Key Takeaways
Pediatric cancers can differ substantially from adult malignancies in their genomic drivers and underlying biology, limiting the value of an exclusively adult-first development strategy.
Small and increasingly molecularly segmented patient populations require trial designs, global recruitment strategies, and cross-program coordination that make more efficient use of scarce participants.
Pediatric dose optimization, developmental pharmacology, and age-appropriate formulations need to enter development earlier rather than follow decisions made primarily for adult patients.
Existing incentives can make some pediatric programs financially attractive while still leaving pediatric-specific assets vulnerable when they lack a strong adult commercial opportunity.
Regulatory reforms, including the RACE for Children Act and subsequent 2026 legislation, are moving pediatric considerations earlier, but broader scientific, operational, and economic changes are still needed.
Pediatric Oncology Requires a Different Starting Point
Drug development in pediatric oncology has long depended on a sequence established largely around adult cancer. Molecules enter first-in-human studies in adults, evidence accumulates around adult indications, and pediatric evaluation follows when the science, regulation, and commercial strategy support it. Historically, that sequence created substantial delays. Among 117 nonhormonal oncology drugs first approved by the U.S. Food and Drug Administration (FDA) between 1997 and 2017, the median interval between first-in-human and first-in-child trials was 6.5 years, and only six initial approvals included children.1
Recent regulatory changes are beginning to alter that pattern, but timing is only one part of the problem. Childhood cancers comprise rare and often biologically distinct diseases. Their limited patient populations constrain conventional trial designs, and molecular stratification can make those populations smaller still. The patients themselves span developmental stages that affect drug disposition, dose selection, formulation requirements, and safety. Pediatric-specific opportunities may also struggle to compete for investment when they lack a larger adult market.
A system built primarily around adult oncology cannot simply be scaled down for children. Pediatric oncology needs a model that recognizes its distinct biology, limited populations, developmental complexity, and economic constraints from the outset.
The Limits of the Adult-First Model
The historical delay between adult and pediatric trials reflected more than conservative sequencing. Adult development often determines which molecules accumulate enough clinical, manufacturing, regulatory, and commercial momentum to reach children at all. If a target supports a substantial adult indication, a drug may advance far enough for a pediatric opportunity to become actionable. If the adult opportunity weakens, the pediatric program may lose the infrastructure that would have carried it forward.
That dependence matters because a drug can remain scientifically relevant to pediatric cancer even after its adult program loses strategic value. Pediatric oncology stakeholders have identified discontinued or shelved adult oncology assets as a potential source of therapies for children, while also documenting barriers to rescuing them, including corporate priorities, transfer of information and ownership, access to data, and the resources needed to restart development.2 The fate of a pediatric opportunity can therefore hinge on the commercial trajectory of an adult program rather than on its value in childhood cancer.
The adult-first model also affects when pediatric-specific work begins. Dose optimization, age-appropriate formulation development, nonclinical questions relevant to growing patients, and operational planning for very small trial populations can all become later additions to a program whose fundamental product strategy was established for adults. A delay in pediatric clinical testing can consequently represent only the visible end of a much earlier sequencing decision.
Regulatory reform has begun to push pediatric consideration forward, particularly for molecularly targeted oncology drugs, but the larger challenge is reducing how heavily pediatric programs depend on adult program architecture.
Different Biology Requires Different Priorities
The scientific case for a distinct paradigm begins with the tumors themselves. Pediatric cancers are not simply adult malignancies occurring at younger ages. Their genomic landscapes can differ substantially in mutation burden, driver events, and the relative importance of structural changes, gene fusions, copy-number alterations, and other mechanisms.3
A pan-cancer analysis of 1,699 pediatric leukemias and solid tumors identified 142 driver genes, only 45% of which matched driver genes identified in adult pan-cancer analyses. Copy-number alterations and structural variants accounted for 62% of the events identified in that analysis.4 These findings illustrate why an adult indication cannot always serve as the most useful starting point for deciding which mechanisms deserve pediatric development.
There are important cases in which adult and pediatric cancers share actionable biology, and molecularly targeted development can create opportunities across age groups. That logic helped motivate the shift toward considering target relevance to pediatric disease rather than relying solely on whether the same tumor type occurs in adults and children.5 The inverse problem is equally important. Some biologic dependencies may matter greatly in childhood cancers without generating a sufficiently attractive adult opportunity to bring a corresponding drug through conventional development. Pediatric-specific initiating events and dependencies can therefore require strategies that originate with childhood cancer biology rather than wait for adult oncology to produce an appropriate asset.6
A biology-first pediatric paradigm would treat adult development as one route to a pediatric therapy rather than the default gateway through which pediatric opportunities are expected to pass.
Rarity Changes the Mathematics of Development
Childhood cancer is rare in aggregate, and each individual malignancy represents only a fraction of that already-small population. The National Cancer Institute estimated 14,910 new cancer diagnoses among U.S. children and adolescents ages 0–19 in 2024.7 For drug developers, however, overall incidence is only the beginning of the population problem.
Modern oncology increasingly divides diseases according to molecular features that may predict therapeutic response. In pediatric oncology, that can produce a difficult tradeoff. Better biological resolution may identify a much more rational treatment population while simultaneously reducing the number of patients eligible for a trial. Investigators working in rare pediatric tumors have noted that, in some settings, the number of patients needed for a conventionally powered randomized phase III trial simply does not exist.8
Eligibility criteria narrow the pool further. A study may require not only a particular diagnosis but also a specific molecular alteration, disease stage, treatment history, performance status, and geographic ability to reach a participating center. The statistical problem cannot therefore be solved by treating the total number of children with cancer as the relevant denominator.
Strategies have to generate reliable evidence from the population that actually exists.
Designing Trials Around Scarce Populations
Pediatric oncology consequently needs a broader trial-design toolkit. Randomized controlled studies remain valuable when feasible, but some questions require approaches that can extract more information from limited populations without sacrificing interpretability.
Single-arm trials and external controls can be useful when conventional randomization is impractical, particularly in very rare diseases, although their credibility depends on careful alignment of populations, endpoints, assessment methods, and available data. Differences between the treated cohort and an external comparator can otherwise create bias that is difficult to separate from a treatment effect.9
Master protocols offer another way to use shared infrastructure more efficiently. A systematic review identified 38 pediatric master-protocol studies and found that oncology accounted for 58% of them, with platform and basket approaches prominent among the designs used. Adoption remained limited, but the experience demonstrates that these structures are already part of pediatric research rather than purely theoretical alternatives.10
The AcSé-ESMART platform provides a concrete example. Its multi-arm phase I/II structure evaluates molecularly selected children with refractory cancers and allows multiple targeted agents and combinations to be investigated within a shared precision-oncology framework.11 Such architecture can allow new hypotheses to enter a common system instead of requiring separate trial infrastructure for each small molecular subgroup.
Programs designed first around large adult indications may also inherit assumptions about cohort size, sequencing, and evidence generation that translate poorly into pediatric disease. Earlier pediatric trial planning creates more room to choose designs suited to the available population.
Coordination Becomes Part of Development
Small populations also create a portfolio-level problem. When several programs pursue similar mechanisms in the same rare population, each may struggle to recruit enough participants to generate useful evidence.
Experience in rare pediatric tumors has shown that competition between groups can slow accrual and, in some cases, threaten trial feasibility.12 Pediatric oncology therefore sometimes requires coordination not only within a trial but across portfolios, institutions, and companies.
Multi-stakeholder prioritization offers one model. Pediatric strategy forums convene regulators, academic investigators, industry, and patient representatives to evaluate classes of agents and identify development priorities. Assets considered high priority through these forums were substantially more likely than non-high-priority assets to subsequently become the subject of a pediatric investigation plan or written request.13
When eligible patients are exceptionally scarce, scientific prioritization and sequencing can matter as much as the number of programs launched. Sharing infrastructure, avoiding redundant studies, and advancing the most compelling candidates first may generate more useful evidence than allowing several poorly accruing trials to proceed in parallel.
Pediatric Oncology Has to Be Global by Design
For some rare malignancies or molecular subsets, a single country may not supply enough eligible participants for a meaningful development program.
Historically, pediatric oncology trials have not consistently operated on that scale. A systematic review of 3,383 therapeutic pediatric cancer trials opened from 2010 through 2020 found that 295, or 8.7%, were international and 182, or 5.4%, were intercontinental.14
More recent evidence shows a related but distinct challenge. A 2026 analysis of 3,149 pediatric-only cancer trials found that 81.2% were conducted by sponsors in high-income countries and documented substantially lower trial availability in lower-income settings.15 The first issue is statistical feasibility: broader geographic recruitment can be necessary to reach enough eligible patients. The second is access: the opportunity to participate in experimental research remains distributed unevenly across regions.
International studies bring regulatory, operational, logistical, and infrastructure complexities of their own. When population size is the binding constraint, however, geography cannot remain an afterthought or a rescue strategy introduced only after enrollment falters.
Dose Development Across Childhood
Pediatric clinical pharmacology is not only a dosing problem. In a field where eligible patients may be exceptionally scarce, it is also a patient-conservation problem.
Age, body size, organ maturation, renal function, metabolic enzymes, transporters, and other developmental factors can influence drug exposure and disposition.16,17 Pediatric dose selection therefore requires more than a simple body-weight or body-surface-area adjustment to an adult regimen. Infants, young children, adolescents, and adults can differ pharmacologically, and those differences may change as a child matures during a development program.
Pediatric extrapolation offers a way to use existing evidence without assuming that adults and children are interchangeable. Current guidance frames extrapolation as a structured assessment of what can reasonably be inferred about disease course, treatment response, pharmacology, and safety, and what uncertainty still requires pediatric data.16 Model-informed approaches, including pharmacokinetic modeling and exposure matching, can then help identify doses while limiting unnecessary experimentation in small populations.18
Every cohort used to answer a dose question consumes patients who may have very few clinical trial options. When validated prior information, modeling, or better developmental planning can resolve part of that uncertainty, good clinical pharmacology can preserve scarce participants for questions that truly require direct pediatric evidence.
Earlier dose planning also reduces the risk that a pediatric program will inherit an adult regimen and exposure target before developers have adequately considered whether those assumptions remain appropriate across childhood.
Formulation Is Part of the Development Strategy
Dose selection is useful only if children can receive the intended dose accurately and consistently. Yet many oncology products begin development in dosage forms created for adults.
Young children may not be able to swallow the tablets or capsules used in adult programs, and the available strength may not permit an appropriate pediatric dose. Clinicians or caregivers may then need to crush tablets, open capsules, disperse products, or otherwise manipulate formulations. A review of kinase inhibitors used in pediatric oncology found that many lacked age-appropriate dosage forms or adequate instructions for manipulation and warned that such changes can affect drug delivery, pharmacokinetics, safety, and efficacy.19
If the pediatric opportunity is considered only after the adult product and manufacturing approach are largely fixed, creating an age-appropriate formulation can become another sequential step. Earlier formulation planning can instead influence dosage form, strength, administration strategy, and the practical feasibility of studying a drug across different pediatric age groups.
Considering formulation earlier reinforces the distinction between including children in a clinical program and developing a medicine for children.
Safety Operates on a Longer Clock
Anticancer treatments may be administered while organs, tissues, and neurological systems are still developing, and regulators have specifically recognized the potential for treatment-related toxicity to affect developmental processes.20
Treatment consequences can also extend far beyond the immediate clinical trial. Late effects after childhood cancer therapy may involve organ function, growth and development, cognition, psychological functioning, and subsequent cancers.21 These risks carry particular weight in patients who may live for many decades after treatment.
Pediatric benefit–risk assessment therefore has to accommodate unavoidable uncertainty while maintaining attention to developmental and long-term effects. That can influence nonclinical planning, follow-up strategy, dose optimization, and the value placed on reducing toxicity when multiple therapies produce comparable antitumor activity.
The Economics Problem Is More Complicated Than a Small Market
Small patient populations can weaken the conventional commercial rationale for development. Low incidence, the resource demands of pediatric trials, and limitations in early-stage funding have all been identified as financial barriers to pediatric oncology innovation.22 But the evidence does not support a simple conclusion that pediatric incentives are uniformly inadequate or that pediatric development cannot produce meaningful returns.
For four oncology drugs examined in one analysis, the estimated revenue associated with pediatric exclusivity substantially exceeded the estimated investment required for the relevant pediatric trials.23 In the broader rare pediatric disease setting, another analysis found substantial revenues among products associated with priority review vouchers and questioned whether that incentive was necessary in every case.24
The more consequential issue is what kinds of development existing incentives encourage. Pediatric oncology remains closely linked to assets that already have adult commercial momentum. Incentive analyses have argued that the resources required for a pediatric program can be disproportionate to the potential pediatric market and that development remains strongly coupled to more lucrative adult indications.25
An incentive system can make some pediatric development financially attractive while still failing to solve the problem of assets whose principal value is pediatric. If an adult program succeeds, pediatric development may be more likely to become economically and operationally feasible. If it is shelved, the pediatric opportunity can disappear even when the underlying mechanism remains compelling for childhood cancer.2
The challenge is to create incentives and development structures that allow scientifically important pediatric programs to survive independently of the commercial fortunes of adult oncology.
Regulation Is Moving Pediatric Development Earlier
U.S. regulation has already begun to challenge the historical sequence. The RACE for Children Act shifted pediatric requirements for certain molecularly targeted oncology drugs toward the relevance of the target to pediatric cancer, weakening the older dependence on whether an adult indication also occurred in children.5
Early implementation data suggest that this change has affected development timing. Among 21 relevant post-RACE adult cancer drugs examined in one analysis, 15 pediatric testing requirements were imposed. Associated pediatric trials began a median 2.8 years before adult approval, compared with approximately the time of adult approval in the pre-RACE cohort. At the same time, the overall rate of early pediatric trials had not clearly increased, indicating that earlier regulatory requirements do not automatically resolve every barrier to pediatric development.26
The framework continued to evolve in 2026. The Mikaela Naylon Give Kids a Chance Act, enacted in February 2026, added provisions allowing certain required pediatric investigations to evaluate a drug alone or, under specified conditions, in combination with another active ingredient, with clinically meaningful pediatric information on dosing, safety, and preliminary efficacy and attention to age-appropriate formulations. The legislation also extended the Rare Pediatric Disease Priority Review Voucher authority through September 30, 2029.27
These reforms can move pediatric planning earlier and broaden the circumstances in which pediatric evidence is required. They do not remove the practical constraints imposed by small populations, developmental pharmacology, formulation needs, global recruitment, or the economics of pediatric-specific assets.
Building a Pediatric Oncology Development Paradigm
A more appropriate pediatric oncology paradigm would involve three broader shifts.
The first is from adult commercial opportunity toward pediatric biological relevance. Adult programs will remain an important source of therapies, particularly when a target spans age groups, but pediatric development also needs routes for mechanisms whose greatest clinical value lies in childhood cancer. That requires identifying pediatric relevance early enough to influence asset selection, dose strategy, formulation, and program planning.
The second is from standardized development sequences toward evidence generation designed around the available population. Small and molecularly segmented populations require trial architectures that use patients efficiently, including conventional randomization where feasible and alternative approaches where justified. Clinical pharmacology, extrapolation, modeling, and formulation planning can serve the same goal by reducing avoidable uncertainty before scarce patients enter studies.
The third is from optimizing each program in isolation toward recognizing that pediatric oncology sometimes depends on shared infrastructure and coordination. Global recruitment, platform trials, prioritization among similar assets, and mechanisms for rescuing pediatric-relevant drugs after adult development stops all address problems that no individual trial design can solve on its own.
These shifts reflect an environment in which the central constraints are different enough that adult oncology cannot remain the default template.
From Pediatric Access to Pediatric Development
For much of the modern oncology era, the central pediatric question was how to bring drugs developed for adults into children sooner. That remains important, and evidence from the RACE era suggests that pediatric evaluation can be moved earlier when regulation requires target relevance to be considered during development.
But earlier access to adult-developed drugs is not the full measure of progress. The larger goal is to ensure that therapies can be developed because they make biological and clinical sense for childhood cancer, even when their path differs from conventional adult oncology.
Pediatric oncology needs a development system designed around the diseases, patients, and constraints it actually confronts.
References
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