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Regulatory guidance paves the way to address ethical concerns in pediatric trials, and how additional strategies can be applied in drug evaluation.
Children get sick. When they do, they have a right to access medications that have been properly evaluated for their use. Recently, thoughtful development of therapeutics for children has called for inclusion of pediatric patients in clinical research, ensuring the safety and efficacy of drugs and devices intended for use by children and for preserving public health. To improve the understanding of drug-drug interactions, absorption and metabolism and evaluation of drug candidates in special populations including children, simulation and modeling are tools that can be used throughout the drug discovery and development process.
To this end, the US Food and Drug Administration (FDA) released three pediatric guidelines in the last quarter of 2022 for comment: Ethical Considerations for Clinical Investigations of Medical Products Involving Children;1 General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products;2 and Measuring Growth and Evaluating Pubertal Development in Pediatric Clinical Trials.3 These provide specific and welcome guidance for drug developers to direct their research, while creating opportunities worth exploring for modeling as alternatives to the direct participation of children as study subjects.
The pharmaceutical industry requires guidance that helps researchers plan and conduct more efficient studies that support products with improved safety and efficacy for the children they are intended to treat. And, due to the unique needs of children, and the clear ethical issues and considerations associated with their inclusion in clinical studies, each of these FDA guidelines will have clinical research ramifications drug developers should consider.
Given the vulnerability of children, safeguards are needed when including them in clinical trials. In addition to describing the ethical framework for conducting pediatric studies, data requirements to support pediatric clinical investigations for both drugs and devices, as well as procedures needed for sedation in pediatric clinical investigations, Ethical Considerations for Clinical Investigations of Medical Products Involving Children outlines situations where studies can be negated, in some cases by using extrapolation.
This guidance suggests that computer modeling may constitute an alternative to the inclusion of pediatric patients in some studies, providing evidence of “prospect of direct benefit,” important with regards to the Code of Federal Regulations (21 CFR 50.52)4 governing safeguards for children in clinical investigations. This recommendation is emphasized also in the General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products guidance, which was previously issued in 2014, and was recirculated for further comments again in 2022. This particular guidance covers three main areas: clinical pharmacology considerations, ethical considerations, and the pediatric study plan design.
Ethical considerations are critical to clinical pharmacology studies, as these studies generally do not provide direct clinical benefit to the patient involved. The section on ethics in this guidance reiterates two cases in the ethical considerations guideline, one which discusses studies that involve “no more than a minor increase over minimal risk” and the other, which offers prospective “direct benefit to the participant.” The final section provides practical and pragmatic approaches to clinical study design in pediatric patients, including important considerations regarding dose formulation and selection, sample size, sample collection and analysis, and drug-drug interactions (DDIs), among others.
Physiologically-based pharmacokinetic (PBPK) simulation and modeling, or models that incorporate tissue and blood flow to help define the PK of a drug, are growing in importance for drug development, especially in pediatrics. Modeling is stressed in the guidance with regard to renal function and DDIs, but also where it would be beneficial to integrate drug-dependent parameters into an in-silico - or computer-based - model so that it can be used to optimize trial design.5
Taking blood and tissue samples is always challenging in children; one section of the guidance discusses alternative approaches to conventional PK studies, which rely on intensive PK sampling. Here the impact that modeling and simulation can have in pediatric drug trials is evident, as these tools have long complemented studies6 that use sparse, opportunistic PK sampling as well as alternative specimens, such as urine, saliva, tissue, and cerebrospinal fluid.
Additionally, the guidance provides details on how various modeling approaches – or model-informed drug development – can be used in planning first-in-pediatric PK studies, optimizing the study design, recommending starting doses, and more. The guidance emphasizes that pediatric PBPK models are being used7 increasingly to leverage existing knowledge to allow a more mechanistic approach to inform dose selection (e.g., small and large molecules) and formulation bridging, extrapolate DDIs, and identify knowledge gaps.
Finally, precise measurement of growth and pubertal development is important for evaluating safety of pediatric populations; it feeds into accurate and reliable data collection for clinical pharmacology studies. Measuring Growth and Evaluating Pubertal Development in Pediatric Clinical Trials provides guidance on various aspects of growth and development in pediatric patients, including height, weight, head circumference, and age. There is a lack of consensus when calculating ages for children less than three months of age, but direction is provided by the guidance, which also shares valuable insights into the agency’s thoughts on what type of measurements and calibrations are required.
Whenever and wherever children are concerned, there is a particular need to ensure that they are protected. In clinical research, drug developers and trial investigators have an overarching responsibility to treat children ethically and with the most stringent safety standards. Children’s limited ability to participate in research must be focused on where they can make essential contributions, and to supplement that participation, modeling should be seriously considered. These very welcome FDA guidelines outline the opportunities for its use, and as they continue to receive comments from external parties and industry, we look forward to seeing their finalization and acceptance in the near future.
Justin Hay is a Senior Director at Certara
1. FDA, OPT, CDER, CBER, CDRA Draft Guidance, Ethical Considerations for Clinical Investigations of Medical Products Involving Children, September 2022 Clinical/Medical. https://www.fda.gov/media/161740/download
2. FDA, CDER Draft Guidance, General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products, September 2022 Clinical Pharmacology Revision 1. https://www.fda.gov/media/90358/download
3. FDA, CDER, CBER, Draft Guidance, Measuring Growth and Evaluating Pubertal Development in Pediatric Clinical Trials, November 2022 Clinical/Medical. https://www.fda.gov/media/162725/download
4. Code of Federal Regulations (21 CFR 50.52)https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=50.52.
5. FDA, CDER Draft Guidance, General Clinical Pharmacology Considerations for Pediatric Studies of Drugs, Including Biological Products, September 2022 Clinical Pharmacology Revision 1. Section G2, lines 796-799 and Section H, lines 808-833.
6. S. Barker, C., Standing J, et al, Archives of Disease in Childhood, Pharmacokinetic studies in children: recommendations for practice and research,2018 Jul; 103(7): 695–702. doi: 10.1136/archdischild-2017-314506
7. Johnson, T., Small B., Yeo K. R., CPT Pharmacometrics Syst Pharmacol, Increasing application of pediatric physiologically based pharmacokinetic models across academic and industry organizations. 2022 Mar;11(3):373-383.doi: 10.1002/psp4.12764.