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 2022, EMA recommended 89 medicines for marketing authorisation, 41 of which had a new active substance. Below is a selection of medicines approved in 2022 that represent significant progress in their therapeutic areas:
Beyfortus, the first medicine for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in newborns and infants during their first RSV season (when there is a risk of RSV infection in the community).
Breyanzi, a gene therapy for the treatment of adult patients with three subtypes of non-Hodgkin lymphoma (diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B)), whose cancer has come back or who have not responded to treatment after two or more lines of systemic therapy.
Carvykti, for the treatment of adults with relapsed and refractory multiple myeloma who have received at least three prior therapies and whose cancer has worsened since they received their last treatment.
Ebvallo, for the treatment of Epstein-Barr virus positive post-transplant lymphoproliferative disease. This somatic cell therapy is intended for adult and paediatric patients who develop this malignancy after transplantation as a result of the immunosuppression caused by the medication required to reduce the possibility of rejection of the transplanted organ or bone marrow.
Hemgenix, the first gene therapy for the treatment of severe and moderately severe Haemophilia B in adults, an inherited disorder characterised by an increased bleeding tendency due to a partial or complete deficiency in the activity of factor IX.
Kimmtrak, a monotherapy for treatment of adult patients with a form of eye cancer called uveal melanoma.
Mounjaro, a first-in-class medicine that activates both the GLP-1 and GIP receptors, which leads to improved blood sugar control in adults with type-2 diabetes mellitus.
Roctavian, for the treatment of severe haemophilia A in adults who do not have factor VIII inhibitors (auto-antibodies produced by the immune system which make factor VIII medicines less effective) and no antibodies to adeno-associated virus serotype 5 (AAV5).
Upstaza, the first treatment for adult and paediatric patients with aromatic L-amino acid decarboxylase (AADC) deficiency, an ultra-rare genetic disorder affecting the nervous system.
Xenpozyme, the first therapy for the treatment of adult and paediatric patients with acid sphingomyelinase deficiency (ASMD), a rare genetic condition, historically known as Niemann-Pick disease type A, A/B and B.
Zokinvy, the first treatment for children with progeroid syndromes, an ultra-rare genetic disease which causes premature aging and death.
COVID-19 Vaccine Valneva and VidPrevtyn Beta, two vaccines for preventing COVID-19 in adults.
Paxlovid (for adults) and Evusheld (for adults and adolescents aged 12 years and older), two treatments for COVID-19.
EARLY ACCESS TO MEDICINES THAT ADDRESS PUBLIC HEALTH NEEDS
In 2022, five medicines received a recommendation for marketing authorisation following an accelerated assessment: Beyfortus, Kimmtrak, Lunsumio, Tecvayli and Xenpozyme. 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 two vaccines and two treatments for COVID-19 recommended for authorisation by EMA in 2022 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.
Nine medicines received a recommendation for a conditional marketing authorisation, one of the possibilities in the EU to give patients early access to new medicines: Carvykti, Hemgenix, Kinpeygo, Lunsumio, Paxlovid, Roctavian, Spevigo, Tecvayli, and Zynlonta.
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 post-authorisation obligations to generate complete data on the medicines.
Five medicines (Ebvallo, Livmarli, Nulibry, Upstaza and Zokinvy) were authorised under exceptional circumstances, a route that allows patients 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, comprehensive data cannot be obtained even after authorisation. These medicines are subject to specific post-authorisation obligations and monitoring.
The enhanced development support provided by EMA’s PRIority MEdicines (PRIME) 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, eight medicines with PRIME designation were recommended for approval (Beyfortus, Breyanzi, Carvykti, Ebvallo, Hemgenix, Roctavian, Tecvayli, Xenpozyme).
13 medicines under development were accepted in the scheme in 2022 pertaining to the following disease areas: endocrinology-gynaecology-fertility-metabolism (2), neurology (2), oncology (2), vaccines (2), haematology – haemostaseology (1), infectious diseases (1), musculoskeletal and connective tissue disorders (1), ophthalmology (1), and uro-nephrology (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 89 medicines recommended for marketing authorisation in 2022, 21 had their orphan designation confirmed by the end of the year.
Three medicines lost their orphan status before receiving a marketing authorisation, which means they were still authorised as medicinal products but not as orphan medicinal products. These are: Breyanzi, Pepaxti and Tecvaily.
New uses for existing medicines
In 2022, 90 extensions of indication were recommended, including 37 for paediatric use. 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:
Adcirca, for the treatment of pulmonary arterial hypertension (PAH) in paediatric patients aged 2 years and above;
Dupixent, for the treatment of eosinophilic esophagitis (a rare, chronic, inflammatory disease of the esophagus) in adults and adolescents 12 years and older who cannot follow conventional medicinal therapy;
Jakavi, for the treatment of paediatric patients with acute and chronic Graft vs Host Disease (when white blood T cells in donated stem cells or bone marrow attack the host’s body cells) from 12 years of age, who have inadequate response to corticosteroids or other systemic therapies;
Jardiance, for the treatment of all types of heart failure, including those with preserved ejection fraction;
Xydalba, for the treatment of acute bacterial skin and skin structure infections in adults and paediatric patients aged 3 months and older.
NEGATIVE OPINIONS
The Committee for Medical Products for Human Use (CHMP) adopted a negative opinion for three medicines in 2022: Hervelous, Omblastys and Tuznue.
98% of all opinions (positive and negative) were reached by consensus among the 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.
52% of applicants that were granted a positive opinion for their medicine had received scientific advice or protocol assistance from EMA during their product’s development phase. The figure increases to 78% for applicants for medicines with new active substances. Early engagement with developers allows EMA to clarify what kind of evidence is required to later evaluate a medicine for authorisation. This encourages the 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 the benefit-risk balance of the medicine used in real-life on the market. This is done 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 a recall of a limited number of batches.
The product information for 467 centrally authorised medicines was updated on the basis of new safety data in 2022. Every year, recommendations by EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) on safety 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 make informed decisions when using or prescribing a specific medicine.
Important new safety advice issued in 2022 included:
- a recommendation to withdraw the marketing authorisations for amfepramone obesity medicines because risk management measures were not sufficiently effective to reduce the risk of serious side effects, such as pulmonary arterial hypertension (high blood pressure in the lung arteries) and dependency. In addition, there was evidence of use during pregnancy, which could pose risks to the unborn baby;
- an update of the product information of dexmedetomidine to highlight the increased risk of mortality when administering dexmedetomidine in intensive care unit (ICU) patients aged 65 years and less, compared with alternative sedatives;
- a recommendation to suspend marketing authorisations for hydroxyethyl-starch (HES) solutions for infusion across the EU to avoid their use outside the recommendations previously included in the product information to minimise the risk of kidney injury and death in certain patients (those critically ill, with burn injuries or with sepsis);
- an update of the product information of infliximab to include a recommendation to postpone the use of live vaccines in infants who are exposed to infliximab during pregnancy or via breastfeeding;
- a recommendation to only use Janus-kinase (JAK) inhibitors if no suitable treatment alternatives are available for people at increased risk of major cardiovascular problems, those who smoke / have smoked and those at increased risk of cancer. In addition, caution is advised for use in patients with risk factors for blood clots in the lungs and in deep veins (venous thromboembolism, VTE). The use of a lower dose is recommended in patients with risk factors;
- an update of the product information of Mavenclad (cladribine) to include the risk of serious liver injury and to conduct liver function tests during treatment. In case a patient develops liver injury, treatment with Mavenclad should be interrupted or discontinued, as appropriate;
- a recommendation to add new measures to use medicines containing nomegestrol or chlormadinone at the lowest effective dose and for the shortest duration possible, and only when other interventions are not appropriate, and not to use these medicines in patients who have, or have had, meningioma;
- a recommendation to withdraw marketing authorisations of pholcodine-containing medicines across the EU given the serious risk of anaphylactic reactions (sudden, severe and life-threatening allergic reactions) to certain medicines called neuromuscular blocking agents (NMBAs) used in anaesthesia in patients who have been previously treated with pholcodine;
- a recommendation to not use Rubraca (rucaparib) as third-line treatment for cancers of the ovary, fallopian tubes or peritoneum with a BRCA mutation in patients whose cancer has come back after at least two platinum-based chemotherapies and who cannot have further platinum-based therapy;
- a revised warning against the use of live vaccines in infants exposed to Stelara (ustekinumab) in utero for six months following birth or until the infant’s serum levels of ustekinumab are undetectable;
- new recommendations to avoid or discontinue the use of Stresam (etifoxine) in patients with severe skin reactions or severe liver problems after taking etifoxine;
- a recommendation to update the product information for terlipressin-containing medicines with warnings to reduce the risk of respiratory failure and sepsis when using terlipressin to treat kidney problems in people with advanced liver disease;
- an update of the product information of Xalkori (crizotinib) to reflect the risk of ocular toxicity, severe visual loss and the need to monitor paediatric patients for vision disorders. In addition, a dose reduction of Xalkori should be considered in patients who develop Grade 2 ocular disorders and treatment should be permanently discontinued if Grade 3 and 4 ocular disorders occur, unless another cause is identified.
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 takes place.
The CHMP recommended the suspension of marketing authorisations for some 100 medicines which obtained approval on the basis of flawed bioequivalence studies conducted by the contract research organisation Synchron Research Services, located in Ahmedabad, India. For around 20 medicines included in this review, bioequivalence data from other sources are available and therefore the medicines concerned are allowed to remain on the EU market. To lift the suspension, companies relying on data from Synchron Research Services must provide alternative data demonstrating bioequivalence.
All marketing authorisation holders (MAHs) have continued to report on finished products at risk of N-nitrosamine presence in line with the requirements of the ‘call for review’ to MAHs. Competent authorities assessed notifications of products containing N-nitrosamines and, where necessary, took actions to protect patient safety whilst avoiding shortages of critical medicines. Some deadlines have been extended to allow companies more time to perform thorough investigations and establish required risk-mitigating actions in light of new scientific developments since 2020.
The Nitrosamine Implementation Oversight Group (NIOG) oversaw a harmonised implementation of the CHMP’s Article 5(3) opinion on nitrosamines adopted in 2020. This involved engaging with industry to discuss challenges and solutions to the ongoing ‘call for review’ process and cooperating with other regulatory authorities to facilitate international alignment. Highlights of these interactions are available here.
The NIOG also issued guidance to facilitate compliance with the call for review, ensuring harmonisation of assessment and prioritisation, and approaches for temporary limits for nitrosamines to mitigate the risk of shortages of medicines while ensuring patient safety.
The EU Regulatory Network implemented measures to reduce potential risks associated with nitrosamines in medicines and ensure that regulators are better prepared to manage cases of unexpected impurities, as agreed in the implementation plan to address the lessons learnt on the presence of nitrosamines in sartan medicines.
Veterinary medicines
New medicines to benefit animal health in Europe
In 2022, EMA recommended ten veterinary medicines for marketing authorisation. Of these, three had a new active substance, which had not previously been authorised in the EU. Among the ten medicines recommended for marketing authorisation, two were vaccines, one of which had been developed by means of a biotechnological process.
A selection of key recommendations in 2022:
DogStem, a new veterinary medicine for reduction of pain and lameness associated with osteoarthritis in dogs.
Neoleish, a plasmid DNA vaccine for the active immunisation of Leishmania-negative dogs from 6 months of age to reduce the risk of developing an active infection and/or clinical disease after exposure to Leishmania infantum.
RenuTend, a new veterinary medicine to improve healing of injuries of tendons and suspensory ligaments in horses.
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 2022
The product information for 24 medicines was updated on the basis of new safety data. The revised information is expected to help animal owners and healthcare professionals 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:
- Bravecto spot-on solution for dogs: muscle tremor (shaking); ataxia (incoordination); convulsion;
- BTVPUR: hypersensitivity reactions;
- Cardalis: lethargy (lack of energy); anorexia (loss of appetite); ataxia; incoordination or signs of fatigue. In dogs with chronic kidney disease, benazepriliBenazepril hydrochloride and Spironolactone are the active substances of Cardalis. may increase plasma creatinine concentrations at the start of therapy very rarely;
- Cerenia: neurological disorders, such as ataxia, convulsion/seizure, or muscle tremor;
- Equilis Prequenza: hypersensitivity reaction, including anaphylaxis (sometimes fatal);
- Equilis Prequenza Te: hypersensitivity reaction, including anaphylaxis (sometimes fatal);
- Equilis Te: hypersensitivity reaction, including anaphylaxis (sometimes fatal);
- Felpreva: neurological disorders, such as ataxia (incoordination) and tremor;
- Hiprabovis IBR Marker Live: hypersensitivity reactions, including anaphylaxis (sometimes fatal) (change of frequency from “very rare” to “rare” and addition of anaphylaxis);
- Librela: polydipsia; polyuria (increase in urine production); addition of anaphylaxis, pruritus (itching) and facial swelling under hypersensitivity reactions; clinical signs of immune-mediated diseases, such as haemolytic anaemia or thrombocytopenia (low blood platelet counts, which can lead to bleeding and bruising);
- Mhyosphere PCV ID: anaphylactic-type reactions (e.g., vomiting, circulatory disorders, dyspnoea), which might be life-threatening;
- Nasym: anaphylactic-type reactions, which may be serious (including fatal);
- Neptra: deafness or impaired hearing, mainly in elderly animals (dogs);
- Nobivac DP Plus: hypersensitivity reaction, including anaphylaxis (sometimes fatal);
- Nobivac Myxo-RHD Plus: anorexia; lethargy;
- Procox: lethargy; muscle tremor; ataxia (incoordination); convulsion;
- Proteq West Nile: injection site abscess;
- Solensia: mild reactions at the injection site (e.g. pain and alopecia (hair loss));
- Stelfonta: compromised circulation; loss of essential tissue;
- Suprelorin: epileptic seizures;
- Zuprevo: anaphylaxis (may be fatal).
- Addition of new special precautions for use of:
- Aservo EquiHaler
A European survey showed that 16 out of 84 horses could not be treated according to the product information due to horses not co-operating. In case a horse has a tendency towards defensive behavioural reactions, additional safety precautions could be considered (e.g. employ a second person to handle the horse). Acclimatising the horse with a training device prior to treatment start has in some cases shown to ease the administration of the veterinary medicine. - Improvac
The safety and efficacy of the veterinary medicine in non-target species, such as horses, has not been evaluated. Adverse events have been observed in horses, including serious anaphylactic-type reactions, which have led to fatalities. - Librela
Where a dog has not been able to properly exercise prior to treatment due to its clinical condition, it is recommended that the dog is gradually (over a few weeks) allowed to increase the amount of exercise it takes (to prevent overexercise). - Stelfonta
Treating tumours at extremities may result in localised impairment of circulation due to a local inflammatory response at the treatment site. This can lead to tissue loss and can sometimes make an amputation necessary. Ingestion of tumour remnants should be prevented. - Suvaxyn Circo
In case of accidental self-injection, the person administering the veterinary medicine should seek medical advice immediately and show the package leaflet or the label to the physician.
- Aservo EquiHaler
- Addition of new advice on correct administration of:
- Stelfonta
The site of application should be covered for the first day after treatment in order to prevent licking of residual or leaking product (in addition to the prevention of direct contact with the residual or leaking product).
- Stelfonta
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 and entered in the annex to Commission Regulation (EU) No 37/2010.
In 2022, positive opinions were adopted recommending the extension of MRLs for the following active substances:
- ketoprofen
extension to chickens; this conclusion was extrapolated to poultry. - praziquantel
extension to fin fish; the entry for ovine species was extrapolated to all ruminants except cattle.
More information and figures on veterinary medicines are available in chapter 2.