Characterize skin physiology parameters utilized in dermal physiologically-based pharmacokinetic model development across different skin disease states (U01) | RFA FD 18 017

Opportunity Information: Apply for RFA FD 18 017

This FDA cooperative agreement opportunity (U01), titled "Characterize skin physiology parameters utilized in dermal physiologically-based pharmacokinetic model development across different skin disease states," focuses on improving dermal physiologically-based pharmacokinetic (PBPK) models so they can better predict how drugs move into, through, and sometimes beyond the skin when applied as topical dermatologic products or delivered via transdermal systems. The core idea is that PBPK models are mechanistic, built from real biology (system-dependent parameters like tissue structure and physiology) combined with drug and formulation properties (drug-dependent parameters like molecular weight, solubility, pKa, logP, and other factors). For skin products, this type of modeling can be especially valuable because it can estimate drug amounts in specific skin layers even when those concentrations are hard or impossible to measure directly in people.

A major driver for the program is the long-standing challenge of demonstrating bioequivalence (BE) for complex topical and transdermal products, particularly generic versions that share the same intended use as the reference product but differ in formulation. Many topical dermatologic drugs act locally, so the most relevant exposure is at or near the site of action in the skin, yet routine clinical sampling of those local tissue concentrations is rarely available. On top of that, many topical products do not produce measurable systemic blood levels, which removes a standard pathway regulators often use for BE testing. Transdermal systems have the opposite concern: they are intended to reach the systemic circulation, but the rate and extent of absorption are still controlled by the skin, which is a complex, variable organ. Dermal PBPK modeling is presented here as a practical way to study both local skin exposure and systemic exposure in a unified framework, and potentially to run "virtual bioequivalence" simulations when conventional pharmacokinetic endpoint studies are not feasible.

Another central theme is that skin is not the same across all people or even across the body, and it changes substantially in disease. The opportunity specifically emphasizes the need to characterize and encode differences between healthy skin and diseased skin into dermal PBPK models. The goal is not just to build models that match observations in healthy adults, but to support credible extrapolation to patients with skin diseases and to special populations where physiology differs (for example pediatrics, the elderly, and groups differing by race and sex). To make that extrapolation believable, the program expects strong baseline characterization of healthy skin by body location, and then careful, evidence-based adjustments for disease states.

The scientific objective is to identify which skin physiology characteristics differ between healthy subjects and people with skin disease, quantify those differences, and incorporate them into model parameters in a way that improves predictive performance. Disease areas called out as examples include psoriasis, acne, athlete's foot and other fungal infections (tinea pedis, tinea cruris, tinea corporis; ringworm; "jock itch"), atopic dermatitis/eczema, rosacea, actinic keratosis, leprosy, dandruff, and dermatitis herpetiformis, with the explicit note that additional disease states may be added in collaboration with the FDA research team depending on regulatory needs. The types of physiological details the FDA highlights as particularly valuable include skin thickness and microstructure, hydration level, temperature, pH, and the presence or density of appendages like glands and hair follicles, with attention to how these vary by body location and by disease.

Methodologically, the opportunity lays out a staged approach. First, applicants are expected to identify key physiological parameters likely to differ between healthy and diseased skin and to matter for dermal absorption and disposition. Second, they should gather evidence for these parameters from multiple independent and credible sources such as peer-reviewed literature and textbooks, supplementing with in-house data when available. Where critical gaps exist, the program anticipates that applicants may need to design and conduct studies to generate missing experimental data, especially for subpopulations of interest. All collected information is expected to be organized into an accessible database, suggesting the FDA wants not just a single model output, but a reusable, transparent knowledge base that supports model development and future regulatory discussions.

Third, the program calls for development of dermal PBPK models covering both topical dermatological dosage forms and transdermal delivery systems, explicitly incorporating the compiled skin physiology information. The FDA signals that model development should span active pharmaceutical ingredients (APIs) with a range of physicochemical and permeability properties, because those properties influence formulation stability, drug release from the dosage form, and partitioning and movement across skin layers. While not mandatory, the announcement welcomes an API selection strategy reminiscent of a biopharmaceutics classification style approach, essentially encouraging applicants to select compounds that represent different corners of the physicochemical space (for example, varying solubility, pKa, and logP). On the formulation side, the models are expected to account for dosage form and formulation critical quality attributes as major determinants of in vivo performance, with examples including creams, ointments, gels, emulsions, suspensions, lotions, solutions, films, and patches. The text also leaves room for additional dosage forms or products to be prioritized jointly with FDA as new regulatory questions emerge.

A repeated emphasis throughout the opportunity is variability. The FDA highlights that skin physiology parameters vary between people (inter-subject variability) and within the same person over time or across sites (intra-subject variability), and that explicitly quantifying and incorporating this variability into PBPK models can produce more realistic predictions aligned with real-world use. Proposals that prioritize representing this variability, rather than relying only on single "typical" parameter values, are viewed favorably because they can better support scenario analysis and risk-based decision-making.

Fourth, after model development, the opportunity requires validation or qualification using appropriate datasets. These datasets should be independent and credible, drawn from literature, in-house sources, or newly conducted studies, and they should match the subpopulations, study designs, and dosage forms represented in the model. The point is to show the model can reproduce relevant experimental observations, not just fit the data it was built from, and to build confidence that the model can be used for regulatory-relevant questions.

Finally, the intended regulatory use case is to apply the qualified dermal PBPK models to evaluate bioequivalence for generic formulations via virtual bioequivalence trials. The program expects simulations under multiple scenarios to demonstrate flexibility, sensitivity to key parameters, and overall predictability. It also describes using both positive and negative control situations: cases where products are known to be bioequivalent and cases where products are known not to be bioequivalent, to test whether the model appropriately classifies them based on model outputs. The broader aim is to create tools that help assess BE between brand and generic dermatological products in patients and special populations where in vivo BE studies with pharmacokinetic endpoints are impractical or impossible.

From an administrative standpoint, this is an HHS/FDA opportunity under a cooperative agreement mechanism (U01), meaning substantial FDA scientific involvement is expected during the project. The funding opportunity number is RFA-FD-18-017 (CFDA 93.103). It was created March 21, 2018, with an original closing date of May 29, 2018. The award ceiling listed is $250,000, with an expectation of two awards. Eligibility is broad and includes federal recognized tribal governments and tribal organizations, state and local governments, public and private institutions of higher education, nonprofits (including and excluding 501(c)(3)), for-profit organizations (including small businesses), public housing authorities/Indian housing authorities, and individuals. The overall direction is clear: build an evidence-backed, variability-aware dermal PBPK modeling framework grounded in disease-specific skin physiology so FDA and developers can more credibly predict local and systemic exposure and, when appropriate, use simulations to support bioequivalence decisions for complex topical and transdermal products.

• The Department of Health and Human Services, Food and Drug Administration in the food and nutrition sector is offering a public funding opportunity titled "Characterize skin physiology parameters utilized in dermal physiologically-based pharmacokinetic model development across different skin disease states (U01)" and is now available to receive applicants.
• Interested and eligible applicants and submit their applications by referencing the CFDA number(s): 93.103.
• This funding opportunity was created on Mar 21, 2018.
• Applicants must submit their applications by May 29, 2018. (Agency may still review applications by suitable applicants for the remaining/unused allocated funding in 2026.)
• Each selected applicant is eligible to receive up to $250,000.00 in funding.
• The number of recipients for this funding is limited to 2 candidate(s).
• Eligible applicants include: State governments, County governments, City or township governments, Special district governments, Independent school districts, Public and State controlled institutions of higher education, Native American tribal governments (Federally recognized), Public housing authorities/Indian housing authorities, Native American tribal organizations (other than Federally recognized tribal governments), Nonprofits having a 501(c)(3) status with the IRS, other than institutions of higher education, Nonprofits that do not have a 501(c)(3) status with the IRS, other than institutions of higher education, Private institutions of higher education, Individuals, For profit organizations other than small businesses, Small businesses.

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