One size does not fit all Integrating ethical and legal guidance into pediatric clinical research

@font-face { font-family: "Cambria Math";}@font-face { font-family: "Calibri";}@font-face { font-family: "Tahoma";}@font-face { font-family: "AdvTT3713a231";}p.MsoNormal, li.MsoNormal, div.MsoNormal { margin: 6pt 0cm 0.0001pt; text-align: justify; text-indent: 14.2pt; line-height: 110%; font-size: 12pt; font-family: Calibri; }h2 { margin: 12pt 0cm 0.0001pt; text-align: justify; line-height: 110%; page-break-after: avoid; font-size: 16pt; font-family: Calibri; }span.Heading2Char { font-family: Calibri; font-weight: bold; }.MsoChpDefault { }div.WordSection1 { page: WordSection1; }Background AlthoughHarry Shirkey reported already in 1968 that in absence of pediatric clinicalresearch minors would be turned into therapeutic orphans, pediatric patientshave been ignored in clinical research for long, and systematic efforts toencourage the inclusion of minors in clinical studies only came decades later.Today, the urgent need for pediatric clinical research in the population ofminors continues to exist, even though it has been generally recognized thatpediatric clinical trials are indispensible to provide minors with an equitablegamut of safe and efficacious drugs as their adult counterparts. Because ofthe important differences between adults and minors both as persons and as populations- paradigms of clinical research, research ethics andresearch regulation that are grafted on the competent adult do not adequatelyrespond to the specifics of pediatric clinical research. Therefore, specificattention must be paid to the ethical, legal, and social issues in pediatricclinical research. In other words: One size does not fit all.Objectives Fourresearch objectives are central to this dissertation: the (1) enhancement ofthe access to and insight in the European legal frameworks that governpediatric clinical research; (2) comparative analysis of relevant regulation atthe supranational level and at the national level; (3) enquiry of theoperational implementation of ethical and legal requirements in informedconsent discussion in clinical research; and (4) ethical analysis of specificissues in pediatric clinical research. Research resultsIn chapter1, the European legal framework (supranational level) governing pediatricclinical trials is analyzed from the perspective of the major ethical concerns inpediatric research. The four principles of biomedical ethics are used as aconceptual framework (1) to map the ethical issues addressed in the Europeanlegal framework, (2) to study how these issues are commonly handled incompetent adults, (3) to detect workability problems of these paradigmaticapproaches in the specific setting of pediatric research, and (4) to illustratethe strong urge to differentiate, specify, or adjust these paradigmaticapproaches to guarantee their successful operation in pediatric research. Inaddition, a concise comparative analysis of the European regulation is made. Toconclude the analysis, our findings are discussed against the background ofexisting ethical discussions on issues specific to pediatric clinical research.In chapter2, the regulation of pediatric clinical research at the level of individual EUmember states is mapped and analyzed. The analysis focuses on the way in whichthe national and supranational legal frameworks address five ethical issuesthat are specific to pediatric clinical research: (a) informed consent, (b) thenecessity to conduct research in minor subjects, (c) the interests of thesubject concerned, (d) the risks and burdens involved, and (e) the pediatricexpertise of protocol review committees. The chapter is concluded by a discussionof the harmonization and diversification of the legal requirements that governpediatric clinical research in the EU.Chapter 3provides an overview of the requirements forinvolving minors in medical experiments in Belgium. In this chapter, the Law of7 May 2004 concerning experiments on the human person (LEH) is analyzed, anddissimilarities between the LEH and the European Directive are discussed.In chapter4, it is analyzed how the enrollment of minors in clinical trials is negotiatedwithin relationships of mutual trust between clinicians, minors, and theirparents. After a brief description of the problems associated with involvingminors in clinical research, it is considered how existing relationships oftrust can be used as a place where the concerns of research subjects can bemore fully discussed and addressed. Building on the tacit recognition of trustfound in The European Clinical Trials Directive, policy recommendations forclearer, more ethically informed guidelines for enrolling minors in clinicalresearch are made.Chapter 5explores seven bottlenecks in the ethical guidance and legal regulation thatcurrently govern pediatric clinical research: (1) the integration of researchin therapy, (2) the education of clinicians, (3) the empowerment of families,(4) the harmonization of protocol review, (5) the assessment of non-clinicalresearch objectives, (6) the control of placebo use, and (7) the provision offair incentives for pediatric research conduct. For all of these issues, a clearview on the way forward is largely lacking, either because these issues havenot been discussed in depth to date, or because the existing debates havefailed to generate a generally supported consensus. In chapter 6, the ethical concerns in twopotential tracks of seeking access to investigational medicinal products forminors are explored: access on an individual basis, or collective access viapatient organizations. In the discourse, several unique ethical and regulatoryconcerns related to the direct negotiation of access to IMP for minor patientsare identified, focusing on product safety, the recruitment of researchsubjects, the unnoticed entry of market mechanisms in the recruitment ofresearch subjects, and the sidelining of third parties in the recruitmentprocess. Chapter 7focuses on the pursuit of non-clinical research objectives in pediatricclinical research. While over the past decades important efforts have been madeto regulate the involvement of children in clinical trials, current ethical andlegal procedures surrounding clinical trials in minors (US/EU) are not designedto consider and assess the non-clinical use of medical technologies such asfMRI. Nonetheless, non-clinical applications of pediatric fMRI cannot bedeveloped without conducting clinical trials in children. In this chapter,diverse ethical issues related to the non-clinical applications of fMRI arediscussed from the perspective of pediatric clinical trial regulation. In chapter 8, major ethical issues in the development and supply oforphan drugs are discussed. This chapter focuses on addressing the commercialdisinterest in developing drugs for rare conditions. While severalinterventions have been made in the regulatory field, existing regulationsleave the overarching question on the righteous place of orphan drugs inresource allocation systems unanswered. In this chapter, major ethical issuesin the development and supply of treatments for rare conditions are analyzed.Subsequently, an ethical framework is proposed, aiming at helping health policymakers in moving forward in the difficult issue of justly allocating resourcesto the prevention and treatment of rare diseases. In chapter9, it is explored how the legal framework governing pediatric clinical researchis implemented in informed consent discussions. In this chapter, the results ofan observational study of informed consent discussions are discussed. ConclusionIn thisdissertation, the ethical, legal and social aspects of clinical research in theEU have been investigated from a multidisciplinary perspective. In the firstfour chapters, the access to and insight in the European legal frameworks thatgovern pediatric clinical research has been increased, by mapping and analyzingnational and supranational legislation. The analysis of legal requirements inchapters 1-3 also covers a comparative analysis of relevant regulation at thesupranational level and at the national level. Specific attention has been paidto the Belgian situation. In addition, the regulation of trust in the Europeanlegal framework surrounding pediatric clinical research has been analyzed, asan illustration of the tacit elements that are essential to the operationalimplementation of legal requirements. Chapters5-8 have focused on the ethical analysis of specific issues in pediatricclinical research, including (1) the integration of research in therapy, (2)the education of clinicians, (3) the empowerment of families, (4) theharmonization of protocol review, (5) the assessment of non-clinical researchobjectives, (6) placebo use, (7) the provision of fair incentives for pediatricresearch conduct, (8) access to investigational medicinal products, and (9) thedevelopment and supply of orphan drugs. An enquiryof the operational implementation of ethical and legal requirements in informed consent discussionhas been presented in chapter 9. To concludethe analysis in this dissertation, seven controversies in contemporarypediatric clinical research are discussed: (1) standard of care versus state ofthe art disease management, (2) protection versus trust, (3) regulation versusdiscretion, (4) harmonization versus heterogeneity, (5) informed consent versusdocumented consent, (6) assent versus procedure compliance, and (7) directbenefit versus valid research results.@font-face { font-family: "Cambria Math";}@font-face { font-family: "Calibri";}@font-face { font-family: "Tahoma";}@font-face { font-family: "AdvTT3713a231";}p.MsoNormal, li.MsoNormal, div.MsoNormal { margin: 6pt 0cm 0.0001pt; text-align: justify; text-indent: 14.2pt; line-height: 110%; font-size: 12pt; font-family: Calibri; }h2 { margin: 12pt 0cm 0.0001pt; text-align: justify; line-height: 110%; page-break-after: avoid; font-size: 16pt; font-family: Calibri; }span.Heading2Char { font-family: Calibri; font-weight: bold; }.MsoChpDefault { }div.WordSection1 { page: WordSection1; }Background AlthoughHarry Shirkey reported already in 1968 that in absence of pediatric clinicalresearch minors would be turned into therapeutic orphans, pediatric patientshave been ignored in clinical research for long, and systematic efforts toencourage the inclusion of minors in clinical studies only came decades later.Today, the urgent need for pediatric clinical research in the population ofminors continues to exist, even though it has been generally recognized thatpediatric clinical trials are indispensible to provide minors with an equitablegamut of safe and efficacious drugs as their adult counterparts. Because ofthe important differences between adults and minors both as persons and as populations- paradigms of clinical research, research ethics andresearch regulation that are grafted on the competent adult do not adequatelyrespond to the specifics of pediatric clinical research. Therefore, specificattention must be paid to the ethical, legal, and social issues in pediatricclinical research. In other words: One size does not fit all.Objectives Fourresearch objectives are central to this dissertation: the (1) enhancement ofthe access to and insight in the European legal frameworks that governpediatric clinical research; (2) comparative analysis of relevant regulation atthe supranational level and at the national level; (3) enquiry of theoperational implementation of ethical and legal requirements in informedconsent discussion in clinical research; and (4) ethical analysis of specificissues in pediatric clinical research. Research resultsIn chapter1, the European legal framework (supranational level) governing pediatricclinical trials is analyzed from the perspective of the major ethical concerns inpediatric research. The four principles of biomedical ethics are used as aconceptual framework (1) to map the ethical issues addressed in the Europeanlegal framework, (2) to study how these issues are commonly handled incompetent adults, (3) to detect workability problems of these paradigmaticapproaches in the specific setting of pediatric research, and (4) to illustratethe strong urge to differentiate, specify, oradjust these paradigmaticapproaches to guarantee their successful operation in pediatric research. Inaddition, a concise comparative analysis of the European regulation is made. Toconclude the analysis, our findings are discussed against the background ofexisting ethical discussions on issues specific to pediatric clinical research.In chapter2, the regulation of pediatric clinical research at the level of individual EUmember states is mapped and analyzed. The analysis focuses on the way in whichthe national and supranational legal frameworks address five ethical issuesthat are specific to pediatric clinical research: (a) informed consent, (b) thenecessity to conduct research in minor subjects, (c) the interests of thesubject concerned, (d) the risks and burdens involved, and (e) the pediatricexpertise of protocol review committees. The chapter is concluded by a discussionof the harmonization and diversification of the legal requirements that governpediatric clinical research in the EU.Chapter 3provides an overview of the requirements forinvolving minors in medical experiments in Belgium. In this chapter, the Law of7 May 2004 concerning experiments on the human person (LEH) is analyzed, anddissimilarities between the LEH and the European Directive are discussed.In chapter4, it is analyzed how the enrollment of minors in clinical trials is negotiatedwithin relationships of mutual trust between clinicians, minors, and theirparents. After a brief description of the problems associated with involvingminors in clinical research, it is considered how existing relationships oftrust can be used as a place where the concerns of research subjects can bemore fully discussed and addressed. Building on the tacit recognition of trustfound in The European Clinical Trials Directive, policy recommendations forclearer, more ethically informed guidelines for enrolling minors in clinicalresearch are made.Chapter 5explores seven bottlenecks in the ethical guidance and legal regulation thatcurrently govern pediatric clinical research: (1) the integration of researchin therapy, (2) the education of clinicians, (3) the empowerment of families,(4) the harmonization of protocol review, (5) the assessment of non-clinicalresearch objectives, (6) the control of placebo use, and (7) the provision offair incentives for pediatric research conduct. For all of these issues, a clearview on the way forward is largely lacking, either because these issues havenot been discussed in depth to date, or because the existing debates havefailed to generate a generally supported consensus. In chapter 6, the ethical concerns in twopotential tracks of seeking access to investigational medicinal products forminors are explored: access on an individual basis, or collective access viapatient organizations. In the discourse, several unique ethical and regulatoryconcerns related to the direct negotiation of access to IMP for minor patientsare identified, focusing on product safety, the recruitment of researchsubjects, the unnoticed entry of market mechanisms in the recruitment ofresearch subjects, and the sidelining of third parties in the recruitmentprocess. Chapter 7focuses on the pursuit of non-clinical research objectives in pediatricclinical research. While over the past decades important efforts have been madeto regulate the involvement of children in clinical trials, current ethical andlegal procedures surrounding clinical trials in minors (US/EU) are not designedto consider and assess the non-clinical use of medical technologies such asfMRI. Nonetheless, non-clinical applications of pediatric fMRI cannot bedeveloped without conducting clinical trials in children. In this chapter,diverse ethical issues related to the non-clinical applications of fMRI arediscussed from the perspective of pediatric clinical trial regulation. In chapter 8, major ethical issues in the development and supply oforphan drugs are discussed. This chapter focuses on addressing the commercialdisinterest in developing drugs for rare conditions. While severalinterventions have been made in the regulatory field, existing regulationsleave the overarching question on the righteous place of orphan drugs inresource allocation systems unanswered. In this chapter, major ethical issuesin the development and supply of treatments for rare conditions are analyzed.Subsequently, an ethical framework is proposed, aiming at helping health policymakers in moving forward in the difficult issue of justly allocating resourcesto the prevention and treatment of rare diseases. In chapter9, it is explored how the legal framework governing pediatric clinical researchis implemented in informed consent discussions. In this chapter, the results ofan observational study of informed consent discussions are discussed.
ConclusionIn thisdissertation, the ethical, legal and social aspects of clinical research in theEU have been investigated from a multidisciplinary perspective. In the firstfour chapters, the access to and insight in the European legal frameworks thatgovern pediatric clinical research has been increased, by mapping and analyzingnational and supranational legislation. The analysis of legal requirements inchapters 1-3 also covers a comparative analysis of relevant regulation at thesupranational level and at the national level. Specific attention has been paidto the Belgian situation. In addition, the regulation of trust in the Europeanlegal framework surrounding pediatric clinical research has been analyzed, asan illustration of the tacit elements that are essential to the operationalimplementation of legal requirements. Chapters5-8 have focused on the ethical analysis of specific issues in pediatricclinical research, including (1) the integration of research in therapy, (2)the education of clinicians, (3) the empowerment of families, (4) theharmonization of protocol review, (5) the assessment of non-clinical researchobjectives, (6) placebo use, (7) the provision of fair incentives for pediatricresearch conduct, (8) access to investigational medicinal products, and (9) thedevelopment and supply of orphan drugs. An enquiryof the operational implementation of ethical and legal requirements in informed consent discussionhas been presented in chapter 9. To concludethe analysis in this dissertation, seven controversies in contemporarypediatric clinical research are discussed: (1) standard of care versus state ofthe art disease management, (2) protection versus trust, (3) regulation versusdiscretion, (4) harmonization versus heterogeneity, (5) informed consent versusdocumented consent, (6) assent versus procedure compliance, and (7) directbenefit versus valid research results.

Jaar van publicatie:2011