(Accessed 3 March 2018)
Delays in completion and results reporting of clinical trials under the Paediatric Regulation in the European Union: A cohort study
Thomas J. Hwang, Paolo A. Tomasi, Florence T. Bourgeois
| published 01 Mar 2018 PLOS Medicine
Few 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 findings
The 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.
The 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.
:: Why was this study done?
Most new medicines are developed and tested in adults, and clinicians often need to treat paediatric patients with products lacking paediatric safety, efficacy, or dosing information.
To increase the number of medicines that are appropriately studied in children, the European Union adopted the Paediatric Regulation in 2007, requiring pharmaceutical companies to study new medicines in children.
Ten years since its implementation, there has been limited assessment of the availability of paediatric trial information resulting from studies required under the regulation.
:: What did the researchers do and find?
For all new medicines centrally authorised in the EU between 2010 and 2014, we identified those with paediatric trial requirements under the Paediatric Regulation. A total of 326 paediatric clinical trials were required for 122 medicines and comprised our study cohort.
After a median follow-up of roughly 7 years, 38% of paediatric trials had been completed, and 17% of medicines had all paediatric requirements fulfilled.
Most paediatric studies (76%) were not planned to be completed until after marketing authorisation. In addition, delays occurred due to changes in the planned completion date, with 50% of studies extending the completion date at the request of pharmaceutical companies.
Overall, trials planned to be completed after marketing authorisation were associated with an 89% lower likelihood of completion compared to trials with planned completion before marketing authorisation.
The results for 85% of completed studies were published or publicly reported in a trial registry, at a median of 1.1 years after the completion date.
:: What do these findings mean?
Many paediatric studies required under the Paediatric Regulation have not been completed due to delays.
Among paediatric trials that were completed, trial results were disseminated in a timely fashion for a majority of the studies.
Our findings highlight the need to examine the implementation of current policies—including requirements around the timing of trial completion—to ensure timely availability of important paediatric information for new medicines.