Bioequivalence Study Recommendations Published for 35 Products

In an ever-increasing effort, the Office of Generic Drugs (OGD) is keeping on top of this aspect of industry’s desire to obtain guidance on establishing bioequivalence for generic drug products. Today FDA published new bioequivalence (BE) guidance for 35 drug products and revised guidance for 8 previously issued recommendations.  The entire listing of the newly issued and revised guidance document can be seen here. There were some recommendations of note in the group of 35 and some interesting issues seen in the BE guidance revisions, as described below.


After taking 7+ years to approve a generic glatiramer acetate injection (the generic for Copaxone), it took yet another year for OGD to articulate the approval criteria for establishing bioequivalence.  As with some other recent complex product BE guidance documents, the glatiramer document outlines the requirement for establishing sameness of active ingredient and requiring the generic product to be quantitatively and qualitatively the same as the reference listed drug (RLD).  The document will permit a waiver of BE if sameness can be demonstrated by:

  1. Equivalence of fundamental reaction scheme;
  2. Equivalence of physicochemical properties including compositions;
  3. Equivalence of structural signatures for polymerization and depolymerization; and
  4. Equivalence of biological assay results.

The guidance document goes on to outlie what FDA expectations are for each of the equivalence tests.


Ferric Carboxymaltose

OGD is recommending a fasting, single-dose, randomized, parallel in vivo study, as well as particle size distribution study for a generic version of Injectafer.  The in vivo study should employ patients with anemia, not healthy volunteers.  At least three lots of test and reference product should be included in the comparative particle size distribution study, as well as in measuring other physicochemical parameters outlines in the guidance.



FDA requests standard fasting and fed single-dose crossover studies for the generic of Iressa, however, due to the risk of teratogenicity of gefitinib, only healthy male subjects should be included in the testing.


Indacaterol Maleate

The OGD recommendation for the generic of Arcapta Neohaler (a dry-powder inhaler) appears very onerous and is indicative of the complexity of inhaled products.  Remember OGD has not approved a generic version of a dry powder inhaler to date.  The guidance recommends various in vitro and in vivo studies, as well as an in vivo fasting, single-does crossover study and a comparative clinical endpoint study.  Good luck on this one!



It took almost 32 years for FDA to officially outline the BE requirements for the cream and ointment dosage forms of this old pre-1962 drug product.  While the requirements are fairly well known, FDA now has taken an official positon.  No in vivo studies, but firms are required to demonstrate “[a]cceptable comparative physicochemical characterization of the test and reference listed drug (RLD) formulations of the product to establish that the test product is a comparable triamcinolone acetonide topical… identical in strength to the RLD.”


Revision of the Cyclosporine Capsule Guidance

The guidance for both the IR and cyclosporine modified guidance were revised to require a fully replicate 4 period design study for both a fasting and a fed study.  Citing the fact FDA has classified this product as narrow therapeutic index (NTI), the Agency says:

The study should be a fully replicated crossover design in order to:

  • Scale BE limits to the variability of the reference product; and
  • Compare test and reference products’ within-subject variability


Good work, OGD, and for those of us out in industry, we still must guess what revisions to BE guidance documents mean to any approved or pending ANDA.