Q&A: 1-15

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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.

Note:
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).

Additional documents:

Questions and Answers will be updated progressively, and will be marked by "New" or "Rev." upon publication.

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1. Which medicinal products are eligible for evaluation under Article 58 of Regulation (EC) No 726/2004?

Medicinal products for human use are eligible for evaluation under Article 58 of Regulation (EC) No 726/2004 if they are intended exclusively for markets outside the Community. The Article responds to the need to protect public health and to give scientific assistance in the context of co-operation with the World Health Organization (WHO), whilst allowing rapid access to medicinal products in countries outside the Community.

Eligible products include medicines that are intended for the prevention or treatment of diseases of major public interest. They include but are not limited to1:

  • vaccines that are or could be used in the WHO Expanded Program on Immunization (EPI);
  • vaccines for protection against a WHO ‘public health priority disease’;
  • vaccines that are part of a WHO-managed stockpile for emergency response;
  • medicinal products for WHO target diseases such as human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), malaria, tuberculosis, lymphatic filariasis (elephantiasis), trachoma, leishmaniasis, schistosomiasis, African trypanosomiasis (sleeping sickness), onchocerciasis (river blindness), dengue fever, Chagas disease, leprosy and intestinal helminths.

Eligible products can include new pharmaceutical forms or routes of administration of medicinal products already authorised in the European Union, fixed combination products and generic products.

Applicants need to request eligibility for evaluation under Article 58 for a medicinal product before submitting an application. The EMA’s Committee for Medicinal Products for Human Use (CHMP), evaluates data on the quality, safety and efficacy of the product contained in the application in collaboration with the WHO, before issuing a scientific opinion concluding on the benefit-risk ratio of the product.

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1 Clarification should be sought from the EMA if necessary.

2. How are requests for eligibility submitted?

The eligibility request which is free of charge is made using the eligibility form, sent to the following address: article58@ema.europa.eu andcpeligibility@ema.europa.eu.

This request includes the following information

  • evidence that the applicant is based in the European Economic Area (EEA), or information of a contact point within the EAA;
  • a draft summary of product characteristics (SPC) or a product profile;
  • a justification for the product’s eligibility for evaluation under Article 58. It is recommended that any available epidemiological data on the disease, data on disease burden and a summary of any efficacy or safety data also be submitted;
  • a statement that the applicant does not intend to market the medicinal product in the European Economic Area (EEA);
  • the proposed classification for the supply of the medicinal product, i.e. not subject to medical prescription or subject to medical prescription (renewable or non-renewable);
  • a list of the countries in which the applicant intends to market the product;
  • a declaration from the applicant agreeing on communication between the EMA and the WHO using the template “Agreement between EMA and the Applicant”;
  • a justification or rationale for a shorter evaluation review, if appropriate.

Confirmation of eligibility is needed before an applicant submits an application for a CHMP scientific opinion. The request should be submitted at least seven months prior to submission of the application. Confirmation is also recommended in advance of a request for scientific advice on the development of the product.

Once eligibility has been confirmed, an applicant can request a pre-submission meeting in order to obtain guidance on the procedure.

References:

3. How is eligibility assessed?

The eligibility of a product for evaluation under Article 58 is assessed on a case-by-case basis by the EMA in consultation with the WHO.

Once the EMA have received the eligibility request by the applicant it is sent to WHO. Within two months of the submission of the eligibility request, the WHO forwards its position to the EMA. The EMA’s Committee for Medicinal Products for Human Use (CHMP) then examines the eligibility for evaluation under Article 58, confirming or not confirming the WHO’s position as appropriate. The outcome of the assessment is sent to the applicant after the next CHMP plenary meeting. The applicant also receives the WHO “eligibility feedback” letter and the EMA/CHMP eligibility letter. If eligibility is refused, the reasons for this are stated.

If a large number of applications is received by the EMA, WHO can prioritise applications, with the highest priority applications being dealt with first.

4. How long is eligibility valid for?

The eligibility of a medicinal product for evaluation under Article 58 is not expected to change once agreed upon, because it is based on the need to protect public health in developing countries, which is unlikely to change between the eligibility request and the submission of the application.

In case there is a long delay between the eligibility request, i.e. more than 2-3 years, and the submission the applicant may be requested to resubmit the eligibility request at the time of notification of intention to submit. Further, where the epidemiological situation or environment changes, the applicant is strongly advised to request reconfirmation of eligibility by the EMA and WHO.

5. Does the applicant need to be established in the EEA?

Applicants or their contact points must be established in the EEA, i.e. a Member State of the European Union (EU), Norway, Iceland or Liechtenstein. Evidence to support this must be provided both at the time of submitting an eligibility request and at the time of submission of the application (in Annex 5.3 of the application form).

References:

6. Can applicants ask for scientific advice?

Yes, Article 58(2) makes provision for scientific advice on medicinal products intended to be marketed exclusively outside the Community. Scientific advice is given by the CHMP’s Scientific Advice Working Party (SAWP) in response to scientific questions concerning quality, non-clinical and clinical aspects. Applicants can request scientific advice during the initial development of a product, before an application for CHMP scientific opinion or after an opinion has been granted.

If an applicant is considering seeking scientific advice ahead of an application for a CHMP scientific opinion, it is recommended that the eligibility request is made at least four months prior to the application for scientific advice. However, if there is a long delay between the request for scientific advice and the application for a CHMP scientific opinion, i.e. more than 2-3 years, the applicant may be requested to resubmit the eligibility request at the time of notification of intention to submit.

The existing procedural guidance on scientific advice for medicinal products intended for use within the EU also applies to scientific advice on possible future applications for a CHMP scientific opinion under Article 58.

The timeframe for a standard scientific advice procedure is 40 days. This is extended to 70 days if there is a need for a face-to-face meeting with the applicant. Further information and a template for request are available on the EMA website ‘Scientific Advice and Protocol Assistance

7. How much does scientific advice cost?

The same fees for scientific advice apply for products to be evaluated under Article 58 as for the centralised procedure.

In exceptional cases, a total or partial waiver of the fee may be granted by the EMA’s Executive Director on the recommendation of the CHMP. Requests for waivers should be sent to the Executive Director with appropriate justification as early as possible, but not later than three months prior to the anticipated date of submission of the application for scientific advice.

References:

8. Can an applicant apply for small and medium-sized enterprise (SME) status?

Applicants can apply for status as a small and medium-sized enterprise (SME). The EMA has set up an ‘SME office’, which offers financial and administrative assistance to SMEs. Details of how to register as an SME with the Agency are available on the EMA’s website.

Although there are no fee reductions for Article 58 procedures per se for SMEs, there is a 90% fee reduction available to SMEs seeking scientific advice from the Agency. Applicants may also request regulatory assistance from the SME office.

9. What is the difference between scientific advice and a CHMP scientific opinion in collaboration with the WHO?

Scientific advice is a service whereby an applicant or opinion holder can ask questions to the CHMP regarding the development of a medicinal product. This advice can be sought either before or after the opinion, in order to confirm whether the CHMP agrees with the scientific strategy chosen. The outcome of a request for scientific advice allows the applicant or opinion holder to take the views of the CHMP into account when generating data that later will become part of an application for an opinion or an update to an existing opinion.

An Article 58 CHMP scientific opinion is an opinion issued by the CHMP, the scientific committee of the EMA, in collaboration with WHO. This opinion is based on the evaluation of an application containing data on the quality, safety and efficacy of the product, and concludes on the benefit-risk ratio of the product.

10. How are pre-submission meetings conducted?

Pre-submission meetings take place at the EMA. They allow applicants to obtain procedural, regulatory and legal advice from the EMA so that they can submit applications that conform with legal and regulatory requirements and that can be validated speedily. Pre-submission meetings also enable applicants to establish contact with the EMA staff who will be involved with the application as it proceeds.

For more information, please see: pre-submission procedural advice question "EMA Pre-Submission Flow-chart".

11. Do the requirements of the paediatric legislation apply to Article 58 applications?

The requirements of the paediatric legislation (Regulation (EC) No 1901/2006 as amended) do not apply to Article 58 applications. These requirements only apply to medicinal products authorised in the Community or intended to be authorised in the Community. There is therefore no requirement to provide results in accordance with agreed paediatric investigation plans (PIPs). However, as most medicinal products falling under the framework of Article 58 could be used in children, applicants are encouraged to discuss the development of these products for the paediatric population in a scientific advice procedure. Scientific advice on paediatric questions is free of charge.

12. What types of application can be submitted under Article 58?

The following types of application can be submitted under Article 58:

  • full complete (or full/ mixed) applications1;
  • well-established use applications2;
  • new fixed combination applications3;
  • informed consent applications4;
  • generic applications5;
  • hybrid applications6;
  • similar biological applications7.

The type of application needs to be identified in the application at the time of submission.

For further information on the different types of application see Notice to Applicants, Volume 2A, Chapter 1, section 5.


1 As described in Article 8(3) of Directive 2001/83/EC.
2 As described in Article 10(a) of Directive 2001/83/EC.
3 As described in Article 10(b) of Directive 2001/83/EC.
4 As described in Article 10(c) of Directive 2001/83/EC.
5 As described in Article 10(1) of Directive 2001/83/EC.
6 As described in Article 10(3) of Directive 2001/83/EC.
7 As described in Article 10(4) of Directive 2001/83/EC.

13. How are dossiers submitted?

For information on how to submit a dossier, please see: Pre-Submission Procedural Advice "How and to whom shall I submit my dossier?" and "What are the names and addresses of the CHMP members?"

For evaluations under Article 58, applicants are also responsible for sending a copy of modules 1 and 2 of the dossier to any WHO experts and observers appointed at the start of the procedure. They also need to send a copy of any other relevant documentation produced during the procedure, such as responses to lists of questions or lists of outstanding issues.

It is strongly recommended that dossiers be submitted electronically if possible. Please see: EMA Pre-Submission Procedural Advice "Can I submit electronic copies of my dossier?". For the latest information regarding e-submission please see the e-submission webpage.

For the dates of CHMP meetings please see: EMA Pre-Submission Procedural advice, "What are the dates of the CHMP meetings".

For information on when the application should be submitted, please see: EMA Pre-Submission Procedural Advice "When to submit the Marketing Authorisation Application?"

14. What format should dossiers be in?

The Common Technical Document (CTD) format is preferred. The old NTA format is acceptable, provided that the applicant supplies appropriate justification for its use.

For information on the CTD format see Notice to Applicants Volume 2B.

15. Do I need an invented name for my medicinal product?

In principle, invented names are not required for “Article 58” medicinal products as the medicinal is exclusively intended to be used outside the Community.

References:

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