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European community weighs in on challenges to pediatric research in this survey from EUCROF.
Clinical research is vital to promote medical knowledge and improve medical care. In children, clinical trials have resulted in significant improvements in their health care. An example is childhood acute lymphoblastic leukemia, in which the conduct of multicenter clinical trials has improved the five-year survival rate from 25% to more than 70%1 . Children and adolescents represent about 25% of the European population2 , however, most medicines given to children are used off-label.3 In hospital pediatric wards this is around 45%4 and in the neonatal intensive care setting this can be as high as 90%. The experience gained in this way is rarely incorporated into clinical practice guidelines or medicinal product labelling. This off-label use of drugs in children represents a danger to the child in terms of potential under dosing (and possible lack of efficacy) and/or overdosing (with resultant toxicity).5 The lack of appropriate pharmaceutical formulations to allow the effective and compliant administration of many drugs in children is a further issue.
The Clinical Trials Directive (2001/20/EC) is a legislative instrument aimed at providing a homogeneous legal, ethical, and scientific context for the conduct of clinical trials in the EU and was expected to simplify clinical trials and, therefore, stimulate clinical research. However, its implementation has not yet had a positive effect on the number of studies being conducted in pediatrics.
In January 2007, the EMEA introduced a new pediatric medicinal products regulation. It requires that for all medicinal products for which a new marketing authorization application will be made or for existing drugs covered by a Supplementary Protection Certificate (SPC) where a variation to the license will be requested, have to be studied in children according to a Pediatric Investigation Plan (PIP). This has to be agreed on with the EMEA's Pediatric Committee (PDCO), in order to generate either positive or negative data that will be mentioned in the label. A waiver to conduct studies in all or some of the pediatric population can be granted if the medicinal product is expected not to be safe or effective in children, if the indication does not occur in children, or if the product is not expected to represent a significant therapeutic benefit over existing products used in children.
It is noteworthy that the EU implemented the Pediatric Law as a Regulation, i.e., as directly effective European Law that cannot be modified by national authorities. This ensures consistent requirements within the entire EU, which may encourage the conduct of studies throughout the EU in children. In contrast, the Clinical Trials Directive was implemented by the national authorities with some country-specific modifications that led to some delay in coming into operation in several EU countries and also to some inconsistencies in requirements between countries.
The European CRO Federation (EUCROF) was founded in October 2005 as an umbrella organization of national CRO associations and represents the interests of CROs in the EU in close communication with regulatory bodies, the pharmaceutical and biotechnological industries, and the medical and affiliated research community. It is a nonprofit organization that promotes clinical research by improving the knowledge, competence/expertise, and skills of clinical researchers in the EU through networking initiatives and information exchange in congresses and meetings.
In 2007, EUCROF created the Pediatric Working Group (PWG). The PWG consists of a group of seven clinical research professionals representing The Czech Republic, France, Germany, Spain, and The Netherlands.
The first objective of the EUCROF PWG was to analyze the current status of pediatric clinical trials in Europe. Results of an initial survey,6 conducted by the EUCROF PWG in 13 EU-countries plus Russia and the Ukraine, which addressed the historical situation from 2005 to 2007, revealed that the number of ongoing pediatric trials during that period was very low. However, it is expected that the EU Pediatric Regulation will stimulate pediatric research, as similar legislation has done in the United States, and that the number of clinical studies in the various European territories will increase.8
To follow up on this development, the EUCROF PWG conducted a second survey to evaluate the situation in 2008, and to determine the main difficulties and constraints in clinical research with children experienced by the organizations involved and to collect additional and more comprehensive information about pediatric clinical trials in Europe.
Figure 1. Other category includes surgery, nutrition, newborns, infectious intestinal disease, vaccines, and more.
This survey was addressed to CROs, pharmaceutical or biotechnological companies, Institutional Review Boards/Ethics Committees (IRB/EC), and investigators. It aimed to determine the respondents' awareness about the more practical aspects of conducting clinical studies in children through gathering statistics on the number of pediatric studies and their nature. The survey methodology is included in the sidebar. A total of 39 questionnaires from 11 countries in Europe were evaluated in this analysis. A minimum of two and maximum of six questionnaires per country were analyzed. Most of the responders were sponsors (pharmaceutical companies) and CROs, 11 (28%) each. A total of nine (23%) respondents were from IRBs/ECs and seven (18%) were investigators.
Table 1. How survey respondents rated their own level of experience working within each of the four phases of clinical trials (I-IV).
Experience in pediatrics. Most respondents stated that the majority of their experience was in Phase III clinical trials. Sixteen of them (41.0%) said this was a good experience. The least experience was in Phase I studies, where 24 (61.5%) of respondents ticked no experience. The most common indications under study were in respiratory and endocrinology disorders, infectious diseases, and oncology (see Figure 1). Table 1 shows the experience of respondents by study phase and Table 2 the number of trials conducted during the last three years by duration of the study.
Table 2. The number of clinical trials conducted by respondents over the past three years by duration of the study.
Difficult aspects. The most important difficulties in pediatric clinical research were related to protocol development and practical issues. More than 50% of the 39 respondents considered the following aspects of pediatric clinical studies as being difficult or very difficult: "Sampling frequency" 24 (61.5%), "invasiveness" 23 (59.0%), "obtaining both parents presence" 23 (58.9%) or "parents' consent" 18 (48.7%), and "to have sufficient patients to include" 21 (53.8%). A detailed table of responses to this question is available online.
Survey respondents provided insight on some of the more difficult and easier areas within pediatric clinical research.
Tasks requiring external support. The majority of the respondents would like to have support on protocol development. Specifically, 14 (35.9%) of the respondents considered external support as "needed" or "maybe needed" in the following to obtain appropriate patient derived data: nine (23.1%) sampling frequency, eight (20.5%) to determine the appropriate use of samples other than blood, seven (17.9%) invasiveness, and 12 (30.7%) composing informed consent forms. Advice radiation exposure was considered as "needed" or "maybe needed" by seven (18%) of the respondents. See Table 3 for a full list of responses.
Table 3. The survey captured respondents outlook toward external support in three areas: Pharmaceutical development, Protocol development, and Regulatory, IRB, administration, and insurance.
Educational activities. Of all responders, 33 (84.6%) were interested in participating in educational workshops on topics such as the European Pediatric Regulation, ethical aspects, writing of the informed consent form, and obtaining informed consent. Interest was greatest in education on the conduct of late phase studies, particularly recruitment and retention of subjects, cited by 17 (43.6%) of the respondents, and compliance in research with children, which was ticked by 18 (46.2%) of the respondents.
Availability of information. The majority of respondents, 30 (76.9%), considered that there was insufficient information available about pediatric clinical trials, while eight (20.5%) considered the available information as adequate and comprehensive. One did not respond. When asked for their preferred information source, dedicated events was the most chosen option, with 28 (71.8%) respondents, followed by dedicated Web pages for 26 (66.7%) respondents. Articles in existing journals and lectures at existing scientific congresses were both preferred by 14 (35.9%) of respondents.
Why pediatric research is not fully developed. The disappointing development of pediatric research was thought to be due to recruitment issues, cited by four (10.3%) respondents, legislation/administrative issues cited by four (10.3%) respondents, and financial concerns mentioned by three (7.7%) respondents. Other issues such as underestimation of the costs by the sponsor, difficulties in obtaining EC approval and low interest of sponsors were mentioned by eight (20.5%) of the respondents.
The future. Finally, the main concerns for the future of clinical research in pediatrics were recruitment, given as a concern by seven (17.9%) respondents, and legislation/administrative hurdles, mentioned by eight (20.5%) respondents. Other concerns were slow improvement of legislation, low investment, parental consent, and the existence of extensive regulation cited by 12 (30.8%) of the respondents.
The answers obtained in this survey clearly indicate that there is a real need for better understanding of the design of pediatric clinical trials and the selection of appropriate and validated endpoints for pediatric use.
The respondents to the survey have demonstrated their interest in obtaining appropriate patient data, through collaborating with experienced investigators with appropriate site staff, in developing a better understanding on how to write a good Patient Information Sheet, in gaining the skills to help to keep both parents and their children motivated during the trial, and ensuring compliance with the protocol. Ethics Committees dealing with applications for pediatric trials should include a member who is experienced in both clinical trials and specifically studies in pediatric subjects. There is a clear need by all parties involved in a study to understand the ethical aspects of conducting trials in children.
With regards to the design of a clinical trial, the majority of the respondents was focused on having a good sample size calculation and less invasive procedures.
The need for external support from experienced professionals such as monitors was evident, but there is also clear interest in participating in international workshops focused on issues related to the conduct of pediatric trials and European regulations. The responses to this survey stated throughout the insufficient information available on pediatric clinical trials and that there is a desire for dedicated events and Web sites to disseminate this information.
The disappointing development of clinical trials in children is ascribed to difficulties with enrollment, underestimation of study costs by sponsors, difficulties in obtaining EC approval, the slow improvement of legislation, and at the same time extensive regulations. This leads to the conclusion that more education and sharing of experience with pediatric studies is very much desired.
The conclusions drawn from the results of this survey may be limited. The total number of questionnaires completed was insufficient to give a representative picture of the state of pediatric research in Europe. Only 39 were completed and returned. Those not responding preferred not to divulge information on clinical studies in children or did not have time to respond within the time frame. The majority of the questionnaires received were from sponsors and CROs. The respective sponsors and CROs may not fully oversee the development of all the pediatric studies in their territory and, therefore, these data may not be necessarily representative of the situation in the broader Europe.
As a conclusion, the results of the survey have clearly demonstrated the need for intensified pediatric research. From all the questionnaires received it is clear that additional education on pediatric studies is desired.
Adam Svobodník is Director of Business Development at Advanced Drug Development Services, Boulogne-Billancourt, France. Amparo Alemany* is Madrid Office Director at TFS Trial Form Support, Madrid Spain, email: email@example.com. Antoine Cournot is President of European Business Operations for RPS Research, France. Jürgen Schäfer is Managing Director at Conreso GmbH, München, Germany. Martine Dehlinger-Kremer is Vice President Global Regulatory Affairs for Omnicare Clinical Research, Bad Soden, Germany. Marta Mas is Scientific Director at TFS Trial Form Support Spain, Barcelona, Spain; Michel Levy is President of Advanced Drug Development Services, Boulogne-Billancourt Cedex, France. And Philippa Smit-Marshall, MD, is Vice President for Europe and Asia Pacific Medical Affairs, at PharmaNet BV, Leusden, The Netherlands.*To whom all correspondence should be addressed.
1. P.H. Caldwell, S.B. Murphy, P.N. Butow, J.C. Craig, "Clinical Trials in Children," Lancet, 364, 2176-2177 (2004).
2. P. Smit-Marshall, "Pediatric Policies Grow Up," Applied Clinical Trials, July 2007.
3. E. Tan, N.E. Cranswick, C.R. Rayner, C.B. Chapman, "Dosing Information for Paediatric Patients: Are They Really Therapeutic Orphans?" The Medical Journal of Australia, 179 (4), 195-198 (2003).
4. S. Conroy, I. Choonara, P. Impicciatore et al., "Survey of Unlicensed and Off-label Drug Use in Paediatric Wards in European Countries," British Medical Journal, 320, 79-82 (2000).
5. The European Table Initiative, "History of the Paediatric Regulation," EMEA Document Reference EMEA/17967/04 Rev 1.
6. M. Dehlinger-Kremer, C. Kreutz, A. Cournot, A. Alemany, K.P. Saalbach, J. Schafer; P. Smit-Marshall, Good Clinical Practice Journal, 10-15 (July 2009).
7. P. Smit-Marshall, "The Globalisation of Paediatric Research," European Pharmaceutical Contractor, 24-27 (June 2009).