A company had experienced challenges in its development and gaining an MAA and NDA had taken longer than anticipated. As part of the US PREA and EU PIP plans there was a requirement to investigate two related diseases in children where there was some possible therapeutic benefit.
Over the time since the PIP was agreed, the standard of care for one of the diseases had changed substantially, making a placebo controlled study impractical. In the other disease area, new therapies had substantially reduced the prevalence and incidence of the disease, making clinical trials impractical and potentially unethical due to their inability to recruit a sufficient sample size and generate any meaningful results. While there is a clear potential patient benefit to generating data, the sponsor was also aware of the fact that there was a deadline for completion and the potential of an exclusivity extension that would fund substantial R&D work should it be achieved.
To address this work we examined the relative urgency and feasibility of the indications, recommending that the indication where the prevalence had fallen be discussed with EMA to remove it from the PIP. As the other indication however was expected to remain in the PIP and there was a tight timeline, we prioritised this work and recommended a PIP modification to amend the study proposal, replacing placebo with standard of care active comparator from the therapeutic group of medicines. This was chosen in preference to a single comparator because of differences between specialist centres and countries. In addition as the standard of care and the company's product could not be blinded (both being injectables), any blinding would require a double dummy approach with multiple injections in this paediatric population. These challenges allowed us to propose an open study, but with objective measures being rated by blinded observers, noting that a larger sample size was required because of the removal of placebo.
After designing the studies we presented this to the Paediatric Development Committee (PDCO) at EMA who mostly agreed with the proposals. Some further negotiation was required to deliver an acceptable and achievable outcome within the required timescale, but a successful agreement was reached on a plan that will provide data of use to patients and the potential of achieving the exclusivity extension.
Once this had been achieved we turned to the second indication, requesting this to be removed from the PIP, developing a comprehensive data set on prevalence, real world evidence and medicines utilisation. We additionally presented recruitment statistics from recent paediatric studies in this indication, demonstrating prolonged and inadequate recruitment before ultimate termination of futile studies. PDCO were resistant to the removal of these studies however, raising several concerns. We discussed these with PDCO, presenting our views on risk, benefit and potential ethical challenges of exposing children to an investigational medicine, when there was a very low chance of generating meaningful data or benefit. After some negotiation, PDCO agreed to remove this indication from the PIP, benefiting patients and the company in removing futile studies based on clarifying and presenting the risks involved.
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