On September 9, 2013, the FDA published a draft guidance designed to provide current agency thinking on the methods and testing necessary to establish bioequivalence between the reference listed drug (RLD) and the generic powder for inhalation.

The guidance articulated the need for both in vitro testing, as well as 2 in vivo studies (a pharmacokinetic study, as well as a bioequivalence study with clinical endpoints).  The complete draft guidance can be found here.

The in vitro studies include a single actuation content study wherein the product should be studied at the beginning, middle, and end of its contents.  The guidance provides various flow rates at which this measurement should be evaluated, and refers the reader to the budesonide inhalation suspension guidance for an explanation of the population bioequivalence analysis.   In addition, an aerodynamic particle size distribution (cascade impactor) evaluation will be required.  Again, FDA wants to see measurements of this characteristic at different flow rates specified in the guidance.

The in vivo pharmacokinetic (pK) study proposed is a single dose, two-way crossover design to be conducted under fasting conditions using normal health subjects. Firms are cautioned to utilize the following instruction in the pK study: Subjects should adhere to labeling as follows: “Rinse your mouth with water after breathing in the medicine. Spit the water out. Do not swallow.”  This step is included likely to assure that pK data is not skewed by swallowed rather than inhaled powder.  Analysis of the following analytes is suggested: Fluticasone propionate and salmeterol in plasma and results should meet a CI of 80.00-125.00% to be acceptable.

The clinical endpoint study should be “[A] randomized, multiple-dose, placebo-controlled, parallel group design consisting of a 2 week run-in period followed by a 4-week treatment period of the placebo, T or R product.”  Criteria for the types of asthma patients are specified as well as the endpoint of interest and criteria for success.  FDA advises that the clinical study should be conducted on the lowest strength of the test and reference product. Inclusion and exclusion criteria are provided. A confidence interval approach should be taken and the results should fall into the 80.00-125.00% range.

FDA also advises that it expects the formulation of the test and reference products to be qualitatively (Q1) and quantitatively (Q2) the same, but if the sponsor has a difference in the Q2 nature of the formulation, that it provide a justification for the difference.  This signals that the FDA may accept different amounts of inactive ingredients in the test formulation.

The FDA also describes the characteristics of the device that must be the same:

The T product should have the following characteristics:

  • Passive (breath-actuated) device
  • Pre-metered multi-dose format
  • 60 doses
  • External operating procedures consisting of (1) Open, (2) Click, (3) Inhale, and (4) Close
  • Similar size and shape to the R product
  • Comparable device resistance to the R product
  • Dose counter 

The Agency strongly suggests that an ANDA sponsor submit a working model to the Office of Generic Drugs (OGD) prior to submission of the ANDA so OGD can determine if the device is similar enough to qualify for submission as a 505(j) application.

FDA is aware that they will likely obtain public comments to this document and stated in the Federal Register notice announcing the availability of this BE guidance that it would use the comments received in the formulation of their response to the GSK pending petition as reported in my blog post yesterday (here).