[Federal Register: December 29, 2004 (Volume 29, Number 249)]
[Proposed Rules]               
[Page 78281-78293]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr29de04-32]                         



[[Page 78281]]


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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.

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

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

Follow the instructions for submitting comments on the agency Web site.
     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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm, 

including any personal information provided. For 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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/default.htm 

and insert the docket number found in brackets in the heading of this 
document, into the ``Search'' box and follow the prompts and/or go to 
the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: 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;
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    \1\ 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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    3. Revise the standard for potency of Tetanus Immune Globulin in 
Sec.  610.21 (21 CFR 610.21); and
    4. Apply the labeling requirements in Sec. Sec.  201.56 and 
201.57 (21 CFR 201.56 and 201.57) to bacterial vaccines and toxoids 
by amending the implementation dates in Sec.  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 
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

[[Page 78282]]

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 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 report\2\ 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.
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    \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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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.
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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 
Sec.  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.
    (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 above-noted process.
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    \3\ See 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.
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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 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 Sec.  201.56) 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 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

[[Page 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      Tetanus Immune          Although the Panel
 Corp., License No.     Globulin (Human)        recommended that Tetanus
 744                                            Immune Globulin (Human),
                                                manufactured by Alpha
                                                Therapeutic Corp., be
                                                placed in Category IIIB,
                                                FDA proposed that it be
                                                placed in Category I\1\
------------------------------------------------------------------------
Advance Biofactures    Collagenase             .........................
 Corp., License No.
 383
------------------------------------------------------------------------
Armour Pharmaceutical  Tetanus Immune          Manufacturer's licensed
 Co., License No. 149   Globulin (Human)        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              Diphtheria and Tetanus  On December 9, 1999, a
 Laboratories, Inc.,    Toxoids and Pertussis   name change to Aventis
 License No. 711        Vaccine Adsorbed, and   Pasteur, Inc. with an
                        Diphtheria Antitoxin    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              BCG Vaccine, Botulism   On February 24, 2000, a
 Laboratories, Ltd.,    Antitoxin (Types A,     name change to Aventis
 License No. 73         B, and E), Botulism     Pasteur, Ltd. with an
                        Antitoxin (Type E),     accompanying license
                        Tetanus Toxoid          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,   Plague Vaccine,         On October 5, 1994, the
 Inc., License No. 8    Tetanus Immune          manufacturing facilities
                        Globulin (Human)        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.,       Diphtheria and Tetanus  On December 2, 1985, FDA
 License No. 56         Toxoids and Pertussis   revoked the license for
                        Vaccine Adsorbed        Diphtheria and Tetanus
                                                Toxoids and Pertussis
                                                Vaccine Adsorbed at the
                                                request of the
                                                manufacturer
------------------------------------------------------------------------
Glaxo Laboratories,    BCG Vaccine             On July 17, 1990, FDA
 Ltd., License No.                              revoked the license for
 337                                            BCG Vaccine at the
                                                request of the
                                                manufacturer
------------------------------------------------------------------------
Istituto               Diphtheria Antitoxin,   On July 17, 1990, FDA
 Sieroterapico          Diphtheria Toxoid       revoked the license for
 Vaccinogeno Toscano    Adsorbed, Tetanus       Diphtheria Antitoxin at
 Sclavo, License No.    Toxoid Adsorbed         the request of the
 238                                            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,  Cholera Vaccine,        On December 23, 1992, FDA
 Division American      Tetanus Immune          revoked the license for
 Cyanamid Co.,          Globulin (Human)        Tetanus Immune Globulin
 License No. 17                                 (Human) at the request
                                                of the manufacturer. On
                                                October 23, 1996, FDA
                                                revoked the license for
                                                Cholera Vaccine at the
                                                request of the
                                                manufacturer
------------------------------------------------------------------------

[[Page 78284]]


Massachusetts Public   Diphtheria and Tetanus  Although the Panel
 Health Biologic        Toxoids Adsorbed,       recommended that Tetanus
 Laboratories,          Diphtheria and          Antitoxin be placed in
 License No. 64         Tetanus Toxoids and     Category IIIB, FDA
                        Pertussis Vaccine       proposed in the December
                        Adsorbed, Tetanus and   1985 proposal that it be
                        Diphtheria Toxoids      placed in Category I. On
                        Adsorbed (For Adult     October 26, 1988, FDA
                        Use), Tetanus           revoked the license for
                        Antitoxin, Tetanus      Typhoid Vaccine at the
                        Immune Globulin         request of the
                        (Human), Tetanus        manufacturer. On January
                        Toxoid Adsorbed,        10, 1994, FDA revoked
                        Typhoid Vaccine         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,   Tetanus Immune          The manufacturer is now
 Division of Merck &    Globulin (Human)        known as Merck & Co.,
 Co., Inc, License                              Inc. On January 31,
 No. 2                                          1986, FDA revoked the
                                                license for Tetanus
                                                Immune Globulin (Human)
                                                at the request of the
                                                manufacturer
------------------------------------------------------------------------
Michigan Department    Anthrax Vaccine         On November 11, 1998, a
 of Public Health,      Adsorbed, Diphtheria    name change to BioPort
 License No. 99         and Tetanus Toxoids     Corporation (BioPort)
                        and Pertussis Vaccine   with an accompanying
                        Adsorbed, Pertussis     license number change to
                        Vaccine Adsorbed,       1260 was granted. The
                        Typhoid Vaccine         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  Tetanus Immune          On November 19, 1983, FDA
 of Warner-Lambert      Globulin (Human)        revoked the license for
 Co., License No. 1                             Tetanus Immune Globulin
                                                (Human) at the request
                                                of the manufacturer
------------------------------------------------------------------------
Swiss Serum and        Tetanus Antitoxin       Although the Panel
 Vaccine Institute                              recommended that Tetanus
 Berne, License No.                             Antitoxin be placed in
 21                                             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               Tetanus Immune          The manufacturer is now
 Laboratories, Inc.,    Globulin (Human)        known as Baxter
 Hyland Therapeutics                            Healthcare Corporation.
 Division, License                              On July 27, 1995, FDA
 No. 140                                        revoked the license for
                                                Tetanus Immune Globulin
                                                (Human) at the request
                                                of the manufacturer
------------------------------------------------------------------------
University of          BCG Vaccine             On May 29, 1987, FDA
 Illinois, License                              revoked the license for
 No. 188                                        BCG Vaccine at the
                                                request of the
                                                manufacturer
------------------------------------------------------------------------
Wyeth Laboratories,    Cholera Vaccine,        On December 23, 1992, FDA
 Inc, License No. 3     Tetanus Immune          revoked the license for
                        Globulin (Human),       Tetanus Immune Globulin
                        Typhoid Vaccine         (Human) at the request
                        (acetone                of the manufacturer. On
                        inactivated), Typhoid   September 11, 2001, FDA
                        Vaccine (heat-phenol    revoked the licenses for
                        inactivated)            Cholera Vaccine and
                                                Typhoid Vaccine (both
                                                forms) at the request of
                                                the manufacturer
------------------------------------------------------------------------
\1\ The 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.

[[Page 78285]]

    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               Diphtheria Toxoid       On July 27, 1993, FDA
 Sieroterapico                                  revoked the license for
 Vaccinogeno Toscano                            Diphtheria Toxoid at the
 Sclavo, License No.                            request of the
 238                                            manufacturer
------------------------------------------------------------------------
Connaught              Diphtheria Toxoid,      On June 21, 1994, FDA
 Laboratories, Inc.,    Pertussis Vaccine       revoked the license for
 License No. 711                                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   Tetanus Toxoid          On October 11, 1989, FDA
 Health Biologic                                revoked the license for
 Laboratories,                                  Tetanus Toxoid at the
 License No. 64                                 request of the
                                                manufacturer
------------------------------------------------------------------------
Merck Sharpe & Dohme,  Cholera Vaccine,        The manufacturer is now
 Division of Merke &    Diphtheria and          known as Merck & Co.,
 Co., Inc., License     Tetanus Toxoids and     Inc. On January 31,
 No. 2                  Pertussis Vaccine       1986, FDA revoked the
                        Adsorbed, Tetanus and   licenses for all the
                        Diphtheria Toxoids      listed products at the
                        Adsorbed (For Adult     request of the
                        Use), Tetanus Toxoid,   manufacturer
                        Typhoid Vaccine
------------------------------------------------------------------------
Michigan Department    Diphtheria Toxoid       On November 12, 1998, the
 of Public Health,      Adsorbed                name of the manufacturer
 License No. 99                                 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,    Diphtheria Toxoid,      On May 19, 1987, FDA
 Inc., License No.3     Diphtheria Toxoid       revoked the licenses for
                        Adsorbed, Pertussis     all listed products at
                        Vaccine                 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\
---------------------------------------------------------------------------

    \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.
---------------------------------------------------------------------------

    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 
1 through 6, 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

[[Page 78286]]

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\
---------------------------------------------------------------------------

    \5\ The 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.
---------------------------------------------------------------------------

    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\
---------------------------------------------------------------------------

    \6\ For 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).
---------------------------------------------------------------------------

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

[[Page 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 Sec.  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 Sec.  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 Sec.  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 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, FDA does not believe that a labeling review is 
necessary at this time. Accordingly, FDA proposes to amend the table in 
Sec.  201.59 by providing that the labeling requirements in Sec. Sec.  
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 Sec.  201.59(a)(3) that specification of a date for submission 
of

[[Page 78288]]

revised product labeling under Sec.  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 Sec.  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

[[Page 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

[[Page 78290]]

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 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 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.
    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 whole-cell 
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 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. 
14). Thus, FDA does not find that available human data justify 
requirement of a single BCG vaccine strain.

[[Page 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 Sec.  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 Sec.  
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

[[Page 78292]]

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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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 Alum-Precipitated 
Protective Antigen,'' Journal of Immunology, 73:387-391, 1954.
    9. 61 FR 40153, August 1, 1996.
    10. ``Table of Reportable Events Following Vaccination,'' http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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://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.
 (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://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.
 (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://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3755t1.pdf    16.http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3805t2_01.pdf
    17.http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3805t2--

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


[[Page 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.


Sec.  201.59  Effective date of Sec. Sec.  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    See footnote\3\    Bacterial vaccines    HFM-99
 months after                          and toxoids with
 date of                               standards of
 publication in                        potency
 the Federal
 Register]
 * *                * *               * *                   *
Nov. 1, 1982\1\    Nov 1, 1980\2\     Viral and             HFM-99
                                       rickettsial
                                       vaccines
 * *                * *               * *                   *
------------------------------------------------------------------------
\1\ Except the effective date for all biological products reviewed
  generically by the advisory panel is 30 months after a final order is
  published under Sec.   601.25(g) of this chapter.
\2\ Except the due date for all biological products reviewed generically
  by the advisory panel is 6 months after a final order is published
  under Sec.   601.25(g) of this chapter.
\3\ FDA 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:


Sec.  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