EMA: Key Notices and Approvals: Q2 2018
EMA launches new online orphan designation portal
The EMA) has launched a new secure online portal for orphan designation applications.
The portal, named ‘Iris’, provides a single space where applicants can submit and manage the information and documents related to their applications for orphan designation.
This is expected to reduce the time needed to prepare and submit the applications.
During the review process, applicants can check the status of their applications from any device and receive automatic notifications when the status of the application changes.
Iris is part of a longer-term programme that aims to make the handling of product-related applications easier and utilises the domains of master data in pharmaceutical regulatory processes (SPOR).
Applicants will still be able to use the existing submission process until 19 September 2018. However, the Agency is strongly encouraging companies to start using the new portal immediately.
Two more EU Member States gain from EU-US mutual recognition agreement for inspections
The EMA has announced that the mutual recognition agreements between the European Union and the the United States to recognise inspections of manufacturing sites for human medicines conducted in their respective territories has made further progress.
The US (FDA) confirmed the capability of two additional EU Member States (Lithuania and Ireland) to carry out good manufacturing process (GMP) inspections at a level equivalent to the US.
There are now a total of 14 Member States whose inspection results the FDA can rely on to replace their own inspections.
Plans for the agreement to be operational in all EU Member States by 15 July 2019 are on track.
EMA publishes updated guidance for pharmaceutical companies to prepare for UK’s withdrawal from EU
The European Medicines Agency (EMA) and the European Commission have updated their guidance to help pharmaceutical companies prepare for the United Kingdom’s (UK) withdrawal from the European Union (EU).
Updates to the questions-and-answers document include information on how the UK’s withdrawal will affect the status of inspection outcomes by the UK national competent authority and batch release processes for medicines that are subject to Official Control Authority Batch Release (OCABR) and Official Batch Protocol Review (OBPR).
The document also clarifies how scientific opinions of the Committee for Medicinal Products for Human Use (CHMP) for ancillary medicinal substances in medical devices requested by UK notified bodies will be affected.
In addition, it includes new information on back-up arrangements for Qualified Persons for Pharmacovigilance (QPPVs) and on marketing multi-country packs of medicines, where one of the countries in which the packs will be sold includes the UK.
The Agency has also published an updated version of its practical guidance for industry which outlines the steps that companies should follow to make sure that necessary changes to their marketing authorisation are made by the end of March 2019, to allow for the continued marketing of their medicine in the Union after Brexit.
Companies are reminded to plan for the UK’s withdrawal from the EU on 29 March 2019 in order to avoid any impact on the continuous supply of medicines for human and veterinary use within the EU and are advised to regularly check EMA’s dedicated webpage on the consequences of the UK’s withdrawal from the EU.
EMA Committee June 2018: Products Approved for Human Use
9 Medicines recommended for approval, including the first two CAR-T cell therapies in the EU
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended nine medicines for approval, including six orphan medicines, at its June 2018 meeting.
The CHMP recommended granting marketing authorisations for the first two chimeric antigen receptors (CAR) T-cell therapies in the European Union: Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) are both advanced therapy medicinal products (ATMPs) intended for the treatment of certain blood cancers.
Kymriah and Yescarta were designated as orphan medicines during their development. They are also the first medicines supported through EMA’s PRIority MEdicines (PRIME) scheme to receive a positive opinion from the Committee.
Together with the approval recommendation for the first CAR-T cell therapies, the Committee also recommended an extension to the therapeutic indication for RoActemra (tocilizumab) to include the treatment of CAR-T-cell-induced cytokine release syndrome (CRS), a known serious side effect of CAR-T cell therapies.
Four other orphan medicines were recommended for approval by the Committee: Cablivi (caplacizumab) for the treatment of acquired thrombotic thrombocytopenic purpura; Mepsevii (vestronidase alfa) for the treatment of mucopolysaccharidosis type VII; Veyvondi (vonicog alfa) for the treatment of von Willebrand disease and Vyxeos (daunorubicin / cytarabine) for the treatment of acute myeloid leukaemia.
Duzallo (lesinurad / allopurinol) received a positive opinion for the treatment of hyperuricaemia in patients with gout.
The CHMP granted a positive opinion for Ulipristal Acetate Gedeon Richter (ulipristal acetate), an informed consent application for the pre-operative treatment of uterine fibroids. An informed consent application makes use of data from the dossier of a previously authorised medicine, with the marketing authorisation holder of that medicine giving consent for the use of their data in the application.
Positive recommendation on a new medicine following re-examination
The CHMP recommended granting a marketing authorisation for Nerlynx (neratinib), for the adjuvant treatment of adult patients with breast cancer, after re-examining its negative opinion for this medicine adopted in February 2018.
EMA Committee May 2018: Products Approved for Human Use
9 medicines recommended for approval, including two orphans
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended nine medicines for approval, including two orphan medicines, at its May 2018 meeting.
The CHMP recommended granting a marketing authorisation for;
* Aimovig (erenumab), the first human monoclonal antibody therapy for prevention of migraine.
* Tegsedi (inotersen), a medicine for patients with hereditary transthyretin amyloidosis that aims to affect the course of the disease and improve quality of life.
* Myalepta (metreleptin) received a positive opinion for the treatment of leptin deficiency. Myalepta was designated as an orphan medicine during its development.
* Rxulti (brexpiprazole), for the treatment of schizophrenia.
Four biosimilar medicines received a positive opinion from the Committee:
* Halimatoz, Hefiya and Hyrimoz, all containing adalimumab, were recommended for the treatment of certain inflammatory and autoimmune disorders
* Trazimera (trastuzumab), was recommended for the treatment of breast and gastric cancer.
The Committee recommended for approval the generic medicine Nityr (nitisinone), for the treatment of hereditary tyrosinemia type 1.
EMA Committee June 2018: Products Approved for Human Use
3 medicines recommended for approval
The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) recommended three medicines for approval at its April 2018 meeting.
The CHMP recommended granting a marketing authorisation for;
* Biktarvy (bictegravir / emtricitabine / tenofovir alafenamide), for the treatment of HIV-1 infection.
* One hybrid medicine, Dzuveo (sufentanil) received a positive opinion for the treatment of pain.
* The Committee recommended for approval the generic medicine Carmustine Obvius (carmustine), for the treatment brain tumours, non-Hodgkin’s lymphoma and Hodgkin’s disease.
EMA: Key Notices and Approvals: Q1 2018
BioCryst Receives European Medicines Agency Approval for Influenza Treatment
BioCryst Pharmaceuticals, Inc., focused on the development and commercialization of treatments for rare diseases, has announced that the European Medicines Agency (EMA) has approved peramivir with the brand name of ALPIVAB, a single intravenous (I.V.) infusion for the treatment of uncomplicated influenza in adults and children from the age of 2 years.
The European Medicines Agency’s (EMA) Committee recommended 3 medicines for approval at its April 2018 meeting.
The committee recommended granting a marketing authorisation for Biktarvy (bictegravir / emtricitabine / tenofovir alafenamide), for the treatment of HIV-1 infection.
One hybrid medicine, Dzuveo (sufentanil) received a positive opinion for the treatment of pain.
The Committee recommended for approval the generic medicine Carmustine Obvius (carmustine), for the treatment brain tumours, non-Hodgkin’s lymphoma and Hodgkin’s disease.
The European Medicines Agency’s (EMA) Committee recommended 6 medicines for approval, including one orphan medicine, at its March 2018 meeting.
The committee recommended granting a conditional marketing authorisation for Rubraca (rucaparib), for the treatment of relapsed or progressive ovarian cancer. Rubraca was designated as an orphan medicine during its development.
Juluca (dolutegravir / rilpivirine) received a positive opinion for the treatment of human immunodeficiency virus (HIV) infection.
Two biosimilar medicines were recommended for approval by the Committee: Kanjinti (trastuzumab) for the treatment of breast and gastric cancer; and Zessly (infliximab) for the treatment of rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis.
Two generic medicines received a positive opinion from the committee : Pemetrexed Krka (pemetrexed), for the treatment of malignant pleural mesothelioma and non-small cell lung cancer; and Prasugrel Mylan (prasugrel), for the prevention of atherothrombotic events.
The European Medicines Agency (EMA)
the U.K. Regulatory Framework post-Brexit
March 5th 2018
Welcome to our latest briefing note on the ongoing challenges affecting the European Medicines Agency and the impact that Brexit is likely to have on the medicines regulatory framework in a post-Brexit U.K.
To Download or Print this briefing note, please click here: Briefing Note: The EMA and the U.K. post-Brexit
Brexit and European Medicines Regulations
With little over 12 months to go before the UK leaves the EU, there is still no clarity on how the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) will interact with the European Medicines Agency (EMA).
From the press releases and notifications issued by both entities to-date, it is clear that they are both hostages to the EU/UK political negotiations and are sticking to the narratives assigned to them.
With the EMA stating that the UK will be a third country from March 2019 and the MHRA stating that it hopes to minimise disruption caused by a potential ‘hard’ Brexit, it is hard to see a reconciliation before that date.
Let’s look at the EMA’s position first, as this is the clearer of the two.
For the EMA:
the UK will become a third country as from March 2019
any marketing authorization holders (MAHs) currently established in the United Kingdom will need to transfer their marketing authorization to a MAH established in one of the remaining countries of the EEA
- Activities such as those relating to batch release are to be performed in the EEA
- Drug safety must be monitored by a Qualified Person for pharmacovigilance residing and operating in the EU
- Manufacturing may take place in the UK, but the batch release must be done in the EU
- Activities such as those relating to batch release are to be performed in the EEA
The MHRA’s – the UK’s drugs regulator – position has primarily been to reiterate its promise to minimise disruption caused by a potential hard Brexit and that there will be no sudden changes to the UK’s regulatory framework when it leaves the EU in March 2019.
In a BBC radio interview on Feb 4th, Professor Sir Michael Rawlins, Chairman of the MHRA, said that he was looking towards a situation of regulatory alignment with the EMA. In his view, Regulatory alignment would mean the MHRA remaining part of the European system for licensing and regulating medicines products, and would continue to do its share of the scientific assessment (the MHRA currently does around 30% of the scientific assessments for the EMA).
Under alignment, the UK would be subject to European Court of Justice (ECJ) rulings. He added that alignment is government policy, even though it would technically break a key pledge to take the UK out of the ECJ’s jurisdiction. This would not matter, he said, because the ECJ is not involved in science policy.
We see this as being extremely difficult politically, especially for the current British government, which has campaigned on regaining British sovereignty from the ECJ.
Where does this leave US Speciality Pharma and Biotech Companies with Marketing Authorisation in the UK ?
In terms of the bespoke deal that the UK is seeking, we do not believe it is credible that the UK will only achieve an off-the-shelf Norwegian / Swiss / Turkish or Canadian type arrangement.
Despite the posturing on both sides of the negotiation table, the idea that the UK, a member of the G7, an ex-member of the EU and geographically located in Europe should not get a bespoke deal is neither logical nor reasonable. There is talk about a “special” deal for the UK from Dublin and Paris, where Premiers Varadkar and Macron have emphasised the role of the UK in Europe.
The key issue is how the MHRA and the EMA will work together. At present, the work carried out by the MHRA has been instrumental in the fabric of the EMA. The MHRA plays a leading role in the entire European licensing system, in both EU-wide licences and national licences. It is the lead regulator on seven in every 10 products, whether they are to be licensed by mutual recognition of national licences or through the decentralised procedure for simultaneous licensing in all countries in which a manufacturer seeks to market its products.
We are of the opinion, in light of the current political posturing by the UK Government and the EU that we will see the UK ending up with a relationship very similar to the one Canada negotiated with the EU. While it will never actually be presented in such a clear fashion, with red lines been drawn up by either side, it looks like the most likely solution.
We do not envisage a form of EU / UK regulatory alignment as set out by the current chair of the MHRA, but do see both agencies continuing to work closely together. If our prognosis is correct, the UK will be a third country for the EU and the MHRA will become the regulatory authority for all medicines in the UK (a role which it currently fulfils) but divergence from the EMA will be controlled.
An area of concern is that the UK may require that all MAHs for the UK will need to have an establishment / legal entity in the UK. This will add additional cost burdens for US speciality pharma companies, requiring one MAH in the EU/EEA and one in the UK.
In addition, drug safety will need to be monitored by a Qualified Person for Pharmacovigilance residing and operating in the UK. This cost will be more noticeable for smaller companies that do not already have a legal entity or QP in the EU and who could be required to set up a legal entity to become the MAH and appoint a QP.
Considering the UK accounts for only 3% of the global pharma sales, as opposed to the EU’s 25%, this will mean that many smaller pharma / biotech companies may not look for approval in the UK until post-EMA approval. This would result in the UK lagging behind on innovate and new medicines.
We are currently working with our speciality pharma clients and assisting them with their UK / EU structures so that they are prepared for the potential outcome of a hard Brexit.
EMA HQ Move and Management Board Meeting
The EMA management board met on the February 6th in an extraordinary session to discuss the EMA HQ move from London to Amsterdam. This was on the back of media reports that the new Amsterdam HQ will not be completed until December 2019, even though the EMA has to be fully operational in Amsterdam by the March 30th 2019.
While the new tailor-made premises are being completed, the EMA will be situated in temporary premises in Amsterdam. A delegation from the Netherlands confirmed that the temporary premises will be refurbished in line with EMA’s requirements and will be available on January 1st 2019.
Italy to challenge the EMA move to Amsterdam
The Court of Justice of the European Union (CJEU) received a request from the Italian government, and from the city of Milan, to annul the decision to move the EMA from London to Amsterdam. Milan was the runner-up for the relocation of the EMA HQ having tied with Amsterdam in a final vote by EU government representatives with the winner then determined by lottery.
The EMA Surveys Pharma companies on Brexit status
The European Medicines Agency (EMA) launched a survey in January to gather information from companies on their Brexit preparedness plans in order to identify any particular concerns with regard to potential issues in the supply of medicines that might impact public or animal health.
The EMA consulted with marketing authorisation holders of centrally authorised medicines who are either located in the United Kingdom, or who have in the United Kingdom;
- Quality Control
- Batch Release
- Import Manufacturing Sites
- A Qualified Person for Pharmacovigilance
- A Pharmacovigilance system master file
The aim of the survey was twofold. Firstly, to identify those companies where there is a need for concerted action to address medicines supply concerns due to Brexit, and secondly to help the EMA and the European Commission to plan resources in the area where these submissions will be processed for the EMA, the European Commission and the European medicines regulatory network.
The survey was sent directly to holders of a centralised marketing authorisation for human and veterinary medicines who are located in the UK, or who have an important part of their operations in the UK. Findings and recommendations from the survey will be shared with the European Commission and presented to EMA’s Management Board.
Denmark Follows Ireland in Dropping Fees for UK based MAHs
The Danish Medicines Agency (DKMA) has offered to waive Reference Member State (RMS) transfer fees for companies affected by Brexit. The DKMA’s offer comes shortly after the Irish drug regulator made the same pitch to Brexit-hit marketing authorization holders (MAHs).
If, as the EMA is planning, the UK becomes a third country in March 2019, companies with drugs approved under the mutual recognition and decentralized procedures that use the UK as their RMS will need to move their records to another agency. Ireland and now Denmark will allow MAHs to appoint them as RMS free of charge.
However, European rules place some limitations on which countries companies can select as their RMS. The new RMS must already be involved with the approved drug as a concerned member state. Companies must also complete all variations and other regulatory procedures before initiating the transfer.
We are expecting the Medicines Evaluation Board, the Dutch Medicines Regulatory Agency to follow Denmark and Ireland.
EMA gets positive ruling from the EU General Court in Transparency Cases
The EU General Court ruled in favour of the European Medicines Agency (EMA) in three cases that challenged the agency’s authority to release documents under EU transparency regulations.
The rulings mark the first time the Court of Justice of the European Union (CJEU) has ruled on an issue related to EMA’s application of Regulation (EC) No 1049/2001, the so called “Transparency Regulation”.
The judgments concern three separate cases;
- Case T-235/15 – Pari Pharma v EMAExternal: related to the disclosure of similarity and superiority reports on an orphan medicine, prepared by the Committee for Medicinal Products for Human use (CHMP)
- Case T-718/15 -PTC Therapeutics International v EMA: related to the disclosure of a clinical study report;
- Case T-729/15 – MSD Animal Health Innovation and Intervet international: related to five toxicology study reports for a veterinary medicine.
In all three cases, the pharmaceutical companies challenged EMA’s decision to release the concerned documents in accordance with the Transparency Regulation and EMA’s 2010 policy on access to documents.
TO DOWNLOAD OR TO PRINT THIS BRIEFING NOTE, PLEASE CLICK HERE: Briefing Note: The EMA and the U.K. post-Brexit
European Medicines Agency News: Key Notices & Approvals: Q4 2017
EMA recommends 7 Medicines for Approval
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended seven medicines for approval at its December 2017 meeting, including two orphan medicines, one of which is also an advanced therapy medicinal product (ATMP).
The CHMP recommended granting a marketing authorisation for the ATMP Alofisel (darvadstrocel), for the treatment of complex perianal fistulas in patients with Crohn’s disease. Alofisel has an orphan designation.
The Committee recommended granting a paediatric-use marketing authorisation (PUMA) for Alkindi (hydrocortisone), for the treatment of primary adrenal insufficiency, a rare hormonal disorder in infants, children and adolescents. PUMAs can be granted for medicines which are already authorised but no longer under patent protection, and have been developed specifically for children.
The committee recommended granting a conditional marketing authorisation for Crysvita (burosumab), for the treatment of X-linked hypophosphataemia with radiographic evidence of bone disease in children and adolescents with growing skeletons. Crysvita has an orphan designation.
Ozempic (semaglutide) received a positive opinion for the treatment of type 2 diabetes.
One biosimilar medicine was recommended for approval by the Committee: Herzuma (trastuzumab), for the treatment of breast and gastric cancer.
Two generic medicines received a positive opinion: Anagrelide Mylan (anagrelide), for the reduction of elevated platelet counts in at risk essential thrombocythaemia patients; and Efavirenz/Emtricitabine/Tenofovir disoproxil Krka (efavirenz / emtricitabine / tenofovir disoproxil), for the treatment of HIV infection.
EMA & UK Gov publish Brexit Guidance for Pharma companies
The European Medicines Agency (EMA) has published the first version of it procedural guidance for industry which outlines the practical and simplified requirements that companies should follow to make sure that necessary changes to their marketing authorisation are made by the end of March 2019, to allow for the continued marketing of their medicine in the European Economic Area (EEA) after Brexit, taking into consideration, that as of 30 March 2019 the United Kingdom will become a third country, from an EMA perspective.
The Agency and the European Commission have published additional and updated guidance to help pharmaceutical companies prepare for the United Kingdom’s withdrawal from the European Union wherein companies are reminded to plan in advance for the situation that the United Kingdom (UK) will leave the EU on 29 March 2019, in order to avoid any impact on the continuous supply of medicines for human and veterinary use within the EU.
The latest version is an update on the initial questions-and-answers document that was published in May 2017 and includes additional information on how the UK’s withdrawal from the EU will affect marketing applications and authorisations for different types of medicinal products, including, generic, hybrid and biosimilar medicines.
The UK Pharma industry had an output of £12.8 billion ($17 billion) in 2016. It accounts for 1% of total UK output, 7% of manufacturing output and provides employment to 36,000 taxpayers. Medicine and pharma products represent 8% of goods exported from the UK and 5% of goods imported into the UK.
In a sector of such importance to the UK economy, the UK’s House of Commons Research Library Service has issued a “Brexit & Medicines Regulation Briefing Paper” in which it says, it refers to a statement from Sir Michael Rawlins, Chairman of the MHRA where he expressed a concern that “one of the biggest worries I have about Brexit and standing alone as a regulator is that we are only 3% of the world market for new drugs and if we are not careful, we are going to be at the back of the queue behind Japan, America and Europe”.
The document also cites the example of Switzerland (a country not within the EMA but has a number of bilateral mutual recognition agreements with the EMA) but where regulatory process mean that marketing approvals are agreed on average 157 days after EMA approval.
PRAC confirms suspension of modified-release paracetamol
The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) has confirmed its recommendation that modified or prolonged-release paracetamol containing medicines (designed to release paracetamol slowly over a longer period than the usual immediate-release medicines) should be suspended from marketing.
It follows a re-examination of a previous suspension recommendation made in September 2017 by the Committee, following which the PRAC is still of the opinion that the advantages of having a longer-acting product did not outweigh the disadvantages – if an overdose of the medicine were taken – since the usual treatment procedures developed for immediate-release products are not appropriate for modified-release paracetamol.
The EMA says that in many cases, medics may not be able to determine whether an overdose of paracetamol involves immediate-release or modified-release products, making it difficult to decide what type of treatment is needed.
The Committee therefore recommended that marketing of modified-release paracetamol medicines should be suspended.
The review of modified-release paracetamol was initiated in June 2016 at the request of Sweden.
Germany’s Boehringer Ingelheim’s Humira biosim approved by E.U.
Germany’s Boehringer Ingelheim has confirmed that the European Commission has granted marketing authorisation for Cyltezo, a biosimilar to AbbVie’s Humira, for the treatment of multiple chronic inflammatory diseases in adults and children, including rheumatoid arthritis, psoriatic arthritis and active ulcerative colitis.
“Cyltezo is the first biosimilar from Boehringer Ingelheim approved in Europe, and marks a significant step forward for us in offering effective, and more affordable treatment options for patients with chronic inflammatory diseases,” said a Company spokesperson.
AbbVie’s Humira – the world’s biggest-selling drug, generated ~ $14 billion in sales in 2016 and accounted for 64 percent of AbbVie’s net revenue.
VBL Therapeutics gets Orphan Drug Designation for VB-111 in Europe
VBL Therapeutics (Nasdaq:VBLT), a clinical-stage biotechnology company focused on the discovery, development and commercialization of first-in-class treatments for cancer has announced that the European Medicines Agency (EMA) has designated ofranergene obadenovec (VB-111) as an “orphan medicinal product” for the treatment of ovarian cancer, adding to the orphan status already granted for glioblastoma in US and Europe.
VB-111 is the Company’s lead product candidate currently being studied in a Phase 3 pivotal trial for recurrent glioblastoma, with launch of a Phase 3 in platinum-resistant ovarian cancer expected by the end of the year.
Immune Design gets Orphan Drug Designation by the EMA for the Treatment of Follicular Non-Hodgkin’s Lymphoma
Immune Design (Nasdaq:IMDZ), a clinical-stage immunotherapy company focused on oncology, has announced that the European Medicines Agency (EMA) has granted Orphan Drug Designation for G100, Immune Design’s investigational intratumoral therapy, for the treatment of follicular non-Hodgkin’s lymphoma.
The EMA orphan drug designation is assigned to products targeting the treatment of rare diseases, which are defined as having a prevalence of not more than 5 in 10,000 people in the European Union (EU). This designation provides the sponsor with certain benefits, including protocol assistance, reduced fees for regulatory activities and up to 10 years of market exclusivity in the EU upon marketing approval for the designated indication.
G100 has also been granted orphan drug designation by the FDA Drug for the treatment of follicular non-Hodgkin’s lymphoma.
Rexahn Pharma gets Positive Opinion from EMA for Orphan Drug Designation
Rexahn Pharmaceuticals, Inc. (NYSE AMERICAN:RNN), a clinical stage biopharmaceutical company developing innovative, targeted therapeutics for the treatment of cancer, has announced that the European Medicines Agency’s (EMA) Committee for Orphan Medicinal Products (COMP) has issued a positive opinion recommending orphan medicinal product (orphan drug) designation for RX-3117 for the treatment of pancreatic cancer.
Pancreatic cancer is classed as a rare disease with a very poor prognosis and limited treatment options.
Applications for orphan designation are initially reviewed by the COMP. Positive opinions are then forwarded to the European Commission, which is responsible for formally granting the orphan designation. Orphan medicinal product designation in the European Union is given to products that are intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating; where prevalence of the condition in the EU is less than 5 in 10,000; and where the product represents a significant benefit over existing treatments.
Herceptin Biosim: Samsung gets green light in E.U.
Samsung Bioepis’ Ontruzant has become the first trastuzumab to be approved in Europe with EMA approval for marketing in the 28 European Union (EU) member states plus the European Economic Area member states of Norway, Iceland, and Liechtenstein.