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FDA Issues Final Rule on the Use of Foreign Marketing Experience to Support Over-the-Counter (OTC) Drug Status in the U.S.

Date: Feb 20, 2002


Under the Federal Food, Drug, and Cosmetic Act, a drug may be eligible forover-the-counter (OTC) status if it (1) is "generally recognized as safe andeffective" (GRAS/E) and (2) has been marketed "to a material extent" and"for a material time." Previously, the Food and Drug Administration (FDA) wouldonly consider marketing history in the U.S. when evaluating the "material time andextent" requirement.  The Agency has nowpublished a final regulation on the circumstances under which foreign marketing experiencemay be used to establish that a particular OTC active ingredient, dosage form, dosagestrength, or route of administration (a "condition") has been marketed "toa material extent" and "for a material time," and would be eligible forfurther consideration in an OTC drug monograph.  New 21 C.F.R. § 330.14; 67 Fed.Reg. 3060 (January 23, 2002).  The finalregulation offers the most promising opportunity yet to pursue the use of additionalconditions in OTC drug products in the United States. Following is an overview of the new regulation, noting some significant differencesfrom the proposed rule issued in December 1999. 

FDA proposed to have detailed marketing information about a condition submitted in a"time and extent application" (TEA).  Ifthe condition is found to be eligible for further consideration, FDA would then requestthe submission of safety and effectiveness data to support the condition (including anofficial or proposed U.S. Pharmacopeia-National Formulary monograph for an activeingredient).  As an initial requirement forconsideration, the condition must have been marketed OTC for a minimum of 5 continuousyears in the same country or countries and in suitable quantity to assure sufficient"extent" of marketing.   

The proposed rule was widely criticized as being unnecessarily burdensome and toocomplex to be of any practical value to the OTC drug industry.  In the preamble to the final rule, FDA defends theproposal, but agreed with many of the comments and made a number of changes in the finalregulation that make the procedure more likely to be used.  

The most significant change is that FDA has scaled back its expectations forinformation about the countries in which a product has been marketed.  The proposed rule demanded detailed information onevery country in which the condition has been marketed.  The final regulation reduces this burden to a moremanageable level.  For a condition that has been marketed OTC in five ormore countries with a minimum of five continuous years of marketing in at least onecountry, the TEA need only include information from the five countries with the longestduration and extent of marketing (although data from more than five countries may besubmitted).  In addition, themanufacturer of an active ingredient (as opposed to a finished drug product), may provideinformation about the quantities of the active ingredient sold, rather than finisheddosage units. 

In other changes, FDA is now requiring the submission of only the currentlabeling for a product in each country (rather than all labeling throughout its history ofmarketing).  The expanded information onpopulation demographics has also been scaled back; use pattern information is needed onlywhen the use varies between countries or has changed within a country. 

At its very basic level, the final regulation requires the TEA to provide the followinginformation:

1) Basic information about the condition, including:

(i) a description of the active ingredient(s) or botanical drug substance(s);

(ii) pharmacologic class(es);

(iii) intended OTC use(s);

(iv) OTC strength(s) and dosage form(s), route(s) of administration, directions for use;

(v) applicable existing OTC drug monograph(s) under which the condition would be marketed or the request and rationale for creation of a new OTC drug monograph(s).

2) A list of all countries in which the condition has been marketed, including the following information for each country (although this information may be limited to five countries for conditions with sufficiently broad marketing):

(i) how the condition has been marketed (e.g., OTC general sales direct-to-consumer; sold only in a pharmacy; dietary supplement; or cosmetic);

(ii) the cumulative number of dosage units sold (active ingredient manufacturers can provide information on the quantity of the bulk drug sold);

(iii) a description of the population demographics (percentage of various racial/ethnic groups), along with the sources of information, to ensure that the condition's use(s) can be reasonably extrapolated to the U.S. population;

(iv) an explanation of how the use pattern of the condition varies between countries, if it does;

(v) a description of the country's system for identifying adverse drug experiences, especially those found in OTC marketing experience, including method of collection if applicable.  

3) A statement of how long the condition has been marketed in each country, how long the current labeling has been in use, and a copy of the current product labeling.

4) A list of all countries where the condition is marketed only as a prescription drug and the reasons why its marketing is restricted to prescription status in these countries.

5) A list of all countries in which the condition has been withdrawn from marketing or in which an application for OTC marketing approval has been denied (including the reasons for such withdrawal or application denial).

The Agency states that it "will strive to complete TEA evaluations within 90 to180 days of receipt," although it declined to commit to specific time frames forreview.  FDA will treat a TEA as confidentialuntil a decision is made on whether the condition is eligible for further review in theOTC process.  If the condition is found to beeligible, FDA will place the TEA on public display after redacting confidentialinformation.  Sponsors must identify whatinformation in the TEA is considered confidential when the TEA is submitted, although FDAindicates that it does not anticipate that much TEA information will properly beconsidered confidential.

Finally, FDA has modified its earlier position against allowing the interim marketingof eligible new conditions following the Agency's review of safety and effectivenessinformation: 

For those OTC drug monographs that are not final yet and where finalization is notimminent, after the agency has evaluated the comments to a proposed rule to include anew condition in a [tentative final monograph] as GRAS/E and the agency has not changedits position as a result of the comments, the agency will then publish a notice ofenforcement policy to allow interim marketing.

67 Fed. Reg. at 3068 (col. 2) (underlining added).

However, FDA has determined that it will not permit interim marketing ofconditions that are proposed to be included in a final OTC drug monograph.  Examples of final monographs include thosecovering OTC antacid, anti-dandruff, and sunscreen drug products.  The Agency's explanation is that it must seekpublic comment on a proposal to amend a final monograph and that "it takes the sameamount of time and agency resources to resolve any outstanding issues [from the publiccomments] and to proceed directly to issuance of a final rule" as it does to processan enforcement notice allowing interim marketing.  Itremains to be seen whether this different treatment is appropriate; this decision may bethe subject of a future challenge if the appropriate circumstances arise.

Despite the possible questions about interim enforcement, the TEA regulation offers theopportunity to start the process of making foreign-marketed OTC conditions available toU.S. consumers.

For further information about the TEA regulation or FDA's OTC drug regulatoryrequirements, please contact Frederick A. Stearns at202-434-4288 or via e-mail at stearns@khlaw.com.