# Regulatory divergence between regions

Source: https://onco.cc/bottlenecks/b-regulatory-fragmentation/  
OnCo record `b-regulatory-fragmentation` (Bottleneck). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Regulatory divergence means a drug approved in one country can take years to reach another, or never arrive.

## Summary

Each of the large national regulators (FDA, EMA, MHRA, PMDA, NMPA, TGA, Health Canada) requires its own dossier, applies its own evidence standards, and reviews on its own timeline, and approval is followed by a separate reimbursement process in each country. The result is a staggered global launch in which the same drug can be available in the US a year before the EU and years before Japan or China, or never filed at all in small or low-income markets. Sponsors also run duplicate or bridging trials to satisfy region-specific requirements, and divergent decisions on accelerated approvals create confusion about what the evidence actually shows. Harmonisation through ICH, collaborative review (Project Orbis, the Access Consortium), reliance pathways for smaller regulators, and the EU's joint clinical assessment are narrowing the gap, but the sequence of separate national decisions remains the norm.

## Fields

- Kind: Bottleneck
- Last checked: 2026-09-08
- Stage: regulation-manufacturing
- Severity: major
- Metrics: Median total review time for novel therapeutics at FDA vs EMA vs Health Canada, 2001-2010: 303 vs 366 vs 352 days (Downing et al., NEJM 2012); Countries participating in FDA Project Orbis concurrent review of oncology products: 7 partner regulators alongside FDA (Australia, Brazil, Canada, Israel, Singapore, Switzerland, UK) (FDA Project Orbis)
- Causes: National sovereignty over drug approval means each agency must reach its own decision on its own dossier.; Evidence standards differ, especially on surrogate endpoints, single-arm trials and accelerated approval.; Reimbursement and health technology assessment are separate from approval and differ in every country.; Small and low-income markets are filed last or not at all because expected revenue does not cover the cost of filing.; Requirements for local trial data (historically in Japan and China) forced duplicate bridging studies.

## Sources

- FDA Oncology Center of Excellence, Project Orbis: https://www.fda.gov/about-fda/oncology-center-excellence/project-orbis
- Downing et al., Regulatory review of novel therapeutics: comparison of three regulatory agencies (NEJM 2012): https://doi.org/10.1056/NEJMsa1200223
- International Council for Harmonisation (ICH): https://www.ich.org/
- EU Regulation on Health Technology Assessment: https://health.ec.europa.eu/health-technology-assessment/regulation-health-technology-assessment_en

## Connected records

- collections: [ESMO Clinical Practice Guidelines & MCBS](https://onco.cc/collections/esmo-guidelines/), [EU Clinical Trials Register / CTIS](https://onco.cc/collections/eudract-ctis/), [FDA Oncology Approvals (OCE) & Novel Drug Approvals](https://onco.cc/collections/fda-approvals/)
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regulatory pathway for new radiotherapy techniques modelled on drug development](https://onco.cc/ideas/idea-fund-radiotherapy-innovation-pathway/), [A regulatory sandbox for continuously learning cancer AI](https://onco.cc/ideas/idea-data-regulatory-sandbox-adaptive-ai/), [A reliance pathway for companion diagnostics so the test arrives with the drug](https://onco.cc/ideas/idea-reg-diagnostic-reliance-pathway/), [A shared AI review assistant that maps one dossier to every regulator's questions](https://onco.cc/ideas/idea-reg-shared-ai-review-assistant/), [A standard for tumour-agnostic approvals: minimum histologies and hierarchical modelling](https://onco.cc/ideas/idea-tr1-tumour-agnostic-approval-standard/), [A standing rulebook for one-patient treatments](https://onco.cc/ideas/idea-bio2-n-of-1-framework/), [Adopt tumour-agnostic cancer drug labels across regions by reliance, not re-review](https://onco.cc/ideas/idea-reg-tumour-agnostic-reliance/), [Agree in advance how to borrow evidence between similar rare cancers](https://onco.cc/ideas/idea-bio2-bayesian-borrowing-acceptance/), [Approve cancer biosimilars on analytics and pharmacokinetics, no efficacy trials](https://onco.cc/ideas/idea-reg-biosimilar-no-efficacy-trial/), [Automatic reciprocity of orphan and rare-paediatric designations between regulators](https://onco.cc/ideas/idea-reg-orphan-designation-reciprocity/), [Comparability by design: a digital twin and sentinel panel for cell process changes](https://onco.cc/ideas/idea-reg-comparability-by-design-digital-twin/), [Conditional approvals that lapse automatically if the confirmatory trial is late](https://onco.cc/ideas/idea-reg-conditional-approval-sunset/), [Continuous prospective validation for every oncology AI tool after deployment](https://onco.cc/ideas/idea-moon-continuous-ai-validation-registry/), [Copy the Cancer Drugs Fund: pay for uncertain drugs while collecting the data](https://onco.cc/ideas/idea-cost-managed-access-everywhere/), 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Agency](https://onco.cc/ideas/idea-reg-african-medicines-agency-oncology/), [Get the one approved appetite drug licensed beyond a single country](https://onco.cc/ideas/idea-bio2-anamorelin-access/), [Good practice standards and inspection for real-world data sources](https://onco.cc/ideas/idea-data-gcp-for-real-world-data/), [Harmonise Europe's hospital exemption for academic cell therapies, with one registry](https://onco.cc/ideas/idea-reg-hospital-exemption-harmonised/), [Harmonise PD-L1 testing for triple-negative breast cancer around one scored assay, with external quality assurance](https://onco.cc/ideas/idea-tnbc-pd-l1-assay-harmonisation/), [Hospital-exemption cell therapies at scale, backed by a shared registry](https://onco.cc/ideas/idea-fund-hospital-exemption-registry/), [Joint FDA-EMA-MHRA-PMDA scientific advice by default before pivotal cancer trials](https://onco.cc/ideas/idea-reg-joint-scientific-advice-default/), [Let non-profits and academics add a cancer indication to an off-patent drug's label](https://onco.cc/ideas/idea-reg-third-party-label-update/), [Live tracker of the lag from first approval to real availability in every country](https://onco.cc/ideas/idea-reg-approval-access-lag-tracker/), [Make post-progression sampling a condition of accelerated approval](https://onco.cc/ideas/idea-bio1-approval-linked-progression-sampling/), [Make pre-approval dose optimisation an ICH standard so it is done once worldwide](https://onco.cc/ideas/idea-reg-global-dose-optimisation-guideline/), [Manufacturing-change passport: one approved CMC change accepted everywhere in 30 days](https://onco.cc/ideas/idea-reg-manufacturing-change-passport/), [Mutual recognition of ethics review across countries](https://onco.cc/ideas/idea-tr1-mutual-recognition-ethics-review/), [Mutual recognition of GMP inspections for cell, gene and radiopharmaceutical plants](https://onco.cc/ideas/idea-reg-mutual-recognition-inspections-atmp/), [One clinical trial application accepted by regulators in every major region](https://onco.cc/ideas/idea-reg-global-trial-application-portal/), [One ethics approval and one consent form for a platform trial across countries](https://onco.cc/ideas/idea-tr2-platform-single-ethics/), [One evidence plan agreed by regulator and payer before the pivotal trial](https://onco.cc/ideas/idea-reg-joint-regulator-hta-plan/), [One global paediatric cancer development plan instead of separate FDA and EMA plans](https://onco.cc/ideas/idea-reg-single-paediatric-plan/), [One global rare cancer network with n-of-1 and Bayesian trial frameworks](https://onco.cc/ideas/idea-moon-rare-cancer-global-network/), [One international registry, not one per country, for conditional approvals](https://onco.cc/ideas/idea-reg-shared-postmarketing-registry-condition/), [One multiregional trial, no bridging studies: enforce ICH E17 in Japan and China](https://onco.cc/ideas/idea-reg-mrct-no-bridging/), [One national master contract and budget template for all cancer trials](https://onco.cc/ideas/idea-tr1-national-master-trial-agreement/), [One structured global dossier: submit the cancer drug file once, to a shared cloud](https://onco.cc/ideas/idea-reg-single-global-dossier/), [Open-source dossier-building software for academic sponsors and generic makers](https://onco.cc/ideas/idea-reg-open-source-dossier-tools/), [Platform designation for ADC linker-payloads so manufacturing data carry across](https://onco.cc/ideas/idea-reg-adc-platform-designation/), [Pre-agreed update rules so an MCED test is not obsolete when its trial reads out](https://onco.cc/ideas/idea-prev-mced-change-control-plan/), [Provisional prices for surrogate-endpoint approvals, reset when survival data arrive](https://onco.cc/ideas/idea-reg-provisional-price-until-os/), [Publish every complete response letter and negative opinion across all regulators](https://onco.cc/ideas/idea-reg-publish-all-rejections/), [Randomised evidence for the T-cell lymphomas, including the ones that are not in Europe or North America](https://onco.cc/ideas/lymphoma-ev-randomised-evidence-for-the-t-cell-lymphomas/), [Reciprocal recognition of tumour-agnostic and rare-indication approvals across regulators](https://onco.cc/ideas/idea-moon-reciprocal-tumour-agnostic-approvals/), [Regional cyclotron hubs for actinium-225 with an agreed actinium-227 impurity limit](https://onco.cc/ideas/idea-reg-ac225-accelerator-pharmacopoeia/), [Regulators recognise each other's companion diagnostic approvals](https://onco.cc/ideas/idea-tr2-cdx-mutual-recognition/), [Require post-approval evidence in patients over 75 and update labels accordingly](https://onco.cc/ideas/idea-acc-post-approval-evidence-over-75/), [Sponsors deposit the confirmatory trial budget in escrow at accelerated approval](https://onco.cc/ideas/idea-reg-confirmatory-trial-escrow/), [Stream trial data to regulators as it accrues; review starts at last patient visit](https://onco.cc/ideas/idea-reg-realtime-streaming-submission/), [Turn Project Orbis into a work-sharing review with one shared assessment report](https://onco.cc/ideas/idea-reg-orbis-work-sharing/), [WHO prequalification plus pooled demand to push biosimilar prices below 10% of the originator](https://onco.cc/ideas/idea-acc-biosimilar-prequalification-pool/)
- drugs: [Camrelizumab](https://onco.cc/drugs/camrelizumab/), [Serplulimab](https://onco.cc/drugs/serplulimab/), [Tislelizumab](https://onco.cc/drugs/tislelizumab/), [Toripalimab](https://onco.cc/drugs/toripalimab/), [Trastuzumab biosimilars](https://onco.cc/drugs/trastuzumab-biosimilars/)
- companies: [Akeso](https://onco.cc/companies/akeso/), [BeOne Medicines (formerly BeiGene)](https://onco.cc/companies/beone/), [Jiangsu Hengrui Pharmaceuticals](https://onco.cc/companies/hengrui/), [Shanghai Henlius Biotech](https://onco.cc/companies/henlius/), [WuXi AppTec](https://onco.cc/companies/wuxi-apptec/), [WuXi Biologics](https://onco.cc/companies/wuxi-biologics/)
- institutions: [ACCELERATE](https://onco.cc/institutions/accelerate-platform/), [Agência Nacional de Vigilância Sanitária](https://onco.cc/institutions/anvisa/), [American Society of Clinical Oncology (ASCO)](https://onco.cc/institutions/asco/), [Bundesinstitut für Arzneimittel und Medizinprodukte](https://onco.cc/institutions/bfarm/), [Cancer Hospital, Chinese Academy of Medical Sciences](https://onco.cc/institutions/cams-cancer-hospital/), [Clinical Data Interchange Standards Consortium](https://onco.cc/institutions/cdisc/), [Comisión Federal para la Protección contra Riesgos Sanitarios](https://onco.cc/institutions/cofepris/), [European Medicines Agency](https://onco.cc/institutions/ema/), [European Society for Medical Oncology (ESMO)](https://onco.cc/institutions/esmo/), [FDA Oncology Center of Excellence](https://onco.cc/institutions/fda-oce/), [Health Canada](https://onco.cc/institutions/health-canada/), [Medicines and Healthcare products Regulatory Agency](https://onco.cc/institutions/mhra/), [National Cancer Center Hospital](https://onco.cc/institutions/ncc-japan/), [National Medical Products Administration / Center for Drug Evaluation](https://onco.cc/institutions/nmpa-cde/), [Paul-Ehrlich-Institut](https://onco.cc/institutions/paul-ehrlich-institut/), [Pharmaceuticals and Medical Devices Agency](https://onco.cc/institutions/pmda/), [Swissmedic](https://onco.cc/institutions/swissmedic/), [Therapeutic Goods Administration](https://onco.cc/institutions/tga/)
- terms: [Accelerated approval](https://onco.cc/terms/accelerated-approval/), [Biosimilar](https://onco.cc/terms/biosimilar/), [Breakthrough Therapy / Priority Review / Priority Voucher](https://onco.cc/terms/breakthrough-designation/), [China Drug Administration Law (2019) and expedited pathways](https://onco.cc/terms/china-drug-administration-law/), [China Human Genetic Resources rules (2019, 2023)](https://onco.cc/terms/china-hgr-rules/), [Clinical Trials Regulation (EU) No 536/2014 and CTIS](https://onco.cc/terms/eu-clinical-trials-regulation/), [EU HTA Regulation (EU) 2021/2282: joint clinical assessments](https://onco.cc/terms/eu-hta-regulation/), [FDASIA 2012 and the origins of the expedited programmes](https://onco.cc/terms/fdasia-2012/), [Federal Food, Drug, and Cosmetic Act and the Kefauver-Harris Amendments](https://onco.cc/terms/fdca/), [Genome-wide loss of heterozygosity (gLOH)](https://onco.cc/terms/genome-wide-loss-of-heterozygosity/), [ICH good clinical practice (E6)](https://onco.cc/terms/ich-gcp/), [ILAP (Innovative Licensing and Access Pathway)](https://onco.cc/terms/ilap/), [India New Drugs and Clinical Trials Rules 2019](https://onco.cc/terms/india-new-drugs-rules-2019/), [Japan conditional early approval and time-limited approval](https://onco.cc/terms/japan-conditional-early-approval/), [Medicines and Medical Devices Act 2021](https://onco.cc/terms/medicines-medical-devices-act-2021/), [Metastasis-free survival (MFS)](https://onco.cc/terms/metastasis-free-survival/), [PIPL (China Personal Information Protection Law 2021)](https://onco.cc/terms/pipl/), [Radiographic progression-free survival (rPFS)](https://onco.cc/terms/radiographic-progression-free-survival/), [Regulation (EC) No 726/2004: the EU centralised procedure](https://onco.cc/terms/eu-regulation-726-2004/), [Sakigake designation (Japan)](https://onco.cc/terms/sakigake/), [Screening survivors: where the UK, American and European answers differ](https://onco.cc/terms/rejuv-second-screening-after-treatment-compared/), [Standard of care](https://onco.cc/terms/standard-of-care/)
- key papers: [CheckMate 649: nivolumab plus chemotherapy as first treatment for advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma](https://onco.cc/key-papers/paper-checkmate-649-lancet-2021/), [FDA's Project Optimus manifesto: cancer drugs are approved at doses that are too high](https://onco.cc/key-papers/paper-drug-dosing-conundrum-nejm-2021/), [HARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancer](https://onco.cc/key-papers/paper-harmoni-2-lancet-2025/), [Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval](https://onco.cc/key-papers/paper-le-mmr-deficiency-science-2017/), [PD-L1 Immunohistochemistry Assay Comparison in Atezolizumab Plus nab-Paclitaxel-Treated Advanced Triple-Negative Breast Cancer](https://onco.cc/key-papers/paper-rugo-pd-l1-assay-comparison-impassion130-jnci-2021/), [Prasad: most surrogate endpoints in cancer trials correlate poorly with survival](https://onco.cc/key-papers/paper-prasad-surrogate-endpoints-jama-im-2015/), [Regulatory review of novel therapeutics--comparison of three regulatory agencies](https://onco.cc/key-papers/paper-downing-n-engl-j-med/), [TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration](https://onco.cc/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/)
- trials: [ROMANA 1 and ROMANA 2](https://onco.cc/trials/romana-1-2/)
- technologies: [GMP, inspections, Form 483s and warning letters](https://onco.cc/technologies/pharmaceutical-gmp-inspections/), [PSK (Krestin) mushroom polysaccharide as adjuvant therapy](https://onco.cc/technologies/psk-krestin-adjuvant/)
- roadmaps: [Global access and affordability roadmap: essential medicines and generics → biosimilars and frugal trials → reliance, pooling and homegrown innovation](https://onco.cc/roadmaps/global-access-roadmap/), [Paediatric oncology roadmap: cooperative-group cures → engineered immunity → drugs developed for children first](https://onco.cc/roadmaps/paediatric-oncology-roadmap/), [Trial modernisation roadmap: the randomised trial → platforms and adaptive designs → decentralised, pragmatic and always-on](https://onco.cc/roadmaps/trial-modernisation-roadmap/)

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