Introduction

Efforts establishing alternative, scientifically valid methods for evaluating therapeutic equivalence of topical drug products are ongoing. These methods support developing appropriate in vitro and in vivo approaches that demonstrate BE based upon dermal PK methods that sample drug concentrations at or near the site of action in the skin. In cases where the influence of manufacturing process variables on the physical, chemical, and microstructural critical product quality attributes are well characterized and found to be equivalent for generics compared with their RLD products, we are exploring whether BE may be established by integrating collective evidence related to product quality and performance from multiple, rationally selected, in vitro and/or in vivo techniques.

Research

One of our investigations evaluates BE for topical dermatological products through dermal PK sampling conducted by inserting a dermal open flow microperfusion (dOFM) probe within the dermis and monitoring the local concentration of drug in the skin across time. This permits the in situ measurement of the rate and extent of drug(s) in the dermis, which can be compared for generic drug products and their RLD.

Another research initiative investigates evaluating BE for topical dermatological products through an in vivo technique known as skin stripping. This is a dermal PK sampling technique performed by collecting the outermost layers of skin through sequential application and removal of tape strips, thereafter analyzing the samples for topically administered drug content. This permits the in situ measurement of the rate and extent of drug delivery in the outermost layer of skin — the stratum corneum — which may be particularly relevant for certain topical products when this layer of skin is the site of drug action.

We are also evaluating the use of an in vitro permeation test (IVPT) with excised human skin mounted in a diffusion cell as part of a BE methodology. This in vitro approach permits direct collection of the drug permeating through the stratum corneum, epidermis, and/or dermis of human skin from a topical dermatological drug product dosed on the skin surface. The merit of this approach is its potential to correlate with and be predictive of human in vivo bioavailability data, as well as the relative efficiency with which one can perform well-controlled studies of comparative bioavailability. As an in vitro methodology, this approach may support the determination of BE as part of a comprehensive, integrated battery of evidence demonstrating that a generic product is equivalent in quality and performance to its RLD, potentially as part of a qualitative risk management approach.

Two grants supporting research in this area focus on the correlation between in vitro and in vivo dermal PK approaches with the potential to evaluate the BE of topical drug products.  The goals of these research initiatives include developing appropriate and relevant study conditions under which to evaluate the BE of topical drug products and developing predictive in vitro methodologies to help evaluate topical BE. To support the evaluation of BE within a quality risk management paradigm, two additional grants funding research in this area focus on investigating the physicochemical properties and associated failure modes of generic topical drug products, with a goal of developing innovative techniques for measuring critical quality attributes in topical dermatologic dosage forms. 

ORS staff facilitating research in this area

• Sam Raney, Priyanka Gosh

Projects and Collaborators

• Novel Methodologies and IVIVC Approaches to Assess Bioequivalence of Topical Drugs
  • Site PI: Frank Sinner
  • Grant #: 1U01FD004946-01
• Bioequivalence of Topical Drug Products: In Vitro – In Vivo Correlations
  • Site PI: Audra Stinchcomb
  • Grant #: 1U01FD004947-01
• Characterization of Critical Quality Attributes for Semisolid Topical Drug Products
  • Site PI: Michael Roberts
  • Grant #: 1U01FD005226-01
• Topical Products and Critical Quality Attributes
  • Site PI: Sathyanarayana Murthy
  • Grant #: 1U01FD005233-01
• Internal Project: Coupling Chemical Analysis to High Resolution Microscopy Methods for Enhanced Physicochemical Characterization of Drug Products Containing Nanomaterials and Other Complex Formulations
  • FDA Collaborator: Katherine Tyner
  • FDA Center/Office/Division: CDER/OPQ/SS

Publications and Presentations

• Raney SG, Franz TJ, Lehman PA, Lionberger R, Chen ML.  Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products. Clin Pharmacokinet. (June 11, 2015)
• Rantou E. Special Cases for the Statistical Evaluation of Bioequivalence: An Example of In Vitro Skin Permeation Test Data. Oral presentation at the DIA Annual Meeting (June 18, 2015)
• Sinner FM. Tissue Specific PK and PD Enabled by Open Flow Microperfusion: From Bioequivalence to Mechanism of Drug Action PoC Studies. Oral presentation at the AGAH 6th Dermatological Product Development Workshop (June 24, 2015)
• Polak S, Patel N, Cristea S, Rose R, Salem F, Abduljalil K, Johnson T, Raney SG, Zhang X, Lin H-P, Newman B, Chow E, Ghosh P, Fan J, Fang L, Jamei M.  Towards mechanistic simulation and prediction of bioequivalence studies of topical formulations case study with two diclofenac formulations. Poster presentation at the Barrier Function of Mammalian Skin Gordon Research Conference (August 18, 2015)
• Patel N, Cristea S, Rose R, Salem F, Abduljalil K, Johnson T, Jamei M, Raney SG, Zhang X, Lin H-P, Newman B, Chow E, Ghosh P, Fan J, Fang L, Polak S. Mechanistic modelling of dermal drug absorption using the Simcyp Multi-phase Multi-layer MechDermA model: Case study of a transdermal patch formulation of weak base drug timolol. Poster presentation at the Barrier Function of Mammalian Skin Gordon Research Conference (August 18, 2015)
• Rantou E. Assessing Bioequivalence of Locally-Acting Generic Products; Statistical Controversies and Arising Issues. Oral Presentation at the ASA Biopharmaceutical Section Statistics Workshop (September 18, 2015)
• Raney SG.  Characterizing Critical Quality Attributes for Topical Semisolid Dosage Forms. Oral presentation at the USP Workshop on Quality Attributes of Drug Products Applied to the Skin (September 22, 2015)
• Cristea S, Patel N, Rose R, Salem F, Abduljalil K, Johnson T, Jamei M, Raney SG, Zhang X, Lin H-P, Newman B, Chow E, Ghosh P, Fan J, Fang L, Polak S. Prediction of cutaneous PK profiles after topical application - a comparison between the novel MPML-MechDermA model and the current MechDermA model in Simcyp Simulator. Case Study: Erythromycin. Poster presentation at the DMDG Meeting: 100 Years of Drug Delivery (October, 2015)
• Tiffner K, Bodenlenz M, Schwingenschuh S, Hajnsek M, Reisenegger P, Kainz S, Augustin T, Baumann P, Tschapeller B, Schwagerle G, Raml R, Kanfer I, Sinner F. Can we predict skin penetration by using TEWL or skin impedance? Poster presentation at the 13th Meeting of the European Epidermal Barrier Research Network (September 9, 2015)
• Raney SG. Considerations Relating to Product Quality Characterization for Topical Semisolid Dosage Forms. Oral presentation at the AAPS Annual Meeting Exhibitor Seminar: The Role of Topical Semisolid Microstructure on Formulation Performance and Efficacy (October 27, 2015)
• Murthy N. Evaluating Quality (Q3) Attributes and Potential Failure Modes for Topical Semisolid Drug Products. Oral presentation and AAPS Annual Meeting Symposium: Bio-Equivalence Standards for Topicals (BEST): Evidence for Integrating Multiple Quality (Q3) and Performance Tests to Evaluate the Best Generic Products (October 28, 2015)
• Stinchcomb A. Evaluating Topical Bioavailability In Vivo by Skin Stripping and In Vitro by IVPT. Oral presentation and AAPS Annual Meeting Symposium: Bio-Equivalence Standards for Topicals (BEST): Evidence for Integrating Multiple Quality (Q3) and Performance Tests to Evaluate the Best Generic Products (October 28, 2015)
• Sinner F. Evaluating Topical Bioavailability In Vivo by Dermal Open Flow Microperfusion and Equivalence by IVRT.  Oral presentation and AAPS Annual Meeting Symposium: Bio-Equivalence Standards for Topicals (BEST): Evidence for Integrating Multiple Quality (Q3) and Performance Tests to Evaluate the Best Generic Products (October 28, 2015)

Outcomes

• Research projects in progress
   

 

ResourcesForYou

• Office of Generic Drugs FY 2015 Regulatory Science Research Report