Pediatr Drugs 2009; 11 (1): 57-59 1174-5878/09/0001-0057/$49.95/0
CONFERENCE PAPER
© 2009 Adis Data Information BV. All rights reserved.
Challenges in Pediatric Drug Development A Pharmaceutical Industry Perspective Klaus Rose Global Head Pediatrics, Roche, Basel, Switzerland
Abstract
A paradigm change is taking place from protecting children against clinical research to protecting them through research. It is based on a better scientific understanding of the child’s physiology, on the increasing potential of biomedical interventions, and on an evolving conviction of children’s right to benefit from scientific and pharmaceutical progress. The WHO campaign ‘Make medicines child size’ is contributing to expand this to a global vision of the health of all children. Research-based pharmaceutical industry develops innovative new medicines for serious and life-threatening diseases. It has built up competency in pediatric drug development and has welcomed US and EU pediatric legislation as well as the WHO campaign. More diseases without effective therapy in the past will become treatable conditions. Eventually these advances will also be reflected in the medical care in developing countries. Research-based pharmaceutical industry can support specific pediatric aspects of drug development in neglected diseases by sharing its learning. The way forward will be a constructive dialog among the key stakeholders to ensure continuing improvement in worldwide child healthcare.
Historic Background Clinical pharmacologists and pediatric clinicians focus predominantly on available medicines that they use for clinical treatment in their daily work. Furthermore, they investigate the pharmacokinetics/pharmacodynamics of these agents in children and work on expanding and improving their clinical use. The research-based pharmaceutical industry develops new medications (i.e. drugs of the future from today’s perspective), and makes them available after registration at least until the end of the patent life. The institutional framework that clinicians and clinical pharmacologists work within differs from that of the pharmaceutical industry. Usually, clinical and academic institutions are publicly funded and have a long life expectancy, whereas pharmaceutical companies work in an extremely competitive environment. Companies that do not adapt fast enough to changing requirements do not survive. They are bought by competitors and/or have to merge. The two spheres of clinicians and research-based pharmaceutical industry touch through various channels, for example, the prescription of drugs, participation of clinicians in clinical registration trials, and strategic advice from academic key opinion leaders to pharmaceutical companies. The off-label use of drugs in children began with the introduction of modern labels in the US with the Kefauver-Harris amendments to the US FDA Act in 1963 and the obligation of manufacturers to prove the safety and effi-
cacy of drugs, which led to the beginning of clinical trials in the modern sense of the word. Pediatric legislation in both the US and EU is now pushing clinicians and research-based pharmaceutical industry more strongly together. We are observing a changing paradigm in drug development.[1,2] Over the last decades, it was believed there was a need to protect children against research. There is now an increasing notion that they also have a right to benefit from research, that keeping them systematically out of the research process amounts to withholding from them the potential benefits of pharmaceutical progress, and that exposing them continuously in daily practice to medicines not properly tested in their age group is ethically challenging. This has led to the new paradigm that children need protection through, not against, research and clinical trials. US and EU Pediatric Legislation The US Act FDAAA (FDA Amendment Acts) of 2007 is a second re-authorization of pediatric legislation that originated in 1997 and will need re-authorization again in 2012. Its two key elements are: 6 months added market exclusivity for generating pediatric data; and exclusivity for the entire moiety (i.e. pediatric and adult use). Secondly, the authority of the FDA to mandate research if the indications a drug is registered for in adults also exists in children. The EU regulation that has been in force since
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2007 has made early consideration of pediatrics in the drug development process mandatory. All in all, pediatric drug development is shifting away from being an appendix at the end of the life cycle of a drug towards becoming an integrated part of the drug development process. This does not imply early routine physical exposure of children to untested substances. However, thinking about the use of a drug in children must now start early in the drug development process. The Complex Process of Drug Development Epidemiology, preclinical safety and toxicology, the development of galenic formulations, clinical safety and pharmacovigilance, modeling and simulation for dose finding, clinical efficacy trials, and many more are essential components of the drug development process. They all have specific pediatric aspects that, through the US and EU legislation, have now to be addressed in a consolidated pediatric document, the Pediatric Investigation Plan in the EU and the Pediatric Plan in the US. When the first clinical studies in children were performed by research-based pharmaceutical companies, many involved parallel teams and pooled experiences and learning; this was necessary because of, for example, the very limited amount of blood available for testing, and the need to ask for informed consent from the parents instead of from the patient directly. Awareness of the impact that consideration of children is having on the general drug development process is now evolving within the pharmaceutical industry. In December 2007, the WHO announced the ‘Make medicines child size’ campaign,[3] drawing attention to the health needs of children. The campaign has a focus on the treatment of HIV, malaria and tuberculosis, neglected diseases, and several other conditions affecting children predominantly in resource-constrained countries. Coordination of Pediatric Aspects in Drug Development In most large research-based pharmaceutical companies, there is now coordination of pediatric drug development. Of course, it is different in each company. However, all major companies have chosen a matrix approach. The development teams continue to be responsible for the development of their respective compound, including development in children. Across line functions, for example, technical development, preclinical safety and toxicology, clinical pharmacology, clinical safety, clinical development, marketing, and communication, coordination on specific pediatric aspects takes place. In some companies this is done more on an informal level; for example, a well known and highly respected clinical pharmacologist who is also a pediatrician may coordinate the pediatric aspects rather informally. In other companies, a more © 2009 Adis Data Information BV. All rights reserved.
formal and organized approach is taken. Now that formalization of pediatric drug development has started to take place, all companies are introducing pediatric policies, standard operating procedures for pediatric development and clinical trials, and more. While the trade associations of research-based pharmaceutical industry in the US and EU, the Pharmaceutical Research and Manufacturers of America (PhRMA),[4] and the European Federation of Pharmaceutical Industries and Associations (EFPIA)[5] have established pediatric groups that focus on regulatory aspects, the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA),[6] the research-based pharmaceutical industry’s global representation, has now implemented a Pediatric Taskforce to address the WHO campaign[3] and pediatric drug development on a global level. Open Questions With the evolving EU pediatric regulation, a number of questions have arisen for which an answer will have to be found during the coming months and years; for example, what should be done if a disease is so rare that ordinary clinical trials are not feasible, and from what stage in the drug development process is it ethical to expose a child to a new compound. Continuous Innovation and the Developing World The research-based pharmaceutical industry develops differentiated and innovative new medicines for serious and life-threatening diseases with a highly unmet medical need. Philanthropic commitment to patients of the developing world has become an integrated element of research-based pharmaceutical industry. Disease-specific private-public partnerships such as the Medicines for Malaria Venture (MMV)[7] or the Drugs for Neglected Diseases initiative (DNDi)[8] are supported by the pharmaceutical industry and develop new drugs for neglected diseases. These disease-specific organizations now also have to address specifically the needs of children in their respective development programs. Many conditions of children in developing countries are a consequence of poverty and lack of adequate infrastructure. However, diseases that were almost a death sentence 50 years ago, even for children in the developed world, can today often be cured (e.g. cancer in children), or have become a chronic condition of adulthood (e.g. cystic fibrosis). The pharmaceutical industry is confident that these advances will eventually be reflected in the medical care in developing countries and will ultimately serve all children of this world. Other tasks such as reducing poverty, addressing education needs, and establishing a sustainable economic and societal infrastructure remain the responsibility of individual countries’ governments. Pediatr Drugs 2009; 11 (1)
Challenges in Pediatric Drug Development
The Way Forward The way forward will be constructive dialog between all partners in healthcare, that is, academia, the pharmaceutical industry, regulatory authorities, patient groups, the WHO, reimbursement institutions, and others to ensure continued improvement in worldwide child healthcare. Acknowledgments This paper describes the challenges of pediatric drug development from the perspective of the pharmaceutical industry. The author is an employee of Roche, Basel, Switzerland and has been employed by Novartis in the past. He is also chairman of the IFPMA Pediatric Task Force. The position in the paper reflects the author’s experiences and is the personal opinion of the author. It is not an official statement of Roche or the pharmaceutical industry in general. No sources of funding were used to assist in the preparation of this article.
References 1. Rose K. Ethical, regulatory and scientific challenges in paediatric drug development. Pharm Med 2008; 22 (4): 221-34
© 2009 Adis Data Information BV. All rights reserved.
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2. Rose K, van den Anker J. Guide to paediatric clinical research. Basel: Karger Publishers, 2007 3. WHO. Essential medicines for children [online]. Available from URL: http:// www.who.int/childmedicines/en/index.html [Accessed 2008 Oct 3] 4. PhRMA [online]. Available from URL: http://www.phrma.org [Accessed 2008 Nov 10] 5. The European Federation of Pharmaceutical Industries and Associations (EFPIA) [online]. Available from URL: http://www.efpia.org [Accessed 2008 Nov 10] 6. International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) [online]. Available from URL: http://www.ifpma.org [Accessed 2008 Nov 10] 7. Medicines for Malaria Venture (MMV) [online]. Available from URL: http:// www.mmv.org [Accessed 2008 Nov 10] 8. Drugs for Neglected Diseases initiative (DENDi) [online]. Available from URL: http://www.dndi.org [Accessed 2008 Nov 10]
Correspondence: Dr Klaus Rose, Global Head Pediatrics, Roche, Grenzacherstrasse, 4070 Basel, Switzerland. E-mail:
[email protected]
Pediatr Drugs 2009; 11 (1)
