153, August 1, 1996.
    6. 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.
    7. http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4087T2.htm
    8. http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4038t1.htm

    9. http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3948t1.txt    10. http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/cber/gdlns/leverhnbk.pdf

ber/gdlns/leverhnbk.pdf

List of Subjects

21 CFR Part 610

    Biologics, Labeling, Reporting and recordkeeping requirements.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public 
Health Service Act, and under authority delegated to the Commissioner 
of Food and Drugs, 21 CFR part 610 is amended as follows:

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

0
1. The authority citation for 21 CFR part 610 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c, 
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a, 
264.

0
2. 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:


Sec.  610.21  Limits of potency.

* * * * *
ANTIBODIES
* * * * *
    Tetanus Immune Globulin (Human), 250 units of tetanus antitoxin per 
container.
* * * * *

    Dated: December 12, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-24224 Filed 12-15-05; 8:45 am]

BILLING CODE 4160-01-S