From class waivers to precision medicine in paediatric oncology

doi:10.1016/S1470-2045(17)30442-4

From class waivers to precision medicine in paediatric oncology

Research output: Contribution to journal › Review article › peer-review

Abstract

New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed for 89 drugs. Mechanisms of action were then assessed as potential paediatric therapeutic targets by both a literature search and an expert review. 48 (54%) of the 89 class-waivered drugs had a mechanisms of action warranting paediatric development. Two (2%) class-waivered drugs were considered not relevant and 16 (18%) required further data. In light of these results, we propose five initiatives: an aggregated database of paediatric biological tumour drug targets; molecular profiling of all paediatric tumours at diagnosis and relapse; a joint academic-pharmaceutical industry preclinical platform to help analyse the activity of new drugs (Innovative Therapy for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform); paediatric strategy forums; and the suppression of article 11b of the European Paediatric Regulation, which allows product-specific waivers on the grounds that the associated condition does not occur in children. These initiatives and a mechanism of action-based approach to drug development will accelerate the delivery of new therapeutic drugs for front-line therapy for those children who have unmet medical needs.

Original language	English
Pages (from-to)	e394-e404
Journal	LANCET ONCOLOGY
Volume	18
Issue number	7
DOIs	https://doi.org/10.1016/S1470-2045(17)30442-4
Publication status	Published - Jul 2017
Externally published	Yes

Keywords

Adolescent
Antineoplastic Agents/pharmacology
Biological Products/therapeutic use
Child
Child, Preschool
Drug Discovery/legislation & jurisprudence
Europe
Humans
Infant
Infant, Newborn
Legislation, Drug
Neoplasms/drug therapy
Precision Medicine

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10.1016/S1470-2045(17)30442-4

Cite this

@article{26c51f56a7604fc0ace3afbce4cce468,

title = "From class waivers to precision medicine in paediatric oncology",

abstract = "New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed for 89 drugs. Mechanisms of action were then assessed as potential paediatric therapeutic targets by both a literature search and an expert review. 48 (54%) of the 89 class-waivered drugs had a mechanisms of action warranting paediatric development. Two (2%) class-waivered drugs were considered not relevant and 16 (18%) required further data. In light of these results, we propose five initiatives: an aggregated database of paediatric biological tumour drug targets; molecular profiling of all paediatric tumours at diagnosis and relapse; a joint academic-pharmaceutical industry preclinical platform to help analyse the activity of new drugs (Innovative Therapy for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform); paediatric strategy forums; and the suppression of article 11b of the European Paediatric Regulation, which allows product-specific waivers on the grounds that the associated condition does not occur in children. These initiatives and a mechanism of action-based approach to drug development will accelerate the delivery of new therapeutic drugs for front-line therapy for those children who have unmet medical needs.",

keywords = "Adolescent, Antineoplastic Agents/pharmacology, Biological Products/therapeutic use, Child, Child, Preschool, Drug Discovery/legislation & jurisprudence, Europe, Humans, Infant, Infant, Newborn, Legislation, Drug, Neoplasms/drug therapy, Precision Medicine",

author = "Pearson, {Andrew D J} and Pfister, {Stefan M} and Andre Baruchel and Jean-Pierre Bourquin and Michela Casanova and Louis Chesler and Fran{\c c}ois Doz and Angelika Eggert and Birgit Geoerger and Jones, {David T W} and Kearns, {Pamela R} and Molenaar, {Jan J} and Bruce Morland and Gudrun Schleiermacher and Schulte, {Johannes H} and Josef Vormoor and Marshall, {Lynley V} and Zwaan, {C Michel} and Gilles Vassal",

note = "Funding Information: Several compounds in the same class and with the same mechanism of action are often developed in parallel by different pharmaceutical companies. In this analysis, we noted that four MEK inhibitors and nine drugs targeting the PI3K/AKT/mTOR pathway were all waivered. Additionally, at least six ALK inhibitors (three already commercialised), more than eight PD-1 or PD-L1 immune checkpoint inhibitors, five MEK inhibitors, and four PARP inhibitors are in development. With the small numbers of children eligible for early-phase and late-phase studies, undertaking full (and similar) development programmes for all drugs with a relevant mechanism of action would not be feasible. Choosing the most promising drugs will be essential to ensure the feasibility and efficiency of a mechanism of action-based model. Many paediatric malignancies have many different drugs developed in adults that have a relevant mechanism of action. For example, the portfolio of oncology drugs developed in B-cell malignancies in adults is increasing rapidly, with compounds and immunotherapies targeting both the leukaemic cell phenotypes, such as CD20 or CD22, and genetic aberrations such as MEK, FLT3, and PI3K. 21 However, therapy combining rituximab, a CD20 monoclonal antibody, and multidrug cytotoxic chemotherapy 22 in children with B-cell non-Hodgkin lymphoma results in an overall survival of 94% with very few relapsed patients. 22 The most promising drugs or cellular therapies need to be chosen, and a strategy established to ensure that patients who die of B-cell malignancy will have innovative therapies proposed. Furthermore, toxic therapy elements should be replaced with less toxic elements while maintaining responses in these malignancies, which requires a different development perspective. The ACCELERATE multistakeholder platform is currently piloting a new concept to facilitate the identification of new oncology drugs for children. Paediatric strategy forums will provide an opportunity for interaction and discussion between all stakeholders (regulators, pharmaceutical companies, scientists, clinical academics, and patient representatives) at a precompetitive level, on topics that might cause a problem from an industry or academic standpoint, in paediatric or adolescent cancer drug development. In a paediatric strategy forum, the epidemiology, clinical features, and biology of the malignancy targeted by the drugs should be reviewed, followed by a presentation by the relevant pharmaceutical company of any preclinical data pertaining to paediatric tumours, pharmacokinetic and safety data in adults, and (if available) clinical data in children for their compound. The output of a paediatric strategy forum should be a perspective that that will enable all stakeholders to have an overview of the landscape with the same level of knowledge. This perspective will facilitate the sharing of information and advance learning, which will help inform subsequent drug development strategic (including regulatory) decisions. These forums should be implemented early in the drug development process because class-specific developments should be harmonised early on in the drug development stage and to prevent delays. We believe that the increased and shared knowledge of each participant at a paediatric strategy forum, including all pharmaceutical companies with relevant drugs in development, will help facilitate paediatric development plans and prioritisation when multiple compounds of the same class exist. In view of the scarcity of paediatric cancer and the current advances in molecular subtyping of molecularly subtyping, paediatric drug development professionals in national and international academic clinical cooperative groups should work closely together through collaboration and coordination of clinical studies. Ideally, worldwide studies for patient populations with rare diseases should be done and international regulatory coordination should be increased. We propose that drug development in paediatric oncology should be based on science and preclinical data relating to the importance of a given drug's mechanism of action, in addition to unmet paediatric therapeutic needs, independent of the adult condition for which the drug will be marketed. A mechanism-driven paediatric drug development programme should be adopted with the suppression of article 11b of the European Paediatric Regulation to enable the implementation of mechanism of action-based PIPs. Molecular profiling of all paediatric tumours should be done at diagnosis and relapse, using a database of tumour targets, a joint pharmaceutical academic–industry preclinical platform to analyse the activity of new drugs, and paediatric strategy forums. These actions will increase the numbers of new drugs and improve the efficiency of introducing them rapidly into front-line therapy for children with life-threatening diseases. Furthermore, a more efficient drug development process will also benefit the pharmaceutical industry by avoiding unnecessary duplication of efforts, but more importantly, it will bring tangible benefit to children and adolescents with cancer. Through such efforts, the original aspiration of the European Paediatric Medicine Regulation to substantially increase the number of new oncology drugs developed for children and adolescents can be realised. Contributors ADJP, SMP, and GV were involved in the study design and literature search. ADJP, SMP, AB, J-PB, MC, LC, FD, AE, BG, DTWJ, PRK, JJM, BM, GS, JHS, JV, CMZ, and GV collected the data. All authors did the interpretation and analysis of the data, and writing, reviewing, and approval of the manuscript. Declaration of interests ADJP was on the international advisory board for Boehringer Ingelheim. AB reports grants from Baxalta and personal fees from Jazz, Roche, and Novartis. J-PB was on the advisory board for Roche. MC has served on international advisory boards for Boehringer Ingelheim, Roche, and Bayer. FD reports financial support for a meeting attendance from Novartis; was on an advisory board for Novartis; and was an investigator for Bayer, Novartis, and Roche. AE reports personal fees from Bayer. BG was on the international advisory boards for Bayer and Roche. PRK reports research funding or provision of drugs from Johnson & Johnson, Celgene, Bayer, and Bristol-Myers Squibb; and was on an advisory board for Johnson & Johnson, AstraZeneca, Pfizer, Gilead, and Roche. JV is on the advisory board for Roche and Abbvie. CMZ was on an international advisory board for Pfizer, Bristol-Myers Squibb, Jazz Pharmaceuticals, Celgene, Novartis, Janssen, and Medac. SMP, LC, DTWJ, JJM, BM, GS, JHS, LVM, and GV declare no competing interests. Acknowledgments Carole Lecinse and Gynette Cook for administrative assistance. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",

year = "2017",

month = jul,

doi = "10.1016/S1470-2045(17)30442-4",

language = "English",

volume = "18",

pages = "e394--e404",

journal = "LANCET ONCOLOGY",

issn = "1470-2045",

publisher = "Lancet Publishing Group",

number = "7",

}

TY - JOUR

T1 - From class waivers to precision medicine in paediatric oncology

AU - Pearson, Andrew D J

AU - Pfister, Stefan M

AU - Baruchel, Andre

AU - Bourquin, Jean-Pierre

AU - Casanova, Michela

AU - Chesler, Louis

AU - Doz, François

AU - Eggert, Angelika

AU - Geoerger, Birgit

AU - Jones, David T W

AU - Kearns, Pamela R

AU - Molenaar, Jan J

AU - Morland, Bruce

AU - Schleiermacher, Gudrun

AU - Schulte, Johannes H

AU - Vormoor, Josef

AU - Marshall, Lynley V

AU - Zwaan, C Michel

AU - Vassal, Gilles

N1 - Funding Information: Several compounds in the same class and with the same mechanism of action are often developed in parallel by different pharmaceutical companies. In this analysis, we noted that four MEK inhibitors and nine drugs targeting the PI3K/AKT/mTOR pathway were all waivered. Additionally, at least six ALK inhibitors (three already commercialised), more than eight PD-1 or PD-L1 immune checkpoint inhibitors, five MEK inhibitors, and four PARP inhibitors are in development. With the small numbers of children eligible for early-phase and late-phase studies, undertaking full (and similar) development programmes for all drugs with a relevant mechanism of action would not be feasible. Choosing the most promising drugs will be essential to ensure the feasibility and efficiency of a mechanism of action-based model. Many paediatric malignancies have many different drugs developed in adults that have a relevant mechanism of action. For example, the portfolio of oncology drugs developed in B-cell malignancies in adults is increasing rapidly, with compounds and immunotherapies targeting both the leukaemic cell phenotypes, such as CD20 or CD22, and genetic aberrations such as MEK, FLT3, and PI3K. 21 However, therapy combining rituximab, a CD20 monoclonal antibody, and multidrug cytotoxic chemotherapy 22 in children with B-cell non-Hodgkin lymphoma results in an overall survival of 94% with very few relapsed patients. 22 The most promising drugs or cellular therapies need to be chosen, and a strategy established to ensure that patients who die of B-cell malignancy will have innovative therapies proposed. Furthermore, toxic therapy elements should be replaced with less toxic elements while maintaining responses in these malignancies, which requires a different development perspective. The ACCELERATE multistakeholder platform is currently piloting a new concept to facilitate the identification of new oncology drugs for children. Paediatric strategy forums will provide an opportunity for interaction and discussion between all stakeholders (regulators, pharmaceutical companies, scientists, clinical academics, and patient representatives) at a precompetitive level, on topics that might cause a problem from an industry or academic standpoint, in paediatric or adolescent cancer drug development. In a paediatric strategy forum, the epidemiology, clinical features, and biology of the malignancy targeted by the drugs should be reviewed, followed by a presentation by the relevant pharmaceutical company of any preclinical data pertaining to paediatric tumours, pharmacokinetic and safety data in adults, and (if available) clinical data in children for their compound. The output of a paediatric strategy forum should be a perspective that that will enable all stakeholders to have an overview of the landscape with the same level of knowledge. This perspective will facilitate the sharing of information and advance learning, which will help inform subsequent drug development strategic (including regulatory) decisions. These forums should be implemented early in the drug development process because class-specific developments should be harmonised early on in the drug development stage and to prevent delays. We believe that the increased and shared knowledge of each participant at a paediatric strategy forum, including all pharmaceutical companies with relevant drugs in development, will help facilitate paediatric development plans and prioritisation when multiple compounds of the same class exist. In view of the scarcity of paediatric cancer and the current advances in molecular subtyping of molecularly subtyping, paediatric drug development professionals in national and international academic clinical cooperative groups should work closely together through collaboration and coordination of clinical studies. Ideally, worldwide studies for patient populations with rare diseases should be done and international regulatory coordination should be increased. We propose that drug development in paediatric oncology should be based on science and preclinical data relating to the importance of a given drug's mechanism of action, in addition to unmet paediatric therapeutic needs, independent of the adult condition for which the drug will be marketed. A mechanism-driven paediatric drug development programme should be adopted with the suppression of article 11b of the European Paediatric Regulation to enable the implementation of mechanism of action-based PIPs. Molecular profiling of all paediatric tumours should be done at diagnosis and relapse, using a database of tumour targets, a joint pharmaceutical academic–industry preclinical platform to analyse the activity of new drugs, and paediatric strategy forums. These actions will increase the numbers of new drugs and improve the efficiency of introducing them rapidly into front-line therapy for children with life-threatening diseases. Furthermore, a more efficient drug development process will also benefit the pharmaceutical industry by avoiding unnecessary duplication of efforts, but more importantly, it will bring tangible benefit to children and adolescents with cancer. Through such efforts, the original aspiration of the European Paediatric Medicine Regulation to substantially increase the number of new oncology drugs developed for children and adolescents can be realised. Contributors ADJP, SMP, and GV were involved in the study design and literature search. ADJP, SMP, AB, J-PB, MC, LC, FD, AE, BG, DTWJ, PRK, JJM, BM, GS, JHS, JV, CMZ, and GV collected the data. All authors did the interpretation and analysis of the data, and writing, reviewing, and approval of the manuscript. Declaration of interests ADJP was on the international advisory board for Boehringer Ingelheim. AB reports grants from Baxalta and personal fees from Jazz, Roche, and Novartis. J-PB was on the advisory board for Roche. MC has served on international advisory boards for Boehringer Ingelheim, Roche, and Bayer. FD reports financial support for a meeting attendance from Novartis; was on an advisory board for Novartis; and was an investigator for Bayer, Novartis, and Roche. AE reports personal fees from Bayer. BG was on the international advisory boards for Bayer and Roche. PRK reports research funding or provision of drugs from Johnson & Johnson, Celgene, Bayer, and Bristol-Myers Squibb; and was on an advisory board for Johnson & Johnson, AstraZeneca, Pfizer, Gilead, and Roche. JV is on the advisory board for Roche and Abbvie. CMZ was on an international advisory board for Pfizer, Bristol-Myers Squibb, Jazz Pharmaceuticals, Celgene, Novartis, Janssen, and Medac. SMP, LC, DTWJ, JJM, BM, GS, JHS, LVM, and GV declare no competing interests. Acknowledgments Carole Lecinse and Gynette Cook for administrative assistance. Publisher Copyright: © 2017 Elsevier Ltd

PY - 2017/7

Y1 - 2017/7

N2 - New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed for 89 drugs. Mechanisms of action were then assessed as potential paediatric therapeutic targets by both a literature search and an expert review. 48 (54%) of the 89 class-waivered drugs had a mechanisms of action warranting paediatric development. Two (2%) class-waivered drugs were considered not relevant and 16 (18%) required further data. In light of these results, we propose five initiatives: an aggregated database of paediatric biological tumour drug targets; molecular profiling of all paediatric tumours at diagnosis and relapse; a joint academic-pharmaceutical industry preclinical platform to help analyse the activity of new drugs (Innovative Therapy for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform); paediatric strategy forums; and the suppression of article 11b of the European Paediatric Regulation, which allows product-specific waivers on the grounds that the associated condition does not occur in children. These initiatives and a mechanism of action-based approach to drug development will accelerate the delivery of new therapeutic drugs for front-line therapy for those children who have unmet medical needs.

AB - New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed for 89 drugs. Mechanisms of action were then assessed as potential paediatric therapeutic targets by both a literature search and an expert review. 48 (54%) of the 89 class-waivered drugs had a mechanisms of action warranting paediatric development. Two (2%) class-waivered drugs were considered not relevant and 16 (18%) required further data. In light of these results, we propose five initiatives: an aggregated database of paediatric biological tumour drug targets; molecular profiling of all paediatric tumours at diagnosis and relapse; a joint academic-pharmaceutical industry preclinical platform to help analyse the activity of new drugs (Innovative Therapy for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform); paediatric strategy forums; and the suppression of article 11b of the European Paediatric Regulation, which allows product-specific waivers on the grounds that the associated condition does not occur in children. These initiatives and a mechanism of action-based approach to drug development will accelerate the delivery of new therapeutic drugs for front-line therapy for those children who have unmet medical needs.

KW - Adolescent

KW - Antineoplastic Agents/pharmacology

KW - Biological Products/therapeutic use

KW - Child

KW - Child, Preschool

KW - Drug Discovery/legislation & jurisprudence

KW - Europe

KW - Humans

KW - Infant

KW - Infant, Newborn

KW - Legislation, Drug

KW - Neoplasms/drug therapy

KW - Precision Medicine

UR - http://www.scopus.com/inward/record.url?scp=85028073306&partnerID=8YFLogxK

U2 - 10.1016/S1470-2045(17)30442-4

DO - 10.1016/S1470-2045(17)30442-4

M3 - Review article

C2 - 28677575

SN - 1470-2045

VL - 18

SP - e394-e404

JO - LANCET ONCOLOGY

JF - LANCET ONCOLOGY

IS - 7

ER -

From class waivers to precision medicine in paediatric oncology

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