A letter to the Commissioner

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[1]. 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[2]. 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[3]. 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[4] 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[6]. 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[7].  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[8]. 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[9]. This is opinion of countless patients/parents’ organisations united under the Unite2Cure umbrella[10]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.

Kind regards,
The Unite2Cure Team

 

Founding Members

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)

[1] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204542/

[2] http://www.fda.gov/; https://www.centerwatch.com/drug-information/fda-approved-drugs/therapeutic-area/12/oncology

[3] http://www.nature.com/nbt/journal/v32/n1/full/nbt.2786.html

[4] http://ec.europa.eu/health/human-use/paediatric-medicines/developments/2013_paediatric_pc_en.htm

[5] http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Flanding%2Fpip_search.jsp&mid=WC0b01ac058001d129&searchkwByEnter=false&alreadyLoaded=true&isNewQuery=true&keyword=Enter+keywords&searchType=Invented+name&taxonomyPath=&treeNumber=&currentCategory=Oncology

[6] EMA Officer – Personal Communication

[7] On-Kos Consulting – Personal Communication http://www.on-kos.it/

[8] http://jco.ascopubs.org/content/27/31/5175.full

[9] http://ec.europa.eu/health/files/paediatrics/2013_pc_paediatrics/37-siop.pdf

[10] https://unite2cure.org/

The Paediatric Regulation – a work in progress?

A guest blog by  Katharine Wright, Assistant Director, Nuffield Council on Bioethics

Katharine Wright

 

Back in 2013, the UK-based Nuffield Council on Bioethics set up a working party to look at the ethical issues arising out of children’s involvement in clinical research. The working party’s subsequent report, drawing on the contributions of over 500 children and young people, parents and professionals, was published in May 2015, and its recommendations are made accessible in both a magazine format and as an animation.

 

The working party tackled not only the thorny issue of how children and young people can ethically be recruited to research, but also the more hidden ethical challenges that arise in connection with the ways in which research is prioritised and developed in the first place. We started from the premise that ‘good’ research (a shorthand for ethically robust and well-designed research that asks questions that are important for the health of children) should be seen as intrinsically good, and as a natural and necessary part of any healthcare system. Building on this point, we made the strong claim that it is not an ethically neutral act to say ‘no’ to research proposals that meet these requirements and might potentially lead to better health care for children. There is similarly a strong ethical imperative actively to promote such research – and as Unite2Cure highlights, the European Paediatric Regulation which mandates the inclusion of children and young people in clinical trials, unless a waiver has been granted, has a critical role to play in this arena.

The working party felt that the European Medicines Agency and the Paediatric Committee (the European institutions responsible for implementing the Regulation) should be commended for the very positive and proactive approach they have taken to their regulatory role. They have used it not only simply to police the system established by the Regulation, but have also sought actively to promote effective, collaborative, research with children and young people through a variety of practical means.

Nevertheless, much more can and should still be done – and our report picked out in particular the class waiver system, whereby medicines targeting ‘adult-only’ conditions have been exempt from the requirement to include children and young people in trials. We argued that this system was clearly not working as originally intended and strongly urged the Paediatric Committee (PDCO) to complete its promised review of the class waiver system as quickly as possible. In particular, we argued that PDCO should ensure that where the ‘mechanism of action’ of a medicine is potentially relevant to children (for example for a different illness from that targeted in adults), research with children should go ahead – a recommendation echoed in Unite2Cure’s proposals for improving research and care for children with cancer.

We therefore regarded PDCO’s announcement in July 2015 that they had revised the class waiver list, revoking eight such waivers, and updating fifteen more, as a “welcome step towards further promoting research with children”. This means that there are now fewer conditions where companies developing new medicines are automatically exempted from any requirement to develop a ‘paediatric implementation plan’ (PIP) setting out how they will involve children and young people in the study. However, under the Regulation, they are still potentially entitled to apply to PDCO on a case-by-case basis, and apply for a product-specific waiver, on the grounds that the condition being targeted by the trial medication does not arise in children. Thus, while PDCO will now be directly involved in discussing such cases with companies, they still cannot actually require them to produce a PIP – unless and until the Regulation is changed to give PDCO these powers.

The ‘ten-year review’ of the 2006 Regulation is coming up soon, offering a perfect opportunity to review the thinking behind the waiver system, and to ensure that PDCO has the powers it needs. We have written to the European Commission to urge the ethical imperative of such a change. In the meantime we urge all sponsors of research to consider the potential benefits of their research to children’s health – and where appropriate to include children and young people in trials on a voluntary basis.

 

 

 

A call for concrete action

Unite2Cure is delighted to be a partner in a multi-stakeholder call for concrete action to improve the availability of effective innovative cancer medicines for children and adolescents with cancer.  The call was launched at the event ‘Development of Paediatric Cancer Medicines – Speeding up Innovation, Saving Lives’. Although cancer remains the first cause of death by disease beyond one year of age; very few new medicines reach children and adolescents with cancer in Europe, even after the implementation of the 2007 EU Paediatric Medicine Regulation.

The proposals were presented at a yearly event by The European Society for Paediactric Oncology (SIOPE) www.siope.eu/activities  to mark International Childhood Cancer Day (15th February 2016).  The aim of the proposals is to suggest solutions to the current lack of drug development for children and teenagers with cancer.

©SIOPE & Joke Emmerechts photography

Chris Copland, one of Unite2Cure’s founding members, and Consumer Representative, National Cancer Research Institute (UK)

 

We are proud that Christopher Copland (UK), one of the founding members of Unite2Cure, spoke at the event of the urgent need to accelerate drug development for these young people.  He called for more attractive rewards for the pharmaceutical industry to develop innovative drugs for children’s malignancies; following the example of the “Creating Hope Act” system in the USA.

Also there was Unite2Cure partner Anne Goeres (Lu) from the Foundation Kriibskrank Kanner.  She stressed the need to join forces with the rare diseases’ community in advocating better treatments.

©SIOPE & Joke Emmerechts photography

Anne Goeres, one of Unite2Cure’s founding members, Fondatioun Kriibskrank Kanner (Lu)

 

 

Member of the European Parliament Glenis Willmott (S&D, UK), a strenuous supporter of the causes of the childhood cancer community over the past years, hosted and introduced the event. Martin Schrappe (DE), President of SIOPE, presented the ‘SIOPE-ITCC-CDDF Multistakeholder Platform’, created in 2013 by representatives of parent/patient advocates, academia, industry and regulators. The Platform works on proposals to increase innovative drug development that are regularly presented to decision-makers during a series of Paediatric Oncology Conferences, the last of which led to three stakeholders’ joint proposals to improve the effectiveness of the Regulation’s implementation.

Unite2Cure is a parent-led movement which aims to mobilise the parent/child/NGO voice to push urgently for better treatments and better access to treatments for young people with cancer.  The  current status quo means that:

– 6,000 children and teenagers die of cancer in Europe each year

– less than 1 in 10 of children with relapsed terminal cancer has access to  innovative new treatments.

– whilst progress has been made; many high risk cancers have not seen any therapeutic improvements in the past two decades

– childhood/teen cancers are largely neglected by industry

– current legislation allows waivers; even when science suggests a potential use

– EMA figures show that basically no drugs are developed for the high risk cancers.

If you care – join our discussion; sign our petition, or talk to us nicole@scobie.com   or deborahjanebinner@gmail.com