Pharmalink Consulting Newsletter Summer 2010
This month we look at how to get approval to market a drug in the European Union (EU) and how this differs from NDA applications in the US. We’ll see there are a number of procedural differences and other factors to take into account when planning a European submission.
What to consider when registering a product in the EU
Getting approval to market a drug in the EU can be a complex process and there are many differences to an NDA filing.
Firstly, filing an NCE application (New Chemical Entity), as it’s known in the EU, can cover up to 30 markets* (referred to as member states) and there are four different filing procedures available –
- National procedure
- Mutual Recognition Procedure (MRP)
- Decentralised Procedure (DCP)
- Centralised Procedure (CP).
* There are 27 countries within the European Union (EU). It is worth noting that the EU legislation governing the use of medicinal products in the EU has also been adopted by the non-EU member countries Iceland and Norway. The Swiss regulatory system also mirrors the EU regulations.
Choosing which process to use can be complex and is dependent on a number of factors, discussed later in this article.
To be able to submit a license application, the company involved must be established in the EU. This means it must have an established legal entity or have a local branch or place of business within at least one EU country. Alternatively, the company can have a legal representative make the submission on their behalf, which results in the legal representative being the license holder for the product.
As of January 2010, the electronic CTD format (e-CTD) is mandatory for all EU submissions made via the Centralised Procedure. While the use of e-CTD for Mutual Recognition Procedure applications or Decentralised applications is not compulsory, it is highly recommended and certain national agencies in Europe will only accept the e-CTD.
Beyond the actual submission process, there are other practical aspects to be considered when looking to market a product in the EU:
- EU law requires all pharmaceutical manufacturers to have a Qualified Person (QP) in place, who oversees release of the product to market. The QP is responsible for ensuring compliance with EU GMP requirements, relating to both the finished product and its active substance. In addition, if a product is manufactured outside of the EU, in a country that is not part of the GMP Mutual Recognition Agreement (the US is not), then the product must be fully re-tested in the EU before release to market.
- EU law also requires a Qualified Person Responsible for Pharmacovigilance (QPPV) to be in place, who is responsible for Pharmacovigilance.
- The manufacturing facility must be equipped to test all excipients to the European Pharmacopoeia (Ph.Eur), unless an in-house monograph is in place. EU legislation allows testing to USP only if there is no Ph.Eur in place.
- Patient Information Leaflet user testing must be undertaken to demonstrate the readability of the patient label.
- An approved Pediatric Investigation Plan (PIP) is required at the time of submission, providing details of any pediatric studies and their timelines (age 0-17). The PIP includes requests for deferrals and waivers (e.g. where the disease occurs only in adults), and so the document is mandatory for new product applications, regardless of whether pediatric indication is sought. A waiver is automatically granted if the new application concerns a well-established use or a generic submission.
Post-licensing
Once the product has been approved and the registration license granted, there are post-licensing requirements to undertake. In the EU, registration licenses are valid for a period of 5 years, at which point they need to be re-evaluated through a renewal application procedure.
In the meantime, any changes to the product need to be identified to the regulatory agencies via the EU variations procedure, updated in January 2010 to follow the new EU variations legislation (Commission Regulation (EC) 1234/2008).
Once renewed, a three year cycle of submitting Periodic Safety Update Reports (PSUR) replaces the renewal procedure.
The sunset clause legislation introduced in 2005 (Article 24 (4-6) of Directive 2001/83/EC) means that the marketing authorization will no longer be valid if a product is not placed on the market within three years of its approval, or if it is removed from the market for a consecutive period of three years or more. If the product is registered via the Centralised Procedure, the product must be marketed in at least one member state. If the National Procedure, Mutual recognition procedure, or Decentralised Procedure was used, the product must be marketed in each individual country.
Choosing the right EU submission procedure
There are two types of regulatory agency in the EU; a national agency for each member country (e.g. MHRA in the UK) and the European-wide agency, the EMA. Each plays a role in the four different submission routes mentioned earlier in this article: National procedure, Mutual Recognition Procedure (MRP), Decentralised Procedure (DCP) and Centralised Procedure (CP).
National Procedure
This procedure aims to secure approval in any given EU country, whereby the national regulatory agency issues a registration license to market a product in that country.
Mutual Recognition Procedure (MRP) and Decentralised Procedure (DCP)
MRP and DCP involve two or more national agencies, where each agency plays a part in reviewing the filing, and a consensus is reached by all involved. Individual registration licenses are then issued by each national agency, on the basis of the consensus opinion.
MRP requires one agency, known as the Reference Member State (RMS), to review the filing on behalf of the other agencies involved (referred to as the Concerned Member States (CMS)), who then mutually recognize the opinion of the RMS.
The difference with the DCP is that both the Reference Member State and the Concerned Member State countries are involved in reviewing the filing from the outset, although the Reference Member State still takes the lead in the review.
Centralised Procedure (CP)
CP is a separate process that involves only the EMA, who conduct a single review that results in a European-wide registration license applicable to all EU member states. No national licenses are issued, only the single European-wide license issued by the EMA.
In summary, MRP and DCP lead to licenses to market only in the countries involved in the submission, whereas CP submission leads to a license to market anywhere in the EU.
The main legislation that the EU submission procedures fall under is:
- Council Directive 2001/83/EC
- Council Directive 2004/27/EC
Guidance can be found in the Notice to Applicants Volume 2A:
http://ec.europa.eu/enterprise/sectors/pharmaceuticals/documents/eudralex/vol-2/index_en.htm
The choice of submission procedure impacts on the registration approval time, cost, level of regulatory risk, and marketing strategy, so these factors should be taken into account when considering which procedure to use. In some cases, however, certain rules mandate the procedure to be used. For example the CP is mandatory for biotech products, cancer, antiviral and auto-immune disease, diabetes and neuro-degenerative disorders, and the National Procedure can only be used if the product is to be registered only in one member state.
Each of the multi-state procedures (MRP, DCP and CP) has benefits and drawbacks:
Fees
The submission fee for the CP is fixed for any given type of application (NCE, generic application, variation procedure, etc). For example, the EMA fee for a registering an entirely new product is €254,100, equivalent to $320,000**. In contrast, the fees payable when registering via the MRP or the DCP procedure are dependent on the chosen Reference Member State and the number of Concerned Member States involved. Each national agency has their own pricing structure, which can make cost calculations challenging.
Since the CP automatically results in approval in all EU member states, it is more cost effective if planning to market the product across all, or most of the EU countries. Using the MRP or DCP procedure for the same strategy would result in much higher submission fees. If, however, the product will be marketed in a small number of EU countries, then the MRP or DCP should be less expensive.
Fees for seeking scientific advice or holding pre-submission meetings should also be taken into account. Unlike the FDA, the EU agencies charge for these services and the cost is not insignificant. EMA fees linked to the CP are generally higher than those incurred when seeking advice from the national agencies, applicable to the MRP and DCP.
**based on May 20th 2010 Euro to US dollar conversion rate.
Approval timelines
The MRP can take anywhere from 120 days to 2 years. By contrast, the CPP offers more consistent timelines for approval, with an official 210-day review, plus an additional 60 days for document translation and administration (24 languages!). Clock stops for any questions during the procedure should also be anticipated.
The DCP is by far the quickest process for registering a new product, with average approval times currently at approximately 155 days (excluding any clock stop to answer questions).
Other time factors to consider include the need to apply for an allocated submission ‘slot’ with both the CP and DCP. Due to the high demand for DCP, the wait to be allocated a submission slot is currently between 1 and 2 years.
Regulatory risk
With the MRP the initial national assessment phase acts as a filter, as the dossier is assessed by the Reference Member State prior to the Concerned Member State’s involvement, and this reduces the burden of managing weak spots in the registration dossier.
This filter stage is not present with the DCP and so more questions tend to arise, which may prolong the review period.
The CP does carry a risk of outright rejection since there is a single agency involved (EMA), whereas the numerous national agencies involved in MRP and DCP are involved in the final decision to approve the product. Choosing the right country as your Reference Member State is an important decision, as this can have significant influence on the outcome of the application. Reference Member States are generally chosen based on a number of criteria, including their integrity and credibility among the other Concerned Member States, the duration of their national registration procedures, their ability to respect the MRP timelines, their openness to dialogue and their medical expertise in a given area.
Marketing strategy
It is important to note that the CP results in a single EU-wide trade name, whereas the other EU procedures allow for multiple trade names in individual countries, impacting on the marketing strategy for the product.
Conclusion
Achieving authorization to market a product in Europe can be a difficult task, with many differences to a US NDA filing. Being aware of these differences and optimizing planning with effective knowledge and understanding of the process can help ensure the application process runs smoothly, avoids costly delays in getting approval to market and maximizes the product’s potential.
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