EU-M4all

EU-M4all (EU Medicines for all, formerly known as the 'Article 58 procedure') is the European Medicines Agency's scientific-opinion procedure under Article 58 of Regulation (EC) No 726/2004 — the foundational regulation establishing EMA + the EU centralised marketing-authorisation procedure. Article 58 was added to the regulation specifically to create a framework where EMA could lend its scientific assessment capability to support medicines intended exclusively for markets outside the European Union, in cooperation with WHO + the recipient-country NRAs. The procedure was originally established in 2004 under the umbrella term 'Article 58' + was formally rebranded EU-M4all (EU Medicines for all) in 2020 with updated EMA Guideline (EMA/CHMP/SAWP/89537/2020) + expanded scope to include treatments for non-communicable diseases + paediatric formulations.

Key structural elements include:

• CHMP Scientific Opinion — the procedure results in a Scientific Opinion (not a marketing authorisation) issued by EMA's Committee for Medicinal Products for Human Use (CHMP); the Opinion is published + supports WHO Prequalification + recipient-country NRA decision-making.
• Exclusively non-EU markets — products assessed under EU-M4all are explicitly intended for markets outside the European Union; products that may eventually be marketed in the EU should use the standard centralised procedure.
• Same scientific assessment standards — EU-M4all uses substantively the same CHMP scientific assessment standards as the EU centralised procedure including the same CHMP Rapporteur + Co-Rapporteur model, the same EMA scientific guidelines + the same EU GMP / GCP / GLP inspection framework.
• WHO + NRA cooperation — EU-M4all procedure is conducted in cooperation with WHO + the recipient-country NRAs from initial scientific advice through final Opinion + post-Opinion lifecycle.
• Eligible products — vaccines + biologics + small molecules + paediatric formulations + treatments for diseases of major public-health interest including HIV, malaria, tuberculosis + neglected tropical diseases; expanded post-2020 to include non-communicable diseases.
• EU manufacturer or non-EU manufacturer eligibility — EU-M4all applications can be filed by EU-established manufacturers OR by non-EU manufacturers (provided they meet specific procedural + GMP requirements).
• Same fee structure as centralised procedure — substantial fees apply but with EMA + WHO + EC discussions on fee reduction or waiver for high-impact LMIC products.
• Post-Opinion lifecycle — variations, line extensions, periodic safety update reports + post-Opinion commitments all follow procedurally similar processes to the EU centralised procedure with WHO + NRA involvement.

The procedure has been used for several high-impact products including: Mosquirix (RTS,S/AS01) — the first WHO-recommended malaria vaccine for children + the first EU-M4all-supported vaccine for sub-Saharan Africa use; Ervebo (rVSV-ZEBOV) — the Ebola vaccine used in the 2014-2016 + subsequent West + Central African outbreaks; Comirnaty for LMIC use — the Pfizer-BioNTech COVID-19 vaccine with EU-M4all support for COVAX + LMIC distribution; tafenoquine + several HIV/tuberculosis/sleeping-sickness treatments. EU-M4all has been particularly important for vaccines + treatments where the primary commercial market is LMIC + where WHO Prequalification + reliance by LMIC NRAs are the principal regulatory targets.

The procedure has evolved substantially since its 2004 establishment, with the most significant change being the 2020 rebranding from 'Article 58 procedure' to 'EU-M4all' (EU Medicines for all) + accompanying scope + procedural updates.

• 2004 — Article 58 of Regulation (EC) No 726/2004 establishes the procedure as part of the broader EMA centralised-procedure regulation; initial scope focused on vaccines + medicines for major communicable diseases (HIV, malaria, tuberculosis).
• 2004-2010 — slow initial uptake; small number of applications + Opinions issued; primary focus on vaccines + treatments for diseases of major LMIC public-health concern.
• 2010-2020 — gradual expansion of use including landmark Opinions for Mosquirix malaria vaccine (2015) + Ervebo Ebola vaccine (2019) + several HIV / tuberculosis treatments; growing recognition of the procedure's value for WHO Prequalification + LMIC NRA reliance.
• 2020 — formal rebranding to EU-M4all (EU Medicines for all) by EMA + publication of updated Guideline EMA/CHMP/SAWP/89537/2020; expanded scope to include treatments for non-communicable diseases + paediatric formulations + improved procedural framework.
• 2020-2021 — extensive use during the COVID-19 pandemic including EU-M4all support for Comirnaty + several COVID-19 vaccines for COVAX + LMIC distribution; demonstrating the procedure's value during global public-health emergencies.
• 2022-present — continued use + progressive adoption by additional manufacturers; growing WHO + EMA + EC support for fee reduction or waiver for high-impact LMIC products; integration with WHO Collaborative Registration Procedure (CRP) for streamlined LMIC NRA assessment.
• The Article 58 / EU-M4all terminology change reflects broader EMA strategic positioning of the procedure as a substantive contribution to global health + LMIC access rather than a narrow technical procedure.
• Procedural distinctions — pre-2020 Article 58 procedure had several procedural ambiguities + limitations that the 2020 EU-M4all Guideline substantially clarified including post-Opinion lifecycle, WHO + NRA cooperation mechanics + extension to non-communicable diseases.
• Future evolution — ongoing discussions on further integration with WHO Listed Authority (WLA) framework + on potential expansion of EU-M4all to support additional therapeutic areas + on fee structure reform for LMIC-impact products.

EU-M4all uses substantively the same procedural framework as the EU centralised procedure for marketing-authorisation applications, with key differences reflecting the procedure's non-EU-market focus + WHO + NRA cooperation requirements.

• Pre-submission scientific advice — applicants are strongly encouraged to engage in EMA Scientific Advice or Protocol Assistance with the EU-M4all option flagged from the outset; WHO + recipient-country NRAs may also participate in scientific advice meetings.
• Letter of Intent + Eligibility Confirmation — applicants submit a Letter of Intent to EMA specifying the EU-M4all procedure + the intended LMIC markets + WHO PQ alignment; EMA confirms eligibility based on Article 58 + EU-M4all Guideline criteria.
• Application submission — applicants submit the EU-M4all application via the same EMA submission portals as the centralised procedure with EU-M4all-specific Module 1 elements including LMIC-market identification + WHO PQ alignment statement.
• CHMP Rapporteur + Co-Rapporteur assignment — EMA assigns a Rapporteur + Co-Rapporteur from CHMP membership (national EU regulator experts); same model as EU centralised procedure.
• Day 120 + Day 180 + Day 210 clock — substantively the same 210-day CHMP assessment clock as the centralised procedure including applicant-response stops; some flexibility for EU-M4all reflecting the procedure's collaborative nature.
• EU GMP / GCP / GLP inspections — EU-M4all applications are subject to the same EU GMP / GCP / GLP inspection framework as the centralised procedure; inspections conducted by EU national inspectorates with EMA coordination.
• WHO + NRA observer participation — WHO + recipient-country NRAs may participate as observers in CHMP discussions + may provide their own scientific perspectives + concerns; substantial collaborative element distinguishing EU-M4all from pure EU centralised procedure.
• CHMP Scientific Opinion — final CHMP Scientific Opinion published + transmitted to WHO + recipient-country NRAs; the Opinion includes summary product characteristics-equivalent information, assessment report + commitments.
• Post-Opinion lifecycle — variations, line extensions, periodic safety update reports + post-Opinion commitments all follow procedurally similar processes to EU centralised procedure with continued WHO + NRA involvement.
• EMA Public Assessment Report (EPAR) equivalent — EU-M4all Opinions are published with an EPAR-equivalent assessment report providing transparency + supporting LMIC NRA reliance.

EU-M4all's value proposition is substantially enhanced by its tight integration with WHO Prequalification (WHO PQ) — the WHO programme that assesses medicines, vaccines, IVDs + vector-control products for UN procurement + LMIC use. EU-M4all-supported products typically receive WHO PQ via streamlined assessment leveraging the CHMP Scientific Opinion.

• WHO PQ submission — once a product has received a CHMP Scientific Opinion under EU-M4all, the manufacturer can submit to WHO PQ with the Opinion + EPAR-equivalent assessment report as the primary basis.
• WHO PQ streamlined assessment — WHO PQ typically conducts a streamlined assessment of EU-M4all-supported products leveraging the CHMP Scientific Opinion + EU GMP inspections; substantial reduction in WHO PQ assessment timeline + effort.
• WHO PQ + EU-M4all collaboration — formal collaboration agreements between EMA + WHO PQ enable joint scientific discussions + reliance on each other's assessments + inspection findings; WHO + EMA staff may participate in each other's processes.
• WHO Collaborative Registration Procedure (CRP) — once a product has received both CHMP Scientific Opinion under EU-M4all + WHO PQ listing, LMIC NRAs participating in the WHO CRP can leverage the WHO PQ assessment to issue national marketing authorisations with substantially reduced national assessment.
• Tri-level reliance — EU-M4all → WHO PQ → LMIC NRAs via CRP provides a three-step reliance cascade that has substantially accelerated LMIC access to high-quality medicines + vaccines.
• Examples — Mosquirix (malaria vaccine, WHO recommendation 2021), Ervebo (Ebola vaccine, WHO PQ 2019 + LMIC NRA registrations), Comirnaty for LMIC use (COVID-19 vaccine, COVAX distribution) all benefited from the EU-M4all → WHO PQ → CRP cascade.
• Limitations — not all EU-M4all-supported products are submitted to WHO PQ; not all WHO PQ-listed products use EU-M4all (many use WHO PQ direct assessment); the cascade is most valuable for high-impact LMIC products where multiple reliance steps are needed.
• WHO Listed Authority (WLA) framework — EMA is a WHO Listed Authority + the WLA framework is progressively replacing the older 'Stringent Regulatory Authority (SRA)' framework; EU-M4all + WLA together provide a comprehensive global reliance architecture.

• Mosquirix (RTS,S/AS01, GSK, CHMP Scientific Opinion 2015) — the first WHO-recommended malaria vaccine for children + the first EU-M4all-supported vaccine for sub-Saharan Africa use; subsequently WHO PQ + WHO Recommendation for pilot implementation + 2021 broader WHO recommendation.
• Ervebo (rVSV-ZEBOV, Merck, CHMP Scientific Opinion 2019) — Ebola vaccine used in 2014-2016 West African outbreak + subsequent 2018-2020 Democratic Republic of Congo outbreak + 2022 Uganda outbreak; WHO PQ 2019 + multiple African NRA registrations via CRP.
• Comirnaty for LMIC use (Pfizer-BioNTech, CHMP Scientific Opinion 2021) — COVID-19 vaccine with EU-M4all support for COVAX + LMIC distribution; substantial use during 2021-2022 pandemic response.
• Tafenoquine (Kozenis / Krintafel, GSK, CHMP Scientific Opinion 2018) — single-dose treatment for Plasmodium vivax malaria relapse prevention; WHO PQ + LMIC NRA registrations supporting global malaria elimination.
• Several HIV antiretroviral combinations + paediatric formulations — EU-M4all has supported several fixed-dose combinations + paediatric formulations of antiretrovirals critical for HIV programmes in sub-Saharan Africa.
• Tuberculosis treatments — EU-M4all has supported several new TB drug regimens including for multidrug-resistant TB; complementing WHO PQ + Global Fund + Stop TB Partnership procurement.
• Sleeping sickness (Human African Trypanosomiasis) treatments — EU-M4all has supported new HAT treatments including fexinidazole + acoziborole (oxaborole class), substantially improving HAT treatment access.
• Visceral leishmaniasis treatments — EU-M4all has supported several treatments for visceral leishmaniasis (kala-azar), a neglected tropical disease primarily affecting LMIC populations.
• Pediatric formulations + non-communicable diseases — post-2020 EU-M4all expansion has supported paediatric formulations + non-communicable disease treatments for LMIC markets.
• Vaccines for future epidemic + pandemic preparedness — ongoing EU-M4all discussions for vaccines for Lassa fever, Nipah, MERS-CoV + other epidemic-prone diseases as part of WHO R&D Blueprint + CEPI portfolio.

EU-M4all provides substantial advantages for manufacturers + WHO + recipient-country NRAs + ultimately LMIC patients — but also has limitations that should be understood when planning regulatory strategy.

• Advantage — EMA scientific assessment credibility: EMA is one of the world's most respected regulators + a WHO Listed Authority; CHMP Scientific Opinion under EU-M4all carries substantial credibility supporting WHO PQ + LMIC NRA reliance.
• Advantage — alignment with EU centralised procedure standards: substantive alignment with EU centralised procedure scientific standards + GMP / GCP / GLP inspections provides consistency + minimises duplicate assessment effort.
• Advantage — WHO + LMIC NRA cooperation: formal cooperation mechanisms with WHO + recipient-country NRAs ensures the Opinion is responsive to LMIC needs + supports downstream reliance.
• Advantage — three-step reliance cascade: EU-M4all → WHO PQ → CRP cascade substantially accelerates LMIC access compared to separate national assessments.
• Advantage — paediatric + non-communicable disease scope expansion: post-2020 scope expansion makes EU-M4all relevant for a broader range of LMIC public-health priorities.
• Limitation — exclusively non-EU market constraint: products that may eventually be marketed in EU should use centralised procedure; this can create strategic constraints for products with potential dual-use.
• Limitation — substantial fees + resources: EU-M4all fees + assessment effort are substantially similar to centralised procedure; can be prohibitive for low-margin LMIC products without external funding (CEPI, BMGF, etc.).
• Limitation — limited LMIC NRA capacity: full benefit of the reliance cascade requires LMIC NRAs with sufficient capacity to engage with CRP + reliance; smaller NRAs may still require substantial direct support.
• Limitation — not all products fit: EU-M4all is most valuable for products with substantial LMIC public-health impact + WHO PQ alignment; products targeting smaller LMIC markets or specific bilateral arrangements may benefit more from alternative reliance pathways.
• Limitation — post-Opinion lifecycle complexity: post-Opinion variations + commitments require continued EMA + WHO + NRA engagement which can be operationally complex for manufacturers.
• Limitation — no EU market authorisation: EU-M4all Opinion does not authorise EU placement; manufacturers seeking EU access must separately file centralised procedure or national MAs.

V5 Ultimate provides the operational infrastructure manufacturers need for EU-M4all preparation + ongoing EU-M4all lifecycle compliance — particularly for vaccines, biologics + sterile products where EU GMP Annex 1 + ICH Q-series compliance are critical.

• EU GMP control framework — full EU GMP including EU GMP Annex 1 (2022 revision) sterile manufacturing compliance, computerised systems compliance per Annex 11 + ICH Q10 PQS implementation; ALCOA+ data-integrity expectations aligned with PIC/S PI 041.
• EMA submission packaging — full EU-CTD eCTD submission packaging with EU-M4all-specific Module 1 elements including LMIC-market identification, WHO PQ alignment statement + recipient-country NRA cooperation arrangements.
• CHMP Rapporteur + Co-Rapporteur engagement workflow — pre-submission Scientific Advice / Protocol Assistance engagement, Day 120 / Day 180 / Day 210 response management, CHMP question + applicant-response tracking.
• EU GMP + GCP + GLP inspection readiness — EU GMP inspection preparation including Annex 1 sterile + Annex 13 IMP requirements, EU GCP inspection preparation for clinical trials supporting EU-M4all applications, EU GLP inspection preparation for preclinical studies.
• WHO PQ + CRP integration workflow — CHMP Scientific Opinion + EPAR-equivalent assessment report packaging for WHO PQ submission, WHO PQ + LMIC NRA CRP coordination, three-step reliance cascade tracking.
• EU-M4all variation + post-Opinion lifecycle — Type IA / IB / II variation packaging following EU centralised procedure framework with WHO + NRA notification + cooperation.
• PSUR + safety reporting — EU-aligned PSUR cycle, ICH E2B(R3) ICSR generation, 15-day SUSAR timeline, EU + WHO + LMIC NRA safety information sharing.
• Multi-LMIC NRA engagement — for products targeting multiple LMIC markets via CRP, V5 surfaces NRA-specific Module 1 customisation + country-specific labelling + pharmacovigilance commitments alongside EU-M4all core dossier.
• Vaccine + biological lot release — EU OMCL (Official Medicines Control Laboratory) lot release coordination for vaccines + biologics under EU-M4all; alignment with WHO PQ NIB (National Institute for Biological Standards and Control)-equivalent lot release.
• CEPI / BMGF / Global Fund / Gavi alignment — for products developed with CEPI, BMGF, Global Fund or Gavi support, V5 surfaces funder-specific reporting + milestone tracking alongside EU-M4all + WHO PQ submissions.
• Cold chain + LMIC distribution — for vaccines + biologics requiring cold chain (2-8°C, -20°C or ultra-cold), V5 surfaces cold-chain qualification + LMIC distribution planning workflow including COVAX-equivalent logistics.
• Pediatric + paediatric-friendly formulation — post-2020 EU-M4all scope expansion supports paediatric formulations; V5 surfaces paediatric clinical development + EU PIP-equivalent planning workflow.