Recently, the FDA released an update to the nearly two-decades old harmonized guidelines on clinical investigations in pediatric patients (originally adopted by the FDA in December 2000). The updated guidance for industry, E11(R1) Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population, was issued by the FDA on April 11, 2018.
The addendum provides clarification and current regulatory perspective on topics in pediatric drug development (participants under the age of 18) and is intended to provide high-level guidance on the implementation of important approaches in pediatric drug development. The addendum attempts to define the current recommendations and reduce the likelihood that substantial regional differences will exist for the acceptance of data generated in pediatric global drug development programs. Finally, the addendum is intended to help ensure timely access to medicines for children.
It is in the context of this updated guidance that we here examine important considerations for the development of pediatric drugs. In this post, we introduce laws and regulations related to pediatric clinical studies, review when bridging and extrapolation from adults is viable, and elaborate on some of the major challenges in pediatric PK/PD clinical trial design.
Pediatric Clinical Study Regulations
Evidence for pediatric efficacy and safety is required by the FDA under the Pediatric Research Equity Act (PREA) in certain drug applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration. Previously approved or marketed drugs may also require pediatric assessments under certain circumstances.
In addition to PREA, the Best Pharmaceuticals for Children Act (BPCA) also addresses pediatric drug development and offers a nice enticement for sponsors by granting an additional six months of marketing exclusivity for voluntarily conducting pediatric studies under the BPCA.
PREA and BPCA work together to drive the labeling of indications in the pediatric population, resulting in a significant increase in pediatric clinical trials. However, this increase also brings challenges for ensuring that these studies are conducted in a way that is both scientifically necessary and ethically sound.
Bridging and Extrapolation from Adults
It may be possible to rely on results from well-controlled adult clinical trials to establish efficacy in the pediatric population. With the assumptions of similar disease progression and similar responses to intervention in pediatric and adult populations, the dose-response relationship in adults can be potentially bridged and extrapolated to children.
Complicated, well-controlled PK/PD studies with clinical endpoints are not necessarily required in pediatric populations. PK-only studies or PK/PD studies with established biomarkers might be enough to provide the indirect evidence for efficacy in children. Importantly, the decision to go with the relatively easy path for proof of drug efficacy can save a lot of money and time for pharmaceutical companies.
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Challenges in Pediatric PK/PD Clinical Trial Design
Variability in Physiological Characteristics: Pediatric patients can be divided into several age groups, including pre-term newborns, full-term newborns, infants and toddlers, children, and adolescents. It is known that pharmacokinetic (PK) parameters can differ greatly among these subpopulations due to the natural development and maturation of hepatic and renal systems. The issue of pharmacokinetic (PK) variability can be solved by using parameters such as gestational age and weight to predict the variability. The variability in pharmacodynamic (PD) parameters raises more questions with inadequate understanding of the disease pathology. Population PK/PD (popPK/PD) modeling and simulation approaches can be very useful in providing variability information for experimental design, data analysis, and interpretation.
Enrollment Difficulties: Pediatric clinical studies rarely enroll healthy volunteers, except for certain studies with minimal or no risk. In most of the studies, pediatric patients are recruited rather than healthy children. In this scenario, with many pediatric diseases being rare disorders, getting enough patients enrolled to satisfy statistical requirements is a huge challenge. To make things worse, these rare pediatric diseases usually do not share similar disease progression with the adult form. Therefore, the easy path of extrapolation from adult studies is invalid, and a full, well-controlled PK/PD study with a sufficient number of patients is required.
Choice of Pharmacodynamic Endpoints: In cases where only PK/PD studies with biomarkers as endpoints are needed, sensitive, robust, clinically relevant, and validated biomarkers are crucial for success. In cases where extrapolation from adult efficacy studies is invalid, well-established, clinically relevant, and meaningful pharmacodynamics (PD) endpoints are the keys to successful trials. However, if disease progression differs significantly in pediatric patients versus adults, then this may complicate the choice of appropriate endpoints.
Difficulties in Allocation to Placebo Arm: Use of a placebo control is relatively restricted in pediatric clinical trial design, as it is often difficult to convince parents/guardians to enroll their child into a study where they may receive a non-efficacious treatment. Outside of certain special circumstances where the use of a placebo control might be justified, standard-of-care treatment is more frequently used as the control in pediatric clinical trials. The active treatment thus needs to be proved non-inferior, equivalent, or superior to the standard-of-care treatment.
Challenges in Determining Dosing Regimen: Dosing strategies in pediatric populations need to be carefully determined. Information from adults may be used for determining pediatric dose. Traditional extrapolation methods are based on anthropometric measures such as body weight, body surface area, or allometric power models. In other cases where allometric scaling is invalid due to immature hepatic and renal function, physiologically based approaches that include detailed information on enzymes in elimination pathways can provide alternatives for determining dosing regimens in pediatric trials.
Sparse Sampling vs. Intensive Sampling: Intensive sampling is the traditional sampling method, where usually 10-20 samples are taken from an individual to allow for the generation of a full pharmacokinetic (PK) profile. Due to constraints in pediatric patients, intensive sampling is often replaced by sparse sampling in pediatric clinical studies. In sparse sampling, only a few samples are obtained per individual instead of a full profile. Sparse sampling greatly facilitates the participation of pediatric subjects and improves the feasibility of clinical trials. It is particularly important in studies in infants and newborns. However, the sparse sampling scheme increases sampling variability, which poses challenges for PK/PD analysis and modeling. The population PK/PD (pop PK/PD) approach, superior to the traditional PK/PD modeling approach, can greatly facilitate data analysis and data interpretation in studies designed with sparse sampling.
Pediatric drug development is not just drug development for small adults. Indeed, the pediatric population presents a number of challenges, from physiological differences to unique study design elements, that must be carefully considered. However, along with these challenges come many opportunities to leverage available data in a way that can expedite development while still ensuring safe and effective treatments for pediatric patients. In recognition of the importance of developing drugs for pediatric patients, the FDA has issued a number of guidances on the topic, including the recent E11(R1) Addendum.
Whether you are specifically pursuing pediatric patients as a target population or simply attempting to navigate the statutory requirements for pediatric studies, Nuventra has the experience and expertise to maximize your chances of success.
Talk to one of our senior consultants about pediatric clinical trials today.