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Trials in children
Epilepsy Research 45 (2001) 133– 136 www.elsevier.com/locate/epilepsyres
Trials in children J.P. Amann *, O. Dulac Hopital Saint Vincent de Paul, 74 -82 A6enue Denfert-Rochereau, 75674 Paris, Cedex 14, France
Abstract Over 20% of epilepsies in children are intractable, and are frequently associated with deterioration of motor and cognitive functions. Some are similar to those seen in adults, but many age-related epilepsies occur only in children. Therefore, a sizeable proportion of intractable epilepsies of childhood are different from those encountered in adults, and there is an urgent need for antiepileptic drug trials to be undertaken in children at an early stage of development. An ethical framework within which these trials can be conducted has been defined. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Paediatric trials; Intractable epilepsies; Ethics; Antiepileptic drugs
1. Introduction Over 20% of paediatric epilepsies are intractable: therefore, 1000 children in France and 5000 in the US develop intractable seizures each year. Intractable epilepsy not only produces seizures, but also deterioration of motor and cognitive functions. Although some types of epilepsy in children are similar to those observed in adults, a whole range of age-related epilepsies do not occur in adults, although some may begin in childhood and persist into adulthood. This is particularly the case for epilepsies that affect cognitive and motor functions. Therefore, a sizeable proportion of intractable epilepsies of childhood are different from those encountered in adults and information on drugs to be used to treat children * Corresponding author. Tel.: + 33-1-40488055. E-mail address: [email protected] (J.P. Amann).
cannot be drawn exclusively from studies performed in adults. There is a great need for drug trials to be performed in children, particularly for epilepsy.
2. Information on new antiepileptic drugs Currently, antiepileptic drugs (AEDs) are being developed primarily for adults, and they are only marketed if they seem promising in this age group. It is only later that studies are done in children, and a mean delay of 5–10 years between studies in adults and in children is usual. This priority given to adults is unjustified and its consequences are potentially severe for children with epilepsy. Indeed, it is most likely that vigabatrin would not have been marketed for children had retinal problems been identified earlier, and a valuable drug for the treatment of infantile
0920-1211/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 1 ) 0 0 2 3 7 - 6
134
J.P. Amann, O. Dulac / Epilepsy Research 45 (2001) 133–136
spasms, one of the most devastating epilepsy syndromes, would never have reached clinical use. Furthermore, when a new compound is launched for adults, usually no data regarding children have been collected: this was the case for tiagabine, levetiracetam and topiramate. Even if valuable data do exist at this stage, they are generally not released because this may be regarded as promotion of the drug outside the restrictions of its licence. Lamotrigine experienced this situation when it was launched for adults, yet it is now clear that the potential benefits of this drug in children suffering major deleterious types of epilepsy, such as myoclonic-astatic epilepsy, are even greater than for any epilepsy occurring in adults. The very high, but preventable, risk of a severe rash in childhood as a result of its combination with valproate, the AED most commonly used in children, had been identified but it was not reported to the clinician: as a result, children with difficult epilepsies were treated before any information was released, with severe consequences. With other compounds such as felbamate, data focusing on children are restricted to partial epilepsy and one type of age-related generalised epilepsy syndrome (Lennox– Gastaut syndrome), but with the latter the data are drawn mainly from an adult population. In any case, data rarely cover the whole range of the various epilepsy syndromes that occur in childhood in order to identify any risk that any may be worsened. Lack of paediatric data on AEDs generates three major risks. Age-related side effects may not be identified, the potential worsening of specific epilepsy syndromes may not be recognised, and effective compounds may not be identified for the benefit of children with age-specific disorders. For example, valproate hepatotoxicity has been shown to be highly age-related, and the behavioural side effects of phenobarbital are also age-specific. Worsening of age-related epilepsy syndromes is a widely recognised feature, for example myoclonic and absence epilepsies may be worsened by vigabatrin, and severe myoclonic epilepsy of infancy (Dravet’s syndrome) may be worsened by lamotrigine. Therefore, knowledge of efficacy and safety cannot be drawn exclusively from studies in
adults. Lack of data in children is both unethical and uneconomical: indeed, chronic epilepsy often becomes established in childhood and any compound active in this situation would be indicated for many years or decades, far into adulthood.
3. Ethical issues The circumstances in which paediatric studies can be performed need to be addressed. According to Article 28 of the United Nations convention on the Rights of Children (1989), primary education should be free and compulsory, and the child has the right to receive the best possible health and rehabilitation. Thus, a child is a person who needs to be educated, and recognised for decisions he may take as a person. The history of children has progressed through several phases over the past centuries. As mentioned by Grodin and Alpert (1988), ‘while progressing from a condition in which children were regarded as a chattel of parents to paternalism and to empowerment, society has grappled with the proper balance between protection and autonomy. In the area of patient care, medicine and society have similarly balanced the protection of the rights of patients with appropriate concern for the benefits and welfare of the patient. This need to promote individuality, while imposing constraint, has been particularly difficult with children. Children as a group should not be orphaned from the benefits of research and yet, as a vulnerable population, they are clearly in need of additional protection’. Currently, the child is considered as ‘a developing person’. The Belmont report suggests that the respect for persons, beneficence and justice should be sacrosanct, but the question then is whether respect for the person and benefit are irreconcilable regarding children. Indeed, benefit for the child requires the best knowledge of age-specific diseases and the effect of treatment on them. This requires studies in childhood. On the other hand, respect for the person requires that studies are done with both the consent and contribution of the person.
J.P. Amann, O. Dulac / Epilepsy Research 45 (2001) 133–136
Several possibilities have been suggested: In the surrogate of libertarian solution, parents replace the child for the decision whether to enter a trial or not. This concept is irreconcilable with several aspects of the law, because although parents can replace children for decisions concerning their belongings, they cannot replace them for decisions concerning their bodies. Indeed, acting to put another in harm’s way may violate the guardian’s protective role. In addition, there are unfortunately some parents who are not protective. The no consent–no research solution of Nuremberg would exclude childhood from the benefits of research in fields in which studies in alternative populations could not generate adequate knowledge. Thus, children would be orphans of research. This is unacceptable for a particularly vulnerable population group. In the no consent– only therapy solution of Helsinki, therapeutic research is encouraged but ‘where there is no possible relation to the child’s recovery, a child is not to be made a mere object in medical experimentation’ (Ramsey, 1970). However, the distinction between therapeutic and non-therapeutic research is often very subjective. The risk – benefit US federal regulation solution is currently considered the most appropriate and has been adopted by most countries with various modifications. Since research involving children is important for health and well-being of all children and can be conducted in an ethical manner, this approach allows research with children, provided it holds out direct benefit to them or does not place them at unwarranted risk of harm, discomfort, or inconvenience. The greater the risk, the more rigorous and elaborate are the procedural protection and consent requirements. 4. Other issues Three major questions remain: (1) what knowledge is required that cannot be drawn from other population groups than children, and when should this information be obtained? (2) How can the number of patients exposed during studies be reduced to the minimum required? (3) How can the information be made available to physicians in charge of sick children as soon as possible?
135
Regarding tolerability, data on at least 200 children-years should be available. This needs prospective and structured collection of data. Children treated with medication and any comedication should be observed in the setting of double-blind, placebo-controlled or comparative studies in order to identify the types of side effects and their incidence compared with a placebo and with alternative therapy. A major issue is that in some countries, as in France, tolerability studies cannot be conducted since they are not considered to involve potential benefit to the child. Pharmacokinetic studies need to be undertaken, starting with the neonatal period if there is any indication that the compound could be useful in that age group. The practice of admitting the child to hospital and obtaining a large number of blood samples may be questioned, because this involves no personal benefit to the child included in such a study. An alternative approach would be to design population pharmacokinetic studies that could be included in both open and controlled trials. In vitro studies on cultured hepatocytes may allow observations on the metabolism of the drug to be made, and this may circumvent the need for some clinical studies. The issue of efficacy according to age-specific epilepsy syndromes is still not well understood. We need to be able to identify those syndromes which respond best in terms of control of seizures, as well as the risk for worsening in some specific syndromes. However, the need for paediatric studies in epilepsy syndromes that occur also in adults, such as partial epilepsy, is questionable when the same AED has been shown to be active under controlled conditions in adults. To date, no marketed compound has failed to show efficacy in childhood partial epilepsy when it had previously been demonstrated to be effective in adults.
5. Conclusion The ethical framework of research in children has been clearly defined. The requirements issued by regulatory bodies for marketing claims have also been defined. However, it is clear that these are often irreconcilable. Studies required for li-
136
J.P. Amann, O. Dulac / Epilepsy Research 45 (2001) 133–136
censing purposes in children may not be ethically acceptable because they may involve experimental procedures (e.g. certain uses of placebo) that cannot be easily justified in children. As a result of insufficient or inappropriate paediatric research, the minimum data necessary for safe use of a new AED in children, i.e. information on tolerability and risk of worsening in specific epilepsy syn-
.
dromes, are usually not available when the drug is introduced into the market.
References Grodin, M., Alpert, J., 1988. Children as participant in medical research. Pediatr. Clin. North Am. 35, 1389 – 1401.
Trials in children J.P. Amann *, O. Dulac Hopital Saint Vincent de Paul, 74 -82 A6enue Denfert-Rochereau, 75674 Paris, Cedex 14, France
Abstract Over 20% of epilepsies in children are intractable, and are frequently associated with deterioration of motor and cognitive functions. Some are similar to those seen in adults, but many age-related epilepsies occur only in children. Therefore, a sizeable proportion of intractable epilepsies of childhood are different from those encountered in adults, and there is an urgent need for antiepileptic drug trials to be undertaken in children at an early stage of development. An ethical framework within which these trials can be conducted has been defined. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Paediatric trials; Intractable epilepsies; Ethics; Antiepileptic drugs
1. Introduction Over 20% of paediatric epilepsies are intractable: therefore, 1000 children in France and 5000 in the US develop intractable seizures each year. Intractable epilepsy not only produces seizures, but also deterioration of motor and cognitive functions. Although some types of epilepsy in children are similar to those observed in adults, a whole range of age-related epilepsies do not occur in adults, although some may begin in childhood and persist into adulthood. This is particularly the case for epilepsies that affect cognitive and motor functions. Therefore, a sizeable proportion of intractable epilepsies of childhood are different from those encountered in adults and information on drugs to be used to treat children * Corresponding author. Tel.: + 33-1-40488055. E-mail address: [email protected] (J.P. Amann).
cannot be drawn exclusively from studies performed in adults. There is a great need for drug trials to be performed in children, particularly for epilepsy.
2. Information on new antiepileptic drugs Currently, antiepileptic drugs (AEDs) are being developed primarily for adults, and they are only marketed if they seem promising in this age group. It is only later that studies are done in children, and a mean delay of 5–10 years between studies in adults and in children is usual. This priority given to adults is unjustified and its consequences are potentially severe for children with epilepsy. Indeed, it is most likely that vigabatrin would not have been marketed for children had retinal problems been identified earlier, and a valuable drug for the treatment of infantile
0920-1211/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 1 ) 0 0 2 3 7 - 6
134
J.P. Amann, O. Dulac / Epilepsy Research 45 (2001) 133–136
spasms, one of the most devastating epilepsy syndromes, would never have reached clinical use. Furthermore, when a new compound is launched for adults, usually no data regarding children have been collected: this was the case for tiagabine, levetiracetam and topiramate. Even if valuable data do exist at this stage, they are generally not released because this may be regarded as promotion of the drug outside the restrictions of its licence. Lamotrigine experienced this situation when it was launched for adults, yet it is now clear that the potential benefits of this drug in children suffering major deleterious types of epilepsy, such as myoclonic-astatic epilepsy, are even greater than for any epilepsy occurring in adults. The very high, but preventable, risk of a severe rash in childhood as a result of its combination with valproate, the AED most commonly used in children, had been identified but it was not reported to the clinician: as a result, children with difficult epilepsies were treated before any information was released, with severe consequences. With other compounds such as felbamate, data focusing on children are restricted to partial epilepsy and one type of age-related generalised epilepsy syndrome (Lennox– Gastaut syndrome), but with the latter the data are drawn mainly from an adult population. In any case, data rarely cover the whole range of the various epilepsy syndromes that occur in childhood in order to identify any risk that any may be worsened. Lack of paediatric data on AEDs generates three major risks. Age-related side effects may not be identified, the potential worsening of specific epilepsy syndromes may not be recognised, and effective compounds may not be identified for the benefit of children with age-specific disorders. For example, valproate hepatotoxicity has been shown to be highly age-related, and the behavioural side effects of phenobarbital are also age-specific. Worsening of age-related epilepsy syndromes is a widely recognised feature, for example myoclonic and absence epilepsies may be worsened by vigabatrin, and severe myoclonic epilepsy of infancy (Dravet’s syndrome) may be worsened by lamotrigine. Therefore, knowledge of efficacy and safety cannot be drawn exclusively from studies in
adults. Lack of data in children is both unethical and uneconomical: indeed, chronic epilepsy often becomes established in childhood and any compound active in this situation would be indicated for many years or decades, far into adulthood.
3. Ethical issues The circumstances in which paediatric studies can be performed need to be addressed. According to Article 28 of the United Nations convention on the Rights of Children (1989), primary education should be free and compulsory, and the child has the right to receive the best possible health and rehabilitation. Thus, a child is a person who needs to be educated, and recognised for decisions he may take as a person. The history of children has progressed through several phases over the past centuries. As mentioned by Grodin and Alpert (1988), ‘while progressing from a condition in which children were regarded as a chattel of parents to paternalism and to empowerment, society has grappled with the proper balance between protection and autonomy. In the area of patient care, medicine and society have similarly balanced the protection of the rights of patients with appropriate concern for the benefits and welfare of the patient. This need to promote individuality, while imposing constraint, has been particularly difficult with children. Children as a group should not be orphaned from the benefits of research and yet, as a vulnerable population, they are clearly in need of additional protection’. Currently, the child is considered as ‘a developing person’. The Belmont report suggests that the respect for persons, beneficence and justice should be sacrosanct, but the question then is whether respect for the person and benefit are irreconcilable regarding children. Indeed, benefit for the child requires the best knowledge of age-specific diseases and the effect of treatment on them. This requires studies in childhood. On the other hand, respect for the person requires that studies are done with both the consent and contribution of the person.
J.P. Amann, O. Dulac / Epilepsy Research 45 (2001) 133–136
Several possibilities have been suggested: In the surrogate of libertarian solution, parents replace the child for the decision whether to enter a trial or not. This concept is irreconcilable with several aspects of the law, because although parents can replace children for decisions concerning their belongings, they cannot replace them for decisions concerning their bodies. Indeed, acting to put another in harm’s way may violate the guardian’s protective role. In addition, there are unfortunately some parents who are not protective. The no consent–no research solution of Nuremberg would exclude childhood from the benefits of research in fields in which studies in alternative populations could not generate adequate knowledge. Thus, children would be orphans of research. This is unacceptable for a particularly vulnerable population group. In the no consent– only therapy solution of Helsinki, therapeutic research is encouraged but ‘where there is no possible relation to the child’s recovery, a child is not to be made a mere object in medical experimentation’ (Ramsey, 1970). However, the distinction between therapeutic and non-therapeutic research is often very subjective. The risk – benefit US federal regulation solution is currently considered the most appropriate and has been adopted by most countries with various modifications. Since research involving children is important for health and well-being of all children and can be conducted in an ethical manner, this approach allows research with children, provided it holds out direct benefit to them or does not place them at unwarranted risk of harm, discomfort, or inconvenience. The greater the risk, the more rigorous and elaborate are the procedural protection and consent requirements. 4. Other issues Three major questions remain: (1) what knowledge is required that cannot be drawn from other population groups than children, and when should this information be obtained? (2) How can the number of patients exposed during studies be reduced to the minimum required? (3) How can the information be made available to physicians in charge of sick children as soon as possible?
135
Regarding tolerability, data on at least 200 children-years should be available. This needs prospective and structured collection of data. Children treated with medication and any comedication should be observed in the setting of double-blind, placebo-controlled or comparative studies in order to identify the types of side effects and their incidence compared with a placebo and with alternative therapy. A major issue is that in some countries, as in France, tolerability studies cannot be conducted since they are not considered to involve potential benefit to the child. Pharmacokinetic studies need to be undertaken, starting with the neonatal period if there is any indication that the compound could be useful in that age group. The practice of admitting the child to hospital and obtaining a large number of blood samples may be questioned, because this involves no personal benefit to the child included in such a study. An alternative approach would be to design population pharmacokinetic studies that could be included in both open and controlled trials. In vitro studies on cultured hepatocytes may allow observations on the metabolism of the drug to be made, and this may circumvent the need for some clinical studies. The issue of efficacy according to age-specific epilepsy syndromes is still not well understood. We need to be able to identify those syndromes which respond best in terms of control of seizures, as well as the risk for worsening in some specific syndromes. However, the need for paediatric studies in epilepsy syndromes that occur also in adults, such as partial epilepsy, is questionable when the same AED has been shown to be active under controlled conditions in adults. To date, no marketed compound has failed to show efficacy in childhood partial epilepsy when it had previously been demonstrated to be effective in adults.
5. Conclusion The ethical framework of research in children has been clearly defined. The requirements issued by regulatory bodies for marketing claims have also been defined. However, it is clear that these are often irreconcilable. Studies required for li-
136
J.P. Amann, O. Dulac / Epilepsy Research 45 (2001) 133–136
censing purposes in children may not be ethically acceptable because they may involve experimental procedures (e.g. certain uses of placebo) that cannot be easily justified in children. As a result of insufficient or inappropriate paediatric research, the minimum data necessary for safe use of a new AED in children, i.e. information on tolerability and risk of worsening in specific epilepsy syn-
.
dromes, are usually not available when the drug is introduced into the market.
References Grodin, M., Alpert, J., 1988. Children as participant in medical research. Pediatr. Clin. North Am. 35, 1389 – 1401.