EMA Handed Down Fewer Positive Drug Opinions in 2018

Megan Brooks

January 09, 2019

In 2018, the European Medicines Agency (EMA) recommended marketing authorization for 84 new medicines, down from 92 in 2017.

The 84 medicines given a thumbs up by EMA's Committee for Medicinal Products for Human Use include 42 agents with a new active substance never before authorized in the European Union (EU).

"Many of these medicines represent a significant improvement in their therapeutic areas; they include medicines for children, for rare diseases and advanced therapies," the agency said in a report released January 4.

The 84 agents include 23 for cancer, 11 for infections, 10 for neurologic conditions, nine for hematology, seven for immunology/rheumatology/transplantation, six for endocrinology, five for metabolism, five for pulmonology/allergy, three vaccines (for dengue, influenza, and herpes zoster), and one each in cardiovascular, hepatology/gastroenterology, ophthalmology, reproductive medicine, and uronephrology conditions.

Significant Progress in Key Areas

The EMA report highlights a selection of medicines approved in 2018 that represent a "significant progress in their therapeutic area," including:

  • Cancer: Tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma), the first two chimeric antigen receptors T-cell therapies in the EU intended for treatment of certain blood cancers

  • Ophthalmology: Voretigene neparvovec (Luxturna, Spark Therapeutics) for treatment of adults and children with inherited retinal dystrophy caused by RPE65 gene mutations, a rare genetic disorder that causes vision loss and usually leads to blindness

  • Neurology: A pediatric formulation of vigabatrin (Kigabeq, Orphelia Pharma) for treatment of infantile spasms (West syndrome) and resistant partial epilepsy, and melatonin (Slenyto, Neurim Pharma) for treatment of insomnia in children and adolescents with autism spectrum disorder or Smith-Magenis syndrome

  • Metabolism: A new oral suspension formulation of glibenclamide (Amglidia, Ammtek) for treatment of neonatal diabetes mellitus in newborns, infants, and children

Ophan medicines for rare diseases make up 21 of the 84 medicines recommended for marketing, most notably, according to EMA, velmanase alfa (Lamzede, Chiesi Farmaceutici) for nonneurological manifestations of mild-to-moderate alpha-mannosidosis; vestronidase alfa (Mepsevii, Ultragenyx Pharmaceutical) for mucopolysaccharidosis type VII; mexiltine hydrochloride (NaMuscla, Lupin Neurosciences) for myotonia in adults with nondystrophic myotonic disorders.

Four medicines were recommended for approval following accelerated assessment, a pathway designed to give patients early access to new medicines that address an unmet need. They are:

  • Emicizumab (Hemlibra, Roche Registration Ltd), a first-in-class medicine to prevent bleeding episodes in patients with hemophilia A who have factor VIII inhibitors

  • Patisiran (Onpattro, Alnylam Netherlands BV) and inotersen sodium (Tegsedi, Ionis USA Ltd) for hereditary transthyretin-mediated amyloidosis

  • Lanadelumab (Takhzyro, Shire Pharmaceuticals Ireland Ltd), the first monoclonal antibody therapy for the prevention of recurrent attacks of hereditary angioedema

One medicine — rucaparib (Rubraca, Clovis Oncology UK Ltd) for treatment of relapsed or progressive ovarian cancer — received a recommendation for a conditional marketing authorization, another pathway to give patients early access to new medicines that address an unmet medical need.

Safety Recommendations

EMA also recommended 65 extensions of indication in 2018 and handed down five negative opinions on drug applications. The drug regulator was also busy monitoring safety and efficacy of drugs once on the market. Among the safety advice and actions issued in 2018:

  • Removal from the market of the multiple sclerosis treatments containing daclizumab (Zinbryta and Zenapax) because of serious and sometimes fatal cases of autoimmune encephalitis

  • Recommendation to suspend some quinolone and fluoroquinolone antibiotics and introduce changes including restrictions on the use of all others following a review of disabling and potentially permanent side effects reported with these medicines

  • Recommendation of new measures to avoid exposure of babies to valproate medicines in the womb, because exposed babies are at high risk for malformations and developmental problems

  • Recommendation to restrict the use of retinoid medicines during pregnancy. The review confirmed that all oral retinoids can harm the unborn child

  • Recommendation of new measures to minimize the risk for rare but serious liver injury with Esmya (ulipristal acetate), for the treatment of moderate-to-severe symptoms of uterine fibroids

  • New recommendation to restrict the use of Keytruda (pembrolizumab) and Tecentriq (atezolizumab) as first-line treatments for urothelial cancer in some patients with low levels of the protein PD-L1

  • Recommendation to restrict the use of Xofigo (radium-223 dichloride) to patients who have had two previous treatments for metastatic prostate cancer or who cannot receive other treatments, in view of the risk for early death and fractures in some patients

  • Warnings for the HIV treatment dolutegravir (Tivicay) about the possible risk for neural tube defects following exposure in very early pregnancy

  • Warnings for fluoroquinolone antibiotics about the rare risk for aortic aneurysm and dissection

  • Warning to healthcare professionals that sildenafil (Revatio, Viagra) has been associated with an increased risk for pulmonary hypertension and death in infants exposed in utero in a clinical trial in growth retardation (off label)

  • Warning to healthcare professionals that rivaroxaban (Xarelto) has been associated with increased mortality, bleeding, and clots in patients treated in a clinical trial for transcatheter aortic valve replacement (off label)

  • Recommendation for new risk minimization measures for hydroxyethyl starch (HES) solutions to protect patients at risk. Measures include training, controlled access, and warning on the packaging

  • Recommendation to harmonize the maximum daily dose of the painkiller metamizole and the contraindications to its use in pregnancy or in women who are breastfeeding

  • Conclusion that omega-3 fatty acid medicines are not effective in preventing further heart and blood vessel problems in patients with prior myocardial infarction and will no longer be authorized for such use

In 2018, EMA also launched a review of the "sartan" angiotensin II receptor antagonists candesartan, irbesartan, losartan, olmesartan and valsartan over impurities found in some batches of these medicines. The impurities, N-Nitrosodimethylamine and N-Nitrosodiethylamine, are classified as probable human carcinogens based on animal studies.

The full report is available online.

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