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

Frequently Asked Questions (FAQs)

What is the title of this FDA cooperative agreement opportunity?

The opportunity is titled "Characterize skin physiology parameters utilized in dermal physiologically-based pharmacokinetic model development across different skin disease states."

What type of funding mechanism is this opportunity using?

This is an FDA cooperative agreement using the U01 mechanism, which means substantial FDA scientific involvement is expected during the project.

What is the funding opportunity number and CFDA listing?

The funding opportunity number is RFA-FD-18-017, and the CFDA listing is 93.103.

When was the opportunity created and when did it close?

It was created on March 21, 2018, with an original closing date of May 29, 2018.

What is the award ceiling and how many awards are expected?

The listed award ceiling is $250,000, and the opportunity indicates an expectation of two awards.

Who is eligible to apply based on the information provided?

Eligibility is broad and includes: federally 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.

What is the main purpose of this program?

The purpose is to improve 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.

What are dermal PBPK models, in plain terms?

Dermal PBPK models are mechanistic models built from biology and physiology (system-dependent parameters such as tissue structure and skin physiology) combined with drug and formulation properties (drug-dependent parameters such as molecular weight, solubility, pKa, logP, and related factors). For skin products, these models can estimate drug amounts in specific skin layers even when those concentrations are difficult or impossible to measure directly in people.

Why is FDA emphasizing PBPK modeling for topical and transdermal products?

A major driver is the long-standing challenge of demonstrating bioequivalence (BE) for complex topical and transdermal products, especially generic products that share intended use with a reference product but differ in formulation. Many topical dermatologic drugs act locally in the skin and often do not produce measurable systemic blood levels, making standard pharmacokinetic BE approaches difficult. For transdermal systems, systemic exposure is intended, but absorption is still controlled by the complex and variable properties of skin. Dermal PBPK modeling is positioned as a way to evaluate local and systemic exposure within a unified framework and to support "virtual bioequivalence" simulations when conventional studies are not feasible.

What is meant by "virtual bioequivalence" in this opportunity?

Virtual bioequivalence refers to using qualified PBPK models to run simulations (virtual trials) to evaluate whether generic and brand products are bioequivalent under multiple scenarios, particularly when conventional in vivo bioequivalence studies using pharmacokinetic endpoints are impractical or impossible.

What is the central scientific focus related to diseased skin?

The opportunity emphasizes characterizing and encoding differences between healthy skin and diseased skin into dermal PBPK models. The goal is to identify which skin physiology characteristics differ between healthy subjects and people with skin diseases, quantify those differences, and incorporate them into model parameters to improve predictive performance and support credible extrapolation to patients and special populations.

Which skin disease areas are specifically mentioned as examples?

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. The announcement also notes that additional disease states may be added in collaboration with the FDA research team depending on regulatory needs.

What kinds of skin physiology parameters does FDA highlight as particularly valuable for modeling?

The opportunity highlights parameters such as skin thickness and microstructure, hydration level, temperature, pH, and the presence or density of appendages like glands and hair follicles. It also emphasizes that these parameters vary by body location and by disease state.

Does the opportunity address differences by body site (anatomical location)?

Yes. It explicitly calls for strong baseline characterization of healthy skin by body location, followed by careful, evidence-based adjustments for disease states.

Does the opportunity emphasize special populations?

Yes. It notes that PBPK models should support credible extrapolation not only to patients with skin diseases, but also to special populations where physiology differs, including pediatrics, the elderly, and groups differing by race and sex.

What is the staged approach described for applicants?

The opportunity lays out a staged approach: (1) identify key physiological parameters likely to differ between healthy and diseased skin and that matter for dermal absorption and disposition; (2) gather evidence from multiple independent and credible sources (peer-reviewed literature and textbooks), supplementing with in-house data when available, and conduct studies when critical gaps exist; (3) organize collected information into an accessible database; (4) develop dermal PBPK models for topical dosage forms and transdermal delivery systems that incorporate the compiled physiology information; (5) validate/qualify the models using appropriate independent datasets; and (6) apply qualified models to assess bioequivalence via virtual bioequivalence trials.

What kinds of sources are expected for parameter evidence?

The opportunity calls for evidence from multiple independent and credible sources such as peer-reviewed literature and textbooks, supplemented by in-house data when available.

Are applicants expected to generate new experimental data?

Potentially, yes. 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.

Why does the opportunity require building an accessible database?

The program indicates that collected information should be organized into an accessible database, suggesting FDA wants a reusable and transparent knowledge base that supports model development and future regulatory discussions, rather than a one-off model output.

What types of products and dosage forms are within scope for the modeling work?

The opportunity calls for dermal PBPK models covering both topical dermatological dosage forms and transdermal delivery systems. Examples of topical dosage forms and formulations include creams, ointments, gels, emulsions, suspensions, lotions, solutions, films, and patches. It also leaves room for additional dosage forms or products to be prioritized jointly with FDA as new regulatory questions emerge.

What drug properties does the opportunity mention as relevant inputs to the models?

It mentions drug-dependent parameters such as molecular weight, solubility, pKa, logP, and other related factors, and it notes these influence formulation stability, drug release from the dosage form, and partitioning and movement across skin layers.

Does FDA expect models to cover a range of APIs?

Yes. The opportunity states that model development should span active pharmaceutical ingredients (APIs) with a range of physicochemical and permeability properties. While not mandatory, it welcomes an API selection strategy similar to a biopharmaceutics classification style approach, encouraging selection of compounds representing different corners of the physicochemical space (for example, varying solubility, pKa, and logP).

How important is formulation in the modeling approach described?

Formulation is described as a major determinant of in vivo performance. The opportunity expects models to account for dosage form and formulation critical quality attributes as key drivers of drug release and skin absorption.

What role does variability play in the proposed modeling framework?

Variability is emphasized repeatedly. The FDA highlights that skin physiology varies between people (inter-subject variability) and within the same person over time or across sites (intra-subject variability). Proposals that quantify and incorporate this variability (rather than relying only on single "typical" values) are viewed favorably because they can yield more realistic predictions and support scenario analysis and risk-based decision-making.

What does the opportunity require for model validation or qualification?

After model development, the opportunity requires validation or qualification using appropriate datasets that are independent and credible. These datasets may come 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 intent is to show the model can reproduce relevant experimental observations, not only fit the data used to build it.

What is the intended regulatory use case for the qualified models?

The intended regulatory use case is to apply 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.

What are "positive and negative controls" in the context of this program?

The opportunity describes using both positive and negative control situations during model-based evaluation: cases where products are known to be bioequivalent and cases where products are known not to be bioequivalent. These controls help test whether the model appropriately classifies products based on model outputs.

How does this program connect to challenges with measuring drug levels in skin?

Many topical dermatologic drugs act locally, making exposure at or near the site of action in the skin most relevant. However, routine clinical sampling of local skin concentrations is rarely available. PBPK models can help estimate drug amounts in specific skin layers when direct measurements are hard or impossible.

How does the opportunity distinguish topical dermatologic products from transdermal systems?

For topical dermatologic products, local skin exposure is often the key concern and systemic levels may be minimal or not measurable. For transdermal systems, systemic delivery is intended, but the skin still controls the rate and extent of absorption. The program frames dermal PBPK modeling as a way to address both product types in a consistent mechanistic framework.

Will additional disease states or product types be considered during the project?

Yes. The opportunity notes that additional disease states may be added in collaboration with the FDA research team depending on regulatory needs, and it similarly allows for additional dosage forms or products to be prioritized jointly with FDA as new regulatory questions emerge.

What does the cooperative agreement nature of U01 imply for project execution?

It implies substantial FDA scientific involvement during the project, meaning applicants should expect active collaboration with the FDA research team as the work progresses, including prioritization decisions as regulatory needs evolve.