Description
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. The FDA has been researching the feasibility of alternative, scientifically valid methods, including in vitro approaches, to support an evaluation of BE for topical drug products. These research initiatives have supported the development of multiple draft product specific guidance's for several topical drug products which have included an in vitro option to demonstrate BE in cases where the prospective generic drug product is Q1/Q2 the same as the RLD product.These in vitro BE approaches include, but are not limited to, comprehensive characterization of the physical and structural properties of complex topical dosage forms, potentially including comparative performance testing by an in vitro release test (IVRT) and/or an in vitro permeation test (IVPT). In certain cases, in vitro approaches have been recommended in concert with in vivo pharmacokinetic (PK) studies to collectively support a demonstration of BE, but again, only in cases where the prospective generic drug product is Q1/Q2 the same as the RLD product. The constraint on Q1/Q2 sameness mitigates the risk of potential failure modes for BE and/or TE that may arise when the composition of the prospective generic drug product is not the same as that of the RLD product.These novel, sophisticated, and most importantly, efficient approaches to demonstrate BE for topical drug products are less resource and risk-intensive than those involving comparative clinical endpoint studies, and facilitate the availability of high-quality topical generic drug products. However, in situations where the prospective generic drug product is non-Q1/Q2 with respect to the RLD product, a comparative clinical endpoint BE study is still routinely relied upon to demonstrate BE.In order to advance FDAs mission to make high quality, safe and effective drug products available to the American public, while supporting innovation, it is essential to explore the potential utility of novel, efficient BE standards for prospective generic topical drug products that are non-Q1/Q2 the same as the RLD product. To support this goal, it is necessary to investigate the potential failure modes for BE and/or TE that may arise from differences in the composition of a topical formulation, and to develop approaches to characterize the influence of such compositional differences on dosage form attributes and performance in a manner that appropriately mitigates the risk of potentially relevant failure modes for BE and/or TE.ObjectiveThe objective of this work is to support the development of accurate, sensitive and reproducible methodologies to characterize the dynamic thermodynamic properties and other aspects of topical dosage forms that are critical to their performance, and that, when found to be similar between compositionally different formulations, mitigate the risk of potential failure modes for BE and/or TE.This research should improve scientific understanding of fundamental mechanistic and/or physical principles that explain how the composition of a topical formulation, which may change as the dosage form undergoes metamorphosis (e.g., drying) on the skin, influences the thermodynamic activity of the drug (and of other components of the formulation), and how this modulates drug delivery into the skin. Considerations beyond thermodynamics should also be explored, and since formulations with different compositions may also exhibit different physical and structural attributes, a related consideration for the research is that it should more broadly elucidate the manner in which different topical formulations must be similar for them to be BE and TE.Detailed DescriptionCompositional differences between topical formulations may have the potential to alter the relative proportions of phase state(s) in the dosage form, the polymorphic form, solubility, stability, and/or thermodynamic activity of the drug and its distribution within the phases of the dosage form, the diffusion of the drug in the dosage form and its partitioning into the skin, and other potentially critical characteristics that may alter the performance of a drug product. The intent of this funding opportunity is to systematically elucidate the fundamental mechanistic principles underlying the complex interplay of such factors, and to identify or develop approaches to characterize and compare relevant information about compositionally different formulations. Such information may include, for example, profiles of the thermodynamic activity of the drug in each formulation variant throughout its metamorphosis on the skin. Collectively, the information should include all formulation characteristics that may be critical to ensuring that the rate and extent to which the drug becomes available at or near the site of action in the skin would be the same from both formulations.The rationale for offering the funding opportunity as a multi-year award is to afford sufficient time and resources to formulate and characterize different types of formulation variants, and to conduct multiple in vitro studies with multiple drugs and formulation variants selected in collaboration with the FDA. 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 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:1. Develop a theoretical framework to describe the fundamental forces that govern topical dosage form performance, potentially based upon thermodynamic principles, incorporating any other considerations that may be relevant. For example, one consideration may be that, in addition to the contribution of the drug substance to efficacy, the vehicle component of the topical formulation (i.e., the placebo formulation) may have the potential to contribute to the efficacy of the drug product, potentially via its physical properties or via a mechanism of action attributable to individual or collective components of the formulation. As part of this phase of the work, potential failure modes for BE and/or TE should be identified, particularly those that are relevant to compositionally different formulations.2. Formulate and characterize topical dosage forms that are systematically varied in composition. It is anticipated that the empirical research will initiate with relatively simple topical dosage forms, beginning with single-phase solutions, advancing to single phase gels, and systematically progressing to more complex topical dosage forms thereafter. Systematic alterations may be made to vary the type (Q1) and/or the amount (Q2) of selected inactive ingredients in the formulations. Some studies may compare formulations that contain the same inactive ingredients (Q1 the same), but that are systematically varied in the amount of an individual inactive ingredient (Q2). For example, the amount of a key inactive ingredient may be systematically varied by ± 10%, 15%, 25%, 50%, etc. of the nominal concentration. Other studies may compare non-Q1 formulations that are systematically varied in composition by using substitutions of similar polymers, oils, or alcohols, for example.3. Evaluate the influence of these compositional differences on the physical, structural and functional properties of the dosage form. This might include an assessment of the solubility of the drug in the formulation when initially manufactured, and at multiple points as the composition of the formulation changes during drying on the skin. Such parameters may be used to help characterize the thermodynamic activity of the drug in the dosage form at multiple points in time, throughout its metamorphosis.4. Characterize and compare the physical, structural, functional and other properties (including thermodynamic properties) among the formulation variants. It is anticipated that IVPT studies will be performed with each formulation variant to characterize the flux of the drug into and through human skin over time (i.e., the cutaneous PK of the drug).5. Correlate the relevant characteristics of each formulation variant (e.g., thermodynamic activity profiles for the drug) with IVPT flux profiles. 6. Verify the influence of the critical formulation characteristics on BE using formulations that represent positive and negative controls for BE.Ultimately, the research with different drugs and different formulations, selected in cooperation with FDA collaborators, should help elucidate what characteristics of topical formulations must remain similar in a given situation, even for compositionally different formulations, to systematically mitigate the risk of potential failure modes for BE and/or TE.