The Office of Generic Drugs (OGD) has been busy in the bioequivalence arena as evidenced by its issuing of 31 new recommendations and revising 17 previously issued recommendations. The list of new and revised recommendations can be found here.
As always, there are some specific recommendations that are of note while others are standard bioequivalence recommendations. Below are some of the more interesting recommendations that have caught our eye.
Budesonide Powder for Inhalation
There are in vitro AND in vivo requirements to establish bioequivalence of the test and reference product for this dry powder inhaler. The in vitro testing should be performed on at least three different lots of test and reference product, and a minimum of 10 units of each batch should be tested. FDA recommends that each of the three batches contain differing lots of API, excipients, and container closure components. The in vitro test should include: single actuation content and aerodynamic particle-size distribution. The criteria for these tests are described in the Guidance. In addition, a single dose, two-way crossover in vivo pharmacokinetic study under fasting conditions should be conducted. Also a comparative clinical endpoint BE study designed to be “a randomized, multiple-dose, placebo-controlled, parallel group design, at minimum consisting of a 2-week run-in period followed by a 4-week treatment period of the placebo, T or R product” should be run.
Epinephrine Injection, intramuscular, subcutaneous (Autoinjector)
The Guidance described the need for the product to be qualitatively (Q1) and quantitatively (Q2) the same. FDA has provided an outline of the various in vitro testing that must be provided and the general conditions for sameness of the device components are articulated in the FDA recommendations. “Prior to product development or submission of an ANDA, FDA strongly encourages applicants to submit to OGD via controlled correspondence and/or pre-ANDA meeting request, the following:
- Working model(s) of the proposed T product and T trainer.
- Sample(s) of the R product and R trainer.
- In certain circumstances, FDA may request additional information and/or data, as appropriate.”
FDA is recommending both a fasting and fed BE study for these products; however, FDA states that “If the Over-the-Counter (OTC) Referenced List Drug (RLD) Esomeprazole Magnesium Delayed Release (DR) Capsule (NDA 204655) is identical to the prescription (Rx) version of RLD (NDA 021153) at the same strength of EQ 20 mg base, the FDA may deem the bioequivalence between the OTC test and OTC RLD Esomeprazole Magnesium DR Capsules at the same strength of EQ 20 mg base by cross-referencing the acceptable in vivo bioequivalence studies conducted on the Rx test product and the Rx RLD (NDA 021153) at the same strength of EQ 40 mg base. The deemed bioequivalence may be based on (i) approval of Esomeprazole Magnesium DR Capsule for Rx use (EQ 20 mg and 40 mg base), (ii) both Rx and OTC products have the same formulation composition, are manufactured with the same manufacturing process and process controls, and conform to the same quality standards, and (iii) comparable in vitro dissolution testing of the Rx and OTC capsules. Two separate Abbreviated New Drug Applications (ANDAs) must be submitted since they are the subject of two separate New Drug Applications (NDAs).” FDA also notes that, if the products are determined to be highly variable, then a reference scaled approach may be employed.
Acyclovir Cream (revised)
In this Guidance document, OGD is providing an in vitro in addition to an in vivo option (BE study with clinical endpoints). The in vitro option contains significant detail on requirements that appear to be much more detailed than that for acyclovir ointment. This revision provides the in vitro option for the first time for this particular dosage form of acyclovir. The previous recommendation provided only for the BE study with clinical endpoint study. For some reason, it was easier for OGD to originally permit an in vitro testing option for the ointment dosage form, but they steadfastly maintained the need for a clinical endpoint study for the cream. This change in requirement again signals OGD’s willingness to consider and accept alternate in vitro testing for some types of products, rather than a BE study with clinical endpoints. Remember that, for the purposes of establishing bioequivalence, clinical endpoint studies are not very sensitive. In addition, since acyclovir cream and ointment are just marginally effective, clinical BE studies would likely involve very large numbers of subjects, and would have a limited chance of success.
Nepafenac Ophthalmic Suspension (revised)
Previous recommendations included BE study with clinical endpoints. The revised Guidance permits two other options. If the product is Q1 and Q2 the same, an in vitro option is offered. In addition, a pharmacokinetic option (study of drug content in aqueous humor) may be employed.
OGD is continually looking for alternate methodologies for products that pose unique bioequivalence issues. The science is evolving and while some decisions may make the hurdle easier to get over for establishing BE, others increase the hurdle – but none lower the bar for establishing that two products are bioequivalent.