European Regulatory Authorities and Pediatric Labeling

Children should not be given medicines that have not been evaluated adequately for use in that age group. There is a responsibility, shared by applicants and the appropriate authorities, to ensure that children have timely access to safe and effective medicines that have accurate, scientifically justified prescribing information. Applicants are encouraged to investigate the safety and efficacy of a product in children, if it is likely to be of therapeutic benefit in this age-group, and to develop suitable formulation, even if use is likely to be small.However important a clinical trial may be to prove or disprove the value of a treatment, individual members of one or both of the groups—subject or control—can suffer injury as a result of inclusion in the trial, even if the whole community benefits. As with adults who participate in clinical trials and who understand the issues involved in giving their informed consent, consent should be obtained from the legal guardian of children in accordance with national legislation. Children should be fully informed about the trial in language and terms they understand and, if able, should personally sign and date the written informed consent. The child should be made aware of his/her rights to decline to participate. The child's wish to be withdrawn from a study must be respected.These measures should be applied in conjunction with 1) part 4 of Directive 75/318/EEC, as amended, which requires “… details concerning patients who may be at increased risk”; the CPMP/ICH guideline for good clinical practice; and 3) the CPMP guideline on biostatistical methodology in clinical trials in applications for marketing authorizations for medicinal products.These measures are intended to assist applicants with specific problems presented by medicinal product testing in children. The child should stand to obtain some direct benefit from the clinical trial, except under very specific conditions, although it is not appropriate to offer financial or other inducements to parents, guardians, or children to participate in clinical trials. However, they may receive reimbursement for their costs, including those for travel and subsistence.Adequate evaluation of medicinal products for use in children cannot be conducted in adult studies because there are physiologic differences between children and adults, and because children suffer from different diseases than adults or show a different natural history for the same disease.The following are some specific age-dependent differences.These differences include reduced protein binding, slow elimination attributable to immaturity of both metabolic pathways and renal functions, and unpredictable absorption in both term and preterm infants at birth and in the first weeks of life. In later infancy and early childhood, faster rates of metabolism may necessitate the administration of higher doses per unit of body weight or surface area than in adults to obtain identical plasma levels and clinical effects (examples are phenytoin and digoxin). In addition, faster rates of elimination may necessitate more frequent administration.At the early stages of development, some receptor functions, effector systems, and homeostasis mechanisms, although adequate for this age, are not developed sufficiently to permit the desired pharmacologically induced change of organ or tissue function.Normal growth and development, both physical and mental, can be influenced adversely by medicinal products (eg, retarded growth with corticosteroids, impaired educational progress with anticonvulsant therapy). Outcomes depend on the timing and the duration of exposure and are not always reversible.Children may need medicinal products for diseases that differ from those in adults because of increased frequency (eg, otitis media, invasive bacterial infections); increased severity (eg, diarrhea); or different natural history (eg, acute leukemia, nephrotic syndrome, or arteriosus, vitamin K deficiency bleeding, inborn errors of metabolism, growth hormone deficiency, pediatric tumors).For all these reasons, the effects of many medicinal products on children may differ considerably from effects observed in adults, even when dosage has been adapted to body weight or body surface area. Thus, the adult experience with the medicinal product may not predict accurately the minimal effective dose, maximum titrated dose, therapeutic effect, or adverse reaction in the child.Every effort must be made to reduce known hazards, and investigators should be fully aware, before the start of a clinical trial, of all relevant preclinical and clinical toxicity that has been seen in the development of the medicinal products.In general, safety studies should be conducted first in animals as a part of the routine preclinical development, then in adults and, finally, in younger patients. The possibility of polymorphic metabolism of the medicinal product should be considered. This sequential approach should identify most toxicity problems, but children of certain ages may have adverse reactions not seen in adults (eg, retinopathy of prematurity, kernicterus, gray syndrome of the newborn with chloramphenicol, tooth discoloration with tetracycline). However, there are circumstances in which parallel evaluation in adults and children is acceptable or even preferable.As is the case for trials in adults, studies should be designed efficiently using the minimum numbers required to provide statistical significance, especially in pivotal studies. A poorly designed trial is unethical. It may provide uninterpretable results and may require additional studies, thereby exposing more children.All staff should be aware of the usual procedure to stop the study at the earliest possible time if a hazard arises. In a blinded, controlled study, there must be no delay in breaking the code.Children should not be exposed knowingly to doses of unneeded products. However, before the start of any investigation of a medicinal product in children, the sponsor and the investigator(s) should agree to emergency protocols so that appropriate studies (eg, pharmacokinetic) can be initiated promptly in the unusual circumstances of accidental overdose or intoxication, or when unusual administration or dose of a medicinal product is required by a child, although such use and dosage schedules have not been evaluated fully.Pharmaceutics companies are encouraged to provide facilities for such emergency assay of the medicinal product, and clinicians should report the results promptly to the appropriate authorities.A widespread concern exists that trials may involve repeated invasive procedures that may be painful or frightening to a child. This is unlikely if the trials are designed and conducted by investigators experienced in the treatment of children. Trials should not be designed or conducted by those inexperienced in working with children.Protocols and investigations should be adapted for children and approved by a responsible research ethics committee, which should ensure that trials are designed and conducted in a manner that minimizes pain, discomfort, and fright, and that includes only the number and extent of examinations and invasive procedures scientifically and clinically essential.Children respond to medicinal products differently, depending on their physiologic and anatomic stage of development. There is wide variation among individuals in terms of weight, surface area, and stage of development (maturity in the preterm infants, stage of puberty in the adolescent) for a given age. Nonetheless, classification of children by age group is useful for evaluation of medicinal products, because age is almost accurately known and, for a given population, an adequate sample defined by age is likely to be sufficiently representative for extrapolation of trial results to prescribing information for that population.Because of the variation among individuals, standardization of age groups is inevitably arbitrary. However, the definition of generally accepted, easily memorable, age groups provides important advantages in terms of assessment and monitoring of efficacy and safety for applicants, appropriate authorities, prescribers, dispensers, and patients.When a clinical trial is to be performed in children, it is usually desirable to begin with older children before extending the trial to younger children and then to infants. Evaluation should be made in the appropriate age group (s) depending on expected use. The extent and type of the studies needed depend on the current knowledge of the medicinal product and the possibility of extrapolation from other age groups.Appropriate formulations are required for different age groups. For example, oral suspensions are preferable for younger children. Also, younger children need special devices when taking medicinal products by inhalation.The following age groups are intended as a guide, considering that individual growth and development will vary from the norm. They represent the development of a so-called average child. Additional consideration must be given to sex differences and to the need to correlate data relating to medicinal product plasma levels, therapeutic dose, adverse reactions, weight, surface area, and maturity/stage of development. Ages are defined in completed weeks, months, or years.Note that the definition is based on estimated gestational age (maturity) at birth, and not birth weight. A distinction should be made for low birth weight infants as to whether they are immature or growth-retarded. If immature, dosage may require modification according to gestational age.Newborn infants, both term and preterm, show an increased sensitivity to pharmacological agents. The newborn body composition differs from that of older infants (eg, more water, limited energy stores), particularly in the case in preterm infants. The newborn period is characterized by rapid renal, hepatic, enzymatic, and homeostatic development. Significant changes occur, affecting glomerular filtration and tubular secretion. Preterm infants have poorly developed regulatory mechanisms and are at risk for respiratory depression.Other potential hazards include enhanced medicinal product penetration to the brain; the possibility of rapid transdermal medicinal product absorption; a very high body surface area to weight ratio; a rapid variation with age of protein binding of medicinal products and changes in bilirubin kinetics; and difficulty in identifying the nature and mechanisms of toxicity.This is a period of CNS maturation associated with the completion of myelination. During this time immune systems develop, and both overall growth and brain growth are rapid. Potential for drug metabolism cannot be extrapolated directly from body weight because of differences in the proportions of different tissues in relation to weight (for example, the ratio of liver volume to unit body weight).Children in this age group reach several important milestones of psychomotor development that could be affected adversely by CNS-active drugs. Somatic growth and development proceed at a constant rate. In this age group, a number of factors can be useful in determining the effects of a medicinal product on such areas as skeletal growth, weight gain, school attendance, and school performance.There are important pharmacokinetic differences in this group that must be considered to avoid therapeutic failures. Although absorption, distribution, and excretion rates in this age range can be extrapolated more confidently from adult data, metabolism per unit weight continues to differ from that seen in adults.This is a period of sexual maturation when a medicinal product may interfere with the actions of sex hormones and impede development. Pregnancy testing and, in relevant trials, review of sexual activity and contraceptive use become necessary.This also is a period of rapid growth. Drugs or illnesses that delay or accelerate the onset of puberty can have a profound effect on the pubertal growth spurt by changing the pattern of growth that may affect final height.Many diseases also are influenced by the hormonal changes that occur in puberty (eg, insulin resistance increases in diabetes mellitus; seizures may recur around menarche; migraine and asthma may change in frequency and severity), and thus may influence the results of clinical trials.Within this age group, children are assuming responsibility for their own health and medication. Noncompliance is a special problem, particularly when drugs, such as steroids, affect appearance. In clinical trials, compliance checks are important, and investigators must be aware of and prepared for the possibility of intentional overdose. Children involved in recreational use of unprescribed drugs need to be specifically excluded.Children of the same age display wide variations in height, weight, and psychosocial and sexual development, and there are significant differences between the sexes in these factors.There are four principal categories of medicinal products in which pediatric testing is necessary. The categories of clinical trial methodology should be adapted specifically to the disease and to the therapeutic class. Note should be taken of guidelines that already exist for certain therapeutic classes and/or for medicinal products intended for long-term use in adults. These can be adapted for pediatric use where appropriate, taking into account the features of the disease in childhood. Clinical trials also should demonstrate that the dosage form is appropriate for administration to the child.Trials in children are essential to demonstrate efficacy and show the safety profiles of the product.Clinical trials in children are needed at an early stage in clinical development to confirm the efficacy of the product and to determine the appropriate conditions of use.Clinical trials in children are needed at an early stage in clinical development, usually as soon as there is evidence of efficacy in adults. The purpose of pediatric trials is to determine a safe and effective dosage schedule in the different age groups and to detect unforeseen and unique effects in childhood.These medicinal products will already have a background of exposure in adults. The purpose of pediatric trials is to demonstrate comparable efficacy, safety, or convenience in children compared with existing treatment; to determine safe and effective dosage schedules in the different age groups; and to detect unforeseen and unique effects in childhood.The pediatric dosage regimen may be determined at different stages in the evaluation of a medicinal product in adults, according to the disease (severity, specificity), the degree of innovation of the medicinal product, potential risks, and therapeutic alternatives.If a product is being developed initially for the treatment of a childhood-specific illness, the clinical development may start in children before any previous adult exposure. In other circumstances, relevant safety and tolerability data from previous adult exposure are needed before proceeding with studies in children. In most cases, reasonable evidence of efficacy in adults also is needed to justify these studies in children. In all cases, pediatric studies nevertheless should be conducted as soon as the medicinal product profile allows, to avoid an excessive delay in obtaining marketing authorization for children compared with adult marketing authorization.Trials in children can start before any previous adult human exposure.Clinical trials in children are needed at an early stage in clinical development, after demonstration of safety and reasonable (phase I/II) evidence of efficacy in adults.Clinical trials in children are needed at an early stage in clinical development, after demonstration of safety and reasonable (phase I/II) evidence of efficacy in adults.Clinical trials in children will follow completion of adult phase III trials.As indicated above, trials are considered necessary in children for at least four categories of medicinal products. The kind of trials and the extent of information needed for registration depend on the category and the information already available.Medicinal product blood levels can provide the basis for determination of the dosage schedule, in particular for those medicinal products for which serum levels can be readily related to the pharmacologic or therapeutic effects. Initial titrating doses may be estimated based on body weight/surface area from an extrapolation of adult data. Radiolabeled studies are not appropriate in children.All studies should lead to an accumulation of data that account for the absorption, distribution, metabolism, and excretion of the medicinal products. Identification and quantification of the principal metabolites of the medicinal product permit comparison with the elimination pattern of adults. If major differences exist, such studies serve as a warning of possible adverse effects and should lead to attempts to identify the unique or unusual pathway of metabolism in the immature patient. Plasma protein binding should be studied, at least in newborns and infants.Each age group requires studies of varying degrees of depth and completeness appropriate to the medicinal product and the intended use. Not all medicinal products need to be subject to full investigations, but judgment should be exercised about requirements for clinically relevant data.The development of appropriate methods for using small blood volumes (eg, radioimmunoassay, high performance liquid chromatography, mass spectrometry, all of which use as little as 20–100 μL) is particularly important. Urinary determinations also are useful (eg, for assessment of biologic half-life and exploration of metabolism); however, collections are not easy (incomplete emptying of the bladder and loss of urine). of medicinal in have been but not always provide information and require the of the for this can be a useful of sample there is a good between and pharmacokinetic methods may provide a to pediatric data and reduce the on individual studies demonstrate or confirm that the medicinal product is effective and unforeseen and that the dosage schedule is appropriate in terms of efficacy and essential is that and/or pediatric must be involved in the trial and Clinical trial methodology is children is not different from that in adults in statistical or trial should be adapted to 1) the therapeutic the clinical 3) the stage of of the and the of treatment (eg, of of efficacy can only be by to in a This is if a suitable medicinal product is not if information on the effect is needed (eg, or if the efficacy of existing is in trials may also be necessary in in which the effect is known to be high or very (eg, trials are considered one acceptable is to demonstrate to an The demonstration of comparable efficacy to an also may be acceptable when no other are the trials to the required under the certain (eg, controlled studies may not be However, the for studies should be exposure of an age group to the medicinal product on a a suitable dosage schedule should be using such studies will on as the groups should be with to 1) the of and 3) other factors such as or studies should be limited to specific age groups or should include several age groups and for will depend on whether the natural history of the disease under study and the expected to the are different in the different age groups. As in all clinical trials, the numbers of patients to be in age group will be determined by the statistical taking into account the disease in age clinical and data should be considered with to for the age groups (eg, profile of blood levels in also may be such as the need for additional as as in school growth and weight gain, their assessment is long-term may differ between adults and children, For example, small children with asthma cannot be by of or studies should include of adverse reactions at the time of the The of of adverse whether by or by or by other must be and appropriate for the age groups being on the nature of the medicinal product and long-term studies also may be required to determine possible effects on and immune maturation and development. studies will confirm the safety profile of the medicinal pediatric patients are in clinical trials, results from previous adult human exposure usually represent the most relevant safety data and, except in unusual circumstances, generally should be before pediatric clinical trials are In all cases, in to appropriate toxicity studies, all toxicity studies and the of should be completed before the of trials in pediatric safety studies should be considered on an individual need for testing should be before long-term exposure in pediatric clinical trials, taking into account the duration of treatment and/or for the use of the medicinal product in children is appropriate will the of clinical trials in children. should be before marketing not only when a medicinal product is to be or in children, but for of when 1) a medicinal product is likely to be in children because of therapeutic effect that is particularly to a pediatric disease or a dosage and a medicinal product a major therapeutic and is likely to be in of data in children in any of the circumstances should be justified by the at the time of for marketing In such the appropriate will into account the timing of clinical trials in children in relation to studies conducted in adults and any or trials in other circumstances, there should be a that the medicinal product should not be in children additional data become The for the should be in the product with any information that may be on use in such children in the product should be and the products that are in children should according to the existing The period provides an to the of variations in terms of efficacy and safety, both and in the different age particularly in preterm and term newborns and in older infants.