[Federal Register Volume 62, Number 10 (Wednesday, January 15, 1997)] [Notices] [Pages 2167-2169] From the Federal Register Online via the Government Publishing Office [www.gpo.gov] [FR Doc No: 97-944] ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES [Docket No. 97N-0002] Policy on Period of Marketing Exclusivity for Newly Approved Drug Products With Enantiomer Active Ingredients; Request for Comments AGENCY: Food and Drug Administration, HHS. ACTION: Notice. ----------------------------------------------------------------------- SUMMARY: The Food and Drug Administration (FDA) is reevaluating its policy on the appropriate period of marketing exclusivity for newly approved drug products whose active ingredient is a single enantiomer of a previously approved racemate. This action is being taken to assess incentives for the development of new enantiomer drug products that may represent significant pharmaceutic advances. The agency is requesting comments on this issue and intends to publish a notice in Federal Register at a later date announcing its policy. DATES: Written comments by March 17, 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: Wayne H. Mitchell, Center for Drug Evaluation and Research (HFD-7), Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855, 301-594-1049. SUPPLEMENTARY INFORMATION: FDA is requesting comments on the agency's policy on marketing exclusivity for drug products whose active ingredient is a single enantiomer of a previously approved racemate. I. Enantiomers and Racemates Stereoisomers are molecules that have the same constitution (i.e., molecular formula and chemical connectivity), but differ in the spatial orientation of the atoms. When two stereoisomers are mirror images, but are not superimposable upon each other (like left and right hands), they are referred to as enantiomers. Enantiomeric molecules are identical in all physical and chemical properties, except in an environment which is also chiral (characterized by handedness). Polarized light is such an environment, and pairs of enantiomers rotate the plane of polarization by equal amounts in opposite directions. Enantiomers may be either right-handed (dextro-rotary) S(+)-isomers or left-handed (levo-rotary) R(-)-isomers. Racemates are equimolar mixtures of enantiomers of the same molecule. [[Page 2168]] Frequently, both enantiomers found in a racemate will have similar desirable pharmacological activity. In other cases, one member of a pair of enantiomers is pharmacologically active and the other inactive or nearly inactive, as in baclofen where the R(-)-isomer is a muscle relaxant and antispastic, and the S(+)-isomer is essentially inactive. In other racemates, the enantiomers show significantly different pharmacological activity. For example, both isomers of sotalol have similar antiarrhythmic effects, but only the R(-)-isomer has significant beta-blocking activity. There are also instances where only one member of a pair of enantiomers has shown significant toxicity; an example of this may be found with thalidomide, where it is generally believed that most, if not all, of the teratogenicity associated with the drug is attributable to the R(-)-isomer. In the past, the usual practice in the pharmaceutical industry has been to develop either a racemate or an enantiomer without fully characterizing or studying its respective properties. When separation of enantiomers was difficult, the question of which stereoisomeric form should be developed was largely an academic question. However, in many cases, current technology permits production of pure enantiomers on a commercial scale. Improved pharmacologic study of enantiomers has been permitted by developments in analytical technology that frequently enable detection of one enantiomer in the presence of the other at concentrations found in biological fluids. The increased feasibility of such efforts led the agency to issue on May 1, 1992,``FDA's Policy Statement on the Development of New Stereoisomeric Drugs'' (Stereoisomeric Drug Policy). (See the Federal Register of May 27, 1992 (57 FR 22249).) The Stereoisomeric Drug Policy provides general recommendations for conducting and reviewing studies of the safety and effectiveness of drug products whose active ingredient is an enantiomer, a racemate, or a nonracemic mixture of enantiomers. Although the Stereoisomeric Drug Policy does not address issues of marketing exclusivity, it does contain the agency's thinking on the approval of stereoisomeric drug products. As such, it may be of interest to anyone commenting on marketing exclusivity for drug products whose active ingredient is a single enantiomer of an approved racemate. II. Marketing Exclusivity A. The 1984 Amendments The 1984 amendments amended the Federal Food, Drug, and Cosmetic Act (the act) to establish two new types of marketing applications: Abbreviated new drug applications (ANDA's), established under section 505(j) of the act (21 U.S.C. 355(j)); and 505(b)(2) applications, established under section 505(b)(2) of the act. The 1984 amendments also provide for the granting of nonpatent marketing exclusivity to certain drug products. Marketing exclusivity gives qualified drug products periods free of competition from drugs approved under ANDA's and 505(b)(2) applications. Marketing exclusivity is provided for in section 505(c)(3)(D) of the act, which limits approval of competing 505(b)(2) applications, and section 505(j)(4)(D) of the act, which limits approval of competing ANDA's. Section 505(c)(3)(D)(ii) and (j)(4)(D)(ii) of the act provides that if an NDA is approved for a drug, no active ingredient of which has been approved in a previous NDA, no 505(b)(2) application or ANDA for a drug product with the same active ingredient as the previously approved NDA drug product may be submitted until 5 years after the date of approval of the first drug product. Section 505(c)(3)(D)(iii) and (j)(4)(D)(iii) of the act provides 3 years of exclusivity to a drug product that includes a previously approved active ingredient, where the NDA for the drug product contains reports of new clinical investigations (other than bioavailability studies), conducted or sponsored by the applicant, that are essential to the approval of the NDA. (Section 505(c)(3)(D) and (j)(4)(D) of the act has other marketing exclusivity provisions which are not relevant to this notice.) The text of the amendments and the legislative history accompanying the amendments do not directly address how these provisions of the 1984 amendments regarding marketing exclusivity should be applied to enantiomers. B. Regulations FDA's regulations implementing the marketing exclusivity provisions of the 1984 amendments are found in Sec. 314.108 (21 CFR 314.108). Section 314.108(b)(2) states that if a drug product that contains a ``new chemical entity'' was approved in an NDA, ``no person may submit a 505(b)(2) application or abbreviated new drug application under section 505(j) of the act for a drug product that contains the same active moiety as in the new chemical entity for a period of 5 years from the date of approval of the first approved new drug application.'' Section 314.108(b)(4) states that if an NDA is for a drug product that contains an active moiety that has been previously approved in another NDA, and includes reports of new clinical investigations (other than bioavailability studies) conducted or sponsored by the applicant that were essential to approval of the NDA, that drug product will be entitled to 3 years of marketing exclusivity. ``New chemical entity'' is defined in Sec. 314.108(a) as ``a drug that contains no active moiety that has been approved by FDA in any other application submitted under section 505(b) of the act.'' ``Active moiety'' is defined in the same section as follows: [T]he molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance. The issue of marketing exclusivity for enantiomers is not addressed in the body of the regulation. In the Federal Register of July 10, 1989 (54 FR 28872), FDA proposed regulations implementing the 1984 amendments. In the preamble to the proposed rule (54 FR 28872 at 28898), FDA briefly examined the issue of whether a single enantiomer of a previously approved racemate is entitled to 5 years of exclusivity under section 505(c)(3)(D)(ii) and (j)(4)(D)(ii) of the act, or 3 years of exclusivity under section 505(c)(3)(D)(iii) and (j)(4)(D)(iii) of the act. The agency stated that: FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis. FDA notes that a single enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity. FDA received one comment disagreeing with the stated policy. This comment was received nearly 4 years after the comment period closed, and the agency responded to it in the preamble to the final rule with a reiteration of the statement from the proposal. (See the Federal Register of October 3, 1994 (59 FR 50338 at 50359).) III. Request for Comments In light of the complexity of the scientific and regulatory issues involved, FDA believes it is appropriate to reexamine the question of exclusivity for enantiomers of previously approved [[Page 2169]] racemates. The agency believes that this issue would benefit from a more focused consideration than it was subject to in the rulemaking process for the regulations implementing the 1984 amendments, where there were many complicated and contentious regulatory matters under consideration, and where this issue was raised by one comment submitted very late in the rulemaking process. Accordingly, FDA is requesting comments on the appropriate period of marketing exclusivity for drug products whose active ingredient is a single enantiomer of a racemate that is an active ingredient of a previously approved drug product. Among the issues that the agency is interested in receiving comment on are as follows: (1) What period of marketing exclusivity would best effectuate the 1984 amendments' dual policy goals of increasing drug price competition and providing incentives for the development of innovative drug products? (2) Would granting a 5-year period of exclusivity to enantiomers of previously approved racemates encourage medically significant pharmaceutical innovation? (3) If the pharmacological action of each enantiomer is described in the approved NDA for the racemate, should a subsequently submitted application for an enantiomer of the racemate receive different treatment for exclusivity purposes than if the pharmacological action of each enantiomer is not described in the approved NDA for the racemate drug product? (4) If the agency were to assess requests for exclusivity for enantiomers of previously approved racemates on a case-by-case basis, what criteria should the agency apply? (5) Compared with other drug products, what are the costs of and technical barriers to obtaining safety and efficacy data for a drug product whose active ingredient is a single enantiomer of a previously approved racemate? (6) How many drug products (whether approved, the subject of pending NDA's, or in development) are likely to be affected by this policy? After considering comments received in response to this notice, FDA will publish a Federal Register notice setting forth its policy on exclusivity for a drug product whose active ingredient is an enantiomer of a previously approved racemate. Interested persons may, on or before March 17, 1997, submit to the Dockets Management Branch (address above) written comments regarding this notice. Two copies of any 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. Copies of the comment on exclusivity for enantiomers submitted to the docket for the July 10, 1989, proposed rule; FDA's Stereoisomeric Drug Policy; and other correspondence and documents relating to the subject matter of this notice have been placed in the docket for this notice. Received comments and other material placed in the docket may be seen in the office above between 9 a.m. and 4 p.m., Monday through Friday. Persons considering submitting a 505(b)(2) application or an ANDA for a drug product that may be affected by any change in FDA's policy on marketing exclusivity for enantiomer drug products should contact the Center for Drug Evaluation and Research's (CDER's) Office of Generic Drugs or the appropriate review division within CDER before submitting the application. Dated: January 10, 1997. William K. Hubbard, Associate Commissioner for Policy Coordination. [FR Doc. 97-944 Filed 1-10-97; 12:29 pm] BILLING CODE 4160-01-F