Strategic Issues – R&D and Innovation
VFA – Association of Research-based Pharmaceutical Companies
In Europe, children enjoy the best healthcare in the history of mankind, as can be easily seen in the very low death rate during and after birth and further on. Yet, on the other hand, children are still not benefiting adequately from the medical progress offered by modern medicines. Thus, depending on the clinical indication, between 50% and 90% of the applied medicines are not specifically tested for children.(1) This fact has led to the widespread off-label use of medicines in children,(2–5) with all the problems that this implies. Yet the only alternative to off-label use would be not to prescribe a drug and thus to withhold a medicine that might help the child. So, the problem of the lack of specifically developed medicines for children needs to be resolved.
Positive experiences in the USA
The first country to address this situation was the USA. The measure – which proved successful – to initiate the development of paediatric medicines was the introduction of the paediatric exclusivity within the FDA Modernization Act (FDAMA) 1997, which was reauthorised as BPCA (Best Pharmaceuticals for Children Act) in 2002.(6) Companies that fulfil all the requirements of a paediatric development plan agreed beforehand with the FDA will get a six-month prolonged exclusivity at the end of the patent life of the drug in question and thus a prolonged protection against generic competition. In five years, this measure has already led to the initiation of more than 300 paediatric studies and nearly 100 authorisations of products for paediatric indications.(7)
The EU initiative
Following the successful US example, the European Commission published a draft proposal for a regulation on medicinal products for paediatric use on 29 September 2004,(8) which is currently being debated at the European Parliament and the correspondent working group of the EU Health Council.
The draft EU regulation provides mandatory paediatric drug development for new products combined with an extension of the Supplementary Protection Certificate (SPC) by six months as a compensatory incentive. To set up an effective process, a Paediatric Committee will be created that will assess all the paediatric investigation plans (PIPs) that the regulation will demand from the pharmaceutical companies. To receive the incentive, all the measures laid down in the PIP have to be fulfilled. Since many orphan medicines do not have patent protection, they will be rewarded with additional two years of market exclusivity if they are also being developed for children. This has been foreseen in Regulation (EC) No. 141/2000 on orphan medicinal products.(9)
To establish a vehicle for providing incentives for off-patent medicines, the proposal includes a new type of marketing authorisation: the Paediatric Use Marketing Authorisation (PUMA). A PUMA utilises existing marketing authorisation procedures but is specifically introduced for off-patent products developed exclusively for use in children. For such a PUMA, the incentive of data protection for the paediatric use should be granted.
On 7 September 2005, the European Parliament had its first reading of the Commission’s draft.(10) Following the previous vote in the leading committee of the European Parliament, all amendments asking for variable incentives depending on turnover or for shorter incentive periods were rejected and the original Commission proposal was maintained. The European Parliament adopted key amendments on the timing for submission of the paediatric investigation plans and the paediatric results. The aim of these amendments is the “de-linkage” of studies in paediatric and adult populations to prevent premature or unwarranted testing in children and delays in the availability of adult medicines.
Another amendment specifies that paediatric studies initiated before the entry into force of the regulation can be included in a paediatric investigation plan. This amendment will help to stimulate paediatric R&D in Europe immediately. Other adopted amendments are aiming at avoiding the duplication of incentives for the same paediatric indications/ forms and for greater access of the public to information on paediatric studies and stricter pharmacovigilance measures.
Furthermore, the Parliament supported the establishment of a paediatric study programme (MICE – Medicines Investigation for the Children of Europe). It should offer funding for studies into the paediatric use of medicines without patent or SPC protection and could be interesting, for universities in particular.
Due to the evolving framework in the USA, the EU and Japan,(11,12) pharmaceutical companies need to integrate paediatric assessments into the standard drug development process and build up paediatric competence. The international guideline ICH E 11(13) describes three major scenarios of drug development in children:
- Severe or life-threatening diseases in children only and no sufficient therapeutic alternatives are available.
- Severe or life-threatening diseases in children and adults and no sufficient therapeutic alternatives are available.
- All other conditions and diseases.
Only in the first two cases is the early development of a new drug in children ethically justified, taking into consideration the risk of exposure to a new substance.
The ongoing discussions on the evolving Paediatric Regulation in Europe helped to highlight the appropriate place of paediatric issues in drug development. Safety and efficacy data in adults will have to be generated before clinical trials in children are initiated where acceptable therapeutic alternatives are on the market and a “deferral” is issued for paediatric development. If the health authority confirms that the disease does not exist in children, no paediatric development will be required (“waiver”). The first two cases (ie, early paediatric development of a drug targeting a life-threatening or serious disease for which no acceptable therapeutic alternatives exist) will therefore remain an exception. The major diseases of the latter type would be cancer or genetic diseases that cause early death in children.
Companies will have to extend clinical drug development to include children and to meet the new requirements. This means that they have to switch preclinical safety and toxicology and the development of paediatric formulations into earlier development stages. Developing paediatric formulations can take up to two years; thus, the decision to do so requires a careful balance of medical, financial and logistic risks and benefits. No company has unlimited resources, and resources that are invested into failed developments will be missed in other developments with a high therapeutic potential.
Due to the current developments, paediatric drug development is evolving into an area of shared responsibility for health authorities, clinicians and the pharmaceutical industry, and parent/patient advocacy groups. To achieve the goal of assuring that children can benefit as early as possible from innovative therapies and new drugs, all stakeholders need to strive towards a high level of trust between each other. For pharmaceutical companies, this will mean keeping commitments made to health authorities and to safeguard a high level of protection in clinical studies with children. For health authorities, this will mean not overloading pharmaceutical companies with research requests that might result in unacceptable bureaucratic burden. Furthermore, the industry hopes that the health authorities of Japan, the USA and the EU, as well as other parts of the world, harmonise their requests to pharmaceutical companies. This would help all partners involved to achieve the goals set up by communities worldwide, and not only in Europe. Specifically, this would allow children to benefit adequately from advances in pharmaceutical treatment – that is what really matters.
- BMJ 2000;320:79-82.
- Acta Paediatr 1999;88:965-8.
- BMJ 2002;324:1313-4.
- Eur J Clin Pharmacol 2003;58:779-83.
- Lancet 2004;364:803-11.
- Best Pharmaceuticals for Children Act. Available from: http://www.fda.gov/cder/Paediatric /PL107-109.pdf ; Paediatric Research Equity Act, Available from: http://www.fda.gov/cder/Paediatric /S-650-PREA.pdf
- US pediatric studies have led to new labeling for nearly 100 drugs, according to Tufts CSDD. Available from: http://csdd.tufts.edu/NewsEvents/NewsArticle.asp?newsid=55
- Proposal for a regulation on medicinal products for paediatric use and amending Council Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004 (presented by the Commission. Available from: http://pharmacos.eudra.org/F2/Paediatrics/docs/Paeds%20reg%20adopted%2029%20September%202004%20English.pdf
- European Orphan Regulation: Availble from: http://europa.eu.int/eur-lex/pri/en/oj/dat/2000/l_018/l_01820000122en00010005.pdf
- Amendments by the European Parliament to the Commissions Proposal. Available from: http://www.europarl.eu.int/omk/sipade3?SAME_LEVEL=1&LEVEL=4&NAV=X&DETAIL=&PUBREF=-//EP//TEXT+TA+P6-TA-2005-0331+0+DOC+XML+V0//EN&L=EN
- Uchiyama A. Paediatric clinical studies in Japan: regulations and current status. Appl Clin Trials 2002;11:57-9.
- Kibosh U. Paediatric clinical studies in Japan: regulations and current status. Appl Clin Trials 2002;7. Available from: http://www.actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=83734
- ICH E 11: Clinical Investigation of Medicinal Products in the Paediatric Population. Available from: http://www.ich.org/MediaServer.jser?@_ID=487&@_MODE=GLB