24 th Jul Obtaining European Regulatory Approval
Obtaining European Regulatory Approval
The European medicines regulatory system is made up of numerous regulations and directives set by the European Commission to ensure the quality, safety and efficacy of all human and veterinary medicinal products. These laws are then implemented by its member states through regulatory agencies/bodies.
The European Union (EU) is made up of 28 sovereign member states, with each member state having its own national regulatory agency; as well as the central European Medicines Agency (EMA).
To be able to market a medicinal product within Europe you must obtain a marketing authorisation (product license) from the relevant regulatory agency.
This document provides an overview of the European regulatory environment and outlines the pharmaceutical regulations and requirements for companies to consider when bringing a new medicinal product to the European market.
EU Regulatory Environment
The European Union (EU) is made up of 28 sovereign member states, with each member state having their own national regulatory agency.
There is also the European Medicines Agency (EMA) which is the body responsible for the evaluation, supervision and pharmacovigilance of medicinal products in the EU. The EMA achieves this through a regulatory network of committees, working parties and related groups formed of scientific experts from the EU member states. For a list of the 29 regulatory bodies and links to their websites see Resources.
Each national agency is responsible for:
-Assessing the Quality, Safety and Efficacy (QSE) of medicine
-Authorising marketing and sale of medicines and medical devices
-Post-marketing surveillance to report, investigate and monitor cases of adverse reaction
-Regulations to clinical trials for medicines and medical devices
-Operating quality control surveillance systems
-Providing the public with authoritative information about medicines and medical devices
Iceland, Liechtenstein and Norway are also part of the EU regulatory environment. As members of the European Economic Area (EEA) they are allowed to trade in the single EU market without EU membership but are required to follow parts of EU law. Switzerland is not a member of the EU or the EEA but has a number of trade agreements with the EU.
Figure 1. Map of Countries in the EU
To be able to market a product within Europe you must obtain a marketing authorisation (product license) from the relevant regulatory agency.
There are a number of different routes to apply for a marketing authorisation depending upon the location(s) companies wish to market their medicinal products. It is worth considering the long term goals as well as immediate plans at this stage as this can facilitate quicker approval of future applications.
Applications must be made in the language of the national agency except for the EMA which requests all submissions to be in English (however patient and labelling information must be provided in the specific language(s) of the countries that your marketing authorisation is for).
Marketing authorisation approval routes are intended for different purposes and do not just serve the purpose of bringing a wholly new medicinal product or substance to market but can be used to introduce a drug product with an already approved drug substance in the EU. There are four routes by which a medicinal product can be authorised for marketing:
1) The National Procedure
2) The Mutual Recognition Procedure
3) The Decentralised Procedure
4) The Centralised Procedure
The National Procedure is used to gain the approval of a marketing authorisation in just one country within the EU. This may be suitable if the drug is intended for a specific market or the applicant does not wish to make use of the drug product in other member states.
Mutual Recognition Procedure
The mutual recognition procedure is used to register a product in multiple additional markets when a national marketing authorisation has already been granted in the EU. The country that has already awarded the product a licence acts as a ‘Reference Member State’ (RMS). The additional markets, in which the application has been submitted (known as the ‘Concerned Member States’ or CMS), receive an assessment report from the RMS. The CMS then have 90 days to accept or reject the application.
This means that the scientific assessment of one state can be used to obtain a licence for the drug in multiple other countries and hence reduces duplication of effort and workload for the CMSs.
The Decentralised Procedure is used to licence products in a select number of countries when a national marketing approval has not yet been granted in the EU. One country is appointed as the ‘Reference Member State’ with the other countries acting as the ‘Concerned Member States’. The RMS produces a draft assessment report which it then circulates amongst the CMS. The CMS review the draft assessment report and a common consensus is reached amongst the states. The RMS also acts a ‘go-between’ to pass any queries or concerns from the CMS to the applicant. In the event of a disagreement in the assessment between the RMS and any of the CMS, a co-ordinating group acts to achieve a resolution.
The Centralised Procedure results in a product receiving a marketing authorisation in all markets in the EU simultaneously. Unlike the MRP and DCP, the centralised procedure is assessed by the EMA’s Committee for Medicinal Products for Human Use (CHMP) as opposed to by a national authority. A Rapporteur and in some cases a Co-Rapporteur, are appointed who will prepare a draft assessment report for discussion and final agreement with the other members of the CHMP. The Rapporteur is chosen to give the most objective scientific opinions and expertise in the relevant scientific area available in the EEA.
There are certain situations when the use of the Centralised Procedure is mandatory. Annex I of (EC) No. 726/2004 provides a list of products that must use the centralised procedure and includes:
– recombinant DNA technology
– gene expression altering technology
– hybridoma and monoclonal antibody methods
– products containing a new active drug substance, not already on the Community market, for the treatment of acquired immune deficiency syndrome, cancer, neurodegenerative disorders, diabetes, auto-immune diseases, immune dysfunctions or viral diseases
– orphan medicinal products
– advanced therapy medicinal products
The Centralised Procedure can also be chosen voluntarily if the product is planned to be marketed to all EU (and EEA) member states simultaneously. It can be applied to medicinal products with a new active ingredient which is not already on the market in the EU/EEA, if the product can be shown to be innovative or if the authorisation is in the interests of patients across the EU/EEA.
The Notice to Applicants provides a detailed insight into how the Mutual Recognition Procedure and the Decentralised Procedure work, the deadlines and requirements. (EudraLex – Volume 2). Further information on the Centralised procedure can be obtained from the website of the EMA.
Before applying for a licence there are some key points that need to be considered:
– Legal basis for the application
– Appropriate naming of the product
– Packaging design meets EU requirements
– Risk Management and Pharmacovigilance is in place and suitable
– Environmental Risk Assessment is performed
– GMP and GCP in place and prepared for audit against EU standards
– Application preparation and submission
A pre-submission meeting is a key tool to identify the legal basis for the application. This assesses the type of application that is required: full, generic, hybrid or similar biological, well-established use, fixed combination and Informed consent. However, for a truly innovative product, the legal basis is most likely to be a full application. In this case, the results of pharmaceutical tests (physico-chemical, biological or microbiological), pre-clinical tests (pharmacological and toxicological), and clinical trials must be submitted. Further information on the legal basis of an application is available in the EMA pre-submission guidance.
It is essential to consider the naming of the medicinal product when placing an application using the centralised procedure. The product must have the same name in all EU countries, except in the case of an exception being made due to trademarks.
A non-confusing invented name or a common name/scientific name along with a trademark of the applicant can be used. The international non-proprietary name (INN) in accordance with World Health Organisation (WHO) guidance is often accepted as the common name. An invented name may be desirable in order to make the innovative medicinal product stand out from other marketed drugs when the product falls out of protection and generics can be marketed.
The invented name must be submitted to the Naming Review Group at the EMA. An invented name will be subject to evaluation in order to assess if there is any safety risk or potential concern for public health if the name was used on the market. The created name should not be confusing in respect to its printing, writing or pronunciation with an existing product. The name cannot be misleading in that the user may believe it has a perceived therapeutic or pharmaceutical effect, or the composition of the product is different to its intended use.
Packaging may have already been considered during product development. However, there are guidelines in order to assure that it is user friendly, effective and safe.
The packaging mock-ups and hard copies of the outer and immediate packaging must be reviewed by the EMA before the product is marketed. The immediate packaging and outer packaging specimens also must be accompanied by the package inserts and leaflets. A mock-up is a presentation of the artwork design so that the layout and text of the labelling is clear: it can be provided in paper or electronic format.
The outer packaging must comply with the requirements of Article 54 of Directive 2001/83/EC, as amended. This includes information such as name, strength, pharmaceutical form, ingredient details, batch number, expiry date, storage conditions and marketing authorisation holder details and product license number.
The immediate packaging must comply with Article 55 of Directive 2001/83/EC and includes less details than the outer packaging, with only product name, strength and pharmaceutical form, marketing authorisation holder, expiry date and batch number required.
Member states may request that additional market specific information is included on the packaging. This can include pricing information, legal status, identification and authenticity information. These additional requests are known as blue box requirements and more information can be found in the Notice to Applicants.
All labelling must be easy to read and understand and must not be able to be removed or changed once applied to the package. The language on the packaging must be in the official language(s) of the member state; however, multi-lingual packaging is sometimes acceptable. The name of the medicinal product must also be in braille format on the packaging for blind and partially sighted patients.
When writing up product information for the medicine, the product needs to be named as Invented Name Strength Form (Name mg capsules). The Summary of Product Characteristics (SPC) must contain the active substance name’s INN or common name when reference to the active ingredient’s properties is made.
The patient information leaflet (PIL) inside the packaging must also be approved with the marketing authorisation. In the EU, the leaflet must be tested to ensure that it can be easily read and understood by the general public, especially those likely to be prescribed a medication.
Risk Management and Pharmacovigilance
A qualified person (QP) for the application is required and it is the responsibility of this person to ensure that due diligence and pharmacovigilance of the product is followed according to EU legislation throughout the product lifecycle. In absolutely no case will a marketing authorisation be granted without an established pharmacovigilance system for the drug product.
The pharmacovigilance system must have a risk management plan (RMP) in place for the product to identify, characterise, prevent and minimise safety risks. The risk management system also includes interventions that can be made against those risks and assessment of their effectiveness against measurable targets.
Benefits to the public health system and/or patient must outweigh the risks associated with the drug. The pharmacovigilance system must have in place a process to report adverse events in EU member states (and in any other countries where the product is marketed). Pharmacovigilance is likely to be already in place from the clinical trials stage but it is essential that all points are thoroughly covered as detailed in the Notice to Applicants.
Environmental Risk Assessment
An Environmental Risk Assessment (ERA) must be submitted with the application but the impact will not constitute grounds for refusal of the authorisation. The assessment analyses the risk to the environment that the use, manufacture, storage and disposal of the medicine may cause. There are two phases; the first phase is the calculation of the Predicted Environmental Concentration, whereas the second phase is only performed when the first phase is above a threshold. The EMA provides guidelines on how to perform the Environmental Risk Assessment.
Another important factor to consider early on is inspection of the manufacturing facilities for good manufacturing practices (GMP) and good clinical practices (GCP). Whilst assessing the application the EMA may request the applicant to be inspected and they can do this without giving any prior notice.
If the manufacturing site is outside of the EU/EEA, consideration needs to be made to check if there is a mutual recognition of GMP inspection between the country of manufacture and the EU/EEA.
For all inspections requested as part of an application under the Centralised Procedure, fees are payable by the applicant under Regulation (EC) No 297/95, as amended (Rules for the implementation of Council Regulation (EC)).
Application Preparation and Submission
For the Centralised Procedure, in order to ensure an appropriate Rapporteur is appointed it is essential that an accurate estimate of the possible submission date be provided during pre-submission. This has to be done between 7 and 18 months before anticipated submission, through a letter of intent. For the Mutual Recognition Procedure the applicant should contact the Reference Member State at least 90 days prior to submission to request the RMS to update the assessment report and provide a procedure number. For the Decentralised Procedure discussions should be had in advance with the Reference Member State so that they are aware of the intended submission date of the dossier.
Common Technical Document
The submission file for the application follows the CTD (Common Technical Document) style. The eCTD is the electronic version of the CTD. There are five modules to the CTD:
Module 1: Regional Administrative information
Module 2: Overall summary
Module 3: Product and Drug Substance details
Module 4: Non-clinical study reports
Module 5: Clinical study reports
Figure 2. The CTD Triangle
More detailed information about the CTD can be found in the EMA Notice to Applicants, EudraLex – Volume 2. The CTD format is used in all four application routes used to obtain marketing authorisations.
The role of regulatory affairs is to help produce modules 1-5 of the application. All modules benefit from the trained attention of experienced regulatory affairs professionals. Knowledge of the CTD modules and their content will help to ensure a quicker approval cycle and better chance of success.
Regulatory Affairs professionals are trained and familiar with the processes of the member state agencies and therefore can prepare a complete and thorough application that will help avoid agency questions, which can delay the timeline for approval. On the other hand, if questions are raised, this experience is necessary to draft responses which will be satisfactory to the applicant and agency.
Compilation of an eCTD can be complex and requires specific software to complete but is designed in a way that allows updates to specific sections during variations to the marketing authorisation to be easily tracked. An application can be rejected if it does not meet the technical requirements for submission.
Timeline for the Mutual Recognition, Decentralised and Centralised procedure can be found below.
The Timeline for a Mutual Recognition Procedure (click to enlarge):
The Timeline for a Decentralised Procedure (click to enlarge):
The Timeline for a Centralised Procedure (click to enlarge):
* Target dates for response submission are published on EMA website.
Finally, after being granted a marketing authorisation the product is ready to go to market. The product must be certified by a QP before it is released into the EEA. The site that this batch certification occurs acts as the importing country.
If the product is imported from outside the EEA, each batch of product must be retested upon entering the EEA unless a Mutual Recognition Agreement (MRA) exists for the GMP of the exporting country. However, batch release must take place inside the EEA regardless of the MRA existence. If any of the processes are contracted out, the QP of the applicant is still responsible.
Post Authorisation Maintenance
The regulatory strategy does not cease with the license approval of the drug product. Once the patient has access to the drug product the Marketing Authorisation Holder (MAH) must ensure they carry out post-marketing surveillance.
Monitoring the pharmacovigilance data and any further clinical studies that are completed helps to establish and improve the safety profile of the drug. Post-marketing surveillance studies can identify potential hazards which can be investigated in order to continuously establish the risks against the overall benefits of the product.
During the first two years of approval the applicant must provide Periodic Safety Update Reports (PSURs) every six months that must be available immediately upon request from the agencies. PSURs are then submitted again after two years and then thereafter at three-yearly intervals. The PSUR serves to give a worldwide view of the safety and efficacy of the drug product. Pharmacovigilance is critical to creating the PSUR. All adverse events must be reported which have occurred since the previous PSUR was submitted.
Occasionally the EMA may request commitments to provide data that was contingent to the approval of the marketing authorisation. These must be managed robustly to ensure that the commitments are kept and met with the appropriate data requirements.
After five years the initial authorisation will expire and a renewal procedure must be started six months before its expiry. The procedures for renewal are available on the EMA website.
During the product’s lifecycle there may be a requirement to make changes to the registered CTD; for example adding an additional manufacturing site of the drug product, amending the shelf-life or making necessary changes to the product information leaflet for patients that have been identified during post-marketing surveillance. Variations procedures can be used to make these changes. Variations are classed according to their risk to the drug product and therefore the type of assessment from the EMA may be different.
Bringing a new drug product into the EU is achievable, although it requires a great deal of planning and knowing from the beginning what is expected can help to make the process smoother. The essentials have been described briefly in this document and further advice can be sought from regulatory experts and the EMA website. Other agency websites such as the MHRA are also helpful in understanding the role of regulatory agencies in assessing the CTD and approving marketing authorisations.