[Federal Register: November 24, 2000 (Volume 65, Number 227)]
[Proposed Rules]
[Page 70538-70540]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr24no00-27]
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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
[[Page 70539]]
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