70538 Federal Register / Vol. 65, No. 227 / Friday, November 24, 2000 / Proposed Rules

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket No. 00N–1610]

RIN 0910–AC12

Digoxin Products for Oral Use;

Revocation of Conditions for

Marketing

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

revoke the regulation that establishes

conditions for marketing digoxin

products for oral use. This regulation is

no longer necessary because the

products, which are new drugs, can be

regulated under the approval process for

new drug applications (NDA’s) and

abbreviated new drug applications

(ANDA’s) as set forth in the Federal

Food, Drug, and Cosmetic Act (the act).

Elsewhere in this issue of the Federal

Register FDA is publishing a notice

with the agency’s conclusions regarding

the approval of the Lanoxin NDA and

the conditions for marketing oral

digoxin products.

DATES: Submit written comments by

February 22, 2001. See section II of this

document for the proposed effective

date of a final rule based on this

document.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 5630 Fishers Lane, rm.

1061, Rockville, MD 20852.

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

The regulation that the agency is

proposing to revoke, § 310.500 (21 CFR

310.500), was published in the Federal

Register of January 22, 1974 (39 FR

2471) (the January 1974 regulation), as

amended March 8, 1974 (39 FR 9184),

and September 30, 1976 (41 FR 43135).

The regulation announced FDA’s

determination that digoxin products for

oral use are new drugs within the

meaning of section 201(p) of the act (21

U.S.C. 321(p)) and set forth conditions

for marketing the products. FDA

established the regulation to provide a

systematic regulatory approach to

ensure uniformity of marketed oral

digoxin products. Studies had shown

clinically significant differences in

bioavailability of certain oral digoxin

products. This variability was a major

concern because of the drug’s narrow

therapeutic range and the potential risk

presented to patients using digoxin

products of varying bioavailability.

The conditions for marketing set forth

in § 310.500 include requirements for

submission of ANDA’s and

bioavailability tests for all oral digoxin

products, a mandatory FDA certification

program for digoxin tablets based on

dissolution testing by the National

Center for Drug Analysis, and labeling

requirements for all oral digoxin

products. The requirements for labeling

and submission of ANDA’s were stayed

(39 FR 9184 and 9219, March 8, 1974);

FDA later lifted the stay as it applied to

the labeling requirements and issued

revised labeling requirements (41 FR

43135, September 30, 1976). The

requirement for submission of ANDA’s,

however, was stayed indefinitely (41 FR

43135). Thus, until recently, FDA has

regulated all digoxin products for oral

use under the labeling requirements set

forth in § 310.500 with digoxin tablets

also subject to the certification

procedure set forth in § 310.500.

Since publication of § 310.500, the

following actions have occurred that

render the regulation unnecessary.

In September 1993, Glaxo Wellcome

(then Burroughs Wellcome) submitted

to the agency an NDA (NDA 20–405)

under section 505(b) of the act (21

U.S.C. 355(b)) for Lanoxin (digoxin)

Tablets. 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 agency’s

Cardiovascular and Renal Drugs

Advisory Committee (the 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 advisory

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 advisory 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

advisory 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, placebocontrolled 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 with the

recommendations of the 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

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, premarket approval of

digoxin products under batch

certification is no longer warranted.

FDA’s conclusions regarding the

approval of the Lanoxin NDA and the

conditions for marketing oral digoxin

products are published in a notice

elsewhere in this issue of the Federal

Federal Register / Vol. 65, No. 227 / Friday, November 24, 2000 / Proposed Rules 70539

1U.S. Department of Labor, Bureau of Labor

Statistics, ‘‘1999 Occupational Earnings Data,’’

Lawyer: ftp://ftp.bls.gov/pub/special.requests/lf/

aat39.txt, 26 April 2000.

Register. In that Federal Register notice,

FDA is reaffirming its determination

that digoxin products for oral use are

new drugs and requiring approved

applications for marketing.

In addition, the dissolution

requirements (i.e., the dissolution rates

and methods of measuring digoxin

tablet dissolution) specified in § 310.500

are no longer used as standards in the

certification program. The current

official United States Pharmacopeia

(USP) includes a monograph, including

dissolution requirements, for digoxin

tablets that FDA considers suitable.

Therefore, the dissolution requirements

specified in § 310.500 for digoxin tablets

are now obsolete.

Accordingly, FDA proposes to revoke

§ 310.500. This regulation is no longer

necessary because the products, which

are new drugs, can be regulated under

the approval process for NDA’s and

ANDA’s as set forth in section 505 of the

act.

II. Proposed Effective Date

FDA proposes that any final rule that

may issue based on this proposal

become effective 30 days after

publication of the final rule.

III. Environmental Impact

The agency has determined under 21

CFR 25.30(h) that this action is of a type

that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

IV. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(5 U.S.C. 601–612) (as amended by

subtitle D of the Small Business

Regulatory Fairness Act of 1996 (Public

Law 104–121)), and the Unfunded

Mandates Reform Act of 1995 (Public

Law 104–4). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize the benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity). Section 202(a) of

the Unfunded Mandates Reform Act of

1995 requires that agencies prepare a

written statement of anticipated costs

and benefits before proposing any rule

that may result in an expenditure by

State, local, and tribal governments, in

the aggregate, or by the private sector, of

$100 million in any one year (adjusted

annually for inflation). Under the

Regulatory Flexibility Act, unless an

agency certifies that a rule will not have

a significant economic impact on a

substantial number of small entities, the

agency must analyze regulatory options

that would minimize any significant

impact of a rule on small entities.

The agency has reviewed this

proposed rule and has determined that

it is consistent with the regulatory

philosophy and principles identified in

the Executive order and these two

statutes. The Unfunded Mandates

Reform Act of 1995 does not require

FDA to prepare a statement of costs and

benefits for the proposed rule because

the proposed rule is not expected to

result in any 1-year expenditure that

would exceed $100 million adjusted for

inflation. The current inflation-adjusted

statutory threshold is $110 million. No

further analysis is required under the

Regulatory Flexibility Act because the

agency has determined that this

proposed rule will not have a significant

effect on a substantial number of small

entities.

Several studies have indicated a

significant variation in the

bioavailability of digoxin products for

oral use. Concerned that this variation

in bioavailability would adversely affect

safety and effectiveness, FDA published

the January 1974 regulation that

established conditions for marketing

digoxin products for oral use. This

regulation included requirements for

ANDA’s and bioavailability test results

for all oral digoxin products, a

mandatory FDA batch certification

program for digoxin tablets, and revised

labeling for all oral digoxin products.

On March 30, 1974, the requirements for

labeling and ANDA submissions were

stayed. On September 30, 1976, the

agency lifted the stay for the labeling

requirement. Digoxin tablets continue to

be regulated under the certification

procedure. On September 30, 1997, FDA

approved an NDA for digoxin tablets. As

a result, manufacturers of digoxin

tablets are now eligible to obtain

ANDA’s. The agency is now publishing

a notice reaffirming its determination

that all oral digoxin products are new

drugs and lifting the stay of the

requirements for submitting ANDA’s.

Therefore, manufacturers of digoxin

products will be required to obtain an

approved marketing application to enter

or remain on the market. As batch

certifications are no longer considered

necessary, this proposed rule would

revoke the January 1974 regulation.

Presently, there are three

manufacturers of digoxin tablets. Two of

these companies have already obtained

either an NDA or an ANDA. Once FDA

requires these products to have

approved applications for marketing,

the remaining company will need to

obtain an ANDA to remain on the

market. In addition, FDA will require

the two manufacturers of digoxin elixir

to obtain approved applications. The

agency estimates that it will take these

companies up to 480 hours to complete

the paperwork requirements associated

with the submission of either an ANDA

or a 505(b)(2) application. Applying the

1999 labor rate of approximately $41 per

hour for a regulatory affairs specialist

(with a 40 percent adjustment for

benefits),1 this one-time cost totals

approximately $60,000 (3 submissions x

480 hours x $41/hour) for all current

manufacturers, or $20,000 (480 x $41)

per submission. FDA estimates that

there were two market entrants over the

past 10 years. Based on this data, the

agency assumes that two manufacturers

of digoxin products for oral use may

enter the marketplace each decade,

resulting in possible future submission

costs for potential new manufacturers.

Some additional annual costs may also

be incurred over the life of the

application. Although manufacturers

may experience some savings from the

removal of the batch certification

requirement, this savings will be

negligible.

According to the Small Business

Administration, manufacturers of

pharmaceutical preparations with 750

or fewer employees are considered

small entities. Applying this definition,

only one of the four current

manufacturers that will incur

submission costs is small. In addition,

these costs are likely to represent less

than 1 percent of gross revenue.

Therefore, the agency certifies that this

action will not have a significant

economic effect on a substantial number

of small entities.

V. Paperwork Reduction Act of 1995

This proposed rule does not require

information collection subject to review

by the Office of Management and

Budget (OMB) under the Paperwork

Reduction Act of 1995 (Public Law 104–

13). The information collection consists

of the submission of NDA’s or ANDA’s

for digoxin products for oral use. The

information collection requirements for

the submission of NDA’s and ANDA’s

are contained in 21 CFR part 314 and

have been approved under OMB Control

Number 0910–0001, which expires on

November 30, 2001.

70540 Federal Register / Vol. 65, No. 227 / Friday, November 24, 2000 / Proposed Rules

VI. Requests for Comments

Interested persons may submit to the

Dockets Management Branch (address

above) written comments regarding this

proposal by February 22, 2001. 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. Received comments may be

seen in the Dockets Management Branch

between 9 a.m. and 4 p.m., Monday

through Friday.

List of Subjects for 21 CFR Part 310

Administrative practice and

procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping

requirements.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, it is proposed that

21 CFR part 310 be amended as follows:

PART 310—NEW DRUGS

1. The authority citation for 21 CFR

part 310 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352,

353, 355, 360b-360f, 360j, 361(a), 371, 374,

375, 379e; 42 U.S.C. 216, 241, 242(a), 262,

263b-263n.

§ 310.500 [Removed]

2. Section 310.500 Digoxin products

for oral use; conditions for marketing is

removed.

Dated: November 17, 2000.

Margaret M. Dotzel,

Associate Commissioner for Policy.

[FR Doc. 00–29997 Filed 11–22–00; 8:45 am]

BILLING CODE 4160–01–F

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Parts 52 and 81

[MI75–7284b; FRL–6907–2]

Approval and Promulgation of State

Implementation Plans; Michigan

AGENCY: Environmental Protection

Agency.

ACTION: Notice of proposed rulemaking.

SUMMARY: The Environmental Protection

Agency (EPA) is proposing to adjust the

applicability date for reinstating the 1-

hour ozone National Ambient Air

Quality Standard (NAAQS) in Allegan

County, Michigan and is proposing on

a determination that this area has

attained the 1-hour ozone NAAQS. This

determination is based on 3 consecutive

years of complete, quality-assured,

ambient air monitoring data for the

1997–1999 ozone seasons that

demonstrate that the area has attained

the ozone NAAQS. On the basis of this

determination, EPA is also proposing

that certain attainment demonstration

requirements, and certain related

requirements of part D of subchapter I

of the Clean Air Act (CAA), do not

apply to Allegan County.

EPA is also proposing to approve the

State of Michigan’s request to

redesignate Allegan County to

attainment for the 1-hour ozone

NAAQS. Michigan submitted the

redesignation request for these areas on

September 1 and October 13, 2000. EPA

is also proposing to approve the State’s

plan for maintaining the 1-hour ozone

standard for the next 10 years as a

revision to the Michigan State

Implementation Plan (SIP). In this direct

final rule, EPA is also notifying the

public that we believe the motor vehicle

emissions budgets for volatile organic

compounds (VOC) and oxides of

nitrogen ( NOX) in the Allegan County

maintenance plan are adequate for

conformity purposes and approvable as

part of the maintenance plan.

In the final rules section of this

Federal Register, EPA is approving the

State’s request as a direct final rule

without prior proposal because EPA

views this action as noncontroversial

and anticipates no adverse comments. A

detailed rationale for approving and

disapproving portions of the State’s

request is set forth in the direct final

rule. The direct final rule will become

effective without further notice unless

the Agency receives relevant adverse

written comment on this proposed rule

within 30 days of this publication.

Should EPA receive adverse comment,

it will publish a document informing

the public that the direct final rule will

not take effect and that EPA will address

adverse comments in a subsequent final

rule based on this proposed rule. If EPA

does not receive adverse comments, the

direct final rule will take effect on the

date stated in that document and EPA

will not take further action on this

proposed rule. EPA does not plan to

institute a second comment period on

this action. Any parties interested in

commenting on this document should

do so at this time.

DATES: EPA must receive written

comments by December 26, 2000.

ADDRESSES: Send written comments to:

Carlton T. Nash, Chief, Regulation

Development Section, Air Programs

Branch (AR–18J), United States

Environmental Protection Agency, 77

West Jackson Boulevard, Chicago,

Illinois 60604.

FOR FURTHER INFORMATION CONTACT: John

Mooney at (312) 886–6043.

SUPPLEMENTARY INFORMATION: For

additional information see the direct

final rule published in the rules section

of this Federal Register. Copies of the

documents relevant to this action are

available for public inspection during

normal business hours at the above

address. (Please telephone John Mooney

at (312) 886–6043 before visiting the

Region 5 Office.)

Authority: 42 U.S.C. 7401–7671 et seq.

Dated: November 15, 2000.

Gary Gulezian,

Acting Regional Administrator, Region 5.

[FR Doc. 00–30005 Filed 11–22–00; 8:45 am]

BILLING CODE 6560–50–P

LEGAL SERVICES CORPORATION

45 CFR Chapter XVI

LSC Regulations Review

AGENCY: Legal Services Corporation.

ACTION: Request for public comment.

SUMMARY: As part of its ongoing efforts

to improve the administration of

regulatory programs and requirements,

Legal Services Corporation is soliciting

public comment on its regulations

toward the development of a regulatory

agenda for 2001 and beyond.

DATES: Written comments must be

received on or before January 8, 2001.

ADDRESSES: Written comments may be

submitted by mail, fax or email to

Mattie C. Condray at the addresses

listed below.

FOR FURTHER INFORMATION CONTACT:

Mattie C. Condray, Senior Assistant

General Counsel, Office of Legal Affairs,

Legal Services Corporation, 750 First

Street, NE, Washington, DC 20002–

4250; 202/336–8817 (phone); 202/336–

8952 (fax); mcondray@lsc.gov.

SUPPLEMENTARY INFORMATION: The Legal

Services Corporation’s mission is to

promote equal access to the system of

justice and improve opportunities for

low-income people throughout the

United States by making grants for the

provision of high-quality civil legal

assistance to those who would be

otherwise unable to afford legal counsel.

As part of its ongoing efforts to better

serve this mission, the LSC Board of

Directors adopted a five-year strategic

plan, ‘‘LSC Strategic Directions 2000—

2005’’ in January of 2000. One element

of this plan involves reviewing ‘‘the

competitive grantmaking process, the

performance standards applicable to

LSC grantees, and LSC’s statutory and