Support for UK Pediatric Studies

Historically, limited numbers of pediatric clinical trials have been conducted. As a result, there is widespread use of unlicensed and off-label medicines by children that are not thoroughly evaluated for safety and efficacy. This has increased the potential for under and overdosing and adverse reactions.¹ Thus, there is clear need for more medicines and formulations for children to be evaluated in appropriate trials.

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It was with these considerations in mind that U.S. and more recently EU legislation was enacted to increase the number of medicines appropriately evaluated for children.

The EU Pediatric Regulation (which came into force January 2007) requires companies to produce a "Pediatric Investigation Plan" (PIP) at the end of Phase I studies in adults for all medicines containing new active substances, detailing the investigations and clinical trials to be undertaken in the pediatric population. PIPs are also required when the use of patented products is being extended.

The EMEA's Pediatric Committee (PDCO) considers all PIP applications. Completion of all studies outlined within approved PIPs brings potential financial reward in terms of patent or data protection as part of the licensing process. In addition, special regulations apply for off-patent medicines to be developed for children, and provision has been made for regular calls for EU-funded research on older medicines.

In the light of the EU regulation and medicines for children increasingly becoming a priority for governments, a number of national pediatric research networks have been established.

For example, in the United Kingdom, the National Institute of Health Research (NIHR) Medicines for Children Research Network (MCRN) was established in 2005 to improve the coordination, speed, and quality of randomized controlled trials and other well-designed studies of medicines for children and adolescents. All clinical study phases are supported by the Network, including early phase, experimental studies.

Other national networks, which conduct clinical studies under this remit, have also been established in other EU countries, including Belgium, Finland, France, Germany and Holland (see Table 1).

Support for pediatric studies

The MCRN supports public, pharmaceutical/biotech sponsored and investigator-initiated (industry funded) clinical studies in over 100 National Health Service (NHS) sites in England that serve approximately 6 million children. The NHS is the world's largest publicly funded health service providing health care to the UK—England, Scotland, Wales, and Northern Ireland. The National Institute of Health Research (NIHR) is responsible for maximizing the research potential of the NHS in England and funds the activities of MCRN and other networks.

Investigators (NHS/academic) and company representatives can approach the MCRN for assistance at all points in the development of a study, from an initial idea through to a full protocol, to help with feasibility, site set up and patient recruitment. The MCRN's aim is to become a single point of contact for all enquiries relating to medicines for children studies and aims to foster close and productive collaborations between Network staff, investigators/sites, companies, and other funders to ensure delivery.

Infrastructure

The six MCRN Local Research Networks (LRNs) assist investigators/sites working on studies in primary, secondary, and tertiary centers (see Figure 1 and Table 2). Local Research Network staff provide a range of support with feasibility, site set up, patient recruitment, and performance management—outlined in the sections that follow.

MCRN Networks in the UK

The Network also collaborates closely with UK Clinical Research Facilities, specialized facilities that can support early phase, experimental studies. In addition, the MCRN has developed an Extended Neonatal Network to promote and support large scale clinical research in neonatology units across the UK. Publicly funded investigators can also obtain assistance from the MCRN Clinical Trials Unit (CTU), the National Perinatal Epidemiology Unit (NPEU), and a wider network of other UK Clinical Trials Units that support pediatric study design and management.

Regulation, protocol, and other advice

Commercial and NHS/academic investigators can approach the MCRN for support with protocol and program development. Advice on protocols and program development can be obtained from the MCRN's advisory Clinical Study Groups (CSGs), which cover the majority of pediatric specialities (see Table 3).

Web Sites for Networks in the UK and Throughout Europe

Clinical Study Groups are multidisciplinary and include senior doctors, nurses, pharmacists, basic scientists, and consumers. Initial, limited advice is usually provided by Clinical Study Groups without charge, but if companies require more extensive advice, the Network assists with the identification of relevant experts (contracting/financial arrangements typically made directly between companies and experts). This contrasts with some other European Networks that derive income from consultancy services offered directly to companies.

The MCRN has received a number of requests for advice on the new EU Pediatric Regulation/preparation of PIPs, and the Network expects the numbers of these types of request to increase. The MCRN can also advise on formulations and on consumer matters, including the preparation of patient information sheets. In addition to their advisory role, Clinical Study Groups identify research priorities and develop their own study proposals to address important research questions.

Contacting the Networks

Feasibility

The MCRN supports top-level, UK-wide assessments of study feasibility through the Clinical Study Groups and can help with site identification. The Network can identify investigators located in Local Research Network supported sites that are interested in working on studies.

Initial site identification is typically completed within a 10 working day time period. Starting with feasibility, the MCRN Local Research Network staff ensure that clinical trials involving children are performed efficiently to the highest standards across NHS sites.

Site set up

Timely site set up is clearly critical to the success of a study, but significant delays are often experienced. To address this, the MCRN assists with study set up following site and country selection and adoption to the Network's portfolio of studies. For a study to be adopted, the MCRN assesses whether the study is well designed and of relevance to the NHS and its patients, and that the Network can deliver the study efficiently.

Following adoption, Local Research Network staff work with sites to assist with study costing, local ethics and R&D approvals, contracting, and staff training. All staff (commercial/noncommercial) associated with adopted studies qualify for free NIHR Clinical Research Network (CRN) and MCRN training, including Good Clinical Practice (GCP) courses.

Actual vs Target Recruitment

Over recent years, the process of obtaining ethical approval has been streamlined in the UK, but delays are still often experienced with NHS R&D approvals (the process that reviews protocols, regulatory approvals, and other information to authorize NHS sites to support studies). To improve this situation, the "NIHR Coordinated System for gaining NHS Permission" (NIHR CSP) was launched in November 2008 to accelerate the R&D approvals process by providing additional resources to a centralized, coordinated team and NHS sites.

Study costing has also recently been significantly assisted by the NIHR CRN costing template. The costing template outlines doctor, nurse, pharmacy, and other costs transparently and MCRN uses it for as many commercial studies as possible. For study contracting, the MCRN also promotes the use of standard contracts—the model Clinical Trial Agreement, mCTA—to expedite negotiations.

Clinical Study Group Specialties

Patient recruitment

The MCRN Local Research Network staffs work with NHS sites and company sponsors to ensure that adopted studies are conducted rapidly to a high standard. In particular, Local Research Networks ensure that research nurse and other site support is appropriate and can provide assistance with patient recruitment and data collection.

MCRN Local Research Networks and the Coordinating Center continually monitor recruitment to studies and provide additional support to studies where recruitment levels are below expectations. Upon closure of the study, Local Research Network staff work with sites/sponsors to ensure that all regulatory and other requirements are addressed.

The support that MCRN provides to companies and public investigators is assisting study performance. For example, Figure 2 shows target and actual recruitment data for a commercial study in a rare condition that MCRN supported in two sites. Despite regulatory delays, MCRN staff was able to rapidly recruit patients and the UK target was exceeded by the end of the study.

Portfolio of MCRN Studies

The Network has successfully recruited children of all ages to both large and small studies and has received positive feedback from companies and NHS/academic investigators that it has helped during feasibility, site set up, and recruitment phases. Going forward, the Network will gather and disseminate more performance data and will continually strive to improve the service that it offers.

Study portfolio metrics

As of early 2009, the MCRN has adopted 33 commercial and 72 public studies into its portfolio, but it is anticipated that commercial studies will form a larger part of the portfolio as clinical trials making up PIPs are rolled out.

The study portfolio covers all topics represented by Clinical Study Groups (see Figure 3). The Diabetes, Endocrinology, and Metabolic Medicine Clinical Study Group has adopted the greatest number of studies (16). The majority of studies in the portfolio are randomized controlled trials (60).

Working across Europe

Given that there are often small numbers of children eligible for studies in individual countries, it will be necessary to collaborate closely with networks in countries across Europe to ensure delivery. Currently, company and public sponsors coordinate activities across multiple countries, but going forward, it will be necessary to promote greater collaboration between the developing European networks. Under the EU Pediatric Regulation, the European Medicines Agency (EMEA) is developing a network of existing national and other networks and in time, this wider grouping will enhance collaboration and coordination.

Conclusions

Due to the new EU Pediatric Regulation and medicines for children increasingly becoming a priority for national governments, a number of national pediatric research networks have been established across Europe to assist companies and public investigators to conduct studies more effectively.

The NIHR MCRN has been established to support pediatric medicines research in the UK and has successfully recruited children into studies. It will be important for networks across Europe to collaborate to ensure that recruitment to studies is efficient. The sooner that studies are completed, the sooner children and families can benefit from the innovations in medicine that they need.

Acknowledgements

We are grateful to Professor Tony Nunn, MCRN Associate Director—Industry Lead, and Dr. Vanessa Poustie, MCRN Assistant Director, for advice in preparing this article.

Andrew Rose,* DPhil, is the industry liaison manager at the MCRN, University of Liverpool, Alder Hey Hospital, Liverpool L12 2AP, UK, and Rosalind Smyth, MD, F Med Sci, is the Director of the MCRN and Brough Professor of Pediatric Medicine at the University of Liverpool.

*To whom all correspondence should be addressed.

References

1. K. Cheng, S. Masters, T. Stephenson et al., "Identification of Suspected Fatal Adverse Drug Reactions by Paediatricians: A UK Surveillance Study," Archives of Disease in Childhood, 93, 609-611 (2008), http://adc.bmj.com/cgi/content/full/93/7/609.

2. European Medicines Agency, http://www.emea.europa.eu/htms/human/paediatrics/introduction.htm.

3. P. O'Donnell, "EU Scorecard on Medicines for Children," Applied Clinical Trials, September 2008, 34-36.

4. The National Perinatal Epidemiology Unit, http://www.npeu.ox.ac.uk.

5. The National Institute for Health Research (NIHR) Coordinated System for gaining NHS Permission, http://www.crncc.nihr.ac.uk/index/clinical/csp.html.

6. The Industry Costing Template, http://www.crncc.nihr.ac.uk/index/industry/costing.

7. EU Pediatric Network, http://www.emea.europa.eu/htms/human/paediatrics/network.htm.