Description
Background Generic drug products demonstrate BE to the (brand name) reference listed drug (RLD) and/or reference standard (RS) product by showing that they can deliver the same amount of the same drug to the site(s) of therapeutic action at the same rate and to the same extent as the RLD/RS drug product. For many systemically-acting drug products, BE is evaluated based upon plasma PK studies, which U.S. regulations consider to provide the most accurate, sensitive and reproducible evidence for establishing BE. This PK-based evaluation of BE also has the potential to be relatively efficient, and is well suited to generic drug development. Evaluating the PK of a locally-administered drug in a solid tissue like the skin can be scientifically and technically challenging. An in vitro cutaneous PK-based approach has been developed to support the evaluation of BE using an in vitro permeation test (IVPT) with excised human skin mounted in diffusion cells. In vivo cutaneous PK-based approaches have also been explored over the last several decades, including some using microdialysis/microperfusion probes inserted in the skin, or using non-invasive spectroscopic/imaging technologies. However, there is currently no in vivo cutaneous PK-based method that has been established to evaluate topical BE, and further research is needed. Of particular relevance, recent advances in non-invasive imaging technologies have indicated a potential for imaging to provide semi-quantitative, and potentially even quantitative measurements of the rate and extent to which a topically administered drug becomes available at or near the site of action (e.g. in the epidermis and potentially in the dermis). However there remain several challenges to be overcome in order to develop imaging as a quantitative or semi-quantitative technique to assess the cutaneous PK of topically applied drugs. One of the potential limitations to the quantitative analysis of a drug (or other compounds of interest) in the skin is the signal interference from the skin, itself. To overcome this limitation, strategies are needed that would make it feasible to evaluate the comparative rate and extent to which a topically applied drug becomes available at or near the site of action in the skin, when administered using commercial drug products. Another potentially significant limitation that would need to be addressed is that signal attenuation typically increases with increasing depth of the measurement in the skin. Objective The objective of this work is to support the development of an accurate, sensitive and reproducible methodology to monitor and compare the cutaneous PK of topically administered drugs using non-invasive spectroscopic/imaging technology and associated study designs. The approach should be amenable to eventual development for characterizing the cutaneous PK of drugs administered from commercially available drug products in vivo using human subjects. This research should improve scientific understanding of fundamental cutaneous spectroscopy/imaging principles and of the viability of different techniques and technologies to monitor the amount of drug in the skin; establish proof-of-principle results illustrating the discrimination sensitivity and reproducibility of the approach to compare cutaneous PK profiles between products; and support the development of in vivo techniques and/or technology. Detailed Description The intent is that the methodologies developed under this cooperative agreement with the FDA will illustrate how the amount of a drug in the skin can be characterized across a period of time, using non-invasive techniques (e.g., spectroscopic/imaging tomography) that would quantify the amount of drug at relevant locations in the skin as it changes over time. The ultimate purpose of the funding opportunity is to identify and develop relevant techniques and technology, and to use these to complete proof-of-principle in vitro and/or in vivo studies to characterize and compare the cutaneous PK of multiple topically administered drugs from different sets of test and reference topical products. The rationale for offering the funding opportunity as a multi-year award is to afford sufficient time and resources to research and develop the relevant technology and methodologies, and to conduct multiple in vitro and/or in vivo studies with multiple drugs and drug products selected in collaboration with the FDA. The drug products may include products for which comparative clinical endpoint BE studies have been completed, and/or where products are available that may represent positive and negative controls for BE. The intent of the cooperative agreement is that the award recipient will work collaboratively with FDA scientists to refine the research strategy, develop study designs and protocols, orchestrate study conduct, analyze data and publish the results. The translation of the science to practical methodologies may require significant technology development and extensive characterization in contexts specifically relevant to evaluating bioavailability and BE. The final research strategy would be developed based upon the innovation and expertise of the award recipient, in collaboration with feedback from the FDA to ensure that the study designs are aligned with the objectives of the award. Specific areas of scientific interest would include research to: Identify or develop accurate, sensitive and reproducible non-invasive quantitative or semi-quantitative techniques to characterize and compare the cutaneous PK of a drug following topical application. Develop suitable approaches to address issues associated with the use of the identified techniques and/or technology using in vitro and/or in vivo studies; such issues may include those related to the selective quantification of the drug, or the temporal resolution, the spatial resolution, and/or the orientation and size of the measurement area(s). Develop suitable approaches to resolve or discriminate the signal and to calibrate the signal intensity associated with specific topical drugs from the background signal interference in the skin. Approaches that are dependent on experimental (chemical) modification of the drug (e.g., by deuteration) may not be aligned with the ultimate objective of this work, which involves the characterization of commercially available topical drug products. Develop suitable approaches to evaluate the depth to which different topical drugs might be monitored and/or quantified with acceptable precision and identify strategies to correct for drug signal attenuation as a function of skin depth. A related consideration is whether the approach can provide supplemental information about the relative distribution and localization of a topically administered drug when dosed from different products/formulations. Understand the limitations of specific techniques for quantitative or semi-quantitative analysis of drug in the skin i.e. it may only be feasible to quantify certain classes of molecules (depending on their chemical structure) using a specific technique or technology, or only certain drug products due to inference from formulation components. Demonstrate that the cutaneous PK profile for a topically administered drug can be reliably quantified at or near the site of action (i.e., in the epidermis and/or the dermis) using appropriate techniques and/or technology. As part of this cooperative research, FDA collaborators may request independent research groups to align key parameters (e.g., drug products, dose, dose duration, etc.) of their respective study designs in order to facilitate the comparison/corroboration of scientific results from different non-invasive techniques/technologies/approaches that are used to compare the cutaneous PK of a drug from a specific set of drug products. The research project should ultimately demonstrate, using multiple drugs and sets of drug products that serve as positive and negative controls for BE, that the non-invasive techniques developed can produce cutaneous PK profiles using which BE can be demonstrated for positive controls for BE (based upon appropriate PK endpoints) and, using which, products that serve as negative controls for BE can be discriminated as not being bioequivalent