PhRMA Urges FDA to Clarify Drug Dose Modeling Guidance

The Pharmaceutical Research and Manufacturers of America (PhRMA) is urging FDA to revise and clarify its draft guidance on using quantitative systems pharmacology (QSP) models to select starting doses in first-in-human clinical trials, arguing that the document should better align with international standards while providing greater flexibility for innovative drug development. In comments submitted to the agency, PhRMA praised the draft guidance as an important milestone in advancing model-informed drug development and reducing reliance on animal studies where scientifically appropriate.

FDA released the draft guidance in June. It focuses on using QSP models to estimate the minimum anticipated biological effect level (MABEL), a dose expected to produce a minimal biological effect in humans. FDA says the approach combines mathematical modeling, disease biology, pharmacology, and multiple sources of preclinical data to improve dose selection and potentially reduce reliance on animal toxicology studies.

According to the agency, QSP modeling may be particularly useful for products such as immunostimulatory monoclonal antibodies and other therapies with human-specific targets that are difficult to evaluate using traditional animal models. The guidance notes that regulatory submissions increasingly include QSP analyses to support decisions ranging from investigational new drug applications to marketing applications.

While supporting FDA's overall approach, PhRMA said the guidance would benefit from additional examples and clearer recommendations on how QSP models should be validated and applied across review divisions. PhRMA asked FDA to align the guidance more closely with the International Council for Harmonization's M15 guideline on model-informed drug development, arguing that the current draft introduces new terminology and reporting expectations that could create unnecessary duplication and inconsistent regulatory expectations.

The group also called on FDA to provide greater flexibility for sponsors developing therapies against novel targets, saying mechanistic models supported by human in vitro data and other non-animal evidence should, in some cases, justify starting doses above the traditional MABEL. PhRMA further requested that FDA clarify when sponsors should notify the agency of updates to QSP models during clinical development and adopt a risk-based, fit-for-purpose validation framework, particularly for first-in-class products where independent clinical validation data may not exist.

In addition, PhRMA asked FDA to address legal questions surrounding the use of published data from other sponsors in biologics applications, noting that unlike certain new drug applications, biologics license applications generally cannot rely on product-specific data without a right of reference. The group concluded that FDA's draft guidance is an important step toward modernizing early clinical development but said additional clarification would improve implementation while maintaining patient safety.