Industry seeks clarity, flexibility, harmonization in guidance for QSP approach for clinical trials
Industry stakeholders have asked the US Food and Drug Administration (FDA) to provide more clarity in a recent draft guidance aimed at helping sponsors determine dose selections using a quantitative systems pharmacology (QSP) approach for first-in-human (FIH) dose in phase 1 trials. Additionally, they want FDA to provide more regulatory flexibility in changing dose selection, especially during early phases, and harmonize with international standards.
In June, FDA published a draft guidance detailing recommendations on the appropriate use of a QSP-based approach The agency emphasized the guidance was part of its efforts to rely less on animal toxicology studies for FIH dose selection, and more specifically, the document was intended to help sponsors determine appropriate dose selection for newer therapies with more complex mechanisms. (RELATED: HHS and FDA propose clinical trial reforms to expedite drug development, Regulatory Focus 23 June 2026)
PhRMA
Several industry stakeholders commented on the draft guidance, including PhRMA, which said the draft guidance is an important milestone for adopting mechanistic modeling to inform regulatory decision-making. The group commended FDA's efforts to use QSP to allow for other sources of data in drug development, including in vivo data from relevant animal species, in silico data, pharmacological data, and translational data from New Approach Methodologies (NAMs).
While praising the draft guidance, PhRMA said it also wants clarification in several areas and urged FDA to emphasize in the guidance that, in certain circumstances, QSP approaches may be better than animal toxicology studies at estimating pharmacological effects of a drug on humans. The group also asked the agency to include illustrative examples to provide more context when evaluating a QSP-based minimum anticipated biological effect level (MABEL) approach.
A significant concern raised by PhRMA is that the draft guidance may be interpreted to suggest that QSP's used within model-informed drug development (MIDD) are limited to this specific situation. I don’t understand previous sentence. The group argued that the underlying principles of QSPs are equally relevant to QSP-based dose-selection decisions across early drug development and the guidance should acknowledge that.I also don’t understand this sentence. Is there a quote you can pull out?
PhRMA also asked FDA to align the draft guidance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidance on General Principles for Model-Informed Drug Development (ICH M15). The group noted that the guidance already partially uses and reinterprets harmonized ICH terminology, and includes new terminology without clear justification. It also says the guidance fails to adequately reference model evaluation and MIDD reporting and submissions recommendations already laid out in ICH M15.
"The Draft Guidance’s recommendations to submit a QSP Study Report documenting methods, assumptions, and uncertainties when applying a QSP approach to FIH dose selection introduces new, QSP-specific reporting recommendations that may be redundant with expectations already set forth under ICH M15," said PhRMA. "PhRMA recommends that FDA more fully align the Draft Guidance with the harmonized ICH M15 framework, introducing new terminology or additional recommendations only where necessary to address QSP-specific considerations not already covered by ICH M15 or to reflect FDA-specific recommendations."
PhRMA said it agreed with FDA's risk-based approach to using QSP models and said it is consistent with the ICH M15. However, it wants more clarity on how sponsors are to determine the levels of risk.
"While the Draft Guidance discusses model influence and decision consequence, it does not provide risk assessment categories (e.g. low, medium, and high as described in ICH M15)12 or the corresponding validation expectations," said PhRMA. "Without additional clarification, sponsors may encounter inconsistent expectations across review divisions regarding appropriate levels of documentation, sensitivity analyses, or external validation. PhRMA recommends that FDA incorporate additional recommendations around risk assessment categories, aligned with ICH M15 as appropriate, that clearly link model risk classifications with recommended validation activities, documentation, and regulatory expectations.
"Such clarification would facilitate implementation, while allowing for diverse application of QSP to MABEL-based FIH dose selection," the group added.
PhRMA recommended additional changes to the draft guidance, including promoting the reduction of animal testing by encouraging the incorporation of animal pharmacokinetic and pharmacodynamic data during model parameterization and considerations for when animal exposure data is recommended when applying QSP approaches to MABEL-based FIH dosing. It also recommended that FDA adopt a fit-for-purpose validation framework for first-in-class drugs, arguing that certain validation recommendations are not feasible for such drugs.
"Specifically, recommendations to compare model predictions against independent datasets may be difficult, or impossible, to satisfy when no prior clinical experience exists for a particular mechanism of action," said PhRMA. "In these situations, mechanistic biological understanding, orthogonal experimental evidence, translational in vitro data, and cross-modality analogues may provide the most scientifically appropriate basis for establishing model credibility.
"Accordingly, PhRMA recommends that FDA explicitly recognize fit-for-purpose validation approaches that rely on mechanistic plausibility, prospective model evaluation during early clinical development, and iterative refinement as additional acceptable approaches when external clinical validation datasets are unavailable," the group added.
While FDA encourages sponsors in the draft guidance to engage regulators early through pre-investigational new drug (pre-IND) and MIDD paired meetings, PhRMA said the agency should also state that INTERACT meetings may be appropriate for discussing new QSP approaches during early development. The group also said that while a new drug application may rely on investigations to which the sponsor has no right of reference or on published literature, it must comply with patent certifications and innovator exclusivities. However, that becomes complicated since the guidance applies to both drugs and biologics.
"The Draft Guidance could be read to suggest that sponsors, including those developing biological products for approval under section 351(a) of the PHS Act, may rely on product-specific literature or data about other sponsors’ biological products for which the sponsor has no right of reference," said PhRMA. "FDA should address this issue in the Draft Guidance by expressly stating that sponsors submitting a BLA under section 351(a) may rely on product-specific published literature only where the BLA sponsor owns or has a right of reference to the data."
Abbvie
Drugmaker AbbVie wrote to FDA asking it to broaden the guidance to reflect how QSP modeling is used across later stages of clinical development, especially since the guidance includes recommendations on incorporating emerging clinical data, validating models against early clinical observations, and iteratively refining models to support subsequent clinical development decisions. It also asked the agency to clarify when a QSP-based MABEL approach is appropriate and to provide regulatory flexibility for alternative, scientifically justified dose-selection methodologies.
"We recommend FDA clarify the scope and applicability of this guidance for situations where there is existing clinical, nonclinical, or mechanistic experience for a specific target, molecule class, or related product," said Abbvie. "Specifically, the guidance should provide greater flexibility and clarify when a QSP-based MABEL approach is warranted versus when sponsors may rely on existing in vitro, nonclinical, pharmacologic, and clinical safety and efficacy data to support FIH dose selection.
We also recommend acknowledging that such evidence may be leveraged across indications and therapeutic areas when supported by a scientifically justified rationale," the company added. "FDA should also clarify whether the recommendations in this guidance are intended to establish a regulatory expectation for FIH dose selection and identify the specific factors that would support use of a QSP-based MABEL approach versus other scientifically valid dose-selection methodologies."
Abbvie asked FDA to clarify the use of nonclinical data to support QSP model development and FIH dose prediction, and using virtual populations and iterative model refinement that takes into consideration changes in emerging clinical data.
Echoing PhRMA, it also asked FDA to harmonize with the model verification and validation requirements of ICH M15 and provide illustrative examples to clarify when starting doses above the absolute MABEL may be appropriate. Furthermore, the company asked for more details regarding the agency's expectations for evaluating and refining QSP models using limited early clinical data.
"Given the inherent variability of pharmacodynamic biomarkers, observations from single subject cohorts or a small number of participants may not be sufficient to meaningfully evaluate model performance or biological response predictions," said Abbvie. "Consider providing guidance on factors that should be considered when determining whether the available clinical data are adequate to support model evaluation and refinement, particularly in settings where early dose-escalation cohorts may include only a limited number of participants."
Moderna
The vaccine company Moderna also wrote to FDA asking for more clarity regarding harmonizing the regulations to promote consistent implementation across therapeutic modalities and product development. The company more specifically asked for clearer operationalization of MABEL, risk-proportionate expectations for model construction and evaluation, and clarity regarding dose-selection decisions.
Moderna notes that the guidance describes limitations of certain toxicology-based approaches and the ability of QSP to integrate mechanistic and exposure–response information. However, it said the guidance doesn't distinguish the role of a QSP-based MABEL analysis from conventional MABEL calculations, traditional PK/PD modeling, or toxicology-based human equivalent dose approaches, without which sponsors may have difficulty determining when QSP provides sufficient value to justify additional modeling complexity.
"It may be helpful for the guidance to include a concise comparative discussion or illustrative examples describing: (1) the scientific questions each approach is suited to address; (2) circumstances in which QSP may provide incremental value, including where relevant human biology is not adequately represented in animal models; and (3) how QSP results should be integrated with conventional MABEL and toxicology-based estimates as part of the totality of evidence," said Moderna. "This clarification would support fit-for-purpose use of QSP without implying that a QSP approach is necessary in every FIH program."
Moderna said the guidance provides limited direction on selecting the pharmacological response threshold that defines a minimal biological effect and asked for more clarity, especially in light of international standards, on how to choose such thresholds and justify them. Similarly, the group also noted that the guidance provides limited direction on translational strategies when surrogate molecules, surrogate targets, or human-derived systems are used because the intended clinical molecule or target is not pharmacologically active in animal species.
The company asked the agency to recommend a scientifically justified bridging strategy to clarify how to translate information from surrogate or human-derived data to the intended clinical molecule and human response.
Moderna also requested additional clarification on the types of information that can be used in the models and the model risks, the reference used for an additional safety margin, and the evidence that may support a minimal active dose above the absolute MABEL.
