Chapter 1 - Key achievements in 2019

Evaluation and monitoring of medicines: highlights

Human medicines

Medicines recommended for approval

New, innovative medicines are essential to advancing public health as they bring new opportunities to treat diseases, particularly those that target an unmet medical need or a rare condition. In 2019, EMA recommended 66 medicines for marketing authorisation. Below is a selection of medicines approved in 2019 that represent significant progress in their therapeutic areas. More information and figures on approval of medicines is available in chapter 2.

Vitrakvi, the first ‘histologyindependent’ treatment in the EU for solid tumours with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. NTRK gene fusions occur very frequently in a number of rare cancers.

Ondexxya, an antidote for adult patients taking the anticoagulant medicines apixaban or rivaroxaban, when reversal of their action is needed due to life-threatening or uncontrolled bleeding.

Baqsimi, the first treatment for severe hypoglycaemia (low blood sugar level) that can be administered without an injection in patients with diabetes aged four years and older.

Zynquista, an oral adjunct to insulin for certain patients with type 1 diabetes. Zynquista blocks the action of two proteins known as glucose transporters (SGLT1 and SGLT2) which are found in the intestine and kidneys.

Zynteglo, an advanced therapy medicinal product (ATMP) for the treatment of beta-thalassaemia, a rare inherited blood condition that causes severe anaemia. Zynteglo is intended for adult and adolescent patients 12 years and older who need regular blood transfusions to manage their disease and have no matching donor for a stem-cell transplant.

Epidyolex, for the treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome, two rare forms of epilepsy. Epidyolex is the first medicine with an active substance derived from cannabis, that received a positive opinion in the EU centralised procedure.

Sixmo, a substitution treatment for opioid dependence. Sixmo is an implant that releases low levels of buprenorphine into the patient’s body for six months.

The first Ebola vaccine – Supporting the response to a public health emergency

In October 2019, EMA’s human medicines committee (CHMP) recommended granting a conditional marketing authorisation in the EU for Ervebo (rVSVΔG-ZEBOV-GP), the first vaccine for active immunisation of individuals aged 18 years and older at risk of infection with the Ebola virus.

Ebola virus disease is a rare but severe illness caused by the Ebola virus. Death rates have varied from 25% to 90% in past outbreaks. The largest outbreak to date occurred in West Africa between 2014 to 2016 with more than 11,000 deaths. Ervebo is a genetically engineered, replication-competent, attenuated live vaccine. Data from clinical trials and compassionate use programmes have shown that Ervebo protects against Ebola virus disease in humans after the administration of a single dose.

EMA is working with regulatory authorities around the world to support the World Health Organization (WHO) and advise on possible pathways for the development, evaluation and approval of medicines and vaccines to fight Ebola. Erbevo benefitted from support of the PRIME scheme and was assessed following an accelerated timetable.

EARLY ACCESS TO MEDICINES THAT ADDRESS PUBLIC HEALTH NEEDS

In 2019, three medicines (Ervebo, Xospata and Zynteglo) were recommended for marketing authorisation following an accelerated assessment. This mechanism is reserved for medicines that address unmet medical needs. It allows for the assessment of eligible medicines by EMA’s scientific committees within a maximum of 150 days rather than the usual 210 days.

Eight medicines received a recommendation for a conditional marketing authorisation, one of the possibilities provided in the EU to give patients early access to new medicines: Ervebo, Libtayo, Lorviqua, Ondexxya, Polivy, Vitrakvi, Waylivra and Zynteglo.

As these medicines address unmet medical needs, the conditional authorisation allows for early approval on the basis of less complete clinical data than normally required (products for use in emergency situations may have less complete pharmaceutical or non-clinical data). These authorisations are subject to specific postauthorisation obligations to generate further data on the medicines.

One medicine (Dectova) was authorised under exceptional circumstances. This route allows for patients’ access to medicines that cannot be approved under a standard authorisation as comprehensive data cannot be obtained, either because very few patients have the disease, or the collection of complete information on the efficacy and safety of the medicine would be unethical, or there are gaps in the scientific knowledge.

Dectova is an antiviral medicine used to treat complicated and potentially life-threatening influenza (flu) caused by either the influenza A or B virus in adults and children from 6 months of age. Medicines authorised under exceptional circumstances are subject to specific postauthorisation obligations and monitoring.

MEDICINES FOR RARE DISEASES

The EU framework for orphan medicines provides incentives for developers to encourage the development and marketing of medicines for patients with rare diseases. A medicine that was granted an orphan designation during its development can benefit from ten years of market exclusivity after its marketing authorisation, provided EMA’s Committee for Orphan Medicinal Products (COMP) confirms its orphan status at the time of approval.

Among the medicines recommended for marketing authorisation, seven had had their orphan designation confirmed by the end of the year: Epidyolex, Isturisa, Palynziq, Polivy, Waylivra, Xospata and Zynteglo.

In 2019, the following applications lost their orphan status before receiving marketing authorisation, which means they were still authorised as medicinal products but not as orphan medicinal products: Trecondi, Cufence, Esperoct, Ultomiris, Vitrakvi and Revlimid. More information can be found in the COMP monthly reports.

NEW USES FOR EXISTING MEDICINES

Sixty extensions of indication were recommended in 2019. The extension of the use of a medicine that is already authorised for marketing in the EU can also offer new treatment opportunities for patients. Important extensions of indication included:

Forxiga and its duplicate Edistride as an oral adjunct treatment with insulin for certain patients with type 1 diabetes.

Victoza, to include the treatment of children and adolescents aged ten years or older with type 2 diabetes.

Dupixent as an add-on maintenance treatment for patients aged 12 years and older with certain forms of severe asthma.

NEGATIVE OPINIONS

The CHMP adopted negative opinions for fouriThis figure does not include the initial negative opinions adopted by the CHMP on Xyndari (glutamine) in May and Evenity (romosozumab) in June 2019. The applicant for Xyndari withdrew its application for marketing authorisation in September 2019. The initial negative opinion for Xyndari was under re-examination at the company’s request at the time of withdrawal. The applicant for Evenity requested re-examination of the Committee’s negative opinion and, after considering the grounds for this request, the CHMP recommended granting marketing authorisation for this medicine in October 2019. medicines in 2019: Cabazitaxel Teva, Doxolipad, Hopveus and Vanflyta. When the Committee finds that the benefits of a medicine do not outweigh its risks, it issues a negative opinion on the marketing authorisation application and elaborates on the grounds. Applicants have the right to request a re-examination of the negative opinion within 15 days of receipt of the notification.

89% of all opinions (positive and negative) were reached by consensus among the 28 CHMP members, which means that, following in-depth discussions, the experts agreed on all aspects of the marketing authorisations and there were no divergent opinions.

Around 59% of applicants who were granted a positive opinion for their medicine had received scientific advice from EMA during their product’s development phase. This early engagement with developers allows EMA to clarify what kind of evidence is required to later evaluate a medicine for authorisation on the basis of the then generated data, and thus protects patients from taking part in unnecessary or poorly designed clinical trials.

Keeping medicines safe

MONITORING MEDICINES AFTER THEIR AUTHORISATION – OPTIMISING SAFE AND EFFECTIVE USE

Once a medicine has been authorised, EMA and the EU Member States continuously monitor its quality and benefit-risk balance. This helps to optimise the use of a medicine to achieve its full benefit and to protect patients from avoidable side effects. If new safety information becomes available, EMA’s safety committee (PRAC) can take regulatory measures ranging from a change to the product information to the suspension or withdrawal of a medicine or the recall of already distributed medicines.

Important new safety advice issued in 2019 included:

Recommendation to add new measures to prevent serious and potentially fatal errors with the dosing of methotrexate for treatment of inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn’s disease. A dedicated stakeholders’ meeting supported the Agency’s safety recommendation.
Recommendation to revoke the marketing authorisations for fenspiride medicines following a review that confirmed that these cough medicines could cause heart rhythm problems.
Recommendation to restrict the use of the multiple sclerosis medicine Lemtrada (alemtuzumab) due to reports of rare but serious side effects, including deaths.
Recommendation of new risk minimisation measures for Xeljanz (tofacitinib) to protect patients at high risk of blood clots. The review concluded that the medicine could increase the risk of blood clots in the lungs and in deep veins in patients who are already at high risk.
Recommendation to restrict the use of the multiple sclerosis medicine Gilenya (fingolimod) in pregnant women and in women able to have children who are not using effective contraception. The review confirmed that the medicine can harm the unborn child.
Warning to healthcare professionals that light-exposed intravenous nutrition products containing amino acids and/or lipids may lead to severe adverse effects in premature newborn babies. These products (containers and administration sets) should be protected from light.
Direct acting oral anticoagulants Eliquis (apixaban), Pradaxa (dabigatran etexilate), Lixiana (edoxaban), Roteas (edoxaban) and Xarelto (rivaroxaban) should not be used in patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome, a disorder that causes an increased risk of blood clots.
Recommendation not to use Xarelto (rivaroxaban) to prevent thrombosis (formation of blood clots in the blood vessels) in patients who have recently undergone transcatheter aortic valve replacement.

The product information for 405 centrally authorised medicines was updated on the basis of new safety data in 2019. Furthermore, every year, PRAC recommendations on safety warnings are included in the product information of many thousands of nationally authorised products (NAPs). The revised information is expected to help patients and healthcare professionals to make informed decisions when using or prescribing a specific medicine.

ENSURING THE INTEGRITY OF CLINICAL TRIAL CONDUCT AND THE MANUFACTURE AND SUPPLY OF MEDICINES

Medicines development and manufacturing are global. It is important for regulators to ensure that EU standards are adhered to, no matter where clinical trials or manufacturing take place.

In 2019, one centralised marketing authorisation application was withdrawn as a result of noncompliance with good clinical practice (GCP).

The CHMP concluded its review of sartan medicines which set strict new manufacturing requirements for these medicines. The review was initiated due to the presence of nitrosamine impurities, including N-nitrosodimethylamine (NDMA), in a number of these medicines used to control high blood pressure. Subsequently, a nitrosamine impurity was also detected in batches of ranitidine, and the CHMP started a review of medicines containing this active substance. Ranitidine medicines are widely used to reduce the production of stomach acid in patients with conditions such as heartburn and stomach ulcers.

In September 2019, EMA initiated a wider review to provide guidance to marketing authorisation holders (MAHs) on how to avoid the presence of nitrosamines impurities in human medicines. As part of this review, the CHMP has requested MAHs for human medicines containing chemically synthesised active substances to review their medicines for the possible presence of nitrosamines and to test all products at risk. More information on this review is available in the section on nitrosamine impurities later in the report.

EMA and NCAs continue to monitor the presence of nitrosamines impurities in medicines, in cooperation with regulators from outside the EU.

More information and figures on inspections and safety monitoring of medicines is available in chapter 2.

Veterinary medicines

New medicines to benefit animal health in Europe

In 2019, EMA recommended 15 veterinary medicines for marketing authorisation – an increase of 50% compared to 2018. Of these, five had new active substances which had not previously been authorised for use in animals. Four were vaccines, one of which had been developed by means of recombinant DNA technology.

Aservo EquiHaler, Nobivac Myxo RHD Plus and Stelfonta were recommended for marketing authorisation under EMA’s minor-use-minor-species (MUMS)/limited market programme. This scheme aims to stimulate development of new veterinary medicines for minor species and for rare diseases in major species that would otherwise not be developed.

Aservo EquiHaler is a medicine for the treatment of horses with clinical signs of severe equine asthma. Nobivac Myxo RHD Plus is a live recombinant vaccine intended for the active immunisation of rabbits from five weeks of age against myxomatosis and rabbit haemorrhagic disease. Stelfonta is a medicinal product for the treatment of non-resectable, nonmetastatic cutaneous and subcutaneous mast cell tumours in dogs.

Optimising the safe and effective use of veterinary medicines

Important new safety advice issued in 2019

The product information for 15 medicines was updated on the basis of new safety data. The revised information is expected to help animal owners and veterinarians to make informed decisions when using or prescribing a medicine.

Addition of further advice in the product information for Bravecto on potential side effects following administration in dogs, in relation to neurological signs.
Inclusion of special precautions and warnings in the product information for Bravecto Plus to ensure the safety of the person handling and administering the treatment. Further advice on potential side effects following administration of Bravecto Plus in cats, such as neurological signs, was also included.
Amendment of the product information on potential side effects affecting vision following administration of Broadline in cats.
Addition of further advice in the product information for Coxevac on potential side effects following administration in cattle, such as systemic reactions.
Inclusion of further advice in the product information for Credelio on potential side effects following administration in dogs and cats, such as neurological reactions.
Addition of further advice in the product information for Cytopoint on potential side effects following administration in dogs, such as neurological reactions.
Amendment of the product information for Draxxin, to include additional special precautions.
Amendment of the product information on potential side effects following administration of Eravac in rabbits to include lethargy and/or inappetence.
Amendment of the product information on potential side effects following administration of Letifend in dogs, such as lethargy, vomiting, diarrhoea and hyperthermia.
Addition of further advice in the product information for Nexgard Spectra on potential side effects following administration in dogs, such as erythema and neurological signs.
Amendment of the product information for Osurnia to include special precautions relating to off-label use of the product in cats.
Addition of further advice in the product information on potential side effects following administration of Simparica and MiPet Easecto in dogs in relation to neurological signs.
Amendment of the product information on potential side effects following administration of Suprelorin in dogs and ferrets, in relation to weight gain and neurological signs.
Addition of further advice in the product information for Zycortal on potential side effects following administration in dogs, such as injection site reactions.

The CVMP adopted six positive opinions for extensions of existing authorisations, broadening the use of the medicines concerned.

PROTECTING CONSUMERS

If a medicine is intended to be used in a foodproducing animal, it needs to be safe for people to eat the food that comes from this animal. The maximum residue limit (MRL) recommended by EMA reflects the level of veterinary medicine residues in food derived from a treated animal that can be considered safe for consumption. In 2019, MRLs were established for the following active substances:

Bambermycin in medicines for rabbits
Ciclesonide in medicines for horses.

More information and figures on veterinary medicines is available in chapter 2.