Conducting a paediatric multi-centre RCT with an industry partner: Challenges and lessons learned

Authors

  • Jessica Maskell,

    Corresponding author
    1. The Centre for Children's Burns and Trauma Research, Queensland Children's Medical Research Institute, Department of Paediatrics and Child Health, The University of Queensland, Royal Children's Hospital
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  • Peter Newcombe,

    1. School of Social Work and Human Services, The University of Queensland, Brisbane
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  • Graham Martin,

    1. Department of Child and Adolescent Psychiatry, The University of Queensland, Herston, Queensland, Australia
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  • Roy Kimble

    1. The Centre for Children's Burns and Trauma Research, Queensland Children's Medical Research Institute, Department of Paediatrics and Child Health, The University of Queensland, Royal Children's Hospital
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Ms Jessica Maskell, The Centre for Children's Burns and Trauma Research, Queensland Children's Medical Research Institute, Department of Paediatrics and Child Health, The University of Queensland, Royal Children's Hospital, Brisbane, Qld 4029, Australia. Fax: +617 3365 5455; email: jessica.jameschadwick@uqconnect.edu.au

Abstract

There are many benefits of multi-centred research including large sample sizes, statistical power, timely recruitment and generalisability of results. However, there are numerous considerations when planning and implementing a multi-centred study.

This article reviews the challenges and successes of planning and implementing a multi-centred prospective randomised control trial involving an industry partner. The research investigated the impact on psychosocial functioning of a cosmetic camouflage product for children and adolescents with burn scarring.

Multi-centred studies commonly have many stakeholders. Within this study, six Australian and New Zealand paediatric burn units as well as an industry partner were involved. The inclusion of an industry partner added complexities as they brought different priorities and expectations to the research. Further, multifaceted ethical and institutional approval processes needed to be negotiated. The challenges, successes, lessons learned and recommendations from this study regarding Australian and New Zealand ethics and research governance approval processes, collaboration with industry partners and the management of differing expectations will be outlined.

Recommendations for future multi-centred research with industry partners include provision of regular written reports for the industry partner; continual monitoring and prompt resolution of concerns; basic research practices education for industry partners; minimisation of industry partner contact with participants; clear roles and responsibilities of all stakeholders and utilisation of single ethical review if available.

Multi-centred trials are becoming increasingly common in health research as they allow researchers to gather large sample sizes that enable increased statistical power, more timely recruitment, clinically meaningful research, and enable generalisability of results.1–5 Challenges of multi-centred studies have been documented to include high financial cost, difficulty maintaining scientific integrity and logistical problems (e.g. the requirement of multiple ethics and research governance submissions).1,4,6–9 However, there is limited literature that discusses the complexities that an industry partner brings to multi-centred health research trials. This is an important consideration as much health research has substantial contributions from industry partners who desire a voice in the research program. The planning and implementation of a paediatric prospective multi-centre randomised control trial (RCT) involving an industry partner will be discussed. This study experienced many common challenges including recruitment, retention and staffing. However of more interest are the experiences and challenges of planning and managing this multi-centred trial that included an industry partner and multiple approval processes.

Key Points

  • 1Multi-centre studies provide researchers with the capability of recruiting large sample sizes and gaining generalisability of results.
  • 2NHMRC is working towards a nation-wide process for single ethical review to enable multi-centre studies to be conducted in a timely and efficient way.
  • 3Research involving industry partners is becoming more common due to the interface between commercialism and health research and therefore researchers must follow clear guidelines to predict, avoid or manage challenges to ensure high quality research.

The Study

Burn injury in children and adolescents is the third most common injury causing death and often results in lifelong burn scarring.10 The most common approaches to burn scarring are surgical procedures and lengthy scar management regimens. However, these cannot fully eliminate the occurrence of scarring. Scarring can influence a child's psychosocial functioning.11 Cosmetic camouflage may be an intervention that could have a positive impact on psychosocial functioning. To investigate this, an Australasian multi-centre prospective RCT was conducted.

A multi-centred study was chosen as the lead hospital, Royal Children's Hospital (RCH), Brisbane completed a pilot study and a larger study was recommended to attempt to replicate the results in other centres.12 Six hospitals with a paediatric burn service within Australia and New Zealand (NZ) participated in the study and 73 participants (aged between 8–17 years) were recruited.

Approvals

At the time of planning this multi-centred study, the researchers needed to negotiate research approval processes at each of the institutions. This necessitated presenting the same information but in different formats to satisfy the requirements of each establishment involved – a time-consuming and daunting task.13 Each study site was driven by different ethical, institutional and legal procedures and requirements. In addition, the lead hospital (RCH) and the industry partner also needed to negotiate and agree on the legal requirements and responsibilities of the study to ensure working relationships.

Ethics

Ethics applications were submitted to the University of Queensland and each study site ethics committee. Australia did not have established single-study Human Research Ethics Committees (HRECs) at the time of conducting this study; therefore, the principal investigator was responsible for writing and submitting multiple ethics applications including one NZ ethics application. NZ has a national health system with the country separated into regions and district health boards. The Health and Disability Ethics Committees (HDECs) that exist in NZ are responsible for reviewing ethics applications within their allocated region. Additionally, NZ have a multi-region ethics committee who are responsible for reviewing applications for national research or research that includes more than one regional ethics committee region. In this case, there was only one NZ study site so ethics review was only needed from one committee.

Gaining ethics approval for all study sites in Australia to participate in the study was very difficult as not all ethics committees involved accepted the National Ethics Application Form (NEAF). There were also numerous inconsistencies between the ethics committees in acceptance of the same study protocol.

The inconsistency in the use of the Australian NEAF despite the National Health and Medical Research Council (NHMRC) recommendations for the use of this form was frustrating as the ethical approval process is already known to be a complex and lengthy one.14 Fuhrer9 states that the administrative load of multi-centred trials is large and this is a potential disadvantage of these types of research studies. In our experience, one committee in particular refused to accept the NEAF. This resulted in a further increase of the administrative load and time frames. The NEAF needs to be accepted by all HRECs within Australia to improve efficiency and quality of ethics applications and review processes for multi-centre studies which will allow research protocols to be completed in a timely manner regardless of the number of sites involved.15

In regards to the New Zealand process the National Application Form for Ethical Approval of a Research Project (NAF-2009-v1) was quite similar to the Australian NEAF. This consistency made the New Zealand process relatively uncomplicated. There were two main issues raised (i) The New Zealand HDEC required the study appoint a New Zealand based principal investigator and did not allow an Australian based principal investigator. This was easily resolved and the NZ investigator became the principal investigator for NZ. (ii) Consultation and approval from a Māori committee was compulsory as this project was of relevance to Māori health and would include participants from the Māori culture. Approval was important and the process was straightforward, hence was not unwieldy to the research team. In contrast, only one Australian ethics committee (South Australia) requested consultation and approval from the relevant indigenous liaison worker.

Further inconsistencies were experienced once the ethical review process began resulting in increased negotiation and approval time frames. For example, the principal investigator aimed to have standard information and consent forms across all sites for consistency and ease of use. However, each of the ethics committees returned particular requests thereby requiring specific changes to be made to the information sheets for each site.

There was also variability between ethics committees regarding obtaining the children's informed assent/consent. For some, child assent was necessary; however, for others, parental consent was sufficient. The research team felt it was important to consider the children's wishes and gain their informed assent as, although parent proxy consent is often seen as sufficient, parent and child views may differ.16 As a result, the research team advocated for all sites to approve child assent as well as parental consent. New Zealand did not require child assent; however, the HDEC allowed the researcher to gain assent alongside parental consent for consistency amongst the various sites.

Some of the HRECs requested further clarification on the services children would be provided if any adverse effects or underlying psychosocial issues were identified throughout the study. The research team understood that the participant group, children, are a vulnerable group and therefore this was a reasonable request and was promptly resolved. The investigators shared the view of Stalker and colleagues16 who reported that ‘ethical considerations, including gaining children's informed consent, respect for confidentiality and the importance of protecting children from harm must be paramount in any research.’

Overall, ethical approval for all study sites was completed over 14 months. Studdert et al.6 hypothesised that researchers' pursuing smaller multi-centred studies, and those without full funding support, are likely to struggle to negotiate an ethics review process of this scale. Such was the experience of this research team. However, from a positive perspective, this study was reviewed and critiqued by many ethics experts, which resulted in the implementation of an ethically sound paediatric study with a strong methodology.

Considering the view of Studdert et al.6 the experiences of this study and researchers' general concerns regarding ethical approval including cost, inefficiency, tardiness, duplication and the inconsistent nature of ethical concerns identified across committees; it is important to recognise that the NHRMC are following NZ and the UK's lead and have been working on the ‘Harmonisation of Multi-Centre Ethical Review’ (HoMER) project since 2006. This project seeks to simplify the process of ethical review and establish single study HRECs for multi-centred studies within Australia that would have authority across all or most sites.6 Centralised ethics review is a logical strategy to achieve efficiency and consistent high quality review processes for multi-centred studies.6 This will assist greatly from an administrative framework as it will streamline the application process without minimising the importance of the ethical review process which is paramount.17 The experiences of this paediatric multi-centred study demonstrates the importance of Australia implementing a streamlined process which will encourage more multi-centred rigorous health research studies involving children to be conducted.

Research governance

Most study sites had established research governance departments. These departments worked alongside the relevant ethics committees. However, often the research governance officers asked for clarification on the same or similar queries to the ethics committees. This demonstrated that these two governing bodies, within specific health services, were operating independently and did not appear to have clear roles and responsibilities.

Primarily, the research governance responsibilities were to review the legal attributes, including insurance, indemnity, intellectual property, roles and responsibilities of the lead study site, the additional study sites and the industry partner. Due to the number of study sites and the industry partner involvement it was essential to clearly negotiate and formally agree in writing on these legal attributes. This became a significant issue as there were differing views regarding the development of this legal document. No available templates applied to this study, as many did not have the capacity to include an industry partner and multiple study sites. Nowak18 reported that, often, approval processes were first designed for single site studies. This was potentially the case, hence the non-existence of an appropriate template. Negotiations between the various legal teams lasted many months until finally a resolution was reached. It was apparent that a multi-centred study with an industry partner within paediatrics in Australia seemed rare and minimal precedents existed that could be used as a reference.

The other challenge was assisting the research governance departments to understand the establishment of the study and the relationship between the lead study site and the industry partner. Some research governance departments believed that, as an industry partner was involved, it was a commercially sponsored trial and therefore incurred a significant administration fee. This cost had not been budgeted for as the lead study site did not share their view. The NHRMC, Association for the Accreditation of Human Research Protection Programs defines a sponsor as one that is responsible for the initiation, management or financing of the research study.19 In our study, the industry partner did not fit this definition as the lead study site initiated, managed and jointly financed the trial. This difference of opinion almost resulted in the withdrawal of one study site. This would have interfered with the research at that site as ethics approval had been gained and recruitment had begun before the issue was raised.

Collaboration, expectations and funding

This study would not have been possible without the commitment of both the lead study site and the industry partner. As Kearney et al.20 states, financial support is crucial to the successful implementation of both data collection and analysis especially when a project involves a substantial number of collaborators and multiple sites.

Due to the financial contribution from the industry partner, it was challenging for the lead study site to constantly gauge the level of information to be shared. The lead study site had a responsibility to work collaboratively with the industry partner however it was essential that the level of information shared was monitored to ensure rigorous research, standardised protocols, and free of commercial bias.

The administration of the intervention involved a 1.5-day training program for participants and their parents to learn how to apply the camouflage. This added a unique challenge to this potential issue as the industry partner had direct contact with the participants for a significant amount of time which is uncommon in health services research. This was a risk, as the potential for participants to modify their behaviour was high due to developing relationships and sensitive discussions about participants' scarring between the participants and the industry partner. Gaskill et al.7 experienced similar difficulties in their collaborative study with adults. The primary participant group for this study, children, are ordinarily a vulnerable group. This greatly increased the potential risk for modification of behaviour as children often strive to please adults.21 This was a constant area of concern and was controlled by following a strict training program format where the researcher led the program and both researcher and industry partner had clearly defined roles. The researcher also continually monitored all interactions occurring during the training to avoid the industry partner compromising the study unintentionally and unknowingly.

The principal investigator found it challenging to elucidate these concerns with the industry partner as the industry partner was a commercial business with a lack of understanding, knowledge and experience in research practices. The industry partner had a different agenda – one driven by their commercial interest. This was managed continually by educating and clarifying basic research practices with the industry partner as well as sharing information, involving and consulting them appropriately due to their financial commitment without running the risk of jeopardising the study.

In addition to the industry partner and the research team having different priorities, these two stakeholders also had differing expectations. The principal researcher was concerned with developing a strong methodology, ensuring rigorous research and gaining reliable and valid results. The industry partner sought prompt results that could be used for product development, improvement and marketing. It was necessary to recognise these differing expectations and negotiate an approach where all needs could be met.

There is limited literature on the differing expectations of researchers and industry partners however similarities can be drawn from the differing expectations of researchers and practitioners documented in health services research. Practitioners seem to place importance on relevance, realism and immediate application to current realities of practice situations whilst researchers valued adherence to strict and accurate research processes to generate high-quality valid findings.13,20

Understandably, for this study, the industry partner was hoping for prompt and positive results that could be used from a business perspective. However, due to a lack of research knowledge, the industry partner struggled to understand time frames, the complexities of approval processes, study methodologies, data collection and analysis. To manage and control this, the researcher provided the industry partner with regular written progress reports. This difficulty needs to be considered not only when working with practitioners but also with industry partners who bring different priorities and agendas to the setting.

Recommendations

A number of lessons were learnt by the research team through the process of this study and from this experience recommendations for paediatric researchers contemplating multi-centred studies with industry partners in the future have been drawn.

  • • Minimise industry partner contact with participants if possible for delivery of intervention to reduce risk of unintentional bias
  • • Provision of regular written progress reports for the industry partner
  • • Continual monitoring, prompt response and resolution of concerns or issues that arise.
  • • Education for industry partners in basic researcher practices to provide understanding of importance of the research processes particularly if industry partner participant contact is unavoidable.
  • • Clarify and have a clear understanding of roles and responsibilities of research governance departments and ethics committees to avoid confusion and potential disagreements.
  • • Utilise single ethical review processes where possible as this will reduce time frames for multi-centred studies and increase efficiency

Conclusion

Multi-centred studies provide researchers with the capability of recruiting large sample sizes and gaining generalisability of results. The current work by the NHRMC to implement a nation-wide single ethical review will reduce the complexity and length of ethics application processes in the future. Research involving industry partners is becoming more common due to the interface between commercialism and health research. It is, therefore, essential that researchers follow clear guidelines when planning and conducting research projects so to predict potential challenges and plan for how these may be avoided, controlled and managed. Further literature that provides information and guidance for multi-centred studies and industry partners is required to assist researchers considering similar multi-centred studies with industry partners in the future.

Acknowledgements

The authors wish to thank the industry partner involved in this study and the staff from each study site for their commitment to this study.

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