The European Medicines Agency’s (EMA) Pediatric Committee has offered a couple of comments, slight tweaks and further suggestions for the International Council for Harmonisation’s (ICH) draft question and answer document on its S9 guideline on the nonclinical evaluation for anticancer pharmaceuticals.
The committee points to a couple of references in the Q&A on S9 on the scope of the guideline and the statement that "the need for juvenile toxicity testing should be a case by case decision.”
But the committee notes that pediatric oncology "is changing as regards testing and using anti-cancer medicines” and some children with previously incurable diseases are surviving for longer periods of time after receiving treatments that were "originally intended as only palliative treatments or in last-line trials, such as an expanding repertoire of individually-selected, targeted and biologic experimental treatments as well as prolonged chemotherapy regimens of moderate toxicity.
"Recent experience suggests that treatments may change rapidly fatal diseases into more chronic diseases with prolonged survival even after multiple previous relapses," the committee says, calling for further efforts "to minimize and or prevent severe toxicities including when investigating further therapies."
The answer to question 3.9 in the Q&A also states that: "Clinical data from adults is typically available prior to initiation of these paediatric trials; this data is used to set a starting dose and inform monitoring plans.”
While noting that this duplicates to recommendations in other guidances, including ICH E11 and ICH E4, the committee says that it "does not seem needed.”
In addition, the committee points to the fact that this answer indicates that safety may be extrapolated from adult non-clinical and clinical data to pediatric cancer patients, which it says "is particularly applicable for adolescents, and there is a willingness to include them in adult cancer studies whenever possible.
"However, this approach is usually not appropriate for the youngest patient populations, for whom pharmacodynamics (e.g. sensitivity and responsiveness due to different biological features [such as infant leukaemia, brain tumours] as well as different tumour load in paediatric cancers), pharmacokinetics and toxicity (e.g. possible interference with organs/systems undergoing maturation) are not necessarily predictable from adult data. As a consequence, the need for additional non-clinical data concerns mainly the youngest populations, below about 2-4 years of age."
In addition, the committee’s comment points to another part of that same draft answer where it says these trials "are usually done in a controlled setting with substantial safety monitoring."
But the committee says it is "unrealistic that much safety data can be generated in youngest children in these initial paediatric trials and if safety monitoring can be relied upon to minimise adverse outcomes in this subset, considering that the major risks are in younger children but these are scarcely included in initial trials. Initial trials are mostly late-line trials and this means that patients after a number of failed treatments are no longer in the youngest age. However, the indication targeted in paediatric patients is often curative (e.g. first or second line) and the treatment of youngest patients is clearly part of the indication targeted by the paediatric development."
Overview of comments received by EMA on 'Questions and answers - ICH S9 guideline on nonclinical evaluation for anticancer pharmaceuticals - Step 2b'