[Federal Register: June 26, 2002 (Volume 67, Number 123)]
[Rules and Regulations]               
[Page 42992-42997]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26jn02-5]                         

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 310

[Docket Nos. 76N-0080 and 00N-1610]
RIN 0910-AC12

 
Digoxin Products for Oral Use; Revocation of Conditions for 
Marketing

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY:  The Food and Drug Administration (FDA) is revoking the 
regulation establishing 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 (NDAs) and abbreviated new drug applications 
(ANDAs) as set forth in the Federal Food, Drug, and Cosmetic Act (the 
act).

DATES: This rule is effective July 26, 2002. FDA does not plan to take 
regulatory action against currently marketed unapproved digoxin elixir 
products before June 28, 2004. Any unapproved digoxin elixir introduced 
after June 26, 2002, will be subject to regulatory action on July 26, 
2002. Any unapproved digoxin tablet will be subject to regulatory 
action on July 26, 2002.

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

    In the Federal Register of November 24, 2000 (65 FR 70538), FDA 
proposed to revoke Sec. 310.500 (21 CFR 310.500), which established 
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 submission of ANDAs 
and bioavailability tests for all oral digoxin products (the 
requirement for the submission of ANDAs was stayed indefinitely (41 FR 
43135, September 30, 1976)), (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 United 
States Pharmacopeia (USP) dissolution specifications, and (5) set forth 
a labeling requirement for all oral digoxin products.
    In the preamble to the proposed rule, FDA described actions that 
have occurred since Sec. 310.500 was published that render the 
regulation unnecessary. The agency discussed the 1997 approval of NDA 
20-405 for Lanoxin (digoxin) Tablets and described the indications for 
the tablets, which differ from the indications for oral digoxin drug 
products set forth in Sec. 310.500. The agency explained that because 
of the approval of NDA 20-405, digoxin tablets are now eligible for 
ANDAs under section 505 of the act (21 U.S.C. 355).
    The agency also noted that the dissolution requirements specified 
in Sec. 310.500 are no longer used as standards in the certification 
program and are therefore obsolete. The agency concluded that 
regulation of these products under batch certification was no longer 
warranted.
    The proposed rule referenced a companion notice published elsewhere 
in the Federal Register of November 24, 2000 (65 FR 70573), reaffirming 
the new drug status of oral digoxin products and requiring approved 
applications for marketing. In that notice, FDA lifted the stay for 
submitting ANDAs for digoxin products for oral use.

II. Comments and the Agency's Response

    Interested persons were given until February 22, 2001, to submit 
comments on the proposal. FDA received comments from four manufacturers 
of drug products subject to the proposal.
    (Comment 1) Three of the four submitted comments agreed that the 
agency should revoke Sec. 310.500. One comment identified several 
public health reasons to revoke Sec. 310.500. Those reasons are 
described in section II of this document and incorporated into the 
agency's response to the one comment that opposed revocation of 
Sec. 310.500.

A. Opposition to Proposed Rule

    (Comment 2) One comment opposed the agency's proposed rule to 
revoke Sec. 310.500, contending that the batch certification procedure 
is sufficient for FDA to regulate digoxin tablets and that the proposed 
rule is inadequate because FDA failed to identify a public health 
reason or change of facts or circumstances to justify revoking its 
regulation of digoxin tablets under batch certification.
    FDA disagrees with this comment. The integrity of the batch 
certification process, the principal concern of the comment, is not the 
relevant issue. The relevant issue is whether the certification 
procedure is still warranted in light of new information or changing 
circumstances. FDA concludes it is not warranted and, as explained in 
section II of this document, has determined that revocation of 
Sec. 310.500 is rationally related to FDA's statutory obligation to 
ensure that marketed oral digoxin drug products are safe, effective, 
and properly labeled as reflected by current scientific knowledge and 
information.
    In its November 2000 proposed rule and a companion notice published 
in the same issue of the Federal Register,

[[Page 42993]]

FDA described the reasons for the agency's plan to revoke Sec. 310.500. 
As discussed in section II of this document, the agency believes those 
reasons are still valid and that revocation of the regulation is 
appropriate and required under the circumstances.
    As noted in the proposed rule and companion notice, along with 
other prior notices referenced in the proposed rule, in 1974 FDA 
established the conditions for marketing oral digoxin drug products in 
Sec. 310.500 because of safety concerns with digoxin products on the 
market. 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 index and the 
potential risk presented to patients using digoxin products of varying 
bioavailability. Therefore, FDA established the regulations to provide 
a systematic regulatory approach to ensure uniformity of marketed oral 
digoxin products.
    The conditions for marketing included, among other things, 
requirements for submission of ANDAs, a batch certification program for 
digoxin tablets based on dissolution testing, and labeling requirements 
for all oral digoxin drug products. The requirement for ANDAs was later 
stayed pending resolution of the agency's ANDA policy. Absent 
submission of ANDAs, the batch certification program was the only 
preclearance requirement for digoxin tablets. The batch certification 
program was not intended to be a permanent solution to the problem of 
digoxin variability, but a stopgap measure to bring the potential for a 
serious health problem under control.
    In that 1974 regulation, the agency also announced its 
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)). Because of 
the need for an optimal regulatory program to ensure the uniformity of 
oral digoxin drug products, FDA has, over the years, considered various 
approaches to bring digoxin into the new drug approval system.
    The approval of NDA 20-405 for Lanoxin Tablets represented the 
first step in regulating all oral digoxin products under the 
requirements of section 505 of the act and the corresponding 
regulations. Approval of that NDA was also important because it 
provided data to help establish in vivo bioavailability and 
bioequivalence standards for oral digoxin drug products.
    The approval of NDA 20-405 and the new information that emerged 
from the agency's review of the NDA provide a rational basis for the 
agency's actions to revoke Sec. 310.500. Because the agency has 
approved an NDA for digoxin tablets, oral digoxin drug products are no 
longer covered by the exemptions set forth in Compliance Policy Guide 
(CPG) 7132c.02. That CPG provides priorities for regulating marketed 
new drugs without approved NDAs or ANDAs, such as oral digoxin products 
regulated under Sec. 310.500.
    As noted in one comment, FDA's decision to revoke Sec. 310.500 is 
also supported by safety concerns related to the differences in 
labeling of the Lanoxin drug product and the labeling required under 
Sec. 310.500. FDA approved NDA 20-405 for treatment of mild to moderate 
heart failure and for atrial fibrillation. The labeling of Sec. 310.500 
provides for use of digoxin in congestive heart failure (all degrees), 
atrial fibrillation, atrial flutter, paroxysmal atrial tachycardia, and 
cardiogenic shock.
    The labeled indications for new drugs, such as oral digoxin drug 
products, must be supported by substantial evidence derived from 
adequate and well-controlled investigations, including clinical 
investigations. (See section 505(d) of the act (21 U.S.C. 355(d) and 
Secs. 314.126, 201.56, and 201.57 (21 CFR 314.126, 201.56, and 
201.57).) Labeling indications that are not supported by adequate and 
well-controlled studies are false and misleading, in violation of 
section 502(a) of the act (21 U.S.C. 352(a)).
    Except for the data to support the two indications approved in NDA 
20-405, the agency is not aware of any adequate and well-controlled 
studies to support the indications for use in Sec. 310.500. Thus, the 
labeling of oral digoxin as set forth in Sec. 310.500 is outdated and 
does not reflect current scientific and medical information about oral 
digoxin. Moreover, marketing of oral digoxin drug products with 
labeling described in Sec. 310.500 could present a risk to patients 
because substantial scientific evidence to establish the safety and 
effectiveness of all of the indications in that labeling has not been 
established.
    In addition, the criteria in Sec. 310.500 are not current because 
the dissolution requirements specified in that regulation are no longer 
used as standards in the certification program. The dissolution 
requirements in Sec. 310.500 differ from those in the current official 
U.S.P. monograph for oral digoxin tablets that FDA considers 
scientifically appropriate. Therefore, the dissolution requirements 
specified in Sec. 310.500 for digoxin tablets are obsolete.
    Furthermore, as described in a comment, Sec. 310.500 lacks the 
uniform standards of the new drug approval system that ensure 
predictable bioavailability for oral digoxin products. Digoxin is a 
potent drug with a narrow therapeutic index. Slight variations in 
bioavailability can result in toxicity or loss of effect. Formulation 
and manufacturing controls are critical to the safe and effective use 
of oral digoxin drug products. Review of oral digoxin through the new 
drug approval process is necessary to provide adequate evidence of 
safety and substantial evidence of effectiveness, as well as adequate 
information about formulation and manufacturing procedures.
    In addition to approval requirements under the new drug approval 
system, all oral digoxin products must be subject to the same 
postmarketing requirements so that changes that may affect the safety 
or effectiveness of the products can be monitored. Sponsors of products 
not approved through the new drug approval process, such as oral 
digoxin products under Sec. 310.500, may reformulate their products or 
make manufacturing changes without seeking FDA approval. Such changes 
may affect bioavailability and hence may affect the safety or 
effectiveness of the products.
    Additionally, although manufacturers of such unapproved products 
are required under 21 CFR 310.305 to report adverse events that are 
serious and unexpected, they are not required to report all adverse 
events associated with drug use. In contrast, manufacturers of approved 
new drug products are required to report all adverse events under 21 
CFR 314.80. Consequently, adverse drug events that may reflect problems 
with the safety or effectiveness of oral digoxin products may not be 
reported.
    Moreover, allowing oral digoxin products to be marketed under 
Sec. 310.500 and the new drug approval process creates confusion in the 
marketplace regarding the substitutability or interchangeability of the 
drug products. Products marketed under Sec. 310.500 and those approved 
under the new drug approval system may have differences in 
bioavailability. Furthermore, marketed oral digoxin products cannot be 
considered to be therapeutically equivalent, and therefore 
substitutable, unless equivalence is demonstrated through appropriate 
bioequivalence studies. Regulating all oral digoxin drug products under 
the same approval

[[Page 42994]]

process would eliminate those safety concerns.
    As discussed in section I of this document and in the November 24, 
2000, proposed rule and its companion notice published in the same 
issue of the Federal Register, the conditions established in 
Sec. 310.500 for marketing oral digoxin products either are obsolete or 
no longer warranted. Because of the approval of the NDA for digoxin 
tablets and the new drug status of oral digoxin drug products, all oral 
digoxin products can and must be regulated under the new drug approval 
process for NDAs and ANDAs as set forth in section 505 of the act. 
Regulation through this process protects the public health by ensuring 
the safety and efficacy of each oral digoxin drug product. Therefore, 
the agency is revoking that regulation.

B. Requests for Extension of Time

    As proposed, the final rule would become effective 30 days after 
its date of publication in the Federal Register.
    (Comment 3) Three comments stated that additional time is needed to 
prepare, submit, and obtain approval of an NDA.
1. Digoxin Elixir
    Two comments from manufacturers of digoxin elixir requested a 2-
year compliance period. One comment, characterizing digoxin elixir as 
medically necessary, noted that there are only two manufacturers of 
digoxin elixir drug products and expressed concern that a shortage of 
digoxin elixir drug products may occur if such products were removed 
from the market 30 days after publication of the final rule in the 
Federal Register. The comment further indicated that preparation of an 
application for digoxin elixir is complicated by the fact that there is 
no reference listed drug for digoxin elixir in FDA's ``Approved Drug 
Products with Therapeutic Equivalence Evaluations'' (Orange Book), and 
therefore, no guidance is currently available from the agency on which 
to base a submission for digoxin elixir drug products.
    Digoxin elixir is a medically necessary dosage form. It is used 
primarily in the pediatric population for the treatment of atrial 
fibrillation and congestive heart failure, both serious and potentially 
life-threatening diseases/conditions. Available alternative therapies 
are not approved for treating atrial fibrillation and congestive heart 
failure in the pediatric population. Such therapies are limited in 
their use because of toxicities, lack of safety and efficacy data in 
the pediatric population, and/or lack of a pediatric formulation 
allowing for consistent administration to children. There should not be 
a disruption in the marketplace for patients who need digoxin elixir. 
In order to protect the public health, FDA plans to exercise its 
enforcement discretion and not take regulatory action against currently 
marketed unapproved digoxin elixir products before June 28, 2004. This 
should allow sufficient time for a manufacturer to conduct the required 
tests, evaluate the data, and prepare and submit a new drug application 
to FDA. After that date, any digoxin elixir drug product on the market 
without an approved NDA or ANDA will be subject to regulatory action.
2. Digoxin Tablets
    A manufacturer of digoxin tablets contends that FDA must extend the 
effective date of the final rule for at least 2 years to allow current 
producers and marketers of the drug products subject to the 
certification program to prepare, submit, and obtain an approved new 
drug application.
    a. Lack of notice. In its comments, the manufacturer implies that 
the firm was not aware of FDA's intent to revoke Sec. 310.500. (The 
comment's allegation that the proposed rule was issued to settle a 
lawsuit is spurious. The agency was preparing the proposed rule long 
before the party to that suit even approached the agency.)
    The proposed rule itself provides reasonable notice of the agency's 
intent. The manufacturer has had more than a year in which to continue 
marketing under Sec. 310.500 and, at the same time, pursue approval of 
an ANDA.
    Moreover, a reasonably observant member of the drug industry would 
have known for a number of years that FDA intended to revoke 
Sec. 310.500 and that applications approved through the new drug 
approval process would be required. For example, articles in the trade 
press have announced the agency's intention to require approval of oral 
digoxin through the new drug approval process. (See e.g., F-D-C 
Reports, July 6, 1992 at 7.) NDA 20-405 for Lanoxin (digoxin) Tablets 
was approved in September 1997. The approval was published in FDA's 
``Approved Drug Products with Therapeutic Equivalence Evaluations,'' 
and also was reported in the trade press. (See e.g., F-D-C Reports, 
October 6, 1997 at T&G-2.) Certainly since that time, if not many years 
before, the drug industry has known that FDA would change its approach 
for regulating oral digoxin products and that the agency would take 
action to revoke Sec. 310.500.
    b. Takings under the fifth amendment. The manufacturer argues that 
if its digoxin drug product is removed from the market 30 days after 
publication of the final rule in the Federal Register, the potential 
loss to its company would be substantial and could constitute a 
``taking'' for which the Federal Government could be financially 
liable. The manufacturer did not submit any evidence or analysis to 
support its views.
    FDA disagrees that this final rule effects a taking in violation of 
the fifth amendment of the United States Constitution. The Supreme 
Court has developed three factors to consider in assessing whether a 
regulatory taking has occurred: (1) The character of the governmental 
action, (2) its economic impact, and (3) its interference with 
reasonable investment-backed expectations. (See Ruckelshaus v. Monsanto 
Co., 467 U.S. 986, 1005 (1984).)
    The force of any one of these factors may be ``so overwhelming * * 
* that it disposes of the taking question'' (Ruckelshaus, 467 U.S. at 
1005) (finding interference with reasonable investment-backed 
expectations by use of trade secret information in pesticide approval 
process to be decisive). So, for example, if the economic impact is to 
rob real property of ``all economically beneficial uses,'' the 
regulation effects a taking (Lucas v. South Carolina Coastal Council, 
112 S. Ct. 2886, 2899 (1992) emphasis in original). Regulations that 
cause a temporary denial of property use, however, are not subject to 
such ``per se'' rules but entail complex factual assessments of the 
purposes and economic effects of government actions. See Tahoe-Sierra 
Preservation Council v. Tahoe Regional Planning Agency, No. 00-1167, 
2002 WL 654431 (U.S. April 23, 2002). When examined in light of these 
three factors, FDA's revocation of Sec. 310.500 clearly does not effect 
a compensable taking under the fifth amendment of the Constitution.
    i. Character of the governmental action. With respect to the first 
factor, courts are more likely to find a taking when the interference 
with property can be characterized as a physical invasion by the 
Government (e.g. United States v. Causby, 328 U.S. 256, 261-62 (1946) 
(characterizing Government's use of flight path just over property as 
physical invasion)) than when the interference is caused by a 
regulatory program that ``adjust[s] the benefits and burdens of 
economic life to promote the common good.'' (See Penn Central Transp. 
Co. v. City of New York, 438 U.S. 104, 124 (1978).) Courts have 
accorded particular deference to governmental action taken

[[Page 42995]]

to protect the public interest in health, safety, and welfare. (See 
Keystone Bituminous Coal Ass'n v. DeBenedictis, 480 U.S. 470, 488 
(1987).)
    In this case the governmental action is associated with a 
regulatory program designed to protect the health and safety of the 
public. Revocation of Sec. 310.500 is intended to ensure that digoxin 
drug products on the market meet the current safety and efficacy 
product approval standards and are regulated in the same manner as 
other drug products under the act. As such, it does not constitute 
governmental action that would be considered a taking.
    ii. Economic impact. The second factor to consider is the economic 
impact of the governmental action. ``There is no fixed formula to 
determine how much diminution in market value is allowable without the 
fifth amendment coming into play'' (Florida Rock Indus., Inc. v. United 
States, 791 F.2d 893, 901 (Fed. Cir. 1986), cert. denied, 479 U.S. 1053 
(1987)). It is clear, however, that a regulation's economic impact may 
be great without rising to the level of a taking. (See Pace Resources 
Inc. v. Shrewsbury Township, 808 F.2d 1023, 1031 (3d Cir.), cert. 
denied, 482 U.S. 906 (1987) (no taking even given reduction in value 
from $800,000 to $60,000); Village of Euclid v. Ambler Realty Co., 272 
U.S. 365 (1926) (no taking despite 75 percent diminution in value).) 
Mere denial of the most profitable or beneficial use of property does 
not require a finding that a taking has occurred. (See Florida Rock 
Indus., Inc. v. United States, 791 F.2d 893, 901 (Fed. Cir. 1986), 
cert. denied 479 U.S. 1053 (1987); see also Andrus v. Allard, 444 U.S. 
51, 66 (1979).)
    In assessing whether a regulation effects a taking, the Supreme 
Court has considered whether the regulation denies an owner the 
``economically viable'' use of its property. See, e.g., Keystone, 480 
U.S. at 499. This analysis involves looking not just at what has been 
lost, but at the whole ``bundle'' of property rights. Andrus v. Allard, 
444 U.S. at 65-66. Courts focus on the remaining uses permitted and the 
residual value of the property. Pace Resources, 808 F.2d at 1031. 
Although it is undeniable that compliance with these regulations will 
cost money and may mean that certain product names must be altered, 
companies will not be denied the economically viable use of their 
property.
    By revoking the regulation, the agency is not taking away the 
ability of manufacturers to market digoxin drug products. The one 
manufacturer that might be affected does not complain in its comments 
that it would be unable to produce digoxin, but that it would face 
``severe difficulty re-entering the market and re-establishing its 
position after an absence which could span a year or more while waiting 
for FDA to approve an NDA or ANDA.'' The manufacturer may submit an NDA 
or ANDA and then market its digoxin drug product after approval. It is 
possible that this could be done with little or no interruption in 
marketing. Therefore, the manufacturer has ``remaining uses'' of its 
property and does not suffer loss of ``economically viable use'' of 
property. (See Pace Resources, 808 F. 2d at 1031; and Keystone, 480 
U.S. at 499.) Consequently, this factor also does not support a 
conclusion that revocation of the regulatory provision is a taking.
    iii. Investment-backed expectation.The final factor to consider is 
whether a company has a reasonable investment-backed expectation in 
continuing to use the property at issue. To be reasonable, expectations 
must take into account the power of the State to regulate in the public 
interest. (See Pace Resources, 808 F.2d at 1033.) Reasonable 
expectations must also take into account the regulatory environment, 
including the foreseeability of changes in the regulatory scheme. ``In 
an industry that long has been the focus of great public concern and 
significant government regulation,'' Monsanto, 467 U.S. at 1008, the 
possibility is substantial that there will be additional regulatory 
requirements. ``Those who do business in the regulated field cannot 
object if the legislative scheme is buttressed by subsequent amendments 
to achieve the legislative end.'' (See Connolly v. Pension Benefit 
Guarantee Corp., 475 U.S. 211, 227 (1986).)
    The manufacturer is a regulated body and, as such, has been aware 
from the time it began manufacturing digoxin that the regulatory scheme 
could be modified. As described in section II.B.2.a of this document, 
the manufacturer has had notice for many years that the regulatory 
scheme in Sec. 310.500 would be changed. As with the other factors, 
analysis of this factor establishes that revoking Sec. 310.500 is not a 
taking under the fifth amendment.
    When examined in light of these three factors, FDA's revocation of 
Sec. 310.500 clearly does not effect a compensable taking under the 
fifth amendment of the Constitution.
    c. Market disruption. Contrary to the comment's assertion, FDA does 
not believe that a disruption in the marketplace of digoxin tablets 
will occur if, should it be necessary, an unapproved digoxin tablet 
product supplying from 15 to 20 percent of the market is taken off the 
market. As the comment recognizes, there are two other manufacturers of 
digoxin tablets, holders of approved NDAs. FDA believes that these 
manufacturers are capable of satisfying an increased demand for digoxin 
tablets.
    d. Levothyroxine sodium. In further support of its contention that 
FDA extend the effective date of the final rule, the comment alleges 
that the digoxin tablet drug products are in a situation similar to 
that in which sponsors of levothyroxine sodium were allowed a minimum 
of 3 years to obtain approved NDAs. The comment contends that FDA 
should accord comparable time for completion and review of digoxin 
NDAs.
    The agency's handling of levothyroxine sodium does not provide a 
necessary precedent for setting an effective date for approval of 
digoxin tablet drug products. The facts involving digoxin tablets and 
levothyroxine sodium differ in at least two significant ways. First, 
the Federal Register notice of August 14, 1997 (62 FR 43535) (announced 
that orally administered drug products containing levothyroxine sodium 
are new drugs and announced the conditions for marketing the products), 
was the first time FDA issued any public announcement of the new drug 
status of levothyroxine sodium products. By contrast, in the Federal 
Register of November 24, 2000 (65 FR 70573), FDA reaffirmed the 
agency's 1974 determination that digoxin products for oral use are new 
drugs requiring approved NDAs. Second, and most importantly, when FDA 
published the notice on levothyroxine sodium drug products, there were 
no approved NDAs for the products. When FDA published the proposed rule 
on digoxin, on the other hand, there were two approved products on the 
market for digoxin tablets under NDA 20-405 and ANDA 40-282. Because 
FDA determined that levothyroxine sodium drug products are medically 
necessary, sponsors of the products were allowed 3 years to obtain 
approved NDAs. In contrast, while digoxin tablets may be medically 
necessary, there is no medical necessity for unapproved digoxin 
tablets. Unapproved digoxin tablets may be indicated for serious 
cardiac conditions, as the comment claims, but there are approved 
digoxin tablets in sufficient quantity to meet the market demand.
    To summarize, the comment has set forth no sufficient reason to 
justify an extension. Industry has been on notice for a number of years 
that Sec. 310.500 would be revoked and that applications approved 
through the new drug

[[Page 42996]]

procedures would be required. It is the manufacturer's responsibility 
to prove the safety and effectiveness of its product(s).

III. Implementation Plan

A. Digoxin Elixir

    In order to protect the public health, FDA plans to exercise its 
enforcement discretion and not take regulatory action against currently 
marketed unapproved digoxin elixir products before June 28, 2004. Any 
unapproved digoxin elixir introduced after June 26, 2002, will be 
subject to regulatory action when this rule becomes effective on July 
26, 2002.

B. Digoxin Tablets

    Any unapproved digoxin tablet will be subject to regulatory action 
when this rule becomes effective on July 26, 2002.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), 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 final rule and 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 final rule because the final 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 
final rule will not have a significant effect on a substantial number 
of small entities.
    As mentioned in the proposed rule, several studies have indicated a 
significant variation in the bioavailability of digoxin products for 
oral use. FDA published the January 1974 regulation that established 
conditions for marketing such products, including a mandatory batch 
certification program for digoxin tablets. In the proposed rule, FDA 
described actions that have occurred since that regulation was 
published that render the January 1974 regulation unnecessary. 
Therefore, under this final rule, manufacturers of digoxin products 
will be required to obtain an approved marketing application to enter 
or remain on the market.
    In the proposed rule, FDA noted that one of the manufacturers of 
digoxin tablets had not already obtained an NDA or ANDA and would need 
to obtain an ANDA to remain on the market. In addition, the two 
manufacturers of digoxin elixir would need to obtain approved 
applications. In the proposed rule, the agency calculated a cost of 
submitting either an ANDA or 505(b)(2) application, based on an 
estimate of 480 hours to complete the necessary paperwork.
    One comment disagreed with the estimate of 480 hours, contending it 
to be a gross underestimate of the actual time required. The comment 
did not provide an alternate estimate. It should be noted that the 
estimate in the proposed rule considered that the three manufacturers 
in question would be submitting an application to market a dosage form 
they were already producing. Nevertheless, the agency acknowledges that 
the 480-hour figure may underestimate the actual time required. 
Accordingly, for this final rule, the agency estimates the time to 
complete an ANDA or 505(b)(2) application to be between 480 and 720 
hours.
    Using a 2001 labor rate of $49 per hour\1\, and assuming 480 to 720 
hours to complete the required application, the one-time cost is 
between $23,500 and $35,300 ($49/hour x 480 to 720 hours). The one-time 
cost to all three firms is between $70,600 and $105,800 (3 x $23,500 to 
$35,300).
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    \1\U.S. Department of Labor, Bureau of Labor Statistics, ``2001 
Occupational Earnings Data,'' Lawyer: FTP://ftp.bls.gov/pub/
special.requests.1f/aat39.txt, 1 February 2002.
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    As stated in the proposed rule, FDA recognizes there will be future 
submission costs for new manufacturers of digoxin for oral use, and 
estimates two manufacturers will enter the market per decade. Some 
additional annual costs may also be incurred over the life of the 
application. While there may be some cost savings from the elimination 
of the batch certification requirement, the 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 a small entity. 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. 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.

VI. Paperwork Reduction Act of 1995

    This final 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 NDAs or ANDAs for digoxin products for 
oral use. The information collection requirements for the submission of 
NDAs and ANDAs are contained in 21 CFR part 314 and have been approved 
under OMB control number 0910-0001, which expires on March 31, 2005.

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, 21 CFR part 
310 is amended as follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR 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.

[[Page 42997]]

Sec. 310.500  [Removed]

    2. Section 310.500 Digoxin products for oral use; conditions for 
marketing is removed.

    Dated: June 17, 2002.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 02-16108 Filed 6-25-02; 8:45 am]
BILLING CODE 4160-01-S