Federal Register / Vol. 61, No. 83 / Monday, April 29, 1996 / Notices 18747

Resettlement Program to submit an

annual report with a count of the

number of refugees receiving cash and

medical assistance or social services

who were initial resettled in another

State. The State does this by counting

the number of refugees with social

security numbers indicating residence

in another State at the time of arrival in

the U.S. (The first three digits of the

social security number indicate the

State of residence of the applicant.)

Data submitted by the States are

compiled and analyzed by the ORR

statistician, who then prepares a

summary report which is included in

ORR’s annual Report to Congress. The

primary use of the data is to quantify

and analyze refugee secondary

migration among the 50 States. ORR

uses these data to adjust its refugee

arrival totals for each State in order to

calculate the social services allocation

formula.

Respondents: State Governments.

Instrument Number of

respondents

Number of

responses

per respondent

Average

burden

hours per

response

Total burden hours

ORR–11 ............................................................................................................................ 50 1 .434 217

Estimated Total Annual Burden Hours: 217.

In compliance with the requirements

of Section 3506(c)(2)(A) of the

Paperwork Reduction Act of 1995, the

Administration for Children and

Families is soliciting public comment

on the specific aspects of the

information collection described above.

Copies of the proposed collection of

information can be obtained and

comments may be forwarded by writing

to the Administration for Children and

Families, Office of Information Services,

Division of Information Resource

Management Services, 370 L’Enfant

Promenade, S.W., Washington, D.C.

20447, Attn: ACF Reports Clearance

Officer. All requests should be

identified by title.

In addition, requests for copies may

be made and comments forwarded to

the Reports Clearance Officer over the

Internet by sending a message to

rkatson@acf.dhhs.gov. Internet messages

must be submitted as an ASCII file

without special characters or

encryption.

The Department specifically requests

comments on: (a) Whether the proposed

collection of information is necessary

for the proper performance of the

functions of the agency, including

whether the information shall have

practical utility; (b) the accuracy of the

agency’s estimate of the burden of the

proposed collection of information; (c)

ways to enhance the quality, utility, and

clarity of the information to be

collected; and (d) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques

or other forms of information

technology. Consideration will be given

to comments and suggestions submitted

within 60 days of this publication.

Dated: April 22, 1996.

Roberta Katson,

Director, Division of Information Resource

Management Services.

[FR Doc. 96–10532 Filed 4–26–96; 8:45 am]

BILLING CODE 4184–01–M

Food and Drug Administration

[Docket No. 93D–0025]

Target Animal Safety and Drug

Effectiveness Studies for AntiMicrobial Bovine Mastitis Products;

Guidance Document; Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing the

availability of the revised guidance

document entitled ‘‘Target Animal

Safety and Drug Effectiveness Studies

for Anti-Microbial Bovine Mastitis

Products (Lactating and Non-lactating

Cow Products)’’ prepared by the Center

for Veterinary Medicine (CVM). This

guidance document serves to interpret

statutory and regulatory requirements

and outlines general procedures for

conducting evaluations for antimicrobials being considered for

approval.

DATES: Written comments on the

guidance document may be submitted at

any time.

ADDRESSES: Submit written requests for

single copies of the revised guidance

document entitled, ‘‘Target Animal

Safety and Drug Effectiveness Studies

for Anti-Microbial Bovine Mastitis

Products’’ to the Communications and

Education Branch (HFV–12), Center for

Veterinary Medicine, Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–594–1755.

Send two self-addressed adhesive labels

to assist that office in processing your

requests. Submit written comments to

the Dockets Management Branch (HFA–

305), Food and Drug Administration,

12420 Parklawn Dr., rm. 1–23,

Rockville, MD 20857. Requests and

comments should be identified with the

docket number found in brackets in the

heading of this document. A copy of the

guidance document and received

comments may be seen at the Dockets

Management Branch between 9 a.m. and

4 p.m., Monday through Friday.

FOR FURTHER INFORMATION CONTACT:

Naba K. Das, Center for Veterinary

Medicine (HFV–133), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–594–1659.

SUPPLEMENTARY INFORMATION: FDA is

announcing the availability of the

revised guidance document entitled

‘‘Target Animal Safety and Drug

Effectiveness Studies for Anti-Microbial

Bovine Mastitis Products (Lactating and

Non-lactating Cow Products)’’ prepared

by CVM. The guidance document is

intended to be used by the

pharmaceutical industry for information

regarding the types of data that will

demonstrate that an anti-microbial

mastitis product is safe and effective for

both lactating and non-lactating cows.

In the Federal Register of February 10,

1993 (58 FR 7893), FDA issued a notice

of availability of the CVM draft

guideline entitled ‘‘Guideline for Target

Animal and Human Food Safety, Drug

Efficacy, Environmental and

Manufacturing Studies for AntiInfective Bovine Mastitis Products.’’

Comments by interested persons were

requested.

In response to the February 19, 1993,

notice, the Animal Health Institute

(AHI) notified CVM, by letter dated June

28, 1993, of its intent to form a working

group, the Dairy Industry Consortium

(DIC), to address the draft CVM

guideline ‘‘Guideline for Target Animal

and Human Food Safety, Drug Efficacy,

Environmental and Manufacturing
18748 Federal Register / Vol. 61, No. 83 / Monday, April 29, 1996 / Notices

Studies for Anti-Infective Bovine

Mastitis Products.’’ Comments and

alternative proposals from the AHI/DIC

were forwarded to FDA/CVM in a letter

dated May 24, 1994.

Because AHI/DIC put forth extensive

complex scientific comments, CVM

agreed to participate in a workshop to

further discuss and clarify the AHI/DIC

comments. FDA/CVM representatives

participated in the workshop, which

was held on June 2, 1994, in Alexandria,

VA. The objective of this workshop was

to hold a public meeting to allow for the

discussion of AHI/DIC comments. The

draft guideline was discussed at the

workshop. In a letter dated July 14,

1994, AHI circulated minutes of the

workshop to all attendees. In a letter

dated August 11, 1994, CVM provided

comments on the July 14, 1994, AHI

minutes of the workshop. As a result of

CVM’s comments, a subsequent meeting

was held on September 23, 1994,

between representatives of FDA/CVM

and AHI/DIC to clarify scientific points

made in the minutes of the workshop.

No other comments on that draft

guideline were received by the agency.

The comments on the draft guideline

from AHI/DIC are discussed below:

1. General Issues

It was recommended that the final

guidance document encompass only the

efficacy and target animal safety of antiinfective bovine mastitis products. The

draft guideline provided a discussion on

other components of the new animal

drug application (NADA).

CVM concurs with this comment. The

guidance document will mainly address

efficacy and target animal safety. Other

components of the NADA will be

addressed under separate guidance

documents (e.g., environmental

assessment and manufacturing).

2. Enrollment in Study for Clinical

Infectious Mastitis

It was recommended that the

enrollment of a clinical mastitis case in

an efficacy study include the presence

of abnormal milk and/or udder clinical

signs at enrollment as the primary

element. The presence of

microorganisms should be strictly

secondary. The experimental unit

should be the lactating dairy cow with

clinical mastitis (abnormal milk and/or

udder clinical signs). For future clinical

studies, only cows with a single quarter

with clinical mastitis should be

enrolled. CVM should use this single

quarter data base to infer efficacy to all

cows with mastitis in one or more

quarters. The diagnosis of clinical

mastitis should be the only signalment

needed for enrollment in the study.

Prior to treatment, single samples for

microbiologic and somatic cell count

(SCC) assessment should be obtained.

Only the single affected quarter will be

treated. Any cow developing mastitis in

additional quarters during her

enrollment should be dropped from the

study and not considered failure. Cows

requiring and/or receiving treatment in

an additional mastitic quarter should be

excluded from consideration in the

study. Only clinical cases of mastitis in

which a mastitis pathogen is isolated in

the pretreatment sample should be used

to calculate cure rate. It should be

necessary to submit to CVM the pre and

posttreatment bacteriological culture

data from those cows that were initially

enrolled in the study but subsequently

cultured negative on the pretreatment

sample.

CVM agrees with these comments.

The guidance document has been

revised to reflect these comments.

3. Definition of Cure

It was recommended that the

definition of cure should include two

parts, a clinical portion and a

bacteriological portion. The current

definition of cure lacks the clinical

assessment. The cure should be assessed

between 14 and 28 days posttreatment

based on the negative control study

design. Clinically, a cured quarter

should have normal milk and no

clinical signs of mastitis in that quarter.

Microbiologically, the mastitis pathogen

isolated in the pretreatment sample

should be absent from two

posttreatment test samples. A minimum

of two single microbiology test samples

should be obtained at least 5 days apart

during the assessment period (14 to 28

days posttreatment). Two single SCC

samples should be obtained at the same

time. SCC should not be used in the

determination of cure for the individual

cow. SCC results should only be used as

a check of the numerical trend between

the means of SCC for ‘‘cured’’ and ‘‘notcured’’ cows within each treatment

group to determine if other studies are

needed for inflammation and safety.

CVM agrees with the proposed

definition of cure. The guidance

document has been revised to reflect

these comments.

4. Enrollment in Study for Subclinical

Mastitis

It was recommended that all new antiinfective products for mastitis in the

lactating dairy cow must show efficacy

for clinical mastitis. No new product

should be licensed with subclinical data

as in the old guidelines. CVM should

consider alternative approaches with

adequate justification. To obtain a

subclinical indication, additional

subclinical data should be required.

With acceptable clinical mastitis

efficacy results, the subsequent

subclinical mastitis study should

require that the new therapy

demonstrate efficacy but at a lower

probability level (p<0.10). This should

require fewer cows to be necessary for

the subclinical study because

elimination of the pretreatment

pathogen is required in the clinical

study. Subclinical trial(s) should select

cows with a positive quarter, thus fewer

cows may be needed. The subclinical

study should be a randomized study.

Prior to treatment, two single

microbiology and SCC samples should

be obtained at a 24-hour interval. At 14

to 28 days posttreatment, two single

microbiologic and SCC samples should

be obtained at least 5 days apart. In the

subclinical study, only one quarter from

any cow would be treated. For cows

infected in multiple quarters, the

quarter to be treated would be randomly

selected. The other quarters would not

be treated. If additional quarters of

clinical mastitis requires additional

treatment, the cow would be ineligible

for inclusion in the study. Definition of

cure for the subclinical study

constitutes the elimination of the

bacteria isolated in both pretreatment

samples. SCC results should be used

similarly in subclinical studies as for

clinical studies to detect changes and

perhaps indicate possible safety

problems. Products with acceptable

efficacy data from both clinical and

subclinical studies should receive the

following indication: ‘‘Effective for the

treatment of clinical and subclinical

mastitis caused by* * *’’.

CVM agrees with these comments.

The guidance document has been

revised to incorporate these comments.

5. Design of Field Studies

It was recommended that clinical

efficacy studies would be multilocation/

multiherd studies. CVM should

eliminate the requirement that a study

herd must have a 20 percent incidence

of clinical mastitis to participate. Herds

participating in a clinical study should

have a sufficient number of clinical

mastitis cases to fill an adequate number

of blocks. Obtaining an adequate

number of pathogens may involve

multiple locations to fulfill the number

needed for each block within the study.

In the clinical study, the distribution of

mastitis pathogens from the study

should be utilized to determine the label

efficacy statement. An example for an

effective antibiotic for staph and strep

mastitis pathogens would be:
Federal Register / Vol. 61, No. 83 / Monday, April 29, 1996 / Notices 18749

‘‘Effective for the treatment of clinical and

subclinical mastitis caused by

Staphylococcus species such as

Staphylococcus aureus, and Streptococcus

species such as Streptococcus agalactiae,

Streptococcus uberis.’’

This would eliminate the need in a

clinical study to enroll 100 clinical

cases per pathogen per treatment group.

The study would need to demonstrate

adequate power to detect an overall

treatment-cure rate above that of the

untreated control group. This would

take into account spontaneous cure

rates.

CVM considered the above comments

and has revised the guidance document

accordingly in light of CVM’s position

on this issue. CVM believes that under

current regulations, use of positive

control studies are permitted, however,

CVM is trying to determine what

constitutes ‘‘efficacy threshold.’’ CVM

would still require a negative controlled

study in order to separate the

spontaneous cure rate from the cure rate

attributable to the drug. If a sponsor is

considering a positively controlled

study, the sponsor should provide a

basis for the need to have such a study,

and thus be exempted from this

standard. It should be discussed with

and approved by CVM prior to the

study. The design of the positively

controlled study needs to be such that

depending on the spontaneous cure

rates, the study would detect an overall

cure rate for the treatment group of 65

to 70 percent per pathogen.

6. Minimum Inhibitory Concentration/

Pharmacokinetic Data (MIC/PK Data)

The comment stated that utilization of

MIC/PK data for intramammary/mastitis

products is still in the scientific

discovery stage. The basis for correlating

milk residue/efficacy/MIC data to draw

a reasonable scientific conclusion is

unavailable.

CVM agrees with the above comment,

however, the use of MIC/PK data for

intramammary products should be

addressed when CVM considers the

flexible labeling issues and should not

be addressed in this current antiinfective bovine mastitis drug guidance

document.

7. Non-lactating Treatment and

Prevention Products

The comment stated that separate

studies would be necessary to obtain a

treatment and prevention label claim.

CVM agrees with the comment and

has revised the draft guidance to

indicate that separate studies would be

necessary to obtain a treatment and

prevention label claim for use in the dry

cow. For the prevention claim, the

sponsor would need to establish,

through a negative controlled group, the

new infection rate (estimates are

approximately 2 to 3 percent) and

demonstrate at least a 50 percent

reduction in the rate of new infections.

The criteria for defining a cure is as for

clinical mastitis in the lactating cow,

i.e., no clinical signs and negative

culture at time of freshening.

Guidelines are generally issued under

§§ 10.85(a) and 10.90(b) (21 CFR

10.85(a) and 10.90(b)). The agency is

now in the process of revising

§§ 10.85(a) and 10.90(b). Therefore, this

guidance document is not being issued

under §§ 10.85(a) and 10.90(b), and it

does not bind the agency, and does not

create or confer any rights, privileges, or

benefits for or on any person. However,

it represents the agency’s current

thinking on this issue. A person may

follow the guidance document or may

choose to follow alternative procedures

or practices. If a person chooses to use

alternate procedures or practices, that

person may wish to discuss the matter

with FDA/CVM to prevent an

expenditure of money and effort on

activities that may later be determined

to be unacceptable. When a guidance

document states a requirement imposed

by statute or regulation, however, the

requirement is law and its force and

effect are not changed in any way by

virtue of its inclusion in the guidance

document.

Interested persons may, at any time,

submit to the Dockets Management

Branch (address above) written

comments on the document. Two copies

of any comments are to be submitted,

except that individuals may submit one

copy. Comments are to be identified

with the docket number found in

brackets in the heading of this

document. The guidance document and

received comments are available for

public examination in the Dockets

Management Branch between 9 a.m. and

4 p.m., Monday through Friday.

Dated: April 23, 1996.

William K. Hubbard,

Association Commissioner for Policy

Coordination.

[FR Doc. 96–10485 Filed 4–26–96; 8:45 am]

BILLING CODE 4160–01–F

[Docket No. 93F-0102]

Ciba-Geigy Corp.; Withdrawal of Food

Additive Petition

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing the

withdrawal, without prejudice to a

future filing, of a food additive petition

(FAP 3B4361), filed by Ciba-Geigy

Corp., proposing that the food additive

regulations be amended to provide for

safe use of the reaction product of 4,4′-

isopropylidenediphenolepichlorohydrin resin, 4,4′-

isopropylidenediphenol bis[(2-

glycidyloxy-3-n-butoxy)-1-propyl ether],

and 4,4′-isopropylidenediphenol as a

component of coatings for food-contact

use.

FOR FURTHER INFORMATION CONTACT:

Julius Smith, Center for Food Safety and

Applied Nutrition (HFS–216), Food and

Drug Administration, 200 C St. SW.,

Washington, DC 20204, 202–418–3091.

SUPPLEMENTARY INFORMATION: In a notice

published in the Federal Register of

April 19, 1993 (58 FR 21173), FDA

announced that a food additive petition

(FAP 3B4361) had been filed by CibaGeigy Corp., Seven Skyline Dr.,

Hawthorne, NY 10532–2188. The

petition proposed to amend the food

additive regulations in § 175.300

Resinous and polymeric coatings (21

CFR 175.300) to provide for the safe use

of the reaction product of 4,4′-

isopropylidenediphenolepichlorohydrin resin, 4,4′-

isopropylidenediphenol bis[(2-

glycidyloxy-3-n-butoxy)-1-propyl ether],

and 4,4′-isopropylidenediphenol as a

component of coatings for food-contact

use. Ciba-Geigy Corp. has now

withdrawn the petition without

prejudice to a future filing (21 CFR

171.7)

Dated: April 10, 1996.

Alan M. Rulis,

Director, Office of Premarket Approval,

Center for Food Safety and Applied Nutrition.

[FR Doc. 96–10547 Filed 4–26–96; 8:45 am]

BILLING CODE 4160–01–F

1996 Gene Therapy Conference:

Development and Evaluation of Phase

I Products and Workshop on Vector

Development; Notice of Public

Conference

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice of public conference.

SUMMARY: The Food and Drug

Administration (FDA) is announcing a

public conference entitled ‘‘1996 Gene

Therapy Conference: Development and

Evaluation of Phase I Products and

Workshop on Vector Development.’’

The objective of this conference is to

educate investigators on the