Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Notices 3043

HIV–1 transmission through

transfusions of blood and blood

products. To further address direct viral

detection methods, FDA brought the

issue of donor screening for HIV–1

antigen to a public meeting of the Blood

Products Advisory Committee (BPAC)

in June 1995. After hearing the most

recent available data on HIV–1 risk in

the blood supply, the estimated efficacy

of antigen screening, and other issues

bearing on a risk/benefit assessment, 9

of the 15 BPAC members present were

of the opinion that donor screening for

HIV–1 antigen by candidate test kits is

not likely to provide a significant public

health benefit which outweighs the

potential risks. After considering the

available information and the opinions

of the BPAC members, FDA

recommended that blood establishments

should implement donor screening for

HIV–1 antigen using licensed tests that

are approved for this indication. FDA

recommended implementation of HIV–1

antigen screening because of the benefit

that it will provide to a small number

of blood product recipients, as a partial

preventive measure against the

possibility of any increase in HIV–1

‘‘window period’’ donations and to

decrease the virus burden in plasma

pools for fractionation.

FDA recommended that the screening

for HIV–1 antigen(s) be implemented

within 3 months of the commercial

availability of the first such test

approved for donor screening for all

donations of Whole Blood, blood

components, Source Leukocytes and

Source Plasma, and all such inventoried

units available for release. FDA also

recommended that consigned withindate units intended for transfusion and

still in the consignee’s inventory be

either replaced with screened units or

tested for HIV–1 antigen(s) as soon as

feasible. The memorandum included

additional recommendations and

information on the following: (1)

Disposition and labeling of units; (2)

donor deferral; (3) Public Health Service

recommendations for donor notification

and counseling; (4) exclusion/retrieval

of potentially contaminated units from

prior collections and notification of

consignees; and (5) notification of

consignees of neutralization test results.

Because HIV–1 antigen testing will

reduce, but not eliminate, the residual

risk of HIV–1 from transfusion, FDA

regards such screening as an interim

measure pending the availability of

better technology for this purpose. FDA

encourages continued development of

new methods to further reduce the risk

of HIV transmissions in the ‘‘window

period.’’

As with other memoranda, FDA does

not intend this document to be allinclusive and cautions that not all

information may be applicable to all

situations. The memorandum is

intended to provide information and

does not set forth new requirements.

The procedures cited in the

memorandum are recommendations.

FDA anticipates that blood and plasma

establishments may develop alternative

procedures and discuss them with FDA.

FDA may find those alternative

procedures acceptable. FDA recognizes

that the scientific technology for

controlling the risk of transmission of

HIV by blood and blood products may

continue to advance and that this

document may become outdated as

those advances occur. The

memorandum does not bind FDA and

does not create or confer any rights,

privileges, or benefits on or for any

private person, but is intended merely

for guidance.

Interested persons may, at any time,

submit to the Dockets Management

Branch (address above) written

comments on the memorandum. 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. A copy of the memorandum

and received comments may be seen in

the office above between 9 a.m. and 4

p.m., Monday through Friday.

Received comments will be

considered in determining whether

further revisions to the memorandum

are warranted.

Dated: January 22, 1996.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 96–1657 Filed 1–29–96; 8:45 am]

BILLING CODE 4160–01–F

[Docket No. 93D–0398]

Microbiological Testing for

Antimicrobial Food-Animal Drugs;

Final Guidance; Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing the

availability of a guidance document

entitled ‘‘Microbiological Testing of

Antimicrobial Drug Residues in Food.’’

The availability of the draft guideline

was announced on January 6, 1994; this

final guidance document addresses the

comments submitted on the draft

guideline. The final guidance document,

which was prepared by the Center for

Veterinary Medicine (CVM), addresses

human food safety issues that may be

associated with food-animal

antimicrobial drug products. This

guidance document also provides points

to consider when determining which

antimicrobials may require

supplemental testing and recommends

test procedures for establishing that

antimicrobial drug residues will not

cause intestinal microflora perturbations

in the consumer.

DATES: Written comments on the

guidance document may be submitted at

any time.

ADDRESSES: Submit written requests for

single copies of the final guidance

document ‘‘Microbiological Testing of

Antimicrobial Drug Residues in Food,’’

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:

Haydee Fernandez, Center for

Veterinary Medicine (HFV–154), Food

and Drug Administration, 7500 Standish

Pl., Rockville, MD 20855, 301–594–

1684.

SUPPLEMENTARY INFORMATION: FDA is

announcing the availability of the final

guidance document entitled

‘‘Microbiological Testing of

Antimicrobial Drug Residues in Food.’’

In evaluating the safety of new animal

drugs, the agency must determine,

among other things, their cumulative

effect in man or other animal as

required by section 512(d)(2)(B) of the

Federal Food, Drug, and Cosmetic Act

(the act) (21 U.S.C. 360b(d)(2)(B)). The

guidance document describes the testing

that may be necessary to establish that

antimicrobial drug residues in food will

be safe and will not cause intestinal

microflora perturbations in the

consumer.

In the Federal Register of January 6,

1994 (59 FR 754), FDA issued a notice

of availability of the draft guideline

entitled ‘‘Microbiological Testing of
3044 Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Notices

Antimicrobial Drug Residues in Food.’’

The draft guideline was made available

for public comment to provide the

agency with views to be considered in

the development of the guideline.

Comments were requested specifically

on: (1) Recommendations for additional

microbiological testing for antimicrobial

drug residues that seek a safe

concentration higher than 1 part per

million (ppm) of microbiologically

active residues in the total diet; (2) how

the proposed guideline should relate the

effect of low doses of antibiotics

observed in model systems to potential

adverse biological effects in humans;

and (3) appropriate endpoints for

monitoring the effects of the different

classes of antibiotics. Interested persons

were given until April 6, 1994, to

comment on the draft guideline.

The agency received comments from

university faculty members and the

animal drug industry. FDA has revised

the draft guideline as a result of these

comments. In addition, FDA is

reviewing its approach to the

development of guidance documents. In

order to eliminate confusion caused by

use of different nomenclature for

guidance documents (e.g., ‘‘guidelines,’’

‘‘points to consider’’) and to make it

clear that this document is not being

issued under current § 10.90(b) (21 CFR

10.90(b)). FDA is issuing this document

as ‘‘guidance,’’ not as a ‘‘guideline.’’

I. General Comments on the Draft

Guideline

1. There was general consensus

among the comments that

microbiologically inactive metabolites

and rapidly absorbed antimicrobials

would not produce any adverse effect

on the intestinal microflora of humans.

CVM agrees that the compounds that

are most likely to raise human food

safety concerns are those that are

microbiologically active.

Microbiologically inactive metabolites

and rapidly absorbed antimicrobials are

not the focus of this guidance

document.

2. Industry commented that the

sponsor of a compound should identify

the active residues and conduct the

appropriate microbiological endpoints

in consultation with the agency.

FDA agrees that, under the act, it is

the sponsor’s responsibility to identify

the microbiological activity of its

product and to monitor the appropriate

microbiological endpoint(s) to establish

the antimicrobial no observed effect

level (NOEL). As with all studies with

animal drugs, the sponsor is encouraged

to discuss the protocol with CVM

representatives prior to initiating the

study.

II. Comments Regarding Model Systems

3. The agency received several

comments on the use of model systems

to evaluate the effect of active residues

on the human intestinal microflora. The

model systems proposed in the

comments were mainly in vitro systems

using continuous flow. According to the

comments, continuous flow systems

allow the study of the effect of ‘‘low

levels’’ of antimicrobials on human

intestinal microflora by studying the

selection for antibiotic resistance, the

change in colonization resistance, the

determination of anaerobic population

counts, and the detection of virulence

enhancement.

The agency agrees that in vitro models

may offer a valid test system for

assessing the effect of ‘‘low levels’’ of

antimicrobials on the human intestinal

microflora.

4. A trade association stated that it

would be very difficult for the sponsors

to undertake de novo development and

validation of test procedures. The

comment suggested that before requiring

testing, CVM should have some

experience with the model systems that

could be used to study the

microbiological endpoints. This could

be done by funding research studies to

develop and, if possible, validate the

test procedures.

CVM is not aware of any validated

model system for the testing of all

antimicrobial agents. CVM does intend

to initiate research which will lead to

the development of validated model

systems for evaluating the effect of low

levels of antimicrobials on the human

intestinal microflora.

III. Comments Regarding the Proposed

Upper Limit of 1 ppm Antimicrobial

Activity

5. Most comments agreed with FDA

that 1 ppm was a level of

microbiologically active residues that

would be unlikely to produce any

adverse effect on the human intestinal

microflora and would, therefore, be safe.

Because there was some confusion

about how 1 ppm in the total diet

should be interpreted in practice, the

guidance document states CVM’s belief,

based on available data, that for

antimicrobial drug residues in edible

tissues from food-producing animals the

acceptable daily intake (ADI) should be

1.5 milligrams per person per day (mg/

person/day). Sponsors may demonstrate

through additional specific testing that

an ADI for drug residues in excess of 1.5

mg/person/day is safe.

6. One comment expressed concern

that 1 ppm might not be a ‘‘very low

level’’ for all antibiotics, mainly for new

and more active molecules (per unit of

weight) than current antimicrobials.

CVM disagrees based on the majority

of scientific opinion. CVM has

concluded that 1 ppm (or 1.5 mg/

person/day) is a conservative level for

determining whether or not antibiotic

residues will produce an adverse effect

on the human intestinal microflora.

However, as the guidance makes clear,

CVM may request information on

microbiological activity of any new

animal drug.

7. One comment from industry agreed

that studies should be conducted by

sponsors to establish microbiological

activity, but disagreed with CVM’s

proposed use of microbiological activity

as a valid endpoint for establishing

tolerances for antimicrobial drugs. The

comment argued that the predictive

value of microbiological activity in

determining the no effect level for the

health and safety of individuals and the

public has not been established.

Therefore, according to the comment,

microbiological activity should not be

used to set the safe concentration but

should only help to evaluate a NOEL

established by classic toxicology.

Instead, the comment stated that ‘‘if

there is a microbiological effect at a safe

concentration higher than 1 ppm

microbiologically active residue, then

the regulated toxicological no adverse

effect level for total residue will need to

be adjusted downward accordingly,

taking into account the percentage of

microbiologically active residue in the

total residue and the nature of the

observed microbiological effect.’’

CVM disagrees. It is well documented

that high levels of antibiotics produce

deleterious effects on intestinal

microflora (see ‘‘Symposium on

Microbiological Significance of Drug

Residues in Food,’’ Veterinary and

Human Toxicology, 35 (supplement 1),

1993). Therefore, CVM has concluded

that microbiological activity is a valid

endpoint for establishing the safe

concentration for antimicrobial drugs.

Thus, when scientifically appropriate,

CVM will determine the no effect level

and calculate the safe concentration

based on the results of microbiological

testing.

IV. Comments Regarding the Proposed

Classification of Intestinal Microflora

Changes

8. One comment suggested that FDA

should classify the changes in the

intestinal microflora as follows: (1)

Changes in the number of

microorganisms and composition of

intestinal microflora; (2) changes in

metabolic activity of the flora related to

metabolism of exogenous and
Federal Register / Vol. 61, No. 20 / Tuesday, January 30, 1996 / Notices 3045

endogenous compounds; and (3)

changes in antimicrobial resistance

patterns and resistant genetic elements

within the microflora.

CVM generally agrees. CVM has

identified the following areas for which

microbiological residues represent a

potential public health concern: (1)

Changes in the metabolic activity of the

intestinal microflora; (2) changes in

antimicrobial resistance patterns of the

intestinal microflora; (3) changes in the

colonization resistance properties

(barrier effect) of the microflora; and (4)

changes in the number of

microorganisms and composition of the

intestinal microflora.

V. Conclusion

The Center specifically invites

comments on how to relate the effect

produced in the model systems to the

identified public health concerns. In

addition, information on the appropriate

endpoints for monitoring the effects of

the different classes of antibiotics is

requested. The public has the

opportunity to comment on this

guidance document at any time. CVM

will consider all comments for future

modifications of this guidance

document.

Guidelines are generally issued under

§§ 10.85(a) (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). This guidance document does

not bind the agency, and it does not

create or confer any rights, privileges, or

benefits for or on any person; however,

it represents the agency’s current

thinking on microbiological testing of

antimicrobial drug residues in food. A

person may follow the guidance

document or may choose to follow

alternate procedures or practices. If a

person chooses to use alternate

procedures or practices, that person may

wish to discuss the matter further with

the agency to prevent an expenditure of

money and effort on activities that may

later be determined to be unacceptable

to FDA.

Interested persons may, at any time,

submit to the Dockets Management

Branch (address above) written

comments on the guidance 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.

Received comments will be

considered to determine if further

revision of the guidance document is

necessary.

Dated: January 22, 1996.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 96–1579 Filed 1–29–96; 8:45 am]

BILLING CODE 4160–01–F

Health Resources and Services

Administration

Proposed Data Collections Submitted

for Public Comment and

Recommendations

In compliance with the requirement

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

Paperwork Reduction Act of 1995 for

opportunity for public comment on

proposed data collection projects, the

Health Resources and Services

Administration (HRSA) will publish

periodic summaries of proposed

projects being developed for submission

to OMB under the Paperwork Reduction

Act of 1995. To request more

information on the proposed project or

to obtain a copy of the data collection

plans and instruments, call the HRSA

Reports Clearance Officer on (301) 443–

1129.

Comments are invited 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.

Proposed Projects

1. Evaluation of the Community

Integrated Service System (CISS)

Program—New—Data will be collected

by mail and in person to assess

demonstration effectiveness for program

management purposes. Mail surveys

will be conducted with four managers in

each of 40 CISS grant funded programs:

(1) Project director, (2) supervisor of

intake/outreach, (3) medical director or

closest equivalent, and (4) supervisors

of care coordination. The purposes are

to describe the organizational structure,

service networks, and expected

decision-making patterns prior to the

more focussed on-site inquiries. Data

subsequently will be collected in person

from managers, staff, and clients of the

40 CISS grant-funded programs: (1)

Project director and director of grantreceiving institution, (2) managers of

each service in the program, (3) staff

providing health services, (4) staff

providing care coordination and

services other than health care, and (5)

a sample of clients who agree to

participate. Numbers (3) and (4) will

respond to focus group protocols. The

purposes of the in-person data

collection are to assess the day-to-day

interaction of the service units, decision

strategies employed by managers, and

the effect on access for targeted clients.

The study will provide the only

evaluation to date of the effectiveness of

the CISS program. The information will

also be used to identify models with

promise for replication. Because this

data collection is targeted to a limited

number of respondents, automated

collection techniques will not be used.

Burden estimates are as follows:

Respondent type Number of

respondents

Responses

per respondent

Average burden per response

(hours)

Total burden hours

Project Director .............................................................................................................. 40 1 2 80

Intake/Outreach Supervisor ........................................................................................... 40 1 1.5 60

Medical Director ............................................................................................................. 40 1 1.5 60

Supervisor of Care Coord .............................................................................................. 40 1 1.5 60

Proj. Dir./Inst. Dir ............................................................................................................ 80 1 2 160

Service Managers .......................................................................................................... 200 1 2 400

Health Service Staff ....................................................................................................... 400 1 2 800

Care Coord./Other Service Staff .................................................................................... 400 1 2 800

CISS clients .................................................................................................................... 200 1 .3 60