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Confidential: For Review Only Does the EU’s Paediatric Regulation work for new medicines for children in Nordic countries? A retrospective database review.

Journal: BMJ Paediatrics Open

Manuscript ID bmjpo-2020-000880

Article Type: Original research

Date Submitted by the 16-Sep-2020 Author:

Complete List of Authors: Lepola , Pirkko ; Helsinki University Central Hospital, Children and Adolescents Wang, Siri; Norwegian Medicines Agency Tötterman, Ann Marie; Finnish Medicines Agency Fimea Gullberg, Ninna; Swedish Medicinal products Agency Moll Harboe, Kirstine ; Danish Medicines Agency Kimland, Elin; Swedish Medicinal Products Agency

Keywords: Therapeutics, Pharmacology http://bmjpaedsopen.bmj.com/

on September 25, 2021 by guest. Protected copyright.

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3 bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 6 7 8 9 I, the Submitting Author has the right to grant and does grant on behalf of all authors of the Work (as defined 10 in the below author licence), an exclusive licence and/or a non-exclusive licence for contributions from authors 11 who are: i) UK Crown employees; ii) where BMJ has agreed a CC-BY licence shall apply, and/or iii) in accordance 12 with the termsConfidential: applicable for US Federal Government For officers Review or employees actingOnly as part of their official 13 duties; on a worldwide, perpetual, irrevocable, royalty-free basis to BMJ Publishing Group Ltd (“BMJ”) its 14 licensees and where the relevant Journal is co-owned by BMJ to the co-owners of the Journal, to publish the 15 Work in this journal and any other BMJ products and to exploit all rights, as set out in our licence. 16 17 The Submitting Author accepts and understands that any supply made under these terms is made by BMJ to 18 the Submitting Author unless you are acting as an employee on behalf of your employer or a postgraduate 19 student of an affiliated institution which is paying any applicable article publishing charge (“APC”) for Open 20 Access articles. Where the Submitting Author wishes to make the Work available on an Open Access basis (and 21 intends to pay the relevant APC), the terms of reuse of such Open Access shall be governed by a Creative 22 Commons licence – details of these licences and which Creative Commons licence will apply to this Work are set 23 out in our licence referred to above. 24 25 Other than as permitted in any relevant BMJ Author’s Self Archiving Policies, I confirm this Work has not been 26 accepted for publication elsewhere, is not being considered for publication elsewhere and does not duplicate 27 material already published. I confirm all authors consent to publication of this Work and authorise the granting 28 of this licence. 29 30 31 32 33 34

35 http://bmjpaedsopen.bmj.com/ 36 37 38 39 40 41 42 43 44

45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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3 Does the EU’s Paediatric Regulation work for new medicines for children in Nordic bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 countries? A retrospective database review. 6 7 Correspondence: 1 8 Pirkko Lepola , 9 1University of Helsinki and Helsinki University Hospital, Department of Children and Adolescents 10 Address: Stenbäckinkatu 11, 00029 Helsinki, Finland 11 Tel.: +358-50-5142646 12 Confidential: For Review Only e-mail: [email protected] 13 14 15 Co-authors: 16 Siri Wang2, Ann Marie Tötterman3, Ninna Gullberg4, Kirstine Moll Harboe5 and Elin E. Kimland4 17 2Norwegian Medicines Agency (NoMA), N-0213 Oslo, Norway; [email protected] 18 3Finnish Medicines Agency (FIMEA), FI-00034 FIMEA, Finland; [email protected] 19 4Swedish Medicinal products Agency (MPA), 751 03 Uppsala, Sweden; [email protected] 20 21 (N.G.); [email protected] (E.K.) 22 5Danish Medicines Agency, 2300 Copenhagen S, Denmark; [email protected] 23 24 Keywords: 25 child; age-appropriate formulation; marketing authorisation; paediatric medicines; paediatric 26 27 regulation; medicines availability; access to medicines 28 29 What is known about the subject? 30  The aim of the Paediatric Regulation (EU 1901/2006) is to improve the health of children by 31 facilitating the development and availability of new medicines. 32 33 34  In 2017, the European Medicines Agency (EMA) published 10-year report, and concluded,

35 that a significant number of new medicines for children have been authorised. http://bmjpaedsopen.bmj.com/ 36 37  Marketing authorisation is no guarantee that a medicine is available for patients, and the 38 access to medicines varies across countries. 39 40 41 What this study adds? 42  In 2019, 22 to 36% of the new medicinal products authorised for children (between 2007 43 and 2016) were not marketed across the four Nordic countries. 44

45 on September 25, 2021 by guest. Protected copyright. 46  Of the new paediatric formulations, 23 to 49% were not marketed, and a significant 47 proportion had never been marketed across the four Nordic countries. 48 49  Despite the intentions of the EU Paediatric Regulation, medicines targeted at children are 50 not all marketed, risking limitations in access and availability. 51 52 53 54 55 56 57 58 59 60

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3 ABSTRACT bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 Objective 6 7 The aim of this study was to assess the marketing status of the new paediatric medicinal products 8 authorised for children between 2007 and 2016 reflecting the product availability in four Nordic 9 countries. 10 11 Design 12 Confidential: For Review Only 13 This is a retrospective analysis of the national Medicine Agency’s databases in Denmark, Finland, 14 Norway and Sweden. 15 16 Setting 17 18 New medicinal products with paediatric indications and new formulations were reviewed according 19 to the list of products in the Annex of European Medicines Agency´s (EMA) EU Paediatric Regulation 20 21 10-year report. The products were classified according to national marketing status; whether a 22 product was still authorised and whether the product was marketed at the time of the study period 23 between January and March 2019. 24 25 Main outcome measures 26 27 The main outcomes are the proportions of the new products which still had a valid marketing 28 authorisation and proportions of products that were being marketed, both in terms of the sums of all 29 countries and separately for each country. 30 31 Results 32 33 Across the four countries, 22 to 36% of the new medicinal products initially authorised for children 34 (between 2007 and 2016) were not marketed. Of the new formulations relevant to children, 23 to 49%

35 were not marketed, and a significant proportion of these products had never been marketed. http://bmjpaedsopen.bmj.com/ 36 37 Conclusions 38 39 This study reflects the reality of the implementation of the Paediatric Regulation. The results show 40 that several new medicinal products and new formulations targeted at children are not marketed. This 41 directly affects the availability of these medicines. These findings indicate the need to further 42 43 investigate how to facilitate the availability of new medicines for children across Europe. 44

45 on September 25, 2021 by guest. Protected copyright. 46 INTRODUCTION 47 48 The benefit of new therapies has not reached children to the same extent as the adult population 49 throughout the history of drug development. Children still lack age-appropriate medicines, dosing and 50 51 labelling information for many medicinal products. Increased knowledge and revised attitudes have 52 prompted practical actions to improve the situation in the form of new legislation. In Europe, the 53 Paediatric Regulation (EU 1901/2006 and 1902/2006) was implemented on 26th of January 2007 [1]. 54 55 The aim of the Paediatric Regulation is to improve the health of children in Europe by facilitating the 56 development and availability of medicines for children. To achieve this, the regulation includes a 57 system of obligations, rewards, and incentives for the pharmaceutical industry. It applies to all new 58 59 medicines aiming for a Marketing Authorisation (MA) in Europe, as well as to authorised, patent- 60 protected medicines, when these are developed with new indications, routes of administration, or

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3 pharmaceutical forms for children. In these cases, the company must make a development plan for bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 the product (paediatric investigation plan, PIP), which must be agreed upon by the European 5 6 Medicines Agency (EMA)’s Paediatric Committee (PDCO) [2]. The PDCO also evaluates the medical 7 need for the product in the paediatric population. For older off-patent products, the regulation offers 8 a new Paediatric-Use Marketing Authorisation (PUMA) status for the new paediatric-only products. 9 10 In the European Commission (EC)’s 10-year report in 2017 on the implementation of the Paediatric 11 Regulation,[3] and the background report from EMA [4] a clear positive effect was demonstrated in 12 several areas.Confidential: One of these was the number ofFor authorised Review new medicines forOnly the period between 2007 13 14 and 2016. The data indicated that the regulation has facilitated paediatric medicine development, 15 resulting in new products with initial paediatric indication, extensions of previously authorised 16 products to children, and new formulations or strengths suitable for children. All these are listed in 17 the Annex (chapter 1) to the EMA 10-year report [4]. 18 19 Safety and efficacy data are required for all medicines seeking market authorisation. After 20 authorisation, the product can be placed on the market, allowing access to the new medicine. 21 22 However, the choice to place an authorised product to market in a specific country is the decision of 23 the MA holder (i.e., the pharmaceutical company). The product may be marketed in some countries 24 but some countries not, resulting in variations in ’real-world access’ to medicines. 25 26 Several recent reports have focused on the various developments and achievements that have 27 followed the Paediatric Regulation [5-11], but to our knowledge, no studies have reported on the 28 actual country-specific marketing status after the Paediatric Regulation implementation. The aim of 29 this study was to assess the marketing status of the medicinal products listed as authorised in the 30 31 annex of the EMA´s 10-year report in each of the included four Nordic countries. 32 33 34 MATERIALS AND METHODS

35 http://bmjpaedsopen.bmj.com/ 36 Patient and Public involvement 37 38 Patients nor the public were not involved in any way in this study. 39 40 Research Ethics Approval 41 42 No patients, no human participants - no ethics review needed for this study. 43 44 Data collection

45 on September 25, 2021 by guest. Protected copyright. 46 The study target was to investigate the marketing status of new medicines for children in four Nordic 47 countries during the predefined period between January and March 2019. The term ‘marketing status’ 48 refers to whether a product was still authorised (having a valid MA) and whether the product was 49 marketed, at the time of the study, based on the regulatory classification of the products. 50 51 The products studied were those listed as having been authorised in Europe between 2007 and 2016 52 according to the Annex of the EMA’s ‘10-year Report to the EC [4]. This included A) new medicinal 53 54 products authorised for children and B) new formulations (i.e., new pharmaceutical forms and 55 strengths) relevant for children. The source data for this study is presented in Table 1. 56 57 Data was collected from the national Medicine Authority databases: Denmark (DK): KAT, the in-house 58 administrative database in the Danish Medicines Agency; Finland (FI): In-house register for Marketing 59 Authorisations, Fimea; Norway (NO): Athene, in-house database at the Norwegian Medicines Agency, 60 version 2019.09.1.; and Sweden (SE): VARA, available at the Swedish eHealth Agency.

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3 bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 6 7 8 9 Table 1. The source data for this study, from the Annex of the 10-year report to the European 10 Commission (EMA/35987/2016), listing new authorised medicines [4, Annex’ chapter 1]. 11 12 Confidential: For Review Only Number of Annex table 13 Tables in the Annex of EMA´s 10-year Report medicinal number* 14 products listed 15 New medicines (centrally authorised products (CAPs), initial marketing 1 82 16 authorisations including a paediatric indication (Product group A) 17 18 New pharmaceutical forms (or routes of administration) of paediatric relevance 19 3 (centrally authorised products, CAPs, line extensions of existing marketing 27 authorisations) 20 (Product group B) 21 New pharmaceutical forms (or routes of administration) of paediatric relevance 22 6 (nationally authorised products, NAPs, line extensions of existing marketing 16 23 authorisations) 24 (Product group B) 25 *Annex’ table 4, listing new nationally authorised medicines, was excluded since the majority were generic 26 products and not new medicinal products. Annex’ tables 2 and 5 (new paediatric indications, variations of 27 already authorised products) were not analysed since our focus was on availability of new products. 28 29 Marketing status was assessed separately for each country. Each medicinal product listed in the tables 30 from the Annex was classified by the following two criteria: 1) having a valid marketing authorisation 31 (MA) or not, and 2) being marketed or not (Figure 1). If products were assessed as ‘not marketed’, the 32 33 additional information regarding whether the product had ever been marketed between 2007 and 34 2016 was collected, where data was available. This information was accessible from three (DK, FI, NO)

35 of the national databases. http://bmjpaedsopen.bmj.com/ 36 37 (Figure 1. in picture format separately) 38 39 Figure 1. Flow chart illustrating how marketing status was assessed for the individual products. 40 ‘Available’/’Not available’ are only indicative, as several factors might affect true availability of a 41 product. 42 43 The Paediatric Regulation may require companies to develop age-appropriate formulations in addition 44 to what is foreseen for use in adults, specified in the agreed-upon paediatric investigation plan (PIP).

45 on September 25, 2021 by guest. Protected copyright. 46 To analyse whether these obligations exerted any impact on the marketing status of new 47 formulations, the agreed-upon PIPs were assessed regarding, whether the formulation were part of 48 the obligations in the PIP. The new formulations (product group B) with an agreed-upon PIP were 49 identified using the information from the EMA’s database [12]. 50 51 52 53 Data analysis 54 55 Results were calculated as proportions of the new products which still had a valid marketing 56 authorisation and proportions that were being marketed. Data was presented both in terms of the 57 sums of all countries and separately for each country. Distributions between different therapeutic 58 areas were identified according to the Anatomical Therapeutic Chemical (ATC) code provided in the 59 60

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3 corresponding Summary of Product Characteristics (SmPC). Descriptive tables, figures, and statistics bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 were created in MS Excel. 5 6 Several of the products in the source lists represent more than one strength or form. For new 7 8 medicinal products (Annex’ Tab 1 [4]), a separate assessment was performed for each strength, and 9 similarly, separate assessment was performed for each form or strength for the new formulations 10 (Annex’ Tab 3 and 6 [4]). 11 12 The productsConfidential: are reported by substance and For pharmaceutical Review form, because Only of possible variations in 13 the product trade names between countries. These represent original products and should not be 14 interpreted as generic products. 15 16 17 18 RESULTS 19 20 New centrally authorised medicinal products (Product group A) 21 22 Products still having a MA and being marketed 23 24 Over 90% (76/82) of the new paediatric medicinal products authorised centrally between 2007 and 25 2016 still retained MA at the time of the study (Q1/ 2019). Out of these 76 newly authorised medicinal 26 products, the most common group was medicines for infections and vaccines (30%). (Table 2). More 27 than one third (27/76) of new medicinal products had several strengths initially authorised, and for 28 nearly all of these (23/27), all strengths were marketed. 29 30 31 32 Table 2. Distribution of new centrally authorised medicinal products (N=76) being marketed* across 33 different therapeutic areas as defined by ATC codes and number of medicinal products in four 34 Nordic countries (DK, FI, NO, SE) 35 http://bmjpaedsopen.bmj.com/ 36 Total number Number of medical products 37 of new being marketed 38 Therapeutic area (ATC-codes) medicinal 39 DK FI NO SE 40 products Antibacterial, antimycotic, anti-HIV agents, vaccines, and 41 23 14 17 17 18 42 immunoglobulins (J01, J02, J05, J06, J07) Antineoplastic and immunosuppressive agents 43 11 7 6 6 7 44 (L01, L03, L04) Anticoagulants, coagulation factors, other haematological 6 45 11 9 9 7 on September 25, 2021 by guest. Protected copyright. 46 agents (B01, B02, B06) 47 Bile enzymes, vitamins, metabolic disease (A05, A11, A16) 10 9 6 9 9 Antiepileptics, sleeping agents, and mitochondrial 48 7 7 7 7 7 49 diseases (N03, N05, N06) 50 Allergy, asthmatic, and cystic fibrosis agents 4 4 3 4 4 51 (R01, R03, R07) 52 Antihypertensives, hyperlipidic agents 3 2 3 3 3 53 (C02, C07, C10) 54 Anti-poison agents (V03) 2 1 1 1 1 55 Contraceptives (G03) 1 1 1 1 1 56 Duchenne muscular dystrophy (M09) 1 1 1 1 1 57 Growth hormone (H01) 1 1 1 1 1 58 Topical antibiotics (D06) 1 0 0 0 1 59 Antimalarial agents (P01) 1 0 0 0 0 60

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3 All (ATC A-V) 76 56 52 59 60 bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 *A new medicinal product was regarded as ‘marketed’ even if not all strengths were marketed 5 6 7 8 On average, 57/76 of the newly authorised medicinal products were currently being marketed in the 9 Nordic countries. Sweden had the highest proportion (79%), followed by Norway (78%), Denmark 10 (74%), and Finland (68%) (Figure 2). 11 12 (Figure 2.Confidential: in picture format separately) For Review Only 13 14 Figure 2. Number of new medicinal products marketed (or not) in four Nordic countries (DK, FI, 15 NO, SE) 16 17 Products not marketed 18 19 A total of six medicinal products had no longer marketing authorisation in the EU at the time of the 20 study. These products contained gadoversetamide, rilonacept, influenza vaccine (live attenuated, 21 22 nasal), somatropin, lamivudine/raltegravir potassium, and pancreas powder. One of these products 23 (gadoversetamide) was withdrawn based on safety signals. The reason for the withdrawal of the other 24 products (N=5) is not stated in the databases used. 25 26 Nearly half of the antineoplastic and immunosuppressive agents were not marketed in any of the 27 Nordic countries. There were additional differences between the countries, regarding distribution 28 among therapeutic areas: In Finland, 4/10 of the products in the group of bile enzymes, vitamins, and 29 medicines for metabolic disease were not marketed; conversely, in the other countries, the proportion 30 31 was 1/10. Similarly, as much as 5/11 of anticoagulants, coagulation factors, and other haematological 32 agents were not marketed in Finland, but in other countries, the proportion was lower: 4/11 in 33 Sweden and 2/11 in both Norway and Denmark (Table 2). 34

35 A total of 29 medicinal products were not marketed in at least one of the included countries (Table 3). http://bmjpaedsopen.bmj.com/ 36 The hydroxycarbamide and cholic acid products are examples of the 13 new medicinal products that 37 were not marketed in any of the Nordic countries. 38 39 40 41 Table 3. New medicinal products not marketed (marked as X in the columns) in four Nordic 42 countries (DK, FI, NO, SE), by therapeutic area (based from ATC-code at second level e.g. B02), 43 44 year, and country.

45 on September 25, 2021 by guest. Protected copyright. Products not marketed, marked with X 46 Therapeutic area Year Medicinal product DK FI NO SE 47 Antihemorrhagic 2012 Catridecacog X X 48 Antihemorrhagic 2013 Human coagulation factor VIII / human X X X X 49 von Willebrand factor 50 Antihemorrhagic 2016 Eftrenonacog alfa X 51 Antihemorrhagic 2016 Albutrepenonacog alfa X X 52 Antihemorrhagic 2016 Human coagulation factor X X X X X 53 Anti-infective agent 2007 Retapamulin X X X 54 for topical use 55 Antineoplastic agent 2007 Nelarabine X 56 Antineoplastic agent 2007 Hydroxycarbamide X X X X 57 Antineoplastic agent 2016 Asparaginase X X X X 58 Antipoisoning agent 2007 Hydroxocobalamin X X X X 59 Bile and liver diseases 2014 Cholic acid X X X X Hypertension 2013 Bosentan X 60

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3 Immunoglobulines 2007 Human normal immunoglobulin (IVIG) X X X bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 Immunosuppressants 2009 Canakinumab X 5 Immunstimulating 2013 Filgrastim X X X X 6 Immunstimulating 2016 Autologous CD34+ enriched cell fraction 7 that contains CD34+ cells transduced X X X X 8 with retroviral vector that encodes for 9 the human ADA cDNA sequence Malaria 2011 Dihydroartemisinin / piperaquine 10 X X X X 11 phosphate Metabolic disease 2008 Sapropterin X 12 Confidential: For Review Only Metabolic disease 2014 Elosulfase alfa X 13 Respiratory tract 2012 Ivacaftor X 14 disease 15 Vaccine 2007 Human papillomavirus vaccine [types X X 16 16, 18] 17 Vaccine 2009 Pneumoccocal polysaccharide conjugate X X 18 vaccine (absorbed) 19 Vaccine 2012 Repandemic influenza vaccine (H5N1) 20 (whole virion, inactivated, prepared in X X X X 21 cell culture) 22 Vaccine 2013 Diphtheria (d), tetanus (t), pertussis 23 (acellular, component) (pa), hepatitis b (rdna) (hbv), poliomyelitis (inactivated) X X 24 (ipv) and haemophilus influenzae type b 25 (hib) conjugate vaccine (adsorbed) 26 Vaccine 2013 Influenza vaccine (live attenuated, nasal) X 27 Vaccine 2013 Diphtheria (d), tetanus (t), pertussis 28 (acellular, component) (pa), hepatitis b 29 (rdna) (hbv), poliomyelitis (inactivated) X X X X 30 (ipv) and haemophilus influenzae type b 31 (hib) conjugate vaccine (adsorbed) Vaccine 2016 Pandemic influenza vaccine (H5N1) 32 X X X X 33 (live attenuated, nasal) Vaccine 2016 Diphtheria, tetanus, pertussis (acellular, 34 component), hepatitis b (rdna),

X X X X http://bmjpaedsopen.bmj.com/ 35 poliomyelitis (inact.) and haemophilus 36 type b conjugate vaccine (adsorbed) 37 Vitamine 2009 Tocofersonal d-alpha tocopheryl X 38 polyethylene glycol succinate 39 Number of all medicinal products not marketed 20 24 17 16 40 41 42 New formulations (Product group B) 43 44 A total of 43 products represent new formulations, of which 27 were centrally authorised, and 16

45 nationally authorised. Five of the nationally authorised products were excluded due to insufficient on September 25, 2021 by guest. Protected copyright. 46 information, rendering it impossible to identify the exact product. The resulting 38 products with new 47 48 formulations, represented a total of 56 different formulations, as several strengths or forms were 49 relevant for some products. Each of these 56 formulations were assessed by marketing status. 50 51 Figure 3 indicates the marketing status in the various countries for these 56 products. In all four 52 countries, the majority (91% to 95%) still had MA. However, the proportion of products being 53 marketed was substantially lower, ranging from 50% to 71%. Sweden had the highest proportion of 54 products marketed, and Norway had the lowest. The proportion of marketed products was lowest for 55 56 nationally authorised products (ranging from 38% to 62%), showing lowest proportion in Finland. 57 58 59 60

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3 (Figure 3. in picture format separately) bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 Figure 3. Marketing status, i.e. whether the product still had marketing authorisation (MA) and was 6 still marketed, per country (DK, FI, NO, SE), for newly authorised formulations of medicinal products. 7 8 NAP: nationally authorised products; CAP: centrally authorised products 9 10 11 One fourth (14/56) of the different specific formulations were not marketed in any of these countries, 12 Confidential: For Review Only 13 and 29% (16/56) were marketed in all countries. Table 4 lists details of the 40 formulations that were 14 not marketed in one or more of the countries. Antivirals represented the largest group of products 15 not marketed in one or more countries. Most of the new formulations that were not marketed, seem 16 never to have been marketed in any of these countries (*). 17 18 Table 4. New pharmaceutical forms and strengths not marketed in the four Nordic countries (DK, 19 FI, NO, SE) by year of MA, therapeutic area, and country. 20 21 Product not marketed, marked with X 22 Therapeutic area Year Medicinal product Formulation 23 24 DK FI NO SE 25 Agents acting on the renin- 2009 Losartan Powder for oral suspension X X X 26 angiotensin system 27 Melt tablet/ oral lyophilisate 28 Analgesic drugs 2011 Rizatriptan X* X* 29 5mg 30 Powder and solvent for Antihemorrhagic drugs 2007 Nonacog alfa X* X* X* 31 solution for injection, 250 IU 32 Eltrombopag / - 33 Antihemorrhagic drugs 2016 Tablet 12.5mg X* X* X* X 34 olamine

35 Eltrombopag / - Powder for oral suspension http://bmjpaedsopen.bmj.com/ Antihemorrhagic drugs 2016 X* X* X* X 36 olamine formulation 25mg 37 38 Antihistamins (systemic) 2007 Desloratadine Orodispersible tablets, 2,5 mg X* 39 Antihistamins (systemic) 2007 Desloratadine Orodispersible tablets, 5 mg X* X* 40 41 Antihistamins (systemic) 2012 Rupatadine Oral solution X X X 42 Anti-inflammatory and 43 2011 Ibuprofen Oral suspension X X* X antirheumatic drugs 44

45 Powder for solution for on September 25, 2021 by guest. Protected copyright. Antineoplastic drugs 2009 Temozolomide X* 46 infusion 47 Antipoisoning agent 2007 Deferiprone Oral solution 100 mg/ml. X 48 49 Antiviral drugs 2015 Ritonavir Oral powder X* X* X* 50 Atazanavir / - 51 Antiviral drugs 2016 Oral powder 50 mg X* N X* X 52 sulfate 53 Antiviral drugs 2009 Tipranavir Oral solution X* X* X* X 54 55 Antiviral drugs 2012 Darunavir Oral suspension 100mg/ml X* 56 Tenofovir 150 mg film-coated tablet (123 57 Antiviral drugs 2012 disoproxil as X* mg Tenofovir disoproxil) 58 fumarate 59 60

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3 Tenofovir bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 200 mg film-coated tablet (163 4 Antiviral drugs 2012 disoproxil as X* mg Tenofovir disoproxil) 5 fumarate 6 Tenofovir 7 250 mg film-coated tablet (204 Antiviral drugs 2012 disoproxil as X* 8 mg Tenofovir disoproxil) fumarate 9 10 Tenofovir Granules 40 mg/g (33 mg/g Antiviral drugs 2012 disoproxil as X* 11 tenofovir disoproxil) 12 Confidential:fumarate For Review Only 13 Antiviral drugs 2011 Nevirapine 50 mg Prolonged-release tablet X* X* X* X 14 15 Antiviral drugs 2011 Nevirapine 100 mg Prolonged-release tablet X* X* X* X 16 17 Antiviral drugs 2013 Etravirine Tablet 25 mg strength X* X* X* X 18 Powder for oral suspension 6 Antiviral drugs 2011 Oseltamivir X* X* 19 mg/ml 20 21 Antiviral drugs 2013 Raltegravir Chewable tablets 100 mg X* 22 Antiviral drugs 2013 Raltegravir Chewable tablets 25 mg X* 23 24 Antiviral drugs 2014 Raltegravir Granules for oral suspension X* X* X* X 25 Drugs for obstructive 26 2009 Montelukast Granules X airway diseases 27 28 Drugs used in diabetes 2010 Insulin glulisine Intravenous use X* 29 Powder for oral solution in 30 Drugs used in diabetes 2009 Metformin HCl X* X* X* X 31 sachets 32 Peginterferon alfa- Immunostimulants drugs 2013 Prefilled syringe 90 microgram X* X* X* X 33 2a 34 Mycophenolate 35 Immunosuppressant drugs 2011 Hard capsules 250 mg X* X* X* X http://bmjpaedsopen.bmj.com/ 36 mofetil 37 Lipid modifying agents 2010 Atorvastatin Chewable tablets 5mg X* X* X* X 38 39 Lipid modifying agents 2010 Atorvastatin Chewable tablets 40mg X* X* X* X 40 Lipid modifying agents 2010 Atorvastatin Chewable tablets 10mg X* 41 42 Lipid modifying agents 2010 Atorvastatin Chewable tablets 20mg X* X* 43 44 Other respiratory products 2015 Ivacaftor Granules 50 mg X*

45 Other respiratory products 2015 Ivacaftor Granules 75 mg X* on September 25, 2021 by guest. Protected copyright. 46 47 Psychoanaleptics 2014 Atomoxetine Oral solution X* 48 Rotavirus vaccine, Vaccines 2008 Oral suspension / liquid X* 49 live 50 51 DTP/Hib/Polio Vaccines 2011 Prefilled syringe X* X* X X 52 vaccine 53 Number of new forms and strengths not marketed 27 25 28 16 54 55 *: Product had never been marketed since MA. 56 57 58 59 The formulations not marketed in any country were often the paediatric specific; such as the lower- 60 strength formulations (5/14), the oral liquid/powder/granules (5/14), and the chewable tablets (2/14).

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3 Conversely, approximately half of the products marketed in all countries were products for which the bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 new formulation seemed to have replaced the old one (e.g., prefilled syringe replacing vials, tablets 5 6 replacing capsules, ‘ready-to-use solution for injection’ replacing ‘powder and solvent for solution for 7 injection’). 8 9 The majority (35/56) of the reviewed new formulations represented products with agreed-upon PIPs 10 where the specific formulation was part of the PIP obligations. Only six of these 35 formulations were 11 marketed in all countries. Of the 14 formulations not marketed in any of the countries, nine were 12 listed as specificConfidential: requirements in the PIP. In contrast,For the Review majority (10/16) ofOnly the formulations available 13 14 in all countries, did not have a PIP or were not included in specific PIP formulation requirements. 15 16 17 DISCUSSION 18 19 The reported results regarding the achievements of the Paediatric Regulation [3, 4] are optimistic, 20 indicating increased number of authorised medicines for children. However, the choice to place an 21 22 authorised product on the market in each country is influenced by several factors. Therefore, assessing 23 the actual marketing status may add important information regarding the medicines’ availability for 24 children. 25 26 Our data reveals that on average, 70% of the new medicines authorised for children between 2007 27 and 2016 (i.e. with a paediatric indication at the time of the initial MA) were marketed at the time of 28 the study (Q1/2019). The divergence between countries was not profound. These new medicines were 29 30 all centrally authorised, which would facilitate to market these products ‘Europe-wide’, targeting the 31 largest possible population throughout Europe. 32 33 Child-friendly and age-appropriate formulations are especially important for the youngest paediatric 34 age groups, however, for three of the four countries, only roughly half of the new formulations were

35 marketed. Notably, the forms or strengths that were not marketed in any country were often the http://bmjpaedsopen.bmj.com/ 36 paediatric-specific ones: lower strengths, oral liquid/powder/granules, or chewable tablets. In 37 contrast, a significant proportion of the new formulations and strengths that were marketed in all 38 39 countries did not necessarily seem to fulfil a specific paediatric need; rather, they appeared to 40 optimise the entire product line, often replacing old formulations. 41 42 The reasons why products were (not) put on, or taken off, the markets were not assessed in this study, 43 however, intuitively, the limited size of the population could anticipate sparse return on investments, 44 e.g. for paediatric-specific formulations targeting a fraction of the patients. Regulatory obligations,

45 like nation-specific packages, in addition to the national pricing and reimbursement systems may on September 25, 2021 by guest. Protected copyright. 46 47 affect the strategic marketing decisions. Furthermore, prescribing habits may play a role, particularly 48 if the established practice of off-label use has been accepted for decades. Finally, there might be some 49 dissimilarities in the unmet therapeutic needs between the countries (e.g. antivirals not marketed due 50 to the smaller number of children affected). 51 52 The Paediatric Regulation requirements to develop a paediatric-specific formulation, as agreed in the 53 PIP, are no indicator of whether the formulation will be marketed. Only 17% of the new formulations 54 agreed upon in a PIP were marketed in all four countries, and almost two out of three of the 55 56 formulations that were not marketed in any country were specifically requested in the PIPs. 57 Importantly, the reward granted through the regulation do not oblige the pharmaceutical company to 58 place a product on the market in all members states, but only to have marketing authorisation in all 59 member states. Marketing is therefore not specifically motivated, and any potential reward (i.e., 60

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3 prolonged protection) will be granted nationally for the full product line regardless of whether all bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 paediatric-specific formulations are marketed in that country. 5 6 Our data indicates that most products that were not currently marketed had never been marketed, 7 8 suggesting that the decision to enter a country-specific market is made up front. Thus, factors like 9 actual low sale, patent expiration or introduction of generics seem of limited relevance. 10 11 12 Confidential: For Review Only 13 Strengths and limitations 14 In this study, a product being ‘marketed’ is interpreted as a surrogate measure for the product’s 15 16 availability, even though it does not guarantee the access. Medicines might be available for the 17 patients even if a product is not marketed (e.g., through special licensing or compassionate use 18 programs), and despite a product is marketed, it may not be available to the patient (e.g. due to 19 reimbursement rules, shortages, or physicians not prescribing the product). 20 21 Nevertheless, placing a product on the market increases the availability, ensures access to national 22 product information, provides proper follow-up by companies and authorities, and, frequently affects 23 24 to the price regulation. While acknowledging that several factors ultimately impact patient ‘real-life’ 25 access to medicines, we consider having a product marketed as one particularly important indicator 26 of the medicine availability. 27 28 We have not assessed the clinical consequences of the marketing status of each product. For some 29 products, alternatives might have been available to cover critical unmet needs, for others not. 30 Moreover, the result from the four Nordic countries may not be typical for the rest of Europe since it 31 represents a group of relatively small countries and, as such, a market with limited financial interest. 32 33 Some limitations were identified for the source data of the 10-year report used in this study, as the 34 nationally authorised products were reported on voluntary basis by National Competent Authorities

35 http://bmjpaedsopen.bmj.com/ 36 and thus may not be complete. Additionally, for the nationally authorised products, generics seem to 37 have been reported extensively, which was the reason why the Annex’ Table 4 was excluded. 38 Nevertheless, the listed products are expected to represent most of the relevant ones authorised. 39 40 Finally, this study provides a snapshot of the situation at a specific time point and will not fully reflect 41 the dynamic processes related to marketing status. 42 43 Compared to single-country data, the collaborative approach enables a broader perspective. 44 Therefore, similar data from other countries would be needed to create a better picture of the overall

45 on September 25, 2021 by guest. Protected copyright. situation. 46 47 In conclusion, the reported success of the Paediatric Regulation in terms of newly authorised products 48 49 is only partially valid. Access to medicines, particularly to specific strengths and formulations for 50 paediatric use, is in practice still limited. 51 52 53 54 Funding 55 This research received no specific grant from any funding agency in the public, commercial or not- 56 57 for-profit sectors. 58 Acknowledgments 59 60

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3 The authors would like to thank the personnel from the Finnish National Medicines Agency for bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 providing administrative and IT support for the Finnish data search. 5 6 Author Contributions 7 8 Conceptualization, PL, SW and EK; data curation, SW, AMT, NG, KMH and EK; formal analysis, SW and 9 EK; investigation, SW, AMT, NG, KMH and EK; methodology, SW, AMT, NG, KMH and EK; project 10 11 administration, PL; supervision; SW and EK; visualization, PL, SW and EK; writing – original draft 12 preparation,Confidential: PL, SW and EK; writing – review For and editing, Review PL, SW, AMT, NG, Only KMH and EK. 13 14 Competing Interests 15 16 The authors declare no competing interests. P. Lepola is the Chair of the European Network of 17 Paediatric Research at the European Medicines Agency (Enpr-EMA). S. Wang, A. M. Tötterman, N. 18 Gullberg, and K. M. Harboe are members of the Paediatric Committee at the European Medicines 19 Agency. The views and opinions expressed in this article are those of the authors and do not 20 necessarily reflect the policies or positions of the Paediatric Committee or the European Medicines 21 22 Agency. 23 24 Ethics approval 25 No ethics approval was required, as study did not include participants nor any personal data was 26 27 processed. 28 Provenance and peer review 29 30 Not commissioned; externally peer reviewed. 31 32 Data availability statement 33 34 The authors acknowledge the value of maintaining the integrity, transparency, and reproducibility of

35 research data, but regret that the original research data cannot be made openly available because it http://bmjpaedsopen.bmj.com/ 36 has mainly been extracted from the National Competent Authorities’ secured databases. However, 37 38 the extracted data in Microsoft Excel format can be provided for reproducibility upon separate request 39 from corresponding authors in each country. 40 41 Open access 42 43 This is an open access article. 44 ORCID ID

45 on September 25, 2021 by guest. Protected copyright. 46 Pirkko Lepola https://orcid.org/0000-0001-9663-087 47 48 Elin Kimland https://orcid.org/ 0000-0002-9701-5895 49 50 51 52 53 54 REFERENCES 55 56 1. European Union. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 57 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 58 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. 26 59 60

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3 January 2007. http://ec.europa.eu/health/files/eudralex/vol- bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 1/reg_2006_1901/reg_2006_1901_en.pdf (accessed 13Sep2020). 5 6 2. European Medicines Agency; Paediatric Committee (PDCO). 7 8 http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000 9 265.jsp&mid=WC0b01ac0580028e9d (accessed 13Sep2020). 10 11 3. European Commission’s ten-year report on the implementation of the Paediatric Regulation. 12 https://ec.europa.eu/health/human-use/paediatric-medicines_enConfidential: For Review (accessed Only 13Sep2020) 13 https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/2017_childrensmedicines_r 14 eport_en.pdf (accessed 13Sep2020) 15 16 4. European Medicines Agency and its Paediatric Committee. A technical 10-year report to the EU 17 Commission. EMA/231225/2015. Human Medicines Research and Development Support Division. 18 19 15August2017. 20 https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/paediatrics_10_years_ema_ 21 technical_report.pdf (accessed 13Sep2020). 22 23 5. Nordenmalm S, Tomasi P, Pallidis C. More medicines for children: impact of the EU paediatric 24 regulation. Arch Dis Child 2018, Jun;103(6):557-564. doi: 10.1136/archdischild-2017-313309. 25 Epub 2018 Feb 28. 26 27 6. Hwang T.J, Tomasi P.A, Saint-Raymond A, et al. Availability of paediatric information in European 28 Medicines Agency approvals. Lancet Child Adolesc Health 2018, May;2(5)e9. doi: 10.1016/S2352- 29 30 4642(18)30101-9. Epub 2018 Apr 12. 31 7. Tomasi P.A, Egger G.F, Pallidis C, et al. Enabling Development of Paediatric Medicines in Europe: 32 33 10 Years of the EU Paediatric Regulation. Paediatr Drugs 2017, 19 (6), 505-513, Dec. 34 8. Turner M.A, Catapano M, Hirschfeld S, et al. Global Research in Paediatrics. Paediatric drug

35 http://bmjpaedsopen.bmj.com/ 36 development: The impact of evolving regulations. Adv Drug Deliv Rev 2014, Jun;73:2-13. doi: 37 10.1016/j.addr.2014.02.003. Epub 2014 Feb 18. Review 38 39 9. Saint-Raymond A, Benjamin P, Zaccaria C, et al. Usage of unpublished paediatric data. Arch Dis 40 Child 2016, Jan;101(1):81-4. doi: 10.1136/archdischild-2015-309519. Epub 2015 Nov 5. 41 42 10. Korppi M, Lepola P, Vettenranta K, et al. Limited impact of EU paediatric regulation on Finnish 43 clinical trials highlights need for Nordic collaboration. Acta Paediatr 2013, Nov;102(11):1035-40. 44

45 11. Naumburg E, Rane A, Halvorsen T, et al. Tardy development of safe medicines for children; A on September 25, 2021 by guest. Protected copyright. 46 Nordic network offers new platform to improve this inequity. Acta Paediatr 2019, Jun;108(6):992- 47 993. 48 49 12. European Medicines Agency; Database of opinions and decisions on Pediatric Investigation Plans. 50 https://www.ema.europa.eu/en/medicines/ema_group_types/ema_pip (accessed 13Sep2020). 51 52 53 54 55 56 57 58 59 60

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31 http://bmjpaedsopen.bmj.com/ 32 33 34 35 36 37 38 39 40

41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmjpo BMJ Paediatrics Open Page 16 of 16 bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from

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41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmjpo Page 17 of 16 BMJ Paediatrics Open bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from

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41 on September 25, 2021 by guest. Protected copyright. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 https://mc.manuscriptcentral.com/bmjpo BMJ Paediatrics Open bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from

Confidential: For Review Only Does the EU’s Paediatric Regulation work for new medicines for children in Denmark, Finland, Norway and Sweden? A cross-sectional study.

Journal: BMJ Paediatrics Open

Manuscript ID bmjpo-2020-000880.R1

Article Type: Original research

Date Submitted by the 17-Nov-2020 Author:

Keywords: Therapeutics, Pharmacology http://bmjpaedsopen.bmj.com/

on September 25, 2021 by guest. Protected copyright.

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35 http://bmjpaedsopen.bmj.com/ 36 37 38 39 40 41 42 43 44

45 on September 25, 2021 by guest. Protected copyright. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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3 Does the EU’s Paediatric Regulation work for new medicines for children in Denmark, bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 Finland, Norway and Sweden? A cross-sectional study. 6 7 Correspondence: 1 8 Pirkko Lepola , 9 1University of Helsinki and Helsinki University Hospital, Department of Children and Adolescents 10 Address: Stenbäckinkatu 11, 00029 Helsinki, Finland 11 Tel.: +358-50-5142646 12 Confidential: For Review Only e-mail: [email protected] 13 14 15 Co-authors: 16 Siri Wang2, Ann Marie Tötterman3, Ninna Gullberg4, Kirstine Moll Harboe5 and Elin E. Kimland4 17 2Norwegian Medicines Agency (NoMA), N-0213 Oslo, Norway; [email protected] 18 3Finnish Medicines Agency (FIMEA), FI-00034 FIMEA, Finland; [email protected] 19 4Swedish Medicinal products Agency (MPA), 751 03 Uppsala, Sweden; [email protected] 20 21 (N.G.); [email protected] (E.K.) 22 5Danish Medicines Agency, 2300 Copenhagen S, Denmark; [email protected] 23 24 Keywords: 25 child; age-appropriate formulation; marketing authorisation; paediatric medicines; paediatric 26 27 regulation; medicines availability; access to medicines 28 29 What is known about the subject? 30  The aim of the Paediatric Regulation (EU 1901/2006) is to improve the health of children by 31 facilitating the development and availability of paediatric medicines. 32 33 34  In 2017, the European Medicines Agency (EMA) published 10-year report, and concluded,

35 that a significant number of new medicines for children have been authorised. http://bmjpaedsopen.bmj.com/ 36 37  Marketing authorisation is no guarantee that a new medicine is available for all patients, as 38 the accessibility to medicines varies across countries. 39 40 41 What this study adds? 42  22 to 36% of the new medicines authorised for children (initial MA between 2007 and 2016) 43 were not marketed across the four Nordic countries. 44

45 on September 25, 2021 by guest. Protected copyright. 46  23 to 49% of the new paediatric formulations were not marketed and a significant 47 proportion had never been marketed. 48 49  Despite the intentions of the EU Paediatric Regulation, medicines targeted at children are 50 not all marketed, risking limitations in availability and accessibility for patients. 51 52 53 54 55 56 57 58 59 60

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3 ABSTRACT bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 Objective 6 7 The aim of this study was to assess the marketing status of the new paediatric medicinal products 8 listed in the 10y report as initially authorised between 2007- 2016, reflecting the product availability 9 in four Nordic countries. 10 11 Design 12 Confidential: For Review Only 13 This is a cross-sectional study. 14 15 Setting 16 17 Analysis of the national Medicine Agency’s databases in Denmark, Finland, Norway and Sweden. 18 19 Data source 20 21 New medicinal products with paediatric indications and new paediatric formulations listed in the 22 Annex of European Medicines Agency´s (EMA) EU Paediatric Regulation 10-year report. 23 24 Data analysis 25 26 The products were classified according to national marketing status between January and March 2019; 27 whether a product was authorised and whether the product was marketed. 28 29 Main outcome measures 30 31 The percentages of the new medicinal products with paediatric indications and new paediatric 32 formulations having a valid marketing authorisation and being marketed, both in terms of the sums 33 of all countries and separately for each country. 34

35 Results http://bmjpaedsopen.bmj.com/ 36 37 Across the four countries, 22 to 36% of the new medicinal products were not marketed. Of the new 38 formulations relevant to children, 23 to 49% were not marketed, and a significant proportion of these 39 products had never been marketed. 40 41 Conclusions 42 43 This study reflects the reality of the implementation of the Paediatric Regulation. The results show 44 that several new paediatric medicines and new formulations are not marketed. This affects the

45 product availability. Similar data from other countries is needed to evaluate the overall European on September 25, 2021 by guest. Protected copyright. 46 47 status to find remedies to current situation and increase the availability of the medicines for children. 48 49 50 51 52 53 54 55 56 57 58 59 60

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3 INTRODUCTION bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 The benefit of new therapies has not reached children to the same extent as the adult population 6 throughout the history of drug development. Children still lack medicines across many therapeutic 7 8 areas and all age groups, as well as age-appropriate formulations, adequate dosing and administration 9 instructions in the product labelling. Increased knowledge and revised attitudes have prompted 10 practical actions to improve the situation in the form of new legislation. In Europe, the Paediatric 11 Regulation (EU 1901/2006 and 1902/2006) was implemented on 26th of January 2007 [1]. 12 Confidential: For Review Only 13 The aim of the Paediatric Regulation is to improve the health of children in Europe by facilitating the 14 development and availability of medicines for children. To achieve this, the regulation includes a 15 system of obligations, rewards, and incentives for the pharmaceutical industry. It applies to all new 16 17 medicines aiming for a Marketing Authorisation (MA) in Europe, as well as to authorised, patent- 18 protected medicines, when these are developed with new indications, routes of administration, or 19 pharmaceutical forms for children. In these cases, the company must make a development plan for 20 the product (paediatric investigation plan, PIP), which must be agreed upon by the European 21 22 Medicines Agency (EMA)’s Paediatric Committee (PDCO) [2]. For older off-patent products, the 23 regulation offers a new Paediatric-Use Marketing Authorisation (PUMA) status for the new paediatric- 24 only products. 25 26 In the European Commission (EC)’s 10-year report in 2017 on the implementation of the Paediatric 27 Regulation,[3] and the background report from EMA [4] a clear positive effect was demonstrated in 28 several areas. One of these was the number of authorised new medicines for the period between 2007 29 and 2016. The data indicated that the regulation has facilitated paediatric medicine development, 30 31 resulting in new products with initial paediatric indication, extensions of previously authorised 32 products to children, and new formulations or strengths suitable for children. All these are listed in 33 the Annex (Chapter 1) to the EMA 10-year report [4]. 34

35 Safety, efficacy and quality data are required for all medicines seeking MA. After MA, the product can http://bmjpaedsopen.bmj.com/ 36 be placed on the market, allowing patient´s access to the new medicine through official commercial 37 channels. However, the choice to place an authorised product on the market in a specific country is 38 39 the decision of the MA holder (i.e. the company). The product may be marketed only in selected 40 countries, resulting in variations in ’real-world access’ to medicines. 41 42 Several recent reports have focused on the various developments and achievements that have 43 followed the Paediatric Regulation [5-11], but to our knowledge, no studies have reported on the 44 actual country-specific marketing status after the Paediatric Regulation implementation. The aim of

45 this study was to assess the current marketing status (having marketing authorisation and being on September 25, 2021 by guest. Protected copyright. 46 marketed) of the new medicinal products and new formulations listed in the annex of the EMA´s 10- 47 48 year report on each of the four countries. 49 50 51 MATERIALS AND METHODS 52 53 Research Ethics Approval 54 55 No patients nor voluntary participants were involved in this study, so no ethics review was needed. 56 57 Data collection 58 59 The study target was to investigate the marketing status of new medicines for children in four Nordic 60 countries during the predefined period between January and March 2019. The term ‘marketing status’

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3 refers to whether a product was authorised (having a valid MA) and whether the product was bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 marketed, during the time of the study period, based on the regulatory classification of the products. 5 6 Data source 7 8 The products studied were those listed as having been authorised in Europe between 2007 and 2016 9 according to the Annex of the EMA’s ‘10-year Report to the EC [4]. This included A) new medicinal 10 11 products authorised with a paediatric indication at the time of the initial marketing authorisation and 12 B) new formulationsConfidential: (i.e., new pharmaceutical For forms Reviewand strengths) relevant Only for children as listed in 13 the Annex-Tables 1, 3 and 6. Information on the source data for this study is presented in Table 1. 14 15 Data was collected from the national Medicine Authority databases: Denmark (DK): KAT, the in-house 16 administrative database in the Danish Medicines Agency; Finland (FI): In-house register for Marketing 17 Authorisations, Fimea; Norway (NO): Athene, in-house database at the Norwegian Medicines Agency, 18 19 version 2019.09.1.; and Sweden (SE): VARA, available at the Swedish eHealth Agency. 20 21 22 Table 1. The source data for this study, from the Annex of the 10-year report to the European 23 24 Commission (EMA/35987/2016), listing new authorised medicines [4, Annex’ chapter 1]. 25 Number of 26 Annex table Tables in the Annex of EMA´s 10-year Report medicinal number* 27 products listed 28 New medicines (centrally authorised products (CAPs), initial marketing 29 1 82 30 authorisations including a paediatric indication (Product group A)** 31 New pharmaceutical forms (or routes of administration) of paediatric relevance 32 3 (centrally authorised products, CAPs, line extensions of existing marketing 27 33 authorisations) 34 (Product group B) New pharmaceutical forms (or routes of administration) of paediatric relevance 35 http://bmjpaedsopen.bmj.com/ 36 6 (nationally authorised products, NAPs, line extensions of existing marketing 16 37 authorisations) (Product group B) 38 *Annex’ table 4, listing new nationally authorised medicines, was excluded since the majority were generic 39 products and not new medicinal products. Annex’ tables 2 and 5 (new paediatric indications, variations of 40 41 already authorised products) were not analysed since our focus was on availability of new products. 42 ** Annex’ table 1 excludes medicines that are not subjected to the obligations of the Paediatric Regulation (e.g. 43 generics, hybrid medicines, biosimilars etc.) 44

45 on September 25, 2021 by guest. Protected copyright. 46 47 Marketing status was assessed separately for each country. Each medicinal product listed in the 48 Annex-tables was classified by the following two criteria: 1) having a valid marketing authorisation 49 50 (MA) or not, and 2) being marketed or not (Figure 1). For the new formulations (product group B), if 51 products were assessed as ‘not marketed’, the additional information regarding whether the product 52 had ever been marketed between 2007-2016 was collected, where data was available. This 53 information was accessible in three (DK, FI, NO) national databases, and not analysed for SE. 54 55 56 57 (Figure 1. in picture format separately) 58 59 Figure 1. Flow chart illustrating how marketing status was assessed for the individual products. 60

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3 bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 The Paediatric Regulation may require companies to develop age-appropriate formulations in addition 6 to what is foreseen for use in adults, specified in the agreed-upon PIP. To analyse whether these 7 8 obligations exerted any impact on the marketing status of new formulations, the agreed-upon PIPs 9 were assessed regarding, whether the formulation were part of the obligations in the PIP. The new 10 formulations (product group B) with an agreed-upon PIP were identified using the information from 11 the EMA’s database [12]. 12 Confidential: For Review Only 13 Data analysis 14 15 Results were calculated as percentages (proportions) of the new products which still had a valid MA 16 and being marketed. Data was presented both in terms of the sums of all countries and separately for 17 each country. Distributions between different therapeutic areas were identified according to the 18 19 Anatomical Therapeutic Chemical (ATC) code provided in the corresponding Summary of Product 20 Characteristics (SmPC). Descriptive tables, figures, and statistics were created in MS Excel. 21 22 Several of the products in the source lists represent more than one strength or form. For new 23 medicinal products (Product group A), a separate assessment was initially performed for each 24 strength. In the final analysis of these products, a new medicinal product was regarded as ‘marketed’ 25 even if not all different strengths were placed on market. For the Product group B, separate 26 assessment was performed for each form or strength for the new. 27 28 The products presented in this study by substance and pharmaceutical form because of possible 29 30 variations in the product trade names between countries. 31 32 33 RESULTS 34

35 New centrally authorised medicinal products (Product group A) http://bmjpaedsopen.bmj.com/ 36 37 Products still having a MA and being marketed 38 39 Over 90% (76/82) of the new paediatric medicinal products authorised centrally between 2007 and 40 2016 still retained MA at the time of the study (Q1/ 2019). Out of these 76 newly authorised medicinal 41 products, the most common group was medicines for infections and vaccines (30%). (Table 2). More 42 43 than one third (27/76) of new medicinal products had several strengths initially authorised, and for 44 nearly all of these (23/27), all strengths were marketed.

45 on September 25, 2021 by guest. Protected copyright. 46 Products not marketed 47 A total of six medicinal products had no longer marketing authorisation in the EU at the time of the 48 49 study. These products contained gadoversetamide, rilonacept, influenza vaccine (live attenuated, 50 nasal), somatropin, lamivudine/raltegravir potassium, and pancreas powder. One of these products 51 (gadoversetamide) was withdrawn based on safety signals. The reason for the withdrawal of the other 52 products (N=5) is not stated in the databases used. 53 54 Nearly half of the antineoplastic and immunosuppressive agents were not marketed in any of the 55 Nordic countries. There were additional differences between the countries, regarding distribution 56 57 among therapeutic areas: In Finland, 4/10 of the products in the group of bile enzymes, vitamins, and 58 medicines for metabolic disease were not marketed; conversely, in the other countries, the proportion 59 was 1/10. Similarly, as much as 5/11 of anticoagulants, coagulation factors, and other haematological 60

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3 agents were not marketed in Finland, but in other countries, the proportion was lower: 4/11 in bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 Sweden and 2/11 in both Norway and Denmark (Table 2). 5 6 A total of 29 medicinal products were not marketed in at least one of the included countries (Table 3). 7 8 The hydroxycarbamide and cholic acid products are examples of the 13 new medicinal products that 9 were not marketed in any of the Nordic countries. 10 11 12 Confidential: For Review Only 13 Table 2. New centrally authorised medicinal products (N=76) having MA and being marketed across 14 different therapeutic areas as defined by ATC codes and number of medicinal products in DK, FI, NO, 15 SE 16 17 Total number Number of medical products of new being marketed 18 Therapeutic area (ATC-codes) 19 medicinal 20 products DK FI NO SE 21 Antibacterial, antimycotic, anti-HIV agents, vaccines, and 23 14 17 17 18 22 immunoglobulins (J01, J02, J05, J06, J07) 23 Antineoplastic and immunosuppressive agents 11 7 6 6 7 24 (L01, L03, L04) 25 Anticoagulants, coagulation factors, other haematological 6 11 9 9 7 26 agents (B01, B02, B06) 27 Bile enzymes, vitamins, metabolic disease (A05, A11, A16) 10 9 6 9 9 28 Antiepileptics, sleeping agents, and mitochondrial 7 7 7 7 7 29 diseases (N03, N05, N06) 30 Allergy, asthmatic, and cystic fibrosis agents 4 4 3 4 4 31 (R01, R03, R07) 32 Antihypertensives, hyperlipidic agents 3 2 3 3 3 33 (C02, C07, C10) 34 Anti-poison agents (V03) 2 1 1 1 1

35 http://bmjpaedsopen.bmj.com/ Contraceptives (G03) 1 1 1 1 1 36 Duchenne muscular dystrophy (M09) 1 1 1 1 1 37 Growth hormone (H01) 1 1 1 1 1 38 39 Topical antibiotics (D06) 1 0 0 0 1 40 Antimalarial agents (P01) 1 0 0 0 0 41 All (ATC A-V) 76 56 52 59 60 42 43 44 Table 3. New medicinal products having MA but not marketed (marked as X in the columns) in DK,

45 FI, NO, SE, by therapeutic area (based from ATC-code at second level e.g. B02), year, and country. on September 25, 2021 by guest. Protected copyright. 46 Products not marketed, marked with X 47 Therapeutic area Year Medicinal product 48 DK FI NO SE 49 Antihemorrhagic 2012 Catridecacog X X Antihemorrhagic 2013 Human coagulation factor VIII / human 50 X X X X von Willebrand factor 51 Antihemorrhagic 2016 Eftrenonacog alfa X 52 Antihemorrhagic 2016 Albutrepenonacog alfa X X 53 Antihemorrhagic 2016 Human coagulation factor X X X X X 54 Anti-infective agent 2007 Retapamulin X X X 55 for topical use 56 Antineoplastic agent 2007 Nelarabine X 57 Antineoplastic agent 2007 Hydroxycarbamide X X X X 58 Antineoplastic agent 2016 Asparaginase X X X X 59 Antipoisoning agent 2007 Hydroxocobalamin X X X X 60 Bile and liver diseases 2014 Cholic acid X X X X

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3 Hypertension 2013 Bosentan X bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 Immunoglobulines 2007 Human normal immunoglobulin (IVIG) X X X 5 Immunosuppressants 2009 Canakinumab X 6 Immunstimulating 2013 Filgrastim X X X X 7 Immunstimulating 2016 Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced 8 X X X X 9 with retroviral vector that encodes for 10 the human ADA cDNA sequence Malaria 2011 Dihydroartemisinin / piperaquine 11 X X X X phosphate 12 Confidential: For Review Only Metabolic disease 2008 Sapropterin X 13 Metabolic disease 2014 Elosulfase alfa X 14 Respiratory tract 2012 Ivacaftor X 15 disease 16 Vaccine 2007 Human papillomavirus vaccine [types X X 17 16, 18] 18 Vaccine 2009 Pneumoccocal polysaccharide conjugate X X 19 vaccine (absorbed) 20 Vaccine 2012 Repandemic influenza vaccine (H5N1) 21 (whole virion, inactivated, prepared in X X X X 22 cell culture) 23 Vaccine 2013 Diphtheria (d), tetanus (t), pertussis (acellular, component) (pa), hepatitis b 24 (rdna) (hbv), poliomyelitis (inactivated) X X 25 (ipv) and haemophilus influenzae type b 26 (hib) conjugate vaccine (adsorbed) 27 Vaccine 2013 Influenza vaccine (live attenuated, nasal) X 28 Vaccine 2013 Diphtheria (d), tetanus (t), pertussis 29 (acellular, component) (pa), hepatitis b 30 (rdna) (hbv), poliomyelitis (inactivated) X X X X 31 (ipv) and haemophilus influenzae type b 32 (hib) conjugate vaccine (adsorbed) Vaccine 2016 Pandemic influenza vaccine (H5N1) 33 X X X X (live attenuated, nasal) 34 Vaccine 2016 Diphtheria, tetanus, pertussis (acellular, 35 component), hepatitis b (rdna), http://bmjpaedsopen.bmj.com/ X X X X 36 poliomyelitis (inact.) and haemophilus 37 type b conjugate vaccine (adsorbed) 38 Vitamine 2009 Tocofersonal d-alpha tocopheryl X 39 polyethylene glycol succinate 40 Number of all medicinal products not marketed 20 24 17 16 41 42 43 On average, 57/76 of the newly authorised medicinal products were currently being marketed in the 44 Nordic countries. Sweden had the highest proportion (79%), followed by Norway (78%), Denmark

45 on September 25, 2021 by guest. Protected copyright. 46 (74%), and Finland (68%) (Figure 2). 47 (Figure 2. in picture format separately) 48 49 Figure 2. Number of new medicinal products marketed (or not) in DK, FI, NO, SE 50 51 52 53 54 55 New formulations (Product group B) 56 57 A total of 43 products represented new formulations, of which 27 were centrally authorised, and 16 58 nationally authorised. Five of the nationally authorised products were excluded due to insufficient 59 information, rendering it impossible to identify the exact product. The resulting 38 products with new 60

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3 formulations, represented a total of 56 different formulations, as several strengths or forms were bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 relevant for some products. Each of these 56 formulations were assessed by marketing status. 5 6 Figure 3 indicates the marketing status in the various countries for these 56 products. In all four 7 8 countries, the majority (91% to 95%) still had MA. However, the proportion of products being 9 marketed was substantially lower, ranging from 50% to 71%. Sweden had the highest proportion of 10 products marketed, and Norway had the lowest. The proportion of marketed products was lowest for 11 nationally authorised products (ranging from 38% to 62%), showing lowest proportion in Finland. 12 Confidential: For Review Only 13 (Figure 3. in picture format separately) 14 15 Figure 3. Marketing status for new formulations of medicinal products (whether the product still 16 had marketing authorisation (MA) and was still marketed) per country (DK, FI, NO, SE). NAP: 17 Nationally Authorised Products; CAP: Centrally Authorised Products. 18 19 20 21 One fourth (14/56) of the different specific formulations were not marketed in any of these countries, 22 and 29% (16/56) were marketed in all countries. Table 4 lists details of the 40 formulations that were 23 24 not marketed in one or more of the countries, having antivirals the largest group of such products. 25 Most of the new formulations that were not marketed, seem never to have been marketed (*). 26 27 Table 4. New pharmaceutical forms and strengths not marketed in DK, FI, NO, SE by year of MA, 28 therapeutic area, and country. 29 30 Product not marketed, marked with X (never been 31 marketed since MA*; DK, FI, Therapeutic area Year Medicinal product Formulation 32 NO – No data available for SE) 33 34 DK FI NO SE

35 http://bmjpaedsopen.bmj.com/ Agents acting on the renin- 36 2009 Losartan Powder for oral suspension X X X angiotensin system 37 38 Melt tablet/ oral lyophilisate Analgesic drugs 2011 Rizatriptan X* X* 39 5mg 40 Powder and solvent for 41 Antihemorrhagic drugs 2007 Nonacog alfa X* X* X* solution for injection, 250 IU 42 43 Eltrombopag / - Antihemorrhagic drugs 2016 Tablet 12.5mg X* X* X* X 44 olamine

45 on September 25, 2021 by guest. Protected copyright. Eltrombopag / - Powder for oral suspension 46 Antihemorrhagic drugs 2016 X* X* X* X olamine formulation 25mg 47 48 Antihistamins (systemic) 2007 Desloratadine Orodispersible tablets, 2,5 mg X* 49 50 Antihistamins (systemic) 2007 Desloratadine Orodispersible tablets, 5 mg X* X* 51 Antihistamins (systemic) 2012 Rupatadine Oral solution X X X 52 Anti-inflammatory and 53 2011 Ibuprofen Oral suspension X X* X 54 antirheumatic drugs 55 Powder for solution for Antineoplastic drugs 2009 Temozolomide X* 56 infusion 57 58 Antipoisoning agent 2007 Deferiprone Oral solution 100 mg/ml. X 59 Antiviral drugs 2015 Ritonavir Oral powder X* X* X* 60

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3 Atazanavir / - bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from Antiviral drugs 2016 Oral powder 50 mg X* X X* X 4 sulfate 5 6 Antiviral drugs 2009 Tipranavir Oral solution X* X* X* X 7 Antiviral drugs 2012 Darunavir Oral suspension 100mg/ml X* 8 Tenofovir 9 150 mg film-coated tablet (123 Antiviral drugs 2012 disoproxil as X* 10 mg Tenofovir disoproxil) 11 fumarate 12 Confidential: For Review Only Tenofovir 200 mg film-coated tablet (163 13 Antiviral drugs 2012 disoproxil as X* mg Tenofovir disoproxil) 14 fumarate 15 Tenofovir 16 250 mg film-coated tablet (204 Antiviral drugs 2012 disoproxil as X* 17 mg Tenofovir disoproxil) fumarate 18 19 Tenofovir Granules 40 mg/g (33 mg/g 20 Antiviral drugs 2012 disoproxil as X* tenofovir disoproxil) 21 fumarate 22 Antiviral drugs 2011 Nevirapine 50 mg Prolonged-release tablet X* X* X* X 23 24 Antiviral drugs 2011 Nevirapine 100 mg Prolonged-release tablet X* X* X* X 25 26 Antiviral drugs 2013 Etravirine Tablet 25 mg strength X* X* X* X 27 Powder for oral suspension 6 Antiviral drugs 2011 Oseltamivir X* X* 28 mg/ml 29 30 Antiviral drugs 2013 Raltegravir Chewable tablets 100 mg X* 31 Antiviral drugs 2013 Raltegravir Chewable tablets 25 mg X* 32 33 Antiviral drugs 2014 Raltegravir Granules for oral suspension X* X* X* X 34 Drugs for obstructive 35 2009 Montelukast Granules X http://bmjpaedsopen.bmj.com/ 36 airway diseases 37 Drugs used in diabetes 2010 Insulin glulisine Intravenous use X* 38 Powder for oral solution in 39 Drugs used in diabetes 2009 Metformin HCl X* X* X* X 40 sachets 41 Peginterferon alfa- Immunostimulants drugs 2013 Prefilled syringe 90 microgram X* X* X* X 42 2a 43 Mycophenolate 44 Immunosuppressant drugs 2011 Hard capsules 250 mg X* X* X* X mofetil

45 on September 25, 2021 by guest. Protected copyright. 46 Lipid modifying agents 2010 Atorvastatin Chewable tablets 5mg X* X* X* X 47 48 Lipid modifying agents 2010 Atorvastatin Chewable tablets 40mg X* X* X* X 49 Lipid modifying agents 2010 Atorvastatin Chewable tablets 10mg X* 50 51 Lipid modifying agents 2010 Atorvastatin Chewable tablets 20mg X* X* 52 53 Other respiratory products 2015 Ivacaftor Granules 50 mg X* 54 Other respiratory products 2015 Ivacaftor Granules 75 mg X* 55 56 Psychoanaleptics 2014 Atomoxetine Oral solution X* 57 Rotavirus vaccine, 58 Vaccines 2008 Oral suspension / liquid X* live 59 60

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3 DTP/Hib/Polio bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from Vaccines 2011 Prefilled syringe X* X* X X 4 vaccine 5 6 Number of new forms and strengths not marketed 27 25 28 16 7 8 9 The formulations not marketed in any country were often the paediatric specific; such as the lower- 10 strength formulations (5/14), the oral liquid/powder/granules (5/14), and the chewable tablets (2/14). 11 12 Conversely,Confidential: approximately half of the products For marketed Review in all countries wereOnly products for which the 13 new formulation seemed to have replaced the old one (e.g., prefilled syringe replacing vials, tablets 14 replacing capsules, ‘ready-to-use solution for injection’ replacing ‘powder and solvent for solution for 15 injection’). 16 17 The majority (35/56) of the reviewed new formulations represented products with agreed-upon PIPs 18 where the specific formulation was part of the PIP obligations. Only six of these 35 formulations were 19 20 marketed in all countries. Of the 14 formulations not marketed in any of the countries, nine were 21 listed as specific requirements in the PIP. In contrast, the majority (10/16) of the formulations available 22 in all countries, did not have a PIP or were not included in specific PIP formulation requirements. 23 24 25 26 DISCUSSION 27 28 Our data reveals that on average, 70% of the new paediatric medicines and 57% of the new paediatric 29 formulations initially authorised for children between 2007 and 2016, were marketed at the time of 30 the study (Q1/2019). 31 32 The reported achievements of the Paediatric Regulation [3, 4] are optimistic, indicating increased 33 number of authorised medicines for children. However, the choice to place an authorised product on 34 the market in each country is influenced by several factors. Therefore, assessing the actual marketing

35 http://bmjpaedsopen.bmj.com/ 36 status may add important piece of information regarding the medicines’ availability for children. Some 37 papers have studied the availability of e.g. paediatric oral formulations and shown variability across 38 Europe [13-15] but, unfortunately none of these studies have assessed the availability related to the 39 reported outcome of the Paediatric Regulation. 40 41 For the new medicines initially authorised for children, the divergence between countries was not 42 profound. These new medicines were all centrally authorised, which would facilitate to market these 43 products ‘Europe-wide’, targeting the largest possible population throughout Europe. 44

45 Despite child-friendly, age-appropriate formulations being especially important for the youngest age on September 25, 2021 by guest. Protected copyright. 46 47 groups, for three of the four countries only roughly half of the new formulations were marketed. It is 48 notable, that the forms or strengths that were not marketed in any country were often the paediatric- 49 specific ones: lower strengths, oral liquids or chewable tablets. In contrast, a significant proportion of 50 the new forms and strengths that were marketed in all countries did not seem to fulfil a specific 51 paediatric need but rather appeared to optimise the entire product line, often replacing old 52 53 formulations. 54 The reasons why products were placed on or not placed, or taken off the markets, were not assessed 55 56 in this study. Intuitively, the limited size of the population could anticipate sparse return on 57 investments, targeting only a fraction of the patients. Regulatory obligations, like nation-specific 58 packages, in addition to the national pricing and reimbursement systems may have strong effect on 59 the strategic marketing decisions. Furthermore, prescribing habits may play a role, particularly if the 60

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3 established practice of off-label use has been accepted for decades. Finally, there might be some bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 dissimilarities in the unmet therapeutic needs between the countries (e.g. antivirals not marketed due 5 6 to the smaller number of children affected). 7 8 The Paediatric Regulation requirements to develop a paediatric specific formulations, as agreed in the 9 PIP, are no indicator of whether the formulation will be marketed. Only 17% of the new formulations 10 agreed upon PIP, were marketed in all four countries, and almost two out of three of the formulations 11 that were not marketed in any country were specifically requested in the PIPs. Importantly, the reward 12 granted throughConfidential: the regulation does not oblige For the company Review to place a product Only on the market in all 13 14 countries, but only to have MA in all member states. Marketing is therefore not specifically motivated, 15 and any potential reward (i.e., prolonged protection) is granted nationally for the full product line 16 regardless of whether all paediatric-specific formulations are marketed in that country. 17 18 Our data indicates that most products that were not currently marketed had never been marketed, 19 suggesting that the decision to entering a country-specific market is made up front. Thus, factors like 20 actual low sale, patent expiration or introduction of generics seem of limited relevance. 21 22 23 24 Strengths and limitations 25 26 In this study, a product being ‘marketed’ is interpreted as a surrogate measure for the product’s 27 availability after it has been placed on the market, because it does not guarantee the access to 28 patients. Medicines can be available for the patients even if a product is not marketed (e.g., through 29 30 special licensing or compassionate use programs), and despite a product is marketed, it may not be 31 available for patients (e.g. reimbursement rules, medicine shortages, or physicians not prescribing the 32 product). 33 34 There are several extremely relevant factors having direct impact on the companies´ market strategies

35 and for the decisions to placing products on markets, such as the targeted market size or country http://bmjpaedsopen.bmj.com/ 36 specific expenditure, pricing and reimbursement practices. If thoroughly investigated, this type of 37 additional data would give more detailed rationale and increase understanding for the current 38 39 situation. However, studying these aspects would need the involvement of other scientific disciplines 40 and other regulatory authorities. 41 42 This study did not assess the clinical consequences of the marketing status of each product and 43 whether these products specifically fulfil a certain paediatric unmet need or not. For some products, 44 alternatives might have been available, for others not. It is assumed that at least for products with a

45 PIP obligation, such a need has been identified. on September 25, 2021 by guest. Protected copyright. 46 47 Some limitations were identified for the source data, as the nationally authorised products were 48 reported on voluntary basis by National Competent Authorities and thus may not be complete. 49 50 Additionally, for the nationally authorised products, generics seem to have been reported extensively, 51 which was the reason why the Annex’ Table 4 was excluded. Nevertheless, the listed products are 52 expected to represent most of the relevant ones authorised. 53 54 Nevertheless, placing a product on the market and having it marketed increases the potential 55 availability, ensures access to national product information, provides proper follow-up by companies 56 and authorities, and, frequently affects the price regulation and therefore serves as important 57 58 indicator of the accessibility. This study provides a snapshot of the `real-world´ situation at a specific 59 time point and will not fully reflect all the dynamic factors and processes related to marketing status. 60

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3 While acknowledging that several factors ultimately impact patient ‘real-life’ access to medicines, we bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 consider having a product marketed as one particularly important indicator of the medicine 5 6 availability. 7 8 These results may not be typical for all European countries since it represents a group of relatively 9 small countries and, as such, a market with limited financial interest. Therefore, similar data from 10 other countries would be needed to create a better picture of the overall situation. 11 12 In conclusion,Confidential: the reported success of the Paediatric For RegulationReview in terms ofOnly new authorised products, 13 is only partially valid. To make more sustainable future changes to the current situation, the ongoing 14 European Commission Pharma Strategy including the evaluation of Paediatric Regulation [16] should 15 consider more carefully to understand reasons and cure the existing hindering factors. Elements like 16 17 targeted rewards, adapted legal requirements, an alternative pricing system and decreasing off-label 18 use, should all be discussed. Truly, the access to medicines for children is in practice still limited. 19 20 21 22 Funding 23 24 This research received no specific grant from any funding agency in the public, commercial or not- 25 for-profit sectors. 26 27 Acknowledgments 28 The authors would like to thank the personnel from the Finnish National Medicines Agency for 29 30 providing administrative and IT support for the Finnish data search. 31 32 Author Contributions 33 Conceptualization, PL, SW and EK; data curation, SW, AMT, NG, KMH and EK; formal analysis, SW and 34 EK; investigation, SW, AMT, NG, KMH and EK; methodology, SW, AMT, NG, KMH and EK; project 35 http://bmjpaedsopen.bmj.com/ 36 administration, PL; supervision; SW and EK; visualization, PL, SW and EK; writing – original draft 37 preparation, PL, SW and EK; writing – review and editing, PL, SW, AMT, NG, KMH and EK. 38 39 Competing Interests 40 41 The authors declare no competing interests. P. Lepola is the Chair of the European Network of 42 Paediatric Research at the European Medicines Agency (Enpr-EMA). S. Wang, A. M. Tötterman, N. 43 Gullberg, and K. M. Harboe are members of the Paediatric Committee at the European Medicines 44 Agency. The views and opinions expressed in this article are those of the authors and do not

45 on September 25, 2021 by guest. Protected copyright. 46 necessarily reflect the policies or positions of the Paediatric Committee or the European Medicines 47 Agency. 48 49 Ethics approval 50 51 No ethics approval was required, as study did not include participants nor any personal data was 52 processed. 53 54 Provenance and peer review 55 56 Not commissioned; externally peer reviewed. 57 Data availability statement 58 59 60

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3 The authors acknowledge the value of maintaining the integrity, transparency, and reproducibility of bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 research data, but regret that the original research data cannot be made openly available because it 5 6 has mainly been extracted from the National Competent Authorities’ secured databases. However, 7 the extracted data in Microsoft Excel format can be provided for reproducibility upon separate request 8 from corresponding authors in each country. 9 10 Open access 11 12 This is anConfidential: open access article. For Review Only 13 14 ORCID ID 15 16 Pirkko Lepola https://orcid.org/0000-0001-9663-087 17 Elin Kimland https://orcid.org/ 0000-0002-9701-5895 18 19 20 21 22 23 REFERENCES 24 25 1. European Union. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 26 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 27 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. 26 28 29 January 2007. http://ec.europa.eu/health/files/eudralex/vol- 30 1/reg_2006_1901/reg_2006_1901_en.pdf (accessed 13Sep2020). 31 32 2. European Medicines Agency; Paediatric Committee (PDCO). 33 http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_000 34 265.jsp&mid=WC0b01ac0580028e9d (accessed 13Sep2020).

35 http://bmjpaedsopen.bmj.com/ 36 3. European Commission’s ten-year report on the implementation of the Paediatric Regulation. 37 https://ec.europa.eu/health/human-use/paediatric-medicines_en (accessed 13Sep2020) 38 https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/2017_childrensmedicines_r 39 40 eport_en.pdf (accessed 13Sep2020) 41 4. European Medicines Agency and its Paediatric Committee. A technical 10-year report to the EU 42 43 Commission. EMA/231225/2015. Human Medicines Research and Development Support Division. 44 15August2017.

45 https://ec.europa.eu/health/sites/health/files/files/paediatrics/docs/paediatrics_10_years_ema_ on September 25, 2021 by guest. Protected copyright. 46 technical_report.pdf (accessed 13Sep2020). 47 48 5. Nordenmalm S, Tomasi P, Pallidis C. More medicines for children: impact of the EU paediatric 49 regulation. Arch Dis Child 2018, Jun;103(6):557-564. doi: 10.1136/archdischild-2017-313309. 50 51 Epub 2018 Feb 28. 52 6. Hwang T.J, Tomasi P.A, Saint-Raymond A, et al. Availability of paediatric information in European 53 54 Medicines Agency approvals. Lancet Child Adolesc Health 2018, May;2(5)e9. doi: 10.1016/S2352- 55 4642(18)30101-9. Epub 2018 Apr 12. 56 57 7. Tomasi P.A, Egger G.F, Pallidis C, et al. Enabling Development of Paediatric Medicines in Europe: 58 10 Years of the EU Paediatric Regulation. Paediatr Drugs 2017, 19 (6), 505-513, Dec. 59 60

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3 8. Turner M.A, Catapano M, Hirschfeld S, et al. Global Research in Paediatrics. Paediatric drug bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 development: The impact of evolving regulations. Adv Drug Deliv Rev 2014, Jun;73:2-13. doi: 5 6 10.1016/j.addr.2014.02.003. Epub 2014 Feb 18. Review 7 8 9. Saint-Raymond A, Benjamin P, Zaccaria C, et al. Usage of unpublished paediatric data. Arch Dis 9 Child 2016, Jan;101(1):81-4. doi: 10.1136/archdischild-2015-309519. Epub 2015 Nov 5. 10 11 10. Korppi M, Lepola P, Vettenranta K, et al. Limited impact of EU paediatric regulation on Finnish 12 clinicalConfidential: trials highlights need for Nordic collaboration.For Review Acta Paediatr 2013, Only Nov;102(11):1035-40. 13 14 11. Naumburg E, Rane A, Halvorsen T, et al. Tardy development of safe medicines for children; A 15 Nordic network offers new platform to improve this inequity. Acta Paediatr 2019, Jun;108(6):992- 16 993. 17 18 12. European Medicines Agency; Database of opinions and decisions on Pediatric Investigation Plans. 19 https://www.ema.europa.eu/en/medicines/ema_group_types/ema_pip (accessed 13Sep2020). 20 21 13. delMoral-Sanchez JM, Gonzalez-Alvarez I, Gonzalez-Alvarez M. et al. Availability of 22 Authorizations from EMA and FDA for Age-Appropriate Medicines Contained in the WHO 23 24 Essential Medicines List for Children 2019. Pharmaceutics. 2020 Apr 1;12(4):316. doi: 25 10.3390/pharmaceutics12040316. 26 27 14. Strickley RG. Pediatric Oral Formulations: An Updated Review of Commercially Available Pediatric 28 Oral Formulations Since 2007. J Pharm Sci. 2019 Apr;108(4):1335-1365. doi: 29 10.1016/j.xphs.2018.11.013. Epub 2018 Nov 14.J Pharm Sci. 2019. PMID: 30447227 Review. 30 31 15. Bajcetic M, Kearns GL, Jovanovic I. et al. Availability of Oral Formulations Labeled for Use in 32 Young Children in Serbia, Germany and the USA. Curr Pharm Des. 2015;21(39):5668-73. doi: 33 10.2174/1381612821666150901105925. PMID: 26323413 Review. 34

35 16. EU Commission. COMMISSION STAFF WORKING DOCUMENT, EVALUATION, Joint evaluation of http://bmjpaedsopen.bmj.com/ 36 Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 37 38 2006 on medicinal products for paediatric use and Regulation (EC) No 141/2000 of the European 39 Parliament and of the Council of 16 December 1999 on orphan medicinal products. Brussels, 40 11.8.2020, SWD(2020) 163 final, PART 1/6. https://ec.europa.eu/health/human-use/paediatric- 41 medicines/evaluation_en (accessed 16Nov2020) 42 43 44

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Confidential: For Review Only Does the EU’s Paediatric Regulation work for new medicines for children in Denmark, Finland, Norway and Sweden? A cross-sectional study.

Journal: BMJ Paediatrics Open

Manuscript ID bmjpo-2020-000880.R2

Article Type: Original research

Date Submitted by the 28-Nov-2020 Author:

Keywords: Therapeutics, Pharmacology http://bmjpaedsopen.bmj.com/

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1 2

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35 that a significant number of new medicines for children have been authorised. http://bmjpaedsopen.bmj.com/ 36 37  Marketing authorisation is no guarantee that a new medicine is available for all patients, as 38 the accessibility to medicines varies across countries. 39 40 41 What this study adds? 42  21 to 32% (16/76 to 24/76) of the new medicines initially authorised for children between 43 2007-2016 were not marketed across the four Nordic countries. 44

45 on September 25, 2021 by guest. Protected copyright. 46  29 to 50% (16/56 to 28/56) of the new paediatric formulations were not marketed and a 47 significant proportion had never been marketed. 48 49  Despite the intentions of the EU Paediatric Regulation, medicines targeted at children are 50 not all marketed, risking limitations in availability and accessibility for patients. 51 52 53 54 55 56 57 58 59 60

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3 ABSTRACT bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 5 Objective 6 7 The aim of this study was to assess the marketing status of the new paediatric medicinal products 8 listed in the 10y report as initially authorised between 2007- 2016, reflecting the product availability 9 in four Nordic countries. 10 11 Design 12 Confidential: For Review Only 13 This is a cross-sectional study. 14 15 Setting 16 17 Analysis of the national Medicine Agency’s databases in Denmark, Finland, Norway and Sweden. 18 19 Data source 20 21 New medicinal products with paediatric indications and new paediatric formulations listed in the 22 Annex of European Medicines Agency´s (EMA) EU Paediatric Regulation 10-year report. 23 24 Data analysis 25 26 The products were classified according to national marketing status between January and March 2019; 27 whether a product was authorised and whether the product was marketed. 28 29 Main outcome measures 30 31 The percentages of the new medicinal products with paediatric indications and new paediatric 32 formulations having a valid marketing authorisation and being marketed, both in terms of the sums 33 of all countries and separately for each country. 34

35 Results http://bmjpaedsopen.bmj.com/ 36 37 Across the four countries, 21 to 32% (16/76 to 24/76) of the new medicinal products were not 38 marketed. Of the new formulations relevant to children, 29 to 50% (16/56 to 28/56) were not 39 marketed, and a significant proportion of these products had never been marketed. 40 41 Conclusions 42 43 This study reflects the reality of the implementation of the Paediatric Regulation. The results show 44 that several new paediatric medicines and new formulations are not marketed. This affects the

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45 columns) in DK, FI, NO, SE, by therapeutic area (based from ATC-code at second level e.g. B02), on September 25, 2021 by guest. Protected copyright. 46 year, and country. 47 48 Products not marketed, marked with X Therapeutic area Year Medicinal product 49 DK FI NO SE 50 Antihemorrhagic 2012 Catridecacog X X Antihemorrhagic 2013 Human coagulation factor VIII / human 51 X X X X 52 von Willebrand factor 53 Antihemorrhagic 2016 Eftrenonacog alfa X 54 Antihemorrhagic 2016 Albutrepenonacog alfa X X Antihemorrhagic 2016 Human coagulation factor X X X X X 55 Anti-infective agent 2007 Retapamulin X X X 56 for topical use 57 Antineoplastic agent 2007 Nelarabine X 58 Antineoplastic agent 2007 Hydroxycarbamide X X X X 59 Antineoplastic agent 2016 Asparaginase X X X X 60 Antipoisoning agent 2007 Hydroxocobalamin X X X X

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3 Bile and liver diseases 2014 Cholic acid X X X X bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from 4 Hypertension 2013 Bosentan X 5 Immunoglobulines 2007 Human normal immunoglobulin (IVIG) X X X 6 Immunosuppressants 2009 Canakinumab X 7 Immunstimulating 2013 Filgrastim X X X X 8 Immunstimulating 2016 Autologous CD34+ enriched cell fraction that contains CD34+ cells transduced 9 X X X X 10 with retroviral vector that encodes for 11 the human ADA cDNA sequence Malaria 2011 Dihydroartemisinin / piperaquine 12 Confidential: For ReviewX OnlyX X X phosphate 13 Metabolic disease 2008 Sapropterin X 14 Metabolic disease 2014 Elosulfase alfa X 15 Respiratory tract 2012 Ivacaftor X 16 disease 17 Vaccine 2007 Human papillomavirus vaccine [types X X 18 16, 18] 19 Vaccine 2009 Pneumoccocal polysaccharide conjugate X X 20 vaccine (absorbed) 21 Vaccine 2012 Repandemic influenza vaccine (H5N1) 22 (whole virion, inactivated, prepared in X X X X 23 cell culture) Vaccine 2013 Diphtheria (d), tetanus (t), pertussis 24 (acellular, component) (pa), hepatitis b 25 (rdna) (hbv), poliomyelitis (inactivated) X X 26 (ipv) and haemophilus influenzae type b 27 (hib) conjugate vaccine (adsorbed) 28 Vaccine 2013 Influenza vaccine (live attenuated, nasal) X 29 Vaccine 2013 Diphtheria (d), tetanus (t), pertussis 30 (acellular, component) (pa), hepatitis b 31 (rdna) (hbv), poliomyelitis (inactivated) X X X X 32 (ipv) and haemophilus influenzae type b 33 (hib) conjugate vaccine (adsorbed) Vaccine 2016 Pandemic influenza vaccine (H5N1) 34 X X X X (live attenuated, nasal)

35 http://bmjpaedsopen.bmj.com/ Vaccine 2016 Diphtheria, tetanus, pertussis (acellular, 36 component), hepatitis b (rdna), X X X X 37 poliomyelitis (inact.) and haemophilus 38 type b conjugate vaccine (adsorbed) 39 Vitamine 2009 Tocofersonal d-alpha tocopheryl X 40 polyethylene glycol succinate 41 Number of all medicinal products not marketed 20 24 17 16 42 43 44 On average, 57/76 of the newly authorised medicinal products were currently being marketed in the

45 Nordic countries. Sweden had the highest proportion (79%), followed by Norway (78%), Denmark on September 25, 2021 by guest. Protected copyright. 46 (74%), and Finland (68%) (Figure 2). 47 48 (Figure 2. in picture format separately) 49 50 Figure 2. Number of new medicinal products marketed (or not) in DK, FI, NO, SE 51 52 53 54 55 56 New formulations (Product group B) 57 58 A total of 43 products represented new formulations, of which 27 were centrally authorised, and 16 59 nationally authorised. Five of the nationally authorised products were excluded due to insufficient 60 information, rendering it impossible to identify the exact product. The resulting 38 products with new

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3 DTP/Hib/Polio bmjpo: first published as 10.1136/bmjpo-2020-000880 on 30 December 2020. Downloaded from Vaccines 2011 Prefilled syringe X* X* X X 4 vaccine 5 6 Number of new forms and strengths not marketed 27 25 28 16 7 8 9 The formulations not marketed in any country were often the paediatric specific; such as the lower- 10 strength formulations (5/14), the oral liquid/powder/granules (5/14), and the chewable tablets (2/14). 11 12 Conversely,Confidential: approximately half of the products For marketed Review in all countries wereOnly products for which the 13 new formulation seemed to have replaced the old one (e.g., prefilled syringe replacing vials, tablets 14 replacing capsules, ‘ready-to-use solution for injection’ replacing ‘powder and solvent for solution for 15 injection’). 16 17 The majority (35/56) of the reviewed new formulations represented products with agreed-upon PIPs 18 where the specific formulation was part of the PIP obligations. Only six of these 35 formulations were 19 20 marketed in all countries. Of the 14 formulations not marketed in any of the countries, nine were 21 listed as specific requirements in the PIP. In contrast, the majority (10/16) of the formulations available 22 in all countries, did not have a PIP or were not included in specific PIP formulation requirements. 23 24 25 26 DISCUSSION 27 28 Our data reveals that on average 75% of the new paediatric medicines initially authorised for children 29 (2007-2016) were still authorised and marketed. Similarly, for the new paediatric formulations 57% 30 were marketed. 31 32 The reported achievements of the Paediatric Regulation [3, 4] are optimistic, indicating increased 33 number of authorised medicines for children. However, the choice to place an authorised product on 34 the market in each country is influenced by several factors. Therefore, assessing the actual marketing

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35 16. EU Commission. COMMISSION STAFF WORKING DOCUMENT, EVALUATION, Joint evaluation of http://bmjpaedsopen.bmj.com/ 36 Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 37 38 2006 on medicinal products for paediatric use and Regulation (EC) No 141/2000 of the European 39 Parliament and of the Council of 16 December 1999 on orphan medicinal products. Brussels, 40 11.8.2020, SWD (2020) 163 final, PART 1/6. https://ec.europa.eu/health/human-use/paediatric- 41 medicines/evaluation_en (accessed 16Nov2020) 42 43 44

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