[Federal Register Volume 70, Number 242 (Monday, December 19, 2005)]
[Rules and Regulations]
[Pages 75018-75028]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-24224]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 610
[Docket No. 1980N-0208]
Biological Products; Bacterial Vaccines and Toxoids;
Implementation of Efficacy Review
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule and final order.
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SUMMARY: The Food and Drug Administration (FDA) proposed to amend the
biologics regulations and proposed to classify the bacterial vaccines
and toxoids on the basis of findings and recommendations of the Panel
on Review of Bacterial Vaccines and Toxoids (the Panel) on December 13,
1985. The Panel reviewed the safety, efficacy, and labeling of
bacterial vaccines and toxoids with standards of potency, bacterial
antitoxins, and immune globulins. After the initial final rule and
final order was vacated by the U.S. District Court for the District of
Columbia on October 27, 2004, FDA published a new proposed rule and
proposed order on December 29, 2004 (69 FR 78281). The purpose of this
final rule and final order is to amend the biologics regulations, issue
a final order in response to the report and recommendations of the
Panel; and, respond to comments on the previously published proposed
rule and proposed order submitted to the Division of Dockets
Management. This final rule and final order does not address Anthrax
Vaccine Adsorbed (AVA). The final order concerning AVA is published
elsewhere in this issue of the Federal Register. FDA is classifying
these products as Category I (safe, effective, and not misbranded),
Category II (unsafe, ineffective, or misbranded), or Category IIIB (off
the market pending completion of studies permitting a determination of
effectiveness).
DATES: This rule is effective December 19, 2006. The final order on
categorization of products is effective immediately.
FOR FURTHER INFORMATION CONTACT: Astrid Szeto, Center for Biologics
Evaluation and Research (HFM-17), Food and Drug Administration, 1401
Rockville Pike, Suite 200N, Rockville, MD 20852-1448, 301-827-6210.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Introduction
II. Background
A. History of the Review
B. Comments on the December 1985 Proposal
III. Categorization of Products--Final Order
IV. FDA's Response to Additional Panel Recommendations
A. Generic Order and Wording of Labeling
B. Periodic Review of Product Labeling
C. Improvement in the Reporting of Adverse Reactions
D. Periodic Review of Product Licenses
E. Compensation for Individuals Suffering Injury From Vaccination
F. Public Support for Immunization Programs
G. Assuring Adequate Supplies of Bacterial Vaccines and Toxoids;
Establishment of a National Vaccine Commission
H. Consistency of Efficacy Protocols
I. The Effect of Regulations Protecting and Informing Human Study
Subjects on the Ability to Conduct Clinical Trials
J. Standards for Determining the Purity of Diphtheria and Tetanus
Toxoids
K. Immunogenic Superiority of Adsorbed Toxoids Over Fluid Toxoids
L. Laboratory Testing Systems for Determining Potency of Tetanus
and Diphtheria Toxoids
M. Potency Testing of Diphtheria and Tetanus Toxoids for Pediatric
Use
N. Potency Requirements for Pertussis Vaccine
O. Weight-Gain Test in Mice for Pertussis Vaccine
P. Agglutination Test to Determine Pertussis Vaccine Response in
Humans
Q. Warnings in Labeling for Pertussis Vaccine
R. Field Testing of Fractionated Pertussis Vaccines
S. Use of Same Seed Lot Strain in Manufacturing Bacillus Calmette-
Guerin (BCG) Vaccine
T. Development of an Improved Cholera Vaccine
U. Plague Vaccine Immunization Schedule
V. FDA's Response to General Research Recommendations
VI. What Comments Did We Receive?
A. FDA's Consideration of Comments on the Panel's Report
B. Biological Products Review Process
C. Plague Vaccine
D. Miscellaneous Comments
VII. Amendment to the Regulations
VIII. Analysis of Impacts
A. Review Under Executive Order 12866, the Regulatory Flexibility
Act, and the Unfunded Mandates Reform Act of 1995
B. Environmental Impact
C. Paperwork Reduction Act of 1995
D. Federalism
IX. References
I. Introduction
On December 13, 1985, FDA proposed to amend the biologics
regulations and proposed to classify the bacterial vaccines and toxoids
on the bases of findings and recommendations of the Panel. The Panel
reviewed the safety, efficacy, and labeling of bacterial vaccines and
toxoids with standards of potency, bacterial antitoxins, and immune
globulins. After reviewing the Panel's report and comments on the
proposal, FDA published a final rule and final order on January 5, 2004
(69 FR 255). On October 27, 2004, the U.S. District Court for the
District of Columbia vacated the January 5, 2004, final rule and final
order. On December 29, 2004, FDA published a withdrawal of the January
5, 2004, final rule and final order. Concurrently with the withdrawal
of the final rule and final order, FDA published again a proposed rule
and proposed order (69 FR 78281) to provide notice and to give
interested persons an opportunity to comment.
The purpose of this document is to: (1) Categorize those bacterial
vaccines
[[Page 75019]]
and toxoids licensed before July 1972 according to the evidence of
their safety and effectiveness, thereby determining whether they may
remain licensed and on the market;\1\ (2) issue a final response to
recommendations made in the Panel's report.\2\ These recommendations
concern conditions relating to active components, labeling, tests
required before release of product lots, product standards, or other
conditions considered by the Panel to be necessary or appropriate for
assuring the safety and effectiveness of the reviewed products; and (3)
revise the standard for potency of Tetanus Immune Globulin in Sec.
610.21 (21 CFR 610.21).
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\1\ The final order concerning AVA is published elsewhere in
this issue of the Federal Register.
\2\ The Panel was convened on July 12, 1973, in an
organizational meeting, followed by multiple working meetings until
February 2, 1979. The Final Report of the Panel was completed in
August 1979.
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II. Background
A. History of the Review
In the Federal Register of February 13, 1973 (38 FR 4319), FDA
issued procedures for the review by independent advisory review panels
of the safety, effectiveness, and labeling of biological products
licensed before July 1, 1972. This process was eventually codified in
Sec. 601.25 (21 CFR 601.25) (38 FR 32048 at 32052, November 20, 1973).
Under the panel assignments published in the Federal Register of June
19, 1974 (39 FR 21176), FDA assigned the biological product review to
one of the following groups: (1) Bacterial vaccines and bacterial
antigens with ``no U.S. standard of potency,'' (2) bacterial vaccines
and toxoids with standards of potency, (3) viral vaccines and
rickettsial vaccines, (4) allergenic extracts, (5) skin test antigens,
and (6) blood and blood derivatives.
Under Sec. 601.25, FDA assigned responsibility for the initial
review of each of the biological product categories to a separate
independent advisory panel consisting of qualified experts to ensure
objectivity of the review and public confidence in the use of these
products. Each panel was charged with preparing an advisory report to
the Commissioner of Food and Drugs which was to: (1) Evaluate the
safety and effectiveness of the biological products for which a license
had been issued, (2) review their labeling, and (3) identify the
biological products that are safe, effective, and not misbranded. Each
advisory panel report was also to include recommendations classifying
the products reviewed into one of three categories.
Category I, designating those biological products
determined by the panel to be safe, effective, and not misbranded.
Category II, designating those biological products
determined by the panel to be unsafe, ineffective, or misbranded.
Category III, designating those biological products
determined by the panel not to fall within either Category I or
Category II on the basis of the panel's conclusion that the available
data were insufficient to classify such biological products, and for
which further testing was therefore required. Category III products
were assigned to one of two subcategories. Category IIIA products were
those that would be permitted to remain on the market pending the
completion of further studies. Category IIIB products were those for
which the panel recommended license revocation on the basis of the
panel's assessment of potential risks and benefits.
In its report, the panel could also include recommendations
concerning any condition relating to active components, labeling, tests
appropriate before release of products, product standards, or other
conditions necessary or appropriate for a biological product's safety
and effectiveness.
In accordance with Sec. 601.25, after reviewing the conclusions
and recommendations of the review panels, FDA would publish in the
Federal Register a proposed order containing: (1) A statement
designating the biological products reviewed into Categories I, II,
IIIA, or IIIB, (2) a description of the testing necessary for Category
IIIA biological products, and (3) the complete panel report. Under the
proposed order, FDA would propose to revoke the licenses of those
products designated into Category II and Category IIIB. After reviewing
public comments, FDA would publish a final order on the matters covered
in the proposed order.
In the Federal Register of November 21, 1980 (45 FR 77134), FDA
issued a notice of availability of the Panel's final report. In the
Federal Register of December 13, 1985 (50 FR 51002), FDA issued a
proposed rule that contained the full Panel report\3\ and FDA's
response to the recommendations of the Panel (the December 1985
proposal). In the December 1985 proposal, FDA proposed regulatory
categories (Category I, Category II, or Category IIIB as defined
previously in this document) for each bacterial vaccine and toxoid
reviewed by the Panel, and responded to other recommendations made by
the Panel. The public was offered 90 days to submit comments in
response to the December 1985 proposal.
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\3\ In addition to publication in the Federal Register of
December 13, 1985 (50 FR 51002), the full Panel report is available
on FDA's Website at http://www.fda.gov/ohrms/dockets/default.htm
(Docket No. 1980N-0208). A copy of the Panel report is also
available at the Division of Dockets Management, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852.
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The definition of Category IIIA as described previously in this
document was applied at the time of the Panel's review and served as
the basis for the Panel's recommendations. In the Federal Register of
October 5, 1982 (47 FR 44062), FDA revised Sec. 601.25, and codified
21 CFR 601.26 which, established procedures to reclassify those
products in Category IIIA into either Category I or Category II based
on available evidence of effectiveness. The Panel recommended that a
number of biological products be placed into Category IIIA. FDA
assigned the review of those products previously classified into
Category IIIA to the Vaccines and Related Biological Products Advisory
Committee. FDA has addressed the review and reclassification of
bacterial vaccines and toxoids classified into Category IIIA through a
separate administrative procedure (see the Federal Register of May 15,
2000 (65 FR 31003), and May 29, 2001 (66 FR 29148)). Therefore, FDA
does not further identify or discuss in this document any bacterial
vaccines and toxoids classified into Category IIIA.
B. Comments on the December 1985 Proposal
FDA received four letters of comments in response to the December
1985 proposal. One letter from a licensed manufacturer of bacterial
vaccine and toxoid products concerned the confidentiality of
information it had submitted for the Panel's review. As provided in
Sec. 601.25(b)(2), FDA considered the extent to which the information
fell within the confidentiality provisions of 18 U.S.C. 1905, 5 U.S.C.
552(b), or 21 U.S.C. 331(j), before placing the information in the
public docket for the December 1985 proposal. Another comment from a
member of the Panel provided an update of important scientific
information related to bacterial vaccines and toxoids that had accrued
since the time of the Panel's review. The letter did not comment on the
December 1985 proposal nor did it contend that the newly available
information should result in modification of the Panel's
recommendations or FDA's proposed actions. FDA's responses to the
comments contained in the remaining two letters follow.
[[Page 75020]]
(Comment 1) One comment from a licensed manufacturer of bacterial
vaccines and toxoids objected to the proposed classification into
Category IIIA of several of its products for use in primary
immunization.
As described previously in this document, FDA has addressed those
products proposed for Category IIIA in a separate rulemaking
process.\4\ This final rule and final order does not take any action
regarding the further classification of those products proposed for
Category IIIA, including those proposed for Category IIIA for primary
immunization. All manufacturers and others in the general public have
been offered additional opportunity to comment on the final
categorization of specific Category IIIA products in the above-noted
process.
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\4\ See the Federal Register of May 15, 2000 (65 FR 31003) and
May 29, 2001 (66 FR 29148), containing the proposed order to
reclassify Category IIIA products into Category I and Category II
based on the review and recommendation of the Vaccines and Related
Biological Products Advisory Committee.
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(Comment 2) In response to FDA's proposal that Pertussis Immune
Globulin (Human) be placed into Category IIIA because of insufficient
evidence of efficacy, one comment stated that FDA should permit
manufacture of Pertussis Immune Globulin (Human) for export only. The
comment noted that medical practices in other countries may differ from
those in the United States and that in some countries Pertussis Immune
Globulin (Human) plays an important role in the augmentation of therapy
with antibiotics in young, very ill infants with pertussis.
Since that time, FDA has revoked all licenses for Pertussis Immune
Globulin (Human) at the requests of the individual manufacturers. The
FDA Export Reform and Enhancement Act of 1996 (Public Law 104-134, as
amended by Public Law 104-180) amended provisions of the Federal Food,
Drug, and Cosmetic Act (the act) pertaining to the export of certain
unapproved products. Section 802 of the act contains requirements for
the export of products not approved in the United States. Under these
provisions, products such as Pertussis Immune Globulin (Human) can be
exported to other countries, if the requirements of section 802 of the
act are met.
(Comment 3) One comment concerned the generic order and wording for
product labeling recommended by the Panel and which FDA proposed to
adopt in its response to the Panel recommendation. The comment
recommended that a labeling section concerning ``Overdose'' be included
only when circumstances dictate. The comment stated that because the
biological products that would be subject to this labeling are
prescription products administered by health care providers, the risk
of overdose should be greatly reduced.
We agree that, in many cases, a labeling section in part 201 (21
CFR part 201) entitled ``Overdosage'' is not necessary. Section
201.56(d)(3) of the labeling regulations provides that the labeling may
omit any section or subsection of the labeling format if clearly
inapplicable. The ``Overdosage'' section, provided for in Sec.
201.57(i) of the regulations, is omitted for many bacterial vaccine and
toxoid products.
(Comment 4) One comment objected to several statements made by the
Panel and provided in the Panel's written report, but did not object to
or comment on FDA's proposed responses to the Panel's recommendations.
The Panel's recommendations represent the scientific opinions of a
panel of experts and are not binding. We believe that the agency should
not modify the statements and recommendations of the Panel as provided
in its report, including through public comment. The purpose of the
opportunity for comment is to allow comment on FDA's responses to the
Panel report and not on the Panel report directly. In reaching our
conclusion, we took into account the Panel report and comments on the
Panel report.
In the December 1985 proposal, FDA provided the opportunity for
comment on FDA's proposals in response to the Panel report. In the
December 29, 2004 (69 FR 78281), proposed rule and proposed order (the
December 2004 proposal), FDA again provided the opportunity for comment
on FDA's proposals. The public was offered 90 days to submit comments
in response to the December 2004 proposal.
In response to the December 2004 proposal, most of the comments
received pertained to AVA. A response to comments about AVA is provided
in a document published elsewhere in this issue of the Federal
Register. A discussion of comments to the December 2004 proposal other
than those pertaining to AVA is provided under section VI of this
document.
III. Categorization of Products--Final Order
Category I. Licensed biological products determined to be safe and
effective and not misbranded. Table 1 of this document is a list of
those products proposed in December 2004 by FDA for Category I. Under
the ``Comments'' column, FDA notes those products for which FDA's
proposed category differs from that recommended by the Panel. Products
for which the licenses were revoked before the December 1985 proposal
and that were identified as such in the December 1985 proposal are not
listed in the tables below. Products for which the licenses were
revoked after the December 1985 proposal are identified in the
``Comments'' column. After review of the comments on the December 1985
and December 2004 proposals, and finding no additional scientific
evidence to alter the proposed categorization, FDA adopts Category I as
the final category for the listed products.
Table 1.--Category I
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Manufacturer/
License No. Products* Comments
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Alpha Therapeutic Tetanus Immune Although the Panel recommended
Corp., License Globulin (Human) that Tetanus Immune Globulin
No. 744 (Human), manufactured by
Alpha Therapeutic Corp., be
placed in Category IIIB, FDA
proposed that it be placed in
Category I. Alpha Therapeutic
Corp. no longer exists. The
new owner is Grifols
Biologicals, Inc. On August
15, 2003, FDA revoked the
license for Tetanus Immune
Globulin (Human)
-------------------
Advance Collagenase ..............................
Biofactures
Corp., License
No. 383
-------------------
[[Page 75021]]
Armour Tetanus Immune The manufacturer's licensed
Pharmaceutical Globulin (Human) name is now ZLB Behring AG.
Co., License No. On July 26, 1999, FDA revoked
149 the license for Tetanus
Immune Globulin (Human) at
the request of the
manufacturer
-------------------
Aventis Pasteur, BCG Vaccine, On February 24, 2000, a name
Ltd., License No. Botulism Antitoxin change to Aventis Pasteur,
1280 (Types A, B, and Ltd. with an accompanying
E), Botulism license number change to 1280
Antitoxin (Type E), was granted. On December 21,
Tetanus Toxoid 2000, FDA revoked the license
for Tetanus Toxoid at the
request of the manufacturer
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Connaught Diphtheria and On December 9, 1999, a name
Laboratories, Tetanus Toxoids and change to Aventis Pasteur,
Inc., License No. Pertussis Vaccine Inc. with an accompanying
711 Adsorbed, and license number change to 1277
Diphtheria was granted to Connaught
Antitoxin Laboratories, Inc. FDA
revoked the licenses for
these products at the request
of the manufacturer on July
6, 2001, and August 2, 2001,
respectively
-------------------
Cutter Plague Vaccine, On October 5, 1994, the
Laboratories, Tetanus Immune manufacturing facilities and
Inc., License No. Globulin (Human) process for Plague Vaccine
8 were transferred to Greer
Laboratories, Inc., License
No. 308. On May 24, 1995, FDA
revoked Cutter's license for
Plague Vaccine at the request
of Cutter, the previous
manufacturer; the license for
Greer Laboratories, Inc.
remains in effect. Bayer
Corp. now holds the license
for Tetanus Immune Globulin
(Human) under License No. 8.
The Bayer Corp. subsidiary
that holds the license for
Tetanus Immune Globulin
(Human) is Talecris
Biopharmaceutics, Inc. under
License No. 1716
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Eli Lilly & Co., Diphtheria and On December 2, 1985, FDA
License No. 56 Tetanus Toxoids and revoked the license for
Pertussis Vaccine Diphtheria and Tetanus
Adsorbed Toxoids and Pertussis Vaccine
Adsorbed at the request of
the manufacturer
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Glaxo BCG Vaccine On July 17, 1990, FDA revoked
Laboratories, the license for BCG Vaccine
Ltd., License No. at the request of the
337 manufacturer
-------------------
Istituto Diphtheria On July 17, 1990, FDA revoked
Sieroterapico Antitoxin, the license for Diphtheria
Vaccinogeno Diphtheria Toxoid Antitoxin at the request of
Toscano Sclavo, Adsorbed, Tetanus the manufacturer. On July 27,
License No. 238 Toxoid Adsorbed 1993, FDA revoked the
licenses for Diphtheria
Toxoid Adsorbed and Tetanus
Toxoid Adsorbed at the
request of the manufacturer
-------------------
Lederle Cholera Vaccine, On December 23, 1992, FDA
Laboratories, Tetanus Immune revoked the license for
Division American Globulin (Human) Tetanus Immune Globulin
Cyanamid Co., (Human) at the request of the
License No. 17 manufacturer. On October 23,
1996, FDA revoked the license
for Cholera Vaccine at the
request of the manufacturer
-------------------
Massachusetts Diphtheria and Although the Panel recommended
Public Health Tetanus Toxoids that Tetanus Antitoxin be
Biologic Adsorbed, placed in Category IIIB, FDA
Laboratories, Diphtheria and proposed in the December 1985
License No. 64 Tetanus Toxoids and proposal that it be placed in
Pertussis Vaccine Category I. On October 26,
Adsorbed, Tetanus 1988, FDA revoked the license
and Diphtheria for Typhoid Vaccine at the
Toxoids Adsorbed request of the manufacturer.
(For Adult Use), On January 10, 1994, FDA
Tetanus Antitoxin, revoked the license for
Tetanus Immune Tetanus Antitoxin at the
Globulin (Human), request of the manufacturer.
Tetanus Toxoid On December 22, 1998, FDA
Adsorbed, Typhoid revoked the license for
Vaccine Diphtheria and Tetanus
Toxoids and Pertussis Vaccine
Adsorbed at the request of
the manufacturer. On August
3, 2000, FDA revoked the
license for Diphtheria and
Tetanus Toxoids Adsorbed at
the request of the
manufacturer. On July 1,
2004, FDA revoked the license
for Tetanus Immune Globulin
(Human) at the request of the
manufacturer. On August 23,
2004, FDA revoked the license
for Tetanus Toxoid Adsorbed
at the request of the
manufacturer
-------------------
Merck Sharp & Tetanus Immune The manufacturer is now known
Dohme, Division Globulin (Human) as Merck & Co., Inc. On
of Merck & Co., January 31, 1986, FDA revoked
Inc., License No. the license for Tetanus
2 Immune Globulin (Human) at
the request of the
manufacturer
-------------------
Michigan Diphtheria and On November 11, 1998, a name
Department of Tetanus Toxoids and change to BioPort Corp.
Public Health, Pertussis Vaccine (BioPort) with an
License No. 99 Adsorbed, Pertussis accompanying license number
Vaccine Adsorbed, change to 1260 was granted.
Typhoid Vaccine* The license for Typhoid
Vaccine was revoked on June
25, 1985, at the request of
the manufacturer. The license
for Diphtheria and Tetanus
Toxoids and Pertussis Vaccine
Adsorbed was revoked at the
request of the manufacturer
(BioPort) on November 20,
2000. The license for
Pertussis Vaccine Adsorbed
was revoked at the request of
the manufacturer (BioPort) on
April 22, 2003
-------------------
[[Page 75022]]
Parke-Davis, Tetanus Immune On November 19, 1983, FDA
Division of Globulin (Human) revoked the license for
Warner-Lambert Tetanus Immune Globulin
Co., License No. (Human) at the request of the
1 manufacturer
-------------------
Swiss Serum and Tetanus Antitoxin Although the Panel recommended
Vaccine Institute that Tetanus Antitoxin be
Berne, License placed in Category IIIB, FDA
No. 21 proposed that it be placed in
Category I. On March 13,
1980, FDA revoked the license
for Tetanus Antitoxin at the
request of the manufacturer
-------------------
Travenol Tetanus Immune The manufacturer is now known
Laboratories, Globulin (Human) as Baxter Healthcare Corp. On
Inc., Hyland July 27, 1995, FDA revoked
Therapeutics the license for Tetanus
Division, License Immune Globulin (Human) at
No. 140 the request of the
manufacturer
-------------------
University of BCG Vaccine On May 29, 1987, FDA revoked
Illinois, License the license for BCG Vaccine
No. 188 at the request of the
manufacturer
-------------------
Wyeth Cholera Vaccine, On December 23, 1992, FDA
Laboratories, Tetanus Immune revoked the license for
Inc., License No. Globulin (Human), Tetanus Immune Globulin
3 Typhoid Vaccine (Human) at the request of the
(acetone manufacturer. On September
inactivated), 11, 2001, FDA revoked the
Typhoid Vaccine licenses for Cholera Vaccine
(heat-phenol and Typhoid Vaccine (both
inactivated) forms) at the request of the
manufacturer
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* The final order for Anthrax Vaccine Adsorbed is published elsewhere in
this issue of the Federal Register.
Category II. Licensed biological products determined to be unsafe
or ineffective or to be misbranded and which should not continue in
interstate commerce. FDA did not propose that any products be placed in
Category II and in this final rule and final order does not categorize
any products in Category II.
Category IIIB. Biological products for which available data are
insufficient to classify their safety and effectiveness and should not
continue in interstate commerce. Table 2 of this document is a list of
those products proposed by FDA for Category IIIB. We have not listed in
this document products for which FDA revoked the licenses before the
December 1985 proposal but we identified them in the December 1985
proposal. Products for which FDA revoked the licenses after the
December 1985 proposal are identified in the ``Comments'' column.
FDA has revoked the licenses of all products proposed by FDA for
Category IIIB. After review of the comments on the December 1985 and
December 2004 proposals, and finding no additional scientific evidence
to alter the proposed categorization, FDA adopts Category IIIB as the
final category for the listed products.
Table 2.--Category IIIB
------------------------------------------------------------------------
Manufacturer/
License No. Products Comments
------------------------------------------------------------------------
Connaught Diphtheria Toxoid, On June 21, 1994, FDA revoked
Laboratories, Pertussis Vaccine the license for Diphtheria
Inc., License No. Toxoid and on December 19,
711 1997, FDA revoked the license
for Pertussis Vaccine, in
both cases at the request of
the manufacturer
-------------------
Istituto Diphtheria Toxoid On July 27, 1993, FDA revoked
Sieroterapico the license for Diphtheria
Vaccinogeno Toxoid at the request of the
Toscano Sclavo, manufacturer
License No. 238
-------------------
Massachusetts Tetanus Toxoid On October 11, 1989, FDA
Public Health revoked the license for
Biologic Tetanus Toxoid at the request
Laboratories, of the manufacturer
License No. 64
-------------------
Merck Sharp & Cholera Vaccine, The manufacturer is now known
Dohme, Division Diphtheria and as Merck & Co., Inc. On
of Merck & Co., Tetanus Toxoids and January 31, 1986, FDA revoked
Inc., License No. Pertussis Vaccine the licenses for all the
2 Adsorbed, Tetanus listed products at the
and Diphtheria request of the manufacturer
Toxoids Adsorbed
(For Adult Use),
Tetanus Toxoid,
Typhoid Vaccine
-------------------
Michigan Diphtheria Toxoid On November 11, 1998, the name
Department of Adsorbed of the manufacturer was
Public Health, changed to BioPort, and the
License No. 99 license number was changed to
1260. On November 20, 2000,
FDA revoked the license for
Diphtheria Toxoid Adsorbed at
the request of the
manufacturer
-------------------
Wyeth Diphtheria Toxoid, On May 19, 1987, FDA revoked
Laboratories, Diphtheria Toxoid the licenses for all listed
Inc., License No. Adsorbed, Pertussis products at the request of
3 Vaccine the manufacturer
------------------------------------------------------------------------
[[Page 75023]]
IV. FDA's Responses to Additional Panel Recommendations
In the December 1985 proposal, FDA responded to the Panel's general
recommendations regarding the products under review and to the
procedures involved in their manufacture and regulation. In this
section of the document, FDA responds in final to the general
recommendations.
A. Generic Order and Wording of Labeling
The Panel recommended changes to the labeling of the biological
products under review. The Panel also recommended a generic order and
wording for information in the labeling of bacterial vaccines. In the
December 1985 proposal, FDA agreed with the labeling changes
recommended by the Panel.
In the December 1985 proposal, FDA proposed that 6 months after
publication of a final rule, manufacturers of products subject to this
Panel review submit, for FDA's review and approval, draft labeling
revised in conformance with the Panel's report and with the
regulations. FDA proposed to require that the revised labeling
accompany all products initially introduced or initially delivered for
introduction into interstate commerce 30 months after the date of
publication of the final rule. The proposed labeling review schedule
was consistent with the scheduling provided in Sec. 201.59 of the
regulations. Although proposed, we are not making this change because
it does not appear to be necessary at this time.
Since the time of the Panel's recommendation, FDA has made a number
of changes to the labeling regulations and related regulatory policies.
FDA has added or revised the requirements in Sec. 201.57 for including
in the labeling, in standardized language, the information concerning
use during pregnancy, pediatric use, and geriatric use. Section 201.57
requires a specific order and content for drug product labeling. A
number of labeling sections included in Sec. 201.57 were not included
in the Panel's recommended ordering and wording of the labeling but are
now required to help ensure clarity in the labeling. FDA has also
provided guidance regarding the wording of sections in which the agency
believes complete and consistent language is important. Because FDA
regularly monitors labeling for the products subject to this Panel
review to determine if the labeling is consistent with applicable
labeling requirements, we do not believe that a labeling review is
necessary at this time.
Section 314 of the National Childhood Vaccine Injury Act (NCVIA) of
1986 required FDA to review the warnings, use instructions, and
precautionary information that are distributed with each vaccine listed
in section 2114 of the Public Health Service Act and to determine
whether this information was adequate to warn health care providers of
the nature and extent of the dangers posed by such vaccine. Since the
December 1985 proposal, FDA has completed this review and labeling has
been revised accordingly.
B. Periodic Review of Product Labeling
In its report, the Panel noted a number of labeling deficiencies.
To improve the labeling, the Panel recommended that labeling be
reviewed and revised as necessary at intervals of no more than every 2
years.
As discussed in the December 1985 proposal and December 2004
proposal, we believe the current system of labeling review will
adequately assure accurate labeling. Periodic review of labeling on a
set schedule is unnecessary. Section 601.12(f) (21 CFR 601.12(f))
prescribes when revised labeling must be submitted, either as a
supplement or, if changes are minor, in an annual report. In addition,
FDA may request revision of labeling when indicated by current
scientific knowledge. We believe that, by these mechanisms, product
labeling is kept up to date, and a scheduled, routine review of
labeling is unnecessary and burdensome for both the agency and
manufacturers.
C. Improvement in the Reporting of Adverse Reactions
The Panel recommended that actions be taken to improve the
reporting and documentation of adverse reactions to biological
products. The Panel particularly noted the need to improve the
surveillance systems to identify adverse reactions to pertussis
vaccine.
Since publication of the Panel's report, the Vaccine Adverse Event
Reporting System (VAERS) was created as an outgrowth of NCVIA and is
administered by FDA and the Centers for Disease Control and Prevention
(CDC). VAERS accepts from health care providers, manufacturers, and the
public, reports of adverse events that may be associated with U.S.-
licensed vaccines. Health care providers must report certain adverse
events included in a Reportable Events Table (Ref. 1) and any event
listed in the vaccine's package insert as a contraindication to
subsequent doses of the vaccine. Health care providers also may report
other clinically significant adverse events. FDA and CDC receive about
1,000 reports each month under the VAERS program. A guidance document
is available which explains how to complete the VAERS form (Ref. 2).
D. Periodic Review of Product Licenses
The Panel recommended that all licensed vaccines be periodically
reviewed to assure that data concerning the safety and effectiveness of
these products are kept current and that licenses be revoked for
products which have not been marketed for years or which have never
been marketed in the licensed form. The Panel noted that, by limiting
the period for which specific vaccines may be licensed, older products
would be assured periodic review, and new products for which additional
efficacy data are required could be provisionally licensed for a
limited time period during which additional data can be generated.
In the December 1985 proposal (50 FR 51002 at 51109), FDA noted
that licensing policies in effect at the time of the review resulted in
licenses being held for some products which were never intended to be
marketed as individual products or which were no longer being marketed
as individual products. FDA had required that manufacturers licensed
for a combination vaccine also hold a license for each individual
vaccine contained in the combination. For example, a manufacturer of
diphtheria and tetanus toxoids and pertussis (DTP) vaccine would also
be required to have separate licenses for Diphtheria Toxoid, Tetanus
Toxoid, and Pertussis Vaccines. Because this policy is no longer in
effect, most licenses are for currently marketed products. In a few
cases, there may be no current demand for a product but, for public
health reasons, a license continues to be held for the product. There
are some vaccines for which there is little current demand but
continued licensure could expedite the manufacture and availability of
the product in the event an outbreak of the targeted disease should
occur. We believe that the routine inspection of licensed facilities
adequately assures that the information held in product licenses is
current and that a routine review of safety and efficacy data is
unnecessary and burdensome. The Panel's recommendation that some new
vaccines be provisionally licensed for only limited periods of time
while additional data are generated is inconsistent with the law that
requires a determination that a biologic product
[[Page 75024]]
is safe, pure, and potent before it is licensed.
E. Compensation for Individuals Suffering Injury From Vaccination
The Panel recommended that compensation from public funds be
provided to individuals suffering injury from vaccinations that were
recommended by competent authorities, carried out with approved
vaccines, and where the injury was not a consequence of defective or
inappropriate manufacture or administration of the vaccines.
A compensation program has been implemented consistent with the
Panel's recommendation. The NCVIA established the National Vaccine
Injury Compensation Program (NVICP) designed to compensate individuals,
or families of individuals, who have been injured by childhood
vaccines, whether administered in the private or public sector. The
NVICP, administered by the Health Resources and Services
Administration, Department of Health and Human Services (HHS), is a no-
fault alternative to the tort system for resolving claims resulting
from adverse reactions to routinely recommended childhood vaccines. The
specific vaccines and injuries covered by NVICP are identified in a
Vaccine Injury Table that may periodically be revised as new vaccines
come into use or new types of potential injuries are identified. The
NVICP has resulted in a reduction in the amount of litigation related
to injury from childhood vaccines while assuring adequate liability
coverage and protection. The NVICP applies only to vaccines routinely
recommended for infants and children. Vaccines recommended for adults
are not covered unless they are routinely recommended for children as
well, e.g., Hepatitis B Vaccine.
F. Public Support for Immunization Programs
The Panel recommended that both FDA and the public support
widespread immunization programs for tetanus, diphtheria, and
pertussis.
The National Immunization Program is part of CDC and was
established to provide leadership to health agencies in planning and
implementing immunization programs, to identify unvaccinated
populations in the United States, to assess vaccination levels in State
and local areas, and to generally promote immunization programs for
children, including vaccination against diphtheria, tetanus, and
pertussis. A recent survey shows that nearly 95 percent of children 19
to 35 months of age have received three or more doses of any vaccine
that contained diphtheria and tetanus toxoids (i.e., diphtheria and
tetanus toxoids and pertussis (DTP), diphtheria and tetanus toxoids and
acellular pertussis (DTaP) or diphtheria and tetanus toxoids vaccines
(DT)) (Ref. 3).
G. Assuring Adequate Supplies of Bacterial Vaccines and Toxoids;
Establishment of a National Vaccine Commission
The Panel recommended that FDA work closely with CDC and other
groups to assure that adequate supplies of vaccines and passive
immunization products continue to be available. The Panel recommended
establishment of a national vaccine commission to address such issues.
Since the publication of the December 1985 proposal, the National
Vaccine Program was created by Congress (Public Law 99-660) with the
National Vaccine Program Office (NVPO) within HHS designated to provide
leadership and coordination among Federal agencies as they work
together to carry out the goals of the National Vaccine Plan. The
National Vaccine Plan provides a framework, including goals,
objectives, and strategies, for pursuing the prevention of infectious
diseases through immunizations. The National Vaccine Program brings
together all of the groups that have key roles in immunizations, and
coordinates the vaccine-related activities, including addressing
adequate production and supply issues. Despite efforts to assure
vaccine availability, shortages may occur (Ref. 4) for a variety of
reasons. FDA will continue to work with the NVPO, the National
Institutes of Health, CDC, and vaccine manufacturers to help facilitate
continued vaccine availability making the establishment of a national
vaccine commission unnecessary.
H. Consistency of Efficacy Protocols
The Panel recommended that the protocols for efficacy studies be
reasonably consistent throughout the industry for any generic product.
To achieve this goal, the Panel recommended the development of industry
guidelines that provide standardized methodology for adducing required
information.
We believe that the standardization of clinical testing methodology
for a group of vaccines is often not practical or useful. Because of
the variety of possible vaccine types, e.g., live vaccines, killed
vaccines, toxoids, bioengineered vaccines, acellular vaccines, and the
diversity of populations in which the vaccine may be studied, it is
difficult to develop guidance that would apply to more than one or two
studies. We routinely meet with manufacturers before the initiation of
clinical studies to discuss the study and will comment on proposed
protocols for efficacy studies. We intend to continue to allow
flexibility in selecting appropriate tests, procedures, and study
populations for a clinical study while assuring that the necessary data
are generated to fulfill the intended objectives of the study.
I. The Effect of Regulations Protecting and Informing Human Study
Subjects on the Ability to Conduct Clinical Trials
The Panel expressed concern that the regulations governing informed
consent and the protection of human subjects involved in clinical
investigations should not establish unnecessary impediments to the goal
of obtaining adequate evidence for the safety and effectiveness of a
product.
We believe that the regulations and policies applying to informed
consent and the protection of human subjects do not inhibit the
adequate clinical study of a product. We note that whenever the
regulations or guidance documents related to these subjects are
modified or amended, FDA offers an opportunity for public comment on
the revisions. We particularly welcome comments on how appropriate
informed consent and protection of human subjects can be maintained
while assuring that the development and study of useful products are
not inhibited.
J. Standards for Determining the Purity of Diphtheria and Tetanus
Toxoids
The Panel recommended that standards should be established for
purity of both diphtheria and tetanus toxoids in terms of limits of
flocculation (Lf) content per milligram (mg) of nitrogen.
In the December 1985 proposal, we agreed that standards should be
set. We have since determined that this approach is overly restrictive
and does not allow FDA to keep pace with advances in manufacturing and
technology. The Center for Biologics Evaluation and Research (CBER)
approves the release specifications for the purity of diphtheria and
tetanus toxoids during the review of a Biologics License Application
(BLA). The purity of diphtheria toxoids in vaccines currently licensed
in the United States is usually at least 1,500 Lf/mg nondialyzable
nitrogen and the purity of tetanus toxoids in vaccines currently
licensed in the United States is usually at least 1,000 Lf/mg of
nondialyzable nitrogen. However, because the purity of tetanus and
diphtheria toxoids in different vaccines is established during
[[Page 75025]]
the BLA review, the purity may vary between products.
K. Immunogenic Superiority of Adsorbed Toxoids Over Fluid Toxoids
The Panel recommended that the immunogenic superiority of the
adsorbed diphtheria and tetanus toxoids over the fluid (plain)
preparations be strongly emphasized in product labeling, especially
with regard to the duration of protection.
Tetanus Toxoid fluid, manufactured by Aventis Pasteur, Inc., is the
only fluid toxoid product that remains licensed in the United States in
2005. This product is licensed for booster use only in persons over 7
years of age. The current package insert for this product states that,
although the rates of seroconversion are essentially equivalent with
either type of tetanus toxoid, the adsorbed toxoids induce more
persistent antitoxin titers than fluid products.
L. Laboratory Testing Systems for Determining Potency of Tetanus and
Diphtheria Toxoids
The Panel noted a need for further studies with tetanus toxoids in
a World Health Organization (WHO) sponsored quantitative potency test
in animals to establish the conditions under which the test results are
reproducible, and to relate these results more closely to those
obtained in the immunization of humans. The Panel also recommended the
development of an animal or laboratory testing system for diphtheria
toxoid that correlates consistently, and with acceptable precision,
with primary immunogenicity in humans.
Diphtheria and tetanus toxoids containing vaccines are tested
during the licensing process for their ability to induce acceptable
levels of protective antibodies in clinical trials in the target
populations. Properties of vaccines used in these clinical trials,
including potency, also are determined during licensing. The acceptance
criteria for commercial lots of these vaccines are set at licensing on
the basis of the properties of the vaccines that induced acceptable
quantitative/qualitative levels of antibodies.
The animal potency tests currently required by WHO, the European
Pharmacopoeia (EP), and FDA differ. Despite these differences, the
potency tests have been adequate to ensure sufficient immunogenic
activity of the vaccines to induce protective immunity in target
populations. However, international efforts to harmonize the diphtheria
and tetanus potency tests under development are based on immunogenicity
in animals. CBER is currently participating in these international
harmonization efforts.
M. Potency Testing of Diphtheria and Tetanus Toxoids for Pediatric Use
The Panel recommended FDA require potency testing after combination
of the individual diphtheria and tetanus toxoid components in
Diphtheria and Tetanus Toxoid vaccines for pediatric use.
We agree with the recommendation. All manufacturers and the FDA
testing laboratory follow this procedure on products submitted to the
agency for release.
N. Potency Requirements for Pertussis Vaccine
The Panel recommended that the regulations concerning the maximum
pertussis vaccine dose should be updated to reflect current
recommendations and practices. At the time of the Panel review, whole
cell pertussis vaccines were in use. Specifically, the Panel
recommended that pertussis vaccine have a potency of four protective
units per single human dose with the upper estimate of a single human
dose not to exceed eight protective units. The Panel also recommended
that the total immunizing dose be defined as four doses of four units
each, compared to the three doses of four units each defined at the
time of the recommendation in the regulations.
We have removed the additional standard regulations applicable to
pertussis vaccine (Ref. 5). As whole cell pertussis vaccines are no
longer licensed for human use in the United States, this recommendation
no longer applies to products available in the United States.
O. Weight-Gain Test in Mice for Pertussis Vaccine
The Panel recommended that the weight-gain test in mice used to
determine toxicity of pertussis vaccines be revised to include a
reference standard and specifications regarding mouse strains to be
used.
At the time of the Panel's deliberations, only DTP vaccines
containing a whole-cell pertussis component were licensed in the United
States. The mouse weight-gain test was a toxicity test used for whole-
cell pertussis vaccines. Whole-cell pertussis vaccines are no longer
licensed in the United States for human use, thus the mouse weight-gain
test is no longer in use. Currently, only DTP vaccines containing an
acellular pertussis component (DTaP) vaccines are licensed in the
United States.
Although not currently licensed in the United States, vaccines
containing a whole-cell pertussis component are still in use in other
countries. CBER continues to participate in international efforts to
improve the tests used to assess toxicity of whole-cell pertussis
vaccines, including the mouse weight-gain test. CBER is represented on
WHO committees and working groups with the goal of improving regulation
and testing of whole-cell pertussis vaccines.
P. Agglutination Test to Determine Pertussis Vaccine Response in Humans
The Panel recommended that the agglutination test used to determine
pertussis vaccine response in humans be standardized and that a
reference serum be used for comparison. It also recommended that a
reference laboratory be available at FDA.
As stated previously in this document, at the time of the Panel's
deliberations, only whole-cell pertussis vaccines were licensed in the
United States. The agglutination test was used for the clinical
evaluation of DTP vaccines. Under the Panel's recommendations, FDA
(CBER) developed and distributed reference materials for the
agglutination assay and served as a reference laboratory. Currently,
only DTaP or DTaP combination vaccines are licensed in the United
States. For the clinical evaluation of DTaP vaccines, the agglutination
test was replaced by antigen-specific immunoassays, specifically
enzyme-linked immunosorbent assays (ELISAs). As had been done with the
agglutination assay, CBER took an active role in standardization of the
ELISAs used to measure the specific antibody to the pertussis
components of DTaP vaccines. Specifically, CBER distributes reference
and control materials for the antigen-specific pertussis ELISA and has
served as a reference laboratory.
Q. Warnings in Labeling for Pertussis Vaccine
The Panel recommended that the pertussis vaccine label warn that if
shock, encephalopathic symptoms, convulsions, or thrombocytopenia
follow a vaccine injection, no additional injections with pertussis
vaccine should be given. The Panel also recommended that the label
include a cautionary statement about fever, excessive screaming, and
somnolence.
We agree with the recommendation except that such information
should be included in product labeling as described in Sec.
201.100(d), i.e., the package insert, rather than the product label.
Labeling applicable to whole-cell
[[Page 75026]]
pertussis vaccines was revised to include much of the information
recommended by the Panel; whole-cell pertussis vaccines are no longer
licensed in the United States. Because the acellular forms of pertussis
vaccine have a different profile of potential adverse events and
contraindications, the product labeling for these products is worded
consistent with available data.
R. Field Testing of Fractionated Pertussis Vaccines
The Panel recommended that any fractionated pertussis vaccine that
differs from the original whole cell vaccine be field tested until
better laboratory methods for evaluating immunogenicity are developed.
The Panel recommended that the field-testing include agglutination
testing and, if possible, evaluation of clinical effectiveness.
The currently approved vaccines containing an acellular pertussis
component were studied in the United States and abroad in human
populations with the antibody response being measured and clinical
effectiveness evaluated.
S. Use of Same Seed Lot Strain in Manufacturing Bacillus Calmette-
Guerin (BCG) Vaccine
The Panel recommended that all BCG vaccines be prepared from the
same seed lot strain with demonstrated efficacy, if available data
justify such action.
BCG vaccines are not recommended for routine immunization in the
United States. The two currently U.S.-licensed BCG vaccines are
produced using different seed strains. Most BCG vaccines produced
globally are manufactured using seed strains with a unique history.
Recent evidence suggests that these different BCG strains do differ
genetically and have slightly varying phenotypes. However, a meta
analysis of the current human BCG vaccination data performed in 1994 by
Harvard University concluded that no strain-to-strain differences in
protection could be detected. Although there have been differences in
immunogencity among strains demonstrated in animal models, no
significant differences have been seen in human clinical trials (Ref.
6). Thus, FDA does not find that available human data justify
requirement of a single BCG vaccine strain.
T. Development of an Improved Cholera Vaccine
The Panel recommended public support for development of an improved
cholera vaccine because unsatisfactory sanitary conditions in many
countries make it clear that control of the disease by sanitation alone
cannot be realized in the foreseeable future.
Cholera is not an endemic disease in the United States. However,
there is risk to U.S. travelers to certain countries where the disease
is endemic. We continue to cooperate with international health agencies
in efforts to evaluate new types of vaccines and to study the
pathogenesis of the disease. CBER personnel have chaired and
participated in the WHO Cholera Vaccine Standardization Committee and
have participated in drafting new WHO guidelines for immune measurement
of protection from cholera.
U. Plague Vaccine Immunization Schedule
The Panel recommended that the following plague vaccine
immunization schedule be considered:
1. A primary series of three intramuscular (IM) injections (1
milliliter (mL), 0.2 mL, and 0.2 mL), 1 and 6 months apart,
respectively;
2. Booster IM injections of 0.2 mL at 12, 18, and 24 months; and
3. For persons achieving a titer of 1:128 after the third and fifth
inoculations, booster doses when the passive agglutination titer falls
below 1:32 and empirically every 2 years when the patient cannot be
tested serologically.
We agree with the recommendation, and the currently licensed
vaccine is labeled consistent with the recommendation. However, this
vaccine is not currently in production or distribution.
V. FDA's Response to General Research Recommendations
In its report, the Panel identified many areas in which there
should be further investigation to improve existing products, develop
new products, develop new testing methodologies, and monitor the
population for its immune status against bacterial disease. In the
December 1985 proposal, we responded to these recommendations in the
responses identified as items 11, 17 (in part), 21, 25, and 27. As
discussed in the December 1985 proposal, we considered the Panel's
recommendations in defining its research priorities at the time the
recommendations were made. Because a considerable amount of time has
elapsed since these recommendations were made and FDA initially
responded to the recommendations, we are not providing specific
responses to each recommendation. As in any area of scientific
research, new discoveries and new concerns require a continual
reevaluation of research priorities and objectives to assure their
relevance to current concerns.
We recognize the Panel's desire to have FDA's research program
evolve with the significant issues and findings of medical science. In
order to assure the continued relevance of its research program, CBER's
research program for vaccines, including bacterial vaccines and related
biological products, is subject to peer review by the Panel's
successor, the Vaccines and Related Biological Products Advisory
Committee (see, for example, the transcripts from the meetings of
February 17, 2005 (Ref. 7), May 6, 2004 (Ref. 8), and May 8, 2003 (Ref.
9). In addition, CBER has defined as part of its strategic plan its
goal of a high quality research program that contributes directly to
its regulatory mission. This goal includes a plan to assure that CBER's
research program continues to support the regulatory review of products
and timely development of regulatory policy, and to have a significant
impact on the evaluation of biological products for safety and
efficacy.
Because of limited resources, we also support the leveraging of
resources to create effective collaborations in the advancement of
science. We have issued a Guidance for FDA Staff: The Leveraging
Handbook, an Agency Resource for Effective Collaborations (Ref. 10).
Through cooperation with international, other Federal, and State health
care agencies and the industry and academia, the agency intends that
its research resources will reap the benefits of a wide range of
experience, expertise, and energy from the greater scientific community
while the agency maintains its legal and regulatory obligations. We
invite comment at any time on ways we may improve our research program
and set our objectives.
VI. What Comments Did We Receive?
We received about 350 comments on the December 2004 proposal. Most
of the comments related to AVA. A response to comments about AVA is
provided in a document published elsewhere in this issue of the Federal
Register. Comments on the December 2004 proposal not relating to AVA
are discussed in this section of this document.
A. FDA's Consideration of Comments on the Panel's Report
(Comment 1) Some comments criticized FDA for stating in the
December 2004 proposal that we were
[[Page 75027]]
not considering comments on the Panel report.
(Response) We wish to clarify our review of comments. We are not
considering comments on the Panel report because the Panel's
recommendations are not binding on the public or FDA. The Panel is
comprised of experts offering scientific opinions for our
consideration. We should not modify the statements and recommendations
of the Panel as provided in their report, including through public
comment. The purpose of the opportunity for public comment allows
comment on FDA's responses to the Panel report and not on the Panel
report directly. We can take action with regard to public comments on
FDA's responses to the Panel report and therefore, we directed comments
to our responses rather than to the report itself.
B. Biological Products Review Process
(Comment 2) One comment submitted by the former Chief Counsel for
FDA during the time that the proposed and final regulations on the
Biological Products Review were issued discussed the historical
development of the Biological Products Review. The commenter did not
comment on the December 2004 proposal nor did he request modification
of FDA's proposed actions.
(Response) We offer no response to this informative general
comment.
C. Plague Vaccine
(Comment 3) One comment noted that the plague vaccine was licensed
and once recommended by the CDC's Advisory Committee on Immunization
Practices, but is no longer produced.
(Response) As mentioned earlier in this document and consistent
with the comment, the plague vaccine remains licensed but is not
currently in production or distribution.
D. Miscellaneous Comments
(Comment 4) Numerous miscellaneous comments on the December 2004
proposal were received. Many of the comments expressed an opinion about
the conduct of vaccination administration programs or activities
associated with the Department of Defense. Other miscellaneous comments
provided links to Internet sites, but did not provide a comment on the
December 2004 proposal. Other submissions to the Docket were electronic
mailings to other parties that copied the Docket.
(Response) These miscellaneous comments noted above are not
relevant or responsive to the December 2004 proposed order and
accordingly, we are not providing any response to them.
VII. Amendment to the Regulations
In the December 1985 proposal and December 2004 proposal, we
proposed to amend Sec. 610.21, limits of potency, by revising the
potency requirements for Tetanus Immune Globulin (Human) (TIG). We
proposed to amend the regulations to require a minimum potency of 250
units of tetanus antitoxin per container for TIG.
The current regulation requires that the minimum potency of TIG
must not be less than 50 units of tetanus antitoxin per mL of fluid.
All currently licensed TIG meets this minimum potency standard, and is
marketed with a labeled potency of 250 units per container. However the
number of units per mL has varied (the current standard provides only a
minimum potency per mL of fluid) and thus, the volume per 250 unit
container has varied. Because the volume of the final products has
varied without any apparent effect on performance of the product, FDA
has determined that it is not appropriate to regulate the potency of
TIG on a per mL basis. We advise that in this discussion and in the
regulation, ``per container'' means that amount of the contents of the
container (vial or syringe) deliverable to the patient in normal use.
FDA believes that TIG should continue to be marketed at a potency of no
less than 250 units per container, which is the dose routinely
recommended for prophylaxis against tetanus. All current manufacturers
of TIG are already conforming to the proposed requirement by labeling
their products with a potency of 250 units per container, while also
complying with the existing regulation. Thus, the FDA believes this
change will better reflect modern labeling practices.
We received no comments opposing the proposed revision to Sec.
610.21 and therefore, we are amending the regulations to require a
minimum potency of 250 units of tetanus antitoxin per container for
TIG.
VIII. Analysis of Impacts
A. Review Under Executive Order 12866, the Regulatory Flexibility Act,
and the Unfunded Mandates Reform Act of 1995
FDA has examined the impacts of this final rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this final rule is not a significant regulatory action under the
Executive order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The agency believes that this final rule is
consistent with the regulatory philosophy and principles identified in
the Executive order. In addition, this final rule is not a significant
regulatory action as defined by the Executive order and so is not
subject to review under the Executive order. Because this final rule
does not impose new requirements on any entity and has no associated
compliance costs, the agency certifies that the final rule will not
have a significant economic impact on a substantial number of small
entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $115 million, using the most current (2003) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
final rule to result in any 1-year expenditure that would meet or
exceed this amount.
B. Environmental Impact
The agency has determined under 21 CFR 25.31(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
C. Paperwork Reduction Act of 1995
This final rule contains no collections of information. Therefore,
clearance by the Office of Management and Budget under the Paperwork
Reduction Act of 1995 is not required.
D. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth
[[Page 75028]]
in Executive Order 13132. FDA has determined that the final rule does
not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the agency has concluded
that the final rule does not contain policies that have federalism
implications as defined in the Executive order and, consequently, a
federalism summary impact statement is not required.
IX. References
The following references have been placed on display in the
Division of Dockets Management (HFA-305), Food and Drug Administration,
5630 Fishers Lane, rm. 1061, Rockville, MD 20852, and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
(FDA has verified the Web site addresses, but we are not responsible
for subsequent changes to the Web sites after this document publishes
in the Federal Register).
1. ``Table of Reportable Events Following Vaccination,'' http://www.vaers.hhs.gov/reportable.htm.
2. ``Guidance for Industry: How to Complete the Vaccine Adverse
Event Reporting System Form (VAERS-1)'', September 1998, http://www.fda.gov/cber/gdlns/vaers-1.pdf.
3. ``Estimated Vaccination Coverage With 3+DTP Among Children
19-35 Months of Age by Race/Ethnicity, and by State and Immunization
Action Plan Area--U.S., National Immunization Survey, Q3/2000-Q2/
2001'', http://www.cdc.gov/nip/coverage/NIS/00-01/tab19-3dpt_race_iap.htm.
4. Protecting Our Kids: What Is Causing the Current Shortage in
Childhood Vaccines?--Testimony Before the Committee on Governmental
Affairs, United States Senate, June 12, 2002, http://www.cdc.gov/nip/news/testimonies/vac-shortages-walt-6-12-2002.htm.
5. 61 FR 40153, August 1, 1996.
6. Colditz, et al., ``Efficacy of BCG Vaccine in the Prevention
of Tuberculosis: Meta Analysis of the Published Literature,''
Journal of the American Medical Association, 271:698-702, 1994.
7. http://www.fda.gov/ohrms/dockets/ac/05/transcripts/2005-4087T2.htm
8. http://www.fda.gov/ohrms/dockets/ac/04/transcripts/4038t1.htm
9. http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3948t1.txt
10. http://www.fda.gov/cber/gdlns/leverhnbk.pdf
List of Subjects
21 CFR Part 610
Biologics, Labeling, Reporting and recordkeeping requirements.
0
Therefore, under the Federal Food, Drug, and Cosmetic Act, the Public
Health Service Act, and under authority delegated to the Commissioner
of Food and Drugs, 21 CFR part 610 is amended as follows:
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
0
1. The authority citation for 21 CFR part 610 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c,
360d, 360h, 360i, 371, 372, 374, 381; 42 U.S.C. 216, 262, 263, 263a,
264.
0
2. Section 610.21 is amended by revising the entry ``Tetanus Immune
Globulin (Human), 50 units of tetanus antitoxin per milliliter'' under
the heading ``ANTIBODIES'' to read as follows:
Sec. 610.21 Limits of potency.
* * * * *
ANTIBODIES
* * * * *
Tetanus Immune Globulin (Human), 250 units of tetanus antitoxin per
container.
* * * * *
Dated: December 12, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-24224 Filed 12-15-05; 8:45 am]
BILLING CODE 4160-01-S