OBJECTIVES

To explore uncertainty in clinical outcomes in the treatment of paediatric rare diseases.

METHODS

Systemic orphan therapies licensed for paediatric indications between January 2017 and March 2020 were identified using OrphaNet and EMA sources. Evidence on efficacy and safety of each therapy was extracted from EMA European Public Assessment Reports and literature. To identify published articles, we systematically searched PubMed, Cochrane and Clinical Key databases using ([Therapy] AND [Indication]) search string, while limiting the results to phase II, III or IV clinical trials published between January 2015 and March 2020. Presentations from congresses on rare diseases from the same period were included. Benefit–risk and degree of uncertainty associated with each therapy were rated using Institute for Clinical and Economic Review Evidence Rating Matrix for Comparative Clinical Effectiveness, and classified under PICOS headings: population (with a focus on clinical trials including children <18 years), intervention, comparator as defined in the clinical study, clinically relevant primary and secondary efficacy and safety outcomes, and study design.

RESULTS

Eleven systemic orphan therapies were identified: burosumab, cannabidiol, chenodeoxycholic acid, cerliponase alfa, dinutuximab beta, glibenclamide, metreleptin, nusinersen, tisagenlecleucel, velmanase alfa, vestronidase. Considerable variation was found in the magnitude of clinical benefit of efficacy and safety, with study design and type of endpoints (hard/objective, surrogate/subjective) found to be the main factors contributing to uncertainty. Nusinersen and dinutuximab beta were found to have the highest evidence rating, followed by tisagenlecleucel and cannabidiol, however subjective judgements implicit in the methodology need to be considered.

CONCLUSIONS

Licensed orphan therapies differ in terms of the strength and uncertainty of their evidence, which can be attributed to constraints in the evidence generation in rare diseases in general, and in paediatric rare diseases in particular. Authorities need to give this due consideration in their decision making.