A Comprehensive List of Items to be Included on a Pediatric Drug Monograph

Introduction

The availability of an information resource specific to pediatric prescribing is essential to guide safe and effective use of medicines for children; these resources are often described as pediatric formularies or compendia.1 Children represent a unique and challenging population to prescribe and administer medicines due to dynamic developmental physiology impacting drug absorption, distribution, metabolism, and excretion as well as drug-end organ interaction. The current lack of evidence-based information on therapeutic use and drug doses and lack of child-size formulations are great concerns, widely recognized by the field.2–4

Formularies consist of a collection of drug monographs that guide national prescribing or are specific for an institution. According to the Health Canada definition, a monograph is “A scientific document on the drug that devoid of promotional material, describes the properties, claims, indications, and conditions of use for the drug, and that contains any other information that may be required for optimal, safe, and effective use of the drug.”5 Drug monographs contain important information for those who select, prescribe, dispense, prepare, administer, monitor, or advise on medicines for children. Drug monograph are often built around the prescribing needs of adults and frequently contain blanket statements that “safety and effectiveness has not been evaluated in patients under the age of 18.” The lack of evidence-based drug monographs containing information regarding pediatric prescribing is a threat to safe and effective use of medications in childhood. Pediatric drug therapy is subject to a high rate of medication dosages and administration errors, and most medication errors in children's hospitals occur in the most vulnerable patients, less than 2 years old and requiring intensive care.67 Many of these drug errors are serious (15%) and even potentially fatal (2%).8 In hospitalized patients, medication errors are 3-times more likely to cause an adverse drug event in children than in adults.9 Some of these errors may be due to a lack of harmonized dosage information. A review of the 2005 Canadian Compendium of Pharmaceuticals and Specialties revealed that 50% of drug monographs were missing safety data for children.10

Although standards exist regarding information required by regulators to issue a marketing authorization for a new drug,11 currently there are no standards for what information health care providers require from a pediatric drug monograph to ensure they have the information needed to safely and effectively provide the right drug in the right dose at the right time, to the right patient, with the right formulation through the right route of administration. Although pediatric formularies are commercially available and are managed nationally in countries such as the United Kingdom, the Netherlands, and New Zealand, it is unclear whether these resources contain all of the available information required by the health care provider. Our objective was to build on currently available pediatric formularies and prioritize a comprehensive list of items to be included in drug monograph for use by health care providers when selecting, prescribing, dispensing, preparing, administering, monitoring, or advising on medicines for children.

Methods

We took the stepwise approach summarized in Table 1. A steering committee of international experts in pediatric drug prescribing was established. Criteria for committee membership included expertise in pediatric therapeutics and experience with compendium/formulary development and management. Steering committee members were recruited through email invitations. Following an environmental scan (e.g., Web-based objective search) of existing national formularies, both pediatric and adult, a preliminary list of items to be included in a pediatric drug monograph was identified. The importance of these items was rated using a Delphi approach12 with participants from 6 continents. Health care providers responsible for prescribing medicines for children were included as participants in this study. “Prescribing” was defined to include selecting, dispensing, preparing, administering, monitoring, or advising on medicines. Participants (n = 46) from 25 countries were invited to participate. A purposive sample was chosen, and the steering committee selected participants with relevant knowledge and experience.

Table 1. Process Used to Generate Items for Inclusion in a Comprehensive Pediatric Drug Monograph

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During the first Delphi round, participants were asked to rate the importance of each monograph item on a 5-point Likert scale where 1 = not important at all, 2 = not very important, 3 = undecided on importance, 4 = important, and 5 = very important. Importance was defined as the item's value to be included in a drug product monograph specific for medication use by any health professional in children of all ages in terms of facilitating the participants' ability to safely prescribe, dispense, administer or monitor a medication for their patients. Items were placed into the following categories: general information, adverse drug reactions and overdose, drug-drug interactions, dosages, precautions, formulation, and drug properties. Study data were collected and managed using Research Electronic Data Capture (REDCap) electronic data capture tools hosted at the Hospital for Sick Children, Toronto, ON, Canada. REDCap is a secure, Web-based application designed to support data capture for research studies.13 During the first round, participants could suggest new items. Demographic information including country of practice, number of years of experience, and subspecialty was collected. Participants were to state their preferred source of prescribing information (open-ended) and were also asked to rank a list of sources according to their preference, where the scale was most preferred (score = 1) to least preferred (score = 11). For the preferred source of prescribing information, the sum of ranks score is reported, where a lower score indicates a preferred source.

Following the first Delphi round, importance scores (mean, median, and standard deviation) were calculated for each pediatric drug monograph item. The items from the environmental scan alongside their importance scores as well as the new items suggested in round 1 underwent a second Delphi round for prioritization. In both rounds, participants could provide comments and ask questions if there were any uncertainties. Pediatric drug monograph inclusion criteria were determined by the steering committee a priori: items scored equal to or greater than a median of 4 of 5. Any item which scored greater than or equal to 3 but less than 4 was voted by the steering group at the consensus meeting. Items scoring a median below 3 of 5 were excluded. The most important items were defined as items which scored a median of 5 and a mean score above 4.5. Items were determined to be pediatric-specific if the steering committee agreed by consensus that this item was unlikely to be of value to those prescribing medicines for adults.

Results

We identified 23 formularies from 12 countries and several international formularies including the World Health Organization (WHO) model formulary for children (Table 2). The directors or managers of 4 large formularies (SickKids, Pediatric and Neonatal Lexi-comp, New Zealand Formulary for Children, and Kinderformularium) were invited and agreed to take a role in the steering committee. We extracted 88 preliminary monograph items (Figure). There were 31 participants in the first Delphi round (67% response rate), of whom 29 also completed the second round. Table 3 provides participant demographics and the sum of ranks scores for sources of information consulted for information. Pediatric formularies were the most frequently consulted resource, and the British National Formulary for Children represented the most frequently consulted formulary (Table 4).

Table 2. Formularies reviewed resulting from Environmental Scan (n = 23)

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Table 3. Participant Demographics (n = 31)

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Table 4. Sources of Information Regarding Prescribing Medicines in Children Reported by Participants^*

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Following 2 Delphi rounds, there were 116 items (90%) having a median importance score of 4 or higher of a possible 5 points (Figure). During the consensus meeting, 10 items required considerable discussion, 7 of which were excluded. Two of the remaining items were condensed as both items scored the same median and mean. Drug-drug interactions that requires an increase or decrease in dose were combined into “drug-drug interactions require a dose modification (increase or decrease).” There were 2 items (previously included) which the steering committee felt were important drug formulary items but were not drug-specific and therefore did not require inclusion on a drug monograph: how to report adverse drug reactions to contribute to phase IV information and an age-weight conversion chart. A final list of all included items (n = 116) can be found in Tables 5–11. Items which were excluded following the Delphi or the consensus meeting can be found in Table 12. Pediatric specific items as defined by the steering committee are identified (Tables 5–12).

Table 5. General Information to be Included in a Pediatric Drug Monograph With Importance Scores (Mean, Standard Deviation, Median)

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Table 6. Adverse Drug Reactions and Overdose Items to be Included in a Pediatric Drug Monograph With Importance Scores (Mean, Standard Deviation, Median)

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Table 7. Drug-Drug Interactions Items to be Included in a Pediatric Drug Monograph With Importance Scores (Mean, Standard Deviation, Median)

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Table 8. Dosing Items to be Included in a Pediatric Drug Monograph With Importance Scores (Mean, Standard Deviation, Median)

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Table 9. Precautionary Items That Should be Included in a Pediatric Drug Monograph With Importance Scores (Mean, Standard Deviation, Median)

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Table 10. Formulation Items to be Included in a Pediatric Drug Monograph With Importance Scores (Mean, Standard Deviation, Median)

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Table 11. Drug Properties to be Included in a Pediatric Drug Monograph With Importance Scores (Mean, Standard Deviation, Median)

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Table 12. Items Excluded From a Pediatric Drug Monograph With Importance Scores (Mean, Standard Deviation, Median)

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There were 24 items with a median score of 5 of 5, and a mean above 4.5 of 5 that were deemed very important items to be included in a pediatric drug monograph (Tables 5–11). The item “contraindications due to drug-drug interactions” was the only item to be scored 5 of 5 for importance by all participants. In the very important items, 11 (44%) were pediatric specific. Variability or range in scoring (measurements by variance) was low among participant response, with the highest coefficient of variance (mean and standard deviation) reported for an included pediatric drug monograph item being the brand name (coefficient of variation = 0.29).

Discussion

As pediatric formularies are a frequently consulted resource for pediatric health care providers, it is imperative they contain all relevant evidence available with regard to prescribing decisions and are updated frequently. The development of standardized, prioritized lists of items is justified and can be useful to inform scientists, funding agencies, and regulators as to pertinent areas of pediatric drug research and serve as a starting point for the development of a national pediatric formulary in countries such as Canada and the United States, where they currently do not exist. We report that pediatric formularies (or compendia) are a top source consulted for information and evidence on use of medication in children. Health care providers identified 116 items that contain important information when prescribing medicines for children. There was a high degree of consistency between the items, and very few items were excluded in the process. This large number of items reflects the complexity of prescribing medicines to children. Also, as many of these items have not yet been formally evaluated in children, it reflects the pediatric health care provider's meticulous approach and desire to consider all information relevant to prescribing decisions. This list of monograph items is comprehensive and improves on existing formularies as it covers what information is requested by the health care provider, not only what information is currently available. These items should be used to inform the research agenda for what clinical evidence is useful for prescribing medicines for children.

Off-label prescriptions are not unique to children, yet the frequency of use is much higher, as an estimated 56% of children receive off-label prescriptions,1415 increasing up to 80% in hospitalized children.1617 The intended use of off-label drugs is not a listed indication on the marketing authorization. Off-label drug use has been associated with an increased risk for adverse drug reactions.1819 The use of monographs primarily conveying adult data presents limitations for clinical practice and research. Dosages for off-label indications and level of evidence for dose selection for off-label indications were scored as very important by respondents. As many drugs are used off-label, to inform bedside decision making it is critical that all available evidence be presented in a clear and agreeable fashion and minimize uncertainty for the prescriber. To agree on which monograph items are important for prescribing medicines for children is the first step in this direction.

Many pediatric subgroups require special dosage considerations resulting from their unique development and physiology. These subgroups included premature infants, neonates, underweight or malnourished children, children receiving renal replacement therapies, obese children, and pregnant teenagers for whom authorized dosage data are rarely available. Many of the most important items were specific to pediatrics and, as such, may not be deduced from adult drug monographs; for example, off-label pediatric dosage recommendations and underlying evidence. This exhaustive, comprehensive list of 116 items should ideally be “populated” in a pediatric drug monograph. As most current pediatric pharmacotherapy is off-label, or unlicensed, some of this information, although deemed important by prescribers, may just not yet be available. Off-label means that enough evidence has not been gathered to support licensing, which may simply be due to insufficient clinical trials or inadequate study population size. The process of licensing is conservative, time consuming and, conventionally, industry driven. Conversely, an approved (on-label) authorization may not contain the most recent international scientific data, as the update process is variable and often slow. Marketing authorization should be an evolving target and should be regularly updated with phase IV long-term safety and effectiveness data.

The limitations of this study include the small sample size and a lack of nurse and nurse practitioner respondents. We recommend including additional health care professional groups, including community care providers, when prioritizing this list prior to implementation. The minimum items for use at the bedside in day-to-day routine prescribing should be determined at a national level, accounting for institutional practices and policy. The authors note the limitation of item “14 Out of pocket costs for the patient” and recommend that cost should be considered regardless of payer as an important consideration for rational use of medicines from a National and health policy perspective. The authors recommend use of a transferable cost categorization code system such as “$,” “$$,” and “$$$.”