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The requirements of an EMA-approved paediatric development plan make paediatrics an integrated aspect of drug development. Outsourcing to specialised CROs can help expedite this complex process.

Since 2007, new medicines can no longer be registered in Europe without a paediatric investigation plan (PIP) agreed between the developing company and the European Medicines Agency (EMA) with its Paediatric Committee (PDCO). The PIP must be submitted well ahead of the marketing authorisation application (MAA), in principle at the end of Phase 1. An agreed PIP is also a condition for the registration of new indications and new formulations of patent-protected medicines (1,2). There is similar legislation in the US, but the FDA asks for paediatric data much later (3). For innovative pharmaceutical companies, there could be no stronger threat than potential denial of access to the market. In consequence, paediatric development has in a very short time become an essential part of drug development in general.

A Hypothetical Example

Axe Pharmaceuticals, based in Alabama, is developing a compound that targets irritable brain disorder (IBD). IBD is increasingly discussed as a separate disease that costs billions of US dollars due to absence from work. IBD patients are slighty to moderately overweight and become irritated and depressed under high work pressure. Axe Pharmaceutical’s new compound stabilises the enzyme that keeps plasma levels of mood challenging protein (MCP) under a clinical threshold and thus prevents IBD in healthy subjects. Axe Pharmaceuticals has limited resources but has managed to finance the Phase 1 and 2 programme. Two pivotal Phase 3 trials have started. The majority of IBD patients are 40 to 60 years old. All trials are performed in North America. Marketing submission in both the US and EU is planned for 2015. Three years in advance, Axe Pharmaceuticals contacts an EU regulatory consultancy and learns about the PIP requirement. Does IBD exist in children? Axe has limited knowledge. They know that the market even in young adults is negligible, but now they must know more. Without an agreed PIP their MAA will not be validated and in consequence marketing authorisation in Europe will not be possible. Axe’s own regulatory department was aware of the US paediatric legislation: paediatric assessment at the end of Phase 2; a paediatric plan at submission. However, lack of a well-prepared paediatric plan will not block adult registration (3). Axe was not sufficiently familiar with the EU situation. Now it learns fast.

Axe’s tasks are as follows:

  1. Find out if IBD exists in children and adolescents. The Axe clinicians and their external advisors will not have sufficient special knowledge, and so must consult paediatric clinical key opinion leaders (KOLs), including European ones, with special knowledge in child and juvenile IBD. These KOLs might be based in paediatric gastroenterology, endocrinology or psychiatry. There might even be a society for child and juvenile IBD
  2. If child and juvenile IBD does exist, develop a strategy which clinical trials are tailored to suit children and adolescents. Establish a lower age limit where the disease does not exist
  3. Write and submit a paediatric investigation plan (PIP). Go through the EMA/PDCO negotiation process until PIP approval
  4. Prepare and perform execution of the agreed studies. From registration on, submit a yearly progress report to the EMA. If the PIP needs revision, submit a request for modification and negotiate with EMA/PDCO
  5. After the last study is concluded, send a final report to EMA, asking for a compliance check. Request an supplementary protection certificate (SPC) extension to prolong the patent in the EU countries by six months

Usually, steps one and two will take six months each, as it takes time to identify appropriate KOLs. Axe Pharmaceuticals needs to put together an internal team and start the dialogue with the KOLs. Usually, at least one face-to-face meeting will be required. These KOLs are needed for initial brainstorming and for later support during the negotations. Step three, the PIP submission and negotiation, usually takes a year – if the company is fast and dedicated and has done its homework. The duration of step four depends of the number and length of studies agreed with EMA. Usually they will start one to two years after the end of Phase 3 and take a few years, but it can also be longer, up to 20 years. Step five is short, just another six months from beginning to end.

That children are not small adults is often emphasised. Increasing understanding of their physiology, and specifically their absorbtion, distribution, metabolisation and excretion of drugs, has made paediatric clinical pharmacology a science in its own right (4). Paediatric clinical pharmacology can help to establish where efficacy can be extrapolated from adults, establish where modelling and simulation will be required, and determine tentative first doses in children.

Axe Pharmaceuticals can ask the CRO that handles their Phase 3 programme if they have overseas experience, specifically with PIPs and paediatric development. Even if the CRO has limited experience, it will assure that it will be happy to handle everything. For specific questions, it is important to find an experienced business partner in Europe.

Finding out about a paediatric corresponding disease and developing a tentative paediatric strategy (steps one and two) is crucial, as during this early stage of preparation, the foundations are laid for later negotiations with EMA. However, there are limits to outsourcing. Axe Pharmaceuticals will want to have a final word in the proposals submitted to the EMA and will pay for the trials. One hundred per cent outsourcing is not feasible. The best model will provide external support with involvement of internal staff. Support can be sought from a large or small CRO, a regulatory consultancy, or a specialised paediatric consultancy.

On its website the EMA lists diseases that officially do not exist in children (5). For these diseases no PIP will be required, provided that EMA has confirmed in writing that the mentioned list of class waivers applies. If IBD is not on this list, a PIP will be required.

PIP Submission

Writing and negotiating the PIP (step three) will include the question of whether the disease exists in children or not. If Axe think it does not, the PIP will ask for a complete waiver. However, Axe might argue that IBD exists in adolescents only. In this instance the PIP will ask for a waiver below 12 years. Writing the PIP and negotiating it with EMA/PDCO can be outsourced to a regulatory consultancy, to a medical writing company, a specialised paediatric consultancy, or a combination of these service providers.

If in doubt, the EMA/PDCO will argue that a disease does exist in children. Two diseases that were initially listed in the original list of class waivers have since been re-classified as paediatric diseases: melanoma and menopausal disorders (6). EMA/PDCO base their classification on scientific publications, registries, and advice from trusted external specialists. They will insist that the paediatric development programme is extensive enough to cover all relevant questions. At the end of the procedure, either common ground is found or the PIP is refused. During the procedure the number of clinical trials, their duration, and the number of enrolled patients are negotiated.

The execution of trials and other measures agreed between Axe Pharmaceuticals and the EMA/PDCO (step four) is the biggest part of the outsourcing package. Specialised companies offer support for formulation development – children under six years cannot swallow tablets – or for juvenile animal studies, for example. The main investment will be in the clinical trials, the classical mainstay of CROs. CROs have expanded considerably over the last decade, mirroring the attempt of big pharma to focus on key activities. A typical clinical trial with 100 patients will usually cost $20,000 to $30,000 per patient, totalling $2 to $3 million. However, paediatric trials are always more complex and expensive. Multiplication with factor p needs to be factored in. p can be roughly between two and five; that is, a trial with 100 children can cost between $4 and $15 million. However, this is not something pharmaceutical companies can avoid; without a paediatric development plan, submission is not possible. After EU PIP negotiation, Axe Pharmaceuticals has still to deal with the FDA. At present, paediatrics is usually discussed with the EMA first and later with the FDA. If the company is lucky and the negotiation with both agencies is done in a smart way, the FDA will accept most of the trials agreed with the EMA. The EU paediatric legislation also plans for penalties in the case of non-compliance. To cut a long story short: the paediatric budget will be ring-fenced. This is a good situation for a CRO. A second reason for CROs to be interested in paediatric clinical trials is that this new challenge might open the door to new sponsors.

The Role of the Sponsor

Even if the entire adult and paediatric clinical trial programme is outsourced, the sponsor must remain involved. The sponsor needs to have an understanding of paediatric drug development to prepare, observe and conclude the outsourcing. This includes scrutinising proposals submitted by the CROs, deciding on one organisation during the bid defence process, undertaking minimal surveillance during the execution phase, and accept/reject proposals to ask for a PIP modification. EMA/ PDCO will only accept requests for PIP modifications if they are supported by convincing evidence.

Step five of the PIP process is often only an afterthought, but it is essential; six months patent extension can be a lot of money. PDCO’s compliance check should be taken very seriously.

This hypothetical example was uncomplicated; the reality could be more complex. Imagine that Axe plans to sell its future drug in North America only. For Europe and the rest of the world it takes as a commercial partner Hatchet Pharmaceuticals, from Finland. If Hatchet negotiates the PIP, who will negotiate paediatrics with the FDA? Will Hatchet share the paediatric data with Axe? Will Axe pay part of the studies?

Later on, Hatchet Pharmaceuticals might be bought by Crowbar Pharma, and so on. If paediatrics are forgotten, you should expect trouble further down the line.

Imagine that IBD is only the first target of our new compound. A later target might be IDD (irritable dream disorder). Prevention of IDD might help IBD patients to sleep better, work harder, and have a better quality of life. A new indication will require a new PIP in the EU.

The agreed PIP is binding. From now on it’s ‘only’ the execution of the key binding elements that needs to be dealt with. If CRO A offers to perform the final programme for €18 million and CRO B asks for €22 million, Axe Pharmaceuticals can save €4 million, provided A works as well as B, or Axe can ask B to lower the price. The number of patients and age distribution, however, are no longer debatable. The foundations for the final number of studies, patients per study and age distribution are laid during the initial steps and finalised in the negotiation process with EMA. The agency is not interested in the costs of the programme. During steps one, two and three, costs are not addressed, but key decisions are made that later translate into high costs. The highest potential to contain costs is during the early steps.

Conclusion

US paediatric legislation began when many new and powerful medications were registered in adults and used liberally in children without proper investigation. Many blockbusters were approaching patent expiry, and the offered patent extention was voluntary and could keep generic erosion away for half a year. The European paediatric legislation goes much further; it forces companies to consider children early and in depth. This can be challenging. For example, the EMA differentiates several epilepsy types in newborns (paediatric epilepsy syndromes; neonatal seizures; epilepsy with partial onset seizure; idiopathic generalised epilepsy with primary generalised tonic clonic seizures) and asks for a number of studies in one or several of these disease clusters (7). Of course, a company can sue the EMA. The first major decision of this kind was made by the EU Court of Justice in December 2011: the company lost (8). Ultimately, no market entry is allowed without an agreed PIP. Children must now be considered in the general drug development process. Sponsoring pharmaceutical companies and CROs need in-depth understanding.

References

  1. Olski TM et al, Three years of paediatric regulation in the European Union, Eur J Clin Pharmacol 67: pp245-252, 2011
  2. Wrigth E and Rose K, European Union paediatric regulation: Theory and practice, in Rose K and van den Anker J (eds), Guide to Paediatric Drug Development & Clinical Research, 2010
  3. Rodriguez W and Maldonado S, United States paediatric legilation impact on paediatric drug studies, in Rose K and van den Anker J (eds), Guide to Paediatric Drug Development & Clinical Research, 2010
  4. Kearns G et al, Developmental pharmacology – drug disposition, action, and therapy in infants and children, N Engl J Med 349: pp1,157-1,167, 2003
  5. Visit: www.ema.europa.eu/ ema/index.jsp?curl=pages/ regulation/general/general_ content_000036.jsp&murl=menus/ regulations/regulations. jsp&mid=WC0b01ac05801177cd, accessed 4th January 2011.
  6. EMA decision on class waivers; document P/345/2010 of 20 December 2010, available at http://www.ema.europa/. eu/docs/en_GB/document_library/ Other/2009/11/WC500011500.pdf, accessed 4th January 2012
  7. PDCO opinion on Brivaracetam, 2nd September 2011, available at www.ema.europa.eu/docs/en_GB/ document_library/PIP_decision/ WC500116542.pdf, accessed 4th January 2012
  8. Judgement of the EU Court of Justice, case T 52/09, pronounced 14th December 2011, available at http://eurlex.europa.eu/LexUriServ/ LexUriServ.do?uri=CELEX:62009TJ005 2:EN:HTML, accessed 4th January 2012

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Klaus Rose is CEO of klausrose Consulting, Basel, Switzerland. He qualified in 1986 in medicine in Berlin after studying Latin languages and Psychology. Klaus completed postgraduate clinical training in General Medicine in Germany and England, and joined the pharmaceutical industry in 1991. He has held various positions in R&D and medical affairs, culminating in the positions of Global Head of Paediatrics at Novartis from 2001-2005, and Global Head of Paediatrics at Roche from 2005-2009. Klaus then worked for a year with a regulatory consultancy before establishing his own business.
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Klaus Rose
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