Federal Register / Vol. 65, No. 227 / Friday, November 24, 2000 / Notices 70573

Instrument Number of

respondents

Number of

responses

per

respondent

Average

burden

hours per

response

Total

burden

hours

ACF–200 .......................................................................................................................... 54 4 40 8,640

Estimated Total Annual Burden

Hours: 8,640.

Additional Information: Copies of the

proposed collection may be obtained by

writing to The Administration for

Children and Families, Office of

Information Services, 370 L’Enfant

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

20447, Attn: ACF Reports Clearance

Officer.

OMB Comment: OMB is required to

make a decision concerning the

collection of information between 30

and 60 days after publication of this

document in the Federal Register.

Therefore, a comment is best assured of

having its full effect if OMB receives it

within 30 days of publication. Written

comments and recommendations for the

proposed information collection should

be sent directly to the following: Office

of Management and Budget, Paperwork

Reduction Project, 725 17th Street,

N.W., Washington, D.C. 20503, Attn:

Desk Officer for ACF.

Dated: November 20, 2000.

Bob Sargis,

Reports Clearance Officer.

[FR Doc. 00–29995 Filed 11–22–00; 8:45 am]

BILLING CODE 4184–01–M

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 00N–1609]

Digoxin Products for Oral Use;

Reaffirmation of New Drug Status and

Conditions for Marketing

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is reaffirming its

determination that digoxin products for

oral use (tablets and elixir) are new

drugs and announcing the conditions

for marketing the products.

Manufacturers who wish to begin to

market or to continue marketing digoxin

products for oral use must submit new

drug applications (NDA’s) or

abbreviated new drug applications

(ANDA’s). Elsewhere in this issue of the

Federal Register, FDA is publishing a

proposed rule to revoke the regulations

that establishes conditions for marketing

digoxin products for oral use.

DATES: This notice is effective

November 24, 2000.

ADDRESSES: All communications in

response to this notice should be

identified with Docket No. 00N–1609

and directed to the appropriate office

listed as follows:

Applications under section 505(j) of

the Federal Food, Drug, and Cosmetic

Act (the act) (21 U.S.C. 355(j)): Office of

Generic Drugs, Center for Drug

Evaluation and Research, Food and

Drug Administration, 7500 Standish Pl.,

rm. E150, Rockville, MD 20855.

Applications under section 505(b) of

the act: Central Document Room, Center

for Drug Evaluation and Research, Food

and Drug Administration, 12229

Wilkins Ave., Rockville, MD 20852.

Requests for an opinion on the

applicability of this notice to a specific

product: Division of Prescription Drug

Compliance and Surveillance (HFD–

330), Center for Drug Evaluation and

Research, Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:

Mary E. Catchings, Center for Drug

Evaluation and Research (HFD–7), Food

and Drug Administration, 5600 Fishers

Lane, Rockville, MD 20857, 301–594–

2041.

SUPPLEMENTARY INFORMATION:

I. Background

Digoxin is a member of a group of

drugs known as cardiac glycosides. The

cardiac or digitalis glycosides are a

closely related group of drugs having in

common specific effects on the

myocardium. These drugs are found in

several plants and animals. The term

digitalis is used to designate the whole

group.

Since ancient times, squill (Urginea

(Scilla) maritima) and foxglove

(Digitalis purpurea) and other natural

sources of cardiac glycosides have been

used for their effects on the heart.

Digoxin, which is extracted from the

leaves of Digitalis lanata, was reportedly

discovered and developed in 1930 at the

Wellcome Chemical Works at Dartford.

According to Burroughs Wellcome (now

Glaxo Wellcome), the company has

manufactured and marketed a digoxin

product in the United States since 1934.

Digoxin has been used in the

treatment of certain cardiac disorders

for many years and labeled for use in

heart failure, atrial fibrillation, atrial

flutter, and paroxysmal atrial

tachycardia. Digoxin is available for oral

and intravenous administration.

Digoxin products for parenteral use

and digoxin solution in capsules have

previously been classified as new drugs

(July 27, 1972, and July 26, 1982,

respectively) and are subjects of

approved applications. This notice

addresses digoxin tablets and elixir.

Because of bioavailability problems

found to exist with digoxin tablets, FDA

has sought, over the years, to provide a

systematic regulatory approach to

ensure the uniformity of all marketed,

oral digoxin products. Since 1968,

digoxin tablets (and related drugs) have

been covered by a number of

compliance programs.

In April 1970, FDA began a program

to systematically test marketed lots of

digoxin tablets. FDA took this action

after the agency became aware of an

apparent potency problem with this

cardiac glycoside. As a result of this

testing program, from April to

November 1970, there were 79 recalls of

digoxin products. In October 1970, FDA

instituted a voluntary certification

program in which participating

manufacturers agreed not to release new

lots of digoxin tablets until samples of

the lots were tested by FDA and found

to meet the United States Pharmacopeia

(USP) requirements for potency and

content uniformity.

Later, studies showed evidence of

clinically significant differences in

bioavailability between some batches of

digoxin tablets made by different

manufacturers, and even between some

batches made by the same manufacturer.

Because of these problems and because

available data showed a general

correlation between bioavailability and

dissolution, the USP monograph for

digoxin tablets was revised to include a

requirement for dissolution.

In the Federal Register of January 22,

1974 (39 FR 2471), FDA issued a

regulation (21 CFR 130.51; now

§ 310.500 (21 CFR 310.500)) establishing

conditions for marketing digoxin

products for oral use (tablets and elixir).

The regulation: (1) Declared all digoxin

products for oral use (tablets and elixir)

to be new drugs, (2) required

70574 Federal Register / Vol. 65, No. 227 / Friday, November 24, 2000 / Notices

submission of ANDA’s and

bioavailability tests for all oral digoxin

products, (3) required a mandatory FDA

certification program for digoxin tablets

based on dissolution testing by the

National Center for Drug Analysis, (4)

required a recall of any previously

marketed batch of digoxin tablets found

to fail USP dissolution specifications,

and (5) set forth a labeling requirement

for all oral digoxin products. The

regulation announced the agency’s

intentions to initiate procedures to

monitor digoxin product formulations to

ensure that products requiring

reformulations complied with in vitro

test requirements and possessed

uniform batch-to-batch bioavailability.

Because of the narrow margin

between therapeutic and toxic levels of

digoxin and the potential for serious

risk to cardiac patients using digoxin

products that may vary in

bioavailability, the agency determined

that immediate implementation of the

corrective procedures detailed in the

regulation was necessary and made

§ 310.500 effective on the date of

publication in the Federal Register.

Even though the regulation was effective

immediately, FDA accepted comments

on § 310.500 for 30 days, until February

21, 1974.

As a result of the comments

submitted, FDA published notices in the

Federal Register of March 8, 1974 (39

FR 9184 and 9219), that stayed the time

for submission of ANDA’s, stayed the

requirement that labeling of digoxin

products conform to § 310.500(e), and

announced a public meeting to discuss

the labeling of digoxin. The notices

stated that the stay for submission of

ANDA’s would be lifted 30 days after a

final decision on labeling revisions had

been reached.

The submitted comments concerning

the labeling requirements were

reviewed by the agency’s Cardiovascular

and Renal Advisory Committee and

discussed at a public meeting. Later,

FDA published a proposed regulation in

the Federal Register of April 28, 1976

(41 FR 17755), to revise the labeling for

digoxin products set out in § 310.500(e).

FDA also proposed to lift the stay only

insofar as it affected the labeling

requirement. The agency believed that

revised labeling was necessary because

the labeling then being used for digoxin

tablets contained dosage information

suitable for the older, less bioavailable

formulations that the agency had

removed from the market through the

digoxin certification program.

Continued use of such older labeling

constituted a potential health hazard.

The agency concluded that revision of

the labeling was necessary as soon as

practicable to protect the public health.

Revisions were needed to correct dosage

and other recommendations for use and

warn against the use of such products in

the treatment of obesity.

FDA published a final regulation in

the Federal Register of September 30,

1976 (41 FR 43135), that amended

§ 310.500(e) by revising the required

labeling for digoxin products for oral

use. The rule lifted the stay for revised

labeling. The requirement for

submission of ANDA’s was stayed

pending resolution of the agency’s

ANDA policy.

This notice reaffirms FDA’s

determination of new drug status for

digoxin products for oral use and

announces the conditions for marketing

the products.

II. Legal Status

Digoxin products for oral use, as set

forth in § 310.500, are new drugs as

defined in section 201(p) of the act (21

U.S.C. 321(p)), and subject to the

requirements of section 505 of the act.

As discussed above, FDA based its

determination of new drug status on

new information that emerged about the

bioavailability of digoxin products for

oral use. Studies had shown significant

variation in bioavailability of the

products that occurred in batches from

a single manufacturer as well as in

batches produced by different

manufacturers. Because variations in

bioavailability can adversely affect the

safety and effectiveness of the products,

FDA concluded that the products could

not be considered generally recognized

as safe and effective and are new drugs

requiring approved applications for

marketing.

At the time that § 310.500 was

published, FDA had not approved any

NDA’s for digoxin products for oral use.

Since FDA stayed the requirement in

§ 310.500 for submission of ANDA’s,

FDA has regulated digoxin products for

oral use under the remaining

requirements in § 310.500.

In September 1993, Glaxo Wellcome

(then Burroughs Wellcome) submitted

to the agency an NDA (NDA 20–405) for

Lanoxin (digoxin) Tablets under section

505(b) of the act. The submission

included safety and effectiveness data

on the drug product. In addition to

published studies from the literature,

the submission included two original

studies sponsored by Glaxo Wellcome.

These were double-blind, placebocontrolled studies of Lanoxin Tablets in

treating congestive heart failure patients

taking angiotensin converting enzyme

(ACE) inhibitors and/or diuretics.

Based on its review of NDA 20–405

for Lanoxin Tablets, FDA concluded

that the application was approvable.

The agency determined that the issue of

labeling, including appropriate

indications, for the drug product should

be presented to the Cardiovascular and

Renal Drugs Advisory Committee.

During this time, the agency began a

systematic review of the labeling for

cardiac drugs in general.

In May 1996, the advisory committee

addressed the issue of labeling for

Lanoxin (digoxin) Tablets. The

committee recommended that digoxin

be indicated for resting and ambulatory

heart rate control in atrial fibrillation

and that use in atrial flutter be

excluded. The committee recommended

that the indication for heart failure

should state that most clinical trial data

came from trials where digoxin was

used in combination with diuretics and

ACE inhibitors. The committee also

considered preliminary results of The

Digitalis Investigation Group (DIG)

clinical trial conducted by the National

Heart, Lung, and Blood Institute of the

National Institutes of Health and the

Department of Veterans Affairs

Cooperative Studies Program. The DIG

trial was a randomized, double-blind,

placebo-controlled multicenter trial to

evaluate the effects of digoxin (Lanoxin)

on mortality from any cause and on

hospitalization for heart failure over a 3-

to 5-year period in patients with heart

failure and normal sinus rhythm. The

committee recommended that the final

results of the DIG trial be submitted to

the Lanoxin Tablets NDA and be

incorporated into the labeling.

Glaxo Wellcome submitted the results

of the DIG trial to the agency in April

1997. The results of the trial showed

that digoxin did not affect mortality

adversely.

Based on the review of NDA 20–405

for Lanoxin Tablets and the

recommendations of the Cardiovascular

and Renal Drugs Advisory Committee,

FDA approved NDA 20–405 for the

following indications:

Heart Failure: LANOXIN is indicated

for the treatment of mild to moderate

heart failure. LANOXIN increases left

ventricular ejection fraction and

improves heart failure symptoms as

evidenced by exercise capacity and

heart failure-related hospitalizations

and emergency care, while having no

effect on mortality. Where possible,

LANOXIN should be used with a

diuretic and an angiotensin-converting

enzyme inhibitor, but an optimal order

for starting these three drugs cannot be

specified. [Glaxo Wellcome received 3

years of exclusivity for this indication.]

Atrial Fibrillation: LANOXIN is

indicated for the control of ventricular

Federal Register / Vol. 65, No. 227 / Friday, November 24, 2000 / Notices 70575

response rate in patients with chronic

atrial fibrillation.

Because of the approval of NDA 20–

405, digoxin tablets are now eligible for

ANDA’s under section 505 of the act.

Therefore, by this notice, FDA is lifting

the stay for submitting ANDA’s for

digoxin products for oral use.

This notice reaffirms FDA’s previous

determination that digoxin products for

oral use are new drugs requiring

approved applications for marketing.

Because the new drug status of digoxin

has already been established by noticeand-comment rulemaking, the agency is

not providing a formal procedure for the

submission of claims that a particular

digoxin product for oral use is not

subject to the new drug provision of the

act. (Cf. 62 FR 43535, August 14, 1997

(oral levothyroxine sodium;

determination of new drug status).)

III. Conditions for Approval and

Marketing

On September 30, 1997, FDA

approved NDA 20–405 for Lanoxin

Tablets (62.5, 125, 187.5, 250, 375, and

500 micrograms) held by Glaxo

Wellcome Inc. for the indications listed

above.

Approval of an NDA under section

505(b) of the act and § 314.50 (21 CFR

314.50) or an ANDA under section

505(j) of the act and § 314.94 (21 CFR

314.94) is required as a condition for

marketing all digoxin products for oral

use. Such an ANDA should use Glaxo’s

NDA 20–405 as the reference listed

drug.

Elsewhere in this issue of the Federal

Register, FDA is publishing a proposed

rule to revoke § 310.500, thus

eliminating the conditions for marketing

digoxin products for oral use

established by that regulation.

Inquiries regarding procedures for

obtaining approval of NDA’s should be

directed to the Division of Cardio-Renal

Drug Products (HFD–110), Center for

Drug Evaluation and Research, Food

and Drug Administration, 5600 Fishers

Lane, Rockville, Maryland 20857, 301–

594–5300.

Inquiries regarding procedures for

obtaining approval of ANDA’s should be

directed to the Office of Generic Drugs

(HFD–600), Center for Drug Evaluation

and Research, Food and Drug

Administration, 7500 Standish Pl.,

Rockville, Maryland 20855, 301–827–

5845.

This notice is issued under the

Federal Food, Drug, and Cosmetic Act

(secs. 502, 505 (21 U.S.C. 352, 355).

Dated: November 15, 2000.

Margaret M. Dotzel,

Associate Commissioner for Policy.

[FR Doc. 00–29998 Filed 11–22–00; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Health Care Financing Administration

[HCFA–2118–CN]

Medicare, Medicaid, and CLIA

Programs; Continuance of the

Approval of COLA as a CLIA

Accreditation Organization; Correction

AGENCY: Health Care Financing

Administration (HCFA), HHS.

ACTION: Correction notice.

SUMMARY: In the October 31, 2000 issue

of the Federal Register (65 FR 64966),

we published a notice announcing the

continued approval of COLA (formerly

the Commission on Office Laboratory

Accreditation) as an accreditation

organization for laboratories under the

Clinical Laboratory Improvement

Amendments of 1988 (CLIA) program.

This document corrects a technical error

that appeared in that document.

EFFECTIVE DATE: The notice published on

October 31, 2000 (64 FR 64966) is

effective for the period October 31, 2000

through December 31, 2002.

FOR FURTHER INFORMATION CONTACT: Val

Coppola, (410) 786–3531.

SUPPLEMENTARY INFORMATION:

I. Background

In FR Doc. 00–27956 of October 31,

2000 (65 FR 64966), there was one

technical error. The error relates to our

inadvertently placing an incorrect

effective date in section II (Notice of

Continued Approval of COLA as an

Accreditation Organization) of the

Federal Register document. That date is

inconsistent with the correct effective

date, as presented in the EFFECTIVE DATE

section of the October 31, 2000 notice.

II. Correction of Error

In FR Doc. 00–27956 of October 31,

2000 (65 FR 64966), make the following

correction:

On page 64966, in the third column,

in the first full paragraph, remove

‘‘August 31, 2002’’ and in its place add

‘‘December 31, 2002’’.

Authority: Section 353 of the Public Health

Service Act (42 U.S.C. 263a).

Dated: November 17, 2000.

Brian P. Burns,

Deputy Assistant Secretary for Information

Resources Management.

[FR Doc. 00–29992 Filed 11–22–00; 8:45 am]

BILLING CODE 4120–01–M

DEPARTMENT OF HOUSING AND

URBAN DEVELOPMENT

[Docket No. FR–4557–N–47]

Federal Property Suitable as Facilities

To Assist the Homeless

AGENCY: Office of the Assistant

Secretary for Community Planning and

Development, HUD.

ACTION: Notice.

SUMMARY: This Notice identifies

unutilized, underutilized, excess, and

surplus Federal property reviewed by

HUD for suitability for possible use to

assist the homeless.

FOR FURTHER INFORMATION CONTACT:

Clifford Taffet, room 7266, Department

of Housing and Urban Development,

451 Seventh Street SW, Washington, DC

20410; telephone (202) 708–1234; TTY

number for the hearing- and speechimpaired (202) 708–2565 (these

telephone numbers are not toll-free), or

call the toll-free Title V information line

at 1–800–927–7588.

SUPPLEMENTARY INFORMATION: In

accordance with 24 CFR part 581 and

section 501 of the Stewart B. McKinney

Homeless Assistance Act (42 U.S.C.

11411), as amended, HUD is publishing

this Notice to identify Federal buildings

and other real property that HUD has

reviewed for suitability for use to assist

the homeless. The properties were

reviewed using information provided to

HUD by Federal landholding agencies

regarding unutilized and underutilized

buildings and real property controlled

by such agencies or by GSA regarding

its inventory of excess or surplus

Federal property. This Notice is also

published in order to comply with the

December 12, 1988 Court Order in

National Coalition for the Homeless v.

Veterans Administration, No. 88–2503–

OG (D.D.C.).

Properties reviewed are listed in this

Notice according to the following

categories: Suitable/available, suitable/

unavailable, suitable/to be excess, and

unsuitable. The properties listed in the

three suitable categories have been

reviewed by the landholding agencies,

and each agency has transmitted to

HUD: (1) Its intention to make the

property available for use to assist the

homeless, (2) its intention to declare the

property excess to the agency’s needs, or