Federal Register / Vol. 65, No. 94 / Monday, May 15, 2000 / Notices 31003

Dated: May 9, 2000.

John L. Williams,

Director, Procurement and Grants Office,

Centers for Disease Control and Prevention

(CDC).

[FR Doc. 00–12107 Filed 5–12–00; 8:45 am]

BILLING CODE 4163–18–P

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.

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 selfaddressed 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.CBERlINFO@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 § 601.25 (21 CFR 601.25) (38

FR 32048 at 32052, November 20, 1973).

Under § 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 § 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.

31004 Federal Register / Vol. 65, No. 94 / Monday, May 15, 2000 / Notices

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 §§ 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

§ 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

§ 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 § 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 § 601.26. According to

§ 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 § 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 § 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

Federal Register / Vol. 65, No. 94 / Monday, May 15, 2000 / Notices 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 § 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), No. 238 Tetanus Toxoid

Lederle Laboratories, Division, American Cyanamid Co., No 17 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

Merck Sharp & Dohme, Division of Merck & Co., Inc., No. 2 Tetanus Toxoid Adsorbed

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. 8 Pertussis Immune Globulin (Human)

Travenol Laboratories Inc.,

Hyland Therapeutics Division, No. 140

Pertussis Immune Globulin (Human)

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.

31006 Federal Register / Vol. 65, No. 94 / Monday, May 15, 2000 / Notices

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. 2The license for Staphylococcus Toxoid, Sclavo, was revoked on May 9, 1979, at the request of the manufacturer and was not, therefore, subject to reclassification. 3The 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. 4This 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

1The 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. 2The 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.

Federal Register / Vol. 65, No. 94 / Monday, May 15, 2000 / Notices 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 Adsorbed1

Lederle Laboratories Division, American Cyanamid Co., No. 17 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

Wyeth Laboratories, Inc., No. 3 Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed

Tetanus Toxoid Adsorbed

1The 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

31008 Federal Register / Vol. 65, No. 94 / Monday, May 15, 2000 / Notices

TABLE 7.—PRODUCTS RECOMMENDED BY THE VRBPAC FOR CLASSIFICATION IN CATEGORY I FOR BOOSTER

IMMUNIZATION AND CATEGORY II FOR PRIMARY IMMUNIZATION—Continued

Manufacturer/License Number Product(s)

Wyeth Laboratories, Inc., No. 3 Tetanus and Diphtheria Toxoids Adsorbed (Adult Use)

1The license for this product was transferred from Connaught Laboratories, Inc., No. 711, to Aventis Pasteur, Inc., No. 1277 on December 9,

1999. 2The 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. 3The licenses for these products were transferred from Michigan Department of Public Health, No. 99, to BioPort Corp., License No. 1260 on

November 12, 1998. 4The 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 § 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. 8 Pertussis Immune Globulin (Human) 3

Travenol Laboratories, Inc., Hyland Therapeutics Division, No. 140 Pertussis Immune Globulin (Human) 4

1The 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. 2The 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. 3The 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. 4The 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.

Federal Register / Vol. 65, No. 94 / Monday, May 15, 2000 / Notices 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 § 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 § 601.26(d)(2),

FDA is announcing the availability of

the final reports of the Vaccines and

Related Biological Products Advisory

31010 Federal Register / Vol. 65, No. 94 / Monday, May 15, 2000 / Notices

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.CBERlINFO@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

§ 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

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 98E–0228]

Determination of Regulatory Review

Period for Purposes of Patent

Extension; Neuro Cybernetic

Prosthesis (NCP) System;

Amendment

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice; amendment.

SUMMARY: The Food and Drug

Administration (FDA) is amending a

previous determination regarding the

regulatory review period for the Neuro

Cybernetic Prosthesis (NCP) System

that appeared in the Federal Register of

November 10, 1998 (63 FR 63066). FDA

is amending the notice because the

agency agrees with the information

provided in a request from the applicant

for revision of the regulatory review

period (Request) (Docket No. 98E–022 8/

PRC 1, dated and received on January 8,

1999).

ADDRESSES: Submit written comments

and petitions to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 5630 Fishers

Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Claudia V. Grillo, Regulatory Policy

Staff (HFD–7), Food and Drug

Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301–594–5645.

SUPPLEMENTARY INFORMATION: In its

original application for patent term

extension, the applicant claimed

December 16, 1991, as the date the

premarket approval application (PMA)

for the Neuro Cybernetic Prosthesis

(NCP) System (PMA 910070) was

initially submitted. FDA first

determined that the PMA was initially

submitted on January 27, 1997, because

FDA records indicated that the PMA

submitted on December 16, 1991, had

not been filed, but an amended PMA,

renumbered as PMA 970003, was the

PMA for the approved product.

The applicant later claimed in its

request that FDA’s determination of the

regulatory review period failed to take

into account an approved amendment to

the applicant’s originally submitted

PMA. Therefore, the applicant requested

that the agency correct the date the PMA

was initially submitted to June 1, 1993,

the date the approved amendment to the

PMA was received by FDA.

FDA reviewed its records and

confirmed that the amended PMA,

received on June 1, 1993, was filed by

the agency based on a threshold

determination that the amended PMA

was sufficiently complete to permit a

substantive review. FDA later

determined that additional studies were

required and issued a major deficiency

letter dated September 30, 1994,

requesting that additional clinical

studies be performed. The applicant

submitted a second amendment to the

PMA, which the agency received on

January 27, 1997. FDA reviewed the

amendment and determined that the

second amendment sufficiently

responded to the September 30, 1994,

deficiency letter, and filed the newly

amended PMA on the date of the receipt

of the completed PMA, January 27,

1997. For administrative reasons, the

second amendment to the PMA was

considered a resubmission of the PMA,

and it was assigned a new PMA number,

P970003, which is the PMA number of

the approved PMA for the product.

In the past, FDA has determined that

the start of the approval phase began

with the submission of the first filed

PMA for an approved product, even if

the original filed PMA was later

withdrawn and filed under a new

number. For this reason, FDA now

accepts the date of June 1, 1993,

submitted by the applicant in its

request, as the date the first PMA was

filed for the product and the date that

the PMA was initially submitted.

Therefore, the applicable regulatory

review period for the Neuro Cybernetic

Prosthesis (NCP) System is 3,237 days.

Of this time, 1,730 days occurred during

the testing phase of the regulatory

review period, while 1,507 days

occurred during the approval phase.

These periods of time were derived

from the following dates, summarized

from the November 10, 1998, notice and

modified by this technical amendment:

1. The date a clinical investigation

involving this device was begun:

September 6, 1988.

2.The date an application was

initially submitted with respect to the

device under section 515 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C.

360e): June 1, 1993.

3. The date the application was

approved: July 16, 1997.

This determination of the regulatory

review period establishes the maximum

potential length of a patent extension.

However, the U.S. Patent and

Trademark Office applies several