[Federal Register Volume 61, Number 193 (Thursday, October 3, 1996)]
[Proposed Rules]
[Pages 51625-51631]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-25259]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 330
[Docket No. 96N-0277]
RIN 0910-AA01
Eligibility Criteria for Considering Additional Conditions in the
Over-the-Counter Drug Monograph System; Request for Information and
Comments
AGENCY: Food and Drug Administration, HHS.
ACTION: Advance notice of proposed rulemaking.
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SUMMARY: The Food and Drug Administration (FDA) is considering
proposing to amend its regulations to include criteria under which
certain additional over-the-counter (OTC) drug active ingredients,
indications, dosage forms, dosage strengths, routes of administration,
and active ingredient combinations (hereafter referred to as
``conditions'') may become eligible for inclusion in the OTC drug
monograph
[[Page 51626]]
system. The proposed criteria would address how OTC marketing
experience in the United States or abroad could be used to meet the
statutory definition of marketing ``to a material extent'' and ``for a
material time'' to qualify a specific OTC drug condition for
consideration under the OTC drug monograph system. Under the approach
being considered, once an OTC drug condition qualified for
consideration in an OTC drug monograph it would be evaluated for
general recognition of safety and effectiveness in accordance with the
FDA regulations. The decision on whether to propose such regulations
will be based, in part, on information and comments submitted in
response to this advance notice of proposed rulemaking. The agency is
open to approaches other than those identified in this document. FDA is
specifically soliciting a broad range of comments to help it decide
whether and how to propose amending its regulations to include
eligibility criteria for considering additional conditions in the OTC
drug monograph system.
DATES: Written comments by January 2, 1997.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: William E. Gilbertson, Center for Drug
Evaluation and Research (HFD-105), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2304.
SUPPLEMENTARY INFORMATION:
I. Background
A. History
1. Historical Development of the OTC Drug Monograph System
Since the passage of the Federal Food, Drug, and Cosmetic Act (the
act) in 1938, submission of a new drug application (NDA) has been
required before marketing a new drug. Under the 1938 act, an applicant
who submitted an NDA for approval had to show that a drug product was
safe for human use. The 1962 amendments to the act added the
requirement that the drug be effective, as well as safe, for its
intended uses.
Not all drugs are considered ``new drugs'' for which premarket
approval is required. A drug is not a new drug if: (1) It is generally
recognized as safe and effective under the conditions of use for which
it is labeled and (2) it has been used to a material extent and for a
material time under those conditions (see section 201(p) of the act (21
U.S.C. 321(p))).
To ensure that all drugs marketed in the United States met the
act's requirements for efficacy imposed under the 1962 amendments, the
agency undertook a review of all the drugs approved for marketing
before 1962 on the basis of safety only, i.e., all products approved
between 1938 and 1962. In 1966, FDA contracted with the National
Academy of Sciences-National Research Council (NAS-NRC) for a review of
these drugs, which were covered by ``safety'' NDA's. Thirty panels of
experts examined the efficacy, by class or therapeutic category, of all
drugs covered by these approved ``safety'' NDA's. The panels considered
factual information from scientific literature, reports from
manufacturers containing the best evidence in support of their drug
efficacy claims, and information provided by FDA and other sources. The
NAS-NRC panels related their conclusions to FDA, and the agency
reviewed their evaluations by a procedure known as the Drug Efficacy
Study Implementation (DESI) program and made efficacy determinations
for the drug products.
Of the approximately 3,900 drugs that NAS-NRC reviewed, about 400
were OTC drugs. These OTC drugs were handled under the DESI program,
and FDA classified some of these drugs as lacking sufficient evidence
of safety and/or effectiveness and ordered their removal from the
market (see Sec. 330.12 (21 CFR 330.12)). In most cases, when deferral
of implementation led to no significant risk to the public health,
conclusions regarding the OTC drugs' safety and efficacy were deferred
to a separate OTC drug review that FDA initiated in 1972.
In the Federal Register of May 11, 1972 (37 FR 9464), FDA
established the OTC drug monograph system (currently in part 330) (21
CFR part 330). The system was established to evaluate the safety and
efficacy of all OTC drug products marketed in the United States before
May 11, 1972, that were not covered by NDA's, and all OTC drug products
covered by ``safety'' NDA's that were marketed in the United States
before the enactment of the 1962 drug amendments to the act. The OTC
drug review was set up to evaluate OTC drugs by designated categories
or classes (e.g., antacids, skin protectants), rather than on a
product-by-product basis, and to develop ``conditions'' under which
classes of OTC drugs are generally recognized as safe and effective and
not misbranded.
FDA publishes these conditions in the Federal Register in the form
of OTC drug monographs, which consist primarily of active ingredients,
combinations of active ingredients, labeling, and other general
requirements. Final monographs for OTC drugs that are generally
recognized as safe and effective and not misbranded are codified in
part 330. Manufacturers desiring to market a monographed condition need
not seek clearance from FDA before marketing.
2. Statutory Requirements Relating to a Drug's Eligibility Under the
OTC Drug Monograph System
Only drugs that are not new drugs may be covered by a monograph. As
stated above, to market a new drug, an NDA must be submitted to and
approved by FDA before marketing. The term ``new drug'' is defined,
under section 201(p) of the act (21 U.S.C. 321(p)), as:
(1) Any drug * * * the composition of which is such that such
drug is not generally recognized, among experts qualified by
scientific training and experience to evaluate the safety and
effectiveness of drugs, as safe and effective for use under the
conditions prescribed, recommended, or suggested in the labeling
thereof, * * * or
(2) Any drug * * * the composition of which is such that such
drug, as a result of investigations to determine its safety and
effectiveness for use under such conditions, has become so
recognized, but which has not, otherwise than in such
investigations, been used to a material extent or for a material
time under such conditions.
The courts have interpreted section 201(p) of the act to mean that
to avoid new drug preapproval requirements, the drug product must be
generally recognized as safe and effective and must have been used to a
material extent and for a material time under the labeled conditions of
use. (See, e.g., Weinberger v. Hynson, Westcott & Dunning, Inc., 412
U.S. 609, 631 (1973); Premo Pharmaceutical Laboratories, Inc. v. United
States, 629 F.2d 795, 801-802 (2d Cir. 1980).) To satisfy the
requirements of section 201(p)(2) of the act for a particular drug,
both the time and the extent of marketing of the drug must be shown to
be material. In addition, as discussed in section I.A.3. of this
document, the agency has interpreted the use required by section
201(p)(2) to mean use in the United States.
3. Application of the Statutory Requirements for Determining
Eligibility in the OTC Drug Monograph System
As stated above, FDA considered in its review all active
ingredients in OTC drug products that were on the U.S. market as of May
11, 1972, when the
[[Page 51627]]
review began, regardless of specific marketing history.
The agency has recognized that the ``newness'' of an OTC drug
product can occur for several reasons. The newness may arise by reason,
among other reasons, of the drug product's new ingredient, indication,
dosage form, dosage strength, route of administration, or combination
of active ingredients. (See 21 CFR 310.3(h).)
Periodically, questions would arise about whether certain
conditions of use introduced after May 11, 1972, caused the products to
be ``new'' drugs requiring marketing approval under NDA's, or whether
the products could be eligible for consideration in the OTC drug
monograph system. The agency determined the eligibility of these
conditions individually on the basis of whether they had been marketed
to a material extent and for a material time. Examples of the agency's
past material extent and material time eligibility determinations are
discussed below.
The agency has taken the position that the marketing of an OTC drug
in a foreign country, but never in the United States, does not satisfy
the requirement of marketing to a material extent and for a material
time. In the Federal Register of December 12, 1980 (45 FR 82014), the
agency concluded that menfegol, a vaginal contraceptive active
ingredient marketed abroad for a number of years as an OTC drug
product, was a new drug within the meaning of section 201(p) of the act
because it had never been marketed as a drug in the United States.
Likewise, in the Federal Register of November 16, 1988 (53 FR 46204 at
46248), the agency stated that it considered a lysine salt of aspirin,
an internal analgesic active ingredient, to be a new drug within the
meaning of section 201(p) of the act. This ingredient had been marketed
OTC abroad but had never been marketed as a drug in the United States.
The agency also has declared new dosage strengths to be ineligible
for the OTC drug review. In 1984, FDA denied a citizen petition
requesting that the agency reopen the administrative record for the
rulemakings for OTC internal analgesic and menstrual drug products to
consider a new dosage strength of ibuprofen (200 milligrams (mg)) (Ref.
1). The agency denied the petition, stating that the 200 mg dosage
strength had not been used to a material extent and for a material time
in the United States and, therefore, was considered a ``new drug'' that
could not be lawfully marketed in the United States without an approved
NDA.
In the Federal Register of July 19, 1983 (48 FR 32872 at 32873),
the agency stated that a labeled indication that had never previously
appeared on any marketed OTC drug product was not eligible for
consideration in the OTC drug monograph system. The agency determined
that products claiming ``to minimize or prevent inebriation'' had not
been marketed to a material extent and for a material time in the
United States and declared that all products with sobriety aid
indications were new drugs within the meaning of section 201(p) of the
act.
Similarly, FDA concluded that an ingredient that had not previously
been marketed in the United States for a specific indication is not
eligible for consideration in the OTC drug monograph system. In the
Federal Register of October 13, 1983 (48 FR 46694 at 46695), the agency
stated that potassium sorbate had not been marketed to a material
extent and for a material time in the United States as a vaginal drug
product active ingredient and, therefore, was considered a new drug
within the meaning of section 201(p) of the act for such use.
More recently the agency has found that avobenzone, a sunscreen
ingredient, is eligible for review in the OTC drug monograph system (61
FR 48645, September 16, 1996). Avobenzone has been continuously
marketed OTC in the United States under NDA's for approximately 8 years
and subject to the NDA adverse events reporting requirements. Over 5
million units of avobenzone-containing products have been sold in the
United States.
In applying the material extent and material time provision of
section 201(p)(2) of the act to determine whether certain conditions
were eligible for consideration in the OTC drug monograph system, FDA
has also applied a ``substantially indistinguishable'' standard. This
standard was first articulated in a September 23, 1977, letter to a
drug manufacturer concerning its submission regarding the ingredient
potassium nitrate for use as an OTC tooth desensitizing agent (Ref. 3).
The letter stated that an ingredient may meet the act's marketing
provision of section 201(p)(2) of the act without having been marketed
under the precise conditions of use sought, provided the ingredient had
been marketed to a material extent and for a material time under other
conditions of use that, although different, are ``substantially
indistinguishable'' in all respects relevant to the drug's safety and
effectiveness. Specifically, the conditions of use would have to be
similar enough that experts could reliably conclude that knowledge
about the safety and effectiveness of a drug derived from experience
with its use under one set of conditions could be applied to the
evaluation of the safety and effectiveness of its use under the
conditions for which approval was being sought.
B. Petitions and Comments
The agency has received one comment and nine citizen petitions
(Refs. 4 through 13) requesting that it accept foreign marketing data
to demonstrate that specific conditions of use have been marketed to a
material extent and for a material time and, on that basis, to consider
these conditions in the OTC drug review. If the agency were to change
its current policy and accept such data, this would allow such
conditions to be considered in the OTC drug monograph system.
This advance notice of proposed rulemaking addresses the primary
issue raised in these petitions regarding acceptance of foreign
marketing experience to demonstrate that OTC drug conditions have been
marketed to a material extent and for a material time. The agency will
provide separate responses to the petitions at a later date.
II. Criteria Under Consideration for Demonstrating Marketing to a
Material Extent and for a Material Time
Currently, the OTC drug regulations in part 330 do not define: (1)
Eligibility requirements for consideration in the monograph system or
(2) what constitutes marketing to a material extent or for a material
time. However, FDA's policy has been not to consider foreign marketing
experience for purposes of determining whether a drug has been marketed
to a material extent or for a material time. The agency is considering
a proposed rule containing criteria for defining material extent and
material time under which an OTC condition with or without U.S.
marketing experience could be considered in the OTC drug monograph
system. As previously indicated, FDA defines a condition as any active
ingredient, indication, dosage form, dosage strength, route of
administration, active ingredient combination, or any combination of
these conditions.
In developing these criteria, FDA is considering three basic
issues: (1) Nature of use, (2) time used (material time), and (3)
extent of distribution (material extent).
These issues are discussed below and the agency is seeking comment
on each.
[[Page 51628]]
A. Nature of Use
When determining if a foreign OTC drug product condition has been
marketed to a material extent and for a material time, FDA is
particularly concerned about certain variables presented by foreign
marketing experience. In the Federal Register of February 22, 1985 (50
FR 7452), the agency amended its regulations pertaining to foreign
clinical studies in Sec. 314.106 (21 CFR 314.106) to provide
specifically for the acceptance of foreign data in NDA's. In doing so,
the agency acknowledged the high quality of drug testing from a number
of foreign research institutions, but recognized that foreign data
present three unique issues not associated with domestic data: (1)
Medical, genetic, and cultural differences between countries; (2) lack
of FDA's familiarity with foreign clinical investigators and
facilities; and (3) FDA's inability to conduct on-site verification of
many foreign studies (see 50 FR 7452 at 7483). To address these
concerns, the agency specified three criteria in Sec. 314.106 that must
be met before the agency can approve an NDA based solely upon foreign
data: (1) The foreign data must be applicable to the U.S. population
and U.S. medical practice; (2) the studies must be performed by
clinical investigators of recognized competence; and (3) the data can
be considered valid without the need for on-site inspection by FDA or,
if FDA considered such an inspection necessary, FDA would be able to
validate the data through on-site inspection or other means. 21 CFR
312.120 contains additional acceptance criteria for foreign clinical
studies not conducted under an IND.
The agency recognizes that foreign marketing experience, like
foreign clinical data, presents several unique issues not associated
with U.S. marketing data: (1) Medical, genetic, or cultural differences
between a foreign country's population and the U.S. population may
affect the way OTC drug products are used and, in turn, the medical
outcomes; (2) the diversity in the way drug products are marketed in
foreign countries (e.g., prescription, OTC general sales, behind the
counter, sold by a pharmacist (third class of drugs)) may make it
difficult to demonstrate suitability for OTC sale in the United States;
and (3) many foreign countries' marketing approval processes and
adverse event reporting requirements would make it difficult to
determine whether adverse reactions to the OTC drug product have been
experienced. Therefore, in establishing what constitutes use for a
material time and to a material extent, FDA must determine whether to
impose any limitations on types of marketing experience it would
consider relevant to whether the drug should be marketed OTC in the
United States under a monograph system. The following discussion
focuses these issues on limitations related to: (1) Where the drug is
marketed and its relevance to the U.S. population; (2) the type of
adverse reporting system that exists in the countries in which the drug
has been marketed and the nature of any adverse event reports
associated with the drug; and (3) the nature of that marketing
experience, such as whether the drug has been marketed by prescription,
OTC, or as a third class of drugs that can be sold only by a
pharmacist. This marketing experience would also be based on consistent
active ingredients and product formulations that do not require
critical manufacturing controls and/or involve complex bioavailability
questions.
1. Where the Drug is Marketed
Because of the concerns discussed above, one petition suggested
that the agency limit its consideration of OTC marketing experience to
the export countries identified in section 802(b)(4)(A) of the act (21
U.S.C. 382(b)(4)(A)), as added by the Drug Export Amendments Act of
1986 (Pub. L. 99-960). Section 802(b)(4)(B) of the 1986 amendments
listed four requirements related to the approval of drugs in foreign
countries. These requirements were similar to requirements in the
United States. Congress declared that 21 countries met these
requirements and were listed in section 802(b)(4)(A) of the act for
purposes of allowing them to receive for general marketing the export
of certain unapproved new drugs from the United States. In April 1996,
Congress amended section 802 of the act (Pub. L. 104-134) to, among
other things, add additional countries to the list, allow the Secretary
of Health and Human Services to add additional countries that meet
certain requirements described in new section 802(b)(1)(B) of the act
(formerly section 802(b)(4)(A)), and allow the export of certain
unapproved drugs from the United States to any country if the drug
complies with the laws of that country and has valid marketing
authorization by the appropriate authority in one of the listed
countries, and certain other conditions are met, as described in the
new sections 802(f) and 802(g).
Although the listed countries may have similar statutory or
regulatory requirements to those of the United States, other countries
may also have acceptable marketing and approval processes. The agency
requests specific comment on whether OTC marketing experience should be
considered solely from countries listed or designated under the new
section 802(b)(1) of the act or whether experience that meets certain
broader criteria should be considered.
2. Adverse Event Reporting
For the agency to rely on adverse event information in assessing
the safety of the condition in OTC marketing and use, the adverse event
information would have to be collected in a country with a drug
marketing approval process and postmarketing surveillance system that
identifies serious and/or important adverse events associated with the
condition's use.
To assist in making the determination regarding whether a condition
has met the requirements of marketing for a material extent and for a
material time, the agency is considering requiring submission of the
following information: (1) A description of each country's system for
identifying adverse events, especially those found in OTC marketing
experience, including method of collection if applicable; (2) all
serious and important adverse event reports from every country where
the condition has been or is currently marketed (whether prescription
or OTC); and (3) a list of all countries in which the condition has
been withdrawn or in which marketing has been restricted for reasons
related to safety or effectiveness, or for any other reason, and a
description of these reasons.
The agency believes that prescription as well as OTC adverse event
reports for the condition should be required to be included in an
eligibility data submission because data on prescription adverse events
may provide useful information for evaluating the safety of the
condition for U.S. OTC drug use. The agency also believes that
information regarding adverse events associated with other doses
(higher or lower) or different indications associated with the
condition marketed as a prescription drug product would be useful for
determining the safety of the condition for OTC use. This information
could result, for example, in different labeling or a different dosing
regimen or could even suggest that the marketing of the condition under
an OTC drug monograph would be inappropriate.
3. Nature of Marketing Experience
Because the criteria under consideration are to determine
eligibility for consideration in the OTC monograph review, FDA must
consider
[[Page 51629]]
whether marketing experience as a prescription drug will be considered
or whether to limit the marketing experience to OTC marketing
experience. FDA is considering limiting eligibility to those conditions
(as defined previously) that: (1) Have been marketed for direct OTC
purchase by consumers; and (2) are not limited to prescription use in
the United States.
Under existing procedures in 21 CFR 310.200, conditions may attain
OTC status in one of two ways:
a. As a new drug. A proposal may be initiated by the Commissioner
of Food and Drugs if it is determined that agency requirements are not
necessary for the protection of the public health, or by any interested
person through the filing of a petition, NDA, or supplemental NDA. A
drug switched to OTC status under these provisions remains a ``new
drug'' unless it meets each of the necessary conditions under section
201(p)(1) and (p)(2) of the act for a drug not to be regarded as a new
drug.
b. As a monograph drug. Through the OTC drug monograph system by
either: (1) Recommendations made by an OTC advisory review panel or
committee, (2) requests from interested parties (usually in the form of
a data submission), or (3) initiated by the agency in an OTC drug
monograph.
When the OTC drug review began, it was designed to address OTC
marketing conditions that were already on the market in the United
States. The agency permitted the OTC advisory panels to consider
prescription to OTC switches and recommend OTC use for prescription
drugs whose safety and efficacy for OTC use they believed had been
demonstrated in the U.S. population through prior marketing experience.
Since the completion of the first phase of the OTC drug review
(i.e., the OTC advisory review panels' evaluations and publication of
their reports), the majority of drug manufacturers have elected to
pursue switches from prescription to OTC status under the new drug
procedures. The agency considers this mechanism appropriate because the
data provided by an NDA, including adverse event reports, manufacturing
controls, and bioavailability data where applicable, provide useful
information during the transition from prescription to OTC marketing
status. In addition, the mandatory reporting of adverse events under an
NDA is important to the agency to monitor safe and effective OTC use
once a switch has occurred.
Currently, no adverse event reporting requirements exist for drugs
in the OTC drug monograph system. In a future issue of the Federal
Register, the agency intends to propose to establish an adverse event
reporting system for OTC monograph drugs. However, at this time, the
agency believes that the transition from prescription to OTC status is
best accomplished by first requiring an OTC drug product to be marketed
under an NDA. After a switch occurs under an NDA and sufficient
marketing experience is obtained or an adverse event reporting system
is in place for OTC monograph drugs, FDA would be willing to include
switched drugs in an OTC drug monograph. If and when an adverse event
reporting system for OTC monograph drugs is established, this system
would better support the use of OTC drug monographs for future
prescription to OTC switches that do not require critical manufacturing
controls for safe and effective use.
At this time, the agency does not believe that the criteria for
determining material time and material extent should apply to drugs
marketed by prescription in a foreign country but not marketed in the
United States. Some drugs that are marketed by prescription in a
foreign country were considered for approval in the United States but
not approved because FDA believed that their safety and efficacy had
not been proven. Furthermore, the agency believes that it is not
appropriate for a drug that has characteristics that have been
determined to require a prescription in a foreign country to enter
directly into the OTC market in the United States when the U.S.
population has no experience with the drug either on a prescription or
OTC basis. The agency considers it essential that any prescription drug
have some U.S. marketing experience before its OTC marketing is
permitted in this country. Further, the agency believes that the
criteria being considered in this document should not be applicable to
establish use to a material time and to a material extent if the drug
has no direct-to-consumer OTC marketing experience in any country.
OTC drugs whose marketing history shows that they were marketed in
the United States without appropriate authorization would not be
eligible for consideration in the OTC drug review based on the new
material time and extent eligibility criteria. To treat such drugs
otherwise would reward those who chose not to comply with the law.
These criteria would not apply to sustained-release products, which
remain new drugs under 21 CFR 200.31 because of the difficulties
associated with developing a standardized monograph that would cover
the wide variety of sustained release formulations. These products
almost always involve complex bioavailability/bioequivalence questions.
The agency recognizes that some of the countries listed in
802(b)(1)(A) of the act (e.g., Australia, Canada, New Zealand, and the
United Kingdom) have a third class of OTC drug products that can be
sold only by a pharmacist. When consumers purchase OTC drugs in this
class, there is intervention by a health professional and an
opportunity for professional consultation. The agency would not
consider this type of OTC marketing to be similar to the broad OTC
marketing in the United States, where products are marketed in many
various outlets, often with no opportunity for professional
consultation. The agency seeks specific comment on whether marketing in
a foreign country as a third class of drugs sold by a pharmacist should
be considered when evaluating whether a drug has been marketed for a
material time and to a material extent.
B. Time Used (Material Time)
The agency is considering proposing that this OTC marketing be for
a minimum of 5 years to satisfy the material time requirements of the
act. In determining how many years should constitute marketing for a
material time, the agency's principal concern is that the condition be
marketed for a sufficient time to detect serious and/or important
adverse events. The agency believes that a minimum 5-year timeframe
should be required to provide an appropriate margin of safety to ensure
that adverse event reporting is sufficient to detect almost all types
of serious and/or important adverse events if sufficient volume of
sales and postmarketing surveillance in this timeframe can be
documented (see section II. C. of this document).
If the condition has not been marketed previously in the United
States, the agency believes that the specific condition should be
marketed for this 5-year minimum time period in a population
demonstrated to be representative of the U.S. population (e.g., by
race, gender, ethnicity, and other pertinent factors) that would be
exposed to the OTC drug if it were marketed in the United States under
an OTC drug monograph. Foreign marketing exposure (i.e., diversity
within the user population) would have to be described sufficiently to
ensure that the condition can be reasonably extrapolated to the U.S.
population. Any cultural or geographic differences in the way drugs are
used in the foreign country and in the United States would
[[Page 51630]]
be required to be explained. The agency seeks specific comment on how
the representation of the population could be established.
C. Extent of Distribution (Material Extent)
The agency believes that there should be some flexibility when
assessing the extent of marketing for an OTC drug product condition.
Because the agency intends to consider numerous factors in determining
whether the condition has been marketed to a material extent, the
agency does not believe that this determination should be based solely
on the sale of a certain established number of dosage units, as one
petition suggested. The agency also believes that the extent of the
condition's use should be sufficient to detect serious and/or important
adverse events, including rare events, to demonstrate a favorable
adverse event profile. The agency is considering using the following
factors to evaluate whether the extent of use of a condition is
sufficient to detect serious and/or important adverse events: (1)
Number of dosage units sold; (2) number and types of adverse event
reports, and the requirements of the reporting system; (3) risks and
consequences associated with the therapeutic category and indication;
(4) use pattern (frequency: Occasional, acute, chronic); (5) potential
toxicity (including dosage form and route of administration); and (6)
history of use (i.e., use indications and exposures, including their
toxicities)
III. Implementation
A. Two-Step Application Process
The agency is considering proposing that sponsors first demonstrate
that a condition meets the basic eligibility requirements of marketing
to a material extent and for a material time, in the appropriate
format, before the agency accepts any data in support of the
condition's general recognition of safety and effectiveness. Upon
evaluation of the eligibility data, the agency would notify the sponsor
of its determination. If the condition were found to be eligible, the
sponsor could then submit its data to demonstrate safety and
effectiveness in accordance with part 330.
The agency believes that sponsors should not incur unnecessary
costs for developing safety and effectiveness data for a condition of
use that may not meet the basic eligibility requirements of marketing
to a material extent and for a material time. In addition, the agency
does not want to expend scarce resources evaluating safety and
effectiveness data for a condition if it does not meet the basic
eligibility criteria.
The agency notes that the advisory review panels mentioned in
Sec. 330.10(a)(1) no longer exist. Therefore, safety and effectiveness
data would be reviewed on an individual basis, with the assistance of
the agency's current Nonprescription Drugs Advisory Committee and other
Drug Advisory Committees when deemed appropriate. If the agency
determined that the data were sufficient to establish that the
condition was generally recognized as safe and effective, it would then
propose in the Federal Register to include the condition in an
appropriate OTC drug monograph.
B. Compendial Monograph
FDA believes there is a need for publicly available chemical
standards to ensure that all OTC drug products contain ingredients that
are chemically equivalent to those described in an OTC monograph. To
ensure that OTC drugs remain safe and effective for their intended
uses, the agency believes that any ingredient included in an OTC drug
monograph should also be recognized in an official compendium (e.g.,
the U.S. Pharmacopeia) setting forth its standards of identity,
strength, quality, and purity. On this basis, the agency is considering
proposing that no final monograph be issued and no interim marketing be
allowed until there is an official compendial monograph that is
consistent with the marketed ingredients used to establish general
recognition of safety and effectiveness.
C. Marketing Policy
All new drugs and drugs marketed under an OTC monograph must be
demonstrated to be safe and effective before they may be marketed in
the United States. Although conditions evaluated under the OTC drug
review were permitted to remain on the market during the review process
in view of their long history of use in this country, the agency
believes that allowing the marketing of a new condition before the
agency has evaluated its safety and effectiveness would subject the
public to unnecessary risk. Therefore, the agency is considering
permitting a new condition to be marketed only after the Commissioner
tentatively determines that the condition is generally recognized as
safe and effective and publishes this conclusion in the Federal
Register as a proposal for comment. Marketing could only occur after
the comments are reviewed and an appropriate notice allowing such
marketing is published in the Federal Register or after inclusion of
the condition in the appropriate OTC drug final monograph.
Any interim marketing that might be allowed, pending issuance of a
final rule, would be subject to the risk that the Commissioner could
adopt a different position in the final rule that would require
relabeling, recall, or other regulatory action. The agency seeks
specific comment on this marketing policy.
IV. Analysis of Impacts
The agency also seeks specific comment regarding any substantial or
significant economic benefit or impact that this rulemaking would have
on manufacturers or consumers of OTC drug products. Comments regarding
the benefit or impact of this rulemaking on such manufacturers or
consumers should be accompanied by appropriate documentation. The
agency will evaluate any comments and supporting data that are received
and will assess the economic impact of this rulemaking in the preamble
to the proposed rule.
V. Requests for Comments
Interested persons may, on or before January 2, 1997 submit to the
Dockets Management Branch (address above) written comments regarding
this advance notice of proposed rulemaking. Three copies of all
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 and may be accompanied by a
supporting memorandum or brief. Received comments may be seen in the
office above between 9 a.m. and 4 p.m., Monday through Friday.
VI. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p m., Monday through Friday.
(1) Comment No. PDN2, Docket No. 77N-0094, Dockets Management
Branch.
(2) Letter from Thomas Scarlett, Associate Chief Counsel for
Enforcement, Bureau of Drugs, FDA, to Harris O. Cutler, Richardson-
Merrell, Inc., September 23, 1977.
(3) Comment No. CP1, Docket No. 78N-0038, Dockets Management
Branch.
(4) Comment No. CP2, Docket No. 78N-0038, Dockets Management
Branch.
(5) Comment No. CP3, Docket No. 78N-0038, Dockets Management
Branch.
(6) Comment No. CP4, Docket No. 78N-0038, Dockets Management
Branch.
(7) Comment No. C105, Docket No. 78N-0038, Dockets Management
Branch.
(8) Comment No. CP1, Docket No. 81N-0033, Dockets Management
Branch.
[[Page 51631]]
(9) Comment No. CP1, Docket No. 92P-0309, Dockets Management
Branch.
(10) Comment No. CP1, Docket No. 94P-0215, Dockets Management
Branch.
(11) Comment No. CP2, Docket No. 94P-0215, Dockets Management
Branch.
(12) Comment No. CP1, Docket No. 95P-0145, Dockets Management
Branch.
This advanced notice of proposed rulemaking is issued under
sections 201, 501, 502, 503, 505, 510, 701 of the Federal Food, Drug,
and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360, 371) and
under the authority of the Commissioner of Food and Drugs.
Dated: September 26, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-25259 Filed 10-2-96; 8:45 am]
BILLING CODE 4160-01-F