Pediatric study differs dramatically from study in adults with the diversity of age groups, ethical implications, the consent, and other aspects of recruitment and trial processes. This is the reason why pediatric trials need special approach and particular attention.
The possibility of pediatric use of a drug being developed should be considered as early as the decision to develop this drug for adults has been made.
The following questions help developers outline the prospect product’s applicability for pediatric use:
- Are children affected by the disease?
- Is the disease and/or its progression the same in children and in adults?
- How likely it is that the therapeutic effect of this product in children will be the same as in adults?
Positive answer to all three of these questions allows to submit an application for pediatric labeling of the product, which features just pharmacokinetic and appropriate safety data in children, without the need for extensive efficacy trials.
In case these conditions are not met or the available information is not sufficient to answer these questions, clinical efficacy trials are most likely to be required. They may be required also if the relationship between response and concentration is expected to be different in children and adults.
Extrapolation of available efficacy data in adults is highly desirable to children. This approach can be applied in case of sufficient similarity in indication, course of disease and the outcome of therapy (beneficial as well as adverse). According to FDA’s pediatric study decision tree (60), to bridge between adults and children, a PK/ safety study would be sufficient.
However, for most new drugs and new compounds, it is difficult to make such predictions, and PD, PK and efficacy/ safety information should be collected.
Other aspects to be considered before planning a pediatric study
- When planning and performing pediatric drug trials, the estimates should include the possibility of such trials to take longer because of the much more difficult recruitment. Difficulties in finding a sufficient number of clinical centers with pediatric expertise for the study may also slow down the process.
- Once the type and timing of pediatric trials is defined, it is crucial to assess the need for pediatric formulations (58) for every age range. In case neither biomarkers nor surrogate endpoints are available, the pharma should consider developing them.
- Preclinical drug pharmacokinetics and metabolism, and preclinical safety assessment are needed in order to identify target organ toxicity and provide safety margins between therapeutic exposure and possible adversity in animal studies.
Pediatric dose determination
Simple scaling approaches widely used in the past – when the pediatric dose was calculated on a fraction of the adult dose, based on scaling such parameters as body surface and weight – generally gave a pretty accurate estimate of the pediatric dose for adolescents. But this approach is not applicable for neonates and infants since it does not account for the ontogeny of drug metabolizing enzymes.
When defining the dose to be administered initially and further on in pediatric population, it is crucial to keep in mind that children are not small adults. Hence, substantial support in determining the pediatric dose may be obtained through such M&S techniques as physiologically based pharmacokinetic (PBPK) modeling and population PK/PD modeling.
The essential thing in selecting the first dose of a pediatric drug is the combination of pharmacology / physiology knowledge and the PK/PD relationship in adults, as well as information from drugs belonging to the same pharmacological class. The inter-patient pharmacokinetic variability in children is higher than in adults. This should be taken into consideration when calculating the dose which in the pediatric population provides the same systemic exposure as in adults, assuming the PK/PD relationship holds.
In addition to that, the safety factor should also be tested before retrieving the starting dose of the pediatric drug. It can be done by starting administering and analyzing an initial dosing on a small cohort (4 – 6 children). If safety, PD and/or PK results of this first dose have proven to be safe, further dose escalation can be carried on until reaching the target response and exposure. Upon reaching the target, the sample cohort size can be increased in order to provide more accurate and revealing data on safety, efficacy and/or PD, and PK.
Since growing older children become physiologically more similar to adults, it is a good idea to conduct studies first among the oldest age group (if you plan studies with different age ranges). The collected data can be further adapted and dose-modified for trials in the younger age groups.
Pediatric drug PK sampling and evaluation
According to EMA guidelines (56), the volume of a blood sample for the trial has to be brought to a minimum and be justified in the protocol. The general recommendation is that blood loss should not be more than 3% of the total blood volume over four weeks and no more than 1% of the total blood volume at any single time.
FDA has no quantitative requirements related to blood volume, but it requires the blood sampling volume and frequency to be minimized by using sparse sampling techniques and micro-volume drug assays. Moreover, non-invasive sampling procedures – like saliva and urine collection – are acceptable in case of the documented correlation with plasma and/or blood levels.
Furthermore, ICH guidelines recommend avoiding repeated procedures whenever possible, for instance, through collecting PK and laboratory safety samples at the same time.
Requirements for pediatric drug formulations
In order to target as wide age range as possible, medicines for children should be available not only in solid dosage forms for oral administration but also in liquid. The latter is more appropriate for younger children (easier to swallow) and neonates (for parenteral administration). In this respect, special care should be paid to the choice of excipients and drug concentrations. They have to be described in PIP along with possible measures to adapt the formulation for easier, safer and more acceptable administration in different groups of the pediatric population.
Along with numerous regulatory documents, health authorities provide also free pediatric scientific guidance and advice. However, the number of companies using these opportunities is relatively small. Being non-binding, such pediatric scientific advice allows for an open up-front discussion about the pediatric strategy and can eventually improve the information exchange processes and minimize the time for PIP procedure.