Research Article: Delays in completion and results reporting of clinical trials under the Paediatric Regulation in the European Union: A cohort study

Date Published: March 1, 2018

Publisher: Public Library of Science

Author(s): Thomas J. Hwang, Paolo A. Tomasi, Florence T. Bourgeois, Aziz Sheikh

Abstract: BackgroundFew medicines have been approved for children, leading to rates of off-label prescribing reported to be as high as 90%. In 2007, the European Union adopted the Paediatric Regulation, which mandates that pharmaceutical companies conduct paediatric studies for all new medicines, unless granted a waiver. We aimed to evaluate the availability of paediatric trial results from studies required under the Paediatric Regulation for new medicines authorised in the EU.Methods and findingsThe European Medicines Agency (EMA) public database of paediatric investigation plans was searched for new medicines centrally authorised in the EU between 1 January 2010 and 31 December 2014 with at least 1 required paediatric study. For our study cohort of paediatric clinical trials required for these medicines, we used internal EMA databases and publicly available trial registries to determine changes to the planned completion date or study design, rates of trial completion, time to trial completion, and results reporting (peer-reviewed publication or posting on trial registry). Cox proportional hazards regression models were constructed to examine factors associated with study completion. A total of 326 paediatric clinical trials were required for 122 novel medicines authorised by the EMA between 2010 and 2014. In all, 76% (247/326) of paediatric studies were not planned to be completed until after the initial marketing authorisation. The planned completion dates for 50% (162/326) were further postponed by a median of 2.2 years. Overall, 38% (124/326) of paediatric studies were completed as of 30 November 2017. The rate of trial completion for paediatric studies planned to be completed after initial marketing authorisation was 23% (56/247), versus 86% (68/79) for trials planned to be completed before authorisation (adjusted hazard ratio 0.11; 95% CI 0.06–0.19). Among completed studies, the results were reported in a public registry or in the peer-reviewed literature for 85% (105/124) at a median of 1.1 years after study completion, and 60% (74/124) were published in a peer-reviewed journal. Limitations of this study include the potential lack of generalisability to medicines not authorised by the EMA and the possibility for more of these trials to be completed or published in the future.ConclusionsThe completion of many paediatric studies required under the Paediatric Regulation has been delayed. Paediatric studies planned to be completed after marketing authorisation were associated with a lower likelihood of eventual completion, highlighting the need to examine the implementation of current policies in ensuring timely availability of important paediatric information.

Partial Text: Historically, information on the safety, efficacy, and appropriate use of new medicines in children has been lacking [1]. In one study, over 90% of surveyed paediatricians reported prescribing medicines off-label [2]. Over the years, this gap in available evidence has led to serious unintended harms: for example, the off-label paediatric use of paroxetine was associated with an increased risk of suicidal ideation and hostility, resulting in warnings by regulators that the medicine should not be used in children and adolescents [3].

Of 246 new medicines (excluding generic and biosimilar products) that were authorised by the EMA during our study period, 122 (50%) with PIPs were included (Fig 1); most of these medicines were anti-infective (34, 28%), antineoplastic or immunomodulatory (23, 19%), or alimentary or metabolic agents (17, 14%). These 122 medicines with PIPs were associated with 326 paediatric clinical trials, cumulatively planning to enrol 51,324 participants (Table 1; Fig 1). In all, 182 of 326 trials (56%) were primarily efficacy studies, 21 (6%) trials had both primary efficacy and safety endpoints, 70 (21%) trials had only safety primary endpoints, and 53 (16%) trials were PK/PD studies. The median duration of follow-up for all studies from the date of PIP publication to 30 November 2017 was 7.6 years (IQR 6.5–8.4 years).

In this study of mandatory paediatric study requirements under the EU’s Paediatric Regulation, we found that most paediatric studies have not yet been completed for new medicines that were authorised for adult use between 2010 and 2014. After a median follow-up of 7 years from publication of the PIP, 17% of medicines initially authorised for adults had completed all required paediatric clinical trials, and 38% of paediatric studies had been completed. In addition, paediatric studies that were planned to be completed after initial marketing authorisation were 89% less likely to be completed than studies planned to be completed before authorisation. This difference in likelihood of completion remained significant when considering only efficacy and safety trials. Once trials were completed, the results for 85% of completed studies were publicly reported in a trial registry or a peer-reviewed journal at a median of 1.1 years after completion.

The Paediatric Regulation was introduced in response to the serious harms caused by exposing children to unauthorised and inadequately tested medicines. Our findings suggest that many required paediatric studies have not been completed, with studies that are postponed to after authorisation significantly less likely to be completed than those performed before authorisation. Policies to limit delays in study completion could accelerate the availability of clinically valuable information on new medicines for children.



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