Marketing Authorisation in Europe

Authorisation Procedures for medicinal products

Procedures for evaluating medicinal products and granting marketing authorisation

The European system for the authorisation of medicinal products for human and animal use was introduced in January 1995 with the objective of ensuring that safe, effective and high quality medicines could quickly be made available to citizens across the European Union.

The European system offers several routes for the authorisation of medicinal products:

• The centralised procedure, which is compulsory for products derived from biotechnology, for orphan medicinal products and for medicinal products for human use which contain an active substance authorised in the Community after 20 May 2004 (date of entry into force of Regulation (EC) No 726/2004) and which are intended for the treatment of AIDS, cancer, neurodegenerative disorders or diabetes. The centralised procedure is also mandatory for veterinary medicinal products intended primarily for use as performance enhancers in order to promote growth or to increase yields from treated animals.
  Applications for the centralised procedure are made directly to the European Medicines Agency (EMA) and lead to the granting of a European marketing authorisation by the Commission which is binding in all Member States.
• The mutual recognition procedure, which is applicable to the majority of conventional medicinal products, is based on the principle of recognition of an already existing national marketing authorisation by one or more Member States.
• The decentralised procedure, which was introduced with the legislative review of 2004, is also applicable to the majority of conventional medicinal products. Through this procedure an application for the marketing authorisation of a medicinal product is submitted simultaneously in several Member States, one of them being chosen as the "Reference Member State". At the end of the procedure national marketing authorisations are granted in the reference and in the concerned Member States.

Purely national authorisations are still available for medicinal products to be marketed in one Member State only.

Special rules exist for the authorisation of medicinal products for paediatric use, orphan drugs, traditional herbal medicinal products, vaccines and clinical trials.

The EMA and the authorisation procedure

In 1993 the European Medicines Agency (EMA) was founded with the primary task of providing scientific advice of the highest possible quality to the Community Institutions on all matters relating to medicinal products for human and veterinary use. EMA's main task is to co-ordinate the scientific evaluation of the safety, efficacy and quality of medicinal products which undergo either procedure. All scientific questions arising in these procedures are dealt with by the EMA.

The agency has today established itself as a world-leading agency for the evaluation of medicinal products. It constitutes a major asset in making Europe an attractive location for new pharmaceuticals and allows for speedy and robust authorisation of new innovative medicines.

EMA's key tasks are to:

• provide Member States and Community institutions with the best possible scientific advice on questions about the quality, safety and efficacy of medicinal products for human and veterinary use;
• establish a pool of multinational scientific expertise (by mobilising existing national resources) in order to achieve a single evaluation via the centralised or mutual recognition marketing authorisation procedures;
• organise speedy, transparent and efficient procedures for the authorisation, surveillance and where appropriate, withdrawal of medicinal products in the EU;
• advise companies on the conduct of pharmaceutical research;
• reinforce the supervision of existing medicinal products (by co-ordinating national pharmacovigilance and inspection activities);

• create databases and electronic communication facilities as necessary to promote the rational use of medicines.

What is a Marketing Authorisation needed for?

In accordance with EU Directive 2001/83 and Regulation (EC) No. 726/2004 governing medicinal products, in order to legally place a medicinal product on the market in the European Economic Area (EEA), a Marketing Authorisation (MA) or ‘licence’ must first be approved. To obtain an MA, a Marketing Authorisation Application (MAA) is submitted to the appropriate Competent Authority(s) (CAs), for assessment and MA approval.

What does an MAA consist of?

An MAA is a comprehensive dossier of information and data describing all aspects (Administrative/Quality/Safety/Efficacy) of a medicinal product demonstrating that it is appropriate for use in patients. There is an internationally agreed standard for the overall content and format for this dossier which is referred to as the Common Technical Document (CTD).

The CTD format is applicable for all MAA regulatory submission routes and all product types, although some modifications may be required for certain application/product types. CTD format is also applicable to other submission types including variations and renewals.

At the top level, a CTD dossier is split into five modules:

Module 1: Administrative information and prescribing information (any additional region-specific information not specified in the CTD is also included in this module)

Module 2: CTD Summaries

Module 3: Quality

Module 4: Non-clinical Study Reports

Module 5: Clinical Study Reports

The overall organisation of the CTD is fixed and should not be changed. Documents and data should be assigned to the most appropriate sections in Modules 1 to 5. The only exceptions to this are the non-clinical and clinical summaries, within which individual formats/tables can be modified as required to best present the data for assessment.

What information and data is required in each CTD Module?

Guidance on the top level structure and content of the CTD dossier can be found in Eudralex Volume 2B of EC Notice to Applicants “Presentation and format of the dossier – Common Technical Dossier”.

CTD does not specify the detailed content in terms of what studies and data are required. There are European Community guidelines regarding the quality, safety and efficacy of medicinal products which must be considered and accounted for in preparation of the MAA dossier. In addition, for medicinal product quality, the general chapters and monographs of the European Pharmacopoeia or other national pharmacopoeias should also be accounted for as appropriate.

Not all data requirements are mandatory or required for each and every application or product type. If an element is considered to be not relevant or not applicable, the absence of such should be fully justified.

There may also be regional differences that will need to be taken into account in dossier preparation.

The following is a summarised description of the information to be included in each Module.

Module 1

This Module includes all of the administrative information relating to the application and the concerned medicinal product. Key items for inclusion are:

• Cover letter
• Application form and annexes (e.g. manufacturing licences, proof of payment of fees, letters of access)
• Product Information including the Summary of Product Characteristics (SmPC), labelling, patient leaflet, braille, results of readability testing
• Information about the experts
• Specific requirements for different types of applications
• Environmental Risk Assessment
• Pharmacovigilance system description
• Risk Management Plan

Module 2

This Module presents summary information for the quality, non-clinical and clinical Modules with so-called expert review of the information and data in the context of the MAA and regulatory framework.

Module 3

Module 3 is the Quality Module which presents all of the information regarding drug substance and drug product development, characterisation, manufacturing and testing to demonstrate that the medicinal product is of suitable quality.

Module 4

This is the Non-clinical Module which includes all of the non-clinical study reports and literature addressing the complete battery of non-clinical testing required for the medicinal product and application type.

Module 5

This is the Clinical Module which includes all of the clinical study reports and literature addressing the clinical requirements for the medicinal product and application type

Are there specified requirements for formatting such as filenames, margins, font type and size, hyperlinking, etc?

There is some general but limited guidance on formatting available, however the aim is obviously to facilitate dossier navigation and review. Margins need to be large enough to ensure that bindings do not obscure any data. The selected font and font size should be easily legible. Times New Roman and 12-point font are recommended for narrative text, although variations to this are accepted, for example for tabulated data where it might be necessary to reduce the font size slightly to ensure a table fits on the page.

In terms of pagination and segregation, documentation should be prepared in line withCHMP/ICH/2887/99 Revision 1 Organisation CTD recommendation.

National-only submissions must consider any Member State-specific requirements. For example in the UK, the MHRA recommends file naming conventions through Special Mail 5. European submissions would be in accordance with Non-eCTD electronic Submissions (NeeS) or fully electronic (eCTD) format.

Is there a requirement to re-format old dossiers?

There is no obligation to reformat approved dossiers. However it is possible to re-format Quality documentation into Module 3 format in order to facilitate ongoing life-cycle management of the licence, as variations, renewals, etc., will need to be submitted in CTD format. Re-formatting is not recommended for Modules 4 and 5 for Non-clinical and Clinical data.

When re-formatting into Module 3, all approved variations must be fully integrated into the re-formatted Module. In terms of the regulatory procedure to be followed to submit the re-formatted Module 3, this does not constitute a variation in itself. Therefore it is recommended that it is submitted as part of another regulatory procedure (e.g. variation or licence renewal), subject to agreement from the concerned CA.

If however, an old format licence is to be used as the basis for MAAs to be submitted via the Mutual Recognition Procedure (MRP), the current approved documentation will need to be reformatted intoCTD format. It is recommended that Applicants discuss any MRP plans with the proposed Reference Member State (RMS) in advance to determine the best means of doing this, as different Member States may prefer different approaches.

Are there different National administrative requirements (i.e. delivery addresses, number of copies, paper/electronic, etc)?

There are likely to be a variety of Member State-specific administrative requirements, some of which are documented in the available EU Guidances. However, there is still the possibility of additional requirements or nuances not readily available in the standard sources of information. In the absence of direct, recent experience of an MAA submission to the concerned Member States (MSs), it is highly recommended that contact be made with the relevant CA to establish any specific national requirements in advance of submission.

Requirements for final submission to the MSs again may vary and therefore needs to be checked in advance. In terms of final publication and dispatch of the MAA, this aspect of MAA preparation is often dismissed as minor, yet it requires the same level of care and attention as preparation of the dossier itself. Timelines frequently do not allow much time for this part of the project. Consequently any delays ahead of publication can mean publication and dispatch activities need to be completed at speed, potentially compromising the quality of the final submission.

What are the different types of MAA procedures?

Medicinal products can only be placed on the European Economic Area (EEA) market when a Marketing Authorisation has been issued by the competent authority of a Member State for its own territory (National Procedure) or when an authorisation has been granted in accordance with a community authorisation (Centralised Procedure (CP), Mutual Recognition Procedure (MRP) and Decentralised Procedure (DCP)).

National Procedure

The competent authorities of the Member States (MS) are responsible for granting MAs for products which are placed on their markets, except for medicinal products which are authorised under DCP,MRP and CP. In order to obtain a national MA, a single application is submitted to the competent authority of the MS.

Mutual Recognition Procedure

The Mutual Recognition Procedure aims at facilitating access to a single market by relying upon the principle of mutual recognition. A marketing authorisation or the assessment in one MS (the Reference Member State (RMS)) will in principle be recognised by the competent authorities of the other MSs (the Concerned Member States (CMS)), unless there are grounds for supposing that the authorisation of the medicinal product concerned may present a potential serious risk to public health.

After the first marketing authorisation is granted in one of the EU Member States, the MA Holder (MAH) may request one or more Member State(s) to recognise an authorisation granted by the RMSby submitting a MR application.

The Mutual Recognition Procedure is divided into the following steps:

Decentralised Procedure

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 MA in any Member State at the time of application.

The Decentralised Procedure is divided into the following steps:

Centralised Procedure

Marketing Authorisation Applications for products that fall under the ‘mandatory’ or ‘optional’ scope of the Centralised Procedure, facilitate simultaneous approval in all EU Member States (including Iceland, Liechtenstein and Norway). The European Medicines Agency (EMA) will act as the Competent Authority for CP submissions.

Mandatory Scope – the Centralised Procedure is ‘mandatory’ for human medicines that are:

• Derived from biotechnology processes, such as genetic engineering
• Intended for the treatment of HIV/AIDs, cancer, diabetes, neurodegenerative disorders or autoimmune diseases and other immune dysfunctions
• Orphan medicinal products

Optional Scope – medicinal products can be accepted for consideration under the ‘optional’ route by the EMA, on the basis that the product contains either a new active substance or constitutes a significant therapeutic, scientific or technical innovation, or the authorisation is in the interests of patients within the community.

What are the differences between the MA procedures?

Centralised Procedure	Decentralised and Mutual Recognition Procedures	National Procedure
Less flexible procedure as only one tradename and one MA holder can be used	More flexible procedure as different tradenames and MA holders can be used	One tradename and oneMAH
The EMA chooses the Rapporteur / Co-Rapporteur for the assessment	The applicant chooses theRMS with the most relevant expertise	The applicant chooses the country
All or nothing procedure as the MAA is either accepted or rejected in all EU Member States	Can withdraw MAA from Member States that are causing difficulties, whilst continuing with applications in other states	Can withdraw the MAA at anytime
One application and one assessment	Multiple assessments and complex administration procedures	One application and one assessment
Well defined timescale throughout the procedure	Although the main assessment has a defined timescale, the national phase can be long and undefined	Undefined assessment timeline

What types of application (legal basis) can be submitted?

The legal provisions covering all procedures for human medicinal products are contained in Directive 2001/83/EC (as last amended by Directive 2004/24/EC and by Directive 2004/27/EC). This Directive provides a number of different legal bases by which to apply for an MA.

• according to Article 8(3) of Directive 2001/83/EC, relating to full applications containing all appropriate quality, nonclinical and clinical data;
• according to Article 10 of Directive 2001/83/EC, relating to generic medicinal products and similar biological medicinal products;
• according to Article 10a of Directive 2001/83/EC, relating to applications relying on well-established medicinal use supported by bibliographic literature;
• according to Article 10b of Directive 2001/83/EC, relating to applications for new fixed combination products;
• according to Article 10c of Directive 2001/83/EC, relating to informed consent from a marketing authorisation holder for an authorised medicinal product.
• 
  

Orphan Medicinal Product Designation in the EU

What is an Orphan Medicinal Product?

What is an Orphan Medicinal Product Designation?

An Orphan Medicinal Product Designation (OMPD) is granted by the European Commission, subsequent to an initial opinion being made by the European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products (COMP) that the product qualifies as an orphan medicinal product.

What are the criteria for orphan designation?

To qualify for orphan designation (as set out in Article 3 of (EC) No 141/2000), a product must meet one of the following criteria:

1. It is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 people in the EU at the time of submission of the application.
2. It is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition and, without incentives, it is unlikely that the revenue after marketing of the medicinal product would cover the investment in its development.

Additionally, irrespective of the criteria met above, either of the following must apply:

1. No satisfactory method of diagnosis, prevention or treatment of the condition concerned is authorised, or;
2. If a satisfactory method exists, the medicine in question must be of significant benefit to individuals affected by the condition.

When can an orphan designation be applied for?

An application for orphan medicinal product designation can be submitted to the EMA at any stage of development; however it must be before an application for marketing authorisation is made.

A sponsor can request orphan designation for a product even if a separate sponsor already holds a designation covering the indication in question. In this instance, the first to gain marketing authorisation would benefit from market exclusivity.

Orphan designation can be requested for new chemical entities (NCEs) and new biological entities (NBEs), but also for existing approved products when the designation concerns a new, potentially orphan, indication for that product.

Any application for orphan designation must be supported by a robust scientific justification of the medical plausibility of the intended use.

How much does an application for OMPD cost?

The EMA do not charge a fee for the designation procedure.

What are the incentives of gaining Orphan Medicinal Product Designation?

Gaining orphan designation for a medicinal product entitles sponsors to the following benefits and/or incentives:

10 years’ market exclusivity: Orphan medicinal products benefit from market exclusivity in the EU for 10 years after receiving a marketing authorisation. An extension of 2 years’ market exclusivity may be granted if paediatric studies are included in the marketing authorisation.

During the 10 (+2) year period, directly competitive similar products for the same indication cannot normally be placed on the market.

Protocol assistance: Protocol assistance (PA) is similar to the EMA Scientific Advice procedure. However, additional benefits are included for PA, and sponsors can take advantage of the following:

1. EMA Scientific Advice procedure, designed to help sponsors optimise development of their orphan medicinal product within the scope of the orphan indication
2. Protocol assistance, also enables sponsors to ask questions related to:
   • significant benefit over other satisfactory methods of treatment, diagnosis, or prevention of the indication in question
   • development of medicinal products for rare conditions (e.g. whether two products are deemed ‘similar medicinal products’)
   • study design related to clinical superiority over similar products in the same indication

This procedure can help applicants maximise the chances of their marketing authorisation application being successful.

Fee reductions: A special fund from the European Commission, agreed annually by the European Parliament, is used by the EMA to grant fee reductions for orphan medicinal products. Reduction of fees will be considered for all types of centralised activities, including applications for marketing authorisation, pre-authorisation inspections, variations and protocol assistance. For organisations holding both orphan designation and ‘SME status’ enhanced fee reductions are applicable.

Automatic access to centralised procedure: Medicinal products holding orphan designation are now required to apply through the centralised procedure in accordance with Article 3.1 of (EC) Regulation 726/2004.

EU-funded research: Sponsors developing orphan medicinal products may be eligible for grants from the EU and Member States’ programmes and initiatives supporting research and development, including the European Commission framework programme.

Points to consider in gaining orphan designation

There are several misconceptions about orphan designation for medicinal products, two of which are detailed below:

• In theory, regulators require the same level of proof of efficacy and safety for orphan drugs as for other drugs. There are examples of pivotal studies being accepted with reduced patient numbers; however, this is condition or drug-specific. Any development plans should be discussed with the EMA through Protocol Assistance procedures.
• Orphan designation will not automatically allow accelerated review for marketing authorisation, conditional approval or approval under exceptional circumstances. Applicants would still need to apply for such procedures.

How to obtain Orphan Medicinal Product Designation?

In order to benefit from the incentives provided for orphan products a sponsor must obtain orphan designation for the product by compiling an OMPD application and submitting this to the EMA. Applications are reviewed by the Committee for Orphan Medicinal Products (COMP) and an opinion on whether the medicinal product meets the criteria for orphan designation will be issued. The opinion is forwarded to the European Commission who makes the final decision on whether orphan designation will be granted.

What is the procedure for gaining orphan designation?

Notification of intent to submit: A sponsor should notify the EMA of their intent to submit an OMPDapplication in the form of a Letter of Intent at least two months in advance of the planned submission date; the Letter of Intent (and ultimately the final application package) should be submitted in accordance with EMA published timelines.

Pre-submission meeting: The OMPD application procedure also offers sponsors the opportunity of a pre-submission meeting with the EMA. It is highly recommended to use this free service as feedback from the EMA on draft OMPD applications can significantly improve the success of OMPDapplications. If a pre-submission meeting is required, this should be stated in the Letter of Intent.

Submission of OMPD application: Following the pre-submission meeting the application is refined and a final package submitted to the EMA. The EMA will validate the submission and, if necessary, the sponsor is given three months to address any validation issues. The date of successful validation is taken as Day 1 of the procedure.

OMPD evaluation: The COMP will evaluate applications within 90 days of the start of procedure (i.e. post-validation) and will adopt either a positive or negative opinion at monthly held COMPmeetings.

At Day 60 the COMP will either:

• Adopt a positive opinion, or
• If a negative opinion is being considered, COMP will forward a list of questions to the sponsor. The sponsor will be advised as to whether written responses or an oral explanation will be required in time for the next COMP meeting

At Day 90 the COMP will either:

• Adopt a positive opinion to be forwarded to the European Commission, or
• In the absence of sufficient justification in the written response or oral explanation, adopt a negative opinion

On receipt of a negative opinion a sponsor can appeal. However, the intent to do so should be notified without delay. Negative opinions will be published on the EMA website, but the EMA offer the possibility of withdrawing applications likely to receive a negative opinion before adoption takes place at the COMP meeting.

Commission Decision: A positive opinion is forwarded to the European Commission and a Decision granted, typically within 30 days; in practice receipt of a Commission Decision can take 2-3 months following adoption of the COMP opinion.

Following receipt of the European Commission Decision a Public Summary of Opinion will be published on the EMA website and the orphan product will be included in the Community Register of Orphan Medicinal Products.

Timeline: The minimum timeframe from Letter of Intent to European Commission Decision is five months, although additional time may be required for validation responses, an oral/written explanation and European Commission Decision.

What information is required for OMPD applications?

In order to submit an application for orphan designation a sponsor (who can be an individual or an organisation) must have a fixed address in the European Union and is required to include the following documentation:

Key documentation

• Cover Letter – identifying sponsor, medicinal product, proposed orphan indication
• Application form – available on EMA website
  The common FDA/EMA application form can be used. However, it is important to note that there are key differences in the required supportive documentation for application in the two regions. Additionally, applications for designation will be reviewed separately by the respective Authorities.
• Core dossier – Parts A-F in accordance with guidance document ENTR/6283/00
  Part A: Description of the Condition
  Part B: Prevalence of the Condition
  Part C: Potential for return on Investment
  Part D: Existence of other methods of diagnosis, prevention or treatment
  Part E: Description of stage of development
  Part F: Bibliography
• Proof of Establishment in the EU
• Letter of Authorisation (if applicable)
• Translations of product name and proposed orphan indication into all official EU languages, plus Icelandic and Norwegian

Key components of application

The key components of the orphan designation application include the following:

Indication: the orphan indication must be a clearly defined, medically plausible, condition or disease. Sub-setting (or salami slicing) can be considered but only if it can be shown that the sub-set is medically plausible, and it can be demonstrated that the medicinal product would have no beneficial effects in the wider population. The orphan indication can be broader than the therapeutic indication proposed for a Marketing Authorisation Application.

Part A – Medical plausibility: this section must include a summary of the medicinal product and the proposed mechanism of action. The condition must be well defined and supported by published literature. Preliminary clinical and/or nonclinical data is required to support the notion that the product may be beneficial in the proposed orphan indication.

Part A – Justification of the life-threatening or debilitating nature of the disease or condition: the sponsor is expected to prove that the proposed orphan indication is life-threatening or debilitating in nature through the use of published literature.

Part B – Prevalence of the condition: in order to meet the prevalence designation criteria, the sponsor is required to demonstrate that less than 5 in 10,000 persons in the EU are affected by the disease or condition at the time of designation application. For products intended for diagnosis or prevention sponsors are required to show that less than 5 in 10,000 persons in the EU will receive or use the diagnostic. Prevalence data should be considered for all EU countries, as well as Iceland, Liechtenstein, and Norway.

Part D – Justification of significant benefit: in the application the sponsor must identify if there are any existing methods of diagnosis, treatment or prevention for the orphan indication. These could include Competent Authority approved methods or those commonly accepted by clinicians within the EU. If such methods exist, sponsors are required to demonstrate how the medicinal product under consideration could offer significant benefit in terms of improved safety, efficacy and/or improved pharmacokinetic properties.

What is required to maintain an OMPD?

In order to maintain orphan designation, sponsors are required to submit an Annual Report to theEMA within two months following the anniversary of the grant of the designation. The report should include details of:

• the progress of development since the initial application
• updated details of the current regulatory status
• any incentives received for development of the product

\When submitting a marketing authorisation application for a product with OMPD, applicants are expected to demonstrate that the OMPD criteria are still met, particularly with regards to significant benefit (if applicable). If these criteria are no longer met, the designation will be removed.

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