Assessing Bioequivalence in Generic Topical Dermatological Products: There Are Alternatives

Posted March 30, 2017

As described in previous blogs, determining bioequivalence (BE) of topical dermatologic products is challenging for both the regulatory and pharmaceutical industries.

FDA guidelines classify how BE studies should be designed and in which cases biowaivers can be requested based on in vivo and in vitro approaches. The guidelines for BE of topical drug products in the U.S. and Canada are identified in FDA, 21 CFR 320.24:

  1. Pharmacokinetics (PK)
  2. Pharmacodynamics (PD)
  3. Comparative well-controlled clinical trials (endpoint is BE) 
  4. In vitro release test (IVRT), in vitro permeation test (IVPT)

Until recently, the clinical endpoint studies routinely advised by the FDA was the default approach to evaluate BE of generic dermatological topical products. However, these studies are not necessarily considered to be the most accurate, sensitive and reproducible, partially for the following reasons:

  • Patient’s diseased skin that could severely alter barrier property and consequently the permeability, ultimately affecting the bioavailability and bioequivalence of the drug(s) applied
  • Placebo effects that can be very high for a variety of reasons
  • Clinical endpoints often based upon subjective assessments and patient compliance to the therapeutic treatment
  • Very large number of subjects required
  • Time-consuming (~ 12-24 months)
  •  Ethical and economical issues (expensive, ~$2-$10M)

Alternative topical BE approaches that are most widely considered by regulatory bodies include human in vivo blanching assays (officially approved as a surrogate method) and human in vivo skin-stripping studies.

The first biowaiver for a dermatological product, a topical acyclovir ointment, was released by the FDA in March 2012 and proposed IVRT as a surrogate method for BE evaluation of generics and reference listed drug formulations. Recently, in October 2016, another draft guidance was released by the FDA where IVRT was considered for a biowaiver for an ophthalmic bacitracin ointment.

Finally, in December 2016, the FDA released newly drafted guidance on acyclovir cream. For the first time, the FDA proposed a surrogate methodology that combines two in vitro approaches: IVRT and  IVPT, using an ex vivo human skin model. 

In terms of IVRT method development and validation procedures, the new draft FDA guidance is largely in concordance with USP general chapter <1724>, Semi-Solid Drug Products – Performance Tests. Nevertheless, there are some additional key recommendations in the guidance that must be taken into consideration in an IVRT study. The U.S. FDA for the first time has given detailed insight into the design and application of IVPT methodology to be used to compare BE of generics and reference listed drugs.

All the key aspects detailed in the FDA guidance have been harmonized in our study protocols, which combine appropriate development and validation of IVRT and IVPT methodologies integrated into a GLP/GMP environment, inspected and approved by the FDA. The combination of IVRT and IVPT methodologies in conjunction with our experience and expertise can enable our sponsors to obtain biowaivers for topically applied generic formulations, avoiding high-cost, time-consuming in vivo bioequivalence studies. 

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