THE REGULATORY FILING MA FOR FORMULATIONS IN THE EU

 

 

THE REGULATORY FILING MA  FOR FORMULATIONS IN THE EU

 What is the process for regulatory filings for formulations in the EU?

• What are the costs involved & the usual timeline for approval?

Either the European Medicines Agency (EMA) or a national Competent Authority considers the dossier submitted by the applicant and determines whether or not to grant a Marketing Authorization.

There are a number of different types of applications, depending on the nature of the medicinal product’s active ingredient (e.g., whether it is new or whether it has been marketed previously). Furthermore, Marketing Authorizations may be amended or renewed, and again.

Applicants must prove the quality, safety, and efficacy of the medicinal product by submitting particulars and documents relating to the results of pharmaceutical (physico-chemical, biological, or microbiological) tests, as well as pre-clinical (pharmacological and toxicological) tests and clinical trials carried out on the medicinal product to be placed on the market.

The 2001 Directive applies to all medicinal products that are authorized by national procedures or the mutual recognition procedure (MRP) relating to medicines for human use; this Directive has itself been amended several times since coming into force. Fundamentally, the Directive provides that no medicinal product may be placed on the market of a Member State unless a Marketing Authorization has been granted by the Competent Authority of that Member State for its own territory, or a Marketing Authorization has been granted by the EC for the entire EU. It sets out in detail all the processes that must be undertaken in order to bring a medicinal product to market, including the form of the application of a Marketing Authorization and the iterative review process whereby the application is reviewed, assessed, and, if necessary, amended.

Article 8(3) of Directive 2001/83/EC contains the requirements for an application for Marketing Authorization (regardless of the procedure to be followed). The application and accompanying documents must be presented in accordance with Annex I of Directive 2001/83/EC and must follow the guidance published by the Commission in the Notice to Applicants, Volume 2B, Common Technical Document (CT Doc).

All four Marketing Authorization procedures require the submission of comprehensive safety and efficacy data, followed by an approval process conducted by the regulatory authority that grants the Marketing Authorization. Article 8 of Directive 2001/83/EC provides that the contents of each application will be very similar, with the submission of a safety and efficacy dossier, which will include the results of pre-clinical and clinical trials, a ‘common technical document’ (CTDoc), which is now in an internationally recognized form, a summary of product characteristics (SmPC), and other information relevant to the Marketing Authorization application.

Article 10 of the Directive provides a simplified procedure for certain generic products.

 The first step in bringing a medicinal product to the market is the consideration of which Marketing Authorization procedure to adopt.

 There are four different Marketing Authorization procedures within the EU:

(1) Centralized procedure (CP): the Commission grants the Marketing Authorization, which will be valid in all Member States. The CP is compulsory for certain types of products and orphan drugs, and it is optional for new active substances that were not available prior to the enactment of Regulation (EC) 726/2004 (20 April 2004 and 20 May 2008, depending upon the disorder treated by the medicinal product).

(2) Mutual recognition procedure (MRP): national Marketing Authorizations are granted in the Member States chosen by the applicant. The Marketing Authorizations are issued following assessment by the Reference Member State (RMS) and reports to the Concerned Member State (CMS). They are based on mutual recognition of the RMS assessment.

(3) Decentralized procedure: this is available before a Marketing Authorization is issued by a Member State, but in many other respects it is procedurally similar to the MRP.

(4) National procedure: this is only now used in very limited circumstances and, as its title now used suggests, is carried out on a Member-State-by-Member State basis.

Options for Pharma companies for filing MA :The decision as to which procedure to use depends on whether the applicant wishes to market the medicinal product in one or more Member States or throughout the whole EU, and whether the medicinal product itself has certain properties or is used to treat specific disorders. In addition, each Marketing Authorization procedure offers various advantages. For example, the CP is used most often by the larger pharmaceutical companies that wish to market products on a global basis. The national procedure may still be preferred by small- and medium-sized enterprises (SMEs) who only wish to market the product in their own Member State. It should be noted that although there are differences in the process among the four procedures, the requirements regarding quality, safety, and efficacy of the medicinal product and the procedures to bring the product to market are the same.

• Required Contents of an Application Dossier

 All information that is relevant to the evaluation of the medicinal product, whether favourable or unfavourable, must be included in the application. For example, the details and information prescribed in Article 8(3) must be provided for any incomplete or abandoned pharmaco-toxicological clinical trial or test relating to the medicinal product, and/or completed trials concerning therapeutic indications not covered by the application.

• Article 8(3) and Annex I of Directive 2001/83/EC contain the legal requirements for making a Marketing Authorization application; they include the following:
• name of the applicant, address of the applicant,
• name of the manufacturer, address of the manufacturer,
• sites involved in the different stages of the manufacture (including the manufacturer of the finished product and the manufacturer(s) of the active substance(s)), and
• name and address of the importer;
• name of the medicinal product, name of the active substance, strength of the medicinal product, final presentation – including packaging, identification of the type of application, indication of what samples (if any) are provided, and copies of Manufacturing Authorizations;
• qualitative particulars of all the constituents of the medicinal product, quantitative particulars of all the constituents of the medicinal product, reference to the international non-proprietary name (INN), or a reference to the relevant chemical name of the medicinal product;
• description of the manufacturing method;
• therapeutic indications, contra-indications, and adverse reactions;
•  dose, pharmaceutical form, method of administration, route of administration, and expected shelf life;
• reasons for any precautionary and safety measures to be taken for the storage of the medicinal product, its administration to patients, and for the disposal of waste products, together with an indication of any potential risks presented by the medicinal product to the environment (if the medicinal product constitutes a genetically modified organism (GMO), further information must be provided);
• description of the control methods employed by the manufacturer;
• results of pharmaceutical (physicochemical, biological, or microbiological) tests, results of pre-clinical (pharmacological and toxicological) tests, and results of clinical trials;
•  the SmPC, one or more mock-ups of the outer packaging, primary packaging, and the package leaflet.

• Applications for a Marketing Authorization are to be accompanied by the name or corporate name and permanent address of the applicant for the Marketing Authorization (and, if applicable, the manufacturer).
• The Marketing Authorization holder may be a natural or legal person and must be established (with a permanent place of business or home) in the Community, including the European Economic Area (EEA).
• Where the manufacturer is not the Marketing Authorization holder (or applicant), both the Marketing Authorization holder and the manufacturer must sign a written agreement to guarantee that the manufacturer’s operations comply with the rules (namely GMP and any local requirements) in force, and with the manufacturing conditions described in the dossier. This is usually in the form of a technical agreement between the parties.
• If the site of manufacture of the medicinal product is outside the EU, the Qualified Person must ensure that each imported batch has undergone, in the importing country, the testing specified in paragraph 1 (b) of Article 51. For medicinal products manufactured within the EU, a Qualified Person must ensure that each batch has been produced and tested/checked in accordance with the directives and the Marketing Authorization.

1. THE CENTRALIZED PROCEDURE

 Scope :

The centralized procedure leads to a European Marketing Authorization that allows the Marketing Authorization holder to market its medicinal product throughout the EU. The centralized procedure is mandatory for medicinal products that are specified in the Annex to Regulation (EC) No. 726/2004.

 For some medicinal products, the centralized procedure is optional. It is an efficient system in that one SmPC can be used across the EU and a Marketing Authorization holder can use a single name for a medicinal product marketed throughout the EU. Applicants must identify at an early stage an invented name that is valid throughout the whole EU. In exceptional cases, the Commission may authorize the use of a different invented name in a Member State where the invented name has been cancelled, opposed, or objected to on the grounds of trademark law.

Advantages: One disadvantage of the centralized procedure is that the fees payable to the EMA to obtain Marketing Authorization through this procedure are high. In addition, although it is intended that a Marketing Authorization should be brought smoothly and efficiently to all Member States simultaneously, it is possible that objections from one or more Member States can delay the introduction of a new medicinal product in all Member States.

• Applications for the CP are submitted to the EMA. The CHMP conducts the scientific evaluation, and upon receiving the EMA’s opinion, the European Commission grants a Marketing Authorization for the entire EU.
• Application Procedure: The application dossier for the CP must be submitted to the EMA. Strict timetables have been established to ensure that the aims of speed and efficiency are achieved. The packaging of a medicinal product registered using CP must state the European registration number, which commences with ‘EU’.
• Approval Procedure Applications for a centralized Marketing Authorization: It must be submitted to the EMA. The application must contain specific information and documents.

In addition, the documents must include a statement that any clinical trials carried out outside the EU meet the ethical requirements of Directive 2001/20/EC. The application must designate a single name for the medicinal product. To market the product under more than one invented name in different Member States, duplicate applications can be made with different names. The application must also include the fee payable to the Agency for the examination of the application.

• The risk/benefit ratio of the medicinal product: is determined by the CHMP. The CHMP has a maximum of 210 days to reach a final decision. This period may be interrupted if the CHMP requests supplementary information or gives the applicant the opportunity to answer questions. In addition, both the CHMP and the applicant have the opportunity to request that the applicant provide a verbal explanation of the submitted data at an oral hearing.
• Timelines: Within fifteen days of the receipt of the opinion from the CHMP, the Commission prepares a draft of the decision regarding the application.

If the draft decision is not in accordance with the opinion, the Commission must annex a detailed explanation of the reasons for the differences.

The Commission sends the draft decision to the Member States and the applicant.

The Commission has a month to organize its decision-making management board, which must arrive at a final decision fifteen days after the end of its decision-making process.

 The Commission sends the final decision to CHMP.

If the CHMP concludes that an application does not satisfy the criteria for authorization, the EMA must immediately inform the applicant.

A Marketing Authorization must be refused if it appears that, after the submission and consideration of the application dossier, the applicant has not properly or sufficiently demonstrated the quality, safety, or efficacy of a medicinal product.

• Marketing Authorizations granted: via the CP are published in the Official Journal of the European Union.

The publication contains: – the date of authorization of the Marketing Authorization.

 The registration number under which the Marketing Authorization is registered in the Community Register.

Any INN of the active substance of the medicinal product that is the subject of the Marketing Authorization.

The pharmaceutical form of the medicinal product

Any Anatomical Therapeutic Classification (ATC) given to the medicinal product.

• Timelines kick in before EMA
• Start the procedure.
• Days 80: CHMP members and EMA receive the Assessment Report(s) or critique from the rapporteur and co-rapporteur(s).

EMA sends rapporteur and co-rapporteur Assessment Report/critique to the applicant, making it clear that it only sets out the preliminary conclusions, and that it is sent for information only and does not yet represent the position of the CHMP.

• Days 100: Rapporteur, co-rapporteur, other CHMP members, and the EMA receive comments from members of the CHMP (including peer reviewers).
• Days 115: CHMP members and the EMA receive a draft list of questions (including the CHMP recommendation and scientific discussion) from rapporteur and co-rapporteur, as discussed with the peer reviewers.
• Days 120: CHMP adopts the list of questions as well as the overall conclusions and review of the scientific data to be sent to the applicant by the EMA.

 Clock stops. At the latest, by day 120, adoption by the CHMP of request for GMP/GLP/GCP inspection, if necessary (and the inspection procedure starts).

• Days 121: Submission of the responses by the applicant, including revised SmPC labelling and package leaflets texts in English, and restart of the clock.
• Days 150: Joint Response Assessment Report from rapporteur and co-rapporteur received by CHMP members and the EMA.

The EMA sends a joint Assessment Report to the applicant, making it clear that it only sets out the preliminary conclusions, and that it is sent for information only and does not yet represent the position of the CHMP. Where applicable, an inspection is to be carried out. EMA/QRD98 subgroup meeting for review of English product information with the participation of the applicant (optional).

• Days 170: Deadline for comments from CHMP members to be sent to rapporteur and corapporteur, the EMA, and other CHMP members.
• Days 180: CHMP discussion and decision on the need for adoption of a list of ‘outstanding issues’ and/or an oral explanation by the applicant.

 If an oral explanation is needed, the clock is stopped to allow the applicant to prepare for the oral examination.

The inspection team submits the final inspection report to the EMA, the rapporteur, and the co-rapporteur team (at the latest by Day 180).

• Days 181: Restart the clock and oral explanation (if needed).
• Days 181 to 210: Final draft of English SmPC, labelling, and package leaflet sent by the applicant to the rapporteur and co-rapporteur, the EMA, and other CHMP members.

By 210 Adoption of the CHMP Opinion and CHMP Assessment Report (and timetable for the provision of product information translations).

1. MUTUAL RECOGNITION PROCEDURE

 Introduction:  The MRP is used when one Member State, the RMS, has already assessed and granted a Marketing Authorization on the basis of a national application to the applicant.

• The MRP may be used on multiple occasions to obtain Marketing Authorizations in additional Member States.
• This ‘repeat use’ authorization may be required when new Member States join the EU or follow a successful decentralized procedure application.
• For instance, when the decentralized procedure has been used in countries where six-year data exclusivity is permitted, a subsequent MRP has been used to obtain Marketing Authorizations for the same product in countries where ten-year data exclusivity applies, until such time as the six- to ten-year disparity in data exclusivity no longer applies.
• For applications made after October 2005, the 8 + 2 + 1 data exclusivity regimen applies. The CMD(h) examines questions relating to Marketing Authorizations of medicinal products in two or more Member States under the MRP or decentralized procedure, thereby making the procedure more efficient.
• A CMS is permitted to raise objections to the Marketing Authorization of a medicinal product on the grounds that it poses a ‘potential serious risk to public health’.
• Although Member States have accepted general EU rules on quality, safety, and efficacy of medicinal products, non-compliance with these rules does not necessarily mean that the product poses a ‘potential serious risk to public health’.
• The Commission’s guidelines impose a higher threshold. A ‘potential serious risk to public health’ may be considered to exist in the following circumstances: – where there is no sound scientific justification to support the claims for efficacy; – where there is not enough evidence to show that all potential safety issues have been appropriately and adequately addressed; – where production and quality control mechanisms may be inadequate.
• The RMS will have already prepared an assessment report prior to the issuance of a Marketing Authorization through the national procedure.
• The assessment report (including SmPC, labelling, and package leaflet) on the medicinal product of the RMS forms the basis for requesting the other CMS to mutually recognize and acknowledge the Marketing Authorization.
• Once the assessment report has been updated, the applicant submits separate copies of the application and accompanying report to the CMS.
• The application is a consolidated file, as it takes into account updates in the assessment report since the Marketing Authorization was issued under the national assessment.
• Timelines kick in
• Day 1: Submission of application to CMS by RMS.
• Days 50: CMSs submit comments/objections to RMS and applicants.
• Days 60: Applicant responds to comments.
• Days 68: RMS circulates its assessment of the applicant’s response.
• Days 90: Consensus ideally reached, after discussion, between RMS, CMS, and applicant. If the procedure is concluded and consensus is reached, the national phase of national Marketing Authorization grants follows (submission of translations by applicant); the national product Marketing Authorizations will be granted within thirty days of the closure of the MRP. If no consensus, points of contention are referred to the CMD(h) within seven days.
• Days 150: Consensus ideally reached, but if objections remain, issues are referred to the CHMP for arbitration.

1. DECENTRALIZED PROCEDURE

 Introduction:  When the applicant has not received Marketing Authorization for its medicinal product in any Member State, the decentralized procedure is applied.

• The decentralized procedure was introduced during changes in the legislation in 2005. It aims to avoid delays resulting from the very slow national phase in some Member States by engaging each of the Member States in which Marketing Authorization is being sought at the same time so that the launch of a product is not determined by the lowest common denominator – that is, the slowest Member State.
• This procedure is therefore available for medicinal products that have not yet received Marketing Authorization in any Member State at the time of application.
• As with the MRP, the applicant asks one Member State to act as the RMS. The other Member States in which an application is pending are the CMSs.
• The procedure differs slightly depending on whether a Member State or the applicant initiates the decentralized procedure, but in all cases, an identical application for Marketing Authorization is submitted simultaneously to the Competent Authorities of the RMS and of the CMSs. At the end of the procedure, the draft assessment report, SmPC, labelling, and package leaflet, as proposed by the RMS, are approved. The CMSs generally adopt the assessment of the RMS and grant the Marketing Authorization for their territory.
• The Marketing Authorization is only valid in the territories of the CMSs that issue the Marketing Authorization.
• However, the CMSs can refuse to recognize a Marketing Authorization approved by another Member State if they have important objections on the grounds of potential risk to public health.
• If a CMS fails to grant a Marketing Authorization, further discussion is held in the coordination group for mutual recognition and the decentralized procedure, the CMD(h).
• Usually, the applicant initiates the procedure by obtaining the agreement of a national Competent Authority to act as the RMS. There is a booking procedure in most Member States, with submission dates being allocated by the Competent Authority; these dates may be reallocated in the event of cancellations or on appeal.
• On the allocated date, the applicant submits the application to the RMS and the selected CMS simultaneously.
• The RMS and CMS validate the application. The RMS assesses the application and prepares a draft assessment report that is submitted to the other CMSs for their consideration and approval.
• The applicant submits the dossier to the RMS and the CMSs, and the dossier is validated by all applicable CMSs within fourteen days (i.e., taking the process to Day 0).
• Timelines kick in
• Days 0; The RMS initiates the decentralized procedure.
• Days 70: The RMS forwards a preliminary assessment report to the CMSs, and the CMSs have until Day 100 to send comments on this report back to the RMS.
• Days 105: The RMS, CMSs, and applicant attempt to reach consensus on the assessment report and any issues raised. During a period of up to three months, during which the clock stops, the applicant agrees to a final response document and also possibly supplements its dossier in order to address the questions raised.
• Days 106–120: Once the clock has restarted, and the applicant has agreed to the final response document, the RMS then updates the preliminary assessment report and prepares a draft assessment report and other product-associated documentation that is sent to the CMSs. If consensus is not reached, then the application must be discussed at the CMD(h) with the potential to refer any matters not resolved to the CHMP for arbitration.

Following consensus, the national grant of product authorization must be. determined within thirty days.

1. THE NATIONAL PROCEDURE

Introduction;  The national procedure is used for medicinal products that are intended for use only in one Member State that do not fall under the mandatory scope of the CP.

In addition, the national procedure was used previously in the initial phase of the MRP; however, an applicant wishing to obtain Marketing Authorizations in more than one Member State will now use the decentralized procedure.

• Application Process

Although specific procedures and timescales are different in each Member State, the basic application process consists of the following:

• submission of a Marketing Authorization dossier to the national Competent Authority;
• risk/efficacy assessment by the Competent Authority, which must be completed within 210 days from the receipt of the application (this period may be suspended if deficiency questions are sent to the applicant);
• determination of SmPC, package leaflet, and label text (including layout);
• the grant of the Marketing Authorization;
• the recording of the decision in the register of medicinal products;
• assignment of a product Marketing Authorization number that must be included in the packaging.
• To find out whether a product can be evaluated under the centralized, applicants should always submit an eligibility request using the specific form accompanied by a justification.
• When:18 to 7 months before submission of marketing authorization application

To notify the Agency of the intended submission date, applicants should send the pre-submission request form via the EMA service desk, selecting the type of question ‘pre-submission phase request’, followed by ‘letter of intent request’

• When:7 months before submission of marketing authorization application

Pre-submission meetings are the best opportunity for applicants to obtain procedural and regulatory advice from the Agency.

• When:6 to 7 months before submission of marketing authorization application

1. MA FEE:

Centralized procedure According to the ‘Standard Terms’ published by the Council of Europe. Strength:

• Application for which a full dossier needs to be presented:

1. 313 200 EURO For a single strength associated with one pharmaceutical form and one presentation.
2. + 31 500 EURO For each additional strength or pharmaceutical form including one presentation, submitted at the same time as the initial application for authorisation.

• + 7 800 EURO For each additional presentation of the same strength and pharmaceutical form, submitted at the same time as the initial application for authorisation.

1. 23 700 EURO For each inspection inside or outside the European Union; for inspections outside the European Union, travel expenses shall be charged extra on the basis of actual cost.
2. 11 800 EURO For each inspection inside or outside the European Union cancelled due to the withdrawal of the application or intended application; or changes to the manufacturing arrangements made by the manufacturer or changes made by the applicant/prospective applicant/MAH that necessitate a cancellation of the inspection before the inspection is carried out.