Chapter 1 - Key achievements in 2021

Evaluation and monitoring of medicines: highlights

Human medicines

Medicines recommended for approval

Authorisation of new medicines is essential to advancing public health as they bring new opportunities to treat certain diseases. In 2021, EMA recommended 92 medicines for marketing authorisation. Below is a selection of medicines approved in 2021 that represent significant progress in their therapeutic areas:

Abecma, the first cell-based gene therapy to treat adults with relapsed and refractory multiple myeloma who have received at least three previous therapies and whose cancer has worsened since receiving the last treatment.

Bylvay, the first treatment for progressive familial intrahepatic cholestasis (PFIC) in patients aged 6 months or older.

Enspryng, a treatment for neuromyelitis optica spectrum disorders (NMOSD) in patients from 12 years of age who are anti-aquaporin-4 IgG (AQP4-IgG) seropositive.

Evrysdi, the first oral treatment for patients with certain types of spinal muscular atrophy, a rare and often fatal genetic disease that causes muscle weakness and progressive loss of movement.

Imcivree, for the treatment of obesity and the control of hunger associated with genetic deficiencies of the melanocortin 4 receptor (MC4R) pathway.

Tavneos, a first-in-class medicine to treat adults with severe, active granulomatosis with polyangiitis or microscopic polyangiitis, a rare type of inflammation of the blood vessels.

Trodelvy, a first-in-class medicine to treat adults with unresectable or metastatic triple-negative breast cancer who have received two or more prior systemic therapies, at least one of them for advanced disease.

Voxzogo, to treat achondroplasia in patients two years of age and above whose epiphyses are not closed. Achondroplasia is a condition that impairs bone growth and causes dwarfism.

Spikevax, Vaxzevria, COVID-19 Janssen vaccine and Nuvaxovid – four vaccines for preventing COVID-19.

Regkirona, Ronapreve and Xevudy - three treatments for COVID-19.

EARLY ACCESS TO MEDICINES THAT ADDRESS PUBLIC HEALTH NEEDS

In 2021, three medicines received a recommendation for marketing authorisation following an accelerated assessment: Bylvay, Evrysdi and Trodelvy. This mechanism is reserved for medicines that are able to address unmet medical needs. It allows for faster assessment of eligible medicines by EMA’s scientific committees (within a maximum of 150 days rather than 210 days).

The four vaccines and three treatments for COVID-19 recommended for authorisation by EMA in 2021 were assessed under a rolling review – EMA can use this regulatory pathway during a pandemic to speed up the evaluation of medicines by assessing data as they become available from ongoing studies.

13 medicines received a recommendation for a conditional marketing authorisation (CMA), one of the possibilities in the EU to give patients early access to new medicines: Abecma, COVID-19 Janssen vaccine, Gavreto, Jemperli, Koselugo, Lumykras, Minjuvi, Nexpovio, Nuvaxovid, Pemazyre, Rybrevant, Spikevax, Vaxzevria.

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) because the benefit of earlier patient access outweighs the potential risks of limited data. These authorisations are subject to specific obligations to generate complete data on the medicines after the authorisation.

Four medicines (Bylvay, Evkeeza, Tecovirimat SIGA and Voraxaze) were authorised under exceptional circumstances, a route that allows patient access to medicines that cannot be approved under a standard authorisation as comprehensive data cannot be obtained, either because there are only very few patients with 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. These medicines are subject to specific post-authorisation obligations and monitoring.

The enhanced development support provided by EMA’s PRIority Medicines (PRIME) scheme aims at helping patients to benefit as early as possible from promising medicines that target an unmet medical need, by optimising the generation of robust data and enabling accelerated assessment. This year, six medicines with PRIME designation were recommended for approval (Abecma, Bylvay, Evrysdi, Imcivree, Oxbryta and SkysonaiThe marketing authorisation for Skysona has been withdrawn at the request of the marketing authorisation holder.).

14 medicines under development were included in the scheme in 2021 in five medical specialties: oncology (6), neurology (3), haematology-haemostaseology (2), immunology-rheumatology-transplantation (2), and endocrinology-gynaecology-fertility-metabolism (1).

MEDICINES FOR RARE DISEASES

The EU framework for orphan medicines aims to encourage the development and marketing of medicines for patients with rare diseases by providing incentives for developers.

Orphan designations are reviewed by EMA's Committee for Orphan Medicinal Products (COMP) at the time of approval to determine whether the information available to date allows maintaining the medicine's orphan status and granting the medicine ten years of market exclusivity. Among the 92 medicines recommended for marketing authorisation in 2021, 19 had orphan designation confirmed by the end of the year.

At the time of marketing authorisation, the status of designated orphan medicines is reviewed. In 2021, the following six applications lost their orphan status before receiving marketing authorisation, which means they were still authorised but not as orphan medicinal products: Brukinsa, Copiktra, Efmody, Nexpovio, Orladeyo and Sibnayal. More information can be found in the COMP monthly reports.

New uses for existing medicines

89 extensions of indication were recommended in 2021. 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. Extensions of indication included:

Benlysta, the first centrally approved medicine for the treatment of active lupus nephritis.

Forxiga, to includethe treatment oftype 2 diabetes in children from 10 years of age whose condition is not controlled well enough.

Nucala, to include an add-on treatment for: i) relapsing-remitting or refractory eosinophilic granulomatosis with polyangiitis in patients aged 6 years and older; ii) inadequately controlled hypereosinophilic syndrome without an identifiable non-haematologic secondary cause in adults; and iii) with intranasal corticosteroids for the treatment of adults with severe chronic rhinosinusitis with nasal polyps for whom therapy with systemic corticosteroids and/or surgery do not provide adequate disease control.

Saxenda, as an adjunct to a healthy nutrition and increased physical activity for weight management in adolescents from the age of 12 years and above with obesity and body weight above 60 kg.

Volibris, to include the treatment of pulmonary arterial hypertension (PAH) in adolescents and children (aged 8 to less than 18 years).

RoActemra and Kineret, to include treatment of adults with COVID-19.

NEGATIVE OPINIONS

The CHMP adopted a negative opinion for five medicines in 2021: Aduhelm, Flynpovi, Ipique, Nouryant and Raylumis.

When the Committee cannot reach an agreement on a positive benefit-risk balance, it issues a negative opinion on the marketing authorisation application and elaborates on the grounds for this opinion. Applicants have the right to request a re-examination of the negative opinion within 15 days of receipt of the notification.

87% of all opinions (positive and negative) were reached by consensus among the 27 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.

71% of applicants who were granted a positive opinion for their medicine had received scientific advice or protocol assistance 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. This encourages generation of more robust data for regulatory assessment, and thus protects patients from taking part in unnecessary or poorly designed clinical trials.

Keeping patients 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 the quality, safety and benefit-risk balance of the medicine used in clinical practice. This is to optimise how the medicine is used by patients to achieve its full benefit and to protect patients from avoidable side effects. Regulatory measures range from a change to the product information to the suspension or withdrawal of a medicine or recall of a limited number of batches.

Important new safety adviceiSafety advice on treatments and vaccines for COVID-19 are included in the ‘European Medicines Regulatory Network’s response to COVID-19’ section.issued in 2021 included:

Recommended actions to minimise the risk of acute adrenal insufficiency in children that may occur when switching from conventional oral hydrocortisone formulations to Alkindi granules, due to potential inaccurate dosing with other oral hydrocortisone formulations.
Update of the product information of immune checkpoint inhibitors (Tecentriq, Bavencio, Libtayo, Imfinzi, Yervoy, Keytruda, Opdivo) to include a class effect of immune-mediated, non-infectious cystitis.
Update of the product information and EU reminder card of infliximab (Remicade and biosimilars) to include stricter recommendations on the administration of live vaccines to infants breastfed by mothers receiving infliximab due to infant exposure via breast feeding or during pregnancy.
Update of product information of Invanz to consider discontinuation of treatment if Invanz-induced encephalopathy is suspected (e.g. myoclonus, seizures, altered mental status, depressed level of consciousness). Patients with renal impairment are at higher risk of Invanz-induced encephalopathy and the resolution may be prolonged.
Update of product information of Kadycla to include new recommendations and measures to closely monitor the infusion site for possible subcutaneous infiltration during drug administration, as cases of delayed epidermal injury or necrosis following extravasation have been observed.
Update of the product information of Ifosfamide solutions to provide further details on the characteristics and risk factors of ifosfamide-induced encephalopathy, as well as highlighting the need to closely monitor patients receiving these medicines.
Update of the product information of Kineret and Ilaris with recommendations and warnings on adverse drug reactions with eosinophilia and systemic symptoms (DRESS) predominantly in patients with systemic juvenile idiopathic arthritis (sJIA).
Update of the product information of Venclyxto to include new recommendations and measures for the mitigation of the risk of tumour lysis syndrome (a serious complication with rapid break down of cancer cells).
New recommendation to only use Xeljanz in patients over 65 years of age, patients who are current or past smokers, patients with other cardiovascular risk factors and patients with other malignancy risk factors when no suitable treatment alternative is available.

The product information for 502 centrally authorised medicines was updated on the basis of new safety data in 2021. Every year, PRAC recommendations on safety warnings are also 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 INTEGRITY OF CLINICAL TRIAL CONDUCT AND THE MANUFACTURE AND SUPPLY OF MEDICINES

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

The identification by marketing authorisation holders of active substances and finished products at risk of N-nitrosamine formation or (cross-)contamination was completed. All human chemical and biological products for which a potential risk of nitrosamine contamination was identified are undergoing confirmatory testing. This applies to 16% of chemical and 1% of biological centrally authorised products (CAPs). Results are expected by September 2022 and July 2023, respectively. In March 2021, the European medicines regulatory network established the Nitrosamine Implementation Oversight Group (NIOG) to oversee the implementation of the CHMP’s Article 5(3) opinion on nitrosamines in human medicines. The group includes representatives from the CHMP, the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh), EMA working parties, the European Directorate for the Quality of Medicines and HealthCare (EDQM) and EMA staff. It also acts as the main interface for pharmaceutical industry stakeholders to discuss regulatory and scientific developments on nitrosamines with EMA and the European medicines regulatory network.

Throughout 2021, EMA continued to contribute to the Nitrosamines International Steering Group (NISG) and the Nitrosamine International Technical Working Group (NITWG). The Agency shared information on substances at risk of containing nitrosamine impurities and discussed the approach for ensuring the safety and quality of such medicines. This also includes agreement on acceptable intake limits, or testing approaches. NISG was created in 2018 when the first case of presence of nitrosamines in sartan medicines was identified. The members of NISG and NITWG are: Australia, Brazil, Canada, Japan, Singapore, Switzerland, the United States of America, the EDQM, the World Health Organisation and EMA.

A system was put in place to ensure patient safety whilst avoiding shortages of critical medicines. A Nitrosamine Multidisciplinary Expert Group (NMEG) proposed interim safe limits for a limited duration of time whilst marketing authorisation holders (MAHs) implement their corrective and preventive actions. This system has facilitated the successful management of nitrosamine levels in metformin and rifampicin. Official medicines control laboratories (OMCLs) have tested products containing these active substances in order to independently evaluate the quality of distributed medicines.

EMA's CHMP carried out a review of the presence of a nitrosamine impurity, N nitroso-varenicline, in Champix (varenicline), a smoking cessation medicine. The CHMP concluded that the marketing authorisation holder has to fulfil certain quality requirements to ensure that Champix conforms to acceptable nitrosamine intake limits for EU medicines, calculated in line with the ICH M7 guideline. As a precaution, the marketing authorisation holder recalled several batches and paused distribution of Champix, as of June 2021.

Veterinary medicines

New medicines to benefit animal health in Europe

In 2021, EMA recommended 12 veterinary medicines for marketing authorisation; seven of these contain a new active substance (i.e. not previously authorised in the EU). Among the 12 medicines recommended for marketing authorisation, five were vaccines. Of these, four were biotechnological vaccines.

A SELECTION OF KEY RECOMMENDATIONS IN 2021:

Fatrovax RHD, a new vaccine used to reduce mortality and signs of rabbit haemorrhagic disease (RHD). The active substances are obtained by means of biotechnology using Trichoplusia ni pupae, avoiding the use of rabbits in the production of the vaccine. This is in line with the so-called 3R principles (replace, reduce and refine animal use for the development, manufacturing and testing of medicines).

Felpreva, a new veterinary medicine for cats with, or at risk from, mixed parasitic infestations.

Strangvac, a vaccine given to horses from 8 months of age to reduce clinical signs of the acute stage of strangles.

Suiseng Diff/A, a new vaccine given to female pigs to protect their offspring from intestinal disease caused by toxins produced by the bacteria Clostridioides difficile (toxins A and B) and Clostridium perfringens type A (alpha toxin). This vaccine has the potential to reduce the need for antimicrobial treatment in animals and could therefore limit the development of antimicrobial resistance (AMR).

Fatrovax RHD, Felpreva and Strangvac 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 under current market conditions.

Optimising the safe and effective use of veterinary medicines

Once a veterinary medicine has been put on the market, EMA and EU Member States continuously monitor the quality and benefit-risk balance of the medicine. The aim is to optimise the safe and effective use of the veterinary medicine, to achieve its full benefit and to protect animals and users from avoidable adverse effects. If the benefit-risk balance of a veterinary medicine changes, EMA can take regulatory measures that range from an amendment to the product information to the suspension or withdrawal of a medicine. The Agency can also recommend recalling batches of the medicine concerned.

IMPORTANT NEW SAFETY ADVICE ISSUED IN 2021

The product information for 27 medicines was updated on the basis of new safety data. The revised information is expected to help animal owners and healthcare professionals to make informed decisions when using or prescribing a medicine. This included:

Adition of further information in the package leaflet on potential side effects following the administration of:
- Advocate spot-on solution for dogs: ataxia (inability to co-ordinate muscle movements); muscle tremor (shaking);
- Bravecto spot-on solution for cats: convulsions;
- Bravecto Plus: ataxia;
- Cerenia tablets for dogs: lethargy (lack of energy);
- Cerenia injection for solution for dogs and cats: lethargy;
- Comfortis: ataxia in cats; muscle tremor in cats;
- Cytopoint: injection-site pain; injection-site swelling; immune-mediated diseases, such as haemolytic anaemia (excessive breakdown of red blood cells) or thrombocytopenia (low blood platelet counts, which can lead to bleeding and bruising);
- Felisecto Plus: convulsions; ataxia; emesis (vomiting); diarrhoea;
- Fevaxyn Pentofel: haematemesis (vomiting of blood); diarrhoea with bleeding;
- Galliprant: elevated liver enzymes; elevated blood urea nitrogen (a marker for liver and kidney problems); elevated creatinine;
- Kriptazen: diarrhoea (change of frequency from “very rare” to “rare”);
- Letifend: hypersensitivity reactions, such as anaphylaxis and skin manifestations, including oedema (swelling), urticaria (itchy rash), pruritus (itching);
- Librela: allergic reactions;
- Osurnia: application-site reactions, such as erythema (reddening of the skin), pain, pruritus, oedema and ulcer; hypersensitivity reactions, including facial oedema, urticaria and shock;
- Prevomax: lethargy;
- Purevax RC: emesis;
- Purevax RCP: emesis;
- Purevax RCP FeLV: emesis;
- Purevax RCPCh: emesis;
- Purevax RCPCh FeLV: emesis;
- Simparica Trio: vomiting; diarrhoea; lethargy, anorexia/inappetence; tremor; ataxia; convulsion;
- Stronghold Plus: convulsions; ataxia; emesis; diarrhoea;
- Ubac: anaphylactic-type reactions (sudden, severe allergic reactions), such as oedema;
- Vectra Felis: muscle tremors; lethargy;
- Vectra 3D: convulsions;
- Vepured: emesis; recumbency (inability to stand due to loss of consciousness, pain or inability to control the body); convulsions; lethargy; loss of consciousness.
Addition of new special precautions to be taken by the person administering the following veterinary medicines to animals:
- Draxxin: reddening of the skin (erythema) and/or dermatitis as a result of contact with the medicine. If there is suspicion of an allergic reaction following accidental exposure (recognisedby itching, difficulty in breathing, hives, swelling on the face, nausea, vomiting, etc.), appropriate treatment should be administered. Seek medical advice immediately and show the package leaflet or the label to the physician.
- Kexxtone: keep dogs away from treated animals. Accidental ingestion of active ingredient by dogs has resulted in fatal consequences. In case of suspected ingestion by dogs, seek veterinary advice immediately.
- Vectra 3D: pregnant women and women suspected of being pregnant should not administer the product and should avoid direct contact with the application site until the application site is no longer noticeable.

PROTECTING CONSUMERS

If a medicine is intended to be used in a food-producing animal, it needs to be safe for people to eat the food that comes from this animal. The maximum residue limits (MRLs) recommended by EMA reflect the level of residues of the veterinary medicine in food derived from a treated animal that can be considered safe for consumption. The MRL is established before the medicine for food-producing animals is authorised in the EU.

In 2021, positive opinions were adopted recommending the establishment of MRLs for the following active substances:

Bambermycin in poultry tissues;
Toltrazuril in poultry eggs.

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