[Federal Register Volume 65, Number 227 (Friday, November 24, 2000)]
[Proposed Rules]
[Pages 70538-70540]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-29997]



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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.

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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, Sec. 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 Sec. 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 Sec. 310.500 with 
digoxin tablets also subject to the certification procedure set forth 
in Sec. 310.500.
    Since publication of Sec. 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, 
placebo-controlled 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, 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 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

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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 
Sec. 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 Sec. 310.500 for digoxin tablets are now obsolete.
    Accordingly, FDA proposes to revoke Sec. 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.
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    \1\ U.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.
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    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.

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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.


Sec. 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