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Notice:  Biological Products; Bacterial Vaccines and Related Biological

Products; Implementation of Efficacy Review; Proposed Order

Federal Register: May 15, 2000 (Volume 65, Number 94) Page 31003-31010

ACTION: Notice.

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__INFO@CBER.FDA.GOV,

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

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

                    Manufacturer/License Number                                                           Product(s)

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

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\

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

\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

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

                    Manufacturer/License Number                                                            Product

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

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

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

\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__INFO@CBER.FDA.GOV.

    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