14 January 2025
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Multidrug-resistant (MDR) pathogens cause significant morbidity and mortality in neonates, infants, and children. In order to deliver critically needed new treatments for these infections, safety and efficacy are evaluated by regulators and are also considered by children and their parents, prescribers, and drug developers. Regulatory approval is granted when the benefit-risk profile is acceptable, and risks and benefits are communicated in the labeling of the approved product. However, with greater severity of the infection, consequences of inadequate treatment, and the lack of effective therapy, patients and physicians are generally willing to accept greater risks and side effects from treatment.
In this Antimicrobial Viewpoint, we hope to share insights into potential regulatory advancements to facilitate development of new agents for MDR pathogens in children.
Deficiencies of current approaches
A key issue that leads to delays in addressing the unmet need is the one-size-fits-all approach to pediatric product development and approval. A tailored approach in designing pediatric programs is needed, considering overall attributes of the product (safety and efficacy, particularly prospective data from adults), what is known about similar products, and its potential to address an unmet need.
While there are significant delays in evaluating products for children overall, the delays in addressing the needs of neonates, a vulnerable population with the greatest unmet need globally, are particularly unacceptable. There is a critical need for timely availability of approved novel antibacterial therapies in neonates (including premature infants). During the first weeks of life, maturational development of renal and hepatic clearance and evolving differences in tissue distribution of drugs result in substantial changes in pharmacokinetics (PK) that can impact the safety and efficacy of products.
Extrapolation of efficacy from adults to pediatrics is generally acceptable for most infectious diseases unless the pathophysiology and clinical manifestations differ between adults and children. Hence, most pediatric antibacterial trials are primarily designed to assess pharmacokinetics (PK) and safety. While efficacy endpoints are evaluated, the trials are generally not designed for inferential statistical testing.1,2
A tailored approach in designing pediatric programs is needed, considering overall attributes of the product (safety and efficacy, particularly prospective data from adults), what is known about similar products, and its potential to address an unmet need.
Considerations for advancing pediatric and adolescent development
Inclusion of adolescents. A concerted effort is needed for inclusion of adolescents in adult trials based on physiologic similarities, to allow for a better assessment of the risks and the prospect of benefit to children. Adolescents could either be enrolled in adult phase 3 trials or studied in a parallel cohort. This approach is consistent with regulatory guidances and has been successfully implemented in other therapeutic areas.1,2 Early availability of adolescent data can facilitate more rapid evaluation in younger children as adolescent data can be used to further support extrapolation from adults to children. Additionally, as an adolescent cohort will not need to be included in the pediatric studies, timelines for the pediatric programs can be shortened.
Extrapolation of safety. Extrapolation of safety from adults to children can help optimize trial size for certain products/age groups, particularly when the drug is a member of a known class, pediatric use information is available for other members of the class, and no specific safety concerns have been identified in nonclinical studies or in adults. In these circumstances, safety can be extrapolated to older children as noted above, with the clinical trial focus on collecting safety data in the younger cohorts.3 Off-target effects and toxicities that are particularly relevant to children should be addressed to justify extrapolation of safety. For some drugs, the risks may be age-dependent, as neonates and young infants may be more likely to have specific end-organ exposure (e.g., CNS exposure due to immaturity of neurons and the blood-brain barrier).4 EMA guidelines acknowledge that a similar safety profile is expected in adults and children with similar systemic exposures, supporting extrapolation of safety from adults to children.2 A wider acceptance of this approach across different regulatory authorities would be beneficial.
As stakeholders involved in ensuring the health of children, we need to collaborate to assess the challenges and design feasible pathways for the evaluation of antibacterials in children.
PK/safety and noncomparative trial designs. Assuming the purpose of the pediatric studies is primarily to address PK and safety, a study design where the investigational product (single/multiple dose) is given concurrently with the standard of care therapy over a wide range of infections, could be considered adequate for approval, acknowledging that safety assessments will be confounded by concurrent therapy. This could expedite development by allowing the study of children beyond certain approved adult indications particularly when the labeled adult indications differ across countries/regions, e.g., pathogen-based versus body site-specific indications. While this may be a feasible option for products from a known class, it may not be appropriate for new classes with less well-defined toxicities.
We also need to consider situations where single-arm, open-label, non-comparative studies in children will suffice instead of the standard requirement for a comparator arm. While the inclusion of a comparator arm has advantages, in the context of small studies whose primary goal is to describe pediatric PK and safety, the utility of larger, more complicated comparative treatment studies is questionable. Single-arm PK and safety studies are the norm in other pediatric infectious disease trials, such as tuberculosis and HIV.
Limited data package. Specific situations may exist for streamlined pediatric development programs, like that in adults, with a clear understanding of the limitations regarding safety and efficacy. Additional data on safety and efficacy collected systematically from publications, post-marketing reports, and relevant databases can support a labeling update or other regulatory action. Tools such as modeling and simulation, extrapolation, and using real-world data (RWD) to complement clinical trials for confirming benefit-risk balance for these products are critical. Although RWD may have some limitations, useful information to better characterize the drug’s safety profile can be obtained, for example to generate long-term safety data post-approval.
Global harmonization. Differences in the pediatric development requirements between different regulatory authorities need to be streamlined. Expanding on the existing pathways for health authority interactions and inclusion of other relevant national regulatory authorities, particularly for products with the most significant role in those regions, should also be explored. As currently successful in adults, a single global development program should be generally acceptable for pediatrics. Developing standardized pediatric protocols for indications such as skin infections, urinary tract infections, pneumonia, and bacteremia could improve efficiency and mitigate some of the delays for each new product being evaluated.
In summary, as stakeholders involved in ensuring the health of children, we need to collaborate to assess the challenges and design feasible pathways for the evaluation of antibacterials in children. Also, given the many economic challenges in the anti-infective space, enhanced funding opportunities and financial incentives can help ensure that neonates, infants and children across the globe have access to safe and effective therapies in a timely manner.5
References
- US Food and Drug Administration (2024) FDA Guidance: Development of Anti-Infective Drug Products for the Pediatric Population. Accessed August 23, 2024.
- European Medicines Agency (2024) EMA Guidelines: Addendum to the guideline on the evaluation of medicinal products indicated for treatment of bacterial infections to address paediatric-specific clinical data requirements. Accessed August 23, 2024
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (2024) ICH guideline E11A on pediatric extrapolation. Accessed August 24, 2024
- Schmitt G, Parrott N, Prinssen E, Barrow P. (2017) The great barrier belief: The blood-brain barrier and considerations for juvenile toxicity studies. Reprod Toxicol. 2017;72:129-135.
- Årdal C, Balasegaram M, Laxminarayan R, et al. (2020) Antibiotic development – economic, regulatory and societal challenges. Nat Rev Microbiol. 2020;18(5):267-274.
Sumathi Nambiar is board certified in pediatrics and pediatric infectious diseases. She is a fellow of the American Academy of Pediatrics and has over 20 years of experience in drug development and regulatory science. Currently, she works in the Child Health Innovation and Leadership Department in Johnson & Johnson.
Prior to joining Johnson & Johnson, Sumathi worked at the US Food and Drug Administration for 22 years in various capacities, including 8 years as Director of the Division of Anti-infectives, providing regulatory oversight for the development of anti-infective products. She trained and worked as a pediatrician in India before moving to the US.
John Bradley is a pediatric infectious diseases physician, Professor of Pediatrics/Infectious Diseases at the University of California at San Diego and Director of Infectious Diseases at Rady Children’s Hospital San Diego, USA. His career has focused on the clinical evaluation of new therapeutic agents (antibiotics and now bacteriophage) using pharmacokinetics/pharmacodynamics to target increasingly resistant bacterial pathogens.
He has served on the FDA’s Anti-infective Drug Advisory Committee and the American Academy of Pediatrics Committee on Infectious Diseases, and represented pediatrics on the IDSA Task Force to spur global commitment for antimicrobial development of new, unique antibiotics. He has participated in writing IDSA/PIDS Guidelines for Pediatric Community Pneumonia, Intra-abdominal Infection, Acute Bacterial Osteomyelitis and Acute Bacterial Arthritis.
The authors declare that they do not have any relationships or affiliations that could be construed as a potential conflict of interest.