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Papachatzakis1, Kalliopi Sofou2
Abstract In the era of biotechnology and sequencing of the human genome, paediatric research is still crying out for attention from drug manufacturers and governmental agencies. At the same time, Europe is welcoming the new legislation with the ultimate hope to stimulate development of adequately tested and authorized medicines for paediatric use. The issues that the pharmaceutical industry encounters remain more challenging then ever. How will the technical obstacles around paediatric study design and long-term pharmacovigilance be overcome? Will the new EU legislation manage to offset the regulatory burden and the development costs? Are the informed consent and assent process and its ethical implications finally resolved?
Introduction Over half a century after the Nuremberg Code, with thalidomide disaster still haunting our memory, paediatric drug development is still struggling to find its way to evolve. Despite the public and scientific call for appropriately tested and authorized paediatric therapies, the majority of medicines administered to the paediatric population are still prescribed on an unlicensed basis. This ‘off-label’ use, even though lacking rigorous scientific scrutiny, accounts for almost half percent of drug use in paediatric wards, while the respective rate in neonatal intensive care exceeds an average of 90 percent1,2. The growing recognition for the need of systematic efforts by all stakeholders to enhance paediatric clinical research has often been heralded by reluctance and legislative delays. After almost one decade of discussions about the need and content of a harmonized approach to the conduct of paediatric clinical trials across the European Union, the new EU Regulation on Paediatric Medicines (Regulation (EC) No 1901/2006) finally came into full force, on January 26th, 20073. Since then, the European Medicines Agency (EMEA) has been reinforced by the establishment of the Paediatric Committee (PDCO), whose main responsibility is to provide scientific input on drug development for paediatric use [Appendix I]4. In order to align with this initiative, the pharmaceutical industry is challenged to address several critical issues, the five major of which we attempt to identify and further discuss in the current article. Study Design The first challenge that the pharmaceutical industry has to face in order to ensure sound paediatric research is the study design. Although the new Regulation introduces a solid framework for the conduct of paediatric clinical trials, the absence of precise and sound design methods presents important countervailing considerations. The role of placebo in paediatric clinical trials is an elaborate example. Is the clinical benefit of a placebo-controlled trial counterbalancing the potentially increased risk of harm during exposure to placebo? Do we need placebo-controlled trials when there is no existing comparator, as in the case of antiviral agents5? The development of guidelines for the ethical use of placebo controls per disease area would be a 2
promising step; still, this initiative will require extensive discussions and advisory boards among experts in order to reach consensus6. An additional constraint is that for many conditions the target paediatric population is relatively small. And there may be a number of distinct age ranges to be considered within this population. Thus, the need for innovative study designs such as cross over studies, with specific stratification methods, is imperative7. As pediatric age groups vary from premature infancy to late adolescence, multiple dosage forms must be foreseen in study design, along with bioavailability and stability evaluation for different formulations8. The lack of validated assessment tools in this population, such as scales and questionnaires, imposes even higher obligations not only to pharmaceutical companies but to academic institutions as well. Informed Consent/Assent Informed consent is considered the cornerstone of biomedical research on human subjects. The difference between informed consent and assent is that the latter, by definition, is the voluntary permission granted by an individual without legal authority9. In order to be genuine, informed consent should incorporate the following four essential components: 1. Disclosure of all relevant information about the research 2. Comprehension of this information by the prospective participant in order to make an informed decision 3. Freedom of the prospective participant from any coercion, undue influence, inducement or intimidation 4. Explicit and formal consent by the participant, usually in written form10. The ultimate purpose of such a multi-step process is to protect and promote the ethical principle of autonomy. However, the process itself raises important ethical issues, when it comes to the conduction of research in children and adolescents. And, first of all, when is a child capable of providing informed assent? Unless circumstances prevent this, children over the age of six must assent to participate in a trial9. In general, consent is sought only from one parent or legal guardian. Children are far more willing than their parents to participate in clinical studies, as shown in an 3
unpublished study of an antibiotic authorized for adult use, conducted in 2001. Only 23 percent of parents gave their consent for their child to participate in the trial, as opposed to an almost double percentage of children willing to participate5. The procedure becomes more complicated as patient information must be adjusted to age and presented to children in a simple and comprehensible manner. Obtaining parental consent on the other hand raises other questions such as whether this is a valid and unforced decision, considering the emotional and ‘timing’ stress the parent is under. Indeed, one of the most intriguing challenges for the pharmaceutical industry is to facilitate the informed consent/assent process, while protecting the privacy rights of the child. Pharmacovigilance The third challenge for the pharmaceutical industry is the new pharmacovigilance requirements, which each of 27 EU member states must comply with. As stated in Paragraph 24 of the Regulation, “it is essential to ensure that pharmacovigilance mechanisms are adapted to meet the specific challenges of collecting safety data in the paediatric population, including data on possible long-term effects.” And continues by adding that “where there is a particular cause for concern, the applicant should submit and implement a risk management system and/or perform specific postmarketing studies as a condition for the granting of the marketing authorization”.3 In order to secure long-term follow-up of adverse reactions, pharmaceutical companies are encouraged to develop and implement appropriate procedures to continue beyond patent expiry. This is particularly the case when the potential for long-term toxicity is of great concern. In view of delayed or chronic toxicities including effects on growth and development, a case-by-case approach should be put in place. Specific guidance on pharmaceutical industry requirements and commitments remains to be issued11. Timelines Regulatory workload has always been considered one of the most crucial challenges for the pharmaceutical industry. A first look at the new EU Regulation fails to raise any hopes of regulatory acceleration. It is now mandatory for pharmaceutical
companies to submit a Paediatric Investigation Plan (PiP) to the Paediatric Committee no later than the first phase of testing a new drug in adults is completed3. However, this may be too early for some therapeutic areas, where a marketing company may choose to wait in order to collect more safety and efficacy data from the adult population. Prior to submitting the PiP, meaning “a research and development program aimed at ensuring that the necessary data are generated determining the conditions in which a medicinal product may be authorized to treat the paediatric population”, the pharmaceutical company must notify EMEA two months in advance of its intention to submit an application for a PiP12. After submission and approval by the PDCO, follows the standard procedure of submission and approval by Local Ethics Committees and Regulatory Authorities. It is noteworthy that, as from July 26th 2008, if a company submitting a Marketing Authorization Application in Europe does not have an approved PiP in place, the new drug will be automatically rejected, leading to significant losses in terms of time and investment13. Economic burden Although there are financial motives, these may not fully offset the development cost for unmet medical needs proposed by the PDCO; let alone the major investment of a marketing company in a PiP that may eventually be rejected. As stated in the Paragraph 32 of the Regulation, “an inventory of the therapeutic needs of the paediatric population should be established by the Paediatric Committee after consultation with the Commission, the Member States and interested parties, and should be regularly updated. The inventory should identify the existing medicinal products used by the paediatric population and highlight the therapeutic needs of that population and the priorities for research and development. In this way, companies should be able easily to identify opportunities for business development..”3.
Moreover, as stated in paragraph 33, “clinical trials in the paediatric population may require specific expertise, specific methodology and, in some cases, specific facilities and should be carried out by appropriately trained investigators”3. Pharmaceutical companies need not only to integrate paediatric assessments into the standard drug development, but also certify the competence of highly trained personnel, within and outside the pharmaceutical field. Conclusion It is unfortunate but true that children have not benefited from advances in drug development to the same extent as adults14. Being of lower marketing potential, paediatric clinical trials have been systematically supplanted. As paediatric research proceeds, the need to develop successful strategies in order to ensure that children and adolescents will benefit from a safe and controlled clinical environment becomes even more imperative. Successful implementation of the new EU Regulation requires close and effective collaboration between all stakeholders concerned, meaning the paediatric population and their parents/care-givers, regulatory authorities, the pharmaceutical industry, health professionals, patient organizations, national health care systems and the media. As for the pharmaceutical industry challenges, ‘Alea Jacta Est’! References 1. Clinical Trials and Children's Medicines. ABPI briefing paper.
http://www.abpi.org.uk/publications/briefings/clinical&child_brief.pdf 2. European Commission Staff Working paper 13880-04 2004 3. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol1/reg_2006_1901/reg_2006_1901_en.pdf
http://www.emea.europa.eu/htms/general/contacts/PDCO/PDCO.html 5. Gill D, Kurz R: Practical and ethical issues in pediatric clinical trials. Applied Clinical Trials 2003;Sep 1 6. Flynn JT: Ethics of placebo use in pediatric clinical trials: The case of antihypertensive drug studies. Hypertension 2003;42;865-869 7. Smit-Marshall P: Pediatric policies grow up. Applied Clinical Trials 2007;Jul 1 8. ICH E11, Clinical Investigation of Medicinal Products in the Pediatric Population. Guidance for Industry, 2000 9. Gans-Brangs KR, Plourde PV: The evolution of legislation to regulate pediatric clinical trials: Present and continuing challenges. Advanced Drug Delivery Reviews 58 (2006) 106– 115 10. Council for International Organizations of Medical Sciences (CIOMS). International ethical guidelines for biomedical research involving human subjects. Geneva: CIOMS, 2002 11. O’Donnell P.: Preparing for Europe’s pediatric rules. Applied Clinical Trials 2007;Aug 1 12. EC/1901/2006: Practical Aspects. http://www.emea.europa.eu/pdfs/human/paediatrics/practical_aspects.pdf 13. Frequently asked questions on regulatory aspects of Regulation (EC) No 1901/2006 (Paediatric Regulation) amended by Regulation (EC) No 1902/2006 http://www.emea.europa.eu/pdfs/human/peg/52008506en.pdfEC/1901/2006 14. Schreiner MS. Safety and effectiveness data: will children gain access? Am Heart J. 1998;136:4–5.
Nikolaos E Papachatzakis is a freelance Medical Writer based in Gothenburg, Kalliopi Sofou is a Medical Advisor based in Athens, Greece.
Conflict of Interests The authors declare that no competing interests exist.
Affiliation/Regulation Council for International Organizations of Medical Sciences (CIOMS) EC/1901/2006 EC/1901/2006: FAQs EC/1901/2006: Practical Aspects EU Directives European Federation of Pharmaceutical Industries and Association European Medicines Agency (EMEA) Good Clinical Practice (GCP) International Conference on Harmonization (ICH) Paediatric Committee (PDCO) US Food and Drug Administration (FDA) Link http://www.cioms.ch/index.html http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol1/reg_2006_1901/reg_2006_1901_en.pdf http://www.emea.europa.eu/pdfs/human/peg/52008506en.pdf http://www.emea.europa.eu/pdfs/human/paediatrics/practical_aspects.pdf http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev1.htm http://www.efpia.org/content/ http://www.emea.europa.eu/ http://www.emea.europa.eu/Inspections/GCPgeneral.html http://www.ich.org/cache/compo/276-254-1.html http://www.emea.europa.eu/htms/general/contacts/PDCO/PDCO.html http://www.fda.gov/
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