Innovation coming to paediatric research

Background and method

Innovations for clinical trials may accelerate bringing new medicines to children, such as through more robustly quantifying treatment effects, combining phases and ages, expanding access, and more often involving patients and their organisations in the design of trials and documenting patient-centric endpoints. The objective of this page is to continually track such innovations using information on clinical trials and to present original insights.

Information from the EU Clinical Trials Register and ClinicalTrials.Gov was used for this analysis . For commenting, the full R code is included below. Paediatric trials were identified based on the protocol-related information that any of the paediatric age groups was to be included in the trial. Interventional trials with medicines were identified in ClinicalTrials.Gov based on type=Drug (which includes agent, pharmaceutical, medications, medicine, medicinal product).

Topics under preparation

  • Expansion cohorts of early trials
  • Estimation of outcomes
  • Patient-reported outcomes
  • Clinical trials and disease burden in children
  • Integrated non-controlled and randomised trials
  • Adaptive trials

Platform trials

A single clinical trial can be designed and used as platform for investigating different diseases and different investigational medicines at the same time . A basket trial, for example, has different arms corresponding to different diseases, thus permitting a broader range of patients to be included. Both, the effects of treatment with a medicine and the susceptibility of the diseases to the treatment may be documented. An umbrellat trial has different arms corresponding to different medicines to which a patient may be allocated. Other terms in the context of platform trials are complex trials, master protocols and matrix trials. Methods to design, conduct and analyse such trials vary much and are increasingly discussed .

In ClinicalTrials.Gov, basket and umbrella trials with children are identified here by non-randomised allocation to one of at least three arms with largely different labels (not counting control arms), and at least as many conditions as arms. In the plot of the trials, larger symbols are more likely basket or umbrella trials (based on dissimilarity of conditions and arms).

Randomisation in early phase trials

Randomisation throughout all development phases has recently been recommended when small populations are to be studied such as for personalised medicines , including for possibilities to separate prognostic importance of a biomarker from treatment effects and to faster transition phases.

While a seizable portion of early phase paediatric trials that include randomisation also include randomisation to placebo or to no treatment, it is not yet clear how much such approaches are used across paediatric therapeutic areas.

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Adolescents in “adult” trials

If adolescent patients are included in trials originally planned only for adults, separate and later trials with these paediatric patients may be avoided. Such an age-inclusive approach would build on scientific and medical considerations for the specific trial, and also on general intentions to improve access for these patients and to shorten timelines of developing a medicines of children. Recommendations for oncology were recently put forward by multiple stakeholders . The approach can also be relevant for later phase trials and perhaps other therapeutic areas. Further analyses may be by type of sponsor or by the authorisation status of the medicine.

To track progress with respect to the recommendations, the analysis is limited to the therapeutic area of oncology and to phase 2 trials (search term "cancer" and phase 2 recorded in the EU Clinical Trials Register), because adult phase 1 trials are not be required to be made public in the registers.

However, phase 2 trials may be therapeutic exploratory trials and therefore for a different cancer(s) than in children; therefore, it is expected that only a portion of such trials is relevant for adolescents with a cancer. The number of phase 2 oncology trials open to adolescents seems to be slightly increasing. More analyses will be done on the subset of trials that are for cancers that occur in the paediatric population.

plot of chunk ados_in_adult_trials_oncology

Involvement of paediatric networks

The involvement of paediatric networks is generally recommended to better prepare and conduct trials of medicinal products with children.

Among paediatric trials in the EU Clinical Trials Register with a commercial sponsor (mostly a pharmaceutical company), excluding phase 4 trials, so far a limited proportion (perhaps some 15%) is documented to involve an investigator network. These networks are tabulated below the histogram. Names of networks are spelled in different ways (not normalised or from a dictionary).

plot of chunk unnamed-chunk-5

Network name Trials
Medicines for Children Research Network 26
Innovative Therapies for Children with Cancer ITCC 5
Cystic Fibrosis Foundation 5
Cystic Fibrosis - National Knowledge Service 5
Cystic Fibrosis Foundation Therapeutics 4
CRN: North Thames Central Office 4
Ancillare 4
Sunovion Pharmaceuticals Inc. 3
European Cystic Fibrosis Society - Clinical Trial Network 3
Cystische Fibrose - Netzwerk Klinische Studien German CF-NKS 3
Cystic Fibrosis Foundation Therapeutics - Therapeutics Development Network 3
Clinical Research Network CRN 3
Vasculair Research Network VRN 2
TREAT-NMD, The University of Newcastle upon Tyne 2
The Experimental Cancer Medicine Centres 2
Teddy Network 2
NIHR CRN National Coordinating Centre 2
NIHR Clinical Research Network 2
National Cancer Research Network Coordinating Centre NCRN CC 2
Medicines for Children Network MCRN 2
Medicines for Children Network 2
Medical Research Network Ltd. 2
MCRN Medicines for Children Research Network 2
ICON Clinical Research LLC 2
European Cystic Fibrosis Society Clinical Trials Network ECFS-CTN 2
ECFS Clinical Trials Network 2
Cystic Fibrosis Foundation Therapeutics, Inc 2
Cystic Fibrosis Foundation Therapeutics CFFT Therapeutics Development Network TDN 2
CRN North Thames, NIHR Clinical Research Network CRN 2
Comprehensive Clinical Research Network and Medicines for Children Research Network 2
Clinical Research Network North Thames 2
Childrens Oncology Group Operations Center 2
Childrens Oncology Group 2


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Gaspar, N., L. V. Marshall, D. Binner, R. Herold, R. Rousseau, P. Blanc, R. Capdeville, et al. 2018. “Joint Adolescent - Adult Early Phase Clinical Trials to Improve Access to New Drugs for Adolescents with Cancer Proposals from the Multi-Stakeholder Platform - ACCELERATE.” Annals of Oncology 29 (3): 766–71.
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Saad, Everardo D., Xavier Paoletti, Tomasz Burzykowski, and Marc Buyse. 2017. “Precision Medicine Needs Randomized Clinical Trials.” Nature Reviews Clinical Oncology 14 (5): 317–23.
Chuk, Meredith K., Yeruk Mulugeta, Michelle Roth-Cline, Nitin Mehrotra, and Gregory H. Reaman. 2017. “Enrolling Adolescents in Disease/Target-Appropriate Adult Oncology Clinical Trials of Investigational Agents.” Clinical Cancer Research 23 (1): 9–12.

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