To analyze the characteristics of the new medicines approved in the pediatric population in the last 3 years, both those with studies only in the pediatric population and those that extend their indication in this population group, as well as the current situation in relation to their marketing and financing.
MethodsDescriptive observational study of all drugs that include an indication in the pediatric population in Spain (by extension of the indications of drugs already authorized or because they are new drugs that already include an indication in this population group), from January 2019 to March 2022.
ResultsDuring the study period, 129 drugs included their indication in the pediatric population. 13.9% of them are not marketed, 46.5% are in a situation of non-financing, under study or without a request for financing, and 4.6% are financed for a specific pediatric subpopulation. 52.7% are original drugs, 4.7% are generic, 38.8% are biological, 3.8% are biosimilar, and 17.8% are orphan drugs. 57.36% of these medicines obtain the pediatric indication due to extension of the indication and 42.64% obtain it because they are new medicines that already include their studies in the pediatric population.
ConclusionsDrugs with authorized indications are increasingly available in the pediatric population and the trend is to extend the indication of authorized drugs to the adult population. However, barriers in terms of financing and marketing need to be expedite and overcome to facilitate access to them.
Analizar las características de los nuevos medicamentos aprobados en población pediátrica en los últimos tres años, tanto de aquellos medicamentos con estudios únicamente en población pediátrica, como de aquellos que amplían su indicación en este grupo de población, así como la situación actual en relación a su comercialización y financiación.
MétodosEstudio observacional descriptivo de todos los medicamentos que incluyen indicación en población pediátrica en España (por extensión de las indicaciones de medicamentos ya autorizados o por ser nuevos medicamentos que ya incluyen indicación en este grupo de población), desde enero de 2019 hasta marzo de 2022.
ResultadosEn el periodo de estudio 129 medicamentos incluyeron su indicación en población pediátrica. A pesar de esto, el 13,9% de ellos, no están comercializados, el 46,5% se encuentran en situación de no financiación, en estudio o sin petición de financiación y el 4,6% están financiados para una determinada subpoblación pediátrica. El 52,7% son medicamentos originales, el 4,7% son genéricos, el 38,8% son biológicos, el 3,8% son biosimilares y el 17,8% son medicamentos huérfanos. El 57,36% de estos medicamentos obtienen la indicación pediátrica por extensión de la indicación y el 42,64% la obtienen por ser nuevos medicamentos que ya incluyen sus estudios en población pediátrica.
ConclusionesLa población pediátrica dispone cada vez más de medicamentos con indicación autorizada siendo la tendencia a extender la indicación de medicamentos autorizados en población adulta. No obstante, es preciso agilizar y superar las barreras en lo que se refiere a financiación y comercialización para facilitar el acceso a los mismos.
Regulation (EC) 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for pediatric use entered into term in 2007. Before that date, research on and authorization of new medicinal products for use in the pediatric population were not adequately regulated by any law. This Regulation guarantees the efficacy and safety of new approved medicinal products for use in the pediatric population. In this sense, the creation of the European Medicines Agency's (EMA) Paediatric Committee in 2007 was a landmark in this field of medicine. The aim of this committee is to provide objective scientific evidence and assess pediatric investigation plans and the development of medicines for children.1
In 2017, the European Commission released an evaluation of the level of implementation of Regulation 1901/2006 in the European Union. The results showed an increase in the volume of authorizations of medicinal products for pediatric patients during the study period. However, the evaluation also demonstrated the need for promoting the development of new medicinal products for diseases that solely affect the pediatric population, which have differences and particularities with respect to the adult population.2
Research on medicinal products in the pediatric population is extremely complex. Firstly, research in children raises ethical concerns associated with the vulnerability of the study population. In addition, there may be scant interest due to limited economic profit. Other challenges to the development of pediatric clinical trials include variability in the pediatric population with respect to adults, with significant differences in pharmacokinetics, pharmacodynamics, and adverse reactions. Other factors include changes in the samples resulting from growing and maturing processes and their specific diseases.3,4
In 2017, a national network of pediatric clinical trials (RECLIP) was created in Spain. RECLIP provides support, experience, and infrastructure to optimize the development of pediatric clinical trials. The purpose is to ensure that the pediatric population benefits from new medicinal products, which efficacy, safety, and dosing have been previously evaluated and validated using standardized methods.
The adaptation of adult treatments for use in the pediatric population entails a variety of challenges. Firstly, dosing is complex due to the lack of availability of pediatric drug formulations. This situation may lead to dosing errors and inadequate drug administration, which may compromise patient safety and cause severe adverse reactions.5
Secondly, according to EMA's 2004 Report, less than 50% of pediatric formulations have been tested in the pediatric population. As a result, these formulations are often prescribed off-label or in conditions different to those indicated in the label. This occurs in 90% of neonatal units, 45% of pediatric hospitalization units, and 10%–20% in primary care.6
According to another EMA evaluation report, a study conducted in a pediatric hospital revealed that 95% of adverse drug reactions were associated with off-label use of prescription drugs, as compared to 3.9% of adverse reactions associated with on-label use.7
In light of the aforementioned evidence, a broader therapeutic armamentarium is required for the pediatric population. For such purpose, the safety and efficacy of pediatric formulations should be correctly assessed and approved by the relevant regulatory authorities. This will guarantee a correct use of drugs and help overcome the limitations described above.
The growing demand for safe, effective drugs in pediatric hospitals in Spain makes it necessary to better understand the characteristics and state of affairs of newly authorized pediatric drugs in our country. The results of this study will ensure a safe, more effective use of pediatric drugs. This study provides a summary of newly approved pediatric medicines, which can be used as an easy-to-use consultation tool.
The aim of this study was to analyze newly approved drugs for pediatric indications and provide a picture of the state of affairs regarding the marketing and funding of these products.
MethodsA descriptive, observational study of all drugs labeled with pediatric indications approved between January 2019 and March 2022. An analysis was performed of the characteristics of recently approved drugs tested either in clinical trials solely performed in children, or which indication has been extended to this population.
As a source of information, we used the monthly newsletter of the Spanish Agency for Medicines and Medical Devices (AEM). This newsletter provides information in relation to changes in the indications of approved medicines and newly approved drugs. We collected and analyzed data on indications for pediatric use. At the end of the study period (March 2022), information about the funding status of drugs was retrieved from BIFIMED, the Spanish Ministry of Health's medicine finder engine that shows the pricing and reimbursement (P&R) status of medicinal products.
ResultsThe medicinal products identified were related to the fields of infectious diseases (30%); oncohematology (10.83%); pulmonology (10%); neurology (9.16%); endocrinology (6.66%); dermatology (5.83%); metabolics-genetics (5%); rheumatology (4.16%); internal medicine (4.16%); nephrology (3.33%); ophthalmology (2.5%); gastroenterology (2.5%); allergology; (2.5%); psychiatry (1.6%), and cardiology (1.6%).
During the study period, 129 new medicines were labeled with a pediatric indication; 13.9% (n=18) are not currently marketed, 46.5% (n=60) have not been approved for P&R, are still being tested or P&R has not been requested; 4.6% (n=6) have been approved for P&R for a specific subpopulation of pediatric patients, but not for all labeled pediatric indications. By type of medicine, 52.7% (n=68) were original; 4.7% (n=6) were generic drugs; 38.8% (n=50) were biologicals; 3.8% (n=5) were biosimilar drugs, and 17.8% (n=23) were orphan drugs.
In 57.36% (n=74) of medicines, the pediatric indication was approved by extension of the indication for the adult population. In contrast, 42.64% (n=55) were new medicinal products that had been tested in the pediatric population. Table 1 summarizes new medicinal products labeled with a pediatric indication or approved for use in pediatrics by extension.
Newly approved medicines for use in pediatrics and medications labeled with indication for the pediatric population by extension.
| New medicinal products labeled with a pediatric indication | ||
|---|---|---|
| Drug (pharmaceutical formulation) | New indications | Marketed/reimbursed |
| Abatacept (Orencia®) | AIJP with MTX, ≥6 years, insufficient response/intolerance FAME and >1 anti-TNF | Yes/Yes |
| Adalimumab (Amsparity®) | Insufficient response/intolerance to DMT. Active PJIA ≥2 years; enthesitis-related arthritis ≥6 years; severe plaque psoriasis ≥4 years; moderate–severe hidradenitis suppurativa ≥12 years; CD ≥6 years; non-infectious uveitis ≥2 years | No/No |
| Adalimumab (Hukyndra®) | Insufficient response/intolerance to DMT. Active PJIA ≥2 years; enthesitis-related arthritis ≥6 years; severe plaque psoriasis ≥4 years; moderate–severe hidradenitis suppurativa ≥12 years; CD ≥6 years; non-infectious uveitis ≥2 years | Yes/Yes |
| Artesunate (Amivas®) | Severe malaria, first-line treatment | No/No |
| Avalglucosidase alfa (Nexviadyme®) | Enzyme replacement medicine, Pompe disease | No/No |
| Baloxavir Marboxil (Xofluza®) | Treatment of non-complicated influenza and post-exposure prophylaxis ≥12 years | No/No |
| Berotralstat (Orladeyo®) | Prevention of recurrent hereditary angioedema in >2 years | No/No |
| Cannabidiol (Epidiolex®) | Convulsions secondary to Lennox–Gastaut or Dravet disease, in associated with clobazam >2 years | Yes/Yes |
| Casirivimab/Imdevimab (Ronapreve®) | Prophylaxis and treatment of COVID-19 ≥12 years and ≥40 kg, without oxygen therapy and higher risk for severe disease progression | Yes/under study or P&R not requested |
| Autologous CD34 cells+vectors encoding the BA-T87Q-GLOBINA 1,2–20 gene +106 cells/ml dispersion for infusion (Zynteglo®) | ≥12 years with non-β0/β0 transfusion-dependent beta-thalassemia | No/No |
| Potassium citrate/Potassium hydrogen carbonate (Sibnayal®) | Renal tubular acidosis >1 years | No/No |
| Methylthioninium chloride (Proveblue) | Acute drug/chemically induced methemoglobinemia, 0–17 years | Yes/Yes |
| Crisaborole (Staquis®) | Mild–moderate atopic dermatitis and ≤40% involvement, ≥2 years | No/No |
| Crizanlizumab (Adakveo®) | Prevention of recurrent vasooclussive crises, ≥16 years with sickle cell disease | Yes/under study or P&R not requested |
| Autogenous CD34+ cell culture enriched in hematopoietic stem cells and progenitor cells transduced ex vivo using a lentiviral vector encoding human Arylsulfatase A gene. (Libmeldy®) | MLD in children with late childhood or early juvenile forms, without clinical manifestations of the disease; in children with early juvenile form, with early clinical manifestations of the disease who can still work without aid and before onset of cognitive deterioration. | Yes/under study or P&R not requested |
| Trientine dihydrochloride (Cufence®) | Wilson disease >5 years intolerance to D-penicillamine | Yes/Yes |
| Dolutegravir/Lamivudine (Dovato®) 50 mg/300 mg | HIV-1 >12 years, ≥40 kg, without resistance to integrase inhibitors or 3TC | Yes/Yes |
| Elexacaftor Tezacafyor/Ivacaftor (Kaftrio®) | In combination with ivacaftor for CF in ≥12 years, with the F508del mutation and minimal function F508del mutation | Yes/Yes |
| Entrectinib (Rozlytrek®) | Monotherapy; ≥12 years with solid tumors expressing the INTRK that are locally advanced or metastatic or without therapeutic options | Yes/P&R not approved |
| Etanercept (Nepexto®) | JIA in >2 years; psoriatic arthritis and arthritis with enthesitis in >12 years; severe plaque psoriasis in >6 years | No/No |
| Fenfluramine (Fintepla®) | In combination, in convulsions associated with Dravet syndrome; ≥2 years | Yes/under study or P&R not requested |
| Givosiran (Givlaari®) | Acute hepatic porphyria; ≥12 years | Yes/No |
| Nasal glucagon (Baqsimi®) | Severe hypoglycemia, ≥4 years with DM | Yes/Yes |
| Glucarpidase (Voraxaze®) | To reduce toxic plasma MTX concentrations in ≥28 days, with reduced clearance or risk of toxicity | Yes/yes (foreign medicinal products) |
| Oral delayed-release hydrocortisone (Plenadren®) | Congenital adrenal hyperplasia >12 years | Yes/P&R not approved |
| Hydroxycarbamide (Xromi®) | Prevention of vaso-occlusive complications of sickle cell disease; ≥2 years | No/No |
| Non-specific human immunoglobulin (Hizentra®) | PID replacement therapy | Yes/Yes |
| Imatinib (Koanaa®) | Newly diagnosed Ph+CML in non-candidate to HPSCT; in Ph+CML in chronic stage after failure of treatment with interferon alfa, or in accelerated phase or blast crisis, and in newly diagnosed Ph+ALL, integrated with CT | No/No |
| Indacaterol/Mometasone furoate (Atectura Breezhaler®/ Bemrist Breezhaler®): | Maintenance therapy for asthma; ≥12 years, not controlled with conventional therapies | Yes/Yes |
| Guanfacine (Intuniv®) | Adjuvant therapy in ADHD | Yes/Yes |
| Larotrectinib (Vitrakvi®) | In solid tumors with neurotrophic receptor tyrosine kinase (NTRK) gene fusions in locally advanced/metastatic cancer or surgical resection associated with high mortality rates and when it is the only therapeutic option available | Yes/P&R not approved |
| Lonapegsomatropin (Lonapegsomatropin Ascendis Pharma®) | Growth disorder for growth hormone hyposecretion ≥3 years | No/No |
| Lumasiran (Oxlumo®) | Type I hyperoxaluria | Yes/under study or P&R not requested |
| Melfalán (Phelinum®) | At high doses in MM, malignant lymphomas, ALL and AML, childhood neuroblastoma, ovarian cancer, and breast adenocarcinoma | No/No |
| Obiltoxaximab (Obiltoxaximab SFL®) | Treatment, in combination with pulmonary carbuncle by Bacillus anthracis post-exposure prophylaxis when alternative therapies are not appropriate or are not available | No/No |
| Onasemnogene Abeparvovec (Zolgensma®) | AME 5q with a biallelic mutation in the SMN1 gene and a clinical diagnosis of type 1 SMA, or SMA 5q with a biallelic mutation in the SMN1 gene and up to 3 copies of the SMN2 gene | Yes/Yes |
| Cholic acid (Orphacol®) | 3β-hydroxy-Δ5-C27-steroid dehydrogenase or Δ4–3-Oxosteroid-5β-reductase deficiency in ≥1 month | Yes/Yes |
| Sodium oxybate (Xyrem®) | Narcolepsy with cataplexy, ≥7 years | Yes/Yes |
| Injectable pegvaliase (Palynziq®) | ≥16 years with phenylketonuria with inadequate phenylalanine control | Yes/P&R not approved |
| Plerixafor (Mozobil®) | 1–18 years, in combination with G-CSF, to boost hematopoietic stem cell mobilization in PB for aHSCT in lymphoma or malignant solid tumors; or in some circumstances involving collected cell count | Yes/Yes |
| Defatted powder of peanuts- Arachis hypogaea L, (Palforzia®) | 4–17 years; allergy to peanuts | No/No |
| Remdesivir (Veklury®) | COVID-19+; ≥12 years; ≥40 kg, with pneumonia, and oxygen therapy | Yes/Yes |
| Risdiplam (Evrysdi®) | 5q SMA in >2 months with a clinical diagnosis of type 1, 2 or 3 SMA, or with 1–4 copies of the SMN2 gene | Yes/under study or P&R not requested |
| Ruxolitinib (Jakavi®) | Acute/chronic GvHD in ≥12 years, with inadequate response to steroids or other systemic diseases | Yes/No |
| Somatrogon (Ngenla®) | Growth disorder in progression 3 years secondary to growth hormone hyposecretion | Yes/under study or P&R not requested |
| Sotrovimab (Xevudy®) | COVID-19 ≥12 years and ≥40 kg, without oxygen therapy and higher risk for severe disease progression | Yes/under study or P&R not requested |
| Tecovirimat (Tecovirimat Siga®) | Smallpox, monkeypox and bovine pox, ≥13 kg and in complications due to vacinnia virus replication following vaccination | No/No |
| Tixagevimab/Cilgavimab (Evusheld®) | COVID-19 pre-exposure prophylaxis + ≥12 years; 40 kg | Yes/under study or P&R not requested |
| Turoctocog alfa pegol (Esperoct®) | Treatment and prophylaxis of hemorrhage in ≥12 years, with A hemophilia | Yes/Yes |
| Conjugated vaccine of meningococcal groups A,C,W and Y (MenQuadfi®) | Active immunization ≥12 months against invasive meningococcal disease by serogroups A, C, W and Y de Neisseria meningitidis | Yes/Yes |
| Vaccination against Ebola: Trivalent, recombinant, non-replicating MVA-BN-FILO (Mvabea®) and vaccination against Ebola: Monovalent recombinant unable to replicate with the AD26 vector that encodes the full-length glycoprotein (GP) of the Zaire Ebolavirus (Zabdeno®) | In combination, in active immunization for the prevention of Ebola virus in ≥1 year | Yes/under study or P&R not requested |
| Living, oral vaccine for recombinant cholera (Vaxchora®) | Active immunization against disease by the cholerae vibrio, O1 serogroup, in ≥6 years | Yes/Yes |
| Voxelotor (Oxbryta®) | In monotherapy/combination with hydroxycarbamide in hemolytic anemia for sickle cell disease; ≥12 years | No/No |
| Zanamivir (Dectova®) | ≥6 months; complicated influenza A virus and life-threatening when Zanamivir is not an option | Yes/P&R not approved |
| Medicinal products with extended indication to pediatrics | ||
|---|---|---|
| Drug (pharmaceutical formulation) | New indications | Marketed/reimbursed |
| Glecaprevir/Pibrentasvir (Marivet®) | HCV+; 12–17 years | Yes/Yes |
| Tenofovir disoproxil (Viread®) | HBV of 6–12 years with active compensated liver disease | Yes/Yes |
| Liraglutid (Victoza®) | >10 years and in DM2 poorly controlled with diet and physical exercise, metformin is not appropriate, in monotherapy/combination | Yes/Yes |
| Ceftaroline (Zinforo®) | IPPBc and CAP | Yes/yes for SSTIs, not for CAP |
| Dupilumab (Dupixent®) | Moderate–severe atopic dermatitis, >12 years | Yes/Yes |
| Non-specific intravenous immunoglobulin (Flebogamma®) | 2–18 years with IDP with lack of antibody production; SID in severe recurrent infection, ineffective or proven failed treatment at PSAF or IgG <4 g/l; Kawasaki disease concomitant to AAS; CID polyneuropathy; MM neuropathy | Yes/Yes |
| Ranibizumab (Lucentis®) | Retinopathy of prematurity with zone I (stage 1 +, 2 +, 3 o 3 +), zone II (estadio 3 +) or aggressive progressive ROP | Yes/Yes |
| Belimumab (Benlysta®) | >5 years in active SEL, positive antibodies and high level of disease activity despite standard treatment | Yes/Yes |
| Ivacaftor Granules (kalydeco®) | In ≥6 months and ≥25 kg with CF with class III mutation in the CFTR gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N or S549R | Yes/No. CF ≥2 years and <25 kg and all those mutations |
| Fidaxomicin (Dificlir®) | Infection by C. difficile ≥12.5 kg. Oral granules in <18 years | Yes/Yes |
| Bedaquiline (Sirturo®) | MDR-TB, in combination, 12–18 years and ≥30 kg | Yes/P&R not approved |
| Ustekinumab (Stelara®) | Moderate–severe plaque psoriasis ≥6 years | Yes/Yes |
| Rituximab | Combined with CTX in ≥6 months, with DLBCL, Burkitt lymphoma, mature B cell ALL or in naive patients with advanced-stage Burkitt lymphoma Combined with glucocorticoids remission induction ≥2 years, with granulomatosis with polyangiitis (Wegener) and with microscopic, active and severe polyangiitis | Yes/Yes |
| Darunavir/Cobicistat (Rezolsta®) | HIV: ≥12 years and ≥40 kg | Yes/Yes |
| Cobicistat (Tybost®) | HIV: as a pharmacokinetic enhancer of atazanavir or darunavir, ≥12 years, with restrictions | Yes/Yes |
| Etravirina (Intellence®) | HIV-1: pretreated ≥2 years | Yes/Yes |
| Conestat alfa (Ruconest®) | Acute angioedema, ≥2 years | Yes/Yes |
| Caplacizumab (Cablivi®) | In >12 years and ≥40 kg, with aTTP, concurrent with plasma exchange and immunosuppression | Yes/Yes |
| Anidulafungin (Ecalta®) | Invasive candidiasis, ≥1 month | Yes/Yes |
| Ledispavir/Sofosbuvir (Harvoni®) | HCV+, ≥years | Yes/No |
| Sofosbuvir (Sovaldi®) | HCV, ≥3 years, in combination | Yes/No |
| Ivacaftor (kalydeco®) | CF and R117H CFTR mutation | Yes/No |
| Tedizolid (Sivextro®) | IPPB ≥12 years | Yes/Yes |
| Ixekizumab (Taltz®) | Moderate–severe plaque psoriasis, ≥6 years and ≥25 kg, candidates for systemic treatment | Yes/Yes |
| Secukinumab (Cosentyx®) | Moderate–severe plaque psoriasis, ≥6 years, candidates for systemic treatment | Yes/Yes |
| Sofosbuvir/Velpatasvir (Epclusa®) | HCV, ≥ 6 years and ≥17 kg | Yes/Yes |
| Burosumab (Crysvita®) | X-linked hypophosphatemia, with signs of bone disease, 1–17 years | Yes/Yes |
| Human immunoglobulin (HyQvia®) | SID with recurrent severe infections, ineffective antimicrobial treatment and non-specific antibody failure (failure to achieve a ≥2-fold increase in IgG antibody titer against pneumococcal polysaccharides and polypeptide antigenic vaccines) or serum IgG concentration <4 g/l | Yes/Yes |
| Ivacaftor (Kalydeco®) | CF, in monotherapy, >6 years or >25 kg and one of the following CFTR gene mutations: R117H, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N o S549R. In combination with Ivacaftor/Tezacaftor/Elexacaftor, in CF in ≥12 years with the F508del mutation and minimal function CFTR mutation. | Yes/Yes |
| Lurasidone (Latuda®) | Schizophrenia, ≥13 years | Yes/Yes |
| Catridecacog (Novothirteen®) | Episodes of bleeding during routine prophylaxis in all groups | Yes/P&R not approved |
| Darunavir (Prezista®) | Co-administered with Cobicistat in HIV, ≥12 years and ≥40 kg | Yes/Yes |
| Delamanid (Deltyba®) | MDR-TB, in combination, ≥30 kg, when other treatment is not possible due to resistance or non-tolerability | Yes/Yes |
| Perampanel (Fycompa®) | Concomitant treatment in partial onset crises in ≥4 years and primary generalized tonic–clonic seizures in ≥7 years with generalized idiopathic epilepsy | Yes/Yes |
| Quadrivalent influenza vaccine (Flucelvax Tetra®) | Prophylaxis of influenza, ≥2 years | Yes/P&R not approved |
| Ivacaftor Granules (kalydeco®) | ≥4 months and ≥25 kg with CF and one of the following CFTR gene mutations: R117H, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N o S549R. In combination with Ivacaftor/Tezacaftor/Elexacaftor, in CF in >6 years with the F508del mutation and minimal function mutation in the CFTR gene | Yes/No |
| Sucroferric oxyhydroxide (Velphoro®) | Serum phosphorus control, ≥2 years with CKD in stage 4–5 or on dialysis | Yes/Yes |
| Ceftazidime-avibactam (Zavicefta®) | >3 months, in complicated IAI and UTI, including pyelonephritis, HAP, including VAP | Yes/No |
| Dupilumab (Dupixent®) | Severe atopic dermatitis, 6–11 years, in candidates for systemic treatment | Yes/Yes |
| Adalimumab (Humira®) | Moderate–severe UC, ≥6 years, and contraindication/inadequate response to conventional treatment | Yes/Yes |
| Lacosamide (Vimpat®) | Primary generalized tonic–clonic crises in ≥4 years | Yes/Yes |
| Dabigatran (Pradaxa®) | VT and prevention of recurrent thromboembolism in <18 years | Yes/No |
| Dolutegravir (Tivicay®) | HIV, >4 weeks, >3 kg | Yes/No, ≥6 years |
| Rivaroxabán (Xarelto®) | VT and prevention of recurrent thromboembolic events in full-term neonates, and <18 years, after initial treatment of ≥5 days with parenteral anticoagulants | Yes/No |
| Bedaquiline (Sirturo®) | MDR-TB, in combination, >5 years and ≥15 kg for resistance/intolerance to first-choice treatment | Yes/P&R not approved |
| Pembrolizumab (Keytruda®) | In ≥3 years, with relapsed or refractory HL, who have not responded to TAHP, after ≥2 years when aHSCT is not a treatment option | Yes/No |
| Cannabidiol (Epydiolex®) | >2 years, convulsions associated with tuberous sclerosis | Yes/No |
| Ivacaftor (Kalydeco®) and Ivacaftor/Tezacaftor (Symkevi®) | >12 years with CF with ≥1CFTR mutation in the F508 gene | Yes/Yes |
| Liraglutide (Saxenda®) | >12 years, in weight control, in combination with a low-calorie diet and physical activity, meeting BMI criteria | Yes/P&R not approved |
| Adalimumab (Humira®) | Combined with MTX in active JIA, 4–17 years and insufficient response ≥1 DMARD or monotherapy when treatment with MTX is not possible | Yes/Yes |
| Nitric oxide (INOmax®) | Concurrently with assisted ventilation and other adequate agents in PAH peri- and post-cardiac surgery, 0–17 years | Yes/Yes |
| Sildenafil (Revatio®) | Primary PAH or associated with congenital cardiac disease, 1–17 years | Yes/Yes |
| Delamanid (Deltyba®) | MDR-TB, in combination, >10 years for resistance/intolerance to first-choice treatment | Yes/Yes |
| Ravulizumab (Ultomiris®) | ≥10 kg with PNH on hemodialysis with active or stable disease after treatment with eculizumab ≥6 months | Yes/Yes |
| Ambrisentan (Volibris®) | OMS functional class II-III PAH, 8–18 years | Yes/Yes |
| Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi®) | HCV +; ≥12 years, ≥30 kg | Yes/No |
| Mepolizumab (Nucala®) | Relapsing–remitting or refractory eosinophilic granulomatosis with polyangiitis ≥6 years | Yes/No |
| Elbasvir/Grazoprevir monohydrate (Zepatier®) | HCV+; ≥12 years, >30 kg | Yes/Yes |
| Dapagliflozin (Edistride/Forxiga®) | Poorly controlled DM2, >10 years in combination with diet and physical exercise | Yes/No |
| Nonspecific human immunoglobulin (Hizentra®) | Replacement therapy in SID with severe infections, ineffective antibiotic treatment and specific antibody failure, or serum level of IgG < 4 g/l | Yes/No |
| Evolocumab (Repatha®) | >10 years with homo/heterozygous familial hypercholesterolemia | Yes/No |
| Dengue tetravalent vaccine (Dengvaxia®) | Dengue prophylaxis for serotypes 1,2,3, and 4; ≥6 years, with previous confirmed infection | No/No |
| Sofosbuvir/Velpatasvir (Epclusa®) | HCV; 3 years | Yes/No |
| Tezacaftor/Ivacaftor/Elexacaftor (Kaftrio®) | In combination with ivacaftor in CF in ≥6 years, with ≥1 F508del mutation in the CFTR gene | Yes/No |
| Ivacaftor (Kalydeco®) | In combination with Ivacaftor/Tezacaftor/Elexacaftor, in CF in ≥6 years, with the F508del mutation and minimal function CFTR mutation. | Yes/No |
| Posaconazol (Noxafil®) | ≥2 years; aspergillosis, fusariosis, chromoblastomycosis, and coccidiodomycosis, refractory or intolerant to first-choice antifungals. Patients receiving remission induction CTX for AML or MDS or TPH receptors with immunosuppressive therapy with a high risk for developing IFI | Yes/Yes |
| Brivaracetam (Briviact®) | Concomitant therapy in partial onset seizures, ≥2 years | Yes/No. ≥ 4 years Yes |
| Duplilumab (Dupixent®) | 6–11 years with severe asthma and eosinophilia and/or high level of fractional exhaled FeNO not controlled with inhaled corticosteroids | Yes/No. ≥12 years Yes |
| Lacosamida (Lacosamida UCB®, Vimpat®) | >2 years in monotherapy for partial-onset epileptic seizures | Yes/No. ≥4 years Yes |
| Dimethyl fumarate (Tecfidera®) | Relapsing–remitting MS, ≥13 years | Yes/Yes |
| Doravirine/Lamivudine/Tenofovir disoproxil fumarate (Delstrigo®) | ≥12 years and ≥ 35 kg, HIV-1+, non-resistance to NNTRI, 3TC, or TDF, and toxicity precluding use of other non-TDF-containing regimens | Yes/P&R not approved |
| Doravirine (Pifeltro®) | ART in combination, ≥12 years and ≥35 kg, HIV-1 +, without resistance to NNRTI | Yes/Yes |
| COVID-19 mRNA vaccine nucleoside modified (Spikevax®) | COVID-19 prophylaxis, ≥6 years | Yes/under study or P&R not requested |
| Ruxolitinib (Jakavi®) | GvHD ≥12 years, with inadequate response to steroids or other systemic diseases | Yes/No |
JIA: Juvenile Idiopathic Arthritis; PJIA: Poliarticular Juvenile Idiopathic Arthritis; SMA: Spinal Muscular Atrophy; ASA: Acetylsalicylic Acid; UC: Ulcerative Colitis; DM: Diabetes Mellitus; CD: Crohn's Disease; GvHD: Graft-Versus-Host Disease; MS: Multiple Sclerosis; CKD: Chronic Kidney Disease; FeNO: Nitric Oxide; CF: Cystic Fibrosis; G-CSF: Franulocyte-Colony Stimulating Factor; PAH: Pulmonary Arterial Hypertension; PNH: Paroxysmal Nocturnal Hemoglobinuria; PID: Primary Immunodeficiency; SID: Secondary Immunodeficiency; IFI: Invasive Fungal Invasion; IAI: Intraabdominal Infection; SSTIs: Skin and Soft-Tissue Infections; UTI: Urinary Tract Infection; DLBCL: Diffuse Large B Cell Lymphoma; Metachromatic Leukodystrophy; SEL Systemic Lupus Erythematosus; HL Hodgkin lymphoma; ALL: Acute Lymphoid Leukemia; AML: Acute Myeloid Leukemia; CML: Chronic Myeloid Leukemia; MDR-TB: Multi drug resistant Tuberculosis; MM: Multiple Myeloma; MTX: methotrexate; CAP: Community Associated Pneumonia; HAP: Hospital Acquired Pneumonia; NNRTI: Non-nucleoside reverse transcriptase inhibitors; Attp: Acquired Thrombocytopenic Purpura; CTX: chemotherapy; ROP: Retinopathy of Prematurity; MDS: Myelodysplastic syndrome; PB Peripheral Blood; aHSCT Autogenous Hematopoietic Stem Transplantation; ART: Antiretroviral treatment; ADHD: Attention deficit disorder; VT: venous thrombosis; HBV: Hepatitis B Virus; HCV: Hepatitis C Virus; HIV: Human Immunodeficiency Virus; MV: Mechanical Ventilation; 3TC: Lamivudine.
Comparison of data for our study period against the 3 previous years in our country reveals that, in 2016, a total of 34 drugs were approved for use in the pediatric population (13 new drugs and 21 by extension of the indication). In 2017, there was a 14.7% increase in the number of these types of drugs (18 new drugs and 21 by extension). In 2018, a 32.4% increase was observed with respect to 2016, including 23 new drugs and 22 by extension of its indication. Between 2019 and early 2022, 129 drugs were approved for use in the pediatric population (74 new drugs and 55 by extension of the indication).
DiscussionThe use of drugs in pediatric patients in Spain and Europe entails a wide variety of legal administrative situations related to drug procurement and funding. Drugs are frequently prescribed and administered without any solid evidence being available of their efficacy and safety. This does not necessarily mean an inadequate use of drugs, as in most cases, their use is supported by extensive clinical experience and scientific evidence and is established in standard protocols.
This diversity poses a challenge to pediatricians and pediatric pharmacists. Thus, these professionals need to be aware of the specific status of each drug, the arrangements required by current regulations, and medical and legal responsibilities related to the off-label use of drugs in children (clinical trials or compassionate drug use). It is necessary that clinical trials are performed in the pediatric population to provide clinicians with tools that ensure a safe and effective use of drugs in this population.
The results obtained in this study demonstrate a growing tendency to approve therapeutic indications for the pediatric population. However, there are still some funding and marketing problems that need to be overcome. Although indications for pediatric use are most frequently approved by extension, there are an increasing number of new drugs that already include clinical trials and potential indication for pediatric patients.
On another note, the increasing complexity of pediatric therapeutics makes it necessary that pharmacies in pediatric hospitals play a proactive role in the development of standard protocols approved by regulatory authorities (committees for the rational use of medicines and pharmacy) to establish and facilitate therapeutic procedures in pediatrics.
An increasing number of drugs are approved for pediatric use every year. However, there are still a number of funding and marketing barriers that need to be overcome to facilitate access to effective, safe pediatric treatments.
Contribution to the scientific literatureThis study contributes relevant information about the considerable efforts made by the scientific community to develop new pediatric drugs and extend indications to pediatric use. This intense activity responds to changes in European laws and regulations on the development of drugs for pediatric use. This study provides a picture of the state of affairs in drugs for pediatric use. In our opinion, it is worth sharing this information with the interested professionals, especially pediatricians.
FundingNone.
Authorship declarationLucía Yunquera Romero and Carmen Gallego Fernández contributed to study conception and design. Juan Diego Paradas Palomo contributed to data collection and analysis. Drafting of the manuscript was carried out by three authors: Lucía Yunquera Romero drafted the Introduction and Methods section; Juan Diego Paradas Palomo drafted the Results, and Carmen Gallego Fernández drafted the Discussion. Finally, three authors reviewed critically the manuscript.
To the Spanish SEFH's Working group of Pediatric Pharmacy.
