Abstract
The evaluation of drugs that are used in children has been neglected historically but is now well established as an essential part of clinical drug development. The increase in pediatric activity among industry, and other sectors, has highlighted the importance of joint working. All participants in pediatric drug development need to be aware of the “big picture.” An increasingly important part of this big picture in pediatrics, as in other populations, is the design and conduct of clinical trials in networks. This narrative review provides an overview of the roles of clinical research networks in pediatric drug development. Networks take many forms as specialty networks and geographic networks but work toward common principles, including sharing resources between trials, and using experience with trial conduct to improve trial design. Networks develop standardized processes for trial conduct (including performance management) that increase the speed and predictability of trial conduct while reducing burdens on sites, sponsors, and intermediaries. Networks can provide validated, real-world information about natural history, participant distribution, and standards of care to inform planning of development programs, including extrapolation and clinical trial simulation. Networks can work across geographic and jurisdictional barriers to promote global interoperability of drug development. Networks support participant centrality. Networks offer an opportunity to develop relationships with investigators, sites, and methodological experts that span pre-competitive foundations for drug development and specific products. Sustainable networks benefit all stakeholders by providing a multifunctional platform that promotes the quality and timeliness of clinical drug development.
Key words
Introduction
Evaluation of new and existing drugs requires collaboration. This is particularly important in pediatrics because children with specific conditions are rare, even though the overall burden arising from ill-health in children is large. This is coupled with the inefficiency in clinical research, particularly clinical trials, that is common in all therapeutic areas.
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Networks have been identified as one way to overcome inefficiencies in clinical research. This article provides a selective, narrative review of the roles of pediatric research networks in pediatric drug development based on the literature and experience of two large speciality networks and two large national networks. To advance the field, we speculate about some opportunities for networks and the implications of those opportunities for network design and practice.We define a clinical research network as a group of sites with persistent governance arrangements that is involved in the delivery of clinical studies (including observational and interventional). Delivery includes the implementation of studies and design of studies. This may or may not involve leading or sponsoring studies. Networks may have other roles, but these roles need to be clearly demarcated from research.
Overview of Pediatric Research Networks
Many pediatric research networks exist. There are 48 members of the European Network of Pediatric Research at the European Medicines Agency, including Canadian and US networks,
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and >70 pediatric research networks in North America.European Network of Pediatric Research at the European Medicines Agency (Enpr-EMA). http://www.ema.europa.eu/ema/index.jsp?curl=pages/partners_and_networks/general/general_content_000303.jsp&mid=WC0b01ac05801df74a. Last accessed July 15, 2017.
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The Pediatric Trials Network has studied a number of off-patent drugs.4
A recent addition is the Institute for Advanced Clinical Trials for Children.Pediatric Trials Network. https://www.pediatrictrials.org. Last accessed July 15, 2017.
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The Pediatric Trials Network of Australia is under development.Institute For Advanced Clinical Trials For Children. https://www.iactc.org. Last accessed July 15, 2017.
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Pediatric Trials Network Australia. http://www.ptna.com.au. Last accessed July 15, 2017.
The networks found a wide variety of structures and levels of activity with different organizational and funding models. Some are based around clinical specialties, others are geographically organized working with multiple specialties.
Broadly, those networks that form around clinical specialties tend to be driven "bottom up" by clinicians intent on optimizing patient outcomes compared with networks that are geographically organized and working with multiple specialties that tend to be driven "top down" by decision makers intent on system improvement for efficiency and economic gain such as attraction to industry or optimizing the efficiency of publically funded studies. These two networking approaches are not mutually exclusive and, in the ideal world, are highly integrated. Clinical specialty networks bring patients and families as more eager participants in clinical research, a wealth of data (or the on-going ability to get data) on biomarkers and disease stratification, and the ability to assure uniform standards of care on which to conduct trials of new therapies and to rapidly implement new evidence. Through high-profile achievements that influence rate of mortality (childhood cancer)
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and quality of life (cystic fibrosis, irritable bowel disease),Children’s Oncology Group. Impact of COG’s Research. https://www.childrensoncologygroup.org/index.php/impact-of-cogs-research. Last accessed August 18, 2017.
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, 9
the value of clinical specialty networks is increasingly recognized, and steps are being taken to reward clinician engagement in networks (eg, American Board of Pediatrics recertification) and to support networking (in Europe, European Reference Networks, and Innovative Medicines Initiative 2–funded Clinical Research Networks; in the United States, National Institutes of Health [NIH]–sponsored networks). Geographically organized networks address barriers and inefficiencies in the conduct of clinical research such as regulatory and ethics affairs, data management, site function, and personnel qualification and training by working with all specialties. The establishment and harmonization of best practices for these areas is under the control of governments and institutions through legislation, policy, and setting procedures. The approach to effect change is well illustrated by the recent NIH policy on the use of a single institutional review board for multisite research.ImproveCareNow. Purpose & Success. http://www.improvecarenow.org/purpose-success. Accessed September 13, 2017.
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The outstanding achievements of the English Medicines for Children Research Network to increase participant engagement and attract clinical trials are testament to the importance of high-level bureaucratic commitment11
that deploys resource to where the patients are and is coupled with a national single ethics committee and institutional approval.12
The potential tensions between geographic and speciality networks need to be proactively managed with clear expectations and arrangements that allow win–win outcomes.HRA approval. http://www.hra.nhs.uk/about-the-hra/our-plans-and-projects/assessment-approval/. Last accessed August 18, 2017.
Networks have found the success that can be achieved through proactive portfolio management, using data sets, operationalizing new technologies, using innovative techniques, encouraging clinical–community partnerships, and improving performance through transparent pursuit of meaningful goals.
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, 14
There are challenges to the network model.
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Amalgamation of organizations or adoption of identical procedures is less important than adopting processes and standards that allow multiple organizations to work effectively on the same project.An NIH study in 2006 reported key elements of success, including relevant and well-managed leadership structure, information technology systems, subject recruitment and retention, network administration, education and training, data management, financial policies, and efforts to build sustainability that have been used to evaluate networks
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; others have reported similar experiences.17
In addition, our experience has found that the attributes of a good network include processes that are easy to use and predictable, service design that accommodates the needs of each clinical situation while using an efficient core of services that are deployed in multiple settings, and capacity building at site level as well as network level.Efficient Implementation of Studies
Good implementation is necessary for the delivery of all studies, irrespective of design. Children, young people, and their families want rapid availability of new and improved drugs, as do study funders. Networks can help overcome pinch points for the rapid conduct of studies through planning, standing infrastructure, agreed processes, and education/training. Good practice for trial implementation has been defined but not universally applied,
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, 19
suggesting that networks can fill a gap in dissemination of good research practices. Active performance management of trials includes tracking of recruitment at site level and external review across a portfolio of trials at network level, frequent communication, moderated by the network, between site principal investigators and study coordinators to identify ways to improve study conduct.20
All of these issues are generic to clinical trials and can be enhanced by network staff working across multiple sites and specialties.Sites have a learning curve that can be expedited by sharing good practice, having clear standards for site management across a network. Most work at sites can be done by “generic” staff who contribute to many clinical studies and clinical areas. Some speciality networks have resisted pooling resources between specialties at site level, and this can reduce the opportunities for sites to be efficient. Adequate staff across sites mean that specialists in clinical areas can make the most of their time-limited investment in trials by working on those tasks that only they can address. Sites that work in networks can benefit from rapid dissemination of information about trials, a structured approach to good practice and economies of scale from marketing and negotiations with sponsors and other funders. Table I shows key functions in trial implementation and how networks can make a positive impact on these. Networks can provide and identify good practice and apply it across a range of studies.
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Table IRoles of Clinical Research Networks in Clinical Trial Functions That Promote Efficiency, Data Quality, and Timely Study Completion.
| Function | Components | Network Roles | Site Roles |
|---|---|---|---|
| Contribute to protocol design | Moderate interactions with people involved in study design inside and outside the network (includes feedback on early drafts from people who will implement the trials) | Brokerage | Contribution when appropriate |
| Provide information that informs choice of key study features | Access network data | Contribute data | |
| Manage registries | Contributing to research priorities and feasibility assessment | Liaison with other central offices | Contribute data |
| Setting up and maintaining infrastructure | |||
| Patient and carer involvement | Provide information that informs choice of key study features | Protocol review | Provide feedback when appropriate |
| Trial setup support/open study | Suggest sites; standardize practice for efficiency and predictability | Site permissions and regulations | |
| Recruitment support | Enabling staff and infrastructure | Deploy research staff at sites | Recruitment support – consent, enrolment |
| Data collection | |||
| Recruitment monitoring | Enabling staff and infrastructure | Study coordination; | |
| Management of study | |||
| Training | Identifying and filling requirements | Delivering/facilitating training programs per study/across research programs/across sites | Deliver site level training |
| Provide feedback when appropriate | |||
| Promotion | Interactions within and out of network | Ongoing promotional and dissemination of findings | In line with study requirements |
| Providing feedback | |||
| Study closure | Study closure procedures | Finalizing data sets | |
| Reporting | Site closure |
Good practice includes the use of contracts and costing templates that have been used in pediatrics, for example, in England.
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Each sponsor, trial, or site can handle these and other arrangements separately. However, autonomy comes at a cost to the sponsor and to the sites, inconsistency and repeated specification of similar documents adds time to trial implementation and increases regulatory and compliance risks, so that precompetitive collaboration is beneficial to all parties. Quite often site independence is promoted by quality assurance and risk management procedures that focus on the perceived risks to the site rather than the benefits of joint working. In addition, localized benefits (such as control over staff and budgets at departmental level) provide short-term benefits to key individuals that reinforce fragmentation within and between sites. Networks can overcome these problems and can facilitate improved trial efficiency by providing supplementary assurances and additional benefits to key individuals and the institution as a whole.Optimal Design of Studies
“Standard” trial designs may not always be possible, appropriate, or efficient in the development of new drugs or repurposing of old drugs for the small study populations in pediatrics. Alternative and innovative approaches to clinical trial design in small populations can overcome the limits related to small sample size and to the acceptability of the trial. Some investigators have found that many factors such as protocol approval by sites, limited knowledge of methodology, lack of in-depth understanding of child physiology, psychology, the social embedding of children may hinder the use of innovative methods,
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but experience is growing.25
, 26
, 27
, 28
Networks can contribute to the design of trials in a number of ways, including registries
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and modelling.30
, 31
Trial design depends on understanding the clinical context of the trial: “trial designs, no matter how novel, will only be as good as the knowledge that underlies them.”32
Information about the clinical context is not proprietary to individual sponsors but needs to be developed in a trusted, verifiable precompetitive space that sponsors, regulators, and investigators can access equally. Independent clinical research networks are ideal for this. Similarly, the views of children, young people, and their families need to be collated in a way that avoids undue pressures and conflicts of interests. Independent groups that support advocacy are required. In both cases transparency about funding is essential.Woodcock J. Reforming Clinical Trials in Drug Development: Impact of Targeted Therapies. https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM530409.pdf. Accessed September 13, 2017.
Experienced specialty groups have developed a range of ways to optimize their advice, including multiple stakeholder meetings that incorporate regulators, sponsors, patient advocates, and investigators.
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These can be particularly helpful when research about multiple drugs in a limited pediatric population is proposed. The aim of these meetings is to better meet patients’ needs to promote the feasibility of development plans.Opportunities for Networks
Given that networks are established in many specialties and geographies, we can identify a number of opportunities for networks to enhance their contributions to excellent research performance. These opportunities include global interoperability, leveraging existing data, standardizing clinical expert groups, standardizing methodological expert groups, strategic alliances between stakeholders, developing research through relationships as well as data, sustainability, and improved understanding of networks.
Global Interoperability
Some conditions need global recruitment pools to address the small sample sizes in children. There has been progress in developing statistical methods and collaborative specialist multinational groups and clinical trials networks that pool their data and resources.
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, The Children's Oncology Group (COG). http://www.childrensoncologygroup.org/. Last accessed July 15, 2017.
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, Children's Cancer and Leukaemia Group (CCLG). http://www.cclg.org.uk/. Last accessed August 2, 2013.
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, Pediatric Rheumatology International Trials Organisation (PRINTO). http://www.printo.it/. Last accessed July 15, 2017.
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, Pediatric European Network for the Treatment of AIDS (PENTA). http://penta-id.org/. Last accessed July 15, 2017.
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Learning from these networks can be extended to other specialities and can be generalized across geographies. The operational implications of interoperability include communication between an extended group of stakeholders and clarity of purpose and process.Pediatric Emergency Care Applied Research Network (PECARN). http://www.pecarn.org/. Last accessed July 15, 2017.
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Leverage Existing Knowledge Held by Clinical Networks and Other Groups
As noted above, knowledge and experience about medicines and natural history is a crucial aspect of medicines development that can inform study designs and contribute to research priority discussions with sponsors and policy makers. Many clinical research networks own relevant data or have relationships with other data owners. The operational implications with respect to shared work about data are that networks should collect and curate data in a way that allows secondary use, develop standards that promote data sharing, build links with people that hold and use data, develop standard legal and policy approaches to data ownership, and privacy taking account of the specific needs of children.
Standardize Clinical Expert Groups
Expert groups can inform the development of information that contributes to trial design and interprets that information (because information will need to be adapted to specific trials and will always be imperfect). However, variation between the scope of expert advice hinders the use of expert groups. We propose a classification scheme for expert groups based on their access to information (Table II). We speculate that expert groups can be benchmarked (with some parallels to sites).
Table IIImproving the Quality of Clinical Advice.
| Contribution of Expert Groups | Requirement for High Quality Clinical Advice | Level 1 Methods | Level 2 Methods | Level 3 Methods | General Methods |
|---|---|---|---|---|---|
| Identification of key features of clinical trials | Incidence, presentation, progression, outcomes, morbidity etc. AND extent of variation AND delineation of important subtypes | Expert group with or without selected case series | Cumulative registry of patients | Characterization using contemporary methods (genomics, proteomics, metabolomics, etc.) | Harmonization of definitions |
| Interoperability | |||||
| Ability to conduct timely studies to fill information gaps | |||||
| Information about the numbers of people who would be eligible for research studies | Aggregated information about demographic characteristics, diagnosis, current condition, and treatment | Expert group with or without selected case series | Cumulative registry of patients | Integrated data from all of Europe that is compatible with global sources | Harmonization of definitions |
| Interoperability | |||||
| Site level identification of children who can be approached about a specific trial | Demographic characteristics, diagnosis, current condition, and treatment | Expert group who are familiar with patients attending their centers | Real-time registry of patients | Extensive data linkage between clinical and other data to allow stratification | Harmonization of definitions |
| Interoperability |
This table suggests a framework to identify which type of advice a clinical advisory group is able to give. We speculate that this framework will provide the basis for comparisons between clinical expert groups in multiple speciality networks. As time goes by, specialties can move to the right for some of the rows, depending on availability of funds and the enthusiasm of the clinical community. The further to the right a specialty is the more likely its input will be sought early in the development of drug development plans or protocols.
Standardize Methodology Expert Groups
The capability of methodology expert groups can also be classified. The simplest methodological advice involves a description of a method and contributions to the application of the methods, for example, by writing or commenting on a draft protocol. Extra value is generated by comparisons between the performance of different methods, preferably based on objective criteria. Some methodologies are well adapted to children, and expert groups can give balanced opinions, based on careful evaluation of the strengths and weaknesses of each study design.
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Other methodologies are new or have not been adapted to children, in which case expert judgment is needed. Expert groups also need to contribute to regulatory policy, for example, through drafting white papers or contributing to regulatory consultations, if they are educated appropriately and supported by people with relevant expertise.Strategic Alliances Between Stakeholders
Currently, strategic collaboration is not a consistent feature of pediatric research. Most pediatric research involves sponsors maximizing recruitment for each trial while minimizing costs to each site. Conversely, individual sites currently focus on maximizing income per trial without considering the bigger picture. There is a widespread perception that adequate resources are not provided to sites to run clinical trials. However, the clinical research community does not deliver information needed to advance drug development: the pediatric research community is not reliable or predictable. Clinical research networks need to develop strategic alliances to maximize impact and resources. Key elements of a strategic alliance include cooperation that is long-term work together that is based on optimizing outcomes rather than maximizing the benefits arising from each interaction.
These deficiencies can be overcome by developing strategic alliances between sponsors and networks. Alliances would provide fair rewards (financial or other resources, including recognition) to sites and networks that overcome bottlenecks in trial design and implementation. Sites and networks would provide sponsors with assurances that the alliance is a good investment. Effective alliances promote efficiency, provide a more comprehensive basis for adapting to changing circumstances, and spread risk. All parties need a good reason to join because working in an alliance will disrupt their current ways of working. Setting up an alliance between experienced networks is more difficult: experienced networks potentially have fewer opportunities to benefit and more legacy procedures to disrupt.
Confidence in an alliance can be enhanced by processes and standards that promote predictable outcomes of clinical trials such as targets for first recruitment and the total recruitment target. These “control mechanisms” will be more effective if partners trust each other. The literature suggests that there are three key control mechanisms in strategic alliances: goal setting and monitoring of outcomes, specification of processes and monitoring of process metrics, and organizational culture blending. There are four key techniques in building trust: communication, fairness and equity, mutual adaptation, and risk taking.
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Operational implications for networks interested in developing strategic alliances are to look at the long term, to compromise on processes that are not mission critical, to develop a culture that cuts across specialties, and to base an alliance on values such as equity, culture, and transparency.
Relationships with patient advocacy groups are essential during pediatric drug development and pediatric research. Children and young people can make substantial contributions if they are educated appropriately and supported by people with relevant expertise.
Developing Research Through Relationships As Well As Data
Resilient alliances can improve the current, fragmented situation. Currently, most drug development plans are prepared as an isolated procedure using standardized approaches and metrics. Frequently, the quantitative estimates of sample size and so forth are inaccurate, leading to inefficiencies as plans are adjusted. Furthermore, the low level of trust between sponsors and regulators (and intermediary organizations and sites) makes the necessary adjustments onerous and rooted in process rather than clinical reality. If consistent relationships are built between stakeholders, then the same results can be obtained with less burden on the stakeholders.
Sustainability
At present a limited number of networks are sustainable. Network sustainability requires continued access to resources that are not bound to specific projects and are not limited by time. Aspects of sustainability that need to be addressed include willingness to host the network by sites, availability of staff with appropriate skills and enthusiasm, and sufficient resources to maintain the network. Maintaining the willingness of sites to be part of the network depends on evidence about the utility of participation in clinical trials (to participants and the institution), ensuring that reasonable costs are met, and finding that network participation maximizes benefits while minimizing the costs that the site has to bear. Maintaining the engagement of relevant staff means ensuring they have relevant skills that can be updated and developed, minimizing the burdens of trial conduct that fall to staff with other responsibilities and finding that the network promotes their personal goals while minimizing the effort needed to meet those goals. Resources that maintain the network can be financial or in-kind. In either case the holders of the resource required by the network need to be informed about the return on their investment and persuaded that the return helps them meet their strategic goals. Many academics are used to working on projects with well-defined outputs. Networks need to move beyond the outputs of individual projects to build programs that ensure that stakeholders experience benefits. Networks need to provide quantifiable evidence about the benefits derived from the functions described in Table I and add predictability and quality. The networks referenced in this review provide useful case studies but do not generally report how much benefit they generate for each invested dollar. Networks add value by providing benefits at less cost than the alternative of fragmented inconsistency. However, it is problematic for networks to identify the value they add because the costs met by study funders and sponsors are not transparent. Networks can define their benefits more easily than they can report reduced costs. Nevertheless, networks need to market their work effectively.
Operational implications with respect to sustainability include the development of a sound business model that will attract resources. Existing funding models include combinations of governmental funding, in-kind contributions from hospitals (such as staff time or use of facilities), membership fees for institutions or pharmaceutical companies, and charges to research funders for specific services. Networks should start by looking beyond their own views about their capabilities and focus on the needs of people who provide the resources (sites, staff and institutions), in addition to the needs of study participants.
Improved Understanding of Networks
Many publications about networks are descriptive and provide case studies. The evidence base that supports networks and their sustainability could be improved by collecting data about network activities and performance that can be aggregated and compared between networks. The evaluation of networks requires complex methodological approaches.
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Conclusions
Although many national, international, and specialty specific networks exist, several issues hamper the consolidation in successful networks such as the establishment of governance models, infrastructure, geographic boundaries, resource, and sustainability. We have described the roles of clinical research networks in the current pediatric research environment and identified some growth points. Clinical research networks provide infrastructure that can be used by multiple studies; the optimal return on investment for all stakeholders comes from sharing infrastructure across as many specialties as possible.
Acknowledgments
None.
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Article info
Publication history
Published online: September 21, 2017
Accepted:
September 6,
2017
Identification
Copyright
© 2017 Elsevier Inc. All rights reserved.
