Search

A workshop on "Pediatric Formulation Development: Challenges of Today and Strategies for Tomorrow" was organized jointly by the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), the U.S. Food and Drug Administration (FDA) and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Drug Product Pediatric Working Group (PWG). This multi-disciplinary, pediatric focused workshop was held over a two-day period (18-19 Jun 2019) and consisted of participants from industry, regulatory agencies, academia and other organizations from both US and Europe. The workshop consisted of sequential sessions on formulation, analytical, clinical, and regulatory and industry lessons learned and future landscape. Each session began with a series of short framing presentations, followed by facilitated breakout sessions and panel discussion. The formulation session was dedicated to three main topics pertaining to drug product acceptability, excipients in pediatrics and oral administration device considerations. The analytical session discussed key considerations for dosing vehicle selection and analytical strategies for testing of different dosage forms, specifically mini-tablets (multiparticulates). The clinical session highlighted the influence of pediatric pharmacokinetics prediction on formulation design, pediatric drug development strategies and clinical considerations to support pediatric formulation design. The regulatory and industry lessons learned and future landscape session explored the regional differences that exist in regulatory expectations, requirements for pediatric formulation development, and key patient-centric factors to consider when developing novel pediatric formulations. This session also discussed potential collaboration opportunities and tools for pediatric formulation development. This manuscript summarizes the key discussions and outcomes of all the sessions in the workshop with a broadened review and discussion of the topics that were covered., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Exposure-response (E-R) modeling provides a quantitative tool to leverage adult data to support pediatric trial design and drug approval. The pediatric E-R studies submitted to US Food and Drug Administration (FDA) between 2007 and 2018 were surveyed in the context of various types of trial designs supporting drug approval in the pediatric population. The applications of E-R evaluation in pediatric drug development programs are mainly focused on three areas: (i) supporting pediatric extrapolation when the E-R relationships are similar between the pediatric and adult populations; (ii) dose selection to balance the risk-benefit profile based on the change in efficacy and safety response with different exposure levels; and (iii) approval of a new formulation, new dosing regimen, or new route of administration, where E-R evaluation helps quantify the change in clinical response between the old and new strategies. E-R modeling will continue to play an expanded role in pediatric drug development in the future., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

The estimated glomerular filtration rate (eGFR) equations based on serum creatinine (SCR) have been used for pediatric dose adjustment in drug labeling. This study evaluated the performance of those equations in estimating individual clearance of drugs that are predominantly eliminated by glomerular filtration, using clinical data from the renally eliminated drugs gadobutrol, gadoterate, amikacin, and vancomycin. The eGFR was compared with the observed drug clearance (CL) in 352 pediatric patients from birth to 12 years of age. Multiple eGFR equations overestimated the drug CL on average, including the original and bedside Schwartz equations, which showed an average eGFR/CL ratio between 1 and 3. Further analysis with bedside Schwartz equation showed a higher eGFR/CL ratio in the subjects with a lower SCR or CL. Supraphysiological eGFR as high as 380 mL/min/1.73 m2 was obtained using the bedside Schwartz equation for some of the subjects, most of whom are children < 2 years of age with SCR < 0.2 mg/dL. Excluding the subjects with supraphysiological eGFR from the analysis did not change the overall trend of overestimation. In conclusion, Schwartz equations led to an overestimation of drug clearance for the drugs evaluated. When greater precision is required in predicting eGFR for pediatric patients, such as in drug dosing, revised k constants for the Schwartz equation or new methods of glomerular filtration rate estimation may be necessary. [ABSTRACT FROM AUTHOR]

A treatment gap exists for pediatric patients with renal impairment. Alterations in renal clearance and metabolism of drugs render standard dosage regimens inappropriate and may lead to drug toxicity, but these studies are not routinely conducted during drug development. The objective of this study was to examine the clinical evidence behind current renal impairment dosage recommendations for pediatric patients in a standard pediatric dosing handbook. The sources of recommendations and comparisons included the pediatric dosing handbook (Lexicomp), the U.S. Food and Drug Administration‐approved manufacturer's labels, and published studies in the literature. One hundred twenty‐six drugs in Lexicomp had pediatric renal dosing recommendations. Only 14% (18 of 126) of Lexicomp pediatric renal dosing recommendations referenced a pediatric clinical study, and 15% of manufacturer's labels (19 of 126) described specific dosing regimens for renally impaired pediatric patients. Forty‐two products had published information on pediatric renal dosing, but 19 (45%) were case studies. When pediatric clinical studies were not referenced in Lexicomp, the renal dosing recommendations followed the adult and pediatric dosing recommendations on the manufacturer's label. Clinical evidence in pediatric patients does not exist for most renal dosing recommendations in a widely used pediatric dosing handbook, and the adult renal dosing recommendations from the manufacturer's label are currently the primary source of pediatric renal dosing information. [ABSTRACT FROM AUTHOR]

Exposure-response (E-R) modeling provides a quantitative tool to leverage adult data to support pediatric trial design and drug approval. The pediatric E-R studies submitted to US Food and Drug Administration (FDA) between 2007 and 2018 were surveyed in the context of various types of trial designs supporting drug approval in the pediatric population. The applications of E-R evaluation in pediatric drug development programs are mainly focused on three areas: (i) supporting pediatric extrapolation when the E-R relationships are similar between the pediatric and adult populations; (ii) dose selection to balance the risk-benefit profile based on the change in efficacy and safety response with different exposure levels; and (iii) approval of a new formulation, new dosing regimen, or new route of administration, where E-R evaluation helps quantify the change in clinical response between the old and new strategies. E-R modeling will continue to play an expanded role in pediatric drug development in the future. [ABSTRACT FROM AUTHOR]

Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas. [ABSTRACT FROM AUTHOR]