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
- 16. In which languages should the product information, mock-ups and specimens be submitted in an application?
The product information should be submitted in English only, as electronic copies. No mock-ups or specimens need to be submitted for products evaluated under Article 58, as they are intended exclusively for markets outside the Community.
- 17. Do the QRD templates for product information have to be used?
It is recommended that the product information is submitted in line with the English QRD templates, in order to ensure standardisation in terms of headings. However, since the product is intended to be used by patients in countries where QRD requirements are not enforced, applicants can deviate from these templates. In this case, they should submit an edited QRD template with tracked changes, together with a justification for the deviations proposed.
- 18. Do scientific opinions benefit from data or market exclusivity?
Scientific opinions under Article 58 are not followed by an EU Commission Decision, the EC incentives such as data or market exclusivity do therefore not apply.
- 19. Do ATC codes and international non-proprietary names agreed by WHO have to be used?
The use of ATC codes and international non-proprietary names (INNs) agreed by WHO is highly recommended, but no legal requirement.
- 20. Is user testing of the package leaflet needed?
User testing of the Package Leaflet is not mandatory because the product is to be marketed outside the European Union. However, applicants are encouraged to carry out user testing.
- 21. What is the timetable for the evaluation of applications?
The evaluation procedure follows the same steps and timeframe as the centralised procedure. As the evaluation is a partnership between the EMA and WHO, WHO experts provide input to the procedure. Observers from WHO and authorities of developing countries recommended by the WHO may also attend CHMP plenary discussions on products being assessed (see question 23).
The procedure starts once the application has been validated and the Rapporteur and Co-Rapporteur have confirmed that they have received the dossier and any additional information requested during the validation phase. The timetable for an individual product’s evaluation is prepared by the EMA in consultation with the Rapporteur and Co-Rapporteur and is adopted by the CHMP. The EMA ensures that the CHMP scientific opinion is given within 210 days.
The standard timetable for the evaluation of an application for a CHMP scientific opinion is below:
Day Action 1 Start of the procedure 80 Receipt of the assessment reports from the Rapporteur and Co-Rapporteur by CHMP members and the EMA. The EMA sends the assessment reports to the applicant, making it clear that they only set out the preliminary conclusions, that they are sent for information only and that they do not yet represent the position of the CHMP. 100 Receipt of comments on the assessment reports from CHMP members (including peer reviewers) by the Rapporteur, Co-Rapporteur, other CHMP members, WHO experts, as appropriate and the EMA. 115 Receipt of draft list of questions (including the CHMP recommendation and scientific discussion) from the Rapporteur and Co-Rapporteur, as discussed with the peer reviewers, by CHMP members, WHO Experts as appropriate, and the EMA. 120 Adoption of the list of questions, overall conclusions and review of the scientific data by the CHMP. The EMA sends these to the applicants and WHO Experts, as appropriate.
Deadline for adoption of a request for a good manufacturing practice (GMP) or good clinical practice (GCP) inspection by the CHMP, if necessary, and start of inspection procedure.
The ‘clock’ is stopped at day 120. By analogy to the evaluation of centralised marketing authorisation applications, the same rules apply with regards the time allowed for applicants to respond to the list of questions and list of outstanding issues (EMEA/75401/2006 Rev. 2).
At day 121, responses are submitted by the applicant, including a revised summary of product characteristics (SPC), labelling and Package Leaflet in English. The clock is then restarted.
After receipt of the responses, CHMP adopts a timetable for the evaluation of the responses. The standard timetable is as follows:
Day Action 150 Receipt of joint response assessment report from the Rapporteur and Co-Rapporteur by CHMP members and the EMA. The EMA sends the joint assessment report to the applicant, WHO Experts, as appropriate, making it clear that it only sets out their preliminary conclusions, that it is sent for information only and that it does not yet represent the position of CHMP.
Inspection is carried out, if applicable.
170 Deadline for comments on joint assessment report from CHMP members and WHO Experts as appropriate. Responses are sent to the Rapporteur and Co-Rapporteur, the EMA and other CHMP members. 180 CHMP discussion and decision on whether the applicant will need to attend an oral explanation. If an oral explanation is needed, the clock is stopped to allow the applicant to prepare.
Deadline for submission of the final inspection report to EMA, Rapporteur and Co-Rapporteur by the inspections team, if applicable.
181 Clock is restarted.
Oral explanation takes place (if needed).
By 210 Final draft of SPC, labelling and package leaflet in English sent by the applicant to the Rapporteur and Co-Rapporteur, the EMA and other CHMP members and WHO Experts, as appropriate.
Adoption of CHMP scientific opinion and assessment report.
After adoption of a CHMP scientific opinion, the annexes to the opinion and European public assessment report on a scientific opinion in co-operation with WHO (EPAR) are prepared according to the following timetable:
Day Action By 240 The EMA forwards the CHMP scientific opinion and its annexes to the applicant, the WHO, EU Member States, Norway and Iceland. By 300 Finalisation of the EPAR in consultation with the Rapporteur, Co-Rapporteur and CHMP, and with the applicant to discuss issues related to commercial confidentiality.
- 22. When and how are the Rapporteur and Co-Rapporteur appointed?
For any scientific evaluation that forms part of a procedure, Rapporteurs are appointed to lead the evaluation. Rapporteurs are selected from among the CHMP members, including the co-opted and alternate members. Each Rapporteur is supported by an assessment team of assessors and experts.
In the pre-opinion phase of an application for a CHMP scientific opinion, two Rapporteurs are appointed – these are named the ‘Rapporteur’ and the ‘Co-Rapporteur’. Normally, the Rapporteur continues on as the leader in the post-opinion phase.
The appointment of the Rapporteur and Co-Rapporteur is made on the basis of criteria that ensure that scientific opinions are made objectively using the best available expertise in the European Economic Area (EEA). The appointment procedure for Rapporteurs, Co-Rapporteurs and their assessment teams is usually initiated seven months prior to the intended submission date of the application, with the actual appointment taking place one month later. Therefore, the deadline for applicants to send their letter of intent to submit an application under Article 58 of Regulation (EC) No. 726/2004 is seven months before the intended submission date.
Applicants are strongly advised to notify the EMA of their intended submission date for their marketing authorisation applications. This date should be as realistic and as accurate as possible. This information is crucial to the EMA and to the future appointed Rapporteurs and their assessment teams for the purposes of planning.
Applicants’ proposals or preferences for the appointment of Rapporteurs and Co-Rapporteurs cannot be considered.
Further information on the objective criteria and the procedure for the appointment of Rapporteurs and Co-Rapporteurs is provided in the EMA paper Procedural Advice on CHMP/CAT rapporteur/co-rapporteur appointment principles, objective criteria and methodology in accordance with Article 62 (1) of Regulation (EC) NO 726/2004.
- Procedural Advice on CHMP/CAT rapporteur/co-rapporteur appointment principles, objective criteria and methodology in accordance with Article 62 (1) of Regulation (EC) NO 726/2004.
- CHMP Rules of Procedure (EMEA/CHMP/45110/2007)
- Regulation (EC) No 726/2004 of the European Parliament and of the Council
- Notice to Applicants, Volume 2A, Notice to Applicants Chapter 4
- 23. How are experts appointed and how are they involved?
The EMA has a list of experts that can be called upon by the CHMP when it needs specific expertise during the evaluation of an application. In addition, for applications evaluated under Article 58, experts and observers are identified by WHO and nominated in consultation with CHMP/EMA Secretariat.
The EMA or the CHMP identifies the need for specific expertise before a request for nomination is sent to WHO for WHO experts or observers. The expertise required varies according to the type of 12/20
medicinal product, application or therapeutic area that are subject to the evaluation in question. The EMA informs applicants of which WHO experts and observers are appointed for an individual procedure.
WHO observers are WHO staff or experts who act as observers or peer reviewers in a specific file or WHO-appointed national drug regulatory authority (NDRA) representatives, who follow the evaluation carried out by the CHMP but do not take part of it. Experts and observers have no voting rights at the CHMP plenary meetings. The precise tasks and responsibilities of WHO experts on a particular procedure are decided on a case-by-case basis. They may be asked to provide comments on all CHMP documents, in the same way as CHMP members. They may also be invited to attend CHMP, working party and scientific advisory group discussions on products submitted for evaluation under Article 58.
All the experts must carry out their tasks and responsibilities in accordance with EMA confidentiality agreements, in order to fully protect the confidentiality of the data submitted to them (see EMA Code of Conduct). Prior to their appointment and participation in meetings, all experts are obliged to submit a completed and signed nomination form, public declaration of interests and confidentiality undertaking form and curriculum vitae. In addition, experts can only participate in discussions on products under the CHMP scientific opinion procedure to an extent that is defined by their individual level of risk, in accordance with the EMA policy and procedure on the handling of conflicts of interest.
Applicants are responsible for sending a copy of modules 1 and 2 of the dossier to WHO experts and observers if they have been appointed, at the start of the procedure. They also need to send them a copy of any other relevant documentation that they produced during the procedure, such as responses to lists of questions or lists of outstanding issues. The EMA is responsible for forwarding the relevant documents circulated and adopted during the evaluation procedure to the appointed WHO observers, such as (Co-)Rapporteurs’ assessment reports, CHMP lists of questions, working party reports, and CHMP lists of outstanding issues, as appropriate.
- 24. Can the evaluation of a medicinal product under Article 58 be accelerated?
Yes, the evaluation of a medicinal product under Article 58 can be accelerated. This is decided on a case-by-case basis, with consultation of the CHMP, the appointed (Co-) Rapporteur and if applicable, WHO. Applicants should provide justification and rationale for any requests for accelerated assessment at the time of the request for eligibility.
- 25. Is it possible to obtain a scientific opinion under Article 58 under conditional or exceptional circumstances?
Yes it is. Article 58 refers to the applicability of Article 9 of the same Regulation, which in turn refers to Article 14(7) and (8). The principles of a “centralised conditional marketing authorisation” or a “marketing authorisation under exceptional circumstances” can therefore apply to scientific opinions under Article 58.
The following guidelines should be taken into consideration:
- Guideline on procedures for the granting of a marketing authorisation under exceptional circumstances, pursuant to article 14 (8) of regulation (EC) no 726/2004
- Guideline on the scientific application and the practical arrangements necessary to implement commission regulation (EC) no 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of regulation (EC) no 726/2004
- 26. What is the fee for an application under Article 58?
The eligibility request is free of charge and the same fees are applied for the assessment of products using Article 58 as for to the centralised procedure, since the same resources are needed. For more information, see the EMA Pre-Submission Procedural Advice, "What fee do I have to pay and how is the appropriate fee for my application calculated"?
In exceptional cases and when an opinion is required for imperative reasons of public health, total or partial fee exemptions may be granted by the EMA’s Executive Director on the recommendation of the CHMP. Fee waivers or fee reductions are granted after consultation of the CHMP.
Where an applicant disagrees on the classification of an application under one of the fee categories described in the Fee Regulation, an appeal should be sent to the Executive Director accompanied by the appropriate justification, as early as possible, and not later than three months prior to the anticipated date of submission of the application. The Executive Director will take a decision following consultation with the CHMP.
- 27. Is a pharmacovigilance system and risk management plan needed?
In principle, the same requirements for pharmacovigilance systems and risk management plans (RMPs) apply for applications under Article 58 as for centrally authorised products and it has to be adapted to the patients and countries where the medicinal product is intended to be used.
The detailed description of the pharmacovigilance system needs to be submitted at time of application in module 1.8.1. An RMP should also be submitted in module 1.8.2 for the following types of application:
- products containing a new active substance;
- similar biological medicinal products;
- generic or hybrid medicinal products where a safety concern requiring additional risk minimisation activities has been identified with the reference medicinal product;
- new dosage forms, routes of administration or manufacturing process of a biotechnologically-derived product;
- when there is a significant change in indication.
For all other type of applications, the need for a RMP submission should be checked well ahead of the submission with the EMA.
Additional risk minimisation measures are required in situations when positive benefit/risk would not be achievable without them. Therefore, no positive Article 58 opinion can be adopted in such a situation.
Opinion Holder, in agreement with the competent authorities of the countries where the product is marketed, should inform the EMA of any deviation to the submitted description of the Pharmacovigilance system and Risk Management Plan, and should provide the reason for such deviations. The CHMP may revise its opinion based on this information.
- 28. Do applicants need to provide an environmental risk assessment in the target markets?
No, an environmental risk assessment (ERA) is not needed for applications under Article 58. However, applicants are encouraged to provide a justification for the lack of an ERA in the application at the time of submission, as appropriate.
For information on the environmental risk assessment see Guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00).
- 29. What information should be provided on the manufacturer in an application?
In the notification of intention to submit, applicants should mention the names, contact points and addresses of the proposed manufacturers of the active substances and finished product. The sequence of all different sites involved should be clearly described in a flowchart.
In the application form, applicants should list the drug products under section 2.5.2 Batch control/Testing arrangements, and all manufacturers involved in all steps of the manufacturing of each active substance in section 2.5.3 Manufacturer(s) of the active substance(s).
During the 210-day review, the addition of a new manufacturing site or a change to the steps of manufacture or batch release described in the application form are not permitted. Such changes should be submitted as variation applications after the adoption of the scientific opinion.
The information on manufacturing sites submitted in Module 1.2 of the application must be consistent with module 3. All the manufacturing/batch release sites mentioned in module 3 must be listed in Module 1.2 and the activities carried out at each.
All sites involved in the production of the finished medicinal product and of the active substance should be described (name and detailed address, including building reference) in the application form of for a Article 58 Scientific Opinion together with a description of the steps performed. This should include:
- active substance manufacture
- bulk medicinal product manufacture
- diluent/solvent manufacture (if any)
- manufacture of any other associated medicinal product
- finished product manufacture and packaging
- any contract manufacturing sites
- any contract laboratories used for testing the finished product
For third country manufacturers, information about any previous EEA inspection in the last 2-3 years (with, if possible, a copy of the inspection report) and/or any planned EEA inspection(s) should be provided and should include details of the inspection dates, product category inspected and the name of the inspecting competent authority.
The following documents should be attached to the application form:
For all sites in the EEA, other than active substance manufacturers, copies of the "Manufacturing Authorisation" authorising the sites involved in the manufacture, importation, control and /or testing and Qualified Person release of batches of the medicinal product.
For all sites other than active substance manufacturers, located in third countries where a Mutual Recognition Agreement is in place, a MRA certificate, not older that 3 years, from the local competent authority that carried out the inspection and/ or a GMP certificate from the EEA inspecting competent authority if the site has been inspected by an EEA competent authority in the last 2-3 years.
For all sites other than active substance manufacturers, located in third countries with no Mutual Recognition Agreement, GMP certificate from the EEA inspecting competent authority if the site has been inspected by an EEA competent authority in the last 2-3 years.
For the sites that have not been inspected by an EEA competent authority in the last 2-3 years, it might be useful to provide copy of the annual registration or other document from the local competent authority demonstrating that the site is authorised for manufacture of the product/pharmaceutical form.
A flow-chart describing all the main steps involved in the manufacture of the active substance and finished product.
A full justification on public health and/or technical grounds of any proposed multiple importing and batch release sites.
A document identifying the contact person responsible for any quality issues including its contact details.
Product defects and recalls:
The Opinion Holder should report to the competent authorities of the countries where the product is marketed and inform the EMA about any defect in a medicinal product that could result in a recall or abnormal restriction in supply, together with the corrective actions proposed. In cases where the quality issues cannot be resolved, the CHMP may revise its opinion.
- 30. Do products need to be tested by an Official Control Laboratory before they are released for sale?
The CHMP may recommend that certain products need testing before they are released for sale, if it would be in the interest of public health. Testing may be required for a live vaccine, an immunological product or a medicinal product derived from human blood or human plasma.
If testing is needed, the opinion holder will be requested to submit samples from each batch of the bulk or medicinal product before release onto the market for testing by an EU official medicines control laboratory (OMCL). A batch of a medicinal product must not be placed on the market until the OMCL has examined the batch in question and declared it to be compliant with the approved specifications by issuing a certificate of batch compliance.
EU OMCLs are appointed by the European Directorate for the Quality of Medicines (EDQM) based on their competencies and workload. The CHMP provides list of key tests to be carried out by an EU OMCL as part of the scientific opinion. The OMCL should complete testing within 60 days after they have received the sample. If the product is compliant, the EDQM provides a European Community certificate of batch compliance to the applicant, who then provides the competent authority of the international area with a copy of the certificate for their formal acceptance.
- 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
- News of the European Directorate for the Quality of Medicines - Pharmacopoeia on the WWWEU Control Authority Certification of compliance
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