[Federal Register Volume 65, Number 94 (Monday, May 15, 2000)]
[Notices]
[Pages 31003-31010]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-12116]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 00N-1219]


Biological Products; Bacterial Vaccines and Related Biological 
Products; Implementation of Efficacy Review; Proposed Order

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a proposed 
order to accept the conclusions and recommendations of advisory review 
panels concerning the safety, effectiveness, and labeling of certain 
bacterial vaccines and related biological products that were previously 
classified into Category IIIA (remaining on the market pending further 
studies in support of effectiveness). On the basis of the advisory 
review panel findings, FDA is proposing to reclassify the relevant 
Category IIIA products into Category I (safe, effective, and not 
misbranded) or Category II (unsafe, ineffective, or misbranded). This 
action is being taken under the reclassification procedures.

DATES: Submit written comments on this proposed order and the 
reclassification of products should be submitted by August 13, 2000. 
Data and information submitted to FDA in connection with these 
reclassified products will be made publicly available after June 14, 
2000. Comments concerning confidentiality should be received by FDA 
before June 14, 2000.

ADDRESSES: Submit written comments on the proposed order to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 5630 Fishers 
Lane, rm. 1061, Rockville, MD 20852. Comments may also be submitted 
electronically at www.fda.gov/ohrms/dockets. Copies of the reports from 
the Vaccines and Related Biological Products Advisory Committee (April 
1984) and the Panel on Review of Allergenic Extracts (December 1983) 
can be obtained from the Office of Communication, Training and 
Manufacturers Assistance (HFM-40), Center for Biologics Evaluation and 
Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, 
MD 20852-1448. Requests for copies that are accompanied by a self-
addressed adhesive label will assist that office in processing your 
requests. The documents may also be obtained by mail either by calling 
the CBER Voice Information System at 1-800-835-4709 or 301-827-1800 or 
by submitting a request electronically at www.CBER__[email protected], 
or by fax by calling the FAX Information System at 1-888-CBER-FAX or 
301-827-3844.

FOR FURTHER INFORMATION CONTACT: Steven Falter, Center for Biologics 
Evaluation and Research (HFM-17), Food and Drug Administration, 1401 
Rockville Pike, Rockville, MD 20852-1448, 301-827-6343.

SUPPLEMENTARY INFORMATION:

I. Background

A. The Review Procedures (21 CFR 601.25)

    On July 1, 1972, responsibility for regulating biological products 
under section 351 of the Public Health Service Act (PHS Act) (42 U.S.C. 
262) was transferred from the National Institutes of Health to FDA (37 
FR 12865, June 29, 1972). Section 351 of the PHS Act provides statutory 
authority to license biological products. In 1973, FDA established a 
procedure to review the safety, effectiveness, and labeling of all 
biological products licensed prior to July 1, 1972 (38 FR 4319, 
February 13, 1973). This process was eventually codified in Sec. 601.25 
(21 CFR 601.25) (38 FR 32048 at 32052, November 20, 1973). Under 
Sec. 601.25, the Commissioner of Food and Drugs assigned responsibility 
for the initial review of all biological products licensed prior to 
1972 to nine independent advisory review panels. These panels consisted 
of qualified nonFDA experts in order to ensure public confidence in, 
and objectivity of the reviews. Each of the advisory review panels was 
assigned to review a specific category of biological products.
    In the Federal Register of June 19, 1974 (39 FR 21176), FDA 
eliminated three previously planned panels (The Panel on Review of In 
Vitro Diagnostic Reagents; The Panel on Review of Immune Serums, 
Antitoxins, and Antivenins; and the Panel on Review of Miscellaneous 
Biological Products) and reassigned the review of the biological 
products originally intended for review by these three panels to the 
remaining six advisory review panels: The Panel on Review of Bacterial 
Vaccines and Toxoids with Standards of Potency, The Panel on Review of 
Bacterial Vaccines and Bacterial Antigens with ``no U.S. Standards of 
Potency,'' the Panel on Review of Skin Test Antigens, The Panel on 
Review of Allergenic Extracts, The Panel on Review of Viral and 
Rickettsial Vaccines, and the Panel on Review of Blood and Blood 
Derivatives. The advisory review panels for bacterial vaccines and 
bacterial antigens with ``no U.S. standard of potency,'' bacterial 
vaccines and toxoids with standards of potency, and skin test antigens 
reviewed the products that are the subject of this notice.
    Under the review and classification procedures specified in 
Sec. 601.25, each advisory review panel was charged with preparing a 
report to the agency that: (1) Evaluated the safety and effectiveness 
of the biological product; (2) reviewed the labeling of the biological 
product; and (3) advised FDA on which biological products under review 
were safe, effective, and not misbranded. Each advisory review panel 
report was to include a statement classifying the products into 
Category I, Category II, or Category III. Category I designated those 
biological products determined to be safe, effective, and not 
misbranded. Category II designated those biological products determined 
to be unsafe, ineffective or misbranded. Category III designated those 
biological products that did not fall within either Category I or 
Category II because of insufficient data 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 report 
recommended license revocation on the basis of the panel's assessment 
of potential risks and benefits.
    After reviewing the conclusions and recommendations of the 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 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.

[[Page 31004]]

B. Section 601.25 and Products Subject to This Proposed Order

1. The Panels on Review of Skin Test Antigens and Bacterial Vaccines 
and Bacterial Antigens with ``No U.S. Standard of Potency''
    In the Federal Registers of September 30, 1977 (42 FR 52674), and 
November 8, 1977 (42 FR 58266), FDA published proposals for the 
implementation of the efficacy reviews for skin test antigens and 
bacterial vaccines and antigens with ``no U.S. standard of potency,'' 
respectively. These proposals were in response to the reports of The 
Panel on Review of Skin Test Antigens, and the Panel on Review of 
Bacterial Vaccines and Antigens with ``no U.S. standard of potency,'' 
and contained each Panel's findings and recommendations to designate 
each of the products reviewed into Categories I, II, IIIA or IIIB. In 
these proposed orders, FDA agreed with each Panel's findings and 
recommendations, and in accordance with Secs. 601.5(b) (21 CFR 
601.5(b)) and 601.25(f)(3), notified manufacturers of those products 
identified for classification into Category II or Category IIIB of the 
agency's intent to publish a notice of an opportunity for hearing to 
revoke the licenses for these products. Additionally, in accordance 
with Sec. 601.25(f)(3), FDA proposed that those products identified for 
classification into Category IIIA remain on the market and that their 
licenses remain in effect on an interim basis pending completion of 
scientifically sound studies to demonstrate efficacy in humans. In the 
Federal Registers of October 28, 1977 (42 FR 56800), and December 9, 
1977 (42 FR 62162), under 21 CFR 12.21(b), FDA published notices of 
opportunity to request hearings, submit additional data, and comment on 
the proposed revocation of licenses for certain skin test antigens and 
bacterial vaccines and antigens with ``no U.S. standard of potency,'' 
respectively. Through these FR notices, manufacturers of skin test 
antigens and bacterial vaccines and antigens with ``no U.S. standard of 
potency'' previously identified for classification into Category II or 
Category IIIB were offered an opportunity for a hearing on the proposed 
revocation of existing licenses for products placed in Category II or 
IIIB.
    The manufacturers of skin test antigens and bacterial vaccines and 
antigens with ``no U.S. standard of potency,'' whose products were 
identified as Category II or Category IIIB either: (1) Did not request 
a hearing, (2) requested a hearing but submitted no data, (3) requested 
a hearing and submitted additional data that justified reclassification 
of products without the need for the requested hearing, or (4) 
requested that their product licenses be revoked. Therefore, FDA 
published in the Federal Register of October 27, 1978 (43 FR 50247), a 
notice reclassifying one bacterial vaccine with ``no U.S. standard of 
potency'' from Category IIIB into Category IIIA, and revoking the 
product licenses for the remaining bacterial vaccines and bacterial 
antigens with ``no U.S. standard of potency'' classified in Category II 
or Category IIIB. In the Federal Register of October 27, 1978, FDA also 
published a notice reclassifying certain skin test antigens from 
Category IIIB into Category IIIA, and revoking the product licenses for 
the remaining skin test antigens classified as Category IIIB (43 FR 
50250).
2. The Panel on Review of Bacterial Vaccines and Toxoids with Standards 
of Potency
    In the Federal Register of December 13, 1985 (50 FR 51002), FDA 
published a proposed rule containing the implementation of the efficacy 
review for bacterial vaccines and toxoids with standards of potency 
(hereinafter referred to as the December 1985 proposal). The December 
1985 proposal was in response to the report of The Panel on Review of 
Bacterial Vaccines and Toxoids with Standards of Potency, and contained 
the Panel's findings and recommendations to designate each of the 
products reviewed into Categories I, II, IIIA or IIIB. In the December 
1985 proposal, FDA: (1) Disagreed with the Panel's findings and 
recommendations to classify some products as Category IIIB, and 
reclassified these products into Category I, (2) agreed with the 
Panel's recommendations to classify the remaining products into 
Category II or Category IIIB, and (3) provided notice that licenses for 
several products recommended by the Panel for classification into 
Category IIIB and the license for the single product recommended for 
classification into Category II were voluntarily revoked at the request 
of the manufacturers prior to publication of the proposed order.
    Subsequent to the Panel's review but prior to the publication of 
the December 1985 proposal, the regulations were revised and 
reclassification review procedures were established under Sec. 601.26 
(21 CFR 601.26) (47 FR 44062 at 44071, October 5, 1982). Therefore, the 
classification process for bacterial vaccines and toxoids with 
standards of potency will be completed in accordance with Sec. 601.26 
as described below.

II. Reclassification Procedures (Section 601.26)

A. The Reclassification Process

    In 1982, FDA issued a regulation that established procedures to 
reclassify those products in Category IIIA into either Category I or 
Category II (47 FR 44062, October 5, 1982). This regulation was 
codified in Sec. 601.26. According to Sec. 601.26, Category IIIA 
products that would be reclassified included: (1) Products that an 
advisory panel had recommended be assigned to Category IIIA, (2) 
products that FDA had proposed to place in Category IIIA, or (3) 
products for which FDA had issued a final order reclassifying the 
products into Category IIIA. Under Sec. 601.26, advisory review panels 
would review all Category IIIA products and make recommendations 
concerning each product's reclassification. During the advisory panel 
reclassification review process, interested persons were permitted to 
attend meetings, appear before the advisory review panels, and submit 
data to the panels for review. The advisory review panels would then 
submit a report to FDA that recommended the reclassification of each 
Category IIIA product into either Category I or II. After reviewing the 
conclusions and recommendations of the advisory panels, FDA would 
publish in the Federal Register a proposed order containing the 
following: (1) A statement designating the products as Category I or 
Category II, (2) a notice of availability of the full panel report, (3) 
a proposal to accept or reject the findings of the advisory review 
panels, and (4) a statement identifying those products that FDA 
proposes should be permitted to remain on the market because of a 
compelling medical need and no suitable alternative exists as described 
in Sec. 601.26(d)(4).

B. Section 601.26 and the Products Subject to this Proposed Order

    FDA assigned the reclassification review of bacterial vaccines and 
related biological products previously classified into Category IIIA by 
FDA based on the recommendations of the Panel on Review of Bacterial 
Vaccines and Antigens with ``no U.S. Standard of Potency'' and the 
Panel on Review of Skin Test Antigens to the Vaccines and Related 
Biological Products Advisory Committee (VRBPAC). FDA also assigned the 
reclassification review of vaccines and related biological products 
previously recommended for classification into Category IIIA by the 
Panel on Review of Bacterial Vaccines and Toxoids with Standards of 
Potency to the VRBPAC. In accordance with the

[[Page 31005]]

procedures specified above, FDA is notifying the public through this 
Federal Register notice of the agency's proposed reclassification of 
the Category IIIA products reviewed by the VRBPAC.
    This proposed order contains notice of FDA's intent to revoke the 
licenses of certain vaccines and related biological products, listed 
below, that FDA proposes, based on VRBPAC recommendations, to 
reclassify from Category IIIA to Category II. The public may submit 
comments to FDA concerning this proposed order. After the end of the 
comment period, if FDA determines to go forward with the license 
revocation proceedings, the agency will publish a notice of opportunity 
for hearing (NOOH) on the revocation of the license of each product in 
Category II. After reviewing the comments on the proposed order, FDA 
will issue a final order on the matters covered in the proposed order. 
Depending upon whether a manufacturer requests a hearing on the 
revocation of its biologics license, FDA may consolidate the final 
order with license revocations.

III. Identification of Category IIIA Products Subject to 
Reclassification

A. Review and Reclassification Procedures, Bacterial Vaccines and 
Toxoids With Standards of Potency. (Bacterial Vaccines and Toxoids with 
Standards of Potency, Antitoxins, and Immune Globulins)

    In the December 1985 proposal, FDA identified those products that 
were originally recommended for classification into Category IIIA and 
that were now subject to review by the VRBPAC under Sec. 601.26.
    Several bacterial vaccines and toxoids with standards of potency 
were classified into two categories based upon their use as a primary 
immunogen or as a booster. For example, a vaccine product could be 
assigned a Category IIIA designation for use as a primary immunogen but 
could be designated as Category I for booster use. The classifications 
were different because the potency tests for diphtheria and tetanus 
toxoids were found suitable for determining the acceptability of the 
toxoids for booster use, but not for determining the acceptability of 
the toxoids for use in primary immunization. Products listed in Table 1 
were those recommended by the Panel on Review of Bacterial Vaccines and 
Toxoids With Standards of Potency for classification into Category I 
when used for booster immunization, and classification into Category 
IIIA when used for primary immunization. In addition, two immune 
globulins were recommended by the Panel for classification into 
Category IIIA (Table 2).

 Table 1.--Bacterial Vaccines and Toxoids Recommended for Classification in Category I for Booster Immunization
    and Category IIIA for Primary Immunization by the Panel on Review of Bacterial Vaccines and Toxoids with
                                              Standards of Potency
----------------------------------------------------------------------------------------------------------------
              Manufacturer/License Number                                       Product(s)
----------------------------------------------------------------------------------------------------------------
Istituto Sieroterapico Vaccinogeno Toscano (Sclavo),     Tetanus Toxoid
 No. 238
Lederle Laboratories, Division, American Cyanamid Co.,   Diphtheria and Tetanus Toxoids Adsorbed
 No 17                                                   Diphtheria and Tetanus Toxoids and Pertussis Vaccine
                                                          Adsorbed
                                                         Tetanus and Diphtheria Toxoids Adsorbed (Adult Use)
                                                         Tetanus Toxoid
                                                         Tetanus Toxoid Adsorbed
Merck Sharp & Dohme, Division of Merck & Co., Inc., No.  Tetanus Toxoid Adsorbed
 2
Connaught Laboratories, Inc., No. 711.                   Tetanus and Diphtheria Toxoids Adsorbed (Adult Use)
                                                         Tetanus Toxoid
                                                         Tetanus Toxoid Adsorbed
Michigan Department of Public Health, No. 99             Diphtheria and Tetanus Toxoids Adsorbed
                                                         Tetanus Toxoid Adsorbed
Swiss Serum and Vaccine Institute Berne, No. 21          Tetanus Toxoid Adsorbed
Wyeth Laboratories, Inc., No. 3                          Diphtheria and Tetanus Toxoids Adsorbed
                                                         Diphtheria and Tetanus Toxoids and Pertussis Vaccine
                                                          Adsorbed
                                                         Tetanus and Diphtheria Toxoids Adsorbed (Adult Use)
                                                         Tetanus Toxoid
                                                         Tetanus Toxoid Adsorbed
----------------------------------------------------------------------------------------------------------------


Table 2.--Immune Globulins Recommended for Classification in Category IIIA for Passive Immunization by the Panel
                      on Review of Bacterial Vaccines and Toxoids with Standards of Potency
----------------------------------------------------------------------------------------------------------------
              Manufacturer/License Number                                       Product(s)
----------------------------------------------------------------------------------------------------------------
Hollister-Stier, a Division of Cutter Laboratories, No.  Pertussis Immune Globulin (Human)
 8
Travenol Laboratories Inc.,                              Pertussis Immune Globulin (Human)
Hyland Therapeutics Division, No. 140
----------------------------------------------------------------------------------------------------------------

B. Review and Reclassification Procedures, Bacterial Vaccines and 
Bacterial Antigens with ``No U.S. Standard of Potency''

    In the Federal Register of January 5, 1979 (44 FR 1544), FDA issued 
a final rule classifying Bacterial Vaccines and Bacterial Antigens with 
``no U.S. standard of potency'' based on the review and recommendation 
of the Panel on Review of Bacterial Vaccines and Bacterial Antigens 
with ``no U.S. Standard of Potency.'' In the January 1979 final rule, 
FDA classified the products listed in Table 3 into Category IIIA.

[[Page 31006]]



                 Table 3.--Bacterial Vaccines and Bacterial Antigens with ``No U.S. Standard of Potency'' Classified into Category IIIA
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                    Manufacturer/License Number                                                           Product(s)
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Eli Lilly and Co., No. 56                                            Respiratory UBA (UBA-32) \1\
Hollister-Stier, a Division of Cutter Laboratories, No. 8            Bacterial Vaccines Mixed Respiratory (MRV or MRVI; licensed as Polyvalent
                                                                     Bacterial Vaccines with No U.S. Standard of Potency)
                                                                     Bacterial Vaccines for Treatment, Special Mixtures containing only the
                                                                     following organisms--Staphylococcus (aureusand albus),
                                                                     Streptococcus (viridans and nonhemolytic), Di plococcus
                                                                     pneumoniae, Neisseria catarrhalis, Klebsiella pneumoniae,
                                                                     Haemophilus influenzae (licensed as Polyvalent Bacterial Vaccines with
                                                                     No U.S. Standard of Potency)
Sclavo Istituto Sieroteraico Vaccinogeno Toscano (Sclavo), No. 238   Staphylococcus Toxoid \2\
Lederle Laboratories Division, No. 17                                Staphylococcus Toxoid; Formalinized: Dilution No. 1, Dilution No. 2; Digest-
                                                                      Modified \3\
Delmont Laboratories, Inc., No. 299                                  Polyvalent Bacterial Antigens with ``No U.S. Standard of Potency'' Staphage Lysate
                                                                      (SPL) Types I and III \4\
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\1\ Respiratory UBA, Lilly, was not reviewed by the Reclassification Committee. However, the license to manufacture this product was revoked at the
  request of the manufacturer on December 2, 1985. Therefore, no further regulatory action was required.
\2\ The license for Staphylococcus Toxoid, Sclavo, was revoked on May 9, 1979, at the request of the manufacturer and was not, therefore, subject to
  reclassification.
\3\ The licenses for Staphylococcus Toxoid, Lederle Laboratories, were revoked on April 3, 1979, and May 21, 1980, at the request of the manufacturer
  and were not, therefore, subject to reclassification.
\4\ This product was originally placed in Category IIIB. However, additional data submitted by the firm were found to be adequate to reclassify the
  product from Category IIIB to IIIA (43 FR 50247, October 27, 1978).

C. Review and Reclassification Procedures, Skin Test Antigens

    In the Federal Register of July 10, 1979 (44 FR 40284), FDA issued 
a final rule classifying skin test antigens into category IIIA based on 
the review and recommendations of the Panel on Review of Skin Test 
Antigens (hereinafter referred to as the July 1979 final rule. The July 
1979 final rule placed the products listed in Table 4 into Category 
IIIA.

                                               Table 4.--Skin Test Antigens Classified into Category IIIA
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                    Manufacturer/License Number                                                            Product
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Michigan Department of Public Health, No. 99                         Histoplasmin \1\
Hollistier-Stier, a Division of Cutter Laboratories, No. 8           Coccidioidin \2\
Iatric Corp., No. 416                                                Coccidioidin \3\
Massachusetts Public Health Biologic Laboratories, No. 64            Diphtheria Toxin for Schick Test \4\
Eli Lilly & Co., No. 56                                              Mumps Skin Test Antigen
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\1\ The license for Histoplasmin, Michigan Department of Public Health was revoked at the request of the manufacturer on July 30, 1979. Therefore, the
  product was not subject to reclassification.
\2\ The license for Coccidiodin, Hollistier-Stier, was revoked at the request of the manufacturer on November 1, 1979. Therefore, the product was not
  subject to reclassification.
\3\ Coccidiodin, Iatric, was not reviewed by the Reclassification Panel. However, the license for Coccidiodin was revoked on June 25, 1997, at the
  request of the manufacturer. Therefore no further regulatory action on this product is required.
\4\ Diphtheria Toxin for Schick Test manufactured by Massachusetts Public Health Biologic Laboratories was reclassified from Category IIIA into Category
  I by FDA in a Federal Register publication of October 16, 1981 (46 FR 51036). This action was based on the manufacturer's completion of studies and
  submission of data to FDA supporting the effectiveness of the product. Accordingly, the product was not subject to reclassification.

IV. Proposed Reclassification of Category IIIA Products

    In the December 1985 proposal, FDA assigned the VRBPAC, as an 
advisory review panel, to review all bacterial vaccines and related 
biological products previously classified into Category IIIA or 
recommended for classification into Category IIIA, and to reclassify 
such products into either Category I (safe, effective, and not 
misbranded) or Category II (unsafe, ineffective, or misbranded).
    The VRBPAC reviewed bacterial vaccines and related biological 
products in Category IIIA, including those products in Category IIIA 
for a particular use and in Category I for another use. For example, 
the Committee reviewed the use of vaccines for primary immunization, 
but did not review their use for booster immunization in cases where 
they were classified in Category IIIA and Category I, respectively. The 
VRBPAC reviewed all Category IIIA products, that FDA assigned to it, 
for effectiveness only; all such products were previously found to be 
safe.
    The VRBPAC held reclassification meetings on January 20 and 21, 
1983, June 9 and 10, 1983, and September 19, 1983, and submitted a 
final report, dated April 1984, to FDA.
    The VRBPAC's recommendations for product classifications and FDA's 
responses to the recommendations are discussed below.

A. Category I. (Biological Products Determined to be Safe and Effective 
and Not Misbranded)

    Products recommended by the VRBPAC for classification into Category 
I for both primary and booster immunization are listed in Table 5.

[[Page 31007]]



     Table 5.--Products Recommended by the VRBPAC for Category I Classification for both Primary and Booster
                                                  Immunization
----------------------------------------------------------------------------------------------------------------
              Manufacturer/License Number                                       Product(s)
----------------------------------------------------------------------------------------------------------------
Aventis Pasteur, Inc., No. 1277                          Tetanus and Diphtheria Toxoids Adsorbed (Adult Use)
                                                         Tetanus Toxoid Adsorbed\1\
Lederle Laboratories Division, American Cyanamid Co.,    Diphtheria and Tetanus Toxoids Adsorbed
 No. 17                                                  Diphtheria and Tetanus Toxoids and Pertussis Vaccine
                                                          Adsorbed
                                                         Tetanus and Diphtheria Toxoids Adsorbed (Adult Use)
                                                          Tetanus Toxoid
                                                         Tetanus Toxoid Adsorbed
Wyeth Laboratories, Inc., No. 3                          Diphtheria and Tetanus Toxoids and Pertussis Vaccine
                                                          Adsorbed
                                                         Tetanus Toxoid Adsorbed
----------------------------------------------------------------------------------------------------------------
\1\ The licenses for these products were transferred from Connaught Laboratories, Inc., No. 711, to Aventis
  Pasteur Inc., No. 1277 on December 9, 1999.

    After reviewing previously submitted data and additionally 
submitted data for the products listed in Table 5, the VRBPAC concluded 
that these products are effective for primary immunization and for 
booster immunization. The Committee recommended that these products be 
classified as Category I.
    FDA agrees with the VRBPAC's conclusions and recommendations 
concerning the Category I classifications of the products listed in 
Table 5. FDA therefore proposes to designate these products as safe, 
effective, and not misbranded, and to accept the VRBPAC's findings.
    In its final report to FDA, the VRBPAC recommended that three 
products be classified into Category II for primary immunization, and 
Category I for booster immunization. This recommendation was based on 
the fact that the manufacturers of these products did not submit data 
demonstrating the efficacy of the products for use in primary 
immunization. However, subsequent to the completion of the VRBPAC's 
review and submission of the final report to FDA, additional data were 
submitted to the agency in support of the efficacy of the use of these 
products for primary immunization. Therefore, FDA proposes to 
reclassify these products as safe, effective, and not misbranded for 
both primary and booster immunization. These products are listed in 
Table 6 followed by a detailed discussion.

    Table 6.--Products Recommended by the VRBPAC for Category II Classification for Primary Immunization and
Category I for Booster Immunization, which FDA Proposes to Classify into Category I for Both Primary and Booster
                                                  Immunization
----------------------------------------------------------------------------------------------------------------
              Manufacturer/License Number                                       Product(s)
----------------------------------------------------------------------------------------------------------------
Wyeth Laboratories, Inc., No. 3                          Tetanus Toxoid
                                                         Diphtheria and Tetanus Toxoids Absorbed
Swiss Serum and Vaccine Institute Berne, No. 21          Tetanus Toxoid Adsorbed
----------------------------------------------------------------------------------------------------------------

    The VRBPAC in its initial reclassification report placed Tetanus 
Toxoid and Diphtheria and Tetanus Toxoids Adsorbed, manufactured by 
Wyeth Laboratories, Inc. (Wyeth), in Category II for primary 
immunization because no additional data had been submitted. However, on 
April 4, 1986, Wyeth submitted clinical study reports to FDA regarding 
the use of both Tetanus Toxoid and Diphtheria and Tetanus Toxoids 
Adsorbed for primary immunization. These data were reviewed by FDA and 
medical consultants from the VRBPAC. Both FDA and the VRBPAC 
consultants agreed that the clinical study data submitted by Wyeth 
supported reclassification of Wyeth's Tetanus Toxoid and Diphtheria and 
Tetanus Toxoids Adsorbed into Category I for both primary and booster 
immunization. Therefore, FDA proposes to designate these products as 
safe, effective, and not misbranded.
    The VRBPAC in its initial reclassification report also placed 
Tetanus Toxoid Adsorbed, manufactured by Swiss Serum and Vaccine 
Institute Berne in Category II because no efficacy data had been 
submitted. However, on June 18, 1991, FDA approved a license supplement 
from Swiss Serum and Vaccine Institute Berne to update the firm's 
product license application for Tetanus Toxoid Adsorbed. The supplement 
included serologic data in support of primary immunization.

B. Category I for Booster Immunization and Category II for Primary 
Immunization. (Biological Products Determined to be Safe and Effective 
and Not Misbranded When Indicated for Booster Use Only)

    Products recommended by the VRBPAC for classification in Category I 
for booster immunization and Category II for primary immunization are 
listed in Table 7.

     Table 7.--Products Recommended by the VRBPAC for Classification in Category I for Booster Immunization and Category II for Primary Immunization
--------------------------------------------------------------------------------------------------------------------------------------------------------
                    Manufacturer/License Number                                                           Product(s)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Aventis Pasteur, Inc., No. 1277                                      Tetanus Toxoid \1\
Merck Sharp & Dohme, Division of Merck & Co., No. 2                  Tetanus Toxoid Adsorbed \2\
BioPort Corp., No. 1260                                              Diphtheria and Tetanus Toxoids Adsorbed \3\
                                                                     Tetanus Toxoid Adsorbed
Istituto Sieroterapico Vaccinogeno Toscano (Sclavo), No. 238         Tetanus Toxoid \4\

[[Page 31008]]

 
Wyeth Laboratories, Inc., No. 3                                      Tetanus and Diphtheria Toxoids Adsorbed (Adult Use)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ The license for this product was transferred from Connaught Laboratories, Inc., No. 711, to Aventis Pasteur, Inc., No. 1277 on December 9, 1999.
\2\ The license for Tetanus Toxoid Adsorbed, Merck, was revoked at the request of the manufacturer on January 31, 1986. Therefore, no further regulatory
  action on this product was required.
\3\ The licenses for these products were transferred from Michigan Department of Public Health, No. 99, to BioPort Corp., License No. 1260 on November
  12, 1998.
\4\ The license for Tetanus Toxoid Vaccine, Sclavo, was revoked at the request of the manufacturer on July 27, 1993. Therefore, no further regulatory
  action on this product was required.

    After reviewing available data, the VRBPAC recommended that the 
products in Table 7 be reclassified from Category IIIA to Category II 
for primary immunization until additional information to support 
effectiveness becomes available. For each of these products, either no 
additional information was submitted by the manufacturer or the VRBPAC 
found the additional information submitted was inadequate to support 
the effectiveness of the vaccine for primary immunization (Final 
Report: Addendum to Previous Panel Reports for the Reclassification of 
Category IIIA Biologics, April 1984).
    FDA agrees with the VRBPAC's conclusions and recommendations 
concerning the Category II classification for primary immunization. FDA 
therefore proposes to designate these products as ineffective and 
misbranded for primary immunization and accept the VRPBAC's findings. 
If FDA classifies these products, under a final order, as Category II 
for primary immunization, it will be necessary for the agency to remove 
the primary immunization use from the license for each product. FDA can 
accomplish this if a manufacturer submits a supplement to its license 
that deletes the primary immunization use while maintaining the booster 
immunization use in the license. In order to change the license of each 
product in a timely manner given the required procedures of this 
Sec. 601.26 reclassification process, FDA recommends that a 
manufacturer submit a license supplement to the agency prior to FDA 
publishing an NOOH on the proposed revocation of the products in 
Category II, which could publish as early as 30 days after the close of 
the comment period of this proposed order. If a manufacturer does not 
wish to remove the primary immunization use from its license at this 
time, FDA will publish an NOOH on the revocation of that use from the 
license after the comment period ends. In this proposed order FDA 
hereby offers notice of its intent to revoke the primary immunization 
use from the licenses of those products that have been classified as 
Category II for that use.
    Furthermore, if a manufacturer wishes to market its product, listed 
in Table 7 above, for booster immunization after FDA issues a final 
order that classifies the product in Category II for primary 
immunization, the manufacturer must change its product labeling to 
reflect only the approved booster immunization use. Therefore, FDA is 
proposing that the container and package labels and the package insert 
include the statement ``For Booster Use Only''. This statement should 
be placed immediately following the proper name of the product and in 
the same size type print as the proper name. Also, any labeling 
references for use as a primary immunogen should be deleted. To make 
such a labeling revision, a manufacturer should submit a Changes Being 
Effected (CBE) supplement to their license in accordance with 21 CFR 
601.12(c)(5) and (f)(2). FDA suggests that a manufacturer submit its 
labeling supplement in a timely manner so that the manufacturer may be 
able to market its product with appropriate labeling after a final 
order classifying the product in Category II for primary immunization.

C. Category II. (Biological Products Determined to be Unsafe, 
Ineffective or Misbranded)

    The VRBPAC and the Panel on Review of Allergenic Extracts 
recommended that the following products listed in Table 8 be 
reclassified into Category II.

   Table 8.--Products Recommended by the VRBPAC and The Panel on Review of Allergenic Extracts for Category II
                                                 Classification
----------------------------------------------------------------------------------------------------------------
              Manufacturer/License Number                                       Product(s)
----------------------------------------------------------------------------------------------------------------
Hollister-Stier Laboratories LLC, No. 1272               Polyvalent Bacterial Vaccines with ``No U.S. Standard
                                                          of Potency''
                                                         (Bacterial Vaccines Mixed Respiratory (MRV or MRVI,
                                                          Bacterial Vaccines for Treatment, Special Mixtures)
                                                          \1\
Delmont Laboratories, Inc., No. 299                      Polyvalent Bacterial Antigens with ``No U.S. Standard
                                                          of Potency'' (Staphage Lysate)
Eli Lilly and Company, No. 56                            Mumps Skin Test Antigen \2\
Hollister-Stier, a Division of Cutter Laboratories, No.  Pertussis Immune Globulin (Human) \3\
 8
Travenol Laboratories, Inc., Hyland Therapeutics         Pertussis Immune Globulin (Human) \4\
 Division, No. 140
----------------------------------------------------------------------------------------------------------------
\1\ The licenses for these products were transferred from Bayer, Inc. No. 8 (formerly Hollister-Stier, a
  Division of Cutter Laboratories, No. 8), to Hollister-Stier, LLC, No. 1272 on June 2, 1999. These products
  were reviewed by the Panel on Review of Allergenic Extracts.
\2\ The license for Mumps Skin Test Antigen, Lilly, was revoked on December 2, 1985, at the request of the
  manufacturer. Therefore no further regulatory action on this product was required.
\3\ The license for Pertussis Immune Globulin, Hollistier-Stier, was revoked on August 18, 1988, at the request
  of the manufacturer. Therefore no further regulatory action on this product was required.
\4\ The licenses for Pertussis Immune Globulin, Travenol, were revoked on April 9, 1982, and July 27, 1995, at
  the request of the manufacturer. Therefore no further regulatory action on this product was required.


[[Page 31009]]

1. Staphage Lysate
    The original Panel on Review of Bacterial Vaccines and Bacterial 
Antigens with ``no U.S. Standard of Potency,'' reviewed SPL 
manufactured by Delmont Laboratories, Inc. (Delmont). This Panel 
recommended that SPL be placed in Category IIIB, and that the license 
be revoked because: (1) There was no evidence of efficacy; and (2) if 
SPL was to be recommended for use as a stimulator of cell mediated 
immunity, either specific or general, this new ``function'' would 
require evaluation as a new biological product.
    In 1978, Delmont requested a hearing in response to initiation of 
revocation proceedings and submitted information resulting in 
reclassification of SPL from Category IIIB to Category IIIA (43 FR 
50247). Following this reclassification and prior to the meeting of the 
VRBPAC in January 1983, Delmont submitted additional information 
concerning SPL to the VRBPAC. This information consisted of a series of 
letters from physicians and patients of a testimonial nature supporting 
the effectiveness of SPL. These letters were accompanied by several 
reprints and exhibits of uncontrolled case reports and papers regarding 
the effectiveness and use of SPL in a variety of clinical conditions 
ranging from warts to hidradenitis suppurativa (HS), to chronic and 
progressive disorders such as multiple sclerosis (MS) and Crohn's 
disease.
    The VRBPAC reviewed the information that Delmont submitted for the 
use of SPL in the treatment of the conditions described above. In 
addition, the VRBPAC reviewed data regarding the nonspecific 
stimulation of the immune response in animals. The VRBPAC noted that 
the information from the completed studies that were submitted 
indicated that the studies were insufficiently designed to support 
claims of SPL's effectiveness for treatment of warts, MS, Crohn's 
disease or nonspecific stimulation of the immune response. At the time 
of the VRBPAC meeting in 1983, the committee noted that two controlled 
trials for the use of SPL in treatment of recurrent furunculosis and HS 
were either in the recruitment phase or in progress. The VRBPAC noted 
that it would likely take additional time for the sponsors to complete 
these trials. However, the VRBPAC concluded that ``it could not 
reasonably continue to defer recommendations on the classification of 
SPL owing to uncertainty when the two existing controlled trials would 
be completed, and uncertainty as to whether the results, when finally 
presented, would be clearly interpretable, owing to lack of 
comparability among patient groups'' (VRPBAC Final Report: Addendum to 
Previous Reports for the Reclassification of Category IIIA Biologics, 
April 1984).
    As a result of its review, the VRBPAC found that it was not able to 
determine that there was substantial evidence of efficacy for SPL. In 
its final report to the agency submitted in April of 1984, the VRBPAC 
recommended that SPL be placed in Category II and that``licensure be 
revoked until additional data to support its reclassification became 
available.''
2. Polyvalent Bacterial Vaccines with ``no U.S. Standard of Potency''
    Product licenses for Polyvalent Bacterial Vaccines with ``no U.S. 
Standard of Potency,'' (MRV, MRVI, and Bacterial Vaccines for 
Treatment, Special Mixtures) manufactured by Hollister-Stier, Division 
of Cutter Laboratories, were transferred to Miles Laboratories, Inc., 
on February 18, 1983, were transferred to Bayer, Inc. on May 24, 1995, 
and were again transferred to Hollister-Stier LLC on June 2, 1999. The 
original Panel on Review of Bacterial Vaccines and Antigens recommended 
that these products (MRV, MRVI, and Bacterial Vaccines for Treatment, 
Special Mixtures) be classified as Category IIIA and could remain on 
the market, and their license remain in effect on an interim basis 
provided that: (1) Group A streptococcal organisms and their 
derivatives, where present, were removed, and (2) satisfactory potency 
standards were developed and acceptable data based on scientifically 
sound studies which demonstrated efficacy in humans be submitted to 
FDA. At the time the agency established the Sec. 601.26 
reclassification panels, FDA, based on a recommendation of the VRBPAC, 
referred these three products to the Panel on Review of Allergenic 
Extracts for reclassification based on the products' attributed mode of 
action.
    The Panel on Review of Allergenic Extracts (the Allergenics Panel) 
held reclassification meetings on November 19 and 20, 1982, February 18 
and 19, 1983, and June 3 and 4, 1983, and a final report was submitted 
to FDA in December of 1983. In this report, the Allergenics Panel noted 
that the manufacturer had removed group A streptococcal organisms from 
MRV, MRVI, and Bacterial Vaccines, Special Mixtures, and had initiated 
preliminary studies as recommended by the original Panel. However, the 
Allergenics Panel found that ``there has been no better definition of 
indications for the use of this product. Neither are there recognizable 
criteria for selection of patients or dosage. No double-blinded 
controlled studies have been performed or started since the original 
Panel made its recommendations in 1977'' (Food and Drug Administration 
Panel on Review of Allergenic Extracts Category IIIA Reclassification, 
Final Report, December 1983). Based on the lack of efficacy studies 
submitted in support of these products, the Allergenics Panel 
recommended that these products be reclassified into Category II for 
both diagnosis and immunotherapy.
    FDA agrees with the conclusions and recommendations of the VRBPAC 
to reclassify SPL into Category II. FDA therefore proposes to designate 
SPL as ineffective and misbranded and to accept the findings of the 
VRBPAC concerning SPL. FDA also agrees with the conclusions and 
recommendations of the Panel on Review of Allergenic Extracts to 
reclassify Hollister-Stier LLC's Polyvalent Bacterial Vaccines with 
``no U.S. Standard of Potency'' (MRV, MRVI, and Bacterial Vaccines for 
treatment, Special Mixtures) into Category II. FDA proposes to 
designate Polyvalent Bacterial Vaccines with ``no U.S. Standard of 
Potency'' (MRV, MRVI, and Bacterial Vaccines for treatment, Special 
Mixtures) as ineffective and misbranded, and FDA proposes to accept the 
findings of the Panel on Review of Allergenic Extracts.
    In this proposed order FDA hereby offers notice of its intent to 
revoke the licenses of SPL and Polyvalent Bacterial Vaccines with ``no 
U.S. Standard of Potency'' (MRV, MRVI, and Bacterial Vaccines for 
treatment, Special Mixtures) as Category II products. After the end of 
the comment period for this proposed order, FDA will subsequently issue 
a notice of opportunity for a hearing on the revocation of the license 
of both SPL and Polyvalent Bacterial Vaccines with ``no U.S. Standard 
of Potency'' (MRV, MRVI, and Bacterial Vaccines for treatment, Special 
Mixtures).
    Section 601.26(d)(4) requires FDA to publish in a proposed order, 
concerning Category IIIA reclassification, a statement identifying 
those products that the agency proposes should be permitted to remain 
on the market pending further testing because there is a compelling 
medical need and no suitable alternative. No such products were 
identified by the VRBPAC for the purposes of this proposed order.

V. Availability of Reports and Public Comments

    In accordance with Sec. 601.26(d)(2), FDA is announcing the 
availability of the final reports of the Vaccines and Related 
Biological Products Advisory

[[Page 31010]]

Committee, dated April 1984, and the Panel on Review of Allergenic 
Extracts, dated December 1983, that are the subject of this proposed 
order. Copies of these reports can be obtained from the Office of 
Communication, Training and Manufacturers Assistance (HFM-40), Center 
for Biologics Evaluation and Research, Food and Drug Administration, 
1401 Rockville Pike, Rockville, MD 20852-1448. By sending a self-
addressed adhesive label, you will assist that office in processing 
your requests more quickly. The documents may also be obtained by mail 
by calling the CBER Voice Information System at 1-800-835-4709 or 301-
827-1800, or by fax by calling the FAX Information System at 1-888-
CBER-FAX or 301-827-3844, or by mail by contacting CBER electronically 
at www.CBER__[email protected].
    Interested persons may, on or before August 13, 2000 submit written 
comments regarding this proposal to the Dockets Management Branch (HFA-
305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. Two copies of any comments should be submitted, 
except that individuals should submit one copy. Comments may also be 
submitted electronically at www.fda.gov/ohrms/dockets. Comments should 
be identified with the docket number found in brackets in the heading 
of this document. Data and information submitted to FDA that fall 
within the confidentiality provisions of 18 U.S.C. 1905, 5 U.S.C. 
552(b), or 21 U.S.C. 331(j) are not available for public disclosure. 
Consistent with the provisions of Sec. 601.25(b), when FDA publishes 
this proposed order and the Reclassification Committee's 
reclassification findings, data and information submitted to FDA in 
connection with these reclassified products will be made publicly 
available after June 14, 2000, and may be viewed at the Dockets 
Management Branch (address above). Data and information submitted and 
shown to fall within the confidentiality provisions of one or more of 
the above statutes will not be disclosed. Comments concerning 
confidentiality should be received by FDA by June 14, 2000. Received 
comments may be seen in the Dockets Management Branch between 9 a.m. 
and 4 p.m., Monday through Friday.
    After review of the public comments received in response to this 
proposed order and in consideration of the results of hearings, if any, 
FDA intends to issue in the Federal Register a final order announcing 
its final conclusions and revoking those licenses which are placed in 
Category II by the final order.

    Dated: May 3, 2000.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-12116 Filed 5-12-00; 8:45 am]
BILLING CODE 4160-01-F