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Applied Drug Research, Clinical Trials and Regulatory Affairs

Author(s): Manfred Kurz*

DOI: 10.2174/2667337109666221207154414

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Combating Childhood Cancer: Paediatric Patients Living with Neuroblastoma - Regulatory Ramifications and Roadblocks

Article ID: e071222211726 Pages: 9

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Abstract

This paper relates to Neuroblastoma (NBL), a rare, solid cancer affecting children and aims to describe regulatory obligations to adhere to during development, marketing authorisation application (MAA) and post-authorisation stage. The focus is on European Union (EU) paediatric legislation, although essential US Food and Drug Administration (FDA) elements are briefly outlined. Practical regulatory aspects and reporting requirements, players in the therapeutic area as well as clinical management are described. The feasibility and limitations of future harmonised clinical development are pointed out.

Graphical Abstract

[1]
Johnsen JI, Dyberg C, Wickström M. Neuroblastoma—a neural crest derived embryonal malignancy. Front Mol Neurosci 2019; 12: 9.
[http://dx.doi.org/10.3389/fnmol.2019.00009] [PMID: 30760980]
[2]
European Medicines Agency - EU/3/11/879: Orphan designation for the treatment of neuroblastoma. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu311879 [Accessed April 7, 2022].
[3]
European Medicines Agency- Search - Categories Human - Medicine Orphan designations-intended use Treatment of neuroblastoma. Available from: https://www.ema.europa.eu/en/medicines/field_ema_web_categories%253Aname_field/Human/ema_group_types/ema_orphan/field_ema_orp_disease_condition%253Aname_field/Treatment%20of%20neuroblastoma [Accessed April 7, 2022].
[4]
European Medicines Agency - 22 May 2015 - EMA recommends treatment for rare cancer in children 2015. Available from: https://www.ema.europa.eu/en/documents/press-release/ema-recommends-treatment-rare-cancer-children_en.pdf Accessed April 7, 2022]
[5]
European Commission - Live, work, travel in the EU - Public Health - Union Register of medicinal products - Qarziba. Available from: https://ec.europa.eu/health/documents/community-register/html/h1191.htm [Accessed April 7, 2022].
[6]
European Commission - Live, work, travel in the EU - Public Health - Union Register of medicinal products - Unitixin. Available from: https://ec.europa.eu/health/documents/community-register/html/h1022.htm [Accessed April 7, 2022].
[7]
Cancer.Net – ASCO / Knowledge conquers cancer - Neuroblastoma- Childhood: Stages and Groups. Available from: https://www.cancer.net/cancer-types/neuroblastoma-childhood/stages-and-groups [Accessed April 7, 2022].
[8]
Tas ML, Reedijk AMJ, Karim-Kos HE, et al. Neuroblastoma between 1990 and 2014 in the Netherlands: Increased incidence and improved survival of high-risk neuroblastoma. Eur J Cancer 2020; 124: 47-55.
[http://dx.doi.org/10.1016/j.ejca.2019.09.025] [PMID: 31726247]
[9]
Cancer.Net – ASCO / Knowledge conquers cancer - Neuroblastoma - Childhood: Statistics Available from: https://www.cancer.net/cancer-types/neuroblastoma-childhood/statistics [Accessed April 8, 2022].
[10]
Chung C, Boterberg T, Lucas J, et al. Neuroblastoma. Pediatr Blood Cancer 2021; 68(S2): e28473.
[11]
European Medicines Agency 2017. Available from: https://www.ema.europa.eu/en/documents/assessment-report/dinutuximab-beta-apeiron-epar-public-assessment-report_en.pdf
[12]
European Medicines Agency - 23 March 2017 - Assessment report - Dinutuximab beta Apeiron. 2004. Available from: https://www.ema.europa.eu/en/documents/other/evidence-harm-label-unlicensed-medicines-children_en.pdf [Accessed April 8,2022].
[13]
Penkov DPT, Irmgard E, Dianne M, Lynne PY, Jean T. Ther Innov Regul Sci 2017; 51(3): 360-71.
[http://dx.doi.org/10.1177/2168479017696265] [PMID: 28674673]
[14]
Vieira I. Paediatric medicines – regulatory drivers, restraints, opportunities and challenges. J Pharm Sci 2021; 110: 1545-56.
[15]
European Medicines Agency - January 2001 - ICH Topic E 11 Clinical Investigation of Medicinal Products in the Paediatric Population. 2001. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/inter national-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-1.pdf [Accessed April 8, 2022]
[16]
Atlant Clinical, Pediatric drug development: us and eu regulatory aspects. Available from : https://www.atlantclinical.com/pediatric-drug-development [Accessed April 8, 2022].
[17]
Pharmaceutical Law Group – November 2020- New FDA Guidance Details How to Submit Pediatric Study Plans. Available from: https://www.pharmalawgrp.com/blog/9/new-fda-guidance-details-how-to-submit-pediatric-study-plans/ [Accessed April 8, 2022].
[18]
Food and Drug Administration – July 2020 - Pediatric Study Plans Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans - Guidance for Industry. Available from: https://www.fda.gov/media/86340/download Accessed April 8, 2022].
[19]
European Medicines Agency – Human Regulatory - Paediatric Regulation. Available from : https://www.ema.europa.eu/en/human-regulatory/overview/paediat ric-medicines/paediatric-regulation [Accessed April 8, 2022].
[20]
European Medicines Agency - Committees - PDCO members. Available from: https://www.ema.europa.eu/en/committees/pdco/members [Accessed April 8, 2022].
[21]
European Medicines Agency - 30 July 2012 - Policy on the determination of the condition(s) for a Paediatric Investigation Plan/Waiver (scope of the PIP/waiver. Available from: https://www.ema.europa.eu/en/documents/other/policy-determination-conditions-paediatric-investigation-plan-pip/waiver-scope-pip/waiver_en.pdf [Accessed April 9, 2022].
[22]
European Medicines Agency – Human Regulatory - Paediatric investigation plans: Templates, forms and submission dates. Available from: https://www.ema.europa.eu/en/human-regulatory/research-development/paediatric-medicines/paediatric-investigation-plans/paediatric-investigation-plans-templates-forms-submission-dates#templates-and-forms-section [Accessed April 9,2022].
[23]
European Medicines Agency – Human Regulatory - Paediatric investigation plans. Available from : https://www.ema.europa.eu/en/human-regulatory/research-development/paediatric-medicines/paediatric-investigation-plans [Accessed April 9, 2022].
[24]
European Medicines Agency – Human Regulatory - Standard paediatric investigation plans. Available from: https://www.ema.europa.eu/en/human-regulatory/research-develop ment/paediatric-medicines/paediatric-investigation-plans/standard-paediatric-investigation-plans [(Accessed April 9, 2022
[25]
European Medicines Agency - 7 August 2020- Validation issues frequently seen with initial MAA. Available from: https://www.ema.europa.eu/en/documents/other/validation-issues-frequently-seen-initial-marketing-authorisation-holders_en.pdf [Accessed April 9, 2022].
[26]
Medicines Law & Policy June 2019- European Union Review ofPharmaceutical Incentives: Suggestions for Change. 2019. Availablefrom: https://medicineslawandpolicy.org/wp-content/uploads/2019/06/MLP-European-Union-Review-of-Pharma-Incentives-Suggestions-for-Change.pdf [Accessed April 9,2022].
[27]
European Medicines Agency- Questions and answers on the procedure of PIP compliance verification at EMA, and on paediatric rewards (revised December 2014). 2014. Available from: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/questions-answers-procedure-paediatric-investigation-plan-compliance-verification-european-medicines_en.pdf [Accessed April 9, 2022]
[28]
Report to the European Commission on companies and products that have benefited from any of the rewards and incentives in the Paediatric Regulation1 and on the companies that have failed to comply with any of the obligations in this regulation. 2019. Available from: https://ec.europa.eu/health/system/files/2021-12/2019_annual_report.pdf Accessed April 9, 2022].
[29]
European Medicines Agency – Human Regulatory- Paediatric investigation plans: Questions and answers. Available from: https://www.ema.europa.eu/en/human-regulatory/research-development/paediatric-medicines/paediatric-investigation-plans/paediatric-investigation-plans-questions-answers#9.-transfers-and-changes-in-contact-details-section [Accessed April 9,2022].
[30]
European Medicines Agency - 25 September 2014 Draft inventory of paediatric therapeutic needs Paediatric oncology. 2014. Available from: https://www.ema.europa.eu/en/documents/other/draft-inventory-paediatric-therapeutic-needs-paediatric-oncology_en.pdf [Accessed April 9, 2022].
[31]
EU Clinical Trials Register - Clinical trials for neuroblastoma. Availablefrom : https://www.clinicaltrialsregister.eu/ctr-search/search?query=neuroblastoma&status=ongoing [Accessed April 9, 2022].
[32]
Medicines output paediatric investigation plan Availablefrom : https://www.ema.europa.eu/sites/default/files/Medicines_output_paediatric_investigation_plans.xlsx [Accessed April 9, 2022].
[33]
Children’s Cancer And Leukaemia Group (Cclg) - Neuroblastoma Special Interest Group. Options for the Treatment of Patients with Relapsed/Progressive High-Risk Neuroblastoma. 2015. Availablefrom : https://www.cclg.org.uk/write/MediaUploads/Member%20area/Treatment%20guidelines/CCLG_Relapsed_Progressive_High_Risk_ Neuroblastoma_Guidelines_March_2015_FINAL.pdf [Accessed April 10, 2022].
[34]
European Medicines Agency decision P/0133/2020. 2020. Available from: https://www.ema.europa.eu/en/documents/pip-decision/p/0133/2020-ema-decision-15-april-2020-acceptance-modification-agreed-paediatric-investigation-plan_en.pdf [Accessed April 10, 2022].
[35]
European Medicines Agency decision P/0361/2018. 2018. Available from: https://www.ema.europa.eu/en/documents/pip-decision/p/0361/2018-ema-decision-7-december-2018-granting-product-specific-waiver-crizotinib-xalkori-emea-001493_en.pdf [Accessed April 10, 2022].
[36]
Pearson ADJ. Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration. European J Cancer 2021; 157: 198-213.
[37]
Fawzy M. Watch and see strategy in selected neuroblastoma case scenarios: success and limitations. J Pediatr Hematol Oncol 2019; 41(6): e384-7.
[38]
Bolislis WR. Optimizing pediatric medicine developments in the european union through pragmatic approaches. Clinic Pharmacol Therap 2021; 110(4): 871.
[39]
Rose K. Paediatric Oncology at the Crossroads: A Call for Change. Pharmaceut Med 2020; 34(5): 297-300.
[http://dx.doi.org/10.1007/s40290-020-00352-x] [PMID: 33026589]
[40]
Changes to pediatric, orphan drug regulations on European horizon. 2022. Available from: https://www.raps.org/news-and-articles/news-articles/2022/5/changes-to-pediatric-orphan-drug-regulations-on-eu
[41]
European Commission - A Pharmaceutical Strategy for Europe. 2020. Available from: file:///C:/Users/223037575/Downloads/pharmastrategy_report_en_0.pdf
[42]
European Medicines Agency decision- P/0021/2020. 2020. Available from: https://www.ema.europa.eu/en/documents/pip-decision/p/0021/2020-ema-decision-6-january-2020-agreement-paediatric-investigation-plan-abemaciclib-verzenios-emea_en.pdf [Accessed April 10, 2022].
[43]
European Medicines Agency decision - P/0322/2020. 2020. Availablefrom: https://www.ema.europa.eu/en/documents/pip-decision/p/0322/2020-ema-decision-10-august-2020-acceptance-modification-agreed-paediatric-investigation-plan-iodine_en.pdf [Accessed April 10, 2022].
[44]
European Medicines Agency decision - P/0094/2014. 2014. Available from: https://www.ema.europa.eu/en/documents/pip-decision/p/0094/2014-ema-decision-7-april-2014-agreement-paediatric-investigation-plan-granting-deferral-granting_en.pdf [Accessed April 10, 2022].
[45]
European Commission- Notice To Applicants - A Guideline On Summary Of Product Characteristics (SmPC) 2009. Available from: https://ec.europa.eu/health/system/files/2016-11/smpc_guideline_rev2_en_0.pdf [Accessed April 10, 2022].
[46]
European Medicines Agency- Draft presentation: Summary of product characteristics. Available from: https://www.ema.europa.eu/en/documents/presentation/presentation-summary-product-characteristics_en.pdf [Accessed April 10,2022].
[47]
European Medicines Agency - Gaucher disease: a strategic collaborative approach from the European Medicines Agency and Food and Drug Administration. Available from: https://www.ema.europa.eu/en/gaucher-disease-strategic-collaborative-approach-european-medicines-agency-food-drug-administration [Accessed April 10, 2022].
[48]
US Food and Drug Administration – International Collaboration Pediatric Cluster. Available from : https://www.fda.gov/science-research/pediatrics/international-collaboration-pediatric-cluster [Accessed April 10, 2022].
[49]
US Food and Drug Administration - European Medicines Agency. Common Commentary - EMA/FDA Common issues requested for discussion by the respective agency (EMA/PDCO and FDA) concerning paediatric oncology development plans (Paediatric Investigation Plans [PIPs] and initial Pediatric Study Plans [iPSPs]). Availablefrom : https://www.ema.europa.eu/en/documents/other/common-commentary-ema/fda-common-issues-requested-discussion-respective-agency-ema/pdco-fda-concerning-paediatric-oncology-development-plans-paediatric-investigation-plans-pips_en.pdf [Accessed April 10, 2022].
[50]
European Medicines Agency Partners & networks - European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA). Availablefrom : https://www.ema.europa.eu/en/partners-networks/networks/european-network-paediatric-research-european-medicines-agency-enpr-ema [Accessed April 10, 2022].
[51]
Esmo guidelines. Availablefrom : https://www.esmo.org/guidelines [Accessed April 10, 2022].
[52]
American Society of Clinical Oncology and Association for ClinicalOncology. Availablefrom : https://www.asco.org/get-involved/membership/member-benefits? cmpid=js_ascoorg_mem_join_psrh_google_join_101920____rsav1&gclid=EAIaIQobChMIurLfpN708wIVENTtCh3nugD1EAAYASAAEgIZOvD_BwE [Accessed April 10, 2022].
[53]
EU Clinical Trials Register - SIOPENRNET003 - Austria Availablefrom: https://www.clinicaltrialsregister.eu/ctr-search/trial/2006-001489-17/AT [Accessed April 10, 2022].
[54]
EU Clinical Trials Register - APN311-304 Germany. Available from: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000588-42/DE [Accessed April 10, 2022].
[55]
SIOPEN Clinical trials. Availablefrom: https://www.siopen.net/siopen-clinical-trials.php [Accessed April 11, 2022].
[56]
The Children’s Oncology Group Availablefrom: https://childrensoncologygroup.org/ [Accessed April 11, 2022].
[57]
ClinicalTrials.gov - High-Risk Neuroblastoma Study 2 of SIOPEuropa- Neuroblastoma (SIOPEN) (HR-NBL2). Available from: https://clinicaltrials.gov/ct2/history/NCT04221035?V_3=View [Accessed April 11, 2022].
[58]
European Medicines Agency – Human Regulatory - Submitting results of paediatric studies. Availablefrom : https://www.ema.europa.eu/en/human-regulatory/post-authorisation/paediatric-medicines/submitting-results-paediatric-studies-0#article-46-section [Accessed April 11, 2022].
[59]
EU Clinical Trials Register – Clinical trials. Available from : https://www.clinicaltrialsregister.eu/ [Accessed April 11, 2022].
[60]
Smith V, Foster J. High-risk neuroblastoma treatment review. Children 2018; 5(9): 114.
[http://dx.doi.org/10.3390/children5090114]
[61]
Ladenstein R. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol 2018; 19(12): 1617-29.
[62]
Simon T, Hero B, Schulte JH, et al. 2017 GPOH guidelines for diagnosis and treatment of patients with neuroblastic tumors. Klin Padiatr 2017; 229(3): 147-67.
[http://dx.doi.org/10.1055/s-2005-836518] [PMID: 28561228]
[63]
The American Cancer Society- Treatment of Neuroblastoma by Risk Group Available from: https://www.cancer.org/cancer/neuroblastoma/treating/by-risk-group.html [Accessed April 11, 2022].
[64]
Nazha B, Inal C, Owonikoko TK. Disialoganglioside GD2 Expression in Solid Tumors and Role as a Target for Cancer Therapy. Front Oncol 2020; 10(10): 1000.
[http://dx.doi.org/10.3389/fonc.2020.01000] [PMID: 32733795]
[65]
US Food and Drug Administration - Drugs@FDA: FDA-Approved Drugs - highlights of prescribing information - unituxi Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125516s000lbl.pdf [Accessed April 11, 2022].
[66]
US Food and Drug Administration - Drugs@FDA: FDA-Approved Drugs - highlights of prescribing information - danyelza. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761171lbl.pdf [Accessed April 11, 2022].
[67]
European Medicines Agency - Qarziba SUMMARY OF PRODUCT CHARACTERISTICS. Available from: https://www.ema.europa.eu/en/documents/product-information/qarziba-epar-product-information_en-0.pdf [Accessed April 11, 2022].
[68]
Martinez Sanz P. G-CSF as a suitable alternative to GMCSF to boost dinutuximab-mediated neutrophil cytotoxicity in neuroblastoma treatment. J Immunother Cancer 2021; 9.
[69]
EU Clinical Trials Register- Clinical trials- Sponsor's Protocol Code Number 201 - Germany Availablefrom : https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-001829-40/DE [Accessed April 12, 2022].
[70]
Furman WL, Federico SM, McCarville MB, et al. A Phase II Trial of Hu14.18K322A in combination with induction chemotherapy in children with newly diagnosed high-risk neuroblastoma. Clin Cancer Res 2019; 25(21): 6320-8.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-1452] [PMID: 31601569]
[71]
Rojas T, Pearson AJ, Scobie N, et al. Intercontinental collaboration in clinical trials for children and adolescents with cancer—A systematic review by ACCELERATE. Cancer Med 2021; 10(23): 8462-74.
[http://dx.doi.org/10.1002/cam4.4356] [PMID: 34687165]
[72]
The information portal of the Society for Paediatric Oncology/ Haematology. Available from : https://www.gpoh.de/kinderkrebsinfo/content/index_eng.html [Accessed April 12, 2022].
[73]
Solvingkidscancer - About Neuroblastoma. Availablefrom : https://www.solvingkidscancer.org.uk/induction-chemotherapy [Accessed April 12, 2022].
[74]
Children’s Neuroblastoma Cancer Foundation - High Risk Neuroblastoma Treatment Available from: https://www.cncfhope.org/about-neuroblastoma/newly-diagnosed/high-risk-neuroblastoma-treatment/#Chemotherapy [Accessed April 12, 2022].
[75]
Coderich LP. High Risk Neuroblastoma Treatment 2019. Available from: https://www.tesisenred.net/bitstream/handle/10803/670156/lpc1de1.pdf?sequence=1&isAllowed=y [Accessed April 12, 2022].
[76]
Y-mAbs - Company Presentation 2022. Availablefrom : https://ir.ymabs.com/static-files/07286921-49a8-481c-b381-f0e60be16b6d
[77]
Mora J, Castañeda A, Flores MA, et al. The Role of Autologous Stem-Cell Transplantation in High-Risk Neuroblastoma Consolidated by anti-GD2 Immunotherapy. Results of Two Consecutive Studies. Front Pharmacol 2020; 11: 575009.
[http://dx.doi.org/10.3389/fphar.2020.575009] [PMID: 33324208]
[78]
Regulation (EU) 2016/679 of the european parliament and of the council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation) 2016. Available from: https://eurlex.europa.eu/legalcontent/EN/TXT/PDF/?uri=CELEX:02016R0679-20160504&from=EN
[79]
Vassal G, Lazarov D, Rizzari C. Szczepański T, Ladenstein R, Kearns PR. The impact of the EU General Data Protection Regulation on childhood cancer research in Europe. Lancet Oncol 2022; 23(8): 974-5.
[http://dx.doi.org/10.1016/S1470-2045(22)00287-X] [PMID: 35901818]
[80]
Clinical trials for childhood cancer drugs are critical, but parents don’t always understand what they are signing up for Available from: https://theconversation.com/clinical-trials-for-childhood-cancer-drugs-are-critical-but-parents-dont-always-understand-what-they-are-signing-up-for-53427
[81]
Geißler J, Isham E, Hickey G, et al. Patient involvement in clinical trials. Commun Med 2 94(2022): 94.
[82]
Ramanan AV, Modi N, de Wildt SN, et al. Improving clinical paediatric research and learning from COVID-19: recommendations by the Conect4Children expert advice group. Pediatr Res 2022; 91: 1069-77.
[http://dx.doi.org/10.1038/s41390-021-01587-3]