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Workshop 7: Special pediatric problems
Workshop
7: Special pediatric
Sheldon C. Siegel, Chairperson, Cochairpersons
Dorothy
problems
D. Sogn, and C. Warren
Bierman,
Rebecca H. Buckley, Elliot F. Ellis, Thomas J. Fischer, Henry Levinson, R. Michael Sly, and William F. Westlin MEMBERS:
I. Introduction II. Specific age-dependent factors A. Adolescent to adult I. General 2. Safety 3. Efficacy 4. Compliance B. Childhood (2 years to adolescence) 1. General a. Safety measurements b. Study designs c. Dosage 2. Parameters of drug effectiveness for children in the 6 years to adolescence age group 3. Parameters of drug effectiveness for children 2 to 5 years of age 4. Special problems in drug testing in children a. Compliance b. Boys versus girls c. Palatability of medication d. Techniques for inhaling medication e. Additive effects f. Consent g. Side effects h. Seasonal variations C. Infant/toddler (1 month to 2 years) 1. General 2. Organ system development a. Immune system b. Gastrointestinal tract and liver c. Kidney d. Pulmonary III. Ethics of research in children IV. Summary of specific age-related guidelines A. Adolescent to adult (12 to 18 years) B. Late childhood (6 years to adolescent) C. Early childhood (2 to 5 years) D. Infant/toddler (I month to 2 years) V. Summary
INTRODUCTION Because of many problems relating to drug testing in children, many of the bronchodilator and NBAAD presently used in the treatment of asthma in infants and children have not been approved for this purpose by the FDA in the United States. Furthermore, there are a limited number of dose response studies of these antiasthmatic agents in the younger age groups, especially in children under 5 years of age. Most of the same difficulties in the evaluation of safety and efficacy of the NBAAD in adults also apply to their in534
vestigation in infants and children. However, there are additional special problems that need to be considered when these agents are tested in childhood. Pediatric studies are essential for this class of drugs because asthma is common in children. Therefore, during drug development appropriate preclinical studies should be carried out in juvenile animals, which will permit the study of these drugs in infants and children. Studies in adolescents should begin either coincidentally or sequentially with the adult studies. if not initiated simultaneous with the adult studies, the early Phase II adolescent studies should be started when the adult studies have reached late Phase II. Studies in the 6 years to adolescent age group should be begun by the time the adult Phase II studies are completed. If there is a dose response relationship, a dose ranging study should be done first to indicate the proper dose that is free from side effects and appears effective. This should be followed by a full clinical trial. Progressively, the 2- to 6-year-old children should be studied when the 6-year-old to adolescent children are at the Phase III level. The infant/toddler age group, 1 month to 2 years, presents a particular problem because it is more difficult to obtain objective measurements in this age group. These studies should be done in a university setting in which appropriate, sophisticated equipment for noninvasive procedures are readily available (see workshop 3). Study design poses a particular problem in the pediatric age group, particularly in children under 6 years of age. The general pediatric guidelines formulated by the American Academy of Pediatrics’ and subsequently published in the Federal Registe? suggest that in younger children, a new drug should be compared with an older drug of known therapeutic value rather than with an inactive placebo. Study design in drug testing in lyounger children and infants and toddlers will be addressed further in this workshop. SPECIFIC AGE-DEPENDENT
FACTORS
It is well known and widely accepted that the age and development status of the infant and child play a significant role in the disposition (absorption, distri-
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bution, storage, metabolism, and excretion) and response to therapeutic agents. In previously published guidelines’, * for the evaluation of drugs to be approved for the treatment of infants and children, the Committee on Drugs of the American Academy of Pediatrics recognized four stages of development with certain characteristics that distinguish each stage from the other stages. The Committee identified the following growth periods: (1) adolescent (onset of adolescence to adult life); (2) childhood (2 years to onset of adolescence); (3) infant/toddler (1 month to 2 years); and (4) neonatal (birth to 1 month). Because asthma rarely occurs in the neonatal period and there are special problems in the evaluation of antiasthmatic drugs in the 2- to 5-year age group, it is more practical to discuss special considerations about drug evaluation in the following growth periods: adolescent, childhood (6 years to adolescence), young child (2 to 5 years), and toddler (1 month to 2 years). Adolescent
to adult
General. Adolescence is defined as “the transition period in which the child undergoes changes in physical, sexual and psychological development transforming him/her into an adult.” At no other time in postnatal life does the individual accelerate as rapidly in the rate of growth or experience such marked changes in bodily function, physical appearance, cognitive capacity, and interpersonal relationships with parents and peers. These changes in bodily function and physiology can produce alterations in the absorption, distribution, metabolism, and excretion of drugs. Similarly, changes in intellectual and psychological functioning can profoundly affect critical factors (such as compliance), which can affect the accuracy of the observed result. Complicating this dynamic situation is the fact that the purely chronologic conception of puberty is of limited value. For example, in any group of 14 year olds, certain individuals are fully mature, others are in the midst of change, and the remainder have not entered puberty at all. Measurement of the developmental age (according to published criteria such as Tanner’s) rather than the chronologic age is the best method of defining the adolescent at any given point in this progression.3, 4 Furthermore, a number of endocrine, biochemical, and hematologic measurement correlate with these stages and must be considered when normative data are used in research studies with adolescent subjects.5 It is therefore apparent that the adolescent research subject cannot be managed exclusively as either a small adult or a large child, but rather must be approached with an awareness of age-dependent effects on safety, efficacy, compliance, and ethical concerns. Safety. Studies of NBAAD in the adolescent pa-
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tient must especially consider five potential “trouble spots” with respect to safety: the potential for abuse (misuse, concomitant use with psychotropic agents, use of abortifacients); the potential for producing psychosocial and behavioral alterations at an unstable time in the individual’s life; the effect on growth (as with corticosteroids) or delay in puberty; the effect on fertility (with antimetabolites such as cyclophosphamide); and the possibility of effects on the fetus (such as certain antihistamines) in the presence of an unknown or hidden early pregnancy. Toxicologic investigation to define study subjects at risk for drug abuse through laboratory means are limited by technical or ethical restraints. Aberrations in growth or puberty advancement must be monitored by careful measurement and assessment with standardized growth charts,6.7 growth velocity charts,’ and systems of staging puherty.4, 5 In the case of inadvertent pregnancy, provisions should be made to assess fetal development and outcome. Finally, it must be considered that the drug can also have an effect on spermatozoa. E’cacy. The same objective measurements used to determine efficacy in adults should be used in adolescents (see workshop 5). Where applicable, normative data based on historic controls should be based on pubertal staging as previously described, and not on chronologic age. Childhood or adolescent disease may go into a natural remission, which complicates drug studies that extend beyond 6 to 12 month periods. Compliance. Study designs of NBAAD whose effects may not be measured immediately but over weeks or even months must include guidelines for assuring a patient’s personal commitment to the study. One must also assure objective monitoring during the study for measuring the presence of the drug, its therapeutic effects, and its side effects (see workshops 5 and 6). Childhood
(2 years to adolescence)
General. Because severe episodes of asthma provoked by viral respiratory infections are particularly frequent in this age group, there may be new drugs that are uniquely suited to this age group. Drugs such as primary antiviral agents or agents that specifically interfere with asthmatic effects induced by viral-induced episodes may be much more appropriately evaluated in children than in adults. Guidelines for drug testing in the childhood years should be separated into two age categories: (1) six years to adolescence; and (2) 2 to 5 years. These age categories separate naturally on the basis of anatomy, intellect, illnesses, seasonal symptoms, problems in compliance, performance on pulmonary function tests, determination of exercise-induced asthma, and
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TABLE
I. Characteristics Category
Anatomic Illnesses Seasonal symptoms Cognitive Self-recognition of symptoms Compliance Exercise-induced asthma documentation Objective measurements Allergic factors
J. ALLERGY
of two different
childhood
CLIN. IMMUNOL. SEPTEMBER 1996
age groups
2 to 5 yr
6 yr to adolescence
Lung developing Otitis media common Viral respiratory infections more common September-April Preschool Poor Parents Difficult
Adult configuration Sinusitis frequent Less common All year Better Better Parents and child Easy
PEFR Food, dust, molds, epidermals
Spirometry Dust, molds, epidermals, pollens
allergic factors. Table I lists such characteristics for the two age groups. Safety measurements. Similar safety information in new drug testing in any older age group should be followed in the childhood age groups. A special problem in this age group, however, is the establishment of normal blood chemistry values for tests not usually done in childhood, such as the measurement of hepatic enzyme and alkaline phosphatase levels. There may be marked differences in the levels of these substances between children and adults. Indeed, differences between the 2- to 5-year old and the 6 years to adolescent age groups may be observed. Various endocrine parameters need to be followed, because some NBAAD have been shown to have an effect on nitrogen balance (for example, glucocorticoids). The usual parameters of weight and height should be followed on a growth grid. When there is a deviation from the usual pattern of growth, bone age may need to be followed, as may other growth parameters. Some drugs may have an effect on advancing or retarding menarche. Trial drugs may interact with other asthma medications. The effect on school performance and school attendance should be noted. These functions may improve as the asthma is controlled, or they may deteriorate because of drug-induced changes in mood, drowsiness, or effects on memory. Study designs. Because study designs are addressed in workshop 3, comments in this section will be related only to special factors that affect the child. In the double-blind crossover study model, a carryover effect may present a problem. This was particularly evident in the early trials of cromolyn sodium, in which efficacy was more apparent in children who initially received placebo than in a parallel group who received active drug first and then crossed over to placebo.’ Parallel studies broach the problem of using a placebo drug in a long-term study. Many investigators and institutional review boards would object to this
study design in children, for both ethical and medical reasons. An alternative approach is to compare the new drug with a drug of proved efficacy. When possible, such a study should use placebo “dummies” for both the study and standard drugs. In this way a double-blind approach could be maintained and the number of patients who received placebo would be reduced. Another approach is to continue regular medications while adding either the new drug or its placebo. The dosage of the regular medication could then be reduced to its lowest effective level and the “medication-sparing” effect of the drug could be determined. One can study the effect of the drug on bronchial hyperresponsiveness elicited by exercise or methacholine challenges. Such challenges could be incorporated serially during the study to observe for tachyphylaxis or long-term effectiveness of the study drug. For drugs with antihistaminic actions, the suppression of the cutaneous histamine dose response curve may serve as a marker of drug effect. Dosage. Before the use of the study drug in large numbers of children, a pediatric dose ranging study is essential to select a dosage that causes maximal benefit and minimal side effects. Coincident with a dose response study, the kinetics of drug action should be studied in specific age groups. This will require the development of micro-level blood or urinary drug assays, so that blood levels can be determined easily on microliter volumes of serum. Ideally, such kinetic studies should also examine the effect of the new drug on the metabolism of other drugs. The theophylline half-life could be determined, for instance, before and after administration of the study drug.” The effects of bronchodilators on study drug kinetics would have to be determined, as would the effects of diet and disease on the study drug (see workshop 2). Parameters of drug effectiveness for children in the 6 years to adolescence age group. Symptom and
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medication diaries with a record of school absences should be included. These must be supervised by parents, who should receive complete instructions. Daily home PEFR monitoring should be accomplished and recorded at specific times twice a day, to account for diurnal fluctuations. Regular measurements of height and weight should be made and the data should be plotted on growth grids. Pulmonary function measurements (spirograms) should be assessedat regular intervals in the clinic. The effect of the drug on intellectual performance should be determined by such techniques as teacher reports or the recording of intellectual performance in school report cards. Serial check lists for parents should include such items as a change in the level of activity, changes in mood or personality, and alterations in short-term memory. Additional studies might include maze diagrams to shed light on tremor, coordination, or fine motor movements. Projective psychologic tests are particularly important with drugs that are taken systemically and that might have a central nervous system effect. Possible psychological tests include the WISC-R, WISC-R Coding Subtest, WISC-R Digit Span Subtest, Name Writing Test (from Halstead N.P. Test Battery), Diagnostic Reading Scales, Developmental Test of Visual Motor Integration, Revised Visual Retention Test, The Stroop Test, and Personality Inventory for Children. Long-term follow-up of the children in the study is highly recommended to determine whether there are any unexpected long-term effects (either adverse or beneficial) from the use of the drug. Parameters of drug effectiveness for children 2 to 5 years of age. Many of the same parameters used in older children can be used in children 2 to 5 years old. However, objective parameters are much more difficult to obtain in this age group, and certain tests such as exercise or methacholine tests for bronchial hyperresponsiveness are much more difficult or impossible to perform. Parameters for the 2- to 5-yearold could include: (1) a symptom and medication diary including the use of antibiotics; (2) a record of respiratory and other illnesses; (3) home PEFR measurements; (4) a parent checklist similar to that provided for older children; (5) psychological tests such as the WISC-R, Personality Inventory for Children, the Connor’s Rating Scale, the Actometer, and play observation; and (6) long-term follow-up studies at the end of the drug trial. Special problems in drug testing in children Compliant-e. See workshop 6 for a discussion of this issue. Boys ver,ws girls. Because there may be a difference in response to the drug for boys than for girls,
Special
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both should be studied. In childhood there is a particular problem of skewing of the patient population, because twice as many boys as girls have childhood asthma. An effort should be made to enter equal numbers of each sex. Palatability of medication. A major challenge is that of making the medication palatable for children. The technique of time-release liquids as a way of increasing duration of the effect, as well as reducing unpleasant tastes, is already available. If granules are used, it is essential that absorption be studied both in a fasting state and after a meal. Techniques for inhaling medication. For inhaled medication, the use of whistles attached to the inhaler, aerochambers, or similar devices for effective inhalation by younger children will contribute to better techniques of drug administration. For aerosolized agents, the use of aerosol solutions with home compressors provides an additional effective delivery system, even in small children. Additive effects. The effects of colors, stabilizers, and preservatives on the patient or a possible interaction with the kinetics of drug metabolism should be studied. Consent. Special problems exist in consent and assent forms. It is important to read the form to younger children. Side effects. Children may have different side effects or idiosyncratic reactions to the drug as compared with adults. For children, missing school because of the drug studies must be considered in the study design. The potential effect of the drug on the growth of the lungs as well as on somatic growth must also be considered. Seasonal variations. Because most children with asthma have an allergic component, subjects should enter the study at the same time of the year to eliminate the effect of seasonal variations in aeroallergen exposure. Infant/toddler
(1 month
to 2 years)
General. The period of life from 1 month to 2 years of age is characterized by rapid somatic growth and functional maturation of all organ systems that influence the response to pharmacologic agents. The developmental influence on drug response is best considered by the individual organ system. Organ system development Immune system. This period of life is characterized by continuing maturation and numerous functional changes that could potentially be altered by pharmacologic agents. Although there is limited information that this occurs, there is some evidence that therapy with some drugs such as phenytoin, d-penicillamine, gold salts, and sulfasalazine has been followed by the
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development of the most common form of immunodeficiency, selective IgA deficiency. Adverse drug reactions induced by immunologic mechanisms are rare during infancy and childhood because of the combination of an immature immunologic apparatus and lack of prior drug exposure. However, the potential for sensitization exists and could be expressed later in life. Gastrointestinal tract and liver. The immaturity of the gastrointestinal tract in terms of drug bioavailability (rate and extent of absorption) may have a profound effect on drugs administered by mouth. Adult gastric acidity is not achieved until 3 years of age and pH may influence gut motility and the dissolution rate of drugs. The microflora of the infant gut differ according to whether the child is breast fed or bottle fed. This may influence the hydrolysis of drug conjugates excreted in the bile. Gastric emptying is slower during the first few months of life and gut motility is irregular and unpredictable. The time at which the maximum plasma concentration of orally fed drugs occurs may be affected, and certain formulations of drugs (such as slow-release products) may be affected by intestinal motility and transit time. The susceptibility of infants and children to gastroenteritis has major implications for drug absorption. In terms of the major organ of drug elimination, the liver, the activities of hepatic drug metabolizing enzymes, hepatic blood flow, and plasma protein binding are all known to affect drug clearance. Data based on in vivo experiments in the human are lacking. However, clearance of a number of drugs is greater during early childhood than during adulthood, at least when expressed in terms of body weight. Differences in the clearance of “low” versus “high” extraction drugs must be considered in drug studies of infants and children. Kidney. Because of the greater percentage of extracellular water space as compared with total body weight in infants versus adults, there is a profound effect on the clearance of drugs that are totally cleared by glomerular filtration from the extracellular space. The plasma half-lives of penicillins and aminoglycosides, as well as of several other drugs, are known to be longer during the first weeks or months of life than during adulthood. Urinary pH is known to influence the rate of renal excretion of drugs subject to nonionic diffusion. For example, diurnal variation in urinary pH has been shown to affect the elimination of acidic drugs. Pulmonary. There are a number of reasons why an infant or young child is predisposed to obstructive airways disease and at times responds poorly to bronchodilators. ”
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CLIN. IMMUNOL. SEPTEMBER 1986
One major factor is the: smaller size of the airways, rendering them more easily obstructed. Until approximately age 5 years, children have disproportionately smaller peripheral airways as compared with adults. In addition, edema, secretions, and cellular debris are more likely to cause airway obstruction because of the small size of the bronchioles. Other factors include: (1) a deficiency of elastic tissue predisposing to airway closure during tidal ventilation with resultant hypoxemia; (2) inadequate development of alveolar pores; and (3) an increase in the percentage of mucoussecreting glands in the airways as compared with adults. These factors confound the interpretation of response to pharmacologic agents. Other major problems in the evaluation of antiasthmatic agents in the young infant and child are the difficulties in establishing, a clear diagnosis of asthma and in performing noninvasive pulmonary function tests in this age group. Recently, several new techniques have been described for the measurements of airway resistance in infants and young children. Ultimately these may prove helpful in the assessment of airway obstruction in wheezing infants.“. I3
ETHICS OF RESEARCH IN CHILDREN Children are at special risk for possible adverse physical and emotional effects of experimentation because of the perspective imposed by their limited understanding and their physical or emotional inability to oppose the proposal of the investigator. Despite repeated explanations, it may be difficult for most children to understand they are in fact subjects of research. Even those who do understand this may under some circumstances develop anxiety. To proscribe research in children, however, would be tantamount to denying children the benefit of advances in the prevention and treatment of disease available to adults, and could perpetuate current practices of uncontrolled experimentation in children each time a new medical advance appears for adults. Guidelines and regulations governing ethical concerns and informed consent have been published. 14-19 Research in infants should be deferred until substantial evidence of safety and effectiveness superior to those of accepted therapy has been gathered in older children and adults. Moreover, drugs with even promising potential application in infants and a favorable risk/benefit ratio should not be marketed without the establishment of safety and efficacy among infants. School and work absenteeism necessitated by research should be included in the assessment of the risk/benefit ratio and should be discussed with parents and the child when permission for participation and assent are obtained. Most children at least 7 years old
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and some who are younger will be capable of providing assent. Most adolescents will be capable of providing assent. Drugs with potential application in children should not be marketed without the establishment of safety and efficacy among children when a favorable risk/benefit ratio is likely. The possibilities of fertility and pregnancy should be considered when possible adverse effects of drugs and procedures are evaluated. Because of dependence on physicians and caretakers who may be investigators and because of distance from family support, patients at residential treatment centers may be at special risk for lack of freedom in assenting and consenting to participation in research. Under these circumstances, investigators have a special responsibility to assure freedom of decision about whether a child should participate in research. SUMMARY OF SPECIFIC AGE-RELATED GUIDELINES Studies in older children and adolescents should be completed before the marketing of new drugs that are potentially useful in children. Studies in younger children and in the infant/toddler group should be well underway before the drug is licensed. It is possible that in this youngest age group, some new drugs may be particularly beneficial, particularly when the child has hard-to-treat asthma. It is also possible that some new drugs, such as antiviral agents, may be uniquely beneficial to children. Specific guidelines for each group can be separated into three specific categories: (1) essential; (2) desirable; and (3) possibly helpful. Essential studies must be performed to document safety and effectiveness. Desirable studies will depend on the type of drug being investigated. These may be necessary to define potential benefit or adverse effects of the agent. Possibly helpful studies may define further the mechanism of action or activity of a particular agent. Adolescent
to adult (12 to 18 years)
Adolescent to adult studies should use the same study parameters being used in the adult. One does need to keep in mind, however, that maturation to adult life occurs during adolescence. In addition to performing routine pulmonary studies, researchers need to look particularly at the effect of the new agent on the growth, development, and maturity of endocrine function. Exercise testing should be included as an essential study, because exercise-induced asthma is a clinical handicap.*’ Knowledge of the effectiveness of a new drug in treatment of exercise-induced asthma may be clinically relevant and an indication of drug action.
Late childhood
pediatric
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539
(6 years to adolescent)
Essential study parameters in this age group should include: (1) symptom and medication diaries; (2) home PEFR monitoring twice daily, with care taken to specify the relationship with aerosolized and oral medication; (3) regular measurements of height/weight and the plotting of data on growth grids; (4) evaluation of pulmonary function by regular spirometry in the clinic; (5) baseline exercise testing and the effect of short- and long-term preadministration of the drug on exercise challenge; (6) serial checklists from parents, including items such as a change in levels of activity, changes in mood or personality, or alterations in shortterm memory; (7) cardiopulmonary monitoring, including blood pressure, pulse, respiration, and electrocardiograms; and (8) protracted follow-up of children who are receiving long-term treatment with NBAAD. Desirable studies in this age group should include: (1) effect on intellectual performance as evaluated by teacher reports and school report cards; (2) serial methacholine or histamine challenges*‘; and (3) projective psychological tests if the drug has any effect on central nervous system activity. Possibly helpful techniques in this age group might include antigen challenge in an equipped clinical research center setting. ” Early childhood
(2 to 5 years)
Essential study components in this age group should include: (1) symptom and medical diaries; (2) records of illnesses (especially respiratory) and use of antibiotics; (3) home PEFR measurements twice daily related to timing of medications; (4) PEFR or other reliable objective measurements of pulmonary function in the office; (5) growth grids; (6) checklist for parents concerning levels of activity, changes in levels of activity, changes in mood or personality, and alterations in short term memory; and (7) cardiopulmonary measurements of vital signs, pulse, respiration, blood pressure, and electrocardiograms. Possibly helpful methods might include: (1) psychologic studies; and (2) methacholine or histamine challenge with PEFR measurements. Infant/toddler
(1 month
to 2 years)
Essential study techniques in this age group should include: (1) symptom and medication diaries; (2) records of illnesses (especially respiratory) and use of antibiotics; (3) growth grids; (4) parent checklist as described above; and (5) long-term studies for effects on growth and development. Desirable studies in this age group should include: (1) response to bronchodilators; and (2) spe-
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cial techniques for measuring pulmonary function, if available. 3.
SUMMARY
4.
The assessment of NBAAD in pediatric patients is essential because asthma is common in children. Special problems of drug assessment in children should be considered in the context of various pediatric growth periods: (1) adolescence; (2) childhood (2 years to onset of adolescence); (3) infants/toddler (1 month to 2 years); and (4) neonatal (birth to 1 month). Rapid acceleration of growth and maturation are special problems in adolescence. In addition, awareness about safety. possible drug abuse, and compliance must be considered in this age group. Drug studies should also take into account the fact that natural remissions may occur more frequently in teenagers, especially in boys. In the childhood age group, asthma is more likely to be induced by respiratory viral infections; various endocrine parameters need to be followed more closely; and special attention should be paid to the detection of variations in growth and bone age. Dose ranging effects should be established in the very early stages of drug development and the kinetics of drug action should be followed in cases in which proper assays are available. Except in very young children, parameters for measuring drug effectiveness are the same as in adults. Special instructions should be devised for aerosolized medications if the drug is available only in this form. Ethical constraints in children are key problems. Double-blind testing with a placebo control is not advisable in the younger groups of children. Instead, drugs should be tested against other agents of known efficacy. Research in infants should be deferred until substantial evidence of safety and effectiveness has been gathered in older children or adults. The commercial marketing of drugs of potential use to children should be deferred until studies in older children and adolescents have been included in the FDA review process.
18.
REFERENCES
19.
1. American Academy of Pediatrics. General guidelines for the evaluation of drugs to be approved for use during pregnancy and for treatment of infants and children. A report of the Committee on Drugs of the American Academy of Pediatrics to the Food and Drug Administration. Washington, DC: US Department of Health, Education and Welfare, 1974. 2. American Academy of Pediatrics. General consideration for the clinical evaluation of drugs in infants and children. A report of the Committee on Drugs of the American Academy of Pe-
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22.
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diatrics to the Food and Drug Administration. Washington, DC: US Department of Health, Education and Welfare, 1977. Tanner JM. Growth at adolescence. 2nd ed. New York: Appleton-Century-Crofts, 1966. Rauh JL., Brookman RR. Adolescent developmental stages. In: Johnson TR, Moore WM, Jeffries JE, eds. Children are different. 2nd ed. Columbus, Ohio: Ross Laboratories, 1978: 25-9. Brookman RR, Rauh JL. Adolescent development: normative data related to physical maturation. In: Johnson TR, Moore WM, Jeffries JE, eds. Children are different. 2nd ed. Columbus, Ohio: Ross Laboratories, 1978:207-13. National Center for Health Statistics. NCHS growth curves for children O-18 years. United States, Vital and Health Statistics, Series 1l-No. 165. Washington, DC: US Government Printing Office, 1917. Pomerance HH. Growth standards in children. Hagerstown, Md: Harper & Row, 1979. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity and the stages of puberty. Arch Dis Child 1976;5 I : 170. Bernstein IL, Siegel SC, Brandon ML, et al. A controlled study of cromolyn soldiuml sponsored by the Drug Committee of the American Academy of Allergy. J ALLERGY CLIN IMMUNOL 1972;50:235. Shapiro GG, Koup JR, Furukawa CT, et al. Individualization of theophylline dosage using a single serum sample following a test dose. Pediatrics 1982;69:70-3. Levison H, Isles A. Response: asthma in childhood. J ALLERGY CLIN IMMUNOL 1983;72:539. Beadsmore CS, Maayan C, Bar-Yishag E, Godfrey S. Flowpressure looping during plethysmography in wheezing infants. Pediatr Pulmonol 1985;1:2.7. Konig P, Hordvick NL, Pimmel RL. Forced random noise resistance determination in childhood asthma. Chest 1984; 86:884. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Research involving children: report and recommendations. Washington, DC: US Government Printing Office, 1’977; DHEW Publications No. (OS) 77-0004. McCartney JJ, Beauchamp TL. Ethical issues in pediatric treatment and research. J Ped Psycho1 1981;6:131-43. Department of Health and Human Services. Final regulations amending basic HHS policy for the protection of human research subjects. Fed Reg 1981;46:8366-92. Janofsky J, Starheld B. Assessment of risk in research on children. J Ped 1981;98:842-6. Skeeg PDG. English law relating to experimentation on children. Lancet 1977;2:754-5. Kapp MB. Children’s assent for participation in pediatric research protocols. Clin Ped 1983;22:275. Eggleston PA, Guerrant JL. A standardization method of eviluating exercise-induced asthma. J ALLERGY CLIN IMMIJNOL 1976;58:414-25. Shapiro GG, Furukawa CT, Pierson WE, Bierman CW. Methacholine bronchial challenge in children. J ALLERGY CLIN IMMUNOL l982;69:365-9. Chai H. Antigen and methacholine challenge in children with asthma. J ALLERGY CLIN IMMUNOL 1979;64:575-9.
7: Special pediatric
Sheldon C. Siegel, Chairperson, Cochairpersons
Dorothy
problems
D. Sogn, and C. Warren
Bierman,
Rebecca H. Buckley, Elliot F. Ellis, Thomas J. Fischer, Henry Levinson, R. Michael Sly, and William F. Westlin MEMBERS:
I. Introduction II. Specific age-dependent factors A. Adolescent to adult I. General 2. Safety 3. Efficacy 4. Compliance B. Childhood (2 years to adolescence) 1. General a. Safety measurements b. Study designs c. Dosage 2. Parameters of drug effectiveness for children in the 6 years to adolescence age group 3. Parameters of drug effectiveness for children 2 to 5 years of age 4. Special problems in drug testing in children a. Compliance b. Boys versus girls c. Palatability of medication d. Techniques for inhaling medication e. Additive effects f. Consent g. Side effects h. Seasonal variations C. Infant/toddler (1 month to 2 years) 1. General 2. Organ system development a. Immune system b. Gastrointestinal tract and liver c. Kidney d. Pulmonary III. Ethics of research in children IV. Summary of specific age-related guidelines A. Adolescent to adult (12 to 18 years) B. Late childhood (6 years to adolescent) C. Early childhood (2 to 5 years) D. Infant/toddler (I month to 2 years) V. Summary
INTRODUCTION Because of many problems relating to drug testing in children, many of the bronchodilator and NBAAD presently used in the treatment of asthma in infants and children have not been approved for this purpose by the FDA in the United States. Furthermore, there are a limited number of dose response studies of these antiasthmatic agents in the younger age groups, especially in children under 5 years of age. Most of the same difficulties in the evaluation of safety and efficacy of the NBAAD in adults also apply to their in534
vestigation in infants and children. However, there are additional special problems that need to be considered when these agents are tested in childhood. Pediatric studies are essential for this class of drugs because asthma is common in children. Therefore, during drug development appropriate preclinical studies should be carried out in juvenile animals, which will permit the study of these drugs in infants and children. Studies in adolescents should begin either coincidentally or sequentially with the adult studies. if not initiated simultaneous with the adult studies, the early Phase II adolescent studies should be started when the adult studies have reached late Phase II. Studies in the 6 years to adolescent age group should be begun by the time the adult Phase II studies are completed. If there is a dose response relationship, a dose ranging study should be done first to indicate the proper dose that is free from side effects and appears effective. This should be followed by a full clinical trial. Progressively, the 2- to 6-year-old children should be studied when the 6-year-old to adolescent children are at the Phase III level. The infant/toddler age group, 1 month to 2 years, presents a particular problem because it is more difficult to obtain objective measurements in this age group. These studies should be done in a university setting in which appropriate, sophisticated equipment for noninvasive procedures are readily available (see workshop 3). Study design poses a particular problem in the pediatric age group, particularly in children under 6 years of age. The general pediatric guidelines formulated by the American Academy of Pediatrics’ and subsequently published in the Federal Registe? suggest that in younger children, a new drug should be compared with an older drug of known therapeutic value rather than with an inactive placebo. Study design in drug testing in lyounger children and infants and toddlers will be addressed further in this workshop. SPECIFIC AGE-DEPENDENT
FACTORS
It is well known and widely accepted that the age and development status of the infant and child play a significant role in the disposition (absorption, distri-
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bution, storage, metabolism, and excretion) and response to therapeutic agents. In previously published guidelines’, * for the evaluation of drugs to be approved for the treatment of infants and children, the Committee on Drugs of the American Academy of Pediatrics recognized four stages of development with certain characteristics that distinguish each stage from the other stages. The Committee identified the following growth periods: (1) adolescent (onset of adolescence to adult life); (2) childhood (2 years to onset of adolescence); (3) infant/toddler (1 month to 2 years); and (4) neonatal (birth to 1 month). Because asthma rarely occurs in the neonatal period and there are special problems in the evaluation of antiasthmatic drugs in the 2- to 5-year age group, it is more practical to discuss special considerations about drug evaluation in the following growth periods: adolescent, childhood (6 years to adolescence), young child (2 to 5 years), and toddler (1 month to 2 years). Adolescent
to adult
General. Adolescence is defined as “the transition period in which the child undergoes changes in physical, sexual and psychological development transforming him/her into an adult.” At no other time in postnatal life does the individual accelerate as rapidly in the rate of growth or experience such marked changes in bodily function, physical appearance, cognitive capacity, and interpersonal relationships with parents and peers. These changes in bodily function and physiology can produce alterations in the absorption, distribution, metabolism, and excretion of drugs. Similarly, changes in intellectual and psychological functioning can profoundly affect critical factors (such as compliance), which can affect the accuracy of the observed result. Complicating this dynamic situation is the fact that the purely chronologic conception of puberty is of limited value. For example, in any group of 14 year olds, certain individuals are fully mature, others are in the midst of change, and the remainder have not entered puberty at all. Measurement of the developmental age (according to published criteria such as Tanner’s) rather than the chronologic age is the best method of defining the adolescent at any given point in this progression.3, 4 Furthermore, a number of endocrine, biochemical, and hematologic measurement correlate with these stages and must be considered when normative data are used in research studies with adolescent subjects.5 It is therefore apparent that the adolescent research subject cannot be managed exclusively as either a small adult or a large child, but rather must be approached with an awareness of age-dependent effects on safety, efficacy, compliance, and ethical concerns. Safety. Studies of NBAAD in the adolescent pa-
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535
tient must especially consider five potential “trouble spots” with respect to safety: the potential for abuse (misuse, concomitant use with psychotropic agents, use of abortifacients); the potential for producing psychosocial and behavioral alterations at an unstable time in the individual’s life; the effect on growth (as with corticosteroids) or delay in puberty; the effect on fertility (with antimetabolites such as cyclophosphamide); and the possibility of effects on the fetus (such as certain antihistamines) in the presence of an unknown or hidden early pregnancy. Toxicologic investigation to define study subjects at risk for drug abuse through laboratory means are limited by technical or ethical restraints. Aberrations in growth or puberty advancement must be monitored by careful measurement and assessment with standardized growth charts,6.7 growth velocity charts,’ and systems of staging puherty.4, 5 In the case of inadvertent pregnancy, provisions should be made to assess fetal development and outcome. Finally, it must be considered that the drug can also have an effect on spermatozoa. E’cacy. The same objective measurements used to determine efficacy in adults should be used in adolescents (see workshop 5). Where applicable, normative data based on historic controls should be based on pubertal staging as previously described, and not on chronologic age. Childhood or adolescent disease may go into a natural remission, which complicates drug studies that extend beyond 6 to 12 month periods. Compliance. Study designs of NBAAD whose effects may not be measured immediately but over weeks or even months must include guidelines for assuring a patient’s personal commitment to the study. One must also assure objective monitoring during the study for measuring the presence of the drug, its therapeutic effects, and its side effects (see workshops 5 and 6). Childhood
(2 years to adolescence)
General. Because severe episodes of asthma provoked by viral respiratory infections are particularly frequent in this age group, there may be new drugs that are uniquely suited to this age group. Drugs such as primary antiviral agents or agents that specifically interfere with asthmatic effects induced by viral-induced episodes may be much more appropriately evaluated in children than in adults. Guidelines for drug testing in the childhood years should be separated into two age categories: (1) six years to adolescence; and (2) 2 to 5 years. These age categories separate naturally on the basis of anatomy, intellect, illnesses, seasonal symptoms, problems in compliance, performance on pulmonary function tests, determination of exercise-induced asthma, and
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TABLE
I. Characteristics Category
Anatomic Illnesses Seasonal symptoms Cognitive Self-recognition of symptoms Compliance Exercise-induced asthma documentation Objective measurements Allergic factors
J. ALLERGY
of two different
childhood
CLIN. IMMUNOL. SEPTEMBER 1996
age groups
2 to 5 yr
6 yr to adolescence
Lung developing Otitis media common Viral respiratory infections more common September-April Preschool Poor Parents Difficult
Adult configuration Sinusitis frequent Less common All year Better Better Parents and child Easy
PEFR Food, dust, molds, epidermals
Spirometry Dust, molds, epidermals, pollens
allergic factors. Table I lists such characteristics for the two age groups. Safety measurements. Similar safety information in new drug testing in any older age group should be followed in the childhood age groups. A special problem in this age group, however, is the establishment of normal blood chemistry values for tests not usually done in childhood, such as the measurement of hepatic enzyme and alkaline phosphatase levels. There may be marked differences in the levels of these substances between children and adults. Indeed, differences between the 2- to 5-year old and the 6 years to adolescent age groups may be observed. Various endocrine parameters need to be followed, because some NBAAD have been shown to have an effect on nitrogen balance (for example, glucocorticoids). The usual parameters of weight and height should be followed on a growth grid. When there is a deviation from the usual pattern of growth, bone age may need to be followed, as may other growth parameters. Some drugs may have an effect on advancing or retarding menarche. Trial drugs may interact with other asthma medications. The effect on school performance and school attendance should be noted. These functions may improve as the asthma is controlled, or they may deteriorate because of drug-induced changes in mood, drowsiness, or effects on memory. Study designs. Because study designs are addressed in workshop 3, comments in this section will be related only to special factors that affect the child. In the double-blind crossover study model, a carryover effect may present a problem. This was particularly evident in the early trials of cromolyn sodium, in which efficacy was more apparent in children who initially received placebo than in a parallel group who received active drug first and then crossed over to placebo.’ Parallel studies broach the problem of using a placebo drug in a long-term study. Many investigators and institutional review boards would object to this
study design in children, for both ethical and medical reasons. An alternative approach is to compare the new drug with a drug of proved efficacy. When possible, such a study should use placebo “dummies” for both the study and standard drugs. In this way a double-blind approach could be maintained and the number of patients who received placebo would be reduced. Another approach is to continue regular medications while adding either the new drug or its placebo. The dosage of the regular medication could then be reduced to its lowest effective level and the “medication-sparing” effect of the drug could be determined. One can study the effect of the drug on bronchial hyperresponsiveness elicited by exercise or methacholine challenges. Such challenges could be incorporated serially during the study to observe for tachyphylaxis or long-term effectiveness of the study drug. For drugs with antihistaminic actions, the suppression of the cutaneous histamine dose response curve may serve as a marker of drug effect. Dosage. Before the use of the study drug in large numbers of children, a pediatric dose ranging study is essential to select a dosage that causes maximal benefit and minimal side effects. Coincident with a dose response study, the kinetics of drug action should be studied in specific age groups. This will require the development of micro-level blood or urinary drug assays, so that blood levels can be determined easily on microliter volumes of serum. Ideally, such kinetic studies should also examine the effect of the new drug on the metabolism of other drugs. The theophylline half-life could be determined, for instance, before and after administration of the study drug.” The effects of bronchodilators on study drug kinetics would have to be determined, as would the effects of diet and disease on the study drug (see workshop 2). Parameters of drug effectiveness for children in the 6 years to adolescence age group. Symptom and
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medication diaries with a record of school absences should be included. These must be supervised by parents, who should receive complete instructions. Daily home PEFR monitoring should be accomplished and recorded at specific times twice a day, to account for diurnal fluctuations. Regular measurements of height and weight should be made and the data should be plotted on growth grids. Pulmonary function measurements (spirograms) should be assessedat regular intervals in the clinic. The effect of the drug on intellectual performance should be determined by such techniques as teacher reports or the recording of intellectual performance in school report cards. Serial check lists for parents should include such items as a change in the level of activity, changes in mood or personality, and alterations in short-term memory. Additional studies might include maze diagrams to shed light on tremor, coordination, or fine motor movements. Projective psychologic tests are particularly important with drugs that are taken systemically and that might have a central nervous system effect. Possible psychological tests include the WISC-R, WISC-R Coding Subtest, WISC-R Digit Span Subtest, Name Writing Test (from Halstead N.P. Test Battery), Diagnostic Reading Scales, Developmental Test of Visual Motor Integration, Revised Visual Retention Test, The Stroop Test, and Personality Inventory for Children. Long-term follow-up of the children in the study is highly recommended to determine whether there are any unexpected long-term effects (either adverse or beneficial) from the use of the drug. Parameters of drug effectiveness for children 2 to 5 years of age. Many of the same parameters used in older children can be used in children 2 to 5 years old. However, objective parameters are much more difficult to obtain in this age group, and certain tests such as exercise or methacholine tests for bronchial hyperresponsiveness are much more difficult or impossible to perform. Parameters for the 2- to 5-yearold could include: (1) a symptom and medication diary including the use of antibiotics; (2) a record of respiratory and other illnesses; (3) home PEFR measurements; (4) a parent checklist similar to that provided for older children; (5) psychological tests such as the WISC-R, Personality Inventory for Children, the Connor’s Rating Scale, the Actometer, and play observation; and (6) long-term follow-up studies at the end of the drug trial. Special problems in drug testing in children Compliant-e. See workshop 6 for a discussion of this issue. Boys ver,ws girls. Because there may be a difference in response to the drug for boys than for girls,
Special
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both should be studied. In childhood there is a particular problem of skewing of the patient population, because twice as many boys as girls have childhood asthma. An effort should be made to enter equal numbers of each sex. Palatability of medication. A major challenge is that of making the medication palatable for children. The technique of time-release liquids as a way of increasing duration of the effect, as well as reducing unpleasant tastes, is already available. If granules are used, it is essential that absorption be studied both in a fasting state and after a meal. Techniques for inhaling medication. For inhaled medication, the use of whistles attached to the inhaler, aerochambers, or similar devices for effective inhalation by younger children will contribute to better techniques of drug administration. For aerosolized agents, the use of aerosol solutions with home compressors provides an additional effective delivery system, even in small children. Additive effects. The effects of colors, stabilizers, and preservatives on the patient or a possible interaction with the kinetics of drug metabolism should be studied. Consent. Special problems exist in consent and assent forms. It is important to read the form to younger children. Side effects. Children may have different side effects or idiosyncratic reactions to the drug as compared with adults. For children, missing school because of the drug studies must be considered in the study design. The potential effect of the drug on the growth of the lungs as well as on somatic growth must also be considered. Seasonal variations. Because most children with asthma have an allergic component, subjects should enter the study at the same time of the year to eliminate the effect of seasonal variations in aeroallergen exposure. Infant/toddler
(1 month
to 2 years)
General. The period of life from 1 month to 2 years of age is characterized by rapid somatic growth and functional maturation of all organ systems that influence the response to pharmacologic agents. The developmental influence on drug response is best considered by the individual organ system. Organ system development Immune system. This period of life is characterized by continuing maturation and numerous functional changes that could potentially be altered by pharmacologic agents. Although there is limited information that this occurs, there is some evidence that therapy with some drugs such as phenytoin, d-penicillamine, gold salts, and sulfasalazine has been followed by the
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development of the most common form of immunodeficiency, selective IgA deficiency. Adverse drug reactions induced by immunologic mechanisms are rare during infancy and childhood because of the combination of an immature immunologic apparatus and lack of prior drug exposure. However, the potential for sensitization exists and could be expressed later in life. Gastrointestinal tract and liver. The immaturity of the gastrointestinal tract in terms of drug bioavailability (rate and extent of absorption) may have a profound effect on drugs administered by mouth. Adult gastric acidity is not achieved until 3 years of age and pH may influence gut motility and the dissolution rate of drugs. The microflora of the infant gut differ according to whether the child is breast fed or bottle fed. This may influence the hydrolysis of drug conjugates excreted in the bile. Gastric emptying is slower during the first few months of life and gut motility is irregular and unpredictable. The time at which the maximum plasma concentration of orally fed drugs occurs may be affected, and certain formulations of drugs (such as slow-release products) may be affected by intestinal motility and transit time. The susceptibility of infants and children to gastroenteritis has major implications for drug absorption. In terms of the major organ of drug elimination, the liver, the activities of hepatic drug metabolizing enzymes, hepatic blood flow, and plasma protein binding are all known to affect drug clearance. Data based on in vivo experiments in the human are lacking. However, clearance of a number of drugs is greater during early childhood than during adulthood, at least when expressed in terms of body weight. Differences in the clearance of “low” versus “high” extraction drugs must be considered in drug studies of infants and children. Kidney. Because of the greater percentage of extracellular water space as compared with total body weight in infants versus adults, there is a profound effect on the clearance of drugs that are totally cleared by glomerular filtration from the extracellular space. The plasma half-lives of penicillins and aminoglycosides, as well as of several other drugs, are known to be longer during the first weeks or months of life than during adulthood. Urinary pH is known to influence the rate of renal excretion of drugs subject to nonionic diffusion. For example, diurnal variation in urinary pH has been shown to affect the elimination of acidic drugs. Pulmonary. There are a number of reasons why an infant or young child is predisposed to obstructive airways disease and at times responds poorly to bronchodilators. ”
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CLIN. IMMUNOL. SEPTEMBER 1986
One major factor is the: smaller size of the airways, rendering them more easily obstructed. Until approximately age 5 years, children have disproportionately smaller peripheral airways as compared with adults. In addition, edema, secretions, and cellular debris are more likely to cause airway obstruction because of the small size of the bronchioles. Other factors include: (1) a deficiency of elastic tissue predisposing to airway closure during tidal ventilation with resultant hypoxemia; (2) inadequate development of alveolar pores; and (3) an increase in the percentage of mucoussecreting glands in the airways as compared with adults. These factors confound the interpretation of response to pharmacologic agents. Other major problems in the evaluation of antiasthmatic agents in the young infant and child are the difficulties in establishing, a clear diagnosis of asthma and in performing noninvasive pulmonary function tests in this age group. Recently, several new techniques have been described for the measurements of airway resistance in infants and young children. Ultimately these may prove helpful in the assessment of airway obstruction in wheezing infants.“. I3
ETHICS OF RESEARCH IN CHILDREN Children are at special risk for possible adverse physical and emotional effects of experimentation because of the perspective imposed by their limited understanding and their physical or emotional inability to oppose the proposal of the investigator. Despite repeated explanations, it may be difficult for most children to understand they are in fact subjects of research. Even those who do understand this may under some circumstances develop anxiety. To proscribe research in children, however, would be tantamount to denying children the benefit of advances in the prevention and treatment of disease available to adults, and could perpetuate current practices of uncontrolled experimentation in children each time a new medical advance appears for adults. Guidelines and regulations governing ethical concerns and informed consent have been published. 14-19 Research in infants should be deferred until substantial evidence of safety and effectiveness superior to those of accepted therapy has been gathered in older children and adults. Moreover, drugs with even promising potential application in infants and a favorable risk/benefit ratio should not be marketed without the establishment of safety and efficacy among infants. School and work absenteeism necessitated by research should be included in the assessment of the risk/benefit ratio and should be discussed with parents and the child when permission for participation and assent are obtained. Most children at least 7 years old
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and some who are younger will be capable of providing assent. Most adolescents will be capable of providing assent. Drugs with potential application in children should not be marketed without the establishment of safety and efficacy among children when a favorable risk/benefit ratio is likely. The possibilities of fertility and pregnancy should be considered when possible adverse effects of drugs and procedures are evaluated. Because of dependence on physicians and caretakers who may be investigators and because of distance from family support, patients at residential treatment centers may be at special risk for lack of freedom in assenting and consenting to participation in research. Under these circumstances, investigators have a special responsibility to assure freedom of decision about whether a child should participate in research. SUMMARY OF SPECIFIC AGE-RELATED GUIDELINES Studies in older children and adolescents should be completed before the marketing of new drugs that are potentially useful in children. Studies in younger children and in the infant/toddler group should be well underway before the drug is licensed. It is possible that in this youngest age group, some new drugs may be particularly beneficial, particularly when the child has hard-to-treat asthma. It is also possible that some new drugs, such as antiviral agents, may be uniquely beneficial to children. Specific guidelines for each group can be separated into three specific categories: (1) essential; (2) desirable; and (3) possibly helpful. Essential studies must be performed to document safety and effectiveness. Desirable studies will depend on the type of drug being investigated. These may be necessary to define potential benefit or adverse effects of the agent. Possibly helpful studies may define further the mechanism of action or activity of a particular agent. Adolescent
to adult (12 to 18 years)
Adolescent to adult studies should use the same study parameters being used in the adult. One does need to keep in mind, however, that maturation to adult life occurs during adolescence. In addition to performing routine pulmonary studies, researchers need to look particularly at the effect of the new agent on the growth, development, and maturity of endocrine function. Exercise testing should be included as an essential study, because exercise-induced asthma is a clinical handicap.*’ Knowledge of the effectiveness of a new drug in treatment of exercise-induced asthma may be clinically relevant and an indication of drug action.
Late childhood
pediatric
problems
539
(6 years to adolescent)
Essential study parameters in this age group should include: (1) symptom and medication diaries; (2) home PEFR monitoring twice daily, with care taken to specify the relationship with aerosolized and oral medication; (3) regular measurements of height/weight and the plotting of data on growth grids; (4) evaluation of pulmonary function by regular spirometry in the clinic; (5) baseline exercise testing and the effect of short- and long-term preadministration of the drug on exercise challenge; (6) serial checklists from parents, including items such as a change in levels of activity, changes in mood or personality, or alterations in shortterm memory; (7) cardiopulmonary monitoring, including blood pressure, pulse, respiration, and electrocardiograms; and (8) protracted follow-up of children who are receiving long-term treatment with NBAAD. Desirable studies in this age group should include: (1) effect on intellectual performance as evaluated by teacher reports and school report cards; (2) serial methacholine or histamine challenges*‘; and (3) projective psychological tests if the drug has any effect on central nervous system activity. Possibly helpful techniques in this age group might include antigen challenge in an equipped clinical research center setting. ” Early childhood
(2 to 5 years)
Essential study components in this age group should include: (1) symptom and medical diaries; (2) records of illnesses (especially respiratory) and use of antibiotics; (3) home PEFR measurements twice daily related to timing of medications; (4) PEFR or other reliable objective measurements of pulmonary function in the office; (5) growth grids; (6) checklist for parents concerning levels of activity, changes in levels of activity, changes in mood or personality, and alterations in short term memory; and (7) cardiopulmonary measurements of vital signs, pulse, respiration, blood pressure, and electrocardiograms. Possibly helpful methods might include: (1) psychologic studies; and (2) methacholine or histamine challenge with PEFR measurements. Infant/toddler
(1 month
to 2 years)
Essential study techniques in this age group should include: (1) symptom and medication diaries; (2) records of illnesses (especially respiratory) and use of antibiotics; (3) growth grids; (4) parent checklist as described above; and (5) long-term studies for effects on growth and development. Desirable studies in this age group should include: (1) response to bronchodilators; and (2) spe-
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cial techniques for measuring pulmonary function, if available. 3.
SUMMARY
4.
The assessment of NBAAD in pediatric patients is essential because asthma is common in children. Special problems of drug assessment in children should be considered in the context of various pediatric growth periods: (1) adolescence; (2) childhood (2 years to onset of adolescence); (3) infants/toddler (1 month to 2 years); and (4) neonatal (birth to 1 month). Rapid acceleration of growth and maturation are special problems in adolescence. In addition, awareness about safety. possible drug abuse, and compliance must be considered in this age group. Drug studies should also take into account the fact that natural remissions may occur more frequently in teenagers, especially in boys. In the childhood age group, asthma is more likely to be induced by respiratory viral infections; various endocrine parameters need to be followed more closely; and special attention should be paid to the detection of variations in growth and bone age. Dose ranging effects should be established in the very early stages of drug development and the kinetics of drug action should be followed in cases in which proper assays are available. Except in very young children, parameters for measuring drug effectiveness are the same as in adults. Special instructions should be devised for aerosolized medications if the drug is available only in this form. Ethical constraints in children are key problems. Double-blind testing with a placebo control is not advisable in the younger groups of children. Instead, drugs should be tested against other agents of known efficacy. Research in infants should be deferred until substantial evidence of safety and effectiveness has been gathered in older children or adults. The commercial marketing of drugs of potential use to children should be deferred until studies in older children and adolescents have been included in the FDA review process.
18.
REFERENCES
19.
1. American Academy of Pediatrics. General guidelines for the evaluation of drugs to be approved for use during pregnancy and for treatment of infants and children. A report of the Committee on Drugs of the American Academy of Pediatrics to the Food and Drug Administration. Washington, DC: US Department of Health, Education and Welfare, 1974. 2. American Academy of Pediatrics. General consideration for the clinical evaluation of drugs in infants and children. A report of the Committee on Drugs of the American Academy of Pe-
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diatrics to the Food and Drug Administration. Washington, DC: US Department of Health, Education and Welfare, 1977. Tanner JM. Growth at adolescence. 2nd ed. New York: Appleton-Century-Crofts, 1966. Rauh JL., Brookman RR. Adolescent developmental stages. In: Johnson TR, Moore WM, Jeffries JE, eds. Children are different. 2nd ed. Columbus, Ohio: Ross Laboratories, 1978: 25-9. Brookman RR, Rauh JL. Adolescent development: normative data related to physical maturation. In: Johnson TR, Moore WM, Jeffries JE, eds. Children are different. 2nd ed. Columbus, Ohio: Ross Laboratories, 1978:207-13. National Center for Health Statistics. NCHS growth curves for children O-18 years. United States, Vital and Health Statistics, Series 1l-No. 165. Washington, DC: US Government Printing Office, 1917. Pomerance HH. Growth standards in children. Hagerstown, Md: Harper & Row, 1979. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity and the stages of puberty. Arch Dis Child 1976;5 I : 170. Bernstein IL, Siegel SC, Brandon ML, et al. A controlled study of cromolyn soldiuml sponsored by the Drug Committee of the American Academy of Allergy. J ALLERGY CLIN IMMUNOL 1972;50:235. Shapiro GG, Koup JR, Furukawa CT, et al. Individualization of theophylline dosage using a single serum sample following a test dose. Pediatrics 1982;69:70-3. Levison H, Isles A. Response: asthma in childhood. J ALLERGY CLIN IMMUNOL 1983;72:539. Beadsmore CS, Maayan C, Bar-Yishag E, Godfrey S. Flowpressure looping during plethysmography in wheezing infants. Pediatr Pulmonol 1985;1:2.7. Konig P, Hordvick NL, Pimmel RL. Forced random noise resistance determination in childhood asthma. Chest 1984; 86:884. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Research involving children: report and recommendations. Washington, DC: US Government Printing Office, 1’977; DHEW Publications No. (OS) 77-0004. McCartney JJ, Beauchamp TL. Ethical issues in pediatric treatment and research. J Ped Psycho1 1981;6:131-43. Department of Health and Human Services. Final regulations amending basic HHS policy for the protection of human research subjects. Fed Reg 1981;46:8366-92. Janofsky J, Starheld B. Assessment of risk in research on children. J Ped 1981;98:842-6. Skeeg PDG. English law relating to experimentation on children. Lancet 1977;2:754-5. Kapp MB. Children’s assent for participation in pediatric research protocols. Clin Ped 1983;22:275. Eggleston PA, Guerrant JL. A standardization method of eviluating exercise-induced asthma. J ALLERGY CLIN IMMIJNOL 1976;58:414-25. Shapiro GG, Furukawa CT, Pierson WE, Bierman CW. Methacholine bronchial challenge in children. J ALLERGY CLIN IMMUNOL l982;69:365-9. Chai H. Antigen and methacholine challenge in children with asthma. J ALLERGY CLIN IMMUNOL 1979;64:575-9.