26186 Federal Register / Vol. 61, No. 102 / Friday, May 24, 1996 / Notices

AUCO-t should be equivalent at any

dosing interval whether or not steadystate is achieved.

29. Page 17, section III.D. Statistical

Analysis, second paragraph. The choice

of whether to use untransformed data

should be made by the sponsor based on

whether transformation is necessary to

allow for homogeneity of variance. It

should not be determined prior to the

study because the data should dictate

which transformation, if any, is

required.

CVM does not agree with this

recommendation. The sponsor has the

option to use untransformed or log

transformed data, but the decision

should be made prior to conducting the

study.

30. Page 19, section III.D., second

from the last paragraph relating to

selection of confidence interval. One

comment noted that CVM states that in

general the confidence interval for

untransformed data should be 80 to 120.

Firstly, percent should be specified.

Secondly, emphasis should be added

that these are general rather than the

adamant and steadfast specifications of

CVM. The opinion of many statisticians

with considerable experience in this

field is that the ±20 percent interval is

entirely too restrictive. In the animal

health market, the potential cost to

evaluate generics or combinations may

be so great as to preclude bringing a

useful drug/combination to the market.

CVM has made the requested editorial

changes. However, CVM will continue

to accept ±20 percent as the acceptable

confidence interval for the pivotal

parameters. CVM invites sponsors to

submit data to justify broadening the

confidence interval for a particular drug.

31. Page 20, section IV.B. Statistical

Analysis. One comment noted that for

pharmacologic endpoint studies as

described, it appears that these studies

described are evaluating significant

differences rather than statistical

equivalence. As such, these

pharmacological endpoint studies are

not as rigorously designed from a

statistical standpoint as classic

bioequivalence plasma level studies,

inasmuch as differences are being

evaluated rather than equivalence. The

comment suggested that

pharmacological endpoint studies

should also be evaluating statistical

equivalence, rather than significant

differences. In fact, a comparable

equivalence testing is alluded to on page

22 regarding clinical endpoint studies,

studies which would be expected to be

less able to prove equivalence than

pharmacologic endpoint studies.

CVM agrees with the comment and

has modified the guidance to read as

follows:

For parameters which can be measured

over time, a time vs effect profile is

generated, and equivalence is determined

with the method of statistical analysis

essentially the same as for the blood level

bioequivalence study.

For pharmacologic effects for which effect

vs time curves can not be generated, then

alternative procedures for statistical analysis

should be discussed with CVM prior to

conducting the study.

32. Page 23, section VI. Human Food

Safety Considerations. One comment

asked if there is a need for determining

a full depletion profile for the generic?

The sponsor proposed that a single

point tissue residue study completed

out to the withdrawal time of the

pioneer would be sufficient.

The Center does not agree with the

use of a single point tissue residue study

at the withdrawal time of the pioneer as

a general practice.

A traditional tissue residue depletion

study has always been required for

generic products where bioequivalence

is determined with a pharmacological or

clinical endpoint study. The need for a

traditional tissue residue depletion

profile is expanded in the revised

guidance to include blood level

bioequivalence studies, because the

Center has concluded that, with the

exception of those examples listed in

section VI. of the guidance, the tissue

residue depletion of the generic product

is not adequately addressed through

bioequivalence studies.

The use of the traditional tissue

residue depletion study provides the

Center with the data needed to compute

a withdrawal period for the drug

product in question, using our statistical

tolerance limit model, whereby the 99th

percentile is calculated with 95 percent

confidence. Use of a single point tissue

residue study ordinarily would not

provide the data needed to use our

current model, since the single-point

study would not contain sufficient

information regarding the variability of

the residue depletion profile.

Additionally, since the analytical

methods approved for regulatory

purposes can rarely measure the marker

residue at the withdrawal time, a single

point residue study at the pioneer

withdrawal time would be limited by

the efficiency of the regulatory

analytical method at the drug

concentrations typically seen at the

pioneer withdrawal time. When the

tissue residue values include negative or

zero values (i.e., values below the limit

of quantitation for the assay), the

number of animals needed in the study

will depend on the method variance and

the number of zero values, and will vary

from drug to drug. It is not possible to

predict, a priori, the number of animals

that will be needed to provide data of

sufficient confidence for a single point

tissue residue depletion study to obtain

the confidence similar to that seen for

the pioneer drug using our traditional

residue depletion study design.

The Center will consider the use of a

single point tissue residue depletion

study in those cases where the

regulatory analytical method can be

validated and demonstrated to measure

reliably residues in the treated animals

at the pioneer withdrawal time so that

a 99th percentile statistical tolerance

limit with 95 percent confidence can be

calculated.

A person may follow the guidance 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. Although this guidance

document does not bind the agency or

the public, and it does not create or

confer any rights, privileges, or benefits

for or on any person, it represents FDA’s

current thinking on bioequivalence

testing for animal drugs. When a

guidance document states a requirement

imposed by statute or regulation, the

requirement is law and its force and

effect are not changed in any way by

virtue of its inclusion in the guidance.

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 documents 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: May 17, 1996.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 96–13106 Filed 5–23–96; 8:45 am]

BILLING CODE 4160–01–F
Federal Register / Vol. 61, No. 102 / Friday, May 24, 1996 / Notices 26187

[Docket No. 95N–0212]

Epitope, Inc.; Premarket Approval of

OraSure HIV–1 Oral Specimen

Collection Device

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is announcing its

approval of the application by Epitope,

Inc., Beaverton, OR, for premarket

approval, under the Federal Food, Drug,

and Cosmetic Act (the act), of the

OraSure HIV–1 Oral Specimen

Collection Device. FDA’s Center for

Biologics Evaluation and Research

(CBER) notified the applicant, by letter

of December 23, 1994, of the approval

of the application. A revised approval

letter was issued on October 18, 1995.

DATES: Petitions for administrative

review by June 24, 1996.

ADDRESSES: Written requests for copies

of the summary of safety and

effectiveness data and petitions for

administrative review to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857.

FOR FURTHER INFORMATION CONTACT:

Sukza Hwangbo, Center for Biologics

Evaluation and Research (HFM–380),

1401 Rockville Pike, Rockville, MD

20852–1448, 301–827–3524.

SUPPLEMENTARY INFORMATION: On May 9,

1991, Epitope, Inc., Beaverton, OR

97008, submitted to CBER an

application for premarket approval of

the OraSure HIV–1 Oral Specimen

Collection Device. The device is

intended for use in the collection of oral

fluid specimens by properly trained

individuals for the purpose of testing for

the presence of antibodies to human

immunodeficiency virus Type 1 (HIV–

1). The OraSure HIV–1 Oral Specimen

Collection Device consists of both an

absorbent cotton fiber pad treated with

a proprietary salt solution and gelatin

affixed to a plastic stick, and a

preservative solution supplied in a

plastic container. OraSure HIV–1 oral

fluid specimens are intended to be used

only with the Oral Fluid Vironostika

HIV–1 Microelisa System screening test

manufactured by Organon Teknika

Corp. The device is intended for use

with subjects 13 years of age or older.

On December 19, 1992, the premarket

approval application (PMA) was

referred to the Blood Products Advisory

Committee, an FDA advisory committee,

for review and recommendation. On

June 22, 1994, the PMA was referred to

the same advisory committee for

discussion of post-approval

requirements for surveillance studies.

On December 23, 1994, CBER

approved the application by a letter to

the applicant from the Acting Director,

Office of Blood Research and Review,

CBER. In response to additional

discussions between the manufacturer

and FDA, a revised approval letter was

issued on October 18, 1995.

FDA has determined that, to ensure

safe and effective use, the device is

restricted within the meaning of section

520(e) of the act (21 U.S.C. 360j(e))

under the authority of section

515(d)(1)(B)(ii) of the act (21 U.S.C.

360e(d)(1)(B)(ii)) insofar as: (1) Before

shipping the device to any customer,

Epitope, Inc., must have on file a ‘‘Letter

of Agreement for Physician’’ signed by

the physician who agrees to assume the

outlined responsibilities on behalf of the

customer; (2) the administration of the

device is restricted to individuals who

have been trained in the use of the

device according to approved labeling;

(3) testing of OraSure samples for

HIV–1 antibodies is restricted to the

Oral Fluid Vironostika HIV–1

Microelisa System screening test

manufactured by Organon Teknika

Corp.; (4) the device is not to be

provided to subjects for home use; (5)

the device is not to be used to screen

blood donors; and (6) prior to specimen

collection, a test subject must receive a

copy of the subject information sheet.

The sale, distribution, and use of the

device must not violate sections 502(q)

and (r) of the act (21 U.S.C. 352(q) and

352(r)).

A summary of the safety and

effectiveness data on which CBER based

its approval is on file in the Dockets

Management Branch (address above)

and is available from that office upon

written request. Requests should be

identified with the name of the device

and the docket number found in

brackets in the heading of this

document.

Opportunity for Administrative Review

Section 515(d)(3) of the act (21 U.S.C.

360e(d)(3)) authorizes any interested

person to petition, under section 515(g)

of the act, for administrative review of

CBER’s decision to approve this

application. A petitioner may request

either a formal hearing under part 12 (21

CFR part 12) of FDA’s administrative

practices and procedures regulations or

a review of the application and CBER’s

action by an independent advisory

committee of experts. A petition is to be

in the form of a petition for

reconsideration under § 10.33(b) (21

CFR 10.33(b)). A petitioner shall

identify the form of review requested

(hearing or independent advisory

committee) and shall submit with the

petition supporting data and

information showing that there is a

genuine and substantial issue of

material fact for resolution through

administrative review. After reviewing

the petition, FDA will decide whether to

grant or deny the petition and will

publish a notice of its decision in the

Federal Register. If FDA grants the

petition, the notice will state the issue

to be reviewed, the form of review to be

used, the persons who may participate

in the review, the time and place where

the review will occur, and other details.

Petitioners may, at any time on or

before June 24, 1996, file with the

Dockets Management Branch (address

above) two copies of each petition and

supporting data and information,

identified with the name of the device

and the docket number found in

brackets in the heading of this

document. Received petitions may be

seen in the office above between 9 a.m.

and 4 p.m., Monday through Friday.

This notice is issued under the

Federal Food, Drug, and Cosmetic Act

(secs. 515(d), 520(h) (21 U.S.C. 360e(d),

360j(h))) and under authority delegated

to the Commissioner of Food and Drugs

(21 CFR 5.10) and redelegated to the

Director, Center for Biologics Evaluation

and Research (21 CFR 5.53).

Dated: May 17, 1996.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 96–13176 Filed 5–23–96; 8:45 am]

BILLING CODE 4160–01–F

Food and Drug Administration

Advisory Committee; Notice of Meeting

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: This notice announces a

forthcoming meeting of a public

advisory committee of the Food and

Drug Administration (FDA). This notice

also summarizes the procedures for the

meeting and methods by which

interested persons may participate in

open public hearings before FDA’s

advisory committees.

FDA has established an Advisory

Committee Information Hotline (the

hotline) using a voice-mail telephone

system. The hotline provides the public

with access to the most current

information on FDA advisory committee

meetings. The advisory committee

hotline, which will disseminate current