FDA, EMA team up on pediatric oncology drug development template

| 01 April 2021 | By Kari Oakes 

In a move that dovetails with other cooperative efforts in regulation of pediatric oncology drugs, regulators in the US and Europe have come together to provide a common template for drugmakers to use when planning clinical trials for pediatric cancer drugs.
A new Common Commentary template gives a framework for seeking scientific advice from both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) on new Pediatric Investigation Plans (PIPs) and initial Pediatric Study Plans (iPSPs), respectively.
FDA’s Oncology Center of Excellence already maintains a pediatric oncology program that collaborates with EMA in pediatric cluster calls, coordinated through FDA’s Office of Pediatric Therapeutics. “Given the global nature of cancer drug development and the relative rarity of childhood cancer, which impacts study populations for clinical trials, the demand for international collaboration in study design and conduct has intensified,” according to the pediatric oncology program’s informational page on the FDA website.
Additionally, citing a 2020 publication in the Journal of Clinical Oncology, FDA now recommends that sponsors of new cancer products submit their new PIPs and iPSPs simultaneously to FDA and EMA “to promote global coordination and international research collaboration.”
The co-developed template lays out which key issues each regulator will want to see sponsors address. “Adequately addressing these issues upfront will permit focused discussions during cluster calls, allowing for coordination of global development plans,” according to the template document.
Specific areas covered by the template include overall development of the medicinal product; for PIPs, the template reminds sponsors that the objective of the PIP is “to generate data for a full pediatric development, [that is] the studies needed to assess the benefit/risk in the target population.”
For iPSPs, the template identifies pediatric-specific data points FDA is looking for, including incidence of the clinical indication in a pediatric population, and specific plans for pediatric studies or rationale for extrapolation from adult studies to children.
As to the question of waivers for PIP applications, EMA’s “default position” is that an age-specific waiver is not generally needed. For FDA, waivers could be considered if the indication is seen rarely or never in children, or if toxicity would make pediatric studies impractical or dangerous.
The template provides information from EMA about non-clinical studies including juvenile toxicity studies. Here, the need for juvenile animal studies should be considered, weighing whether the study will address safety concerns that cannot otherwise be answered, as well as whether existing studies for a related product might inform planning for human trials. The template lists additional factors that make it more or less likely that additional nonclinical studies are likely to be warranted.
For FDA, “Non-clinical testing of new drugs for toxicity in juvenile animals is not generally required as data on potential toxicity concerns that would inform monitoring strategies in proposed pediatric studies would be adequately provided by accumulated adult experience.”
Quality development issues are also covered in the template. Here, FDA’s approach is “in complete alignment” with EMA’s, which has developers taking a risk-based approach to the choice of excipients for a pediatric population. Alternative administration strategies should be considered, including administration with feeding tubes, “if likely to be used for drug administration.”  Sponsors should be able to address if a formulation is appropriate “across all pediatric age groups,” and share a plan to develop age-appropriate formulations for the target population.
In terms of developing the clinical program, EMA advises trying to include adolescents in adult studies to speed access, particularly for cancers “where the clinical indication spans the adult and adolescent age group.” Acknowledging that the randomized controlled trial remains the gold standard, EMA acknowledges in the template that a single-arm trial or other evidence generation strategy may be justified. Such an approach should include a method for generating comparative evidence from, for example, real-world data, patient-level data, or a Bayesian approach that draws on adult data. EMA directs: “Justify your statistical assumptions.”
FDA’s position on the clinical program is that the study “should be designed to provide sufficient information on dosing, toxicity and tolerability, and signal(s) of activity to both inform labelling and to inform further development of appropriate drug products as warranted by early, initial data within the context of clinical research strategies for specific diseases as supported by the clinical investigator community and in accordance with existing unmet clinical needs supported by patients, advocates, and clinicians.” Sponsors should explain how they sought input from external experts and “competent clinical investigators.
The position of EMA on pediatric investigation timelines is clear: “By default any pediatric development should start without delay;” sponsors should justify any delay that might occur for such reasons as safety concerns.
FDA largely concurs: “It is anticipated that pediatric studies described in the iPSP begin as soon as possible and before the submission of a NDA/BLA for the adult indication under development.” As with EMA, FDA acknowledges that safety considerations may require that adult studies be underway before the pediatric trials can commence.


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