The Unite2Cure team has composed the following letter, which has been sent to Mr. Andriukaitis, Health and Food Safety Commissioner, European Commission.
Dear Mr Andriukaitis,
We are writing regarding your reply to the letter (dated 10 November) in which MEPs Glenis Wilmott and Françoise Grossetête, draw attention to the failure of European legislation to address the needs of children with cancer.
We appreciate the time you took to review this issue but we strongly feel the need to respond to some of your comments, which in our view do not paint a realistic picture of childhood cancer drug development and, above all, fail to recognize the urgent needs of these young patients.
We all know that the development of new drugs, not just anti-cancer drugs, is a very challenging and risky endeavor and that, ultimately, it is dependent on research and development efforts that cannot be dependent upon legislative measures. We are also well aware that there are legislative tools, such as Orphan Drug legislation and the Paediatric Medicine Regulation that seek to promote, in one way or another, the development of new medicines for children. The point that should be clear by now is that these measures have a limited impact on childhood cancer drug development and this is the specific problem we would like to address. Just looking at the big picture without analyzing the details will not lead us anywhere.
Orphan drug incentives have been around since the early 80s in the US and were introduced a little later in Europe. It is now crystal clear that these incentives are not powerful enough to stimulate the development of new drugs for childhood cancer. If we look at the US experience, where more solid drug approval records are available, we see that over the past 20 years a total of 180 drugs were approved for the treatment of cancer in adults. During the same time only 3 were approved specifically to treat cancer in children. The record within the EU is even more dismal.
The current incentives provided by Orphan Drug Legislation are sufficiently powerful to support development of drugs for other rare conditions in children. However, for scientific and financial reasons, they fail to meet the needs of childhood cancer. These are very complex diseases to tackle and oncology drug development has on average the highest failure rate. On the other hand, rare genetic diseases are often more treatable because the pathology is driven by one or very few specific genetic drivers. This makes drug development relatively less risky. In economic terms, the tendency of these diseases to become chronic when treated increases the revenue potential of any new drug, which is also likely to be prescribed at a premium price. This financial return is harder to achieve with a paediatric cancer drug as the treatment times are generally shorter and the drugs are unlikely to qualify for premium price, particularly if the same drug is used in more common, adult cancers.
If the Orphan Drug Legislation incentives do not work for childhood cancer drug development, it is equally clear by now that the obligations and incentives envisaged in the Paediatric Medicine Regulation (PMR) do not work either and do not have any meaningful impact on the development of new drugs for children with cancer. Whereas the PMR has indeed stimulated an increase in R&D investment in many paediatric areas, it has failed to make an impact on childhood cancer.
This is not a matter of parental opinion. This is the unanimous conclusion of all key paediatric oncology stakeholders in the 2012 five-year review of the PMR and it is a conclusion that is supported by the very same data you produced to demonstrate impact of this legislation.
Let us be more specific.
As pointed out by Ms Wilmott and Ms Grossetête, up to 6000 children and adolescents die of cancer every year in Europe. We have made some progress in the treatment of certain cancers such as some forms of blood cancers (e.g. lymphomas, leukaemia). However, in a number of high risk cancers that are very specific to children and adolescents (cancers such as neuroblastoma, bone cancers such as Ewing’s Sarcoma and aggressive brain cancers in general), we have not seen any significant therapeutic improvement over the past two decades. These are diseases that take the biggest toll in terms of young patients’ lives on a yearly basis. These are the diseases for which new drug development is the most urgently needed.
Yet, these cancers are largely neglected by industry. In addition, the current legislation allows for waivers even when the science suggests a potential use of certain investigational drugs in specific childhood cancers on the basis of a common mechanism of action. In other words, we are missing opportunities to study compounds that may bring benefit to patients.
You quote some figures provided by EMA experts. The problem with this is that these are just numbers if they are not interpreted and analysed in the right context. You rightly state that more than 80 paediatric investigation plans (PIPs) have been agreed by the EMA Paediatric Committee. The exact number is actually 81 on the EMA website (accessed Jan 5, 2016 ). Actually only 10 of these positive decisions targeted at least one of those high risk cancers that primarily affect children, a mere 12% of the total study number.
It is true that a number of studies (16) involved haematological malignancies that do indeed frequently occur in children with cancer but for these diseases we generally already have some valid therapeutic alternatives, unlike for the above mentioned solid cancers. Furthermore, to put things in perspective, the biggest group (17 studies) is made up of studies that do not target cancer but, rather, side effects such as nausea, vomiting, anemia etc. When you consider these details the overall impact is less impressive.
Therefore, it is fair to say that these studies largely fail to address the most urgent need for the paediatric oncology community, which is the development of new drugs for the most aggressive cancers, those which cause the highest number of deaths among children and adolescents.
You mentioned that 5 drugs with a paediatric indication have been approved for children since the PMR was implemented, drawing the conclusion that it is very likely that these programmes would not have been conducted without the PMR. It is not clear which drugs you are referring to but, in any case, we would argue that the data does not support your conclusion.
As far as we know, 9 anti-cancer drugs have been approved for paediatric use since 2007. These are the following (target disease and date of EMA approval in brackets):
nelarabine (2007) *
imatinib (CML, 2009) * A
mifamurtide (OS, 2009) *
mercaptopurine (ALL, 2009) *
everolimus (SEGA, 2011) PIP # A
mercaptopurine (ALL, 2012) * F
imatinib (ALL, 2013) PIP A
dinutuximab (NBL, 2015) PIP
asparaginase (ALL, 2015) PIP
* = did not fall under paediatric regulation (e.g. before regulation came into force or well-established use)
# = anti-neoplastic medicine (concerned neoplasm is not a cancer)
+ = nationally authorised in certain Member States
F = new paediatric pharmaceutical form
PIP = based on studies in an agreed PIP
A = paediatric use was granted only after authorisation was granted for adult use
As shown by the above, only a few of these drugs can claim to be the direct result of the PMR. With the exception of Dinutuximab, none of the drugs above have been specifically developed to treat a form of childhood cancer.
We do not see how the data above can support the conclusion that the PMR has had any significant impact on childhood cancer drug development. The figures become also less impressive when taken in the context of global oncology drug development in general. It is estimated that every year approximately 100 to 150 new investigational drugs begin clinical testing and that any point in time there are up to 800-900 anti-cancer compounds in clinical evaluation. It is clear that not enough drugs are developed for children and adolescents. In our view, the approval record of paediatric cancer drugs suggests that this is just “baseline” activity of industry completely unaffected by the current legislation.
The EMA figures clearly show that, basically, no drugs are being developed for the high risk childhood cancers and that companies tend to delay paediatric development as much as possible, as it is regarded as a hurdle on the path of adult development. As you rightly note, the legislation is intended to encourage the development of drugs for children without delaying adult development. However, it was concluded in the 5 year –review published in 2013 that there is no evidence of a slowdown in adult drug development. On the other hand, the negative impact of waivers and deferrals on patients’ lives should not be underestimated.
While it is important to recognize that sometime a delay is indeed recommended in order to evaluate product safety in adults, we must also understand that whenever the paediatric development of a drug is waived or deferred for whatever reasons, there might be a heavy price to pay in terms of missed opportunities for patients. There have been examples of drugs that have been initially granted waivers or had paediatric development delayed only to recognize a few years down the line that the compound is highly beneficial to children. The targeted drug Imatinib was first approved for adults in 2001 for the treatment of a specific genetic subtype of chronic myeloid leukaemia (CML) and later for acute lymphoblastic leukaemia (ALL). The same drug was not approved for the treatment of ALL in children before 2013. Meanwhile, academic sponsored-trials in the US demonstrated a dramatic effect resulting in greatly enhanced survival rates, from 35% up to approximately 80%l. Surely we don’t need to explain that many more children could have been cured had the drug been made available earlier.
The implications of all these facts and figures are very clear.
We may have different views on how to reform the PMR and to what extent we may want to enforce stricter obligations and/or offer more attractive incentives. But one point should be clear by now. The PMR, as it stands, does not address the needs of children and adolescents with cancer. All key stakeholders and key opinion leaders agree upon this point. This was the conclusion of the Europe Society of Paediatric Oncology (SIOPE) in 2012 after the first review of the PMR requested by EMA. This is opinion of countless patients/parents’ organisations united under the Unite2Cure umbrella. If we simply acknowledge the problem we can start to have a sensible and constructive discussion with all stakeholders, with the probability of enacting reforms that will make sense for all parties.
If, by contrast, we do not acknowledge this fact and insist we need more time to judge, we are, indirectly, harming all those young patients that will be diagnosed with cancer in the near future. Time is exactly what children and adolescents with cancer do not have.
Those of us whose children have been and are being impacted by cancer know first-hand the urgent need to tackle the disease which causes the highest number of deaths amongst our children in Europe. We want our political representatives and European legislators to recognize this need for urgency and to facilitate changes that will give children diagnosed with cancer a better chance of life.
As Ms Wilmott and Ms Grossetête clearly wrote, the time for action is NOW.
We very much look forward to your thoughts and comments.
The Unite2Cure Team
Nicole Scobie, Zoé4life (Switzerland)
Debbie Binner, Create for Chloe and trustee of aPODD (UK)
Patricia Blanc, Imagine for Margo children without cancer (France)
Anne Goeres, Fondatioun Kriibskrank Kanner (Luxembourg)
Danielle Horton Taylor, PORT and Consumer Representative National Cancer Research Institute (UK)
Anita Kienesberger, Österreichische Kinder-Krebs-Hilfe (Austria)
Angela Polanco, Bethany’s Wish (UK)
Cesare Spadoni, aPODD (UK)
Chris Copland, Consumer Representative, National Cancer Research Institute (UK)
Gerlind Bode, Board Member of Förderkreis Bonn e.V. (Germany)
Kevin and Karen Capel, Christopher’s Smile (UK)
 EMA Officer – Personal Communication