Is the European Pediatric Medicine Regulation Working for Children and Adolescents with Cancer?

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.

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.

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.

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