This Road Has Been Traveled Before? Chance of Success Approaching Zero!

IntelGenx Corporation of Saint Laurent, Quebec, Canada submitted petition FDA-2013-P-1058 (here) on August 22, 2013, asking the FDA to designate its Rizatriptan Oral Film product as AB rated (or therapeutically equivalent [TE]) when approved to Maxalt-MLT Orally Disintegrating Tablets, the reference listed drug (RLD) cited in its 505(b)(2) application. 

IntelGenx argues that their proposed film version:

  • Has the same active ingredient in the same strength;
  • Is very similar in their performance as dosage forms;
  • Has the same oral route of administration as both rapidly disintegrate on the tongue; and
  • Both meet the applicable compendial or other standards of strength, quality, purity and identity.

While these statements are all true, there is one gamebreaker in their four arguments.  The fact that the two products might perform similarly does not overcome the fact that the products are different dosage forms.  An oral film is not an orally disintegrating tablet, no more than a tablet is a capsule (which can be bioequivalent, but are never rated as therapeutically equivalent).  To receive an AB rating and be considered therapeutically equivalent, the FDA requires a product to be both pharmaceutically equivalent (has the same dosage form strength, same route of administration and same active ingredient) and bioequivalent. The FDA describes these requirements in the preface to the Approved Drug Products with Therapeutic Equivalence Evaluations (better known as the Orange Book) when describing the terms used to define TE as follows:

Therapeutic Equivalence-Related Terms

Pharmaceutical Equivalents.  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 (e.g., chlordiazepoxide hydrochloride, 5 mg capsules).  Pharmaceutically equivalent drug products are formulated to contain the same amount of active ingredient in the same dosage form and to meet the same or compendial or other applicable standards (i.e., strength, quality, purity, and identity), but they may differ in characteristics such as shape, scoring configuration, release mechanisms, packaging, excipients (including colors, flavors, preservatives), expiration time, and, within certain limits, labeling.

Pharmaceutical Alternatives.  Drug products are considered pharmaceutical alternatives if they contain the same therapeutic moiety, but are different salts, esters, or complexes of that moiety, or are different dosage forms or strengths (e.g., tetracycline hydrochloride, 250 mg capsules vs. tetracycline phosphate complex, 250 mg capsules; quinidine sulfate, 200 mg tablets vs. quinidine sulfate, 200 mg capsules).  Data are generally not available for FDA to make the determination of tablet-to-capsule bioequivalence.  Different dosage forms and strengths within a product line by a single manufacturer are thus pharmaceutical alternatives, as are extended-release products when compared with immediate-release or standard-release formulations of the same active ingredient.

Therapeutic Equivalents.  Drug products are considered to be therapeutic equivalents only if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.

FDA classifies as therapeutically equivalent those products that meet the following general criteria:  (1) they are approved as safe and effective;  (2) they are pharmaceutical equivalents in that they (a) contain identical amounts of the same active drug ingredient in the same dosage form and route of administration, and (b) meet compendial or other applicable standards of strength, quality, purity, and identity; (3) they are bioequivalent in that (a) they do not present a known or potential bioequivalence problem, and they meet an acceptable in vitro standard, or (b) if they do present such a known or potential problem, they are shown to meet an appropriate bioequivalence standard.

Quite simply, then, because a film dosage form and an orally disintegrating tablet are pharmaceutical alternatives, they cannot be rated as therapeutically equivalent or AB rated no matter how similar they may appear to behave.

For these and other issues related to therapeutic equivalence, please contact Joan Janulis, Vice President, Regulatory Affairs, at j.janulis@lachmanconsultants.com.