Critical quality attributes and regulatory outcomes of generic and follow-on GLP-1 receptor agonists — a systematic narrative review

Critical Quality Attributes and regulatory outcomes of generic and follow-on GLP-1 Receptor Agonists: A systematic narrative review with structured synthesis Date of protocol: 10/11/2026 Registration: Open Science Framework Registries Authors: Rajath Samagaa, Sachin D Pawara* a: Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Science, Manipal, Udupi-576104 ORCID IDs: 1. Rajath Samaga: 0009-0006-2936-8783 2. Sachin D Pawar: 0000-0002-9085-029X Corresponding Author: Sachin D Pawar 1. Background and Rationale Glucagon-like-peptide-1 receptor agonist (GLP-1RAs) are complex lipidated peptides now facin generic entry worldwide. Generic manufacturers may reproduce by solid phase chemical synthesis an active ingredient that the originator produces by recombinant DNA technology, generating different impurity classes. The comparative quality evidence is small, concentrated among interested parties and often conflates compounded material with approve generics. No published study demonstrates a clinical outcome difference between an approved generic GLP-1 RA and its reference product. Regulatory decisions have diverged across jurisdictions. An integrated analysis mapping critical quality attributes to clinical relevance across product types and regulatory frameworks has not been published. 2. Objectives a. Systematically identify, appraise and synthesis the evidence on comparative quality, immunogenicity risk and clinical equivalence of originator, generic, follow-on and compounded GLP-1 RAs. b. Map the critical quality attributes for which evidence exists and for which it does not. c. Compare how regulators in seven jurisdictions (United states, European Union, Canada, India, United Kingdom, Japan and China) have resolved the resulting scientific questions. d. Identify priority evidence gaps and research directions. 3. Eligibility criteria 3.1 Inclusion criteria Studies will be included if they meet atleast one of the following criteria: • Report measured quality attributes of atleast two batches or at least two sources (originator, generic, follow-on or compounded) of a GLP-1 RA or dual GIP/GLP-1 RA • Report Pharmacokinetic or clinical comparisons of a generic, follow-on or biosimilar GLP-1 RA with an originator • Report immunogenicity risk assessment of peptide-related impurities using in silico, in vitro or ex vivo methods applied to GLP-1 RAs or structurally related therapeutic peptides (teriparatide, salmon calcitonin) • Report comparative device human factors studied for GLP-1 pen injectors Teriparatide and salmon calcitonin studies are included where they provide the only worked example of a method or regulatory approach directly applicable to GLP-1 RAs. 3.2 Exclusion criteria • Single batch characterisation without comparison • Animal pharmacology or toxicology without quality attribute data • Editorials, commentaries or opinion pieces without original data • Studies of non-GLP-1 peptides without direct methodological relevance • Clinical outcome trials of GLP-1 RA without a generic or follow-on comparator 3.3 Contextual Sources Regulatory guidance documents, pharmacopeial texts, ICH guidelines, public assessment reports and product information documents will be used as contextual sources for the regulatory and pharmacopeial analysis but will not be subject to the systematic database search. This distinction will be stated throughout the results. 4. Information source and search strategy 4.1 Databases PubMed/MEDLINE, embase via Ovid and Web of Sciences Core Collection will be searched from database inception to 11/11/2026. 4.2 Search Strategy The search combines three concept blocks: Block 1 (molecule): semaglutide OR liraglutide OR tirzepatide OR exenatide OR dulaglutide OR lixisenatide OR “GLP-1 receptor agonist” OR “glucagon-like peptide-1” OR “incretin mimetic” OR “GIP/GLP-1” Block 2 (quality/variability): impurity OR “related substances” OR variability OR comparability OR aggregation OR fibrillation OR oligomer OR “higher order structure” OR generic OR biosimilar OR “follow-on” OR compounded OR bioequivalence OR immunogenicity OR “human factors” OR “dose accuracy” OR “critical quality attribute” Block 1 AND Block 2 The full electronic search strategies adapted for each database will be provided as supplementary material. 4.3 Additional Sources Reference lists of included studies and relevant narrative reviews will be screened. Regulatory assessment reports will be identified by targeted searching of FDA, EMA, Health Canada, MHRA, CDSCO, NMPA and PMDA websites. 5. Study Selection Titles and abstracts will be screened by [one reviewer / two reviewers independently — state honestly what you will do]. Full-text review will be conducted for all potentially eligible records. [If two reviewers: Disagreements will be resolved by discussion. Inter-rater agreement will be quantified using Cohen’s kappa.] [If one reviewer: A second reviewer will verify a random 20% sample of inclusion/exclusion decisions to check consistency. 6. Data Extraction Data will be extracted using a structured form capturing: • First author, year, country • Molecule(s) studied • Product sources and regulatory status (originator, approved generic, follow-on of uncertain status, compounded) • Manufacturing route where reported • Quality attributes measured • Analytical methods employed • Number of batches or product units • Principal findings • Author affiliations, funding source and declared conflicts of interest The regulatory status and author affiliation fields are included because these are central to the interpretation of the evidence. 7. Quality approval No validated quality appraisal tool exists for analytical quality-comparison studies. An adapted checklist will be developed covering: (1) number of batches or products tested; (2) traceability of source material; (3) method validation status; (4) use of a qualified reference standard; (5) replicate design; (6) blinding of analysts to source identity; (7) inclusion of a reference product comparator; (8) completeness of quantitative reporting; (9) disclosure of affiliations and conflicts. Pharmacokinetic studies will be appraised using RoB 2 (Sterne et al., 2019). 8. Synthesis Quantitative meta-analysis will not be performed because the included studies are heterogenous in design, methods, attributes measured and outcome metrics. Structured narrative synthesis will be conducted following SWiM reporting guideline (Campbell et al., 2020). Studies will be grouped by quality attributes class, comparison type and evidence type. A critical quality attribute by evidence type matrix will be constructed to map where evidence exists and where it does not. The certainty of evidence for the clinical outcomes question will be assessed using the GRADE framework (Guyatt et al., 2008). Regulatory assessment reports and guidance documents will be synthesized contextually alongside, but separately from, the peer-reviewed evidence. 9. Prior Framework Exploratory literature mapping was conducted before this protocol was finalised to assess the feasibility of the review to inform the eligibility criteria and search strategy. This mapping identified the approximate scope of the evidence base (five head-to-head GLP-1 analytical comparisons, eight immunogenicity method studies, three to four pharmacokinetic studies, three device human factor studies). The formal systematic search described in this protocol will be conducted after registration and will supersede the exploratory mapping. 10. Reporting The review will be reported as per PRISMA 2020 (Page et al., 2021) and SWiM (Campbell et al., 2020). The PRISMA checklist will be provided as supplementary material. 11. Amendments Any amendments to this protocol made after registration will be documented and reported in the final manuscript with the date and the rationale for the change. 12. Funding and conflicts of interest NA