[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