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Allergen Immunotherapy (AIT) in children: a vulnerable population with its own rights and legislation – summary of EMA-initiated multi-stakeholder meeting on Allergen Immunotherapy (AIT) for children, held at Paul-Ehrlich-Institut, Langen, Germany, 16.1.2019

Allergen Immunotherapy (AIT) in children: a vulnerable population with its own rights and... Concerning development of medicinal products, children belong to a so-called “special population” for which addi- tional legislation applies: Regulation (EC) No 1901/2006 on medicinal products for paediatric use sets up a system of requirements, rewards and incentives to ensure that medicinal products are researched, developed and authorized to meet the therapeutic needs of children. Allergen Immunotherapy (AIT ) is believed to contain a strong potential for immunomodulatory effects inducing sustained clinical efficacy after cessation of treatment (disease modifying effect) and thereby may prevent the progression of the atopic march towards asthma manifestation. However, to this day only few data on long-term effects in general exist and even fewer in children. These are predominantly data from open studies, which are strongly influenced in their validity by the known placebo effect of AIT. Furthermore, there are no studies allowing for the conclusion that efficacy in adults are mirrored by a similar efficacy in children and thus, up to now, it is not possible to extrapolate data from adults to children. The Paediatric Committee (PDCO)—European Medicines Agency’s (EMA) scientific committee responsible for activities on medicines for children—initiated a Multi- Stakeholder Meeting on AIT for Children held at the Paul-Ehrlich-Institut in Langen, Germany, to provide a platform for discussion and exchange of thoughts to this topic between allergy experts from academia, regulators and AIT-manu- facturers. The consented meeting minutes, conclusions and participants are presented. Keywords: Allergen Immunotherapy (AIT ), Children, Paediatric Investigation Plan (PIP), Therapy Allergen Ordinance ( TAO), Paediatric Committee (PDCO), European Medicines Agency (EMA) Introduction Concerning development of medicinal products, children belong to a so-called “special population” for which addi- *Correspondence: vera.mahler@pei.de tional legislation applies: Regulation (EC) No 1901/2006 Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany on medicinal products for paediatric use sets up a system Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mahler et al. Clin Transl Allergy (2020) 10:28 Page 2 of 7 of requirements, rewards and incentives to ensure that can modify the PIPs for all other products of his portfolio medicinal products are researched, developed and and replace the long-term study with a short-term study. authorized to meet the therapeutic needs of children [1, PIP-compliance is a prerequisite for granting a market- 2]. Allergen Immunotherapy (AIT) is believed to contain ing authorization not only for children, but also for the a strong potential for immunomodulatory effects induc - use in the adult population. To this point, however, none ing sustained clinical efficacy after cessation of treatment of the necessary AIT trials in children for the NPPs under (disease modifying effect) and thereby may prevent the the development plan of TAO have been initiated by the progression of the atopic march towards asthma manifes- manufacturers, yet, raising increasing concerns in the tation. However, to this day only few data on long-term future provision of licensed AIT products for children effects in general exist and even fewer in children. These and adults. are predominantly data from open studies, which are PDCO therefore initiated [as follow-up meeting to strongly influenced in their validity by the known placebo a workshop on AIT for Children, held at EMA, 26th effect of AIT. Furthermore, there are no studies allowing June 2018 (see Box  1)] a Multi-Stakeholder Meeting on for the conclusion that efficacy in adults are mirrored by Allergen Immunotherapy for Children held at the Paul- a similar efficacy in children and thus, up to now, it is not Ehrlich-Institut in Langen near Frankfurt, Germany, possible to extrapolate data from adults to children. to provide a platform for discussion and exchange of In 2008 the Therapy Allergen Ordinance (TAO) came thoughts to this topic between allergy experts from aca- into force in Germany to assure that all AIT products demia, regulators and AIT manufacturers [5]. The con - against frequent allergen sources, which were to this date sented meeting minutes, conclusions and participants are on the market in Germany as Named Patient Products presented. (NPP), are assessed for their benefit/risk-balance within a marketing authorization procedure [2]. For this pur- Multi‑stakeholder Meeting on Allergen pose, for 123 AIT NPPs national marketing authorization Immunotherapy (AIT) for Children applications were submitted in 2010. All these market- Date: 16 January 2019, Paul-Ehrlich-Institut, Langen, ing applications for NPPs under the development plan Germany. of TAO had to be accompanied by a Paediatric Investi- This was a follow-up meeting on the workshop on AIT gation Plan (PIP) approved by the Paediatric Commit- for Children (26th June 2018 at EMA, London,—see tee (PDCO) of the European Medicines Agency (EMA) Box 1 for short summary). according to Article 7 of Regulation (EC) No 1901/2006. The purpose of this follow-up meeting (with partici - To simplify the assessment of 123 PIPs on short notice a pation of several PDCO members) was to discuss with Standard PIP for AIT products was developed. industry representatives, clinicians and investigators the According to Article 20 of Regulation (EC) No proposals agreed at the June workshop with the aim to 1901/2006 PDCO [3] concluded that clinical trials in chil- speed up initiation and conduct of paediatric clinical tri- dren as a vulnerable group may only be initiated after data als with those products. on the efficacy and safety of the drug have been collected in adults and therefore according to Article 21 deferrals for the completion of clinical studies in children were granted in the PIPs. In addition, the PDCO determined that for Participants: children only the assumed disease modifying effect out - Nominated stakeholders: Birgit Ahrens (PEI), Sophia Aldous (ROXALL Medizin), Silke Arzberger (Lofarma Germany GmbH), Nicole Armbrüster weighs the risks associated with AIT. To prove long-term (BPI), Andreas Bonertz (PEI), Albrecht Bufe (Ruhr‑Universität Bochum), immunomodulatory effects a placebo-controlled blinded Caroline Dorrepaal (HAL Allergy), Irmgard Eichler (EMA), Gabriele‑Cornelia study design of 3-year-treatment with 2  years of follow- Fox (Allergopharma), Marek Jutel (EAACI), Efstrathios Karagiannis (Stal‑ lergens GmbH), Susanne Kaul (PEI), Stephan Kerkojus (Lofarma Germany up is required and to be planned in the PIPs. However, GmbH), Denise Lee (ATL), Vera Mahler (PEI), Dirk Mentzer (PEI, PDCO), the Standard PIP [Revision 4 (of February 2015)] [4] lays Marek Migdal (PDCO), Antonella Muraro (EAACI), Dirk‑Jan Opstelten (HAL down that every manufacturer has to select ONE product Allergy), Oliver Pfaar (EAACI), Johanna Rost (PEI), Sabine Scherer (PDCO), Lindsay Schüler (Bencard Allergie GmbH), Hugo Tavares (PDCO), Eva‑Cor ‑ (the so-called “selected product”) from his portfolio and to nelia Ticinelli (LETI Pharma GmbH), Jenny Uhlig (ROXALL Medizin), Ulli perform ONE long-term study in adults and in parallel—if Umpfenbach (Charité Universitätsmedizin Berlin), Stefan Vieths (PEI). necessary with a small time lag—ONE in children with this Excused nominated stakeholders: Susanne Lau (Charité Universiätsmedizin Berlin), Andy Möckel (LETI Pharma GmbH), Francesca Rocchi (PDCO). product to gain basic data for comparability and extrapo- Further participants: Jean Bousquet (EAACI TF on Clinical Trials in Chil‑ lation purpose. After successful performance of these two dren), Philippe Eigenmann (EAACI TF on Clinical Trials in Children), studies with the ONE selected product the manufacturer Susanne Halken S (EAACI TF on Clinical Trials in Children), Ulrich Wahn (EAACI TF on Clinical Trials in Children). M ahler et al. Clin Transl Allergy (2020) 10:28 Page 3 of 7 Box 1 Short summary of outcomes from the first Workshop on AIT for Children, held at EMA, 26th June 2018 in London, UK Aim of the first workshop: to exchange views with experts (from PEI, PDCO, EMA, EAACI nominated representatives and further external experts) on respiratory allergen immunotherapy in children, on the need for and feasibility of long-term studies General agreement among experts There is a relative need for more clinical studies to confirm sustained and long-term efficacy in children At least 3 year treatment duration is required to elicit long-term effect (expert opinion based on clinical observation) Three year placebo-controlled trials considered feasible, possible and acceptable (at least from investigator’s point of view—need to get parent’s view) for SLIT products; however considered unfeasible and unacceptable for SCIT products Need to have same scoring systems in adults and in children among different manufacturers to allow future comparison of results not only between manufacturers but also between adults and children as basis for extrapolation—(agreed PIPs require the use of the combined score proposed by the EAACI Taskforce Group [6]) at least as secondary endpoint) At present there is a lack of validated outcome measures for both adults and children. However, the combined symptom medication score (pro- posed by EAACI) has been used in well-powered studies in adults and children; this could be accepted as “validation” of this outcome At present, there is no agreement on the most appropriate or optimal primary outcome measure to assess long-term efficacy of AIT for allergic rhinitis (AR) and allergic asthma (AA) There is an urgent need to move to evidence generation and development of outcome measures which are not dependent on varying pollen exposure which is different from one season to the other Manufacturers have been encouraged to explore the use of exposure chambers and compare results to field results, at least in adults—but not many manufacturers so far have followed this recommendation; consequently this comparison between field-exposure and exposure chambers is lacking at present Proposal to increase likelihood and feasibility of long-term studies in children For the PIP, it is recommended to separate SCIT and SLIT protocols Proposal: First year double blind evaluation in field and in chamber, then open study and continue with chamber if results were comparable with those in double-blind period—possible to split comparison into 2 studies obviating need to do it in same study/same season? Need to ask parents/patients about their expectations—what is important to achieve in term of resolution of symptoms, QoL, no need for medica- tions (in order to improve adherence/compliance during the CTs) A follow-up meeting with manufacturers, academia, EUnetHTA, regulators and parent/patient representatives should be considered to find solu- tions to the discussed proposals Background • After successful long‑ term studies with the selected The Therapy Allergen Ordinance in Germany (TAO, effec - product, manufacturer can choose duration of clin‑ tive since November 2008) mandates a marketing authori- ical trials for other products (via PIP modification). sation (MA) for most prevalent therapy allergen products • Studies in children are supposed to start as soon as short‑ already on the market as named patient products (NPP), term efficacy and safety has been proven in adults. including sweet grasses, early flowering trees (birch, alder, hazel), house-dust mites and wasp or bee venom. 123 MA As of January 2019, 65 out of the initial 123 appli- applications with an agreed PIP were received. cations by 7 manufacturers are still in development, The requirements for the paediatric development partly due to considerable challenges with the clinical plans as per the standard PIP for allergen products for development in adults: specific immunotherapy, are: • Dose‑finding studies (DFS) are still lacking for a • Per manufacturer: long‑ term studies in adults and considerable number of products. paediatrics (normally 3  years treatment + 2  years • Several DFS were inconclusive. follow‑ up) double‑blind, placebo‑controlled for • According to the results of DFS, for some products a ONE product (selected product). higher dose than currently marketed as NPP suggests a • Selected product for these studies to be chosen by better benefit r ‑ isk balanc ‑ e. Yet, for most of these prod ‑ the manufacturer. ucts convincing phase III study data are still lacking. • For all other products from the manufacturer (prior • Until now no currently marketed dose was con‑ to successful conclusion of long‑ term studies with firmed in a valid DFS. selected product) long‑ term studies in paediatrics • To date, only two products have received a marketing are required. authorisation for a higher dose than originally mar‑ keted—however, until now, no study in children was Mahler et al. Clin Transl Allergy (2020) 10:28 Page 4 of 7 performed and thus the products are only indicated The following suggestions by clinicians and/or industry in adults. representatives were made: As a consequence the clinical development in adults is • To keep children only for 1  year in the placebo arm; hugely delayed. As according to current legislation and only possible once validated innovative endpoints the standard PIP paediatric studies should only start after independent of allergen exposure are available. confirmation of short-term efficacy in adults, the start of • To investigate products from different companies com ‑ paediatric trials is also seriously delayed. bined (e.g. 2–3 birch pollen products) using one joint As of today, one manufacturer fulfilled the requirement placebo arm (industry representatives did not com‑ regarding long-term studies with the selected product in ment this proposal by investigators). adults and children (selected product not being subject • Start with 1‑ year trial in adults and in children to gen‑ to TAO); for 6 selected products long-term studies in erate evidence that the product is safe and efficacious, adults and children are still needed. Until now no stud- and only then do a 5‑ year, potentially combined (sev‑ ies in children were/are performed with products being eral different active arms with only one joint placebo– subject to TAO. arm) trial. Although the main reason for the delay in initiating Difficulty: once the product is on the market, it will no paediatric studies is due to the major challenges with longer be feasible to conduct a long‑ term study. dose finding for adults, allergen manufacturers repeat - • Combined adult/adolescent and children (< 12 years of edly point out that the requirements for long-term stud- age) studies; this has the disadvantage that in the latter ies (both in adults and particularly in children) are a too age group not the children themselves but the parents high hurdle and the requested studies are not feasible for do the scoring. This raises the question if results scored several reasons, including unwillingness or ethical con- by the parents for the younger children are comparable cerns of patients/parents/investigators to enrol into a with those generated by adolescent or adult patients 3-year placebo-controlled study with 2 years blinded fol- themselves. low-up, and the high administrative and financial burden • Need for input from patient/parent what they consider of conducting large long-term studies. relevant in terms of disease control (symptom control, In addition, it was mentioned that due to the availability decrease in rescue medication use, …). of alternative products on the market, patients/parents • The use of real world data instead of prospective pla ‑ are not willing to participate in a trial in which the child ceboc‑ ontrolled randomised studies; Problem: data has the chance to receive placebo. Moreover, the risk of collection would have to fulfil regulatory quality stand ‑ long-term study failure is too high as there are currently ard; at present, this is not the case. no validated standardized endpoints for children and • To consider active controlled studies; there is insufficient knowledge regarding patient eligibil - ity criteria. Initiating a long-term trial before these gaps However, non-inferiority studies would require even have been resolved is therefore considered to be neither larger study population, and up to now no authorised com- ethical nor meaningful. parator is available for many allergen groups. Following this comment disappointment was expressed that after so many years of use of AIT in the currently • It was proposed to perform safety studies only in chil‑ marketed but not authorised way these well-known dren, as for all products on the market the dose for gaps in knowledge have been not yet been adequately adults and children is the same, and there is currently addressed. no indication that the efficacy is lower in children than The discussion focused on three main issues: in adults. Based on the available studies experts con‑ cluded that in general even a higher efficacy is generally observed in children. However, the hypothesis, that the 1. Paediatric study design efficacy is equal or higher in children as in adults needs Among clinicians and investigators there was consensus yet to be proven to reduce the current uncertainty of that long-term studies are considered feasible in children knowledge. with sublingual immunotherapy products (SLIT) but not with subcutaneous immunotherapy (SCIT) products; the requirement for placebo injection for 3 years within SCIT trials is seen as a too high burden; M ahler et al. Clin Transl Allergy (2020) 10:28 Page 5 of 7 2. Endpoints, alternatives to medication and symptom • Manufacturer may submit data to regulatory scores agencies in between for the purpose of marketing authorisation provided PIP compliance is fulfilled, • Need for harmonised endpoints to allow compari‑ e.g. once 3‑ year treatment period is completed for son of various studies of different manufacturers, and sustained efficacy while the trial is continued with between adults and children. blinded treatment‑free period of 2  years. Regula ‑ • The combined symptom medication score developed tory assessment of submitted data will be per‑ by the European Academy of Allergology and Immu‑ formed in parallel to the proceeding trial; hence nology (EAACI) has been used in well‑ powered stud‑ no need to wait until full 5  year study period is ies in adults; however, the score is not validated (also completed. not for adults) and usefulness for children has to be • During the 2 year treatment‑free follow ‑ up period shown in clinical trials. study participants and investigators to remain • Need for outcome measures which are not depend‑ blinded for the treatment allocation during the ent on varying pollen exposure being different from 3‑ year treatment period. one season to the other, e.g. exposure chambers for • There is no need for DFS in children. primary endpoint analysis. • An EAACI task force is working on a proposal for a • Manufacturers were informed that EAACI is estab‑ hybrid study design to compare exposure chamber lishing a network of independent sites with the with field study results (recommendation for techni ‑ capacity to conduct large (paediatric) clinical studies. cal specifications and validation have been previously published). Finally the discussion also touched upon extrapolation: • Precompetitive collaboration among manufactures is suggested for validation of new, innovative end‑ • Clinicians and investigators stressed the need for evi‑ points, such as the use of allergen challenge cham‑ dence of safety and efficacy; bers. • Such evidence should mainly be generated in adults. • Manufacturers are encouraged • There was agreement among regulators and investi ‑ gators that at this point in time extrapolation is not • to explore the use of exposure chambers and com‑ yet possible, as evidence in the source population, i.e. pare results to field results, at least in adults. adults, is still missing. • to seek regulatory qualification advice for new • Extrapolation of efficacy data from adults and per ‑ outcome measures and use of exposure chambers. form only safety studies in paediatrics is only possi‑ • to collaborate among themselves to explore new ble after scientific proof of concept that extrapolation biomarkers (as endpoint or for prediction/therapy from adults to paediatrics is feasible. This proof may decision), study designs, study networks and oth‑ be performed in SLIT products. ers. • Once long‑ term efficacy of SLIT products has been convincingly demonstrated in adults and children, • Need for harmonised and agreed appropriate end‑ generating evidence from long‑ term efficacy of SCIT points to assess long‑ term efficacy of AIT on preven ‑ products only in adults may be sufficient to use for tion of/impact on allergic asthma. extrapolating long‑ term efficacy in the paediatric population. 3. Timing of initiation of paediatric studies 4. General information about pending PIP revisions of TAO • Clarification of current standard PIP requirement: products The timelines of the originally approved PIPs of the TAO • Manufacturers have the right to select ONE products are running out in most cases. Thus, a PIP allergen product out of their portfolio for the revision is necessary for nearly all companies to be PIP long‑ term studies in adults and children and ini‑ compliant. tiate long‑ term study in children as soon as dose– response and first efficacy (e.g. after one year) and • PIP compliance is mandatory to start MAA assess‑ safety data in adults are available. Manufacturers ment. are not obliged to conduct long‑ term studies for • Most companies dealing with TAO products need a both SCIT and SLIT products; PIP‑revision agreed by PDCO to be PIP compliant (at Mahler et al. Clin Transl Allergy (2020) 10:28 Page 6 of 7 immunotherapy; SLIT: Sublingual immunotherapy; STE: Short-term efficacy; least the timelines of the paediatric trials have to be TAO: Therapy Allergen Ordinance; TF: Task force. modified in the approved PIPs). • Changes in the PIP opinion (re timelines) will be Acknowledgements The authors thank all participants of the multi-stakeholder meeting for the accepted by PDCO once a long‑ term efficacy (LTE) open and constructive discussion. trial in the paediatric population (aged 5–12  years) has been initiated; the earliest time point for this Authors’ contributions A Bonertz is head of Section Test and Therapy Allergens at Paul-Ehrlich-Institut. modification of a PIP opinion is first paediat ‑ He attended the meeting, contributed to the meeting minutes, the abstract ric patient passed first visit (definition by Irmgard and introduction of the manuscript. J Bousquet, P Eigenmann, S Halken is a Eichler, EMA). member of the EAACI Task Force on Clinical Trials in Children and attended the meeting. M Jutel attended the meeting as nominated stakeholder and represenative of EAACI. He is a member of the EAACI Task Force and contrib- This means: no TAO product will pass future compli - uted to the meeting minutes. S Kaul is head of Section Clinical Allergology ance check before at least the LTE of the selected allergen at Paul-Ehrlich-Institut, attended the meeting, contributed to the meeting minutes, abstract and introduction of the manuscript. V Mahler is head of Divi- product has been started in children. (As stated above: sion Allergology at Paul-Ehrlich-Institut and a member of the EAACI Task Force. Studies in children are supposed to start as soon as short- She attended the meeting, contributed to the meeting minutes, drafted the term efficacy and safety has been proven in adults). abstract and introduction of the manuscript, edited and compiled texts into the final article. D Mentzer is PDCO member (at time of meeting PDCO chair). He called and hosted the meeting, prepared the meeting minutes, supervised • Paediatric trials (STE or LTE) can be started at any the stakeholder commentation process and the adoption of the meeting min- time, provided the trial is compliant with the key utes by PDCO. A Muraro attended the meeting as nominated stakeholder and representative of EAACI. She is the chair of the EAACI Task Force on Clinical Tri- binding elements (KBE) in the PIP opinion. (as stated als in children and contributed to the meeting minutes. O Pfaar attended the above). meeting as nominated stakeholder and represenative of EAACI. He is a mem- • Provided PIP compliance is confirmed, each TAO ber of the EAACI Task Force and contributed to the meeting minutes. S Vieths is Vice President of Paul-Ehrlich-Institut. He chaired the meeting, contributed product can go for MAA for its individual indication. to the meeting minutes, abstract and introduction of the manuscript. U Wahn is a member of the EAACI Task Force, the EUFOREA board and coordinator of the Immunotherapy Expert group, and attended the meeting. Funding Conclusions None. PDCO to discuss the various suggestions and to consider potential changes of the standard PIP. Availability of data and materials Not applicable. EAACI and manufacturers invited to propose alterna- tive approaches for development of SCIT products. Ethics approval and consent to participate Not applicable. Consent for publication Next steps All authors and all meeting participants gave their informed consent. • Based on feedback from investigators, no change Competing interests A Bonertz, S Kaul, V Mahler, D Mentzer and S Vieths reports not having com- considered necessary for paediatric development of peting interests.J Bousquet reports personal fees and other from Chiesi, Cipla, SLIT products. Hikma, Menarini, Mundipharma, Mylan, Novartis, Sanofi-Aventis, Takeda, Teva, • PDCO will await proposals from EAACI and manu‑ Uriach, outside the submitted work.P Eigenmann reports personal fees and other from ThermoFisher Scientific, DBV technologies, Nestlé, Danone, Abbott, facturers how to investigate long‑ term efficacy and Novartis, ALK, UpToDate, Wiley and Elsevier, outside the submitted work.S safety for SCIT products. Halken reports personal fees and non-financial support from ALK-Abelló, • PDCO supports multi‑company studies on the same outside the submitted work.M Jutel reports personal fees from ALK-Abello, personal fees from Allergopharma, personal fees from Stallergenes, personal allergen class with one common placebo arm. fees from Anergis, personal fees from Allergy Therapeutics, personal fees from • PDCO encourages precompetitive collaboration to Circassia, personal fees from Leti, personal fees from Biomay, personal fees increase knowledge base. from HAL, during the conduct of a study; personal fees from Astra-Zeneka, personal fees from GSK, personal fees from Novartis, personal fees from Teva, personal fees from Vectura, personal fees from UCB, personal fees from Takeda, personal fees from Roche, personal fees from Janssen, personal fees from Medimmune, personal fees from Chiesi, outside the submitted work.A Muraro reports speaker’s fees from: Aimmune, DBV, Nestlé-Health Institute, Abbreviations Nestlé Purina, Nutricia, ALK, HAL outside the submitted work. O Pfaar reports AIT: Allergen Immunotherapy; CT: Clinical trial; DFS: Dose finding study; EAACI: grants and personal fees from ALK-Abelló, grants and personal fees from European Academy of Allergy and Clinical Immunology; EC: European Com- Allergopharma, grants and personal fees from Stallergenes Greer, grants mission; EMA: European Medicines Agency; EUnetHTA: European Network for and personal fees from HAL Allergy Holding B.V./HAL Allergie GmbH, grants Health Technology Assessment; KBE: Key binding elements; LTE: Long-term and personal fees from Bencard Allergie GmbH/Allergy Therapeutics, grants efficacy; MA: Marketing authorisation; MAA: Marketing authorisation applica- and personal fees from Lofarma, grants from Biomay, grants from Circassia, tion; NPP: Named patient product; PDCO: Paediatric Committee (of EMA); grants and personal fees from ASIT Biotech Tools S.A., grants and personal PIP: Paediatric Investigation Plan; QoL: Quality of Life; SCIT: Subcuteaneous fees from Laboratorios LETI/LETI Pharma, personal fees from MEDA Pharma/ M ahler et al. Clin Transl Allergy (2020) 10:28 Page 7 of 7 MYLAN, grants and personal fees from Anergis S.A., personal fees from Mobile C, Barber D, Palomares O, Sheikh A, Pawankar R, Hamerlijnk D, Klimek L, Chamber Experts (a GA2LEN Partner), personal fees from Indoor Biotechnolo- Agache I, Angier E, Casale T, Fernandez-Rivas M, Halken S, Jutel M, Lau S, gies, grants from Glaxo Smith Kline, personal fees from Astellas Pharma Global, Pajno G, Sturm G, Varga EM, Gerth van Wijk R, Bonini S, Muraro A, Vieths S. personal fees from EUFOREA, personal fees from ROXALL, personal fees from Challenges in the implementation of EAACI guidelines on allergen immu- NOVARTIS, personal fees from SANOFI AVENTIS, outside the submitted work.U notherapy: a global perspective on the regulation of allergen products. Wahn reports lecture and consultation fees from Novartis, Sanofi-Aventis, Allergy. 2018;73:64–76. Berlin-Chemie, StallergenesGreer, ALK, Leti, and Roxall. 2. Mahler V, Bonertz A, Ruoff C, Hartenstein D, Mentzer D, Kaul S, Vieths S. What we learned from TAO—10 years of German therapy allergen Author details ordinance. Allergo J Int. 2019;28:33–337. https ://doi.org/10.1007/s4062 1 2 Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany. Food 9-019-0101-7. Allergy Referral Centre Veneto Region, Department of Women and Child 3. Regulation (EC) No 1901/2006 of the European Parliament and of the Health, Padua General University Hospital, Padua, Italy. Pediatric Allergy Unit, Council of 12 December 2006 on medicinal products for paediatric use, University Hospitals of Geneva, Geneva, Switzerland. Charité, Universitäts- OJ L 378, 27.12.2006, p. 1–19. medizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 4. European Medicines Agency (EMA). EMA/PDCO Standard Paediatric Comprehensive Allergy Center, Department of Dermatology and Allergy, Investigation Plan for Allergen Products for Specific Immunotherapy Berlin, Germany. University Hospital Montpellier, Montpellier, France. (EMA/PDCO/737605/2009) (Revision 4), 16 February 2015. 6 7 MACVIA-France, Montpellier, France. Hans Christian Andersen Children’s 5. Mahler V, Esch RE, Kleine-Tebbe J, Lavery WJ, Plunkett G, Vieths S, Bern- Hospital, Odense University Hospital, Odense, Denmark. Department of Oto- stein DI. Understanding differences in allergen immunotherapy products rhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, and practices in North America and Europe. J Allergy Clin Immunol. University Hospital Marburg, Phillipps-Universität Marburg, Marburg, Germany. 2019;143:813–28. Department of Clinical Immunology, Wrocław Medical University, Wrocław, 6. Pfaar O, Demoly P, Gerth van Wijk R, Bonini S, Bousquet J, Canonica 10 11 Poland. ALL-MED Medical Research Institute, Wrocław, Poland. Pediatric GW, Durham SR, Jacobsen L, Malling HJ, Mösges R, Papadopoulos NG, Department, Charité, Berlin, Germany. Rak S, Rodriguez del Rio P, Valovirta E, Wahn U, Calderon MA, European Academy of Allergy and Clinical Immunology. Recommendations for the Received: 2 April 2020 Accepted: 30 May 2020 standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI Position Paper. Allergy. 2014;69:854–6. Publisher’s Note References Springer Nature remains neutral with regard to jurisdictional claims in pub- 1. Bonertz A, Roberts GC, Hoefnagel M, Timon M, Slater JE, Rabin RL, Bridge- lished maps and institutional affiliations. water J, Pini C, Pfaar O, Akdis C, Goldstein J, Poulsen LK, van Ree R, Rhyner Ready to submit your research ? 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Allergen Immunotherapy (AIT) in children: a vulnerable population with its own rights and legislation – summary of EMA-initiated multi-stakeholder meeting on Allergen Immunotherapy (AIT) for children, held at Paul-Ehrlich-Institut, Langen, Germany, 16.1.2019

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Abstract

Concerning development of medicinal products, children belong to a so-called “special population” for which addi- tional legislation applies: Regulation (EC) No 1901/2006 on medicinal products for paediatric use sets up a system of requirements, rewards and incentives to ensure that medicinal products are researched, developed and authorized to meet the therapeutic needs of children. Allergen Immunotherapy (AIT ) is believed to contain a strong potential for immunomodulatory effects inducing sustained clinical efficacy after cessation of treatment (disease modifying effect) and thereby may prevent the progression of the atopic march towards asthma manifestation. However, to this day only few data on long-term effects in general exist and even fewer in children. These are predominantly data from open studies, which are strongly influenced in their validity by the known placebo effect of AIT. Furthermore, there are no studies allowing for the conclusion that efficacy in adults are mirrored by a similar efficacy in children and thus, up to now, it is not possible to extrapolate data from adults to children. The Paediatric Committee (PDCO)—European Medicines Agency’s (EMA) scientific committee responsible for activities on medicines for children—initiated a Multi- Stakeholder Meeting on AIT for Children held at the Paul-Ehrlich-Institut in Langen, Germany, to provide a platform for discussion and exchange of thoughts to this topic between allergy experts from academia, regulators and AIT-manu- facturers. The consented meeting minutes, conclusions and participants are presented. Keywords: Allergen Immunotherapy (AIT ), Children, Paediatric Investigation Plan (PIP), Therapy Allergen Ordinance ( TAO), Paediatric Committee (PDCO), European Medicines Agency (EMA) Introduction Concerning development of medicinal products, children belong to a so-called “special population” for which addi- *Correspondence: vera.mahler@pei.de tional legislation applies: Regulation (EC) No 1901/2006 Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany on medicinal products for paediatric use sets up a system Full list of author information is available at the end of the article © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/ zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Mahler et al. Clin Transl Allergy (2020) 10:28 Page 2 of 7 of requirements, rewards and incentives to ensure that can modify the PIPs for all other products of his portfolio medicinal products are researched, developed and and replace the long-term study with a short-term study. authorized to meet the therapeutic needs of children [1, PIP-compliance is a prerequisite for granting a market- 2]. Allergen Immunotherapy (AIT) is believed to contain ing authorization not only for children, but also for the a strong potential for immunomodulatory effects induc - use in the adult population. To this point, however, none ing sustained clinical efficacy after cessation of treatment of the necessary AIT trials in children for the NPPs under (disease modifying effect) and thereby may prevent the the development plan of TAO have been initiated by the progression of the atopic march towards asthma manifes- manufacturers, yet, raising increasing concerns in the tation. However, to this day only few data on long-term future provision of licensed AIT products for children effects in general exist and even fewer in children. These and adults. are predominantly data from open studies, which are PDCO therefore initiated [as follow-up meeting to strongly influenced in their validity by the known placebo a workshop on AIT for Children, held at EMA, 26th effect of AIT. Furthermore, there are no studies allowing June 2018 (see Box  1)] a Multi-Stakeholder Meeting on for the conclusion that efficacy in adults are mirrored by Allergen Immunotherapy for Children held at the Paul- a similar efficacy in children and thus, up to now, it is not Ehrlich-Institut in Langen near Frankfurt, Germany, possible to extrapolate data from adults to children. to provide a platform for discussion and exchange of In 2008 the Therapy Allergen Ordinance (TAO) came thoughts to this topic between allergy experts from aca- into force in Germany to assure that all AIT products demia, regulators and AIT manufacturers [5]. The con - against frequent allergen sources, which were to this date sented meeting minutes, conclusions and participants are on the market in Germany as Named Patient Products presented. (NPP), are assessed for their benefit/risk-balance within a marketing authorization procedure [2]. For this pur- Multi‑stakeholder Meeting on Allergen pose, for 123 AIT NPPs national marketing authorization Immunotherapy (AIT) for Children applications were submitted in 2010. All these market- Date: 16 January 2019, Paul-Ehrlich-Institut, Langen, ing applications for NPPs under the development plan Germany. of TAO had to be accompanied by a Paediatric Investi- This was a follow-up meeting on the workshop on AIT gation Plan (PIP) approved by the Paediatric Commit- for Children (26th June 2018 at EMA, London,—see tee (PDCO) of the European Medicines Agency (EMA) Box 1 for short summary). according to Article 7 of Regulation (EC) No 1901/2006. The purpose of this follow-up meeting (with partici - To simplify the assessment of 123 PIPs on short notice a pation of several PDCO members) was to discuss with Standard PIP for AIT products was developed. industry representatives, clinicians and investigators the According to Article 20 of Regulation (EC) No proposals agreed at the June workshop with the aim to 1901/2006 PDCO [3] concluded that clinical trials in chil- speed up initiation and conduct of paediatric clinical tri- dren as a vulnerable group may only be initiated after data als with those products. on the efficacy and safety of the drug have been collected in adults and therefore according to Article 21 deferrals for the completion of clinical studies in children were granted in the PIPs. In addition, the PDCO determined that for Participants: children only the assumed disease modifying effect out - Nominated stakeholders: Birgit Ahrens (PEI), Sophia Aldous (ROXALL Medizin), Silke Arzberger (Lofarma Germany GmbH), Nicole Armbrüster weighs the risks associated with AIT. To prove long-term (BPI), Andreas Bonertz (PEI), Albrecht Bufe (Ruhr‑Universität Bochum), immunomodulatory effects a placebo-controlled blinded Caroline Dorrepaal (HAL Allergy), Irmgard Eichler (EMA), Gabriele‑Cornelia study design of 3-year-treatment with 2  years of follow- Fox (Allergopharma), Marek Jutel (EAACI), Efstrathios Karagiannis (Stal‑ lergens GmbH), Susanne Kaul (PEI), Stephan Kerkojus (Lofarma Germany up is required and to be planned in the PIPs. However, GmbH), Denise Lee (ATL), Vera Mahler (PEI), Dirk Mentzer (PEI, PDCO), the Standard PIP [Revision 4 (of February 2015)] [4] lays Marek Migdal (PDCO), Antonella Muraro (EAACI), Dirk‑Jan Opstelten (HAL down that every manufacturer has to select ONE product Allergy), Oliver Pfaar (EAACI), Johanna Rost (PEI), Sabine Scherer (PDCO), Lindsay Schüler (Bencard Allergie GmbH), Hugo Tavares (PDCO), Eva‑Cor ‑ (the so-called “selected product”) from his portfolio and to nelia Ticinelli (LETI Pharma GmbH), Jenny Uhlig (ROXALL Medizin), Ulli perform ONE long-term study in adults and in parallel—if Umpfenbach (Charité Universitätsmedizin Berlin), Stefan Vieths (PEI). necessary with a small time lag—ONE in children with this Excused nominated stakeholders: Susanne Lau (Charité Universiätsmedizin Berlin), Andy Möckel (LETI Pharma GmbH), Francesca Rocchi (PDCO). product to gain basic data for comparability and extrapo- Further participants: Jean Bousquet (EAACI TF on Clinical Trials in Chil‑ lation purpose. After successful performance of these two dren), Philippe Eigenmann (EAACI TF on Clinical Trials in Children), studies with the ONE selected product the manufacturer Susanne Halken S (EAACI TF on Clinical Trials in Children), Ulrich Wahn (EAACI TF on Clinical Trials in Children). M ahler et al. Clin Transl Allergy (2020) 10:28 Page 3 of 7 Box 1 Short summary of outcomes from the first Workshop on AIT for Children, held at EMA, 26th June 2018 in London, UK Aim of the first workshop: to exchange views with experts (from PEI, PDCO, EMA, EAACI nominated representatives and further external experts) on respiratory allergen immunotherapy in children, on the need for and feasibility of long-term studies General agreement among experts There is a relative need for more clinical studies to confirm sustained and long-term efficacy in children At least 3 year treatment duration is required to elicit long-term effect (expert opinion based on clinical observation) Three year placebo-controlled trials considered feasible, possible and acceptable (at least from investigator’s point of view—need to get parent’s view) for SLIT products; however considered unfeasible and unacceptable for SCIT products Need to have same scoring systems in adults and in children among different manufacturers to allow future comparison of results not only between manufacturers but also between adults and children as basis for extrapolation—(agreed PIPs require the use of the combined score proposed by the EAACI Taskforce Group [6]) at least as secondary endpoint) At present there is a lack of validated outcome measures for both adults and children. However, the combined symptom medication score (pro- posed by EAACI) has been used in well-powered studies in adults and children; this could be accepted as “validation” of this outcome At present, there is no agreement on the most appropriate or optimal primary outcome measure to assess long-term efficacy of AIT for allergic rhinitis (AR) and allergic asthma (AA) There is an urgent need to move to evidence generation and development of outcome measures which are not dependent on varying pollen exposure which is different from one season to the other Manufacturers have been encouraged to explore the use of exposure chambers and compare results to field results, at least in adults—but not many manufacturers so far have followed this recommendation; consequently this comparison between field-exposure and exposure chambers is lacking at present Proposal to increase likelihood and feasibility of long-term studies in children For the PIP, it is recommended to separate SCIT and SLIT protocols Proposal: First year double blind evaluation in field and in chamber, then open study and continue with chamber if results were comparable with those in double-blind period—possible to split comparison into 2 studies obviating need to do it in same study/same season? Need to ask parents/patients about their expectations—what is important to achieve in term of resolution of symptoms, QoL, no need for medica- tions (in order to improve adherence/compliance during the CTs) A follow-up meeting with manufacturers, academia, EUnetHTA, regulators and parent/patient representatives should be considered to find solu- tions to the discussed proposals Background • After successful long‑ term studies with the selected The Therapy Allergen Ordinance in Germany (TAO, effec - product, manufacturer can choose duration of clin‑ tive since November 2008) mandates a marketing authori- ical trials for other products (via PIP modification). sation (MA) for most prevalent therapy allergen products • Studies in children are supposed to start as soon as short‑ already on the market as named patient products (NPP), term efficacy and safety has been proven in adults. including sweet grasses, early flowering trees (birch, alder, hazel), house-dust mites and wasp or bee venom. 123 MA As of January 2019, 65 out of the initial 123 appli- applications with an agreed PIP were received. cations by 7 manufacturers are still in development, The requirements for the paediatric development partly due to considerable challenges with the clinical plans as per the standard PIP for allergen products for development in adults: specific immunotherapy, are: • Dose‑finding studies (DFS) are still lacking for a • Per manufacturer: long‑ term studies in adults and considerable number of products. paediatrics (normally 3  years treatment + 2  years • Several DFS were inconclusive. follow‑ up) double‑blind, placebo‑controlled for • According to the results of DFS, for some products a ONE product (selected product). higher dose than currently marketed as NPP suggests a • Selected product for these studies to be chosen by better benefit r ‑ isk balanc ‑ e. Yet, for most of these prod ‑ the manufacturer. ucts convincing phase III study data are still lacking. • For all other products from the manufacturer (prior • Until now no currently marketed dose was con‑ to successful conclusion of long‑ term studies with firmed in a valid DFS. selected product) long‑ term studies in paediatrics • To date, only two products have received a marketing are required. authorisation for a higher dose than originally mar‑ keted—however, until now, no study in children was Mahler et al. Clin Transl Allergy (2020) 10:28 Page 4 of 7 performed and thus the products are only indicated The following suggestions by clinicians and/or industry in adults. representatives were made: As a consequence the clinical development in adults is • To keep children only for 1  year in the placebo arm; hugely delayed. As according to current legislation and only possible once validated innovative endpoints the standard PIP paediatric studies should only start after independent of allergen exposure are available. confirmation of short-term efficacy in adults, the start of • To investigate products from different companies com ‑ paediatric trials is also seriously delayed. bined (e.g. 2–3 birch pollen products) using one joint As of today, one manufacturer fulfilled the requirement placebo arm (industry representatives did not com‑ regarding long-term studies with the selected product in ment this proposal by investigators). adults and children (selected product not being subject • Start with 1‑ year trial in adults and in children to gen‑ to TAO); for 6 selected products long-term studies in erate evidence that the product is safe and efficacious, adults and children are still needed. Until now no stud- and only then do a 5‑ year, potentially combined (sev‑ ies in children were/are performed with products being eral different active arms with only one joint placebo– subject to TAO. arm) trial. Although the main reason for the delay in initiating Difficulty: once the product is on the market, it will no paediatric studies is due to the major challenges with longer be feasible to conduct a long‑ term study. dose finding for adults, allergen manufacturers repeat - • Combined adult/adolescent and children (< 12 years of edly point out that the requirements for long-term stud- age) studies; this has the disadvantage that in the latter ies (both in adults and particularly in children) are a too age group not the children themselves but the parents high hurdle and the requested studies are not feasible for do the scoring. This raises the question if results scored several reasons, including unwillingness or ethical con- by the parents for the younger children are comparable cerns of patients/parents/investigators to enrol into a with those generated by adolescent or adult patients 3-year placebo-controlled study with 2 years blinded fol- themselves. low-up, and the high administrative and financial burden • Need for input from patient/parent what they consider of conducting large long-term studies. relevant in terms of disease control (symptom control, In addition, it was mentioned that due to the availability decrease in rescue medication use, …). of alternative products on the market, patients/parents • The use of real world data instead of prospective pla ‑ are not willing to participate in a trial in which the child ceboc‑ ontrolled randomised studies; Problem: data has the chance to receive placebo. Moreover, the risk of collection would have to fulfil regulatory quality stand ‑ long-term study failure is too high as there are currently ard; at present, this is not the case. no validated standardized endpoints for children and • To consider active controlled studies; there is insufficient knowledge regarding patient eligibil - ity criteria. Initiating a long-term trial before these gaps However, non-inferiority studies would require even have been resolved is therefore considered to be neither larger study population, and up to now no authorised com- ethical nor meaningful. parator is available for many allergen groups. Following this comment disappointment was expressed that after so many years of use of AIT in the currently • It was proposed to perform safety studies only in chil‑ marketed but not authorised way these well-known dren, as for all products on the market the dose for gaps in knowledge have been not yet been adequately adults and children is the same, and there is currently addressed. no indication that the efficacy is lower in children than The discussion focused on three main issues: in adults. Based on the available studies experts con‑ cluded that in general even a higher efficacy is generally observed in children. However, the hypothesis, that the 1. Paediatric study design efficacy is equal or higher in children as in adults needs Among clinicians and investigators there was consensus yet to be proven to reduce the current uncertainty of that long-term studies are considered feasible in children knowledge. with sublingual immunotherapy products (SLIT) but not with subcutaneous immunotherapy (SCIT) products; the requirement for placebo injection for 3 years within SCIT trials is seen as a too high burden; M ahler et al. Clin Transl Allergy (2020) 10:28 Page 5 of 7 2. Endpoints, alternatives to medication and symptom • Manufacturer may submit data to regulatory scores agencies in between for the purpose of marketing authorisation provided PIP compliance is fulfilled, • Need for harmonised endpoints to allow compari‑ e.g. once 3‑ year treatment period is completed for son of various studies of different manufacturers, and sustained efficacy while the trial is continued with between adults and children. blinded treatment‑free period of 2  years. Regula ‑ • The combined symptom medication score developed tory assessment of submitted data will be per‑ by the European Academy of Allergology and Immu‑ formed in parallel to the proceeding trial; hence nology (EAACI) has been used in well‑ powered stud‑ no need to wait until full 5  year study period is ies in adults; however, the score is not validated (also completed. not for adults) and usefulness for children has to be • During the 2 year treatment‑free follow ‑ up period shown in clinical trials. study participants and investigators to remain • Need for outcome measures which are not depend‑ blinded for the treatment allocation during the ent on varying pollen exposure being different from 3‑ year treatment period. one season to the other, e.g. exposure chambers for • There is no need for DFS in children. primary endpoint analysis. • An EAACI task force is working on a proposal for a • Manufacturers were informed that EAACI is estab‑ hybrid study design to compare exposure chamber lishing a network of independent sites with the with field study results (recommendation for techni ‑ capacity to conduct large (paediatric) clinical studies. cal specifications and validation have been previously published). Finally the discussion also touched upon extrapolation: • Precompetitive collaboration among manufactures is suggested for validation of new, innovative end‑ • Clinicians and investigators stressed the need for evi‑ points, such as the use of allergen challenge cham‑ dence of safety and efficacy; bers. • Such evidence should mainly be generated in adults. • Manufacturers are encouraged • There was agreement among regulators and investi ‑ gators that at this point in time extrapolation is not • to explore the use of exposure chambers and com‑ yet possible, as evidence in the source population, i.e. pare results to field results, at least in adults. adults, is still missing. • to seek regulatory qualification advice for new • Extrapolation of efficacy data from adults and per ‑ outcome measures and use of exposure chambers. form only safety studies in paediatrics is only possi‑ • to collaborate among themselves to explore new ble after scientific proof of concept that extrapolation biomarkers (as endpoint or for prediction/therapy from adults to paediatrics is feasible. This proof may decision), study designs, study networks and oth‑ be performed in SLIT products. ers. • Once long‑ term efficacy of SLIT products has been convincingly demonstrated in adults and children, • Need for harmonised and agreed appropriate end‑ generating evidence from long‑ term efficacy of SCIT points to assess long‑ term efficacy of AIT on preven ‑ products only in adults may be sufficient to use for tion of/impact on allergic asthma. extrapolating long‑ term efficacy in the paediatric population. 3. Timing of initiation of paediatric studies 4. General information about pending PIP revisions of TAO • Clarification of current standard PIP requirement: products The timelines of the originally approved PIPs of the TAO • Manufacturers have the right to select ONE products are running out in most cases. Thus, a PIP allergen product out of their portfolio for the revision is necessary for nearly all companies to be PIP long‑ term studies in adults and children and ini‑ compliant. tiate long‑ term study in children as soon as dose– response and first efficacy (e.g. after one year) and • PIP compliance is mandatory to start MAA assess‑ safety data in adults are available. Manufacturers ment. are not obliged to conduct long‑ term studies for • Most companies dealing with TAO products need a both SCIT and SLIT products; PIP‑revision agreed by PDCO to be PIP compliant (at Mahler et al. Clin Transl Allergy (2020) 10:28 Page 6 of 7 immunotherapy; SLIT: Sublingual immunotherapy; STE: Short-term efficacy; least the timelines of the paediatric trials have to be TAO: Therapy Allergen Ordinance; TF: Task force. modified in the approved PIPs). • Changes in the PIP opinion (re timelines) will be Acknowledgements The authors thank all participants of the multi-stakeholder meeting for the accepted by PDCO once a long‑ term efficacy (LTE) open and constructive discussion. trial in the paediatric population (aged 5–12  years) has been initiated; the earliest time point for this Authors’ contributions A Bonertz is head of Section Test and Therapy Allergens at Paul-Ehrlich-Institut. modification of a PIP opinion is first paediat ‑ He attended the meeting, contributed to the meeting minutes, the abstract ric patient passed first visit (definition by Irmgard and introduction of the manuscript. J Bousquet, P Eigenmann, S Halken is a Eichler, EMA). member of the EAACI Task Force on Clinical Trials in Children and attended the meeting. M Jutel attended the meeting as nominated stakeholder and represenative of EAACI. He is a member of the EAACI Task Force and contrib- This means: no TAO product will pass future compli - uted to the meeting minutes. S Kaul is head of Section Clinical Allergology ance check before at least the LTE of the selected allergen at Paul-Ehrlich-Institut, attended the meeting, contributed to the meeting minutes, abstract and introduction of the manuscript. V Mahler is head of Divi- product has been started in children. (As stated above: sion Allergology at Paul-Ehrlich-Institut and a member of the EAACI Task Force. Studies in children are supposed to start as soon as short- She attended the meeting, contributed to the meeting minutes, drafted the term efficacy and safety has been proven in adults). abstract and introduction of the manuscript, edited and compiled texts into the final article. D Mentzer is PDCO member (at time of meeting PDCO chair). He called and hosted the meeting, prepared the meeting minutes, supervised • Paediatric trials (STE or LTE) can be started at any the stakeholder commentation process and the adoption of the meeting min- time, provided the trial is compliant with the key utes by PDCO. A Muraro attended the meeting as nominated stakeholder and representative of EAACI. She is the chair of the EAACI Task Force on Clinical Tri- binding elements (KBE) in the PIP opinion. (as stated als in children and contributed to the meeting minutes. O Pfaar attended the above). meeting as nominated stakeholder and represenative of EAACI. He is a mem- • Provided PIP compliance is confirmed, each TAO ber of the EAACI Task Force and contributed to the meeting minutes. S Vieths is Vice President of Paul-Ehrlich-Institut. He chaired the meeting, contributed product can go for MAA for its individual indication. to the meeting minutes, abstract and introduction of the manuscript. U Wahn is a member of the EAACI Task Force, the EUFOREA board and coordinator of the Immunotherapy Expert group, and attended the meeting. Funding Conclusions None. PDCO to discuss the various suggestions and to consider potential changes of the standard PIP. Availability of data and materials Not applicable. EAACI and manufacturers invited to propose alterna- tive approaches for development of SCIT products. Ethics approval and consent to participate Not applicable. Consent for publication Next steps All authors and all meeting participants gave their informed consent. • Based on feedback from investigators, no change Competing interests A Bonertz, S Kaul, V Mahler, D Mentzer and S Vieths reports not having com- considered necessary for paediatric development of peting interests.J Bousquet reports personal fees and other from Chiesi, Cipla, SLIT products. Hikma, Menarini, Mundipharma, Mylan, Novartis, Sanofi-Aventis, Takeda, Teva, • PDCO will await proposals from EAACI and manu‑ Uriach, outside the submitted work.P Eigenmann reports personal fees and other from ThermoFisher Scientific, DBV technologies, Nestlé, Danone, Abbott, facturers how to investigate long‑ term efficacy and Novartis, ALK, UpToDate, Wiley and Elsevier, outside the submitted work.S safety for SCIT products. Halken reports personal fees and non-financial support from ALK-Abelló, • PDCO supports multi‑company studies on the same outside the submitted work.M Jutel reports personal fees from ALK-Abello, personal fees from Allergopharma, personal fees from Stallergenes, personal allergen class with one common placebo arm. fees from Anergis, personal fees from Allergy Therapeutics, personal fees from • PDCO encourages precompetitive collaboration to Circassia, personal fees from Leti, personal fees from Biomay, personal fees increase knowledge base. from HAL, during the conduct of a study; personal fees from Astra-Zeneka, personal fees from GSK, personal fees from Novartis, personal fees from Teva, personal fees from Vectura, personal fees from UCB, personal fees from Takeda, personal fees from Roche, personal fees from Janssen, personal fees from Medimmune, personal fees from Chiesi, outside the submitted work.A Muraro reports speaker’s fees from: Aimmune, DBV, Nestlé-Health Institute, Abbreviations Nestlé Purina, Nutricia, ALK, HAL outside the submitted work. O Pfaar reports AIT: Allergen Immunotherapy; CT: Clinical trial; DFS: Dose finding study; EAACI: grants and personal fees from ALK-Abelló, grants and personal fees from European Academy of Allergy and Clinical Immunology; EC: European Com- Allergopharma, grants and personal fees from Stallergenes Greer, grants mission; EMA: European Medicines Agency; EUnetHTA: European Network for and personal fees from HAL Allergy Holding B.V./HAL Allergie GmbH, grants Health Technology Assessment; KBE: Key binding elements; LTE: Long-term and personal fees from Bencard Allergie GmbH/Allergy Therapeutics, grants efficacy; MA: Marketing authorisation; MAA: Marketing authorisation applica- and personal fees from Lofarma, grants from Biomay, grants from Circassia, tion; NPP: Named patient product; PDCO: Paediatric Committee (of EMA); grants and personal fees from ASIT Biotech Tools S.A., grants and personal PIP: Paediatric Investigation Plan; QoL: Quality of Life; SCIT: Subcuteaneous fees from Laboratorios LETI/LETI Pharma, personal fees from MEDA Pharma/ M ahler et al. Clin Transl Allergy (2020) 10:28 Page 7 of 7 MYLAN, grants and personal fees from Anergis S.A., personal fees from Mobile C, Barber D, Palomares O, Sheikh A, Pawankar R, Hamerlijnk D, Klimek L, Chamber Experts (a GA2LEN Partner), personal fees from Indoor Biotechnolo- Agache I, Angier E, Casale T, Fernandez-Rivas M, Halken S, Jutel M, Lau S, gies, grants from Glaxo Smith Kline, personal fees from Astellas Pharma Global, Pajno G, Sturm G, Varga EM, Gerth van Wijk R, Bonini S, Muraro A, Vieths S. personal fees from EUFOREA, personal fees from ROXALL, personal fees from Challenges in the implementation of EAACI guidelines on allergen immu- NOVARTIS, personal fees from SANOFI AVENTIS, outside the submitted work.U notherapy: a global perspective on the regulation of allergen products. Wahn reports lecture and consultation fees from Novartis, Sanofi-Aventis, Allergy. 2018;73:64–76. Berlin-Chemie, StallergenesGreer, ALK, Leti, and Roxall. 2. Mahler V, Bonertz A, Ruoff C, Hartenstein D, Mentzer D, Kaul S, Vieths S. What we learned from TAO—10 years of German therapy allergen Author details ordinance. Allergo J Int. 2019;28:33–337. https ://doi.org/10.1007/s4062 1 2 Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, 63225 Langen, Germany. Food 9-019-0101-7. Allergy Referral Centre Veneto Region, Department of Women and Child 3. Regulation (EC) No 1901/2006 of the European Parliament and of the Health, Padua General University Hospital, Padua, Italy. Pediatric Allergy Unit, Council of 12 December 2006 on medicinal products for paediatric use, University Hospitals of Geneva, Geneva, Switzerland. Charité, Universitäts- OJ L 378, 27.12.2006, p. 1–19. medizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 4. European Medicines Agency (EMA). EMA/PDCO Standard Paediatric Comprehensive Allergy Center, Department of Dermatology and Allergy, Investigation Plan for Allergen Products for Specific Immunotherapy Berlin, Germany. University Hospital Montpellier, Montpellier, France. (EMA/PDCO/737605/2009) (Revision 4), 16 February 2015. 6 7 MACVIA-France, Montpellier, France. Hans Christian Andersen Children’s 5. Mahler V, Esch RE, Kleine-Tebbe J, Lavery WJ, Plunkett G, Vieths S, Bern- Hospital, Odense University Hospital, Odense, Denmark. Department of Oto- stein DI. Understanding differences in allergen immunotherapy products rhinolaryngology, Head and Neck Surgery, Section of Rhinology and Allergy, and practices in North America and Europe. J Allergy Clin Immunol. University Hospital Marburg, Phillipps-Universität Marburg, Marburg, Germany. 2019;143:813–28. Department of Clinical Immunology, Wrocław Medical University, Wrocław, 6. Pfaar O, Demoly P, Gerth van Wijk R, Bonini S, Bousquet J, Canonica 10 11 Poland. ALL-MED Medical Research Institute, Wrocław, Poland. Pediatric GW, Durham SR, Jacobsen L, Malling HJ, Mösges R, Papadopoulos NG, Department, Charité, Berlin, Germany. Rak S, Rodriguez del Rio P, Valovirta E, Wahn U, Calderon MA, European Academy of Allergy and Clinical Immunology. Recommendations for the Received: 2 April 2020 Accepted: 30 May 2020 standardization of clinical outcomes used in allergen immunotherapy trials for allergic rhinoconjunctivitis: an EAACI Position Paper. Allergy. 2014;69:854–6. Publisher’s Note References Springer Nature remains neutral with regard to jurisdictional claims in pub- 1. Bonertz A, Roberts GC, Hoefnagel M, Timon M, Slater JE, Rabin RL, Bridge- lished maps and institutional affiliations. water J, Pini C, Pfaar O, Akdis C, Goldstein J, Poulsen LK, van Ree R, Rhyner Ready to submit your research ? 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