Palliative Care Clinical Trials: Building Capability and Capacity

Abstract

Clinical trials are a key component of expanding the evidence base in palliative care. A key strategic objective of the Victorian Comprehensive Cancer Centre (VCCC), a multisite cancer center alliance, was to increase palliative care clinical trial expertise. The palliative care services within the VCCC alliance presented substantial trial development opportunities with large number of patients and established relationships, but few trial-active centers.

Objectives:

To establish a multi-site “Building Capability in Palliative Care Clinical Trials” program as a service development, and to assess the strategies, activities, and the outcomes resulting from this program.

Methods:

A series of strategies and activities were developed linked to the key program objectives of increasing the number of clinical sites and skilled clinicians conducting clinical trials, increasing the number of trials available and patients participating, broadening research opportunities in palliative care, and establishing the program sustainability.

Results:

In the two years of implementation, the program resulted in the establishment and conduct of several Phase 4 postmarketing pharmacovigilance studies, nine Phase 2 and 3 trials across five palliative care services, and a Phase 1 clinical trial. During the program, 150 patients were recruited to clinical trials, and 258 prospective pharmacovigilance monitoring cases were recorded. Five investigator-initiated trials were developed by clinical trial fellows and achieved competitive (n = 3) or commercial (n = 2) funding. Clinicians reported that undertaking clinical trials had increased attention to the evidence base of care provision, and increased service research activity more broadly. Long-term sustainability remains a challenge, particularly in the context of the COVID-19 pandemic.

Conclusions:

Clinical trials in palliative care services are feasible, acceptable, and result in increased attention to the evidence base of care. The strategies detailing the framework, activities, and outcomes have been collated to facilitate implementation of clinical trials in other sites and with other trial-naive disciplinary groups.

Background

The conduct of clinical trials is an important component of accruing evidence for sets of practices and pharmacological interventions. A number of immediate benefits have also been identified for participants in clinical trials including access to new treatments,¹ scrutinized decision making, careful monitoring, additional clinical relationships, and improved emotional well-being,^1–5 whereas for those with advanced disease, trial participation is often welcomed as a demonstration of autonomy, achieving a sense of altruism through helping future patients, and contributing to science.^6,7 Clinical services that are trial active have been shown to have better patient outcomes, including overall reduced mortality compared with nonresearch active centers.⁸

The Victorian Comprehensive Cancer Centre (VCCC) is a collaboration of clinical, academic, and research centers established to improving the care and outcomes of people with cancer.⁹ The VCCC brings together university and cancer research institutes as well as clinical services including tertiary and quaternary cancer treatment centers who together provide >400,000 occasions of service to cancer patients annually. The clinical services available across VCCC sites include screening, specialist surgery, intensive and emergency care, hematology transplantation and CAR-T cell therapy, medical oncology, palliative care, survivorship and rehabilitation care, and a range of psychosocial support services. In Victoria, ∼59% of patients admitted with cancer will access palliative care, a median of 24 days before death.¹⁰ A key platform of the VCCC research strategy has been to improve access to clinical trials. Since the VCCC member organizations already had large clinical trial portfolios in medical oncology and hematology, it was recognized that this strategy must be expanded to other disciplines by building the capability of new craft groups within the cancer workforce to conduct clinical trials.

Palliative care was recognized as a key clinical discipline for the Building Trial Group Capability Program; since palliative care had long been highlighted by cancer patients as a priority for generating new translational research,¹¹ there was a large pool of patients across the VCCC (up to 3000 new patients annually) who could potentially participate and there was an established network of providers with existing academic and trial leadership. Although clinical trials undertaken in the field of palliative care are increasing in number accounting for 11.4% of prospective controlled clinical studies to 2015 compared with 4.3% in 2006,¹² this remains much fewer than, for example, in cancer care where clinicaltrials.gov lists 83,275 trials to 2021, including 7584 trials currently open to recruitment in the United States alone.¹³ Before the initiation of the program, three of the seven VCCC palliative care clinical sites had established clinical trial teams.

Clinical Palliative Care Program(s)

Program structure

The VCCC includes six adult and one pediatric hospital palliative care services. Each of the adult services includes a consultative team who provide consultation to acute hospital inpatients, an outpatient service staffed by palliative medicine physicians and nurses, and inpatient palliative care units. In total there are 84 inpatient palliative care beds across the 6 adult services, ranging from 12 to 34 beds. The pediatric hospital includes a consultative palliative care service that provides consultation to inpatients in the specialist children's hospital and also to the state of Victoria, Australia. All palliative care services within the VCCC are publicly funded with no costs incurred by patients.

Team staffing

Each of the hospital palliative care services has multiple full time equivalent (FTE) each of physicians, advanced practice or nurse practitioners, registered nurses, social workers, allied health, and chaplains. All physicians and nurse practitioners have board certification for specialist palliative care practice.

Program availability

Palliative care services are delivered to patients in the acute hospital and in outpatient and inpatient specialist palliative care unit settings. Community palliative care at home is delivered by community-based providers, not the hospital teams. Nevertheless, strong relationships exist with these community providers in each of the local regions.

Patient volume and interactions

Each of the hospitals has tertiary and quaternary referral level cancer care services. The number of patients seen by each of the 6 adult and 1 pediatric palliative care service differs but >3000 new patients are admitted to the specialist palliative care units annually, whereas number of outpatients seen by the adult services ranges from ∼620 to >7000 patients per annum.

The collaborative Palliative Care Clinical Trials Program was established as a service development activity across these VCCC hospitals, and implemented with a series of objectives (Table 1), goal-driven strategies, associated activities, and outcomes. An assessment of this program implementation and achievements was undertaken,^14,15 and the presentation of its strategies, activities, and outcomes is the subject of this article.

Table 1.

Overarching Objectives of the Building Trial Group Capability Program

1. Increase the number of clinical sites and clinicians engaged in clinical trials conduct

2. Increase the capability of clinicians to conduct clinical trials

3. Increase the number of trials available and the number of patients participating

4. Broaden research interest and opportunities in palliative care clinical services

5. Ensure sustainability of the program

Program Implementation: Activities and Outcomes

The VCCC provided investment for two years to establish and support the foundations of the program as part of the VCCC Strategic Research Plan. Seed funding was primarily utilized to establish key positions at clinical sites and provide central mentorship positions (Table 2). The allocation of funding was determined by the Building Trial Capability Program Steering Group whose membership and role are described in more detail hereunder. This involved the proposal of different funding models according to the program objectives (by the program head), and over a series of three meetings, agreement was reached by the steering group on the most appropriate funding allocation.

Table 2.

Program Resources Funded by the Victorian Comprehensive Cancer Centre

Site specific	Supportive and mentoring positions
Clinical trial research fellows • At three sites • 0.2, 0.2, and 0.1 fractional positions Clinical trial coordinators • At two sites • 0.4 and 0.4 fractional positions	Trial group clinical lead (0.1 fractional position) Program trial coordinator (0.5 fractional position) VCCC program manager (0.2 fractional position) Program head, palliative care clinical trials (unfunded)

All funds were expended on the positions as described, apart from a small fraction (<$10,000) used to support program events.

VCCC, Victorian Comprehensive Cancer Centre.

The program's goals and strategies are summarized in Table 3, with activities and outcomes following. A census of all activity, training, and recruitment was undertaken at the beginning and the conclusion of the program.

Table 3.

Victorian Comprehensive Cancer Centre Palliative Care Building Clinical Trial Capability Program: Goals and Strategies

Goals	Strategies
Goal 1: Engagement	• Established clear governance for the program • Ensured trials conducted across sites were of high quality • Invested in infrastructure including support for positions to “kickstart” the clinical trial workforce and provide central coordination • Established processes and strategies for communication about the program and individual trials
Goal 2: Capability	• Dedicated personnel to be trained in trials and support site development • Established a structured mentorship and training program from central collaborative—program lead, clinical trial group lead and program trial coordinator • Supported and promoted the development of investigator-initiated trials
Goal 3: Accrual	• Established infrastructure support to engage in instituting and recruiting to trials • Established trials commensurate with the site capability • Built relationships with national collaborative trials groups
Goal 4: Opportunity	• Concept development workshops • Clinical trial fellows stimulated broader research activities at clinical sites • Encouraged clinical staff to develop relationships with research and researchers
Goal 5: Sustainability	• Progressive steps toward establishing and maintaining the program including • Building financial sustainability • Building and consolidating relationships toward sustainability

Goal 1: Engagement

Activities

It was recognized at inception that a strong governance structure for transparent decision making and reporting was required. A steering group comprising representation from service heads of each clinical site, a consumer, and an early career researcher was responsible for all aspects of reporting, leadership, and strategic decision making and, in turn, reported to an overarching VCCC research committee, ensuring accountability for all program activities. Involvement of site service directors facilitated program endorsement and acceptability, oversaw appointment to positions, and negotiated with their local sites building processes toward sustainability. A scientific committee, which reported to the steering group, was established with the function of providing advice, critical review, and feedback on the trials proposed/undertaken, thereby ensuring quality benchmarks were met. The members included experienced trialists, a mix of disciplines and members of other collaborative networks, and an early career researcher. Steering group members were invited as coauthors of relevant academic outputs.

Program funding was primarily invested in creating capacity at clinical sites (Clinical Trials Fellows and Clinical Trials Coordinators—Table 2), and in central coordination and leadership positions, thereby promoting local clinical site participation, study conduct, guidance, and mentoring. The fellow positions were engaged to build the future workforce leadership in the area, with the central coordination and leadership positions mentoring this developing workforce. New staff were hired to fill the program trial coordinator and manager roles, whereas existing clinical staff took on additional fractional appointments as the trial fellows and clinical lead role. Meanwhile, specific early attention was given to the development of a communication plan to facilitate both site and institutional-level engagement, and to raise the profile of palliative care research more broadly.

Outcomes

Participation in all aspects of the program was high. Steering committee members were very engaged, participating in reaching consensus decisions, including around funding dissemination, working assiduously to achieve the program goals. The scientific committee reviewed five new trials and, through feedback, contributed to the training of early career trialists. The communication plan involved holding events including local clinical site “launches” to create awareness of the impact and contributions of clinical trials, as well as a collaborative “showcase” event to bring together staff and consumers across the network to celebrate the program, and simultaneously strengthen the collaborative relationships. Regular teleconferences of all clinical trial site staff enabled sharing of experiences including challenges and solutions, and fostered collegial networks. Regular updates and achievements from the program were highlighted to affiliated hospital site communication departments for dissemination, and monthly local program newsletters were produced to keep the collaborative informed of activities and opportunities.

Goal 2: Capability

Activities

The funding of positions enabled dedicated clinical site personnel to be trained in clinical trial conduct and supported their development at sites. Where possible these were fractional appointments to existing staff positions, thereby enhancing the embedded nature of clinical trials as part of “usual” work at the site. The program central personnel (program lead, clinical trial group lead, and program trial coordinator) established a structured mentorship and training program for the fellows and all site staff involving formal monthly meetings as well as informal guidance to support new protocol development, submissions for competitive funding, and the building of collaborative networks such as with biostatisticians, and other discipline-specific experts. Clinical trial fellows also were supported in protocol development through broader VCCC network resources including targeted support for protocol writing, ethics submissions, and contractual processes. New trialists were encouraged to join national collaborative clinical trials groups, which also offered support for trial development, whereas the scientific committee also offered mentorship as described earlier. Site clinical trial coordinators were supported through the monthly collegiate meetings coordinated by the program trial coordinator.

Outcomes

During the two-year program, clinical trial fellows developed three investigator-initiated clinical trials, each successfully achieving competitive funding for a Phase 2 or 3 trial. One trials fellow, in partnership with industry, was involved with the development of a further investigator-initiated trial, and two clinicians working alongside the trials program each developed investigator-initiated trials—both funded (competitive grant and industry). In the two years before the program implementation, no palliative care investigator-initiated trials had been developed within VCCC sites. The engagement of clinicians not directly funded by the trials program demonstrated the reach and broader impact of the program.

Goal 3: Accrual

Activities

Infrastructure in the form of personnel to support naive clinical sites to establish, implement, and recruit to trials and to provide mentorship was essential. Infrastructure also included sharing common resources and tools, for example, standard operating procedures, key contacts, and a database to track trial procedures, costs, and participants' progress.

A commitment to ensure those trials undertaken at a given site were commensurate with the site's capability meant a staged introduction was undertaken, with trial-naive sites beginning by participating in Phase 4 postmarketing pharmacovigilance or monitoring studies to be followed in time by studies of increasing complexity. This staged approach facilitated gradual building of processes, confidence, and staff skills. The collaborative network and leveraging relationships with national trials cooperative groups [Palliative Care Clinical Studies Collaborative (PaCCSC), and Cancer Symptom Trials (CST)] meant a range of trials were existing enabling this approach. All trial and clinical site staff were encouraged to join the key national trials collaborative groups to raise awareness and research interest.

The program communication strategy involved regular site updates, thereby informing and engaging clinicians, building enthusiasm and pride in the program, and further enhancing patient accrual to studies.

Outcomes

The number of trials open for recruitment increased at all sites—both those trial-naive sites and those with established trials teams. The initial strategy of recruitment to Phase 4 postmarketing studies was fully embraced with two new sites contributing 64 and 50 participants each in the first 12 months, and a total of 278 participants over all sites in the 2 years (previously 59 in the 2 years before the program implementation). The number of clinical trials available to palliative care patients increased from 9 at the start of the program (across 3 sites) to 26 trials (9 trials at 5 sites) within the two-year program, including a Phase 1 trial. In the two years, there were 150 participants recruited to Phases 2 and 3 clinical trials, an increase from 29 in the two years before the program.

The program included a pediatric palliative care facility, with no prior clinical trial activity, who was instrumental in establishing an international pediatric Phase 4 postmarketing trials collaborative, with the first study to date having accrued data from 75 participants across seven countries.

Membership from VCCC-affiliated sites to the national cooperative trials groups increased from 16 to 42 in the two years, and clinical trials fellows were appointed to scientific committee and advisory group of two national cooperative trials groups. Investigator-initiated trial ideas were presented and were successful in achieving support for protocol development by the national cooperative trials group.

Goal 4: Opportunity

Activities

Two concept development workshops were held across clinical sites to canvas new ideas and prioritize research questions, with secondary goals of building engagement and research training. The workshops' content was tailored according to the research capability of attendees, with the first seeking to develop trial ideas in a themed area, whereas the second sought to explore research questions and appropriate methodologies based on the work at the clinical sites. A number of staff also attended national collaborative concept development workshops held by particular craft groups. The clinical trial fellows instigated research meetings at their respective sites and provided assistance to clinical staff to conduct research projects leading to increasing staff engagement and interest in research broadly.

Outcomes

The two concept development workshops were attended by 46 participants in total, and each resulted in a research agenda with planned future strategies. In addition to the investigator-initiated trials already highlighted, weekly journal clubs/clinical research meetings and regular research newsletters were established. The clinical site staff increased membership of and attendance at scientific meetings at the national cooperative trials groups.

Goal 5: Sustainability

Activities

Since funding for the program provided by the VCCC was limited to two years, activities to build sustainability were a key focus throughout. A regular evaluation process was built into the program to ensure milestones were met. The regular communication to stakeholders highlighted the collaborative's track record of success, thereby promoting the group to potential new trial sponsors.

A formal strategic planning process, with a focus on sustainability, examined the different financial models and sources of support, the mix of studies required to maintain financial viability, and the models of ongoing mentorship to ensure personnel support. Advice and guidance were sought from external trials groups regarding the appropriate trials mix and appropriate structures for smaller groups to ensure longevity. The strong collaborative relationships with national trials networks were considered important for the ongoing support and mentorship, as well as facilitating future trial opportunities.

Outcomes

A sustainability model for trial sites was developed that detailed the ratio of sponsored–unsponsored studies of 60:40 should be maintained. For smaller trial groups, a partnership with local larger trial groups, such as hematology or oncology, would enable fluctuations in trial income to be better absorbed, and would simultaneously facilitate ongoing professional development and mentorship of trial staff.

The COVID-19 pandemic in the second year of the program meant that almost all trial activities were paused with a substantial financial impact upon sites that were paid per participant enrolled and presented a significant threat to sustainability. In response, novel methods to conduct clinical trials for “remote” participants were developed, including mechanisms for recruitment and study conduct using telehealth.

Finally, a set of guidelines were developed outlining key attributes to assist decision making for other craft groups who wish to undertake a similar program of building capability in clinical trials. These guidelines were reviewed and endorsed by the steering group and subsequently also by the VCCC research committee (Appendix A1).

Discussion

The establishment of a multisite program of clinical trials in palliative care is a complex implementation process requiring attention to multiple facets of activity, substantial investment, and high levels of clinical and service leader commitment. Ambitious in outlook, the program was able to achieve many of its goals as a result of these key requisites being present at inception. The planning and development of strategies, such as the communication plan to improve clinician understanding and broader engagement, also contributed substantially.

Our experiences mirror the recommendations and processes put forward by other groups, such as the attention to trial design and development,¹⁶ a focus upon preplanning with audits of current clinical site patient cohorts and their concerns,¹⁷ and formal feasibility and pilot studies.¹⁸

Study selection according to the site's access to those patient groups is particularly important in palliative care where patients relevant for trials may present across a range of settings, including medical oncology clinics, emergency departments, and inpatient palliative care settings.¹⁹ Furthermore, a process must exist to ensure the quality of trials selected by the sites, including the offer of guidance and support to trial-naive sites. In our program, this quality review was offered by the scientific committee, but others have developed different although equally effective mechanisms.²⁰

The existing literature predominantly focuses upon the key trial attributes and recruitment strategies to successfully conduct palliative care trials, with less attention focused upon the requirements for clinical sites to be undertaking these trials. One of the most successful national trial collaboratives in palliative care, PaCCSC, established in 2006 has now overseen recruitment of >1000 participants to Phase 3 clinical trials. The PaCCSC lead investigators have detailed the elements critical to clinical trial success that include ethics committee engagement, central coordination and support, clinician engagement to highlight quality-of-care improvement, working with key groups outside palliative care who may identify eligible patients, establishment of recruitment key indicators, and regular shared communication between sites to work through difficulties and share successes.²¹ Ultimately all groups have stressed the substantial commitment required to establish and maintain an active trial portfolio, as, for example, Christakis points out that ∼10 times as many patients as were ultimately enrolled needed to be identified.²²

As detailed, our program has benefitted from the support and resources of existing collaboratives, most notably PaCCSC and CST. The access to Phase 4 pharmacovigilance studies as an early introduction to patient identification and data collection^23,24 was invaluable to the trial-“naive” sites to develop confidence and research relationships.

There were many achievements of this program, yet there are also some areas that demonstrate limitations. Most notably, the longer term sustainability of this multisite trials program is uncertain particularly after the impact of COVID-19. Future activities will be focused particularly upon building relationships with industry sponsors in attempt to increase the proportion of sponsored studies in a clinical trial site portfolio. We would recommend that those undertaking future similar program building have a key focus on this area at the outset.

Conclusion

The establishment of a multisite collaborative clinical trials program in palliative care services is feasible and highly acceptable, and has many benefits. For patients, these translate to an ability to make choices about clinical trial participation, contribute to the care of future patients, and ensure better care is delivered in research active units. For clinicians, the program facilitates access to new knowledge and skills, and new collegiate relationships, and for palliative care itself, it means an expansion of the evidence base underpinning practice. The implementation of such a program requires attention to multiple levels of service delivery, training, and key relationships. The strategies and their outcomes that have emerged from this program will have utility to other groups who are considering establishing clinical trials within their service.

Footnotes

Authors' Contributions

The authors have contributed to the underpinning work described in this article, its conception, drafting, and have approved this final version.

Funding Information

There is no funding or grant supporting this article.

Author Disclosure Statement

The authors have no conflicts of interest to disclose in relation to this article.

Appendix A1. The Victorian Comprehensive Cancer Centre “Building Trial Group Capability” Program

The following are selection criteria developed to inform the Victorian Comprehensive Cancer Centre (VCCC) “Building Trial Group Capability” program for future planning and targeting craft groups.

The goal of this program is to broaden and diversify clinical trial groups as a means to expand patient access to clinical trials and increase trial participation rates across a range of clinical disciplines.

The key elements of this program are:

Palliative care was identified as the first clinical discipline to be supported in this program. As part of the work program, criteria to assist in the selection of clinical disciplines that may be supported in future programs were developed.

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