EMA Updates on Nasal Product Therapeutic Equivalence and Good Pharmacogenomic Practice
The European Medicines Agency (EMA) has published two important regulatory documents addressing pharmaceutical equivalence and pharmacogenomic practices. The draft Guideline on the requirements for demonstrating therapeutic equivalence for nasal products outlines the evidence needed to demonstrate equivalence between nasal medicines. The Concept paper on the guideline revision on good pharmacogenomic practice describes proposed updates to pharmacogenomic methodology, genetic data interpretation, clinical study design and pharmacovigilance.
Together, these documents highlight the importance of robust scientific evidence, appropriate study designs and reliable data to support medicine development, regulatory assessment and patient safety.
The EMA’s draft Guideline on the requirements for demonstrating therapeutic equivalence for nasal products (EMA/220888/2026) was adopted for public consultation on 5 October 2026. The consultation began on 8 October 2026, with comments due by 28 February 2027.
The guideline covers both locally acting products, which act mainly within the nasal mucosa, and systemically acting products, where the active substance enters the systemic circulation. Examples include nasal products containing fluticasone or azelastine for local action and naloxone, fentanyl or zolmitriptan for systemic action.
The approach depends on the intended action of the medicine. For locally acting products, therapeutic equivalence may be established through a stepwise assessment using in vitro comparisons and, where necessary, pharmacokinetic studies. For systemically acting products, bioequivalence generally needs to be demonstrated through an in vivo study, although a waiver based on in vitro data may be possible for solutions when the specified criteria are fulfilled.
In vitro comparison requirements
In vitro testing is the first step in assessing equivalence and should be performed even when pharmacokinetic studies are planned. Applicants should establish a predefined study protocol, appropriate comparison methods and justified acceptance criteria.
Relevant characteristics may include:
Qualitative and quantitative composition, pharmaceutical form and device handling.
Delivered dose and physicochemical properties of the formulation.
Active-substance particle size and other physical characteristics, where relevant.
Droplet or particle size distribution, spray pattern and plume geometry.
The amount of active substance contained in droplets or particles smaller than 10 micrometres, where applicable.
The parameters requiring comparison depend on the dosage form, such as nasal sprays, nasal drops or nasal powders. Applicants should justify which critical quality attributes affect product performance, efficacy, safety and local tolerability.
Pharmacokinetic and clinical evidence
When in vitro results do not establish therapeutic equivalence for locally acting products, pharmacokinetic studies may be used to assess systemic exposure as a marker for safety and local absorption or deposition as a marker for efficacy. Study design should account for the possible contribution of drug swallowed into the gastrointestinal tract. Activated charcoal may be needed to distinguish absorption associated with nasal administration from gastrointestinal absorption.
For systemically acting nasal products, pharmacokinetic bioequivalence studies generally evaluate parameters such as maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC). The draft generally refers to a 90% confidence interval within 80.00–125.00 for the relevant primary pharmacokinetic parameters, subject to the applicable provisions and justified exceptions.
Pharmacodynamic or clinical studies are generally less preferred for locally acting products because their endpoints may not be sufficiently sensitive to identify differences between test and reference products. If these approaches are used, the study design should demonstrate adequate assay sensitivity. If equivalence cannot be established through the relevant approaches, reformulation or a stand-alone clinical data package may be necessary, depending on the product and application.
Local tolerability, paediatric use and usability
Local tolerability is important because nasal formulations may cause irritation, sneezing, discharge or other discomfort. When excipients differ in composition or quantity, applicants should assess the potential impact on local safety through a human tolerability study or a scientifically justified literature-based approach.
For products intended for children and adolescents, the suitability of a new nasal delivery device must also be considered. Usability studies may be required to demonstrate that intended users, including children and caregivers where appropriate, can use the device safely and correctly.
Regulatory implications
The draft is particularly relevant to generic and other abridged applications, as well as line extensions, variations and product development activities that rely on equivalence to a reference product. Regulatory teams should review formulation composition, device characteristics, critical quality attributes and the proposed evidence strategy early in development.
Applicants should also ensure that study protocols, batch selection, acceptance criteria and any proposed deviations are adequately justified. As this document remains a draft, its recommendations may change following consultation.
The EMA’s Concept paper on the guideline revision on good pharmacogenomic practice (EMA/282050/2025) outlines the proposed revision of the existing guideline on good pharmacogenomic practice. The concept paper was adopted by the Committee for Medicinal Products for Human Use (CHMP) on 5 October 2026.
Updated pharmacogenomic methodologies
The revision is expected to address advances in sequencing technologies, including third-generation long-read sequencing. These methods can help distinguish complex gene structures, highly similar sequences and genomic phasing. The revised guideline is also expected to provide additional recommendations on quality control.
Specific analytical considerations will include highly polymorphic genes such as CYP2D6, substrate specificity, the interaction between CYP3A4 and CYP3A5, and relevant drug transporters such as ABCB1 and SLCO1B1.
The concept paper also highlights the importance of considering DNA variants across different ancestries. Genetic variation can influence medicine exposure, response and benefit-risk profiles. The revised guideline is expected to address population-specific variant selection and the appropriate consideration of pharmacogenomic differences during medicine development, regulatory assessment and product information preparation.
Genotype-phenotype interpretation and recommendations
The revised guideline is expected to clarify how genotype information relates to phenotype and clinical recommendations. It will distinguish established clinical recommendations from theoretical conclusions based on enzyme function and address phenoconversion associated with the use of enzyme inducers or inhibitors.
Further clarification is also planned for medicine-specific recommendations before and after marketing authorisation. Where dosing recommendations depend on particular DNA variants or haplotypes, these should be clearly identified to support appropriate interpretation and clinical use.
Reporting and nomenclature
Consistent terminology is essential for interpreting pharmacogenomic results and supporting regulatory decisions. The revision is expected to provide recommendations on internationally accepted allele and genotype nomenclature and recognised sources for defining relevant genotypes and phenotypes.
Definitions of terms such as allele, haplotype, variant, loss-of-function and gain-of-function are expected to be clarified. The document will also address the interpretation of common and rare variants, recognising that variant frequencies can differ across populations and that many genetic variations remain insufficiently characterised.
Pharmacogenomic study design
The revised guideline is expected to cover pharmacogenomic study design across clinical development, from Phase 0 to Phase IV. For interventional studies, topics may include genotype-guided dosing supported by pharmacokinetic and pharmacodynamic data, sample-size planning, statistical power for rare variants, multiple-testing correction and complex clinical trial designs.
It will also address genome-wide association studies in randomised controlled trials and the incorporation of pharmacogenomic findings into product information.
For non-interventional studies, the revision is expected to introduce recommendations on generating and using real-world data. Such data may help address evidence gaps in populations that are underrepresented in clinical trials, including different ancestry groups, older people, patients with renal or hepatic impairment, people receiving long-term concomitant medicines and patients at risk of rare adverse drug reactions.
Integration with pharmacovigilance
An important objective is to consolidate pharmacogenomic aspects relevant throughout the medicinal product lifecycle into a single guidance document. The revised guideline is expected to incorporate and update relevant elements from the existing pharmacogenomics and pharmacovigilance guideline.
This integration is intended to support consistent application of pharmacogenomic evidence during medicine development, regulatory decision-making and post-marketing safety monitoring.
Proposed timeline and regulatory implications
The concept paper proposes that the draft revised guideline will be released for public consultation in 2027–2028, with finalisation expected in 2028.
References
European Medicines Agency. Guideline on the requirements for demonstrating therapeutic equivalence for nasal products — Draft. EMA/220888/2026, 5 October 2026. EMA document.
European Medicines Agency. Concept paper on the guideline revision on good pharmacogenomic practice. EMA/282050/2025, adopted 5 October 2026. EMA document.
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