Why the Pediatric Population May Be More Vulnerable

WHY THE PEDIATRIC POPULATION MAY BE MORE VULNERABLE TO EXPERIENCING ADVERSE EVENTS FROM THERAPIES AND WHY THEY MAY GO UNRECOGNIZED

The areas unique to pediatrics which increase the probability a child may experience either an adverse event or have the adverse event remain unrecognized are of four general types:

·   Differences in the disease process and/or physiol-ogy of drug disposition because of differences in maturational and developmental stages of the pedi-atric population;

·   Difficulties in determining an exposure in some earlier stage of childhood which has a delayed effect on later development or maturation;

·   Formulation issues, which may encompass prepa-rations or medication errors because of extempora-neous or compounded preparations, and exposures to excipients not present in adult preparations; and

·   Communication or recognition oversights because infants, small children and mentally disabled chil-dren may not be able to articulate what is wrong and/or the caretakers assume it is part of the normal maladies that beset childhood development.

1. Differences in disease process and/or drug phar-macokinetics in children: Children, by definition, are growing, maturing, developing and acquiring skills and information. In addition, many enzymatic, endocrine and metabolic systems and processes have yet to be expressed at the time the child is exposed to an infection or develops a condition and is given a therapy. A disease may not manifest itself in the same way in children as in adults. A high fever in children is more frequently associated with benign processes than a high fever in adults; adults are usually much more symptomatic when exposed for the first time to viral infections such a Hepatitis B. Children have high normal levels of hepatic enzymes and lower levels of creatinine than adults. To recognize the untoward effects of a therapy, one must know what is normal and not all physicians and caretakers are aware of all of the differences in pediatric values for various laboratory tests at the different stages of pediatric development. Numerous studies now demonstrate that children at various ages are going to handle a prod-uct’s absorption, distribution, metabolism and elim-ination differently. Trileptal is an example where children younger than 4 years of age have an apparent increased clearance (L/HR/KG) such that they may require twice the dose per body weight compared to adults. There have been a number of products where younger, pre-school children have not cleared a prod-uct as rapidly as older children and other products where the younger children have cleared the prod-uct more rapidly. Clearly these differences can result in overdosing and an increase in adverse events or underdosing and a failure to resolve the condition or benefit from the product, respectively.

2. Ascertainment of delayed effects of drugs on growth and development: Children are maturing and chang-ing over a time spectrum. It is difficult to know if any deviation from the normal process was going to occur independently of any exposure to a ther-apy. Children are ‘unfinished’ by definition. Attribu-tion of an exposure to a therapy as the cause of a delay/problem in growth, development or cognitive abilities is often difficult. We know a certain percent-age of the pediatric population would experience these problems/delays without any exposure to any therapy. It is difficult to ascertain if the child’s problem would have occurred without the exposure, when the ‘base-line’ was not yet established for that particular child. Confounding this issue is the possibility that an expo-sure in infancy or early childhood may not express the adverse effect until years later when normally some other maturation event, such as puberty, was to occur. Long-term studies are not usual in pediatrics and are very difficult to ‘power’ because there are so many unknowns for each child and there are many expo-sures occurring over a long duration of time.

3. Pediatric formulation issues: Formulations are always a difficult pediatric issue. The excipients required to dissolve solids for liquid preparations or the materials used for sweetening or masking of unpleasant tastes may in themselves cause problems. Small amounts of alcohol may be tolerated in older children but not by infants. Attempts to make pedi-atric formulations are usually expensive and difficult and sponsors are not usually enthusiastic to develop these or to market them. Liquid preparations have a shorter shelf life also. Often pharmacists, care-takers and parents devise their own preparations. These preparations have usually not been tested for bioavailability or for interactions with the foods or liquids used to prepare them. Overdosing, underdos-ing and an increase in frequency of medication errors occur because of the lack of age-appropriate pediatric therapies.

4. Unique issues with recognition, communication and reporting of adverse events in children: Reporting of adverse events for pediatrics is ‘indirect’ and gener-ally involves intermediaries such as parents or care-takers. The younger the child, the fewer ways he/she can visibly react to an untoward effect of drugs. An infant’s repertoire of reactions are limited to physi-cal expressions such as crying, somnolence, vomiting and diarrhea, and cardiac and respiratory abnormal-ities. It is easy to see why only fairly impressive adverse effects would be identified by parents or care-takers for this population. The younger verbal child has a limited vocabulary to express his or her discom-fort or pain. Because behaviour is normally changing, parents may be confused or think a child’s behaviour change is normal when it really is a reaction to a therapy. Even teenagers present a challenge as we know communication with their parents is not always optimal. In addition, they may self-medicate and not want their parents to know they are taking certain drugs. All of these ‘normal’ events or processes that occur in the pediatric population make ascertainment of adverse effects of therapies even more difficult than for the adult population. This is particularly relevant to being able to identify events postmarketing. Parents may not be provided information about what to look for during the usual therapeutic intervention, as they would be during the conduct of a trial.