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 2020, EMA recommended 97 medicines for marketing authorisation. Below is a selection of medicines approved in 2020 that represent significant progress in their therapeutic areas:
Zolgensma, to treat babies and young children with spinal muscular atrophy, a rare and often fatal genetic disease that causes muscle weakness and progressive loss of movement.
Givlaari, the first treatment for acute hepatic porphyria in adults and adolescents aged 12 years and older.
Rybelsus, for the treatment of adults with insufficiently controlled type 2 diabetes to improve glycaemic control as an adjunct to diet and exercise. It is the first glucagon-like peptide (GLP-1) receptor agonist treatment – a class of non-insulin medicines for people with type 2 diabetes – developed for oral use, providing patients with another option to treat the disease without injections.
Enerzair Breezhaler, the first asthma triple combination therapy that includes an optional electronic sensor to collect data on the use of the inhaler by the patient.
Zabdeno and Mvabea, the two components of a new vaccine that provides active immunisation to prevent Ebola virus disease in individuals aged one year and older.
Idefirix, the first treatment for adult patients waiting for a kidney transplant, who are highly sensitised against tissue from the donor and who have a positive crossmatch test against an available kidney from a deceased donor.
Kaftrio, the first triple combination therapy for the treatment of cystic fibrosis in patients aged 12 years and older who are homozygous for the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or heterozygous for F508del in the CFTR gene with a minimal function (MF) mutation.
Blenrep, to treat adult patients with relapsed and refractory multiple myeloma (a cancer of the bone marrow) who no longer respond to treatment with an immunomodulatory agent, a proteasome inhibitor and a CD-38 monoclonal antibody.
Tecartus, for the treatment of adult patients with a rare cancer of white blood cells called mantle cell lymphoma (MCL) when the symptoms or the disease come back (relapse) or when they are not responding (refractory) after two or more lines of systemic therapy.
Oxlumo, for the treatment of the rare inherited disorder primary hyperoxaluria type 1.
Libmeldy, to treat metachromatic leukodystrophy (MLD), a rare inherited metabolic disease that affects the nervous system.
Rekambys and Vocabria, to be used together for the treatment of patients with human immunodeficiency virus type 1 (HIV-1) infection. They are the first antiretroviral (ARV) medicines that come in a long-acting injectable formulation.
Rozlytrek, for the treatment of patients whose solid tumours have a neurotrophic tyrosine receptor kinase gene fusion, or patients with ROS1-positive advanced non-small cell lung cancer.
11th medicine recommended for use outside the EU
In July 2020, the CHMP adopted a positive opinion for Dapivirine Vaginal Ring (dapivirine) used to reduce the risk of infection with HIV-1, in combination with safer sex practices when oral preexposure prophylaxis (PrEP) is not used, cannot be used or is not available. Placed in the vagina, the ring slowly releases the antiretroviral medicine dapivirine over a period of 28 days.
This is the 11th medicine recommended by EMA under EU Medicines for all (EU-M4All), a mechanism that allows the CHMP to assess and give opinions on medicines that are intended for use in countries outside the EU under Article 58 of Regulation (EC) No 726/2004.
Spotlight on COVID-19
EMA is contributing to tackling the COVID-19 pandemic by expediting the development and approval of safe and effective treatments and vaccines.
In December 2020, the CHMP recommended granting a CMA for the vaccine Comirnaty, developed by BioNTech and Pfizer, to prevent COVID-19 in people from 16 years of age. By the end of the year, the Committee was already reviewing the formal marketing authorisation application for another vaccine (Moderna’s mRNA-1273 COVID-19 vaccine) and rolling reviews of two additional vaccines were also ongoing – one for the vaccine being developed by AstraZeneca with the University of Oxford and one for the vaccine from Janssen-Cilag.
In June 2020, the CHMP recommended granting a CMA for Veklury (remdesivir) for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen. In December, the Committee recommended to use Veklury only in COVID-19 patients who require supplementary oxygen but do not need mechanical ventilation.
In September 2020, the Committee completed its review of results from the RECOVERY study arm that involved the use of the corticosteroid medicine dexamethasone in the treatment of patients with COVID-19 admitted to hospital and concluded that dexamethasone can be considered a treatment option for patients who require oxygen therapy (from supplemental oxygen to mechanical ventilation).
Earlier in the year, EMA warned healthcare professionals to closely monitor patients with COVID-19 who received chloroquine or hydroxychloroquine, given the serious side effects that can result from treatment with these medicines. Both chloroquine and hydroxychloroquine, which are authorised for malaria and certain autoimmune diseases, were used early in the pandemic to treat patients with COVID-19 but their beneficial effects in these patients have not been established.
EARLY ACCESS TO MEDICINES THAT ADDRESS PUBLIC HEALTH NEEDS
In 2020, six medicines received a recommendation for marketing authorisation following an accelerated assessment: Blenrep, Enhertu, Givlaari, Mvabea, Oxlumo and Zabdeno. 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).
Thirteen medicines received a recommendation for a CMA, one of the possibilities in the EU to give patients early access to new medicines: Adakveo, Ayvakyt, Blenrep, Comirnaty, Enhertu, Hepcludex, Idefirix, Dovprela, Retsevmo, Rozlytrek, Tecartus, Veklury and Zolgensma.
The conditional authorisation allows for early approval on the basis of less complete clinical data than normally required, because the benefits of earlier patient access outweigh the potential risks of limited data. This is particularly important in the response to a public health emergency such as COVID-19. These authorisations are subject to specific post-authorisation obligations to generate complete data on the medicines.
Five medicines (Elzonris,Lumoxiti, Mvabea,Obiltoxaximab SFL and Zabdeno) 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. This can be the case if there are only very few patients with the disease, if the collection of complete information on the efficacy and safety of the medicine would be unethical, or if 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 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, eight PRIME-designated medicines were recommended for approval (Blenrep, Givlaari, Hepcludex, Idefirix, Oxlumo, Rozlytrek, Tecartus and Zolgensma).
20 medicines under development were included in the scheme in 2020: oncology (5), haematology-haemostaseology (3), endocrinology-gynaecology-fertility-metabolism (2), vaccines (2), cardiovascular diseases (2), and one each for ophthalmology, infectious diseases, neurology, pneumology-allergology, gastroenterology-hepatology, immunology-rheumatology-transplantation.
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 97 medicines recommended for marketing authorisation in 2020, 22 had their orphan designation confirmed by the end of the year.
In 2020, 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: Calquence and Sarclisa. More information can be found in the COMP monthly reports.
NEW USES FOR EXISTING MEDICINES
83 extensions of indication were recommended in 2020. The extension of the use of a medicine that is already authorised for marketing in the EU can offer new treatment opportunities for patients. Important extensions of indication included:
Orfadin, to include the treatment of alkaptonuria in adult patients.
Velphoro, to include control of serum phosphorus levels in children aged 2 years or older with chronic kidney disease (CKD) stages 4-5 or with CKD on dialysis.
Olumiant (baricitinib), to include the treatment of moderate to severe atopic dermatitis in adult patients who are candidates for systemic therapy.
NEGATIVE OPINIONS
The CHMP adopted negative opinions for twoiThis figure does not include the initial negative opinion adopted by the CHMP on Elzonris (tagraxofusp) in July 2020. The applicant for this medicine requested re-examination of the Committee’s negative opinion and, after considering the grounds for this request, the CHMP recommended granting a marketing authorisation for Elzonris in November 2020. medicines in 2020: Gamifant and Turalio.
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.
93% 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.
Around 70% 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. 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 the benefit-risk balance of the medicine used in real life on the market. 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 advice issued in 2020 included:
- Restrictions in the use of cyproterone acetate due to risk of meningioma (brain tumour). The risk of meningioma increases with increasing cumulative doses. The use of cyproterone acetate is contraindicated in patients with a meningioma or a history of meningioma.
- Recommendation to update the safety information for hormone replacement therapy (HRT) used to treat symptoms of the menopause. As already indicated in the product information of HRT medicines, women should only take hormone replacement therapy for the treatment of symptoms of menopause at the lowest dose and for the shortest possible time that works for them. The updates are based on evidence from a large study published in The Lancet in August 2019, which confirmed the known higher risk of breast cancer in women using HRT. The results showed that the risk may continue to be increased for ten years or more after stopping HRT, if it has been used for more than five years.
- The product information for fluoroquinolone antibiotics was updated to reflect that systemic and inhaled fluoroquinolones may increase the risk of heart valve regurgitation/incompetence.
- Recommendation to restrict the use of medicines containing ulipristal acetate 5 mg (Esmya and generic medicines) as a result of cases of serious liver injury. The medicines can now only be used to treat uterine fibroids in premenopausal women for whom surgical procedures are not appropriate or have not worked. The medicines must not be used for controlling symptoms of uterine fibroids while awaiting surgical treatment.
- Recommendation to use fosfomycin medicines given by infusion (drip) into a vein only to treat serious infections when other antibiotic treatments are not suitable. Fosfomycin medicines given by mouth can continue to be used to treat uncomplicated bladder infections in women and adolescent girls. They can also be used to prevent infection in men undergoing a procedure whereby a tissue sample is taken from their prostate (biopsy). Fosfomycin medicines given by mouth to children (under 12 years of age) and intramuscular formulations (fosfomycin medicines for injection into a muscle) should no longer be used as there are insufficient data available to confirm their benefits to patients.
- Recommendation to test patients for the lack of the enzyme dihydropyrimidine dehydrogenase (DPD) before starting cancer treatment with fluorouracil given by injection or infusion (drip) and related medicines containing capecitabine and tegafur. Patients who completely lack DPD must not be given these fluorouracil medicines because of high fluorouracil toxicity which can have a fatal outcome.
- Recommendation to limit the use of high-strength creams containing 100 micrograms/gram (0.01%) of estradiol to a single treatment period of up to 4 weeks. Data on these creams showed that in postmenopausal women who use them, the levels of estradiol in the blood were higher than normal postmenopausal levels. The absorption of estradiol into the bloodstream is of concern and could result in side effects such as venous thromboembolism (formation of blood clots in the veins), stroke, endometrial cancer (cancer of the lining of the womb) and breast cancer.
- Updated recommendations for dimethyl fumarate to help minimise the risk of progressive multifocal leukoencephalopathy (a rare brain infection) in patients treated with this medicine. Dimethyl fumarate is authorised in the EU for the treatment of adults with relapsing-remitting multiple sclerosis.
- Recommendation on measures to avoid handling errors in preparation and administration of leuprorelin depot medicines, which are used to treat prostate cancer, breast cancer, certain conditions that affect the female reproductive system and early puberty. Handling errors resulted in some patients receiving insufficient amounts of their medicine.
- The data from the Tsepamo study confirmed that there is no indication of an overall increased risk of major birth defects in children exposed to dolutegravir (anti-HIV treatment) during pregnancy. Furthermore, the signal for a potentially increased risk of neural tube defects has weakened when the number of exposed patients has increased. The product information was updated accordingly.
- Update of product information, introduction of a patient card and prescriber checklist to minimise the risk of fatal outcomes as a result of interaction between brivudine and fluoropyrimidines (e.g. fluorouracil, capecitabine, tegafur, flucytosine). At least 4 weeks must be awaited after the end of brivudine treatment before starting treatment with a fluoropyrimidine.
- Recommendation to perform a liver function test before starting a treatment with pirfenidone, and subsequently every month for the first 6 months and then every 3 months for the duration of the treatment, to prevent drug-induced liver injury. Pirfenidone is an anti-fibrotic and anti-inflammatory medicine indicated for the treatment of idiopathic pulmonary fibrosis.
- Recommendation to suspend all ranitidine medicines in the EU due to the presence of low levels of an impurity called N-nitrosodimethylamine (NDMA). Ranitidine medicines are used for reducing levels of stomach acid mainly in patients with conditions such as heartburn and stomach ulcers. NDMA is classified as a probable human carcinogen (a substance that could cause cancer), based on animal studies. More information is available in the next section.
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.
In 2020, EMA undertook several reviews to provide recommendations to marketing authorisation holders (MAHs) to avoid/mitigate the risk of presence of nitrosamine impurities in medicines.
In April 2020, EMA recommended to suspend all ranitidine medicines in the EU due to the presence of low levels of an impurity called N-nitrosodimethylamine (NDMA). The available safety data did not show that ranitidine increased the risk of cancer, and any possible risk was likely to be very low. However, NDMA had been found in several ranitidine medicines above levels considered acceptable, and there were unresolved questions about the source of this impurity and potential increase of NDMA over the shelf life. Companies were asked to provide reassuring data on degradation of ranitidine and endogenous formation of NDMA to support a positive benefit-risk balance and lift the suspended marketing authorisations.
In June 2020, EMA finalised its review of nitrosamine impurities in human medicines and recommended companies to review their manufacturing processes and, where necessary, take measures to limit the presence of nitrosamines in human medicines. These measures are meant to ensure that nitrosamines are either not present or are present below levels identified to protect public health.
In November 2020, the Agency adopted an opinion on the impact of the above review on the outcome of the review for sartans with a tetrazole ring that was finalised in January 2019. This led to an amendment of the previous conclusions, now requiring companies to carry out risk assessments, establish control strategies and carry out testing for nitrosamines at the level of the finished product.
In 2020, EMA recommended to suspend the marketing authorisations for generic medicines tested by Panexcell Clinical Laboratories Priv. Ltd at its site in Mumbai, India. This was due to irregularities found by inspectors in how the company carried out bioequivalence studies, which are used to show that a generic medicine delivers the same amount of active substance in the body as the reference medicine.
Applications for three centralised marketing authorisations and one type II-variation were withdrawn due to non-compliance with good clinical practice (GCP). The CHMP adopted one negative opinion (refusing the granting of the marketing authorisation) for a medicine for which there were GCP-related non-compliance issues in the clinical study submitted by the applicant.
Veterinary medicines
New medicines to benefit animal health in Europe
In 2020, EMA recommended 20 veterinary medicines for marketing authorisation; 13 of these contain a new active substance (i.e. one that had not previously been authorised in the EU). Among the 20 medicines recommended for marketing authorisation, ten were vaccines – more than double the number of vaccines authorised in 2019. Of these, eight were biotechnological vaccines.
The Agency’s Committee for Medicinal Products for Veterinary Use (CVMP) also recommended the granting of a marketing authorisation for two immunological products that were developed through biotechnological processes. Solensia is the first monoclonal antibody to manage osteoarthritis in cats. Librela is a new canine monoclonal antibody for alleviation of pain associated with osteoarthritis in dogs.
NexGard Combo was 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.
NexGard Combo is an antiparasitic veterinary medicine for the treatment of cats with, or at risk from mixed infections by cestodes, nematodes and ectoparasites.
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 2020
The product information for 12 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.
- Addition of further information in the package leaflet for special precautions for use of Activyl Tick Plus in animals.
- Amendment to the product information in relation to the use during pregnancy and lactation and other special precautions for use of Advocate in animals.
- Addition of further information in the package leaflet on potential side effects following administration of Cardalis in dogs, such as gastrointestinal signs and pruritus.
- Addition of further information in the package leaflet on potential side effects following administration of Convenia in dogs, such as haematological reactions, gastrointestinal signs, neurological signs and hypersensitivity reactions.
- Addition of further information in the package leaflet on potential side effects following administration of Credelio in dogs and cats, such as neurological and gastrointestinal signs.
- Clarification of the information in the package leaflet on potential side effects following administration of Galliprant in dogs, in relation to gastrointestinal signs.
- Addition of special precautions to the product information for Metacam/Novem to ensure the safety of the person handling and administering the treatment to cattle, pigs, horses, dogs, cats and guinea pigs.
- Amendment to the product information on potential side effects following administration of Neptra in dogs to include eye disorders.
- Amendment to the product information on potential side effects following administration of Onsior in cats and dogs to include renal disorders.
- Amendment to the product information on potential side effects following administration of Purevax FeLV in cats to include gastrointestinal signs and anaphylaxis. Update of the frequency of the adverse reactions.
- Modification of special precautions for Vectra Felis to include transient adverse reactions after accidental ingestion by cats.
- Amendment to the product information for Vectra 3D in dogs to clarify the potential follow-up of rare application site reactions.
The CVMP adopted two positive opinions for extensions of existing authorisations, broadening the use of the medicines concerned:
- Aivlosin, to be also used for the treatment and metaphylaxis of swine respiratory disease associated with Mycoplasma hyopneumoniae and Pasteurella multocida in pigs.
- Cytopoint, to be also used for the treatment of pruritus associated with allergic dermatitis in dogs.
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 2020, positive opinions were adopted recommending the establishment of MRLs for the following active substances:
- Bupivacaine and Lidocaine in medicines for pigs and cattle.
- Imidacloprid in medicines for finfish.
More information and figures on veterinary medicines are available in chapter 2.