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

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

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

For more information on the procedure, see Medicines for use outside the EU.

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Regulatory and procedural steps involved 

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

The flowchart below contains:

  • tailored guidance on the Article 58 procedure;
  • key differences from the centralised procedure;
  • forms to be used by applicants for the Article 58 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. Article 58 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 Article 58 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:

 

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Eligibility request 

7-18 months before submitting an application

To find out whether a product can be evaluated under the Article 58 procedure, applicants should submit the pre-submission request form to article58@ema.europa.eu and cpeligibility@ema.europa.eu. The selected scope of request should be: 'Art. 58 scientific opinion application - eligibility request':

 

 

EMA encourages medicine develoeprs to submit this request as early as possible. 

 

EMA liaises with WHO to confirm eligibility.

 

For more information, see:

 

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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:

 

 

To do this, they should email the pre-submission request form to pa-bus@ema.europa.eu. The selected scope of request should be: 'Centralised Procedure – Intent to submit a MAA':

 

 

When EMA receives the notification, the CHMP and the Pharmacovigilance Risk Assessment Committee (PRAC) appoints rapporteurs to conduct the scientific assessment. 

 

WHO-nominated experts and observers from the taget 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.

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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. 

 

To request a pre-submission meeting, applicants should send the completed pre-submission meeting request form to article58@ema.europa.eu:

 

 

EMA has published a question-and-answer document with regulatory and procedural guidance specific to the Article 58 procedure, which complements EMA's pre-authorisation guidance for the centralised procedure:

 

 

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Preparing the dossier

The dossier requirements are mostly the same as for the centralised procedure with a few important differences.

 

However, for an application under Article 58, the following are not mandatory:

 

 

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 Article 58 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.

 

For more information, see:

 

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Submission and validation of the application

Applicants should use the Article 58 application form and submit the application through the eSubmission gateway or web client:

 

 

If the Agency needs additional information to validate the application, it will ask the applicant to supply this by a deadline.

 

for more information, see:

 

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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

 

For more information, see:

 

EMA publishes information on the outcome of assessments under Article 58 on Medicines for use outside the EU.

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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:

 

The opinion holder must fulfil the pharmacovigilance requirements agreed with EMA. They should:

 

 

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:

 

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Use of opinion

WHO may include the medicine in public health recommendations.

 

WHO provides a streamlined assessment for the prequalification programme for medicines evaluated under the Article 58 procedure. For more information concerning vaccines, see:

 

 

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:

 


Templates and forms 

Pre-submission forms

Post-opinion forms

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