Generic drugs now represent the major part of the US pharmaceutical market. They are an attractive alternative to brand products for consumers because they are bioequivalent and therefore the same in terms of quality, safety and efficacy, but available at a considerably reduced cost. However, there are still products for which no or few generic alternatives are available. A big barrier to generic drug development is that the sponsor must demonstrate that their product is bioequivalent to the reference-listed drug (RLD). This is a particular challenge for the development of dermatological drugs because these drugs act locally, whereas most tests for bioequivalence (BE) use blood measurements. Thus, manufacturers must rely on clinical endpoint studies, which are not only expensive and time consuming, but also rather unreliable. Hence, there is an urgent need for new, more efficient ways to demonstrate BE of topical drugs. In particular, in vitro methods that correlate well with the in vivo situation would significantly facilitate the development of topical generic drugs. We will investigate in vitro and in vivo methods to show BE of topical products and will establish in vitro - in vivo correlations (IVIVC) at the level of pharmacokinetics in the dermis. First, we will conduct a clinical study to assess BE and non-BE in skin using dermal open flow microperfusion (dOFM) according to GCP and GLP. The results will serve as a "gold standard" for the in vivo situation in the dermis, and as a reference for validating all present and future in vitro methods for their ability to predict the in vivo situation. Secondly, we will examine in vitro methods to establish BE, starting with the only FDA- accepted in vitro approach as per the "FDA Draft Guidance on Acyclovir". We will then investigate innovative in vitro systems based on dOFM as a new in vitro approach for BE. We will use Zovirax 5% ointment (RLD) to demonstrate BE and Zovirax 5% creme to demonstrate non-BE against Zovirax 5% ointment. The same formulations will be used to demonstrate BE and non-BE in all in vitro and in vivo systems. All experiments will be performed under quality-controlled standards (ISO 9001, GCP, GLP. EN ISO 13485). One analytical HPLC-MS/MS method suitable for all project samples will be developed and validated according to ICH guidelines in a GLP-certified laboratory. All results of the BE and non-BE pairs using different methods will be analyzed for their predictive power. By cross- referencing the results, we plan to correlate in vitro with in vivo data to establish IVIVC.

Public Health Relevance

Generic drugs are an attractive alternative to reference listed drugs for consumers, because they have the same treatment effect but are generally available at considerably reduced cost. However, there are many skin drugs for which no or few generic alternatives are available. One huge barrier to generic drug development is that the manufacturer must demonstrate that the generic product is bioequivalent to the reference listed drug. This is no simple task for skin drugs, because there is no FDA-approved general method to show bioequivalence in skin. Thus, manufacturers must rely on clinical endpoint studies, which are not only expensive and time consuming, but can also be rather unreliable. Hence, there is an urgent need to develop and validate new, more efficient methods to demonstrate bioequivalence of topical drug products. In this project, we will develop and validate existing and new in vitro methods to predict the in vivo situation, thus lowering the barrier to future topical generic drug development.

Agency
National Institute of Health (NIH)
Institute
Food and Drug Administration (FDA)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01FD004946-01
Application #
8691506
Study Section
Special Emphasis Panel (ZFD1-SRC (99))
Project Start
2013-09-15
Project End
2014-08-31
Budget Start
2013-09-15
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Joanneum Research
Department
Type
DUNS #
300687654
City
Graz
State
Country
Austria
Zip Code