[Federal Register: January 5, 2004 (Volume 69, Number 2)]
[Rules and Regulations]               
[Page 255-267]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr05ja04-6]                         

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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: Final rule and final order.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is amending the 
biologics regulations in response to the report and recommendations of 
the Panel on Review of Bacterial Vaccines and Toxoids with Standards of 
Potency (the Panel). The Panel reviewed the safety, efficacy, and 
labeling of bacterial vaccines and toxoids that have standards of 
potency, bacterial antitoxins, and immune globulins. On the basis of 
the Panel's findings and recommendations, FDA is classifying these 
products as Category I (safe, effective, and not misbranded), Category 
II (unsafe, ineffective, or misbranded), or Category IIIB (off the 
market pending completion of studies permitting a determination of 
effectiveness).

DATES: This rule is effective January 4, 2003. The final order on 
categorization of products is effective January 5, 2004.

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

    The purposes of this document are:
    1. To 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. To issue a final response to recommendations made in the Panel's 
report. These recommendations concern conditions relating to active 
components, labeling, tests required before release of product lots, 
product standards, or other conditions considered by the Panel to be 
necessary or appropriate for assuring the safety and effectiveness of 
the reviewed products;
    3. To revise the standard for potency of Tetanus Immune Globulin in 
Sec.  610.21 (21 CFR 610.21); and
    4. To 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. 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

[[Page 256]]

include recommendations classifying the products reviewed into one of 
three categories.
    [sbull] Category I designating those biological products determined 
by the Panel to be safe, effective, and not misbranded.
    [sbull] Category II designating those biological products 
determined by the Panel to be unsafe, ineffective, or misbranded.
    [sbull] Category III designating those biological products 
determined by the Panel not to fall within either Category I or 
Category II on the basis of the Panel's conclusion that the available 
data were insufficient to classify such biological products, and for 
which further testing was therefore required. Category III products 
were assigned to one of two subcategories. Category IIIA products were 
those that would be permitted to remain on the market pending the 
completion of further studies. Category IIIB products were those for 
which the Panel recommended license revocation on the basis of the 
Panel's assessment of potential risks and benefits.
    In its report, the Panel could also include recommendations 
concerning any condition relating to active components, labeling, tests 
appropriate before release of products, product standards, or other 
conditions necessary or appropriate for a biological product's safety 
and effectiveness.
    In accordance with Sec.  601.25, after reviewing the conclusions 
and recommendations of the review panels, FDA would publish in the 
Federal Register a proposed order containing: (1) A statement 
designating the biological products reviewed into Categories I, II, 
IIIA, or IIIB, (2) a description of the testing necessary for Category 
IIIA biological products, and (3) the complete panel report. Under the 
proposed order, FDA would propose to revoke the licenses of those 
products designated into Category II and Category IIIB.
    After reviewing public comments, FDA would publish a final order on 
the matters covered in the proposed order.
    In the Federal Register of December 13, 1985 (50 FR 51002), FDA 
issued a proposed rule responding to the recommendations of the Panel 
(the December 1985 proposal). In the December 1985 proposal, FDA 
proposed regulatory categories (Category I, Category II, or Category 
IIIB as defined previously in this document) for each bacterial vaccine 
and toxoid under review by the Panel, and responded to other 
recommendations made by the Panel. The public was offered 90 days to 
submit comments in response to the December 1985 proposal.
    The above stated definition of Category IIIA 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.

III. Comments on the December 1985 Proposal and Our Response

    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 of comment follows.
    (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. 
This final rule does not take any action regarding the further 
classification of those products proposed for Category IIIA, including 
those proposed for Category IIIA for primary immunization. All 
manufacturers and others in the general public have been offered 
additional opportunity to comment on the final categorization of 
specific category IIIA products in the above-noted process.
    (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 (21 U.S.C. 382) contains 
requirements for the export of products not approved in the United 
States. Under these provisions, products such as Pertussis Immune 
Globulin (Human) could 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 ``Overdosage'' is 
not necessary. Section 201.56(d)(3) of the labeling regulations 
provides that the labeling may omit any section or subsection of the 
labeling format (outlined in Sec.  201.56) if clearly inapplicable. The 
``Overdosage'' section,

[[Page 257]]

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 
rulemaking. 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 was to allow comment on FDA's 
responses to the Panel's report and not on the Panel's report directly.

IV. Categorization of Products--Final Order

    Category I. Licensed biological products determined to be safe and 
effective and not misbranded. Table 1 of this document is a list of 
those products proposed in December 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 
are not listed but were identified in the December 1985 proposal. 
Products for which the licenses were revoked after the December 1985 
proposal are identified in the ``Comments'' column. After review of the 
comments and finding no additional scientific evidence to alter the 
proposed categorizations, FDA adopts 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 recommended
 Corp., License No.   Globulin (Human)     that Tetanus Immune Globulin
 744                                       (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               Tetanus Immune       Manufacturer's licensed name
 Pharmaceutical       Globulin (Human)     is now Centeon L. L. C. On
 Co., License No.                          July 26, 1999, FDA revoked
 149                                       the license for Tetanus
                                           Immune Globulin (Human) at
                                           the request of the
                                           manufacturer.
------------------------------------------------------------------------
Connaught            Diphtheria and       On December 9, 1999, a name
 Laboratories,        Tetanus Toxoids      change to Aventis Pasteur,
 Inc., License No.    and Pertussis        Inc. with an accompanying
 711                  Vaccine Adsorbed,    license number change to 1277
                      and Diphtheria       was granted to Connaught
                      Antitoxin            Laboratories, Inc. FDA
                                           revoked the licenses for
                                           these products at the request
                                           of the manufacturer on July
                                           6, 2001, and August 2, 2001,
                                           respectively.
------------------------------------------------------------------------
Connaught            BCG Vaccine,         On February 24, 2000, a name
 Laboratories,        Botulism Antitoxin   change to Aventis Pasteur,
 Ltd., License No.    (Types A, B, and     Ltd. with an accompanying
 73                   E), Botulism         license number change to 1280
                      Antitoxin (Type      was granted. On December 21,
                      E), Tetanus Toxoid   2000, FDA revoked the license
                                           for Tetanus Toxoid at the
                                           request of the manufacturer.
------------------------------------------------------------------------
Cutter               Plague Vaccine,      On October 5, 1994, the
 Laboratories,        Tetanus Immune       manufacturing facilities and
 Inc., License No.    Globulin (Human)     process for Plague Vaccine
 8                                         were transferred to Greer
                                           Laboratories, Inc., License
                                           No. 308. On May 24, 1995, FDA
                                           revoked Cutter's license for
                                           Plague Vaccine at the request
                                           of Cutter, the previous
                                           manufacturer; the license for
                                           Greer Labs, Inc. remains in
                                           effect. Bayer Corp. now holds
                                           the license for Tetanus
                                           Immune Globulin (Human) under
                                           License No. 8.
------------------------------------------------------------------------
Eli Lilly & Co.,     Diphtheria and       On December 2, 1985, FDA
 License No. 56       Tetanus Toxoids      revoked the license for
                      and Pertussis        Diphtheria and Tetanus
                      Vaccine Adsorbed     Toxoids and Pertussis Vaccine
                                           Adsorbed at the request of
                                           the manufacturer. FDA
                                           inadvertently omitted this
                                           information in the December
                                           1985 proposal.
------------------------------------------------------------------------
Glaxo Laboratories,  BCG Vaccine          On July 17, 1990, FDA revoked
 Ltd., License No.                         the license for BCG Vaccine
 337                                       at the request of the
                                           manufacturer.
------------------------------------------------------------------------
Istituto             Diphtheria           On July 17, 1990, FDA revoked
 Sieroterapico        Antitoxin,           the license for Diphtheria
 Vaccinogeno          Diphtheria Toxoid    Antitoxin at the request of
 Toscano Sclavo,      Adsorbed, Tetanus    the manufacturer. On July 27,
 License No. 238      Toxoid Adsorbed      1993, FDA revoked the
                                           licenses for Diphtheria
                                           Toxoid Adsorbed and Tetanus
                                           Toxoid Adsorbed at the
                                           request of the manufacturer.
------------------------------------------------------------------------
Lederle              Cholera Vaccine,     On December 23, 1992, FDA
 Laboratories,        Tetanus Immune       revoked the license for
 Division American    Globulin (Human)     Tetanus Immune Globulin
 Cyanamid Co.,                             (Human) at the request of the
 License No. 17                            manufacturer. On October 23,
                                           1996, FDA revoked the license
                                           for Cholera Vaccine at the
                                           request of the manufacturer.
------------------------------------------------------------------------

[[Page 258]]


Massachusetts        Diphtheria and       Although the Panel recommended
 Public Health        Tetanus Toxoids      that Tetanus Antitoxin be
 Biologic             Adsorbed,            placed in Category IIIB, FDA
 Laboratories,        Diphtheria and       proposed that it be placed in
 License No. 64       Tetanus Toxoids      Category I. On October 26,
                      and Pertussis        1988, FDA revoked the license
                      Vaccine Adsorbed,    for Typhoid Vaccine at the
                      Tetanus and          request of the manufacturer.
                      Diphtheria Toxoids   On January 10, 1994, FDA
                      Adsorbed (For        revoked the license for
                      Adult Use),          Tetanus Antitoxin at the
                      Tetanus Antitoxin,   request of the manufacturer.
                      Tetanus Immune       On December 22, 1998, FDA
                      Globulin (Human),    revoked the license for
                      Tetanus Toxoid       Diphtheria and Tetanus
                      Adsorbed, Typhoid    Toxoids and Pertussis Vaccine
                      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 &        Tetanus Immune       The manufacturer is now known
 Dohme, Division of   Globulin (Human)     as Merck & Co., Inc. On
 Merck & Co., Inc,                         January 31, 1986, FDA revoked
 License No. 2                             the license for Tetanus
                                           Immune Globulin (Human) at
                                           the request of the
                                           manufacturer.
------------------------------------------------------------------------
Michigan Department  Anthrax Vaccine      The license for Typhoid
 of Public Health,    Adsorbed,            Vaccine was revoked on June
 License No. 99       Diphtheria and       25, 1985, at the request of
                      Tetanus Toxoids      the manufacturer. FDA
                      and Pertussis        inadvertently omitted this
                      Vaccine Adsorbed,    information in the December
                      Pertussis Vaccine    1985 proposal. On November
                      Adsorbed, Typhoid    11, 1998, a name change to
                      Vaccine              BioPort Corp. (BioPort) with
                                           an accompanying license
                                           number change to 1260 was
                                           granted. 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,         Tetanus Immune       On November 19, 1983, FDA
 Division of Warner-  Globulin (Human)     revoked the license for
 Lambert Co.,                              Tetanus Immune Globulin
 License No. 1                             (Human) at the request of the
                                           manufacturer. FDA
                                           inadvertently omitted this
                                           information in the December
                                           1985 proposal.
------------------------------------------------------------------------
Swiss Serum and      Tetanus Antitoxin    Although the Panel recommended
 Vaccine Institute                         that Tetanus Antitoxin be
 Berne, License No.                        placed in Category IIIB, FDA
 21                                        proposed that it be placed in
                                           Category I. On March 13,
                                           1980, FDA revoked the license
                                           for Tetanus Antitoxin at the
                                           request of the manufacturer;
                                           FDA inadvertently omitted
                                           this information in the
                                           December 1985 proposal.
------------------------------------------------------------------------
Travenol             Tetanus Immune       The manufacturer is now known
 Laboratories,        Globulin (Human)     as Baxter Healthcare Corp. On
 Inc., Hyland                              July 27, 1995, FDA revoked
 Therapeutics                              the license for Tetanus
 Division, License                         Immune Globulin (Human) at
 No. 140                                   the request of the
                                           manufacturer.
------------------------------------------------------------------------
University of        BCG Vaccine          On May 29, 1987, FDA revoked
 Illinois, License                         the license for BCG Vaccine
 No. 188                                   at the request of the
                                           manufacturer.
------------------------------------------------------------------------
Wyeth 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 of the
                      (acetone             manufacturer. On September
                      inactivated),        11, 2001, FDA revoked the
                      Typhoid Vaccine      licenses for Cholera Vaccine
                      (heat-phenol         and Typhoid Vaccine (both
                      inactivated)         forms) at the request of the
                                           manufacturer.
------------------------------------------------------------------------
\1\ The Panel recommended that Tetanus Immune Globulin (Human)
  manufactured by Alpha Therapeutic Corp. 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. 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
  final 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 did not propose that any products be placed in 
Category II and in this final rule does not categorize any products in 
Category II.
    Category IIIB. Biological products for which available data are 
insufficient to classify their safety and effectiveness and should not 
continue in interstate commerce. Table 2 of this document is a list of 
those products proposed by FDA for Category IIIB. We have not listed 
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.
    FDA has revoked the licenses of all products proposed by FDA for 
Category IIIB. After review of the comments and finding no additional 
scientific evidence to alter the proposed categorization, FDA adopts 
Category IIIB as the final category for the listed products.

[[Page 259]]



                         Table 2.--Category IIIB
------------------------------------------------------------------------
 Manufacturer/
  License No.              Products                    Comments
------------------------------------------------------------------------
Istituto         Diphtheria Toxoid            On July 27, 1993, FDA
 Sieroterapico                                 revoked the license for
 Vaccinogeno                                   Diphtheria Toxoid at the
 Toscano                                       request of the
 Sclavo,                                       manufacturer.
 License No.
 238
------------------------------------------------------------------------
Connaught        Diphtheria Toxoid,           On June 21, 1994, FDA
 Laboratories,    Pertussis Vaccine            revoked the license for
 Inc., License                                 Diphtheria Toxoid and on
 No. 711                                       December 19, 1997, FDA
                                               revoked the license for
                                               Pertussis Vaccine, in
                                               both cases at the request
                                               of the manufacturer.
------------------------------------------------------------------------
Massachusetts    Tetanus Toxoid               On October 11, 1989, FDA
 Public Health                                 revoked the license for
 Biologic                                      Tetanus Toxoid at the
 Laboratories,                                 request of the
 License No. 64                                manufacturer.
------------------------------------------------------------------------
Merck Sharpe &   Cholera Vaccine, Diphtheria  On January 31, 1986, FDA
 Dohme,           and Tetanus Toxoids and      revoked the licenses for
 Division of      Pertussis Vaccine            all the listed products
 Merke & Co.,     Adsorbed, Tetanus and        at the request of the
 Inc., License    Diphtheria Toxoids           manufacturer.
 No. 2            Adsorbed (For Adult Use),
                  Tetanus Toxoid, Typhoid
                  Vaccine
------------------------------------------------------------------------
Michigan         Diphtheria Toxoid Adsorbed   On November 12, 1998, the
 Department of                                 name of the manufacturer
 Public Health,                                was changed to BioPort,
 License No. 99                                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            Diphtheria Toxoid,           On May 19, 1987, FDA
 Laboratories,    Diphtheria Toxoid            revoked the licenses for
 Inc., License    Adsorbed, Pertussis          all listed products at
 No. 3            Vaccine                      the request of the
                                               manufacturer.
------------------------------------------------------------------------

V. Anthrax Vaccine Adsorbed

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\2\.
---------------------------------------------------------------------------

    \2\ 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 and will not further address 
those issues in this final rule.
---------------------------------------------------------------------------

    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. 1) 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 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 has determined that the data do support the 
safety and efficacy of the vaccine and, thus, the agency continues to 
accept the Panel's recommendation and places AVA in Category I.\3\
---------------------------------------------------------------------------

    \3\ 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.
---------------------------------------------------------------------------

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 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

[[Page 260]]

(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, the indication section of the labeling for 
AVA does not specify the route of exposure, and the vaccine is 
indicated for active immunization against Bacillus anthracis, 
independent of the route of exposure.\4\
---------------------------------------------------------------------------

    \4\ 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 were 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 Department of Defense (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 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.\5\
---------------------------------------------------------------------------

    \5\ For example: The Brachman study (Ref. 1); 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. 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. These data were 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 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. 1). The DoD version of the 
anthrax vaccine used in the Brachman study was manufactured using an 
aerobic culture method (Ref. 7). 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

[[Page 261]]

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 labeling of AVA since at least 1978 has described the 
vaccination schedule as three ``primary'' doses followed by three 
``booster'' doses for a total of six doses followed by annual boosters. 
This labeling is not inconsistent with Sec.  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. 8).

VI. 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 in final 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. 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, the agency does not believe that a labeling 
review is necessary at this time. Accordingly, FDA is amending 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 
this final rule. Because FDA regularly monitors the labeling of all 
products on an ad hoc basis, FDA is also explaining in a footnote that 
specification of a date for submission of 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, the agency has completed this review and 
labeling has been revised accordingly. FDA is also taking this 
opportunity to update 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 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 
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. 9) 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. 10). To facilitate electronic reporting, FDA is currently 
revising the reporting form.

[[Page 262]]

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 under the Health Resources and Services 
Administration, Department of Health and Human Services (DHHS), is a 
no-fault alternative to the tort system for resolving claims resulting 
from adverse reactions to routinely recommended childhood vaccines. The 
specific vaccines and injuries covered by NVICP are identified in a 
Vaccine Injury Table that may periodically be revised as new vaccines 
come into use or new types of potential injuries are identified. The 
NVICP has resulted in a reduction in the amount of litigation related 
to injury from childhood vaccines while assuring adequate liability 
coverage and protection. The NVICP applies only to vaccines routinely 
recommended for infants and children. Vaccines recommended for adults 
are not covered unless they are routinely recommended for children as 
well, e.g., Hepatitis B Vaccine.

F. Public Support for Immunization Programs

    The Panel recommended that both FDA and the public support 
widespread immunization programs for tetanus, diphtheria, and 
pertussis.
    The National Immunization Program is part of CDC and was 
established to provide leadership to health agencies in planning and 
implementing immunization programs, to identify unvaccinated 
populations in the United States, to assess vaccination levels in State 
and local areas, and to generally promote immunization programs for 
children, including vaccination against diphtheria, tetanus, and 
pertussis. A recent survey shows that nearly 95 percent of children 19 
to 35 months of age have received 3 or more doses of diphtheria and 
tetanus toxoids (DTs) and the acellular pertussis vaccine (Ref. 11).

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 publication of the December 1985 proposal, the National 
Vaccine Program was created by Congress (Public Law 99-660) with the 
National Vaccine Program Office within DHHS 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, short-term shortages may occur (Ref. 12) for a 
variety of reasons. FDA will continue to work with the National 
Institutes of Health, CDC, and vaccine manufacturers to assure 
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 intends 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.

[[Page 263]]

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 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 1985, FDA agreed that standards should be set. FDA has since 
determined that this approach is overly restrictive and does not allow 
FDA to keep pace with advances in manufacturing and technology. The 
Center for Biologics Evaluation and Research (CBER) 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 non-
dialyzable 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 non-dialyzable 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 
2003. 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 suboptimal 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 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 4 protective units 
per single human dose with the upper estimate of a single human dose 
not to exceed 8 protective units. The Panel also recommended that the 
total immunizing dose be defined as 4 doses of 4 units each, compared 
to the 3 doses of 4 units each defined at the time of the 
recommendation in the regulations.
    FDA has removed the additional standard regulations applicable to 
pertussis vaccine (61 FR 40153, August 1, 1996). 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.

[[Page 264]]

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

T. Development of an Improved Cholera Vaccine

    The Panel recommended public support for development of an improved 
cholera vaccine because unsatisfactory sanitary conditions in many 
countries make it clear that control of the disease by sanitation alone 
cannot be realized in the foreseeable future.
    Cholera is not an endemic disease in the United States. However, 
there is risk to U.S. travelers to certain countries where the disease 
is endemic. 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. The current recommendations of 
the Advisory Committee on Immunization Practices (ACIP) (Ref. 14) are 
consistent with the Panel's recommendation, and the currently licensed 
vaccine is labeled consistent with these recommendations.

VII. 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 in this final rule. 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

[[Page 265]]

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.

VIII. 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 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 proposed 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 found it 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 is amending the regulations to require a minimum 
potency of 250 units of tetanus antitoxin per container for TIG.

IX. Analysis of Impacts

A. Review Under Executive Order 12866, the Regulatory Flexibility Act, 
and the Unfunded Mandates Reform Act of 1995

    FDA has examined the impacts of the final 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 final rule is consistent with the 
regulatory philosophy and principles identified in the Executive order. 
In addition, this final rule is not a significant regulatory action as 
defined by the Executive order and so is not subject to review under 
the Executive order. Because this final rule does not impose new 
requirements on any entity it has no associated compliance costs, and 
the agency certifies that the 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 final 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 final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget under the Paperwork 
Reduction Act of 1995 is not required.

D. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the 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 
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.

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. 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. Lois M. Joellenbeck, 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, 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).

[[Page 266]]

    3. Fellows, P. F., M. K. Linscott, B. E. Ivins, M. L. 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. Irvins, B. E., P. F. Fellows, M. L. M. Pitt, J. E. Estep, S. 
L. Welkos, P. L.Worsham & 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. Irvins, B. E., P. F. Fellows, J. W. Farchaus, B. E. Benner, 
D. M. Waag, S. F. Little, G. W. Anderson, 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. Wright, G. G., et al, ``Studies on Immunity in Anthrax: 
Immunizing Activity of Alum-Precipitated Protective Antigen,'' 
Journal of Immunology, 73:129-391, 1954.
    8. 61 FR 40153, August 1, 1996.
    9. ``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).
    10. Guidance for Industry: How to Complete the Vaccine Adverse 
Reporting System Form (VAERS-1) - 9/8/1998, 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.)
    11. ``Estimated Vaccination Coverage with Individual Vaccines 
and Vaccination Series Among Children 10-35 Months of Age by Race/
Ethnicity--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. (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. ``FDA's Role in Maintaining the Supply of Childhood 
Vaccines--Testimony Before the Committee of Governmental Affairs; 
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).
    13. 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.
    14. Centers for Disease Control and Prevention, ``Prevention of 
Plague: Recommendations of the Advisory Committee on Immunization 
Practices (ACIP),'' Morbidity and Mortality Weekly Report, 45 (No. 
RR-14), 1996.
    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://www.fda.gov/ohrms/dockets/ac/01/transcripts/3805t2--

01.pdf
    17. 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_02.pdf
    18. http://www.fda.gov/ohrms//dockets/ac/02/transcripts/

3842t1.pdf
    19. http://frwebgate.access.gpo.gov/cgi-bin/leaving.cgi?from=leavingFR.html&log=linklog&to=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.

0
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, 21 CFR parts 201 and 610 are amended as follows:

PART 201--LABELING

0
1. The authority citation for 21 CFR part 201 continues to read as 
follows:

    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.

0
2. Amend Sec.  201.59 in the table in paragraph (a)(3) to read as 
follows:
    a. In the BIOLOGICS section of the table, under ``Mail Routing 
Code'' by removing ``HFB-240'' everywhere it appears and adding in its 
place ``HFM-99'';
    b. In the BIOLOGICS section of the table, under the headings 
``Effective'' and ``Revised labeling due'' by revising the entries for 
the drug classes ``Bacterial vaccines and toxoids with standards of 
potency'' and ``Viral and rickettsial vaccines'' to read as follows;
    c. In the NEW DRUG AND ANTIBIOTIC DRUGS section of the table for 
the drug class ``Sulfonylurea blood glucose regulators'', under ``Mail 
routing code,'' by removing ``HFN-130'' and adding in its place ``HFM-
99''.


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
----------------------------------------------------------------------------------------------------------------
July 5, 2006                       See footnote\3\          Bacterial vaccines and toxoids                HFM-99
                                                             with standards of potency
* * * * * * *
Nov. 1, 1982\1\                    Nov. 1, 1980\2\          Viral and rickettsial vaccines                HFM-99
* * * * * * *
----------------------------------------------------------------------------------------------------------------
New Drugs and Antibiotic Drugs
----------------------------------------------------------------------------------------------------------------
* * * * * * *
Oct. 9, 1984                       July 10, 1984            Sulfonylurea blood glucose                    HFM-99
                                                             regulators
* * * * * * *
----------------------------------------------------------------------------------------------------------------
\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

0
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.

0
4. Amend Sec.  610.21 to revise 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.

* * * * *

[[Page 267]]

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

    Dated: December 23, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-32255 Filed 12-30-03; 3:23 pm]

BILLING CODE 4160-01-S
