[Federal Register Volume 63, Number 77 (Wednesday, April 22, 1998)]
[Rules and Regulations]
[Pages 19799-19802]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-10578]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 310
[Docket Nos. 75N-183F, 75N-183D, and 80N-0280]
RIN 0910-AA01
Status of Certain Additional Over-the-Counter Drug Category II
and III Active Ingredients
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
stating that certain ingredients in over-the-counter (OTC) drug
products are not generally recognized as safe and effective or are
misbranded. FDA is issuing this final rule after considering the
reports and recommendations of various OTC drug advisory review panels
and public comments on proposed agency regulations, which were issued
in the form of a tentative final monograph (proposed rule). Based on
the absence of substantive comments in opposition to the agency's
proposed nonmonograph status for these ingredients, as well as the
failure of interested parties to submit new data or information to FDA
under the regulation, the agency has determined that the presence of
these ingredients in an OTC drug product would result in that drug
product not being generally recognized as safe and effective or would
result in misbranding. This final rule is part of the ongoing review of
OTC drug products conducted by FDA.
DATES: Effective October 19, 1998.
FOR FURTHER INFORMATION CONTACT: Gerald M. Rachanow, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2307.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of November 7, 1990 (55 FR 46914), FDA
published under Sec. 330.10(a)(7)(ii) (21 CFR 330.10(a)(7)(ii)), a
final rule on the status of certain OTC drug Category II and III active
ingredients. That final rule declared as not generally recognized as
safe and effective certain active ingredients that had been proposed as
nonmonograph (Category II or Category III) under the agency's OTC drug
review. The periods for submission of comments and new data following
the publication of a notice of proposed rulemaking (NPRM) had closed
and no significant comments or new data had been submitted to upgrade
the status of these ingredients. In each instance, a final rule for the
class of ingredients involved had not been published to date.
In the Federal Register of May 10, 1993 (58 FR 27636), FDA
published a final rule establishing that certain additional active
ingredients in OTC drug products are not generally recognized as safe
and effective or are misbranded. That final rule included active
ingredients from a number of OTC drug rulemakings that were not covered
by the November 7, 1990, final rule. (See Table I (58 FR 27636 at 27639
to 27641) for a list of OTC drug rulemakings and active ingredients
covered by that final rule.)
At that time, there were other OTC drug review rulemakings for
which the period for submission of comments and/or new data was still
pending. Those periods have now closed, and there are a number of
active ingredients for which no significant comments or new data were
submitted. In each instance, a final rule for the class of ingredients
involved has not been published to date. This final rule addresses some
of the Category II and Category III active ingredients in those classes
of ingredients, specifically active ingredients considered in the
rulemakings for OTC vaginal contraceptive, first aid antiseptic, and
antimicrobial diaper rash drug products.
In the advance notice of proposed rulemaking (ANPRM) for OTC
vaginal contraceptive drug products (45 FR 82014, December 12, 1980),
the Advisory Review Panel on OTC Contraceptives and Other Vaginal Drug
Products placed phenylmercuric acetate and phenylmercuric nitrate in
Category II for safety and placed dodecaethylene glycol monolaurate
(polyethylene glycol 600 monolaurate), laureth 10S, and
methoxypolyoxyethyleneglycol 550 laurate in Category III for efficacy.
In the tentative final monograph (TFM) for OTC vaginal contraceptive
drug products (60 FR 6892, February 3, 1995), the agency proposed that
all of these ingredients be nonmonograph. In response to this TFM
(NPRM), the agency received no comments or data relating to the safety
and effectiveness of these ingredients.
In the ANPRM for mercury-containing drug products for OTC topical
antimicrobial use (47 FR 436, January 5, 1982), the Advisory Review
Panel on OTC Miscellaneous External Drug Products placed all mercury
compounds in Category II for topical antimicrobial use. This included
the following ingredients: Ammoniated mercury; calomel (mercurous
chloride); merbromin (mercurochrome); mercuric chloride (bichloride of
mercury, mercury chloride); mercufenol chloride (ortho-
chloromercuriphenol, ortho-hydroxyphenylmercuric chloride); mercuric
salicylate; mercuric sulfide (red mercuric sulfide); mercuric oxide,
yellow; mercury; mercury chloride; mercury oleate; nitromersol; para-
chloromercuriphenol; phenylmercuric nitrate; thimerosal; vitromersol;
and zyloxin. In the NPRM for OTC first aid antiseptic drug products (56
FR 33644, July 22, 1991), the agency proposed that all of these
ingredients were either Category II or Category III. In response to
this NPRM, the agency received no comments or data relating to the
safety and effectiveness of these ingredients.
In an amendment to the proposed rulemaking for OTC topical
antimicrobial drug products (55 FR 25246, June 20, 1990), the agency
proposed that p-chloromercuriphenol and all other ingredients
containing mercury were Category II for the treatment and prevention of
diaper rash. In response to this NPRM, the agency received no comments
or data relating to the safety and effectiveness of these ingredients.
II. Affected Rulemakings and Category II and III Ingredients
Table I of this document lists the titles and docket numbers of the
specific rulemakings containing active ingredients that are addressed
in this document, together with the publication dates of the ANPRM and
the NPRM, as well as the closing dates for comments and submission of
new data for each rulemaking. FDA advises that the active ingredients
discussed in this document (see Table II of section II of this
document) will not be included in the relevant final monographs because
they have not been shown to be generally recognized as safe and
effective for their intended use. The agency further advises that these
ingredients should be eliminated from OTC drug products 6 months after
the date of publication in the Federal Register of this final rule
regardless of whether further testing is undertaken to justify future
use.
[[Page 19800]]
The agency points out that publication of a final rule does not
preclude a manufacturer's testing an ingredient. New, relevant data can
be submitted to the agency at a later date as the subject of a new drug
application that may provide for prescription or OTC marketing status.
(See part 314 (21 CFR part 314).) As an alternative, where there are
adequate data establishing general recognition of safety and
effectiveness, such data may be submitted in an appropriate citizen
petition to amend or establish a monograph, as appropriate. (See
Sec. 10.30 (21 CFR 10.30).)
Table I.--OTC Drug Rulemakings Covered by This Final Rule
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Publication Comment New data
Rulemaking and action date closing date closing date
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(1) Vaginal contraceptive
drug products
(Docket No. 80N-0280)
Advance notice of December 12, March 12, Not
proposed rulemaking 1980 1981 applicable
(ANPRM) (N/A)
Notice of proposed February 3, June 5, 1995 February 5,
rulemaking (NPRM) 1995 1996
(2) First aid antiseptic
drug products
(Docket No. 75N-0183)
ANPRM January 5, April 5, N/A
1982 1982
(Docket No. 75N-183F)
NPRM July 22, 1991 January 2, July 22,
1992 1992
(3) Antimicrobial diaper
rash drug products
(Docket No. 75N-0183)
ANPRM September 7, December 6, January 5,
1982 1982 1983
(Docket No. 75N-183D)
NPRM June 20, 1990 December 17, June 20,
1990 1991
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Based on the criteria discussed above, FDA concludes that the
following ingredients are not generally recognized as safe and
effective and are misbranded when labeled as OTC drugs for the
following uses:
Table II.--Ingredients Covered by This Final Rule
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Ingredient classification
Rulemaking and ingredients -----------------------------------------------------------------------------
Advance notice of proposed rulemaking Notice of proposed rulemaking
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(1) First aid antiseptic drug
products:
(Docket No. 75N-183F)
Ammoniated mercury II II
Calomel (mercurous chloride) II III
Merbromin (mercurochrome) II III
Mercufenol chloride (ortho-
chloromercuriphenol, ortho-
hydroxyphenylmercuric
chloride) II III
Mercuric chloride (bichloride
of mercury, mercury chloride) II II
Mercuric oxide, yellow II II
Mercuric salicylate II II
Mercuric sulfide, red II II
Mercury II II
Mercury oleate II II
Mercury sulfide II II
Nitromersol II II
Para-chloromercuriphenol II II
Phenylmercuric nitrate II III
Thimerosal II II
Vitromersol II II
Zyloxin II II
(2) Vaginal contraceptive drug
products:
(Docket No. 80N-0280)
Dodecaethylene glycol
monolaurate) (polyethylene
glycol 600 monolaurate) III III
Laureth 10S III III
Methoxypolyoxyethyleneglycol
550 laurate III III
Phenylmercuric acetate II II
Phenylmercuric nitrate II II
(3) Antimicrobial diaper rash drug
products:
(Docket No. 75N-183D)
Para-chloromercuriphenol NA II
Any other ingredient
containing mercury NA II
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[[Page 19801]]
III. The Agency's Final Conclusions on Certain OTC Drug Category II
and III Ingredients
No substantive comments or additional data have been submitted to
the OTC drug review to support any of the ingredients listed in Table
II of this document as being generally recognized as safe and effective
for the specified OTC uses. The agency has determined that these
ingredients should be deemed not generally recognized as safe and
effective for OTC use before a final monograph for each respective drug
category is established. Accordingly, any drug product containing any
of these ingredients and labeled for the OTC use identified in Table II
of this document will be considered nonmonograph and misbranded under
section 502 of the Federal Food, Drug, and Cosmetic Act (the act) (21
U.S.C. 352) and a new drug under section 201(p) of the act (21 U.S.C.
321(p)) for which an approved application under section 505 of the act
(21 U.S.C. 355) and part 314 of the regulations is required for
marketing. As an alternative, where there are adequate data
establishing general recognition of safety and effectiveness, such data
may be submitted in a citizen petition to amend the appropriate
monograph to include any of the above ingredients in OTC drug products
in Table II of this document. (See Sec. 10.30.) Any OTC drug product
containing any of the ingredients in Table II of this document and
labeled for the use identified in Table II of this document initially
introduced or initially delivered for introduction into interstate
commerce after the effective date of this final rule that is not the
subject of an approved application will be in violation of sections 502
and 505 of the act and, therefore, subject to regulatory action.
Further, any OTC drug product subject to this final rule that is
repackaged or relabeled after the effective date of the rule would be
required to be in compliance with the rule regardless of the date the
product was initially introduced or initially delivered for
introduction into interstate commerce. Manufacturers are encouraged to
comply voluntarily with the rule at the earliest possible date.
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).
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 net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Under the Regulatory
Flexibility Act, if a rule has a significant impact on a substantial
number of small entities, an agency must analyze significant regulatory
options that would minimize any significant impact of the rule on small
entities.
Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et
seq.) requires that agencies prepare a written statement and economic
analysis before proposing any rule that may result in an expenditure in
any 1 year by State, local, and tribal governments, in the aggregate,
or by the private sector, of $100 million (adjusted annually for
inflation).
The agency believes that this final rule is consistent with the
principles set out in the Executive Order and in these two statutes.
The purpose of this final rule is to act on the proposed nonmonograph
status of certain ingredients in advance of finalization of other
monograph conditions in order to expedite completion of the OTC drug
review. There are a limited number of products currently marketed that
will be affected by this rule. Of the 17 mercury active ingredients
included in the final rule, the agency is aware of 12 OTC drug products
containing merbromin, 1 product containing phenylmercuric nitrate, and
7 products containing thimerosal. These products are marketed by eight
different manufacturers, most of which are considered small entities,
using the U.S. Small Business Administration designation for this
industry (750 employees). The agency is not aware of any topical
antimicrobial diaper rash or vaginal contraceptive drug products
containing any of the active ingredients included in this final rule.
Manufacturers of these products will no longer be able to market
products containing the ingredients included in this final rule after
its effective date. While the manufacturers will incur a loss of
revenue for these products, the agency believes the economic impact
will be minimal for several reasons. A. C. Nielsen (Nielsen), a
recognized provider of market research business information and
analysis, maintains product data from a sample of 4,000 retail outlets
selected to represent the geographical and retail characteristics of
the U.S. OTC market. Based on these Nielsen data, the agency estimates
that total sales for these products represent less than 0.1 percent of
all sales of OTC first aid drug products. For the affected companies,
these product sales comprised less than 1 percent of OTC drug revenues.
The industry has been aware of the status of these products since 1982,
and all of the manufacturers identified by FDA also produce products
containing ingredients proposed for inclusion in the monograph. The
lost sales from the nonmonograph products are expected to be offset by
increased sales of the substitute products.
The agency considered, but rejected, not acting on these
ingredients in advance of the finalization of other monograph
conditions. The final monographs for OTC topical antimicrobial and
vaginal contraceptive drug products are not expected to be completed
for a period of time. The agency also considered publishing an
additional notice specifying that the determinations on the ingredients
in this final rule would be included in a final rule prior to
publication of a final rule including the determinations on ingredients
for which new data and information have been submitted. However, safety
and effectiveness have not been established for the ingredients
included in this current final rule and manufacturers have not
submitted the necessary data in response to earlier opportunities. The
agency's experience has been that under these circumstances companies
have not submitted data in response to yet another opportunity.
Consumers will benefit from the early removal from the marketplace of
products containing ingredients for which safety and effectiveness have
not been established. Consumers can then purchase products containing
only ingredients proposed for monograph status. Manufacturers who
choose to reformulate or replace affected products will be able to use
alternative ingredients that are proposed as monograph conditions
without incurring any additional expense of clinical testing for those
ingredients. As noted previously, FDA believes that most manufacturers
currently produce such products.
While this final rule may cause manufacturers to discontinue
marketing or to reformulate some products prior to issuance of the
applicable final monograph, these manufacturers have known for some
time that if adequate data were not submitted to support safety and
effectiveness, cessation of marketing of the current products would be
required, in any event, when the final monographs are published.
Because this rule imposes no additional reporting or recordkeeping
requirements, no additional professional skills are necessary to
comply.
[[Page 19802]]
The analysis shows that this final rule is not economically
significant under Executive Order 12866 and that the agency has
considered the burden to small entities. Based on the above analysis,
the agency does not believe that the majority of manufacturers will
incur a significant economic impact. However, there may be a few that
could incur significant reformulation costs or inventory losses. Thus,
this economic analysis, together with other relevant sections of this
document, serves as the agency's final regulatory flexibility analysis,
as required under the Regulatory Flexibility Act. Finally, this
analysis shows that the Unfunded Mandates Reform Act does not apply to
the final rule because it would not result in an expenditure in any 1
year by State, local, and tribal governments, in the aggregate, or by
the private sector, of $100 million.
V. Environmental Impact
The agency has determined under 21 CFR 25.31(c) 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.
List of Subjects in 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 part 310 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
360b-360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241,
242(a), 262, 263b-263n.
2. Section 310.545 is amended by adding paragraphs (a)(27) and
(a)(28), by revising paragraph (d) introductory text, by reserving
paragraphs (d)(26) and (d)(27), and by adding paragraph (d)(28) to read
as follows:
Sec. 310.545 Drug products containing certain active ingredients
offered over-the-counter (OTC) for certain uses.
(a) * * *
(27) Topical antimicrobial drug products--(i) First aid antiseptic
drug products.
Ammoniated mercury
Calomel (mercurous chloride)
Merbromin (mercurochrome)
Mercufenol chloride (ortho-chloromercuriphenol, ortho-
hydroxyphenylmercuric chloride)
Mercuric chloride (bichloride of mercury, mercury chloride)
Mercuric oxide, yellow
Mercuric salicylate
Mercuric sulfide, red
Mercury
Mercury oleate
Mercury sulfide
Nitromersol
Para-chloromercuriphenol
Phenylmercuric nitrate
Thimerosal
Vitromersol
Zyloxin
(ii) Diaper rash drug products.
Para-chloromercuriphenol
Any other ingredient containing mercury
(28) Vaginal contraceptive drug products.
Dodecaethylene glycol monolaurate (polyethylene glycol 600 monolaurate)
Laureth 10S
Methoxypolyoxyethyleneglycol 550 laurate
Phenylmercuric acetate
Phenylmercuric nitrate
Any other ingredient containing mercury
* * * * *
(d) Any OTC drug product that is not in compliance with this
section is subject to regulatory action if initially introduced or
initially delivered for introduction to interstate commerce after the
dates specified in paragraphs (d)(1) through (d)(28) of this section.
* * * * *
(28) October 22, 1998, for products subject to paragraphs (a)(27)
and (a)(28) of this section.
Dated: April 8, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-10578 Filed 4-21-98; 8:45 am]
BILLING CODE 4160-01-F