Adverse drug effects and adverse drug reactions in pediatric patients: Workshop summary and recommendations

VOL. 62, No. 12, DECEMBER 2001

Adverse Drug Effects and Adverse Drug Reactions in Pediatric Patients: Workshop Summary and Recommendations

George P. Ciacoia, MD

National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland

The papers presented in this supplement were based on presentations at the Workshop on Adverse Drug Events in Pediatrics, a 2-day meeting held in Rock- ville, Maryland, April 9-10, 2001. This report presents the highlights of the de- liberations and summarizes the conclusions of conference participants.

The discussions revolved around 2 major issues: estimation of adverse drug events (ADEs) and mechanisms of adverse drug reactions (ADRs) in children. The teratogenicity of drug exposure during pregnancy and the carcinogenic potential of therapeutically administered drugs in children were beyond the scope of this workshop.

ESTIMATION OF ADVERSE DRUG EVENTS The following problems were identified during the workshop:

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Limited physician participation in the reporting of ADEs Inaccurate reporting of ADE incidence rates because the number of patients exhibiting ADEs is uncertain and the total number of patients exposed to a drug is estimated Limitations in the discovery of new ADEs, particularly if the clinical manifestations are unique to children Limited data available on drug-associated diseases Relationships between environmental exposure and drug toxicity not ad- equately assessed Frequency of ADEs in intensive-care units (both neonatal and pediatric) not well characterized Lack of involvement of caretakers, parents, and children in the reporting of ADEs Overreliance on passive rather than active reporting systems Lack of standardization of data-collection instruments Inadequate drug formulations for young infants (eg, too concentrated) Lack of an effective system for the detection and characterization of ADEs associated with the use of herbal and nutritional products given alone or in combination with drugs (drug-herbal interactions)

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. Lack of automation in the reporting of ADEs

. Inadequate training and education of physicians and health care professionals in the identification of ADEs

. Failure of health care delivery systems to report serious ADRs to avoid law- suits

. Poor reconciliation of records (eg, in children with chronic conditions, of medications through the cycle of hospital discharge, outpatient care, and back-to-hospital care)

. Lack of appreciation that exposure to drugs occurs mostly outside the hospital setting

. Lack of appreciation of the existence of windows of vulnerability (eg, exposure to drugs acting on the central nervous system [CNS] are likely to pro- duce more significant long-term consequences in newborns than in older children)

. Lack of consensus on the length of follow-up needed to ascertain long-term effects of drug exposure

. Lack of incentives to use available reporting systems (eg, US Food and Drug Administration MedWatch)

. Limited funding available to carry out targeted postmarketing surveillance in children

. Limited access to data sets from different pharmaceutical sponsors and inability to link data sets from different sponsors of similar drug molecules

. Scarcity of psychometric data to ascertain long-term outcomes

. Difficulties in obtaining informed consent and existence of other confidentiality issues.

The conferees agreed that underreporting is a major problem and that we need to increase awareness of the importance of recognizing pediatric ADEs and ADRs among physicians and health care workers as well as parents. Phy- sician training in both pharmacology and the public health implications of ADEs and ADRs are woefully inadequate. The medical students’ curriculum in a number of medical schools limits or even eliminates the teaching of pharmacology. Furthermore, no mechanism is available for postgraduate training in clinical pharmacology or toxicology. Focus groups that educate and encourage the involvement of parents and older children deserve consideration; these groups could develop strategies that lead to self-reporting and/or use of parents as surrogates for reporting ADEs in infants and young children.

Fears of financial losses that would follow liability claims against hospitals and physicians have been a major stumbling block for the reporting of ADEs, including serious and life-threatening events, in children. Even in Europe, where a less litigious climate prevails, underreporting is common. Sweden has re- cently passed legislation making it mandatory for physicians to report ADEs, and reporting of even trivial reactions is mandated for 5 years after a drug is

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licensed. Obligatory reporting of ADEs by physicians has been in effect in France for several years.

Workshop participants agree that although passive reporting is a rich data resource, we need to develop active surveillance methods. Data mining allows for early discovery of new drug-associated ADEs, permits the examination of large data sets, and may advance our current understanding of drug effects. Progress in this area is seriously hampered by the lack of standardization of data-collection systems. For data mining to achieve its full potential, standardization is needed not only for ADE and ADR data-collection systems, but also across databases that contain information on the intake of drugs, dietary supplements, and herbal medicines, as well as demographic data and diagnos- tic and treatment information. Collection of data for thousands of children across institutions, medical specialties, and health care delivery systems would allow the establishment of accurate estimates of ADE rates and related epidemiologic data. There is a wealth of descriptive data in the large data sets of health maintenance organizations that treat millions of children, as well as in data compiled by academic institutions and their academic departments. The integration and standardization of these large data sets would require the development of new methodologic approaches as well as solutions for maintain- ing the confidentiality of patient information.

The long-term consequences of drug exposure at different times during development are largely unknown. Of particular concern are the effects of CNS- active drugs on neurocognitive development. We need to develop instruments that can accurately predict adult neurocognitive function early in life (ie, child- hood). So far, this goal has been elusive. Long-term follow-up studies remain the only available option. A Framingham-type study conducted in children may provide the needed information. The new longitudinal cohort study of environmental effects on child health and development, sponsored by a consortium of federal agencies, plans to follow a large group of children from birth to adulthood. This project may be ideal in terms of providing definitive answers on the effects of therapeutically administered drugs on cognitive development and/or growth and development of different organ systems.

Advances in pharmacogenomics, proteomics, and the discovery of biomar- kers of toxicity will generate the information needed to further delineate, characterize, diagnose, and even prevent ADEs in children. Several issues related to reporting, documenting, and preventing ADEs and medication errors in the hospital setting were discussed.

Pediatric hospitals have a patient population with extensive drug utilization. It was suggested that active, prospective surveillance could be instituted within an academic institution or within a network of academic institutions. Conferees agreed unanimously on the need to assign a full-time health care professional trained in ADE surveillance to analyze, integrate, and report both ADEs and the results of intervention studies to minimize the occurrence of ADEs. As is done with hospital infection-control activities, ADE surveillance should become part

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of hospital quality-assurance programs. Providing feedback from ADE surveillance activities to practicing physicians is paramount to increasing their awareness and promoting their involvement and cooperation.

Hospitalized children who are chronically exposed to drugs or take multiple medications could be categorized by disease-drug combinations. It was suggested that an ADE registry be created to link information derived from spe- cialty clinics or special-care units (eg, seizure, cardiology, cystic fibrosis, asthma clinics) into an overall surveillance system from a single academic institution or a network of academic institutions.

Workshop participants also addressed the lack of adequate ADE information for drugs that have been in use in pediatric patients for many years. Instead of conducting lengthy and costly prospective studies, it was suggested that ret- rospective studies be designed using existing databases and information contained in distributed databases of thousands of patient records. However, methodologic and confidentiality issues must be resolved before such an approach can be undertaken.

Medication errors are largely preventable, and efforts must be made to develop short-term strategies and targeted efforts to prevent their occurrence. Glenn Billman (Children’s Hospital, San Diego, California) reported on the use of a rapid-cycle, process-improvement program in pediatric intensive-care units. The study was performed by the Child Health Accountability Initiative (CHAI), an organization consisting of 14 major children’s hospitals in the United States. The major aim of the CHAI is to promote evidence-based medicine. The program targets specific initiatives. For example, medication errors in the pediatric intensive-care units (PICUs) of 10 hospitals were studied in 3 steps within an 8-week period: (1) determination of the scope of the problem (2 weeks); (2) implementation of an improvement strategy (4 weeks); and (3) postinter- vention analysis (2 weeks). Twelve thousand medication orders were reviewed, 73% of which contained no errors. Most of the potential errors (98%) were intercepted. Medication errors were associated with injury in 16 patients. Two major problems involved the use of verbal orders and the availability of drug stocks in the PICUs. The implementation of strategies to resolve these problems resulted in the elimination of preventable errors requiring intervention.

Workshop participants agreed on the need for automation to facilitate reporting and increase the efficiency of ADE reporting. For example, filling out MedWatch forms is time consuming for the busy practitioner. Automation may improve reporting and eliminate the need for spontaneous reporting. The Chil- dren’s Hospital of San Diego is developing a program of targeted surveillance by incorporating error identification triggers that use ICD-9 coding. This approach is deemed more accurate and complete than spontaneous reporting. The system targets specific outcomes and diagnosis; in turn, these sentinel items may lead to the identification of ADEs.

Multiple case-control studies for rare events, as well as hospital monitoring of index diseases and follow-up of genetic and pharmacogenetic data collection

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were recommended. Potential toxicity uncovered in clinical pharmacology studies should form the basis for planning definitive trials.

Pediatric networks (eg, the Pediatric Pharmacology Research Unit Network, the Pediatric Asthma Network, and the Research Units on Pediatric Psyche pharmacology sponsored by the National Institute of Child Health and Human Development [NICHD], the National Heart Lung and Blood Institute, and the National Institute of Mental Health) can be used for testing and validating bio- markers of toxicities and for collecting safety data.

The rapid development of and exposure to new therapies are major problems in some pediatric patient populations (eg, antiretroviral treatment for pediatric HIV). Children with acquired immunodeficiency syndrome can be expected to live for decades on multidrug therapy. There is an urgent need to perform targeted studies of acute and chronic toxicity of the antiretroviral drugs to which fetuses and children are exposed. Pharmacogenetic studies are also needed to determine susceptibility to drug toxicity. The establishment of registries for the long-term follow-up of children receiving antiretroviral therapies is urgently needed.

The recent increase in use of herbal medicines and nutritional supplements dictates the need for epidemiologic studies of the prevalence and incidence of their use in infants, children, and adolescents. Conferees expressed concern over the lack of regulatory oversight of the sale of herbal products and for the need of an ADE surveillance system for such products in children. It was also noted that only limited information is available on the extent of drug-herbal interactions in the pediatric age group.

PATHOCENESIS OF ADRs AND DEVELOPMENTAL TOXICOLOGY Many of the ADRs in children are due to differences in exposure to a drug, and it is well known that a major source of ADEs is related to inappropriate formulations. The use of concentrated formulations in infants has been associated with toxic reactions (eg, available methadone formulations for the treatment of drug withdrawal can result in up to a IO-fold dosing error).

Workshop participants agreed on 2 major research priorities: (1) characterization of the ontogeny of metabolic detoxification enzymes, transporters, and drug targets (eg, receptors), and (2) elucidation of the basic mechanisms involved in the pathogenesis of idiosyncratic drug reactions.

Role of Ontogeny Many ADRs are due to differences in exposure to drugs. Dose-related ADRs may be due to differences in drug metabolism or in the transporters that are involved in the absorption, distribution, and excretion @ME) of drugs. However, current knowledge of the ontogeny of drug DME is spotty and fragmentary. The conferees agreed on the need to characterize the time-course of the expression of these enzymes and the relative expression of the various enzymes in a

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metabolic pathway. Research efforts should also be directed to determine the relative contribution of different enzyme isoforms in the metabolism of specific drugs. The extent of “shifts” in the relative contribution of the various isoforms that occurs during development remains unknown. Longitudinal studies are needed not only to determine the ontogenetic expression, but also to establish the point in the developmental continuum at which pharmacogenetic polymorphisms are manifested. It was agreed that although animal models may answer a number of research questions, the pattern of ontogenetic development and expression should be similar in the studied animal species and in humans. Overriding considerations in research are the appropriateness of testing animal models and the extrapolation of animal data to humans.

Genetic polymorphisms of some enzymes (eg, thiopurine Smethyltransferase) may profoundly affect drug metabolism. Enzyme-deficient individuals exhibit toxic manifestations at standard doses. It is now recognized that genetic polymorphisms in drug targets can be associated with drug toxicity.’

There is a dearth of information on the ontogeny of export pumps (eg, P-glycoproteins, multiple resistance-associated proteins, and families of anion and cation transporters). The clinical significance of polymorphisms of drug transporters remains to be elucidated.

Conferees agreed on the need to stimulate research to characterize pediatric ADRs associated with pharmacogenetic differences. Daniel Nebert (University of Cincinnati, Cincinnati, Ohio) described the application of extreme discordant phenotype (EDP) methodology to identify individuals likely to develop drug toxicity due to pharmacogenetic differences.* The identification of sensitive phenotypes using EDP methodology permits correlation with DNA sequence variants (genotype) and targets the relatively small number of patients at increased risk for drug toxicity.

Study of Basic Mechanisms Responsible for Idiosyncratic Drug Reactions The mechanisms involved in idiosyncratic reactions are poorly understood. A large body of circumstantial evidence points to a major role of reactive metabolites interacting with elements of the immune system. An important patho- genetic hypothesis to be tested is whether an increase in the mass of reactive metabolites is associated with the increased activity of certain DMEs (eg, cy- tochrome P450 [CUP] 3A4, 2C9, and lA2) that occurs in young children. An imbalance favoring the development of idiosyncratic reactions may occur if a relative deficiency in drug detoxification mechanisms is also present.

The cascade of events leading to immune reactions is complex, as discussed in the article by Rieder in this issue. Prospective studies are difficult to perform because of the rarity of idiosyncratic reactions and the inability to predict their occurrence.

Although animals develop idiosyncratic reactions, attempts to develop animal models have been largely unsuccessful. For example, Doberman pinschers

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exhibit a relatively high incidence of idiosyncratic reactions to sulfonamides similar to reactions seen in humans.3 However, attempts to elicit such reactions in this animal model often fail or are produced by mechanisms other than the one being investigated. The penicillamine-induced autoimmune reaction in brown Norway rats is a notable exception.4 Conferees considered the development of animal models to be a major priority for advancing knowledge in this area.

Expression genomics and proteomics are currently the focus of major research efforts in adult medicine, but application of these methodologies to pediatrics is limited. Genomic techniques are important in defining patterns of genes that are associated with idiosyncratic drug reactions. It is likely that a number of genes are involved. Identification of candidate genes would require the study of patients who are well characterized. A sample size large enough to achieve sufficient power will be needed to detect differences in the occurrence of single nucleotide polymorphisms that are pathogenetically linked type B ADRs.

RECOMMENDATIONS A number of recommendations were made at the workshop and are summa- rized here:

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More comprehensive pharmacoepidemiologic studies are needed to docu- ment and characterize patterns of ADEs in children, Efforts should be made to identify new pediatric ADRs and to determine differences in the expression of ADEs in children and adults. Because of the limitations of passive surveillance systems, these systems should be complemented by active, prospective surveillance systems, registries, study cohorts, and targeted epidemiologic studies. A major goal of drug surveillance systems must be to obtain accurate incidence rates of ADEs. There is an urgent need to standardize databases and methods of data collection, and to further develop and perfect data-mining techniques. A uniform coding system is essential. Standardization of ADE reporting and outcomes across drug products, health care delivery systems, institutions, and specialties is highly recommended. Data-collection systems should be comprehensive and include demographic, clinical, and biochemical data in addition to ADEs and drug information. We need to integrate multiple, diverse data systems that will eventually incorporate data on proteomics, mRNA expression, and pheno- typic-genotypic correlations. Confidentiality and intellectual property issues must be addressed before a large, comprehensive global data- surveillance system for ADEs in children can be recommended. Increased awareness of the public health importance of recognizing ADEs in children is needed. Postgraduate continuing education of physicians and

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other health care professionals in the recognition of ADEs is essential. Publication of a morbidity and mortality report of ADEs in children similar in format to the Morbidity and Mortulify Weekly Report of infectious diseases published by the Centers for Disease Control and Prevention was proposed. Because of the large number of medications used, variations in the severity and types of illness, and the impact of the child’s developmental stage, there is an urgent need to develop active surveillance systems specifically designed and targeted to children in neonatal ICUs and PICUs, children with HIV infections, and those undergoing organ transplantation. Quantitative epidemiologic studies of prevalence and incidence of the use of herbal products in infants, children, and adolescents are needed. In addition, characterization of ADEs associated with herbal-product intake alone or in combination with drugs is urgently needed in the pediatric population. Whether exposure to therapeutically administered drugs between concep- tion and adolescence is associated with long-term effects in adulthood remains a major question that must be addressed through the development of appropriate studies and methods of inquiry. A major concern is the long-term effects of drugs in the developing CNS. Although registries and case-control studies have been suggested, the best hope for a definitive answer is to conduct a prospective study of a large cohort of children. It is recommended that ADEs and ADRs be included with other environmental exposures in the NICHD’s large longitudinal cohort study of environmental effects on child health and development that is now being planned. Research for the study of ADRs in children should exploit innovations such as genomics, microarray and differential-display assays, and proteomics. Research is needed to determine the role of the ontogeny of drug- metabolizing enzymes, transporters, and receptors in the pathogenesis of dose-related and idiosyncratic ADRs in children. In general, the pathogenesis of idiosyncratic drug reactions is not well understood. Because of the significant morbidity and mortality associated with these types of ADRs in the pediatric age group, there is an urgent need to study the basic biology that underlies their occurrence. These studies should be complemented by well-designed, prospective, controlled clinical studies.

ACKNOWLEDGMENTS In addition to the contributors to this supplement, workshop participants included: Jack Uetrecht (University of Toronto) and Daniel A. Notterman (Prince- ton University), Chairs; Daniel W. Nebert (University of Cincinnati); Sumner Yaffe (University of California, Los Angeles); William Evans (University of Ten- nessee); Kenneth McIntosh (Harvard University); Glenn Billman (Children’s Hospital, San Diego); Gregory Kearns (Children’s Mercy Hospital, Kansas City);

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Joseph Di George (US Food and Drug Administration); and William Campbell (University of North Carolina).

The views expressed in this report are those of the author and are not to be construed as official or as reflecting the views of the National Institute of Child Health and Human Development or the US Department of Health and Human Services.

REFERENCES 1. Evans EW, Relling MV. Pharmacogenomics: Translating functional genomics into ra-

tional therapeutics. Science. 2000;286:487. 2. Nebert DW. Extreme discordant phenotype methodology: An intuitive approach to

clinical pharmacogenetics. Eur J Clin Pharmacol. 2000;410:107-120. 3. Giger U, Werner LL, Millichamp NT, Gorman NT. Sulfadiazine-induced allergy in six

Doberman pinschers. J Am Vet Med Assoc. 1985;186:479-484. 4. Sayeh E, Uetrecht JP. Factors that modify penicillamine-induced autoimmunity in

brown Norway rats: Failure of the Thl/Th2 paradigm. Toxicology. 2001;163:195-211.

Address correspondence to: George P. Giacoia, MD Director, Developmental/Pediatric Pharmacology Program National Institute of Child Health and Human Development National Institutes of Health 6100 Executive Boulevard, Room 4B-11 Rockville, MD 20852 E-mail: [email protected]

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Adverse drug effects and adverse drug reactions in pediatric patients: Workshop summary and recommendations