Eligibility Criteria for Considering Additional Conditions in the Over-the-Counter Drug Monograph System; Request for Information and Comments

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