This document addresses a number of questions that users of Article 58 of Regulation (EC) No 726/2004 may have. It provides an overview of the European Medicines Agency's position on issues that are typically addressed in pre-submission meetings.
This document has been produced for guidance only and should be read in conjunction with the Guideline on procedural aspects regarding a CHMP scientific opinion in the context of co-operation with the World Health Organization (WHO) for the evaluation of medicinal products intended exclusively for markets outside the Community (EMEA/CHMP/5579/04).
- Article 58 Eligibility Request Form
- Pre-submission meeting request form for Article 58 scientific opinion application submissions
- Application form for a scientific opinion according to Article 58 of Regulation (EC) 726/2004
- 31. When is a good manufacturing practice or good clinical practice inspection needed? How are inspections carried out?
The same principles apply for good manufacturing practice (GMP) and good clinical practice (GCP) inspections for evaluations under Article 58 as for the evaluation of a centrally medicinal product. For details, see: question "When can I expect a pre-approval GMP inspection and how are they conducted?" of the EMA Pre-submission guidance document.
- 32. What is the fee for an inspection?
A separate, full inspection flat rate fee of €19,100 is charged for each distinct inspection of an individual site. Additional fees may be charged for activities on the same site that require a separate inspection and also for each contract manufacturing site and contract testing laboratory that needs to be inspected in connection with an application.
For inspections outside the Community, the applicant is also required to pay the travel and accommodation expenses for the inspectors and any experts or Rapporteurs involved. These expenses are paid directly by the applicant to the inspectors’ authorities.
For more information on inspection fees, please see Annex IV of the Rules for the implementation of Regulation (EC) No 297/95 as amended on fees payable to the European Medicines Agency and other measures (Annex IV): “Policy on financial transactions and payments for inspections requested by the CHMP or CVMP.”
- 33. How are active substance master files submitted?
ASMFs are needed for active substances that are prepared in accordance with the published guidelines on ASMF. Applicants should include information on their intention to present the equivalent of an EU active substance master file (ASMF) when they send their notification of intention to submit an application.
Applicants should refer to the Guideline on Active Substance Master File Procedure (CPMP/QWP/227/02) for information on what to send and the procedure to follow. If an ASMF already exists, the applicant should ensure that the active ingredient manufacturer’s (AIM’s) restricted part of the ASMF is submitted by the AIM to the EMA, the Rapporteur and the Co-Rapporteur at the same time as the main application.
Please note that the applicant should include a commitment to inform the EMA of any changes in the ASMF either as a separate letter included in Annex 5.11 or within the letter of access provided in Annex 5.11 of the application form.
If the applicant wishes to use existing vaccine antigen master file (VAMF) or plasma master file (PMF) certificates in the application, it will be required to provide the valid VAMF or PMF certificate of compliance to Community legislation and accompanying evaluation reports together with the respective VAMF or PMF data.
- Guideline on procedural aspects regarding a CHMP scientific opinion in the context of cooperation with the World Health Organization (WHO) for the evaluation of medicinal products intended exclusively for markets outside the Community
- Guideline on Active Substance Master File Procedure (CPMP/QWP/227/02)
- Annex I to the Directive 2001/83/EC, as amended
- 34. What information is needed for medicinal products that contain or use material of animal or human origin in the manufacturing process?
If a product contains material of animal or human origin or uses it in its manufacture, the applicant should comply with the Part I Module 3.2 (9) “Content: basis and principle” of the Annex I to Directive 2001/83/EC, as amended. This requires the applicant to demonstrate that the medicinal product is manufactured in accordance with the “Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products” and its updates.
This can be achieved by either of the following means:
- submitting certificates of suitability from the European Directorate for the Quality of Medicines (EDQM) in Annex 5.13 of the application form;
- inclusion of scientific data to back up this compliance in module 3.2 of the dossier, together with a review of these data in Module 2.3 (expert reports).
For all applications, table A on Materials of animal origin covered by the Notice for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products should be completed and included in Module 3.2.R.
For material from animals that is not covered by the Notice for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products and annex I of Directive 2001/83/EC as amended, applicants are requested to complete table B on ‘Other materials of animal origin’, and include it in Module 3.2.R.
If an application relates to a medicinal product that contains or uses material of human origin in its manufacture, applicants are requested to complete table C on albumin and other human tissue derived materials and include it in Module 3.2.R.
- 35. Is there a European decision-making process after adoption of a scientific opinion?
There is no European decision-making process after adoption of a scientific opinion, since the purpose of opinions under Article 58 is to allow the evaluation of medicinal products for use exclusively in markets outside the Community.
- 36. Is a European public assessment report published following a scientific opinion under Article 58?
Yes, a European public assessment reports (EPAR) is published following an opinion under Article 58, as for all products assessed by the CHMP. In the case of Article 58 opinions, it is known as a ‘European public assessment reports on a scientific opinion in co-operation with WHO (EPAR)’. The EPAR is published by day 300.
The EPAR reflects the scientific conclusions reached by the CHMP at the end of the evaluation process. The legal basis for its creation and availability is contained in Article 13(3) of Regulation
(EC) No 726/2004, by analogy. It is made available by the EMA for information to the public, after deletion of commercially confidential information.
The EPAR is updated throughout the opinion period as changes to the original terms and conditions of the opinion are made, such as variations, pharmacovigilance issues and changes to specific obligations. EPARs also contain a summary written in a manner that is understandable by the public.
Other types of EPAR may also be published following the withdrawal of an application of a scientific opinion or following a negative scientific opinion. In such cases, the basis for publication is Articles 11 and 12 of Regulation (EC) No 726/2004, by analogy.
- 37. Can the EMA certify scientific opinions under Article 58?
The current WHO certification scheme allows for a Certificate of a Medicinal Product to be issued for a product that has received a positive CHMP scientific opinion under Article 58. The certificate certifies that the medicinal product has been evaluated for quality, safety and efficacy by the EMA.
As for centrally authorised products, the EMA issues these certificates upon request from the opinion holder.
For more information regarding certificates please see the Inspections Homepage On Certificates.
- 38. What happens after the opinion?
In some cases, the CHMP concludes that a medicinal product is only approvable on the condition that certain data are provided after the opinion. In these cases, the data requested should be submitted within the timeframe agreed with the CHMP and the applicant.
Any data submitted as part of post-opinion follow-up are evaluated by the CHMP, and the opinion holder is informed of the outcome. If the outcome requires an update of the CHMP opinion, the opinion holder will be requested to submit an application for a variation to the opinion within an agreed timeframe.
If any post-opinion commitments are not met, the CHMP can revise its opinion after consulting the WHO. In these cases, the revised opinion will be based on the re-assessment of the benefit/risk profile of the product.
All serious adverse events should be recorded by the opinion holders and reported to the EMA and the competent authorities of the countries where the product is marketed within the time frames and format recommended by the International Conference on Harmonisation (ICH).
Furthermore, the opinion holders are required to submit periodic safety update reports (PSURs) on their product. These are reports on the worldwide safety experience of a medicinal product that are submitted to the (Co-) Rapporteurs and the EMA at defined time points after the opinion. PSURs include a succinct summary on the product’s safety, together with a critical evaluation of the benefit/risk balance of the product in the light of any new information, indicating whether further investigation is needed and whether changes should be made to the opinion.
To keep the opinion valid throughout the life of a medicinal product, the opinion holder shall reflect any technical and scientific progress. Any amendments to the opinion that may be required need to be approved by the EMA in collaboration with the WHO via variation procedures. By analogy, the same categories of variations apply for opinions under Article 58 as for centralised marketing authorisations, with the same data requirements.
- Regulation (EC) No 726/2004, Article 24(3)
- Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs, ICH E2C
- Volume 9A of the Rules Governing Medicinal Products in the European Union - Guidelines on Pharmacovigilance for Medicinal Products for Human Use
- Notice to Applicants Volume 2A, Chapter 5 “Variations”
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