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Applied Clinical Trials
New regulation provides the EU with a solid framework to stimulate R&D for children's medicines.
The Pediatric Regulation has been born after a gestation period lasting some seven years. The objective of the regulation is to stimulate pediatric clinical research, which is still in its infancy in terms of defining the best usage of everyday medications for children. This article discusses some aspects of the Regulation and the hopes that it will bring pediatric research successfully to adulthood.
The Regulation on Medicinal Products for Pediatric Use (Regulation (EC) No 1901/2006) entered into force in the EU on January 26, 2007,1 and will be adopted by each of the 27 EU member states.
This Regulation aims to improve health among children in Europe by stimulating the development of new medicines for use in the pediatric population, ensuring that they are appropriately tested and authorized, and improving the availability of information about the use of these medicines.2
The Task Force in Europe for Drug Development for the Young (TEDDY), established in 2005 and involving 18 partners from 11 countries, is expected to contribute significantly to the success of the Regulation since it too has the aim of promoting the availability of safe and effective medicines for children.
Many medicines prescribed for children are given "off-label." In hospital pediatric wards, this figure is approximately 45% and in neonatal intensive care units it is over 90%.3,4 This off-label use is not always published nor adopted in Best Practice guidelines.
Tending to the Young
Since there has been generally a lack of clinical research in children, they may be exposed to unnecessarily high risks, not in the least by being dosed ineffectively or by being given harmful doses of medicines. Children and adolescents represent a significant portion of the European population, about 25%. These are vulnerable patient groups with developmental, physiological, and psychological differences from adults; therefore, the need for adequate clinical research is evident.
Several factors have contributed to the pediatric knowledge gap, including:
The most important reason for the lack of spontaneous basic academic or industry-led research is the practice of extrapolating the use of medicines used in adult indications and formulations to children on the basis of body weight.
Clinical studies will be performed in accordance with the Clinical Trial Directive6 and the ICH guidance 11.7
One of the greatest hurdles in the clinical research of medicines in children has been issues relating to the ethical conduct of studies—particularly consent and assent. A "Considerations" document is in consultation currently, aiming to give guidance for the appropriate ethical environment for studying the pediatric population.8
Recruitment of children in clinical studies is a challenge since populations may be smaller and consent may be problematic. Obtaining consent from parents when their child may be very ill requires special diligence and care. They must be provided adequate information and time to make informed decisions about the risk and benefits of a particular study. There are also questions as to the validity of parental consent obtained under the stress of dealing with their child's illness.
Table 1. The FDA receives requests for pediatric studies from pharmaceutical companies as well as the agency itself and grants written requests based on clinical need.
It should also be recognized that children have a developing capacity to give assent (or consent) and should be consulted if possible on their participation in a clinical study. Information should be presented in an age-specific manner, perhaps using formats such as magazines/comics/pictures. If a child refuses participation in the study and is considered capable of making that judgement, that should be respected.
Retention of study participants is important since patients may need long-term follow-up for safety reasons, and the nurse practitioner/parent relationship is recognized as the most critical to successful patient recruitment and retention.
Because regulatory agencies will require long-term data to be able to assess potential effects on growth and development, it is conceivable that ethical committees and insurers themselves will demand stricter insurance requirements including long-term liability cover.
Pediatric studies require special design considerations. Placebo control can be used in short-term situations, provided rescue therapy is provided for and is more acceptable if alternative treatment is unavailable.
Consideration needs to be given to invasiveness, conducting tests not within normal clinical practice. The limited blood volume, especially in babies and very small children, makes the conduct of Phase I studies particularly challenging and the use of pharmacokinetic and pharmacodynamic modeling techniques using data from adults and population pharmacokinetics may offer solutions.
Many diseases relevant to the pediatric population are rare or infrequent. Design strategies to reduce patient numbers may include innovative study designs such as adaptive designs, cross over designs, and Bayesian analyses. Stratification may also be required to adjust for age, weight, and height and may additionally complicate study design.
Studying a medicine as adjunctive therapy is a common method of demonstrating the potential efficacy of a new compound without denying the patient access to current gold standards. Subsequent studies may then confirm efficacy as monotherapy.
Objective measures of efficacy may be difficult to apply in children. Objective measures such as death are fortunately rare, so surrogate markers of efficacy have to be found. Moreover, the competency of children to use techniques in taking medication in diseases such as asthma may affect the homogeneity of the data collected (e.g., peak flow readings, ability to inhale medication) and, therefore, efficacy measures.
Age specific measures of endpoints, such as pain, need to be developed. Common techniques in children over the age of six years include assigning poker chips and smiling/frowning faces. Quality of life is often an important outcome, but scales need to be sufficiently child centered or family focused. They are often inadequately validated in children or tested for responsiveness to change.
Children may not be able to communicate adverse effects satisfactorily. A medicine may also have long-term effects on growth and development, creating the need for continued pharmacovigilance and careful data mining to pick up signals for concerns. Adequate risk management plans are required.
The European Medicines Agency (EMEA) through the Committee for Medicinal Products for Human Use (CHMP) has produced a guideline on the conduct of pharmacovigilance for medicines used by the pediatric population, highlighting the need to involve as many interested parties as possible.9
The Regulation is similar to the Pediatric Exclusivity offered by the Food and Drug Administration (FDA) in the United States, where the Best Medicines for Children Act 200210 and the Pediatric Research Equity Act 200311 have been in force to increase pediatric drug information.12 A request to conduct pediatric studies may be made by the FDA or a pharmaceutical company. The request is granted based on the clinical need; if the data generated by the studies satisfies the FDA, then patent exclusivity will be granted for six months on all forms of the medicine with a patent.
As of September 2006, 480 requests for pediatric studies had been received by the FDA with 326 written requests issued by the FDA either as approval of a request from a manufacturer or from the FDA itself.13 This represents a significant increase in the number of pediatric studies conducted. Additional labeling information on the safety, efficacy, dosing, and unique risks in children has been included on 100 drugs, and more than 250 pediatric studies of 125 products have been conducted.
The Pediatric Exclusivity provision is due to sunset in Fall 2007, and it is not known whether FDA will continue to provide rewards after that time. The period of exclusivity has already been reduced to three months for products whose yearly sales exceed $1 billion. Reauthorization of the laws is strongly supported by the American Academy of Pediatricians.14
The final Regulation is not significantly different than that published in draft form in 2004.15 Essentially, the Regulation requires that for any new medicinal product in Europe (including new indication, pharmaceutical form or route of administration for an existing authorized product), a Pediatric Investigational Plan (PiP) must be drawn up and submitted to the EMEA. The Regulation was formulated with the input of the Pediatric Expert Group (PEG), which is also conducting an inventory of the unmet therapeutic needs of children in various disease areas.
This month, the PEG is being replaced by a Pediatric Committee (PC), which is a new committee of scientific experts in the EMEA that will be operational within six months of the Regulation coming into force. The committee will comprise representatives from the CHMP, representatives of the 27 member states, health care professionals, and patient associations.
The primary responsibilities of the PC will be the assessment and agreement of PiPs, the evaluation of requests for waivers, and granting deferrals. The PC will also continue to identify the unmet clinical needs of the pediatric population.
The EMEA recommends that the PiP should be formulated after the completion of the adult pharmacokinetic studies in order to stimulate early dialogue with the PC. This may be too early for some medicines where additional safety and efficacy studies in the adult population may be advisable before premature or unwarranted trials in children are conducted.
If the product has a Supplementary Protection Certificate (SPC), the execution of a PiP will be rewarded with a six-month extension of the patent, provided data is incorporated into the Summary of Product Characteristics (SmPC). Authorization is required in all member states for this extension.
This incentive is not considered adequate by European Pharmaceutical companies represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA). They see the six-month period as the absolute minimum and would prefer longer protection to recoup costs.14 Conversely, generic companies would like a shorter period of patent protection.16
The reward requires significant studies to be presented in the application dossier. Studies that were completed previously are not eligible for a reward but will be taken into account for the PiP. Additional rewards, such as tax allowances, may be provided by individual member states.
The Regulation does not apply to products that have been reviewed and approved on a fast-track basis, such as those for HIV/AIDS or cancer, since they do not usually qualify for an SPC but represent indications where there is unmet clinical need. Also, the CHMP has been requested to provide within six months an opinion for the use of carcinogens, mutagens, and substances toxic to reproduction in the pediatric population.
Submission of pediatric data in compliance with the PiP will constitute a validation of any marketing authorization application. For new products, this obligation applies 18 months from entry into force of the Regulation and for licensed products 24 months thereafter. The conduct of clinical studies in children that are not completed at the time of the marketing authorization application will not delay approval of a drug for adult use.
For orphan medicinal products, a two-year extension of the period of market exclusivity to 12 years will be granted. For off-patent products (generics) to be used in children, a new category of marketing authorization, the Pediatric Use Marketing Authorization (PUMA), is proposed to encourage companies to conduct research in children. The PUMA is associated with a reduced regulatory burden allowing companies to refer to data that has been used by other companies to obtain any registration in a member state, and applications may use a centralized route. If a product is approved by the PUMA route, it may use the same brand name as the product with the same active ingredient for which the same holder has been granted authorization for use in adults and gives a 10-year period of data and marketing protection.
The Regulation does not apply to products that are biosimilars, well-established use products or herbal and homeopathic products.
Waivers to the obligation to produce a PiP can be granted when it is considered that pediatric studies are not required or desirable, provided adequate justification is provided. Deferrals can be granted if pediatric studies can only be conducted when appropriate studies have been performed in adults.
The Regulation requires that details of pediatric studies and all existing pediatric data should be added to the European Clinical Trials Database (EudraCT) to improve information levels.
The Regulation stipulates that within three years of coming in force, the EMEA will establish a European Clinical Trials Network to link existing national networks and clinical trial centers. This should facilitate the conduct of clinical studies and avoid duplication of studies. An example is the UK Medicines for Children Network, which was set up in 2005 and receives funding from the Department of Health. Similar networks exist in The Netherlands and Germany.
In order to avoid unnecessary replication of trials, the EMEA will meet regularly with the FDA to ensure compatibility between written requests from the FDA and PiPs from the EMEA. The process for collaboration is still under discussion, and the consequences for products for which studies have been conducted under the pediatric exclusivity ruling are uncertain.
Since patent protected medicines are generally more expensive, there is concern from the House of Lords in the UK that this Regulation may increase the total amount spent on medicines. In some countries, this may deny children access to useful medicines through the extended period of patent protection. In the UK, the House of Lords estimated that the six-month extension would cost the National Health Service an extra Â£30 to Â£120 million.17
There is limited experience with the scientific, ethical, and practical implications of performing clinical trials in children of different age groups. Ethics committees, parents, investigators, and clinical research personnel will have to become more familiar with the ethical and practical requirements of performing GCP-compliant clinical trials in all pediatric age groups.
The EU Clinical Trial Directive (CTD) lays down specific requirements for the protection of children participating in clinical studies. However, many patients participating in studies under a PiP may be recruited from countries where the CTD has not been adopted. The ICH 11 should provide the framework for the conduct of such studies.
The potential cost to the pharmaceutical industry for conducting pediatric clinical research is significant. Although there are financial incentives, these may not fully offset the major investment in a PiP or the cost for developing new formulations for an unmet medical need identified by the PC.
Pharmacovigilance and long-term follow-up to identify effects on growth and development are expensive if safety is to be monitored adequately. These costs may, in fact, represent a disincentive to the industry to conduct studies in children. A company may choose not to apply for a new indication or route of administration for a patented product and so avoid the obligation to conduct clinical studies.
Sufficient funding provided by the EU across many sectors is needed to stimulate research in children. The Regulation provides for this to some extent through European Research Framework programs and incentives provided to the industry. However, a fundamental change in attitude and culture by all interested parties including pediatricians, clinical research centers, regulators, pharmaceutical companies, parents, and national health authorities is needed in order to fully satisfy the aims of the Regulation. Support for basic academic research should be assured, and it is clear that commercial, governmental, and charitable financial support is required if the goal of the Regulation is to be achieved.
The Pediatric Regulation has been some seven years in the making and provides an ambitious framework to stimulate research and development of medicines for use in children through rewards and incentives. The pediatric knowledge gap will probably fill slowly, but whether the Regulation can offset the development costs of new medicines or formulations and support the necessary pharmacovigilance obligations remains to be seen.
1. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on Medicinal products for pediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 (Official Journal L 378, 27/12/2006 pages 1–19). http://eur-lex.europa.eu/LexUriServ/site/en/oj/2006/l_378/l_37820061227en00010019.pdf.
2. EMEA Document reference EMEA/9224/2007.
3. Clinical Trials and Children's Medicines. ABPI briefing paper, http://www.abpi.org.uk/publications/briefings/clinical&child_brief.pdf.
4. European Commission Staff Working paper 13880-04 2004.
5. Reflection Paper: Formulations of Choice for the Pediatric Population. EMEA/CHMP/PEG/19410/2005. Date of adoption September 2006.
6. Directive 2001/20/EC of the European Parliament 4 April 2001.
7. ICH E 11: Clinical Investigation of Medicinal Products in the Pediatric population. CPMP/ICH/2711/99 (January 2001).
8. Ethical Considerations for Clinical Trials Performed in Children. Recommendations of the Ad Hoc group for the development of implementing guidelines for Directive 2001/20/EC. Draft for Consultation 6 October 2006.
9. CHMP Guidelines on conduct of Pharmacovigilance for Medicines used by the Pediatric Population, EMEA/CHMP/PhVWP/235910/2005.
10. Best Medicines for Children Act 2002 Public Law 107–109.
11. Pediatric Research Equity Act (PREA) Public Law 108–155.
12. Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients; Final Rule (63FR 66632; 2 Dec 1998).
14. Testimony of R.L. Gorman, MD, FAAP, before the U.S. Senate Committee on Health, Education, Labor and Pensions, 27 March 2007.
15. European Commission 2004: "Proposal for a Regulation of the European Parliament and of the Council on medicinal products for pediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004." http://
16. EFPIA views on the European Commission's Proposal for a Regulation on Medicinal Products for Pediatric Use, http://extranet.efpia.eu/docs/1/BKEBCAJDOIFCMGGPHLNLAAIDKH66V647K9HKQ9VTQL6P/EFPIA/docs/DLS/PositionPaediatricsmay03-20061208-023-EN-v1.pdf.
17. House of Lords of the United Kingdom. HL 101 Session 2005–2006.
Philippa Smit-Marshall, MBChB, BSc, MFPM, MICR, is executive medical director, Europe and Asia Pacific, for PharmaNet, Storkstraat 18-20, 3833 LB Leusden, The Netherlands, +31 33 4326200, firstname.lastname@example.org