FDA Petition Response Reaffirms FDA Orange Book Dosage Form Nomenclature Policy

By Kurt R. Karst –      

FDA’s recent decision to grant in part and deny in part a citizen petition concerning generic versions of DORYX (doxycycline hyclate) Delayed-Release Tablets reaffirms FDA’s policy that in order for two drug product to be in the same “dosage form,” they must share the same Orange Book dosage form descriptor, and that a drug product’s release mechanism does not provide a scientific basis to distinguish dosage forms.  Dosage form “sameness” is a prerequisite for two products to be pharmaceutically equivalent (and therapeutically equivalent).  Indeed, the Orange Book Annual Preface and FDA’s regulations state: “Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or concentration . . . Pharmaceutically equivalent drug products . . . may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration time, and, within certain limits, labeling.” (emphasis added)

The term “dosage form” is not specifically defined in the FDC Act or in FDA’s regulations.  FDA’s regulations at 21 C.F.R. §§ 314.3(b) and 320.1(b), however, include the term “dosage form” in the definition of “drug product:” “[A] finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more active ingredients.”  Over the past several years, FDA has had occasion to more fully define “dosage form.”  For example, FDA has stated that “[a] dosage form is the way of identifying the drug by its physical form, which is linked both to physical appearance of the drug product and to the way it is administered” (FDA-1993-P-0037) and that “dosage form is generally determined based on the form of the product prior to dispensing to the patient” (1996P-0459).

FDA lists dosage forms in the Orange Book at Appendix C (Uniform Terms).  Currently, Appendix C, which serves as informal guidance on what constitutes the “same” or “identical” dosage form, lists 76 distinct dosage forms.  The list of dosage forms in Appendix C is intended to be flexible. Dosage forms are added and deleted by FDA as necessary.  For example, in 1990, 62 dosage forms were listed, and in 1995, 67 dosage forms were listed).

In order for FDA to approve an ANDA (except when approved pursuant to an approved suitability petition), the FDC Act requires that a generic drug contain the “same” dosage form.  FDA has interpreted the term “same” to mean “identical” in the context of dosage forms (21 C.F.R. § 314.92(a)(1)), and has used its discretion to interpret the term “identical” to mean products that have the same dosage form identified in the Orange Book at Appendix C.  For example, FDA has stated that “a proposed drug product has the same dosage form if it falls within the identical dosage form category, as listed in the Orange Book, Appendix C” (FDA-1993-P-0037).  Even though two drugs may have the same dosage form nomenclature and are considered by FDA to be in “identical” dosage forms, some variability may exist.  For example, FDA treats hard and soft gelatin capsules to be in the identical “Capsule” dosage form (FDA-1990-P-0030).  Both FDA and the courts have ruled that “a drug’s dosage form is not based on its release mechanism but on its appearance and the way the drug was administered” (Pfizer, Inc. v. Shalala, 1 F. Supp. 2d 38 (D.D.C. 1998), rev’d on other grounds 182 F.3d 975 (D.C. Cir. 1999)).

In November 2008, Warner Chilcott requested, among other things that FDA “not consider doxycycline hyclate tablets that contain an outer coating alone pharmaceutically equivalent tablets with coated pellets,” and “only permit an ANDA to reference Doryx DR Tablets if FDA has granted a suitability petition.”  DORYX DR Tablets contain coated pellets of doxycycline hyclate.

In denying these requests (FDA granted the petition with respect to certain bioequivalence requirements), FDA ruled:

A review of the dosage form classifications in the Orange Book demonstrates that the Agency has consistently chosen not to base its dosage form descriptions on release mechanisms.  In the regulation detailing reasons to refuse to approve an application, the Agency implicitly acknowledges that the “release mechanism” is a part of the composition or formulation of the drug rather than the “dosage form” of the drug (see 21 CFR 314.127(a)(8)(ii)(A) . . . .

Once it is established that the enteric coated tablets and tablets containing coated pellets can be the same dosage form, it follows that enteric coated tablets and tablets containing coated pellets can be pharmaceutical equivalents.  FDA regulations recognize that extended-release products that deliver the identical amounts of the active ingredient over the same dosing period can be pharmaceutical equivalents . . . .  FDA has considered numerous products with different release mechanisms to be pharmaceutically equivalent.  Furthermore, as FDA has noted previously, there is “no scientific basis for distinguishing dosage forms on the basis of release mechanisms.” 

Following from FDA's decision that doxycycline hyclate tablets containing an outer coating alone and doxycycline hyclate tablets with coated pellets are in the same dosage form (i.e., "Tablets, Delayed Release"), FDA denied Warner Chilcott’s request to “only permit an ANDA to reference Doryx DR Tablets if FDA has granted a suitability petition:” “we disagree that an ANDA for a doxycycline hyclate delayed-release tablet would be required to submit a suitability petition before submitting an ANDA referencing Doryx DR Tablets.”