Obtaining and maintaining a scientific opinion on a medicine for use outside the European Union

The European Medicines Agency (EMA) provides guidance on obtaining and maintaining a scientific opinion under the 'EU-M4all' procedure (previously known as Article 58) on high priority human medicines intended for markets outside of the European Union (EU).

EMA provides these opinions in cooperation with the World Health Organization (WHO).

The legal basis for the EU-M4all procedure is Article 58 of Regulation (EC) No 726/2004.

For more information on the EU-M4all procedure, see Medicines for use outside the European Union.

Regulatory and procedural steps involved (updated)

The pre-submission requirements and evaluation procedure for the EU-M4all procedure are similar to the centralised marketing authorisation procedure.

Applicants may apply in parallel for an EU marketing authorisation under the centralised procedure and an opinion under EU-M4all for their medicine to be used outside the EU. For more information, see Parallel application for EU-M4all opinion and EU marketing authorisation.

The flowchart below contains:

• tailored guidance on the EU-M4all procedure;
• key differences from the centralised procedure;
• guidance on applying in parallel for an EU marketing authorisation and an EU-M4all opinion;
• forms to be used by applicants for the EU-M4all procedure.

Product development support
Any stage of the medicinal product lifecycle
Medicine developers can request scientific advice from EMA at any stage of development although EMA advises seeking scientific advice early, to allow necessary amendments to the development programme. This provides scientific and regulatory guidance on the appropriate tests and studies during the development of a medicine. EU-M4all applicants can also ask questions on the adequacy of pharmacovigilance and risk minimisation measures to be implemented in the countries where they intend to market the medicine. Products confirmed to be eligible for EU-M4all assessment may also be eligible for the PRIME scheme, which supports development of medicines that target an unmet medical need. Experts from WHO or regulatory agencies in target countries may also participate. For more information, see: Scientific advice and protocol assistance EMA procedural advice for medicinal products intended exclusively for markets outside the European Union in the context of co-operation with the World Health Organisation (WHO) - questions 8-9 Support for applications on Article 58 PRIME: priority medicines

Eligibility request
7-18 months before submitting an application
To find out whether a product can be evaluated under the EU-M4all procedure, applicants should submit the pre-submission request form to [e-mail]. The selected scope of request should be: 'Art. 58 scientific opinion application - eligibility request'. Update:In parallel, applicants should send the form via EMA service desk, selecting the tab 'Business Services', category 'Human Regulatory'. The subcategory to be selected is 'Pre-Submission Phase - Human', followed by the sub-option 'Eligibility Request'. If you do not have an EMA account, please create it via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance 'Create an EMA Account'. Presubmission request form for a EMA procedure prior to the submission of a marketing authorisation application or Article 58 Application  EMA encourages medicine developers to submit this request as early as possible. EMA liaises with WHO to confirm eligibility. Applicants who apply for an EU marketing authorisation in parallel should submit separate eligibility requests for the two applications. For more information, see: EMA procedural advice for medicinal products intended exclusively for markets outside the European Union in the context of co-operation with the World Health Organisation (WHO) - questions 2-6 pre-authorisation guidance - section 2: Steps prior to submitting the application Public guidance - Parallel application for EU-M4all (Article 58) opinion and Centralised Marketing Authorisation procedure Obtaining an EU marketing authorisation, step-by-step

Notification of intended submission and appointment of EMA rapporteurs and WHO-nominated experts
7 months before submitting an application
Applicants should notify EMA of their intent to submit an application and intended submission date. Applicants should consider the date of submission carefully, taking into account the published submission dates and the guidance below: Best practice guide on measures improving predictability of submissions/responses and adherence to communicated submission/responses deadlines Update:To do this, applicants should send the pre-submission request form via EMA service desk, selecting the tab 'Business Services', category 'Human Regulatory'. The subcategory to be selected is 'Pre-Submission Phase - Human', followed by the sub-option 'Letter of Intent Request'. If you do not have an EMA account, please create it via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance "Create an EMA Account". Presubmission request form for a EMA procedure prior to the submission of a marketing authorisation application or Article 58 Application When EMA receives the notification, the CHMP and the Pharmacovigilance Risk Assessment Committee (PRAC) appoints rapporteurs to conduct the scientific assessment. If applying for an EU marketing authorisation in parallel, the same CHMP and PRAC rapporteurs will evaluate both applications. WHO-nominated experts and observers from the target country authorities may take part in the evaluation to provide specific local expertise and input. EMA will inform the applicant of the assessors and experts taking part. For more information, see: Public guidance - Parallel application for EU-M4all (Article 58) opinion and Centralised Marketing Authorisation procedure

Pre-submission meeting
Pre-submission meetings usually take place 6 to 7 months before submitting an application
Pre-submission meetings are the best opportunity for applicants to obtain procedural and regulatory advice from EMA. Successful pre-submission meetings along with EMA guidance documents should enable applicants to submit applications in line with legal and regulatory requirements. This speeds up the validation process. Update: To request a pre-submission meeting, applicants should send the completed pre-submission interactions form via EMA service desk, selecting the tab 'Business Services', category 'Human Regulatory'. The subcategory to be selected is 'Pre-Submission Phase - Human', followed by the sub-option: 'Pre-Submission Interaction Request'. If you do not have an EMA account, please create it via the EMA Account Management portal. For further information or guidance about how to create an EMA Account reference the guidance 'Create an EMA Account'. Marketing authorisation application (MAA) - pre-submission interactions form EMA has published a question-and-answer document with regulatory and procedural guidance specific to the EU-M4all procedure, which complements EMA's pre-authorisation guidance for the centralised procedure: EMA procedural advice for medicinal products intended exclusively for markets outside the European Union in the context of co-operation with the World Health Organisation (WHO) Pre-authorisation guidance – section 2: Steps prior to submitting the application Public guidance - Parallel application for EU-M4all (Article 58) opinion and Centralised Marketing Authorisation procedure

Preparing the dossier

The dossier requirements are mostly the same as for the centralised procedure with a few important differences. For an application under the EU-M4all procedure, the following are not mandatory: invented name; paediatric investigation plan (although scientific advice on paediatric development is encouraged); mock-ups and specimens; environmental risk assessment, with justification; requirements for location of entities and activities. If applicants request an accelerated assessment, they need to justify their request on public health interest grounds in the target countries as opposed to the EU. They should submit their request for accelerated assessment as early as possible and at least 2-3 months before submitting the application. EMA's requirements for pharmacovigilance systems and a risk management plan (RMP) apply to EU-M4all procedures, but the RMP has to be adapted to patients and the health system of the target countries. Some modules of the RMP can be omitted on justified grounds. Applicants who apply for an EU marketing authorisation in parallel should identify the differences between the two dossiers regarding quality, non-clinical and clinical requirements. They should reflect any differences in Modules 1–5 in their submissions (e.g. with a comparative table annexed to Module 1).  For more information, see: EMA procedural advice for medicinal products intended exclusively for markets outside the European Union in the context of co-operation with the World Health Organisation (WHO) - questions 13-23 and 28-38 Pre-authorisation guidancesection 3: Preparing the dossier Public guidance - Parallel application for EU-M4all (Article 58) opinion and Centralised Marketing Authorisation procedure

Submission and validation of the application

Applicants should use the EU-M4all application form and submit the application through the eSubmission gateway or web client: Administrative information Application form for a Scientific Opinion according to Article 58 of Regulation (EC) 726/2004 If the Agency needs additional information to validate the application, it will ask the applicant to supply this by a deadline. Applicants who apply for an EU marketing authorisation in parallel should submit the two application dossiers separately. for more information, see:  What is eSubmission? Pre-authorisation guidancesection 4: Submission, validation and fees EMA procedural advice for medicinal products intended exclusively for markets outside the European Union in the context of co-operation with the World Health Organisation (WHO) - questions 24 Obtaining an EU marketing authorisation, step-by-step Public guidance - Parallel application for EU-M4all (Article 58) opinion and Centralised Marketing Authorisation procedure

Scientific evaluation
Up to 210 active days of assessment
The CHMP evaluates the application with input from WHO experts and observers from target countries, as needed. The PRAC provides input on aspects related to risk management. The CHMP may also request inspections of sites used for clinical trials and manufacturing or of pharmacovigilance systems. For more information, see Compliance. The evaluation timetables for EU-M4all opinions and EU marketing authorisations may differ. If applying for both procedures in parallel, applicants may receive the opinions on different dates. For more information, see: Pre-authorisation guidance – section 5: Assessment of the application The evaluation of medicines, step-by-step Public guidance - Parallel application for EU-M4all (Article 58) opinion and Centralised Marketing Authorisation procedure EMA publishes information on the outcome of assessments under EU-M4all on Medicines for use outside the EU.

After CHMP opinion

The opinion holder should inform EMA of any changes concerning their medicine following the CHMP opinion. They should consult EMA's Post-authorisation guidance, including on variations and and periodic safety update reports. They should use the following forms, if applicable: Application form for variation to Article 58 CHMP scientific opinion Cover letter for change of scientific opinion holder Attachment 1 for change of scientific opinion holder Attachment 2 for change of scientific opinion holder The opinion holder must fulfill the pharmacovigilance requirements agreed with EMA. They should: record all serious adverse reactions and submit to EMA within the timeframes and format of Guideline on good pharmacovigilance practices (GVP) - Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products (Rev. 2) and guidance available on Eudravigilance; submit periodic safety update reports; manage safety signals. The opinion holder should submit to EMA any information that may affect the medicine's benefit-risk balance. Opinion holders should note that EMA's requirements are additional to the pharmacovigilance requirements of the regulatory authorities where the medicine is authorised. In some cases, EMA may request the opinion holder to submit further post-authorisation measures. EMA can also recommend further monitoring and risk-minimisation programmes and conduct a benefit-risk review at any time if new safety information becomes available. For more information, see: EMA procedural advice for medicinal products intended exclusively for markets outside the European Union in the context of co-operation with the World Health Organisation (WHO) - questions 42-47 Post-authorisation guidance Pharmacovigilance: post-authorisation

Use of EU-M4all opinion

WHO may include the medicine in public health recommendations. WHO provides a streamlined assessment for the prequalification programme for medicines evaluated under the EU-M4all procedure. For more information concerning vaccines, see: WHO: Prequalification procedure for vaccines evaluated by EMA under Article 58 of Regulation (EC) No 726/2004 Opinion holders can use EMA's opinion to support marketing authorisation applications to regulators in non-EU countries and may benefit from a streamlined procedure. They may also share the CHMP assessment and inspection reports with non-EU regulators in support of their applications. For more information, see: Pr-authorisation guidance - question 5.1.12 'Can EMA assessment or inspection documents be shared with third parties?'

Templates and forms

Pre-submission forms

• Presubmission request form for a EMA procedure prior to the submission of a marketing authorisation application or Article 58 Application 
• Marketing authorisation application (MAA) - pre-submission interactions form
• Administrative information Application form for a Scientific Opinion according to Article 58 of Regulation (EC) 726/2004

Post-opinion forms

• Application form for variation to Article 58 CHMP scientific opinion
• Cover letter for change of scientific opinion holder
• Attachment 1 for change of scientific opinion holder
• Attachment 2 for change of scientific opinion holder