New ASMF - Aim to support and improve the ASMF procedure across the European Regulatory Network

EMA has released the new ASMF guideline, which is effective from 1 October 2012. 

Updates: 

• ASMF holders shall not modify the contents of their ASMF (e.g. manufacturing process or specifications) without informing each Applicant/MA holder and each National Competent Authority/EMA. This obligation remains valid until the Letter of Access has been withdrawn by the ASMF holder. ASMF holders should provide the updated ASMF to all interested Authority/EMA. This obligation remains valid until the Letter of Access has been withdrawn by the ASMF holder. ASMF holders should provide the updated ASMF to all interested parties with reference to the revised version number.

• Any change to the ASMF should be reported by every MA holder to the relevant National Competent Authority/EMA by means of an appropriate variation procedure. A Submission Letter should be provided.

• In cases where the contents of the ASMF cannot be changed for a certain period of time because of other procedural provisions (i.e. mainly because of on-going MRP procedures), the ASMF holder should still provide the aforementioned data to the MA holder and National Competent Authorities/EMA making reference to this reason and requesting a later date of implementation. 

• At the occasion of the 5-year renewal of a medicinal product, MA holders are required to declare that the quality of the product, in respect of the methods of preparation and control, has been regularly updated by variation procedure to take account of technical and scientific progress, and that the product conforms with current CHMP/CVMP quality guidelines. They will also declare that no changes have been made to the product particulars other than those approved by the Competent Authority/EMA.

• MA holders should therefore verify with their ASMF holders whether the above declaration can be met in respect to the active substance particulars. In case changes have not been notified to the MA holder and National Competent Authority/EMA, the necessary variation procedure should be initiated without delay.

Reference: Guideline on Active Substance Master File Procedure

Article 58 Applications

 

Medicinal products for human use are eligible for evaluation under Article 58 of Regulation (EC) No. 726/2004 if the are intended exclusively for markets outside the community. Eligible products include medicines that are intended for the prevention or treatment of disease of major public interest.

Following products are eligible for Article 58 of the Regulation (EC) No 726/2004:

• Vaccines that used in the WHO Expanded Program of 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 disease such as HIV/AIDS, malaria, tuberculosis, lymphatic filarisis, trachoma, leishmaniasis, schistomiasis, African trypansomiasis (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 authorized in the European Union, fixed combination products and generic products. 

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

Eligibility request includes the following information:

• Evidence that the applicant is based in the European Economic Area (EEA).
• A draft summary of product characteristics (SmPC).
• A justification for product's eligibility for a 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. 
• 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".

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 CHMP then examines the eligibility for evaluation under Article 58, confirming or not confirming the WHO' position as appropriate. The applicant receives the WHO "eligibility feedback" letter and the EMA/CHMP eligibility letter. 

Types of applications:

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

• Full complete (or full/mixed) applications
• Well-established use applications
• New fixed combination applications
• Informed consent applications
• Generic applications
• Hybrid applications
• Similar biological applications

Time period

The evaluation procedure follows the same steps and time-frame as the centralsied procedure. As the evaluation is a partnership between the EMA and WHO, WHO experts provide input to the procedure. Total time for evaluation is takes 300 days.

Reference:

1. Guideline on Procedural aspects regarding a CHMP scientific opinion in the context of cooperation with the World Health Organisation (WHO) for the evaluation of medicinal products intended exclusively for markets outside the community.

Referral Procedures

A medicinal product can only be placed on the market in the European Union (EU) when a marketing authorisation (MA) has been issued. There are different types of procedures, national authorisation, centralised procedure (CP), mutual recognition (MRP) and decentralised procedure (DCP). If a MA has granted for particular product by CP, applicant can launch product in entire community at same time. If a MA has granted by particular member state, product can launch in own territory only.

If no MA has been granted in the Community, the applicant can also make use of a DCP and submit an application in all the MSs where he intends to obtain a MA at the same time, and choose one of them as reference MS. The decentralised procedure is to be used in order to obtain marketing authorisations in several Member States where the medicinal product in question has not yet received a marketing authorisation in any Member State at the time of application.

In cases where national authorisations are requested for the same medicinal product in more than one Member State (MS) and the applicant had already received a marketing authorisation in a MS, the applicant can submit an application in the MS concerned using the procedure of mutual recognition. The MSs concerned should then recognise the MA already granted by the reference MS and authorise the marketing of the product on their national territory.

In centralised procedure, product information (SmPC, Labelling and Package leaflet) of the community marketing authorization is same in all countries. But in case of other procedures (DCP & MRP), potential differences are there in product information due to divergent decisions taken by some member states (i.e. medicinal product is approved in different indications in several MSs), could have an impact on the final marketing authorization and free movement of goods in European union.

There are several procedures that involved parties (i.e. MSs, applicant/MAH, the European Commission) have through a referral to address such heterogeneity of MAs and resulting prescribing information following authorisation (via national procedure or MRP) or prior to authorisation (via MRP or DCP), in order to achieve harmonisation of such information.

A referral is an European procedure that allows to address any concerns related to a medicinal product via an arbitration mechanism leading to an EU-wide, binding decision. When a Member State (MS), Applicant, Marketing Authorisation Holder (MAH) or the European Commission (EC) decides to initiate a referral, a notification form is sent to the CHMP/European Medicines Agency Secretariat, clearly identifying its legal basis, the product(s) concerned and a detailed explanation of the issue(s) referred.

Types of Referrals - Legal basis

From Directive 2001/83/EC
Article 29(4) referral ("Mutual Recognition and Decentralized Referral"):  If the MS involved in a MRP/DCP fail to reach an agreement within the 60-day period in the coordination group procedure, a referral according to Article 29(4) shall be triggered. The referral is then triggered by the reference MS in the MRP, on the grounds of potential serious risk to public health, where no agreement was reached during the coordinating group procedure on the assessment report (AR), the SmPC, the labelling or the Package Leaflet (PL), prepared by the Reference Member State (RMS)

Article 30 referral ("Divergent Decision Referral"): An article 30 (1) referral may be initiated when divergent decisions have been adopted by MSs concerning the authorization, suspension or withdrawal of a particular product. For example, where such medicinal product has been nationally authorized in two or more MSs and the authorization diverge (e.g. different indications, contraindications or posology). It may be triggered by the EC, a MS, a MAH or an Applicant.

An article 30(2) referral may be initiated for the same reasons stated above when the medicinal product is on the list laid down yearly by the coordination group.

Article 31 referral ("Community interest referral"): It may be initiated in specific cases where the interest of the community is involved. The expression 'Community interest' has a broad meaning but it refers particularly to the interests of the public health in the Community, for example following concerns related to the the quality, efficacy and/or safety of a medicinal product or new Pharmacovigilance information.

Article 31(1) referral relates to a medicinal product while article 31(2) referral refers to a class/range to medicinal products. Both may be triggered by the EC, a MS, a MAH or an Applicant.

Article 35 and 36 ("Follw-up referrals"): An article 36 referral my be initiated to resolve any post-harmonization divergences that may arise between MSs. It may be triggered by a MS when it is considered that a variation, suspension or withdrawn of a harmonized Marketing Authorization (MA) is necessary for the protection of public health.
These referrals may be triggered by MSs or MAH in the frame of follow-up procedure for medicinal products which have been granted a MA via MRP or which have been subject to complete harmonization in  the frame of a referral procedure.
Article 107 ("Unilateral action by MS in Urgent cases"):  This type of procedure is triggered when a Member state varies, suspends or revokes the marketing authorization for a medicine in its territory because of a safety issue. It informs the CHMP so that a EU-wide decision can be reached.
From Regulation (EC) 1084/2003
Article 5(11): This type of referral is triggered for a medicine that has been authorized by mutual recognition or via the dcentralised procedure when there is disagreement between member states on a variation (type IB)
Article 6(12) and 6(13): This type of referral is triggered for a medicine that has been authorized by mutual recognition or via the decentralised procedure when there is disagreement between Member states on a variation (Type II)
Article 6(12) ------------------------>May be triggered by a MS.
Article 6(13)------------------------>May be triggered by the MAH.
From Regulation (EC) 726/2004
Article 20: This type of procedure is triggered for the medicines that have been authorized via the centralsied procedure.The outcome of these procedures is published with the European public assessment report for the medicine.
From Regulation (EC) 1901/2006:
Article 29 (Paediatric): This type of procedure may be triggered by a marketing authorization holder when applying for a new indication, new pharmaceutical form or new route of administration for use in the paediatric population a product authorized under directive 2001/83/EC.
From Regulation (EC) 1234/2008:
Article 13: This type of referral is triggered for a medicine that has been authorized by mutual recognition or via the decentralized procedure when there is disagreement between MSs on a variation (Type II).

Reference:

1. Chapter 3 : Community referral Procedures, The Notice to Applicants Volume 2A Procedures for marketing authorization
2. Referrals procedures

Informed Consent Applications

Informed Consent Application - Article 10c of Directive 2001/83/EC

An Informed consent application is an application according to Article 10c of Directive 2001/83/EC as amended.

Definition: 

Following the granting of a marketing authorisation (Reference product), the authorisation holder may allow use to be made of the pharmaceutical, preclinical and clinical documentation contained in the file on the medicinal product, with a view to examining subsequent applications relating to other medicinal products possessing the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form.

Reference Product: 

Marketing authorisation for a medicinal product supported by a complete dossier. (Reference product cannot be based on an Article 10 application)

Criteria:

• The marketing holder for the reference product has consented that the applicant could refer to all three modules containing the pharmaceutical, preclinical and clinical data for the reference product.
• The product applied for must have the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form as the reference product.
• An informed consent application can only be submitted in Member States where the reference product is authorised, i.e. the application cannot be submitted in parallel to the application for the reference product.
• The authorisation of the informed consent application should follow the same authorisation route as the initial authorisation. Therefore a national, MRP or DCP informed consent application cannot refer to a centralised approved medicinal product.
• The applicant for the second product must during the lifetime of the product have permanent access to the references in the documentation for the reference product or be in possession of this information.
• If an Active Substance Master File (ASMF) has been used for the reference product a new letter of access should be included in the application for the second product.
• The applicant could be the same as the marketing authorisation holder for the reference product or not.
• The two products must have different tradenames.
• The informed consent application is not legally obliged to cover all pharmaceutical form(s)/strength(s) of the reference medicinal product.

Dossier Requirements:

Dossier Requirements varies from one member state to other member state. As per HMA recommendation, the applicant is advised to contact the national competent authorities regarding dossier requirements.  

UK - MHRA Requirements:

• Module 1
• Informed consent letter
• Manufacturers of active ingredient and finished product 
• If using a contracted service to submit the application, include a letter of access for direct communication concerning the application
• Letter confirming the company has access to all of the data supporting the application and is in possession of the quality section of the dossier  
• If the product manufacturer is not the applicant, a letter from the manufacturer confirming that they are prepared to manufacture the product on the applicant’s behalf.
• Suppliers statements concerning TSE risk (e.g. lactose, glycerol).
• Detailed Description of the Pharmacovigilance System.

Ireland - IMB Requirements:

• A completed application form
• A Letter of access form the Marketing Authorization holder of the reference product consenting that the dossier of that product may be used for examining the application in question
• 3 copies of Module 1
• Electronic copy of SPC on disk, CD or by email to IMBReceiptsandvalidation@imb.ie
• A completed Fee Application Form

Further Reference:

1. Better Regulation of Medicines: National informed consent (Article 10c, simple abridged) applications

2. IMB - Frequently Asked Questions

3. Informed Consent Applications in Mutual Recognition and Decentralized Procedures Recommendations