The European Pediatric Medicine Regulation was launched in 2007 to provide better medicines for children. Five years later, the number of new anticancer drugs in early development in the pediatric population remains low, and most children with cancer are still largely denied access to innovative drugs in Europe, as compared with the United States. We analyzed individual pediatric investigation plan (PIP) and waiver decisions for oncology drugs and all oncology drugs that have been approved for marketing authorization since 2007 in Europe. Among the 45 approved PIPs, 33% concern leukemias and lymphomas, 29% solid tumors, 13% brain tumors, and 20% a drug for supportive care. No specific PIP exists for life-threatening diseases such as high-risk neuroblastoma, whereas there are several PIPs in extremely rare malignancies in children and adolescents such as gastrointestinal stromal tumor, melanoma, thyroid cancer, and chronic myeloid leukemia. This paradoxical situation is due to approval of a PIP being driven by the adult indication. Twenty-six of 28 authorized new oncology drugs have a potentially relevant mechanism of action for pediatric malignancies, but 50% have been waived because the adult condition does not occur in children. The most striking example is crizotinib. Implementation of the pediatric regulation should no longer be driven by the adult indication but should be guided instead by the biology of pediatric tumors and the mechanism of action of a drug. This change will be achievable through voluntary PIPs submitted by Pharma or revocation of the oncology class waiver list. Clin Cancer Res; 19(6); 1315–25. ©2013 AACR.

On January 26, 2007, the Pediatric Medicine regulation was launched in Europe to provide better medicines for children (1). This regulation is based on rewards, incentives, and obligations for pharmaceutical companies.

In brief, the marketing-authorization application for a new medicinal product (or a new indication, new pharmaceutical form, or new route of administration) must include the results of studies conducted in the pediatric population in compliance with an agreed pediatric investigation plan (PIP). The development can be deferred until sufficient data are available to show the efficacy and safety of the product in adults (deferral). Waivers may be granted when a pediatric development is not needed or not appropriate (for example, when a disease, such as Alzheimer disease, does not occur in the pediatric age group). Once authorization is obtained and study results are included in the product information, even when results are negative, the medicine is eligible for a 6-month supplementary protection certificate (SPC) extension.

The regulation was expected to facilitate access to anticancer drugs that are in development in adults and to increase significantly the number of those drugs in clinical development for children and adolescents in Europe (2). As a result, in the pediatric oncology community, there was great anticipation and hope for children suffering with cancer. Despite major improvements in the treatment of pediatric malignancies (up to 80% of children with cancer can be cured with current therapies; ref. 3), cancer remains the most common cause of death by disease in children over the age of 1 year. Each year, 3,000 children and adolescents die of cancer in Europe (4). Thus, an urgent need remains for new effective and safe drugs.

After nearly 5 years of the regulation being in place (as of June 2012), 45 PIPs have been approved for 43 oncology drugs (5). Oncology has the second highest number of PIPs after endocrinology (6).

However, the number of new oncology drugs in pediatric early-phase trials remains low in Europe, and most pediatric patients with a relapsed or refractory disease unlikely to be cured with conventional therapy are still denied access to an innovative drug in clinical trials. This situation raises major safety, ethical, and societal concerns. When a new drug is not available in a clinical trial, European pediatric oncologists are often compelled to prescribe it off-label. Moreover, many parents are tempted to go to the United States to have their child participate in a clinical trial with innovative drugs that may represent a “last hope” for many families. Possibly as a result of the National Cancer Institute—Clinical Therapy Evaluation Program (NCI-CTEP), a publicly funded academic program to develop drugs that are provided free by pharmaceutical companies, a significantly larger number of drugs are being investigated in early trials in the United States than in Europe. Parents often make major sacrifices to cover the cost for such treatments, feeling that they “need to have done everything possible” before accepting a palliative outcome.

What are the reasons for this paradoxical situation: a reasonable number of oncology PIPs approved but no significant increase in new drugs in clinical development in Europe? The purpose of this article is to analyze current publicly available information about PIPs and waivers for oncology drugs to answer this question and to propose solutions to improve the current situation.

The European Medicine Agency's (EMA) decision on a PIP, a waiver, or a modification of an agreed PIP is publicly available on the EMA website for each individual product (5). For each PIP, the decision describes the pediatric conditions and indications, the subset(s) of the pediatric population required by the pediatric development (mainly age ranges), and the titles of the studies to be conducted. The start of some of these studies may be deferred. The need for long-term follow-up and the date for completion of the PIP are stated.

We analyzed all individual decisions for oncology drugs and drugs for supportive care to assess whether these PIPs meet the needs of children with cancer.

A waiver for development in children can be issued when a drug is (i) likely to be ineffective or unsafe in part or all of the pediatric population, (ii) intended for conditions that occur only in adult populations, or (iii) does not represent a significant therapeutic benefit over existing treatments for pediatric patients. To facilitate and speed up the process, a list of conditions that occur only in the adult population has been adopted by the Pediatric Committee (class waiver list; Table 1), and all drugs intended to treat these conditions are exempt from the requirement for a PIP.

Table 1.

List of class waiver: malignancies not occurring in children [from the EMA website (5)]

  • Treatment of adenocarcinoma of the colon and rectum

  • Treatment of adenocarcinoma of the pancreas

  • Treatment of basal cell carcinoma

  • Treatment of breast carcinoma

  • Treatment of cervix and corpus uteri carcinoma

  • Treatment of chronic lymphocytic leukemia

  • Treatment of endometrial carcinoma

  • Treatment of fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumors)

  • Treatment of follicular lymphoma

  • Treatment of gastric adenocarcinoma

  • Treatment of gastric carcinoids

  • Treatment of gastroenteropancreatic neuroendocrine tumors (excluding neuroblastoma, neuroganglioblastoma, andpheochromocytoma)

  • Treatment of hairy cell leukemia

  • Treatment of kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma, and rhabdoid tumors of the kidney)

  • Treatment of liver and intrahepatic bile duct carcinoma (excluding hepatoblastoma)

  • Treatment of lung carcinoma (small cell and non–small cell carcinoma)

  • Treatment of melanoma (from 0 to less than 12 years old)

  • Treatment of primary myelofibrosis

  • Treatment of mesothelioma

  • Treatment of melanoma (from 12 to less than 18 years old; revoked July 14, 2008)

  • Treatment of multiple myeloma

  • Treatment of oropharyngeal, laryngeal, or nasal epithelial carcinoma (excluding nasopharyngeal carcinoma or lymphoepithelioma)

  • Treatment of ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumors)

  • Treatment of peritoneal carcinoma (excluding blastomas and sarcomas)

  • Treatment of prostate carcinoma (excluding rhabdomyosarcoma)

  • Treatment of ureter and bladder carcinoma

  • Treatment of vaginal and vulvar carcinoma (excluding rhabdomyosarcoma and soft tissue sarcoma)

  • Treatment of vulvar intraepithelial neoplasia

 
  • Treatment of adenocarcinoma of the colon and rectum

  • Treatment of adenocarcinoma of the pancreas

  • Treatment of basal cell carcinoma

  • Treatment of breast carcinoma

  • Treatment of cervix and corpus uteri carcinoma

  • Treatment of chronic lymphocytic leukemia

  • Treatment of endometrial carcinoma

  • Treatment of fallopian tube carcinoma (excluding rhabdomyosarcoma and germ cell tumors)

  • Treatment of follicular lymphoma

  • Treatment of gastric adenocarcinoma

  • Treatment of gastric carcinoids

  • Treatment of gastroenteropancreatic neuroendocrine tumors (excluding neuroblastoma, neuroganglioblastoma, andpheochromocytoma)

  • Treatment of hairy cell leukemia

  • Treatment of kidney and renal pelvis carcinoma (excluding nephroblastoma, nephroblastomatosis, clear cell sarcoma, mesoblastic nephroma, renal medullary carcinoma, and rhabdoid tumors of the kidney)

  • Treatment of liver and intrahepatic bile duct carcinoma (excluding hepatoblastoma)

  • Treatment of lung carcinoma (small cell and non–small cell carcinoma)

  • Treatment of melanoma (from 0 to less than 12 years old)

  • Treatment of primary myelofibrosis

  • Treatment of mesothelioma

  • Treatment of melanoma (from 12 to less than 18 years old; revoked July 14, 2008)

  • Treatment of multiple myeloma

  • Treatment of oropharyngeal, laryngeal, or nasal epithelial carcinoma (excluding nasopharyngeal carcinoma or lymphoepithelioma)

  • Treatment of ovarian carcinoma (excluding rhabdomyosarcoma and germ cell tumors)

  • Treatment of peritoneal carcinoma (excluding blastomas and sarcomas)

  • Treatment of prostate carcinoma (excluding rhabdomyosarcoma)

  • Treatment of ureter and bladder carcinoma

  • Treatment of vaginal and vulvar carcinoma (excluding rhabdomyosarcoma and soft tissue sarcoma)

  • Treatment of vulvar intraepithelial neoplasia

 

When analyzing individual decisions on a waiver as published on the website, it seems that information was not available about drugs that were known to be class waived. Because any drug approved after 2006 must have an agreed PIP or a waiver at the time of filing for marketed authorization, we analyzed the status of all oncology drugs approved since 2007 using information publicly available on the EMA website, and we cross-analyzed with the list of products with a PIP or a known waiver. This was an attempt to identify which drugs were likely to be class waived before filing for a marketed authorization in adults.

As of June 2012, 45 PIPs had been approved for 43 oncology drugs (Table 2). These included 15 PIPs (33%) for the treatment of leukemias and/or lymphomas, 13 PIPs (29%) for malignant solid tumors, and 6 PIPs (13%) for the treatment of brain tumors. Nine PIPs (20%) concerned a medicine for supportive care to treat such symptoms or conditions as nausea and vomiting, secondary thrombopenia and anemia, tumor-lysis–related hyperuricemia, and mobilization of hematopoietic stem cells. The median duration of a PIP was 6 years, with a range from 1.5 to 26 years. The start had been deferred for 82% of these PIPs. No information is available on the current status of all PIPs. As of June 2012, 8 PIPs were supposed to be completed, whereas the remaining 37 PIPs still had a median of 73% of their duration to run.

Table 2.

Approved PIPs in pediatric oncology (as of June 2012)

ConditionAgentCompanyPediatric indicationDate
Brain tumors Cediranib AstraZeneca High-grade glioma June 2, 2010 
 Cilengitide Merck KGA High-grade glioma August 30, 2011 
 Bevacizumab Roche High-grade glioma March 11, 2011 
 AdenoTK ARK Therapeutics High-grade glioma May 23, 2008 
 Veliparib Abbot High-grade glioma April 8, 2011 
 Everolimus Novartis Subependymal astrocytoma December 5, 2008 
Leukemias and lymphomas l-Asparaginase erythro ERYtech Pharma ALL October 29, 2010 
 Imatinib Novartis ALL December 2, 2009 
 6-Mercaptopurine Stallegernes ALL April 20, 2009 
 Elacytarabine Clavis Pharma Acute myeloid leukemia February 28, 2012 
 Decitabine Jansen-Cilag Acute myeloid leukemia March 4, 2011 
 Midostaurin Novartis Acute myeloid leukemia January 3, 2011 
 Nilotinib Novartis Chronic myeloid leukemia March 27, 2009 
 Bosutinib Wyeth Chronic myeloid leukemia September 3, 2010 
 Dasatinib Bristol-Myers Squib Chronic myeloid leukemia and Philadelphia+ ALL November 3, 2009 
 L-Asparaginase Medac ALL and non-Hodgkin lymphoma February 1, 2008 
 ABT263 (anti-bcl2) Abbot ALL and non-Hodgkin lymphoma December 14, 2009 
 SGN-35 Takeda Hodgkin and non-Hodgkin lymphoma February 21, 2011 
 Pralatrexate Allotherapeutics Non-Hodgkin lymphoma December 2, 2010 
 Rituximab Roche Non-Hodgkin lymphoma July 14, 2009 
 Docetaxel Sanofi-Aventis Nasopharyngeal carcinoma May 16, 2008 
Solid tumors Sunitinib Pfizer GIST February 24, 2009 
 Ipilimumab Bristol-Myers Squib Melanoma June 8, 2011 
 Vemurafenib Roche Melanoma April 8, 2011 
 Dabrafenib GlaxoSmithKline Melanoma and solid tumors February 27, 2012 
 Trametinib GlaxoSmithKline Melanoma and solid tumors February 28, 2012 
 Ombrabuline Sanofi-Aventis Rhabomyosarcoma June 7, 2011 
 IGF-IR MoAb Roche Ewing tumors April 20, 2009 
 Pazopanib GlaxoSmithKline Rhabdomyosarcoma and Ewing tumors January 3, 2011 
 Bevacizumab Roche Rhabdomyosarcoma October 1, 2008 
 Linifanib (ABT869) Abbot Solid tumors July 15, 2009 
 Ipilimumab Bristol-Myers Squib Solid tumors November 3, 2008 
 Deforolimus Merck Sharpe Dome Solid tumors January 25, 2010 
 Vandetanib Bristol-Myers Squib Thyroid cancer November 3, 2008 
Mixed conditions Cyclophosphamide Keocyt Malignant diseases January 27, 2012 
 Pixantrone CTI Life Non-Hodgkin lymphoma and solid tumors January 16, 2010 
 Treosulfan Medac Hematopoietic stem cell transplantation conditioning June 7, 2011 
Supportive care Darbopoietin Amgen Anemia March 11, 2011 
 Denosumab Amgen Bone metastasis October 14, 2008 
 Plerixafor Genzyme Mobilization of hematopoietic stem cells February 23, 2009 
 Pegloticase Savient Pharmaceuticals Hyperuricemia January 28, 2011 
 Elthrombopag GlaxoSmithKline Secondary thrombopenia September 30, 2011 
 Casopitant GlaxoSmithKline Vomiting January 27, 2009 
 Aprepitant Merck Sharpe Dome Vomiting November 3, 2008 
 Fosaprepitant Merck Sharpe Dome Vomiting July 15, 2009 
ConditionAgentCompanyPediatric indicationDate
Brain tumors Cediranib AstraZeneca High-grade glioma June 2, 2010 
 Cilengitide Merck KGA High-grade glioma August 30, 2011 
 Bevacizumab Roche High-grade glioma March 11, 2011 
 AdenoTK ARK Therapeutics High-grade glioma May 23, 2008 
 Veliparib Abbot High-grade glioma April 8, 2011 
 Everolimus Novartis Subependymal astrocytoma December 5, 2008 
Leukemias and lymphomas l-Asparaginase erythro ERYtech Pharma ALL October 29, 2010 
 Imatinib Novartis ALL December 2, 2009 
 6-Mercaptopurine Stallegernes ALL April 20, 2009 
 Elacytarabine Clavis Pharma Acute myeloid leukemia February 28, 2012 
 Decitabine Jansen-Cilag Acute myeloid leukemia March 4, 2011 
 Midostaurin Novartis Acute myeloid leukemia January 3, 2011 
 Nilotinib Novartis Chronic myeloid leukemia March 27, 2009 
 Bosutinib Wyeth Chronic myeloid leukemia September 3, 2010 
 Dasatinib Bristol-Myers Squib Chronic myeloid leukemia and Philadelphia+ ALL November 3, 2009 
 L-Asparaginase Medac ALL and non-Hodgkin lymphoma February 1, 2008 
 ABT263 (anti-bcl2) Abbot ALL and non-Hodgkin lymphoma December 14, 2009 
 SGN-35 Takeda Hodgkin and non-Hodgkin lymphoma February 21, 2011 
 Pralatrexate Allotherapeutics Non-Hodgkin lymphoma December 2, 2010 
 Rituximab Roche Non-Hodgkin lymphoma July 14, 2009 
 Docetaxel Sanofi-Aventis Nasopharyngeal carcinoma May 16, 2008 
Solid tumors Sunitinib Pfizer GIST February 24, 2009 
 Ipilimumab Bristol-Myers Squib Melanoma June 8, 2011 
 Vemurafenib Roche Melanoma April 8, 2011 
 Dabrafenib GlaxoSmithKline Melanoma and solid tumors February 27, 2012 
 Trametinib GlaxoSmithKline Melanoma and solid tumors February 28, 2012 
 Ombrabuline Sanofi-Aventis Rhabomyosarcoma June 7, 2011 
 IGF-IR MoAb Roche Ewing tumors April 20, 2009 
 Pazopanib GlaxoSmithKline Rhabdomyosarcoma and Ewing tumors January 3, 2011 
 Bevacizumab Roche Rhabdomyosarcoma October 1, 2008 
 Linifanib (ABT869) Abbot Solid tumors July 15, 2009 
 Ipilimumab Bristol-Myers Squib Solid tumors November 3, 2008 
 Deforolimus Merck Sharpe Dome Solid tumors January 25, 2010 
 Vandetanib Bristol-Myers Squib Thyroid cancer November 3, 2008 
Mixed conditions Cyclophosphamide Keocyt Malignant diseases January 27, 2012 
 Pixantrone CTI Life Non-Hodgkin lymphoma and solid tumors January 16, 2010 
 Treosulfan Medac Hematopoietic stem cell transplantation conditioning June 7, 2011 
Supportive care Darbopoietin Amgen Anemia March 11, 2011 
 Denosumab Amgen Bone metastasis October 14, 2008 
 Plerixafor Genzyme Mobilization of hematopoietic stem cells February 23, 2009 
 Pegloticase Savient Pharmaceuticals Hyperuricemia January 28, 2011 
 Elthrombopag GlaxoSmithKline Secondary thrombopenia September 30, 2011 
 Casopitant GlaxoSmithKline Vomiting January 27, 2009 
 Aprepitant Merck Sharpe Dome Vomiting November 3, 2008 
 Fosaprepitant Merck Sharpe Dome Vomiting July 15, 2009 

Abbreviations: ALL, acute lymphoblastic leukemia; IGF-IR, insulin-like growth factor I receptor; MoAb, monoclonal antibody.

PIPs have been approved for extremely rare malignancies in children such as chronic myeloid leukemia (CML), metastatic melanoma, gastrointestinal stromal tumor (GIST), and thyroid cancer. In some cases (e.g., CML), more than one drug has been approved for subsequent pediatric investigation. Indeed, these drugs have shown activity in these diseases in adults. This raises the issue of feasibility, in particular when several PIPs have to be run in parallel in malignancies occurring extremely rarely in children. The implementation of 6 PIPs (l-asparaginase, anti-Bcl2 ABT 263, pralatrexate, rituximab, SGN35, and pixantrone) for non-Hodgkin lymphomas may prove to be challenging as well. The current cure rate in non-Hodgkin lymphomas is high (more than 90%), and patients with relapsed or refractory disease eligible for new drug trials are rare. Only one PIP (approved in December 2008) has been successfully completed, leading to a full-marketed authorization. Everolimus (Votubia) was authorized in September 2011 for the treatment of subependymal giant cell astrocytoma associated with tuberous sclerosis complex in patients over the age of 3 years.

From July 2007 until June 2012, the marketed authorization of 28 new oncology drugs (generic compounds and drugs for supportive care excluded) has been approved by the EMA (Table 3). Only 2 drugs have a mechanism of action that is not relevant to a pediatric malignancy. Abiraterone is an androgen-biosynthesis inhibitor. Tegafur is 5-fluorouracil prodrug, and we know that 5-fluorouracil has little or no activity in pediatric malignancies. Among the 26 drugs with a potentially relevant mechanism of action, 4 drugs (15%) have been approved for use in children, namely everolimus, nelarabine, thiotepa, and an oral suspension of 6-mercaptopurine. At least one PIP has been approved for 8 of these drugs (30%). However, 14 drugs with a potentially relevant mechanism of action (50%) have been waived, with the vast majority having been class waived.

Table 3.

Status of new oncology drugs approved by the EMA since 2007 with regard to their development in children and adolescent

Common nameMedicine nameMarketing authorization holderYearIndication in adultsApproved for use in childrenPIPPediatric indication in the PIPPublished waiverCommentIs the mechanism of action potentially relevant for pediatric malignancies?
Everolimus Votubia Novartis Europharm Ltd. 2011  SEGA associated with tuberous sclerosis complex Drug authorized for treatment of patients ages 3 years and older; authorization was based on the completion of a PIP 
Nelarabine Atriance Glaxo Group Ltd. 2007  T-cell ALL and T-cell lymphoblastic lymphoma Drug indicated in children for the treatment of the same condition 
Thiotepa Tepadina Adienne Srl 2010  HPCT in hematologic diseases and solid tumors in adult and pediatric patients Drug indicated in children for the treatment of hematologic malignancies and malignant solid tumors 
6-Mercaptopurine monohydrate Xaluprine Nova Laboratories Ltd. 2012  ALL in adults, adolescents and children. First oral suspension of 6-mercaptopurine 
Ipilimumab Yervoy Bristol-Myers Squibb Pharma EEIG 2011 Advanced melanoma Melanoma; solid tumors  
Everolimus Afinitor Novartis Europharm Ltd. 2009 Neuroendocrine tumors and renal cell carcinoma SEGA associated with tuberous sclerosis complex Waiver in neuroendocrine tumors and renal cell carcinoma; a PIP was approved for SEGA 
Nilotinib Tasigna Novartis Europharm Ltd. 2007 Philadelphia-chromosome-positive chronic myelogenous leukemia Chronic myelogenous leukemia  
Plerixafor Mozobil Genzyme Europe B.V. 2009 Mobilization of hematopoietic stem cells Mobilization of hematopoietic stem cells  
Pazopanib Votrient Glaxo Group Ltd. 2010 Renal cell carcinoma Soft tissue sarcomas A class waiver was issued for renal cancer. Then a PIP was approved when the drug was developed in adult sarcomas 
Pixantrone dimaleate Pixuvri CTI Life Sciences Ltd. 2012 Non-Hodgkin B-cell lymphoma NHL leukemia  
Vemurafenib Zelboraf Roche Registration Ltd. 2012 BRAF V600 mutation-positive unresectable or metastatic melanoma BRAF V600 mutation-positive metastatic melanoma Pediatric tumors other than melanoma have B-RAF mutations 
Vandetanib Caprelsa AstraZeneca AB 2012 Thyroid cancer Thyroid cancer  Vandetanib targets are altered in pediatric malignancies other than thyroid cancer 
Lenalidomide Revlimid Celgene Europe Ltd. 2007 Multiple myeloma  Immunomodulating agent; ongoing pediatric development 
Temsirolimus Torisel Pfizer Ltd. 2007 Renal-cell carcinoma  mTOR is a relevant target in pediatric malignancies; ongoing pediatric development 
Lapatinib Tyverb Glaxo Group Ltd. 2008 HER2-positive (ErbB2) breast cancer (ErbB2):  Inhibitor of EGFR and HER2-neu receptors 
Panitumumab Vectibix Amgen Europe B.V. 2007 Wild-type KRAS metastatic colorectal cancer  Monoclonal antibody inhibiting the EGFR TK receptor 
Trabectedin Yondelis Pharma Mar S.A. 2007 Advanced soft tissue sarcoma  Cytotoxic compound to be evaluated in children; ongoing development in children with solid malignancies 
Nab-paclitaxel Abraxane Celgene Europe Ltd. 2008 Metastatic breast cancer  Cytotoxic compound that proved to be more active than paclitaxel 
Thalidomide Thalidomide Celgene Celgene Europe Ltd. 2008 Multiple myeloma  Immunomodulating agent 
Azacitidine Vidaza Celgene Europe Ltd. 2008 Myelodysplastic syndromes, chronic myelomonocytic leukemia, acute myeloid leukemia  Ongoing development in children with leukemias 
Vinflunine Javlor Pierre Fabre Médicament 2009 Transitional cell carcinoma of the urothelial tract  Vinca-alkaloids are a major class of drugs in the treatment of several pediatric malignancies 
Gefitinib Iressa AstraZeneca AB 2009 Non–small cell lung carcinoma with activating mutations of EGFR-TK  Ongoing development in children with solid tumors 
Ofatumumab Arzerra Glaxo Group Ltd 2010 Chronic lymphocytic leukemia  An anti-CD20 monoclonal antibody; CD20 is expressed on B lymphocytes and B-cell tumors (CLL and NHL) 
Cabazitaxel Jevtana Sanofi-Aventis group 2011 Hormone-refractroy metastatic prostate cancer  A taxoid that crosses blood brain barrier. Studies in children are warranted 
Eribulin mesylate Halaven Eisai Europe Ltd. 2011 Metastatic breast cancer  Tubulin-based antimitotic drug 
Axitinib Inlyta Pfizer Ltd. 2012 Renal cell carcinoma  Angiogenesis is a major therapeutic target in pediatric malignancies as well 
Tegafur/gimeracil/oteracil Teysuno Nordic Group BV 2011 Advanced gastric cancer  5-Fluorouracil did not show antitumor activity in pediatric malignancies 
Abiraterone acetate Zytiga Janssen-Cilag International N.V. 2011 Metastatic castration-resistant prostate cancer  Androgen biosynthesis inhibitor; mechanism of action is not relevant for pediatric malignancies 
Common nameMedicine nameMarketing authorization holderYearIndication in adultsApproved for use in childrenPIPPediatric indication in the PIPPublished waiverCommentIs the mechanism of action potentially relevant for pediatric malignancies?
Everolimus Votubia Novartis Europharm Ltd. 2011  SEGA associated with tuberous sclerosis complex Drug authorized for treatment of patients ages 3 years and older; authorization was based on the completion of a PIP 
Nelarabine Atriance Glaxo Group Ltd. 2007  T-cell ALL and T-cell lymphoblastic lymphoma Drug indicated in children for the treatment of the same condition 
Thiotepa Tepadina Adienne Srl 2010  HPCT in hematologic diseases and solid tumors in adult and pediatric patients Drug indicated in children for the treatment of hematologic malignancies and malignant solid tumors 
6-Mercaptopurine monohydrate Xaluprine Nova Laboratories Ltd. 2012  ALL in adults, adolescents and children. First oral suspension of 6-mercaptopurine 
Ipilimumab Yervoy Bristol-Myers Squibb Pharma EEIG 2011 Advanced melanoma Melanoma; solid tumors  
Everolimus Afinitor Novartis Europharm Ltd. 2009 Neuroendocrine tumors and renal cell carcinoma SEGA associated with tuberous sclerosis complex Waiver in neuroendocrine tumors and renal cell carcinoma; a PIP was approved for SEGA 
Nilotinib Tasigna Novartis Europharm Ltd. 2007 Philadelphia-chromosome-positive chronic myelogenous leukemia Chronic myelogenous leukemia  
Plerixafor Mozobil Genzyme Europe B.V. 2009 Mobilization of hematopoietic stem cells Mobilization of hematopoietic stem cells  
Pazopanib Votrient Glaxo Group Ltd. 2010 Renal cell carcinoma Soft tissue sarcomas A class waiver was issued for renal cancer. Then a PIP was approved when the drug was developed in adult sarcomas 
Pixantrone dimaleate Pixuvri CTI Life Sciences Ltd. 2012 Non-Hodgkin B-cell lymphoma NHL leukemia  
Vemurafenib Zelboraf Roche Registration Ltd. 2012 BRAF V600 mutation-positive unresectable or metastatic melanoma BRAF V600 mutation-positive metastatic melanoma Pediatric tumors other than melanoma have B-RAF mutations 
Vandetanib Caprelsa AstraZeneca AB 2012 Thyroid cancer Thyroid cancer  Vandetanib targets are altered in pediatric malignancies other than thyroid cancer 
Lenalidomide Revlimid Celgene Europe Ltd. 2007 Multiple myeloma  Immunomodulating agent; ongoing pediatric development 
Temsirolimus Torisel Pfizer Ltd. 2007 Renal-cell carcinoma  mTOR is a relevant target in pediatric malignancies; ongoing pediatric development 
Lapatinib Tyverb Glaxo Group Ltd. 2008 HER2-positive (ErbB2) breast cancer (ErbB2):  Inhibitor of EGFR and HER2-neu receptors 
Panitumumab Vectibix Amgen Europe B.V. 2007 Wild-type KRAS metastatic colorectal cancer  Monoclonal antibody inhibiting the EGFR TK receptor 
Trabectedin Yondelis Pharma Mar S.A. 2007 Advanced soft tissue sarcoma  Cytotoxic compound to be evaluated in children; ongoing development in children with solid malignancies 
Nab-paclitaxel Abraxane Celgene Europe Ltd. 2008 Metastatic breast cancer  Cytotoxic compound that proved to be more active than paclitaxel 
Thalidomide Thalidomide Celgene Celgene Europe Ltd. 2008 Multiple myeloma  Immunomodulating agent 
Azacitidine Vidaza Celgene Europe Ltd. 2008 Myelodysplastic syndromes, chronic myelomonocytic leukemia, acute myeloid leukemia  Ongoing development in children with leukemias 
Vinflunine Javlor Pierre Fabre Médicament 2009 Transitional cell carcinoma of the urothelial tract  Vinca-alkaloids are a major class of drugs in the treatment of several pediatric malignancies 
Gefitinib Iressa AstraZeneca AB 2009 Non–small cell lung carcinoma with activating mutations of EGFR-TK  Ongoing development in children with solid tumors 
Ofatumumab Arzerra Glaxo Group Ltd 2010 Chronic lymphocytic leukemia  An anti-CD20 monoclonal antibody; CD20 is expressed on B lymphocytes and B-cell tumors (CLL and NHL) 
Cabazitaxel Jevtana Sanofi-Aventis group 2011 Hormone-refractroy metastatic prostate cancer  A taxoid that crosses blood brain barrier. Studies in children are warranted 
Eribulin mesylate Halaven Eisai Europe Ltd. 2011 Metastatic breast cancer  Tubulin-based antimitotic drug 
Axitinib Inlyta Pfizer Ltd. 2012 Renal cell carcinoma  Angiogenesis is a major therapeutic target in pediatric malignancies as well 
Tegafur/gimeracil/oteracil Teysuno Nordic Group BV 2011 Advanced gastric cancer  5-Fluorouracil did not show antitumor activity in pediatric malignancies 
Abiraterone acetate Zytiga Janssen-Cilag International N.V. 2011 Metastatic castration-resistant prostate cancer  Androgen biosynthesis inhibitor; mechanism of action is not relevant for pediatric malignancies 

Abbreviations: EGFR, EGF receptor; HPCT, hematopoietic progenitor cell transplantation; NHL, non-Hodgkin lymphoma; SEGA, subependymal giant cell astrocytoma; TK, tyrosine kinase.

Article 12 of the European regulation states that a waiver can be adopted when the disease or indication for which a drug is developed does not exist in children. The oncology class waiver list includes more than 20 adult malignancies that do not occur in children, such as breast cancer and kidney cancer (Table 1). A waiver can be claimed for any drug submitted for the treatment of these cancers in adults, even though its target or targeted pathway may have been established as potentially relevant for a pediatric malignancy.

The regulation seems to have simply ignored the fact that more than 90% of anticancer drugs used in pediatric malignancies to cure children are also used in adults but in different cancers. As an example, neuroblastoma is a pediatric malignancy of the sympathetic nervous system that occurs in young children. With current intensive multiagent chemotherapy and surgery, only 40% of children with a high-risk neuroblastoma are cured, and there is a major need for innovative therapies (7). Among the drugs used are anthracyclines, cyclophosphamide, cisplatin, and carboplatin, all of which are approved for breast, ovarian, or lung cancer. If the pediatric regulation would have been running for the past 30 years, a class waiver could potentially have been obtained and none of these drugs would have been studied in pediatric malignancies, including neuroblastoma. Fortunately, large academic phase III trials have been run in Europe and in the United States to establish standard treatments for high-risk neuroblastoma using those chemotherapy drugs that are not licensed in this disease, a practice widespread in pediatric medicine (8, 9). We cannot afford to allow the good intentions of the Pediatric Medicine regulation to hamper this academic endeavor.

In the United States, the Best Pharmaceuticals for Children Act (since 1997) is an incentive-based regulation that provides a patent extension for pharmaceutical companies providing information for the use of medicines in the pediatric population (1). This is a voluntary process based on an approved written request. The vast majority of oncology drugs with a written request were cytotoxic compounds, very few were innovative-targeted agents. In 2003, the Pediatric Research Equity Act (PREA) was passed to mandate the pediatric development of a medicine (excluding biologics) when relevant (1). However, the PREA refers only to drugs used for treatment of the same condition in adults and children. This is very much the same situation as the European class waiver list.

By way of an example, we can use crizotinib, a MET–ALK inhibitor, which proved to be an active treatment of lung cancer with an EML4–ALK translocation (10). The relevance to pediatrics is that NPM–ALK translocations are found in more than 60% of cases of anaplastic large cell lymphoma (ALCL), and ALK mutations are found in 8% to 10% of cases of sporadic neuroblastoma (11). The drug is approved for adult lung cancer in the United States and in Europe. Because lung cancer does not exist in children, the company was issued a class waiver in 2010, and no pediatric development was started in Europe. PREA waivers in the United States would similarly have resulted in crizotinib not being investigated in children. However, Best Pharmaceuticals for Children Act legislation resulted an a written request from the U.S. Food and Drug Administration (FDA) that was issued in 2010 and led to a phase I trial of crizotinib run by the Children's Oncology Group. The preliminary results showed responses (including prolonged complete remissions) in patients with ALK-mutated neuroblastoma and in ALCL (12). We are aware of 2 families who went from Europe to the United States to get access to crizotinib for their child. This is the perfect illustration of the negative impact of the class waiver list for children in Europe.

The European Union regulation is driven by the adult indication. This partly explains why there are 3 PIPs approved for the treatment of CML and 4 PIPs approved in metastatic melanoma, 2 rather common malignancies in adults but extremely rare malignancies in children. On the other hand, 50% of newly approved oncology drugs in Europe (since 2007) that exhibit a potentially relevant mechanism of action for pediatric malignancies have been class waived. We conclude that the implementation of the European Union pediatric regulation in pediatric oncology should no longer be driven by the adult indication. Because a revision of the regulation will not be considered before 2017, there is an urgent need to modify its implementation.

Pharmaceutical companies can submit a voluntary PIP, for example, an investigation plan to study a drug in a pediatric cancer that is different from the adult indication. The V600 BRAF mutation is found in 40% to 60% of melanomas. The incidences of melanoma in children (<12 years) and adolescents (>12 years) are 7 and 13 per million, respectively, and the overall survival is more than 90% (13). In children, V600 BRAF has been observed in gangliogliomas, pilocytic astrocytomas, pleomorphic xanthoastrocytoma (14), and Langherans cell histiocytosis (15). Vemurafenib is approved in the United States and Europe for the treatment of V600 BRAF–mutated melanoma (16), and a PIP has been approved but only for pediatric patients from 12 to less than 18 years old with V600 BRAF mutation–positive unresectable stage IIIC or stage IV melanoma (4). This PIP was based only on the adult indication rather than on the target.

Dabrafenib is another V600 BRAF inhibitor in development for use in melanoma. A voluntary PIP has been recently approved for dabrafenib in the indication of advanced V600 BRAF pediatric solid tumors, including melanoma in children over the age of 12 years (5). Thus, children with BRAF-mutated tumors will have access to a relevant targeted drug, and importantly the program will define whether dabrafenib is active in tumors other than melanoma as well.

Another way of improving the PIP process in pediatric oncology would be simply to revoke the EMA class waiver list and to consider the drug mechanism of action, using widespread existing knowledge of the biology of pediatric malignancies instead of the adult condition (17). As a result, an ALK inhibitor for the treatment of lung cancer would no longer be waived for a pediatric development in children with neuroblastoma or ALCL. We ask for science-driven PIPs that meet the needs of children with cancer.

Several international cooperative groups dedicated to early drug development, such as the Innovative Therapies for Children with Cancer European network, run a biology-driven new drug development strategy for children with cancer (18). This strategy is based on identification and validation of relevant targets in pediatric malignancies to choose and prioritize drugs to be developed in children through innovative designs using biomarkers. This strategy is in line with the voluntary PIP for dabrafenib, and it may become the rule if the class waiver list is revoked. We believe that the changes we are asking for will increase the feasibility and relevance of oncology PIPs. In addition, a significant increase in cooperation is needed between the cooperative groups, the regulatory agencies and the pharmaceutical companies to run biology-driven drug development and mechanism of action–based PIP. Then the European Union pediatric regulation will meet the needs of children with cancer and safe and effective innovative drugs will be introduced in standard care.

Pediatric development of anticancer drugs is now being actively affected by the European Pediatric Medicine Regulation worldwide. However, the regulation failed so far to facilitate an increase of early drug trials in Europe and many children with advanced malignancies are still denied access to innovative drugs. The process whereby PIPs are driven by the adult indication rather than by the biology of tumors and the mechanism(s) of action of the drug is a major barrier. Targeted voluntary PIPs as well as the revocation of the oncology class waiver list are potentially effective solutions. In addition, an increase in the early collaboration of EMA, Pediatric Committee, and pharmaceutical companies with the Pediatric Oncology Cooperative Groups as well as parents' advocacy groups is mandatory to ensure that PIPs are feasible, scientifically robust, and most importantly, meet the needs of children with cancer.

G. Vassal is a consultant/advisory board member of GSK and Roche. B. Geoerger is a consultant/advisory board member of GSK. No potential conflicts of interest were disclosed by the other author.

Conception and design: G. Vassal, B. Geoerger, B. Morland

Development of methodology: G. Vassal, B. Geoerger

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): G. Vassal, B. Geoerger

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): G. Vassal, B. Geoerger

Writing, review, and/or revision of the manuscript: G. Vassal, B. Geoerger, B. Morland

Study supervision: G. Vassal

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