Good clinical trial funding practices: how can public funders reduce the risk of trial failure and improve health impact?

Abstract

Background

Clinical trial funders aim for trials conducted with high quality, within the planned time and budget. The majority of non-commercial investigator-initiated clinical trials do not complete participant recruitment in time or are discontinued early. In addition, the implementation of the results may be challenging. We aim to list the good practices available for public funders of clinical trials in Europe. Our focus is on practice-oriented trials exploring research questions not studied by industry.

Methods

We list the funding practices at the public trial funder KCE Trials in Belgium, together with good practices identified at the National Institute of Health and Care Research (NIHR) in England and ZonMw in The Netherlands. The literature on practices of public trial funders was searched.

Results

Assessment of the effectiveness of individual clinical trial funding practices is an under-studied area of research. Many funding practices have been integrated for decades in the NIHR HTA program, resulting in trials with significant health impact. Some practices of the commercial sector are now also used by public trial funders, such as on-site feasibility checks for recruitment capacity and paying sites based on participant recruitment and retention.

The array of public funder practices with the collective aim to reduce risk and enhance impact can be grouped into ten categories: integration of the funder in the research user landscape; the funder’s team and transparency in the use of public money; support for the sponsor’s team; the terms and conditions of the funding, access rights and data sharing; an efficient and pragmatic trial design; trial selection and improvement; budget and payments, the importance of feasibility checks and site payments; recruitment and retention; dissemination and implementation of results; collaboration between funders and multi-national clinical trials in the EU.

Conclusions

Public funders of practice-oriented clinical trials have tools available to improve the health impact of the trials they fund. The relative contribution of each practice in a funding program in relation to its cost remains to be studied. Challenges remain for recruitment in non-commercial trials and efficient funding and management of multi-national non-commercial trials.

Introduction

Investigator–initiated trials answer important questions with no commercial interest [1, 2]. In theory, clinical trials are conducted with high quality, within the planned time and budget. In practice, this ambition is often not fully realized. The majority of non-commercial trials do not complete participant recruitment in time [3, 4] or are discontinued early because of poor recruitment or insufficient funding [5–8].

The adherence to good practices such as trial registration and results publication is lower for non-commercial trials compared with commercial trials [7, 9–11]. Negative academic trials may be at especially high risk not to get published [12]. Funders of non-commercial trials have a key role in promoting successful completion and trial transparency, but practices vary greatly [7, 10, 11, 13, 14].

The WHO points to the importance of sufficient and sustained funding of clinical trials and calls for the engagement of health technology assessment (HTA) bodies throughout the process [15]. The WHO, HTA bodies, and the European Medicines Agency (EMA) stress the importance of randomization to obtain a reliable estimation of the benefits and harms of an intervention [15–17].

Despite a frequently reported positive return on investment [2, 18–23], the impact of publicly funded clinical trial programs is not always systematically evaluated or publicly reported. Furthermore, no studies were found evaluating the impact of specific practices of public funders. Based on the 2014 Lancet series on ensuring value and minimizing waste in research [24], a total of 17 good research funding practices were identified, resulting in an assessment tool [25] used by research funders [26, 27].

In this paper, we start from the risk-reducing or impact-enhancing practices at a recently created public funding program of practice-oriented non-commercial clinical trials at the Belgian health care knowledge centre (KCE), launched in 2016 and named KCE Trials (https://kce.fgov.be/en/kce-trials/what-is-the-kce-trials-programme).

While best funding practices are broadly applicable to clinical trials across various types and stages, the focus of this paper is specifically on large confirmatory pragmatic trials conducted (as trial sponsor) by academic or non-profit research institutions in Europe. Pragmatic in this context means the evaluation of the effectiveness of an intervention under real-world conditions, rather than in a highly controlled environment.

Methods

We start from the experience gained from the risk-reducing or impact-enhancing practices at KCE Trials, the National Institute for Health and Care Research (NIHR) HTA program in England and the clinical trial funding streams at ZonMw in The Netherlands. Based on discussions among the authors, the practices are grouped under ten headings. References are added based on a literature search, with a focus on Europe (Appendix 1).

Results

A total of 28 publications were selected based on the literature search (Appendix 1). The authors contributed additional papers or webpages.

Integration of the funder in the research user landscape

In a 2015 KCE report on publicly funded trials [1, 2], three key success factors were identified: (1) selection of the most relevant trials; (2) a professional trial conduct; (3) implementation of the results. Research funders should take the needs of the potential users of research into account when setting priorities for funding [28]. The users of the results of practice-oriented trials are the patients, the healthcare professionals, and the healthcare payers.

In order to address the needs of regulators and payers, and to implement the trial results, public funders of clinical trials should be well integrated in the healthcare landscape of the jurisdiction they cover. The most important integrated trial funder in Europe is the NIHR in England [1]. Similar healthcare-oriented trial funding programs were identified at ZonMw in the Netherlands, with attention for implementation of the trial results [29].

KCE is a federal scientific advisory body active in health services research, the development of practice guidelines, and HTA. The KCE board of directors includes the various ministries, agencies, and stakeholders in the Belgian healthcare landscape. It is an essential facilitator for public health impact creation based on the KCE reports and trial results. KCE Trials is inspired by the NIHR HTA program [30, 31]. The focus is on non-commercial, confirmatory randomized comparative-effectiveness trials for all types of interventions, including repurposed drugs. The KCE Board is represented in the KCE Trials Prioritization Group, which oversees, prioritizes, and approves the funding of the selected trials and manages the portfolio of funded studies.

In many EU countries, the funding of clinical trials is part of broader research and innovation efforts, with a primary emphasis on academic advancement, economic development, or job creation. These trials often miss the input of the regulators, payers, and other policymakers in the healthcare system [1]. This might explain why some early-phase academic clinical trials are not part of a full clinical development plan aiming for a later integration of the intervention in the healthcare system [32]. For instance, in Belgium, the funding of early phase trials is regarded as innovation-driven research and therefore supported through regional funding mechanisms, while the healthcare system is funded mainly by the federal government.

Both early and late phase academic clinical trials could benefit from a low threshold single point of contact for regulatory and HTA advice to position the clinical trial in an overall development and funding plan [15, 32–34]. Regulatory review of drug repurposing trial applications is encouraged at KCE and ZonMw [35], in collaboration with the regulators.

The funder’s team and transparency in the use of public money

About 10% of the 10 million euros yearly budget of KCE Trials is used for personnel costs of the funder’s team and for operational costs such as payments of reviewers of applications, legal advisors, contract organizations, and grant management software. Such tools can help to efficiently manage proposal submission, conflict of interest checks, proposal review, selection meetings, subsequent submissions, tracking of contracts, recruitment milestones, and outcomes. Offices, standard information technology, and human resources services are not included in the 10%. The funder’s team is composed of personnel with a medical, scientific, economic, or legal background and experienced in the various aspects of clinical trial conduct, especially pragmatic trials [36]. This allows for the selection of appropriate reviewers and interactions during the review meetings, resulting in well-argued feedback to the applicants. During the trial conduct, online meetings of the funder and the sponsor team every 2 to 4 weeks allow for timely corrective actions taken in consensus with the sponsor team.

KCE Trials strives to be highly transparent about the spending of public money and the stage of advancement of the trials funded. As mandated by law [37], good clinical practice [38], medical ethics [39], and journals [40], all trials are to be registered in a publicly accessible registry before the start of recruitment. This should preferably include the full protocol after ethics committee approval. Publications of the protocol or the main results of trials funded by KCE should be open access. The associated costs are part of the trial budget [41].

A plain language summary of each funded trial and the results is posted on the website in English (https://kce.fgov.be/en/kce-trials), Dutch and French. Publications and details on the progress, including the anticipated study report date, are shared using a dashboard on the KCE website (https://trials.kce.be/dashboard). It is updated weekly and shows the actual recruitment at each site for all ongoing trials.

KCE Trials newsletters and social media announce a.o. the calls for funding and for reviewers. The website lists resources for investigators such as the processes, contract templates, and training material (https://kce.fgov.be/en/kce-trials/resources), similar to the NIHR online Research Funding Good Practice Guide [42].

Support for the sponsor’s team

When KCE Trials was started in Belgium in 2016, academic centers had clearly more experience participating in commercial clinical trials compared with managing all sponsor responsibilities of a large multicentric randomized trial [43–46]. Academic reward systems may incentivize quantity more than quality, and novelty more than reliability [8, 47]. Therefore, candidate investigators may not be inclined to set up a large multicentric or international trial. They should be supported by a clinical trial unit (CTU) where trial sponsor expertise is centralized [48]. Efficiency gains are obvious for applicants in obtaining support for protocol development [49], funding [50], legal and regulatory compliance, contracting, statistics, data management, and monitoring. CTUs need to have a sufficient workload to maintain resourcing to keep well trained staff. Therefore, interested smaller hospitals or general practice associations [51] should be able to source these services from an existing CTU. In the UK, Germany, Switzerland, and Spain, the CTUs form networks, improving efficiencies [1, 44, 52].

At the start, KCE Trials organized a sponsor capacity gap analysis of twelve interested CTUs in Belgian universities and hospitals, each resulting in an improvement plan [53]. Often, the expertise was found to be scattered over several clinical departments and not centralized. KCE Trials regularly organizes training courses and discussion sessions with CTU staff. The topics include e-CRFs, safety reporting, risk-based monitoring [54], and low intervention trials [55]. In addition, KCE Trials symposia (https://kce.fgov.be/nl/kce-trials/resources/presentations-from-kce-trials-symposia) focus on topics ranging from registry-based and pragmatic trials [56] to clinical trials in surgery. The trial funding received as well as the educational efforts have contributed to increasing the expertise and capacity of the (centralized) CTUs. Finally, having a better trained workforce might also make the country more attractive for commercial clinical trials, a topic that is high on the agenda of many countries, the European Commission, the EMA [57], and the industry [58].

The terms and conditions of the funding, access rights, and data sharing

Contracting is often cited as an inefficiency [4]. This concerns agreements between funder and sponsor and between sponsor and the trial sites. KCE minimizes delays by working with templates developed together with the academic sponsors.

Data sharing in general is required and the sponsor of the trial is expected to set up a data sharing policy. Recommendations for preparing clinical trials data sets for sharing have been published [59]. Funders should consider the costs involved in the preparation of anonymized trial data sets [60, 61].

The funding agreement defines that KCE and similar institutes in Europe have the right to use the pseudonymized trial database for public health purposes, including HTA. Health-economic evaluations alongside clinical trials have been reported for Australia [62]. Also KCE and ZonMw conduct such analyses for selected trials [63]. For health-economic evaluations or for long-term survival analyses, the trial data set can be linked to other data sets such as billing data, vital statistics, or other registry data after the appropriate data privacy and data security approvals [63]. Participants are informed during the consent procedure. In our experience, this additional public health purpose of the funded trials did not have any negative impact on recruitment. Based on a rough estimate, the data linkage at KCE was less costly compared with a full data collection [63]; however, in contrast with two cases in New Zealand [64].

Protecting intellectual property based on publicly funded research, especially early phase or drug repurposing, is relevant from a healthcare payer perspective as it can influence access and affordability [65]. KCE and similar institutes in Europe automatically receive non-exclusive, royalty-free access rights to use the trial results for public health purposes. In addition, and similar to the NIHR policy [66], the KCE contract includes so-called “socially responsible licensing clauses,” of relevance when commercialisation of trial results is intended [32].

An efficient and pragmatic trial design

The annual KCE Trials calls fund investigator-led (bottom-up) trials. Commissioned calls (top-down), where the research question is, e.g., based on a healthcare payer priority topic, have been tried, but the response from possible sponsors was low. A lower response to commissioned calls has also been observed in the NIHR efficacy and mechanism evaluation program [20]. For reasons that are not entirely clear, the trials funded under a commissioned call at NIHR yielded fewer high-impact publications compared with investigator-led trials [67].

Funded trials should optimally inform HTA. This can be achieved with randomized clinical trials that compare the tested intervention against standard care, recruit a representative and inclusive patient population, and assess patient-relevant outcomes [37, 68]. Trials should therefore be as pragmatic as appropriate [56, 69–72]. Efforts are needed to familiarize investigators and sponsors with pragmatic trials [73]. The PRECIS-2 tool can also be used [74]. Both benefits and harms should be measured and reported [75]. Care should be taken to obtain complete data sets, also for health-economic analyses [76]. Core outcome sets are to be checked and used where available [77]. The use of a generic quality of life instrument such as EQ-5D-5L at several time points allows for a calculation of quality-adjusted life years (QALYs) gained, an important outcome for health-economic analyses [37, 78].

Important efficiency gains have been obtained using randomized registry-based trials or trials within cohorts [79]. In the Swedish cardiology registry 70% of the patients accepted to be randomized in a comparative effectiveness trial [80], leading to a shorter recruitment period. Registry-based randomized trials can be run at a small fraction of the usual trial cost, e.g., 0.5 M euros instead of 15 M euros for a similar RCT, provided the registry is of high quality [80]. Platform trials can be very informative as they provide comparative evidence on the multiple interventions tested in parallel. However, there is currently little reported experience by funders on the trial budget impact of dropping or adding intervention arms. Also the health-economic potential may be impacted when changes are made in an adaptive platform trial [81]. Research is ongoing on value-adaptive trial designs optimized for HTA and public health decision making [82].

Trial selection and improvement

KCE, similar to NIHR and ZonMw, installed a two-stage selection process, consisting of a research outline (first stage) and full proposal (second stage) (Fig. 1). The review and scoring of the outlines are performed by a Panel of healthcare professionals and patient representatives covering the clinical areas concerned. Only the outlines that are of high clinical relevance and considered acceptable from a health economic point of view by KCE health economists are reviewed by the Trials Board. These independent statisticians and study design experts evaluate the quality of the trial during the two stages. An application may need first to be improved before it can move on. Overall, for the two stages, the number of Trials Board review rounds per application has been capped at five. The average time from application to selection is 10 months, with an additional 8 months for feasibility checks until the funding contract is signed.

Fig. 1.

Funder steps at KCE trials, from opening a call to implementation of trial results

All experts participating in the selection process declare their interests (https://kce.fgov.be/en/kce-trials/resources/kce-trials-policies-and-procedures). The policy to avoid possible conflicts of interests needs to be both rigorous and flexible enough to be workable.

Before applying, applicants are expected to check the research priorities [83], obtain the input of patients on the research question, the outcome measures, and the feasibility of the trial procedures. Patients are also present at each selection meeting and have voting rights.

Funders need to have an appeal procedure for applicants but should be aware that such procedure may delay the selection and funding process of the other applications.

Budget and payments, the importance of feasibility checks and site payments

While trial underfunding is a frequently reported problem [1, 6, 84], there is limited expertise in correctly budgeting academic trials [85, 86]. Public funders should aim to cover the real costs of the trial both for the sponsor and the recruiting sites. KCE and others have developed budgeting tools, which are updated regularly [41, 87, 88].

Even before the final funding decision, a number of risk-reducing tasks can be performed. The drafting of a full protocol requires the input from patients, statisticians, third-party suppliers of goods or services, and definitely site investigators. KCE, as a funder, is rather unique as it pays a non-reimbursable lump sum of 12,500 euros to the sponsor for protocol development when an outline is selected (Fig. 1). A similar advance payment is made to support the sponsor for the on-site feasibility check in a representative set of sites. The non-commercial sponsor is supported by a contract research organization hired by KCE, adding to a more standardized and independent approach. The sponsor team’s feedback so far was mainly positive as it leads to further protocol improvement and risk reduction for the sponsor and funder. If there are doubts about the feasibility, a pilot trial may first be funded. A pilot study is a miniature version of the main study to test whether the components of the main study can all work together [89, 90].

Even for pragmatic trials, some site activities are not part of routine care and need to be reflected in the trial site budget. For KCE funded trials, site payments typically account for 30–60% of the overall budget. Compensation of trial participants for travel and time spent is needed when trial procedures extend beyond the routine care visits.

Upon signing the funding contract, a payment of 15–20% of the sponsor costs is made, covering the initial personnel costs for project management and data management. In addition, each funded trial should have a trial steering committee. It should include experts independent of the sponsor team [91]. Milestone payments to the sponsor are mainly driven by trial recruitment (first patient, 25% of planned number, 50% etc.), while sites are paid twice a year for the number of patients included and study visits performed. Ideally, the funder should keep a small reserve to maintain flexibility if unforeseen justifiable expenses occur.

Database lock should follow within 3 months after the last patient’s last visit. This is possible if data cleaning and query resolution are managed carefully. This requires trained personnel for data management and monitoring. The statistical analysis plan should be finalized well in advance of the database lock. No time should be lost after the database lock to start producing the results and the report writing, which is expected 6 months after the last patient’s last visit. A last milestone is paid to the sponsor when the manuscript containing the main results of the trial has been submitted for journal publication.

Co-funding

For national trials, co-funding is not stimulated as the funding tries to be comprehensive. Co-funding by industry or free supply of study materials needs a thorough review of the contract with the sponsor as it needs to be in agreement with the KCE funding contract.

For international trials with a non-Belgian sponsor, a national coordinating center in Belgium will take up certain sponsor responsibilities, if applicable. The trial budget is lower when less sponsor-related activities are delegated but will always cover the patient fees for the participating sites. When the trial is selected, KCE will fund the activities in Belgium using a contract with the Belgian coordinating center. A commitment letter is required from the international sponsor which specifies a.o. the non-commercial purpose of the trial, the trial registration, the publication and the access rights to the Belgian pseudonymized trial data set.

Recruitment and retention

The main reason for non-commercial trials not completing in time or even being discontinued early is a recruitment rate that is lower than planned. The perception by investigators and patients of equipoise between the different interventions studied is a key requirement for successful patient recruitment. Experience has shown that patient inclusion in randomized trials comparing surgical techniques or surgery versus a non-surgical intervention is challenging if not all surgeons–investigators are fully convinced of the equipoise.

On-site feasibility visits can help identify competing trials and any financial disincentives of trial participation for the investigator and the hospital. Paying sites for the specific trial activities based on trial recruitment and follow-up visits is a well-accepted standard in commercial trials and may also be critical for recruitment in non-commercial trials, including pragmatic trials.

Patients may not perceive equipoise for trials that test a drug dose or duration that is lower than the (conditionally) approved (and reimbursed) standard [92]. This is often the case for new oncology drugs conditionally approved for prolonged use based on limited clinical data [93]. The treatment duration may be questioned as side effects need to be balanced with any additional therapeutic benefit of prolonged use [94–97]. National public payers or charities may fund such treatment optimization trials in cases where there is no interest from the marketing authorization holder [72, 94, 95, 97]. The purpose of such trials may be better reflected in a comparative design rather than the common non-inferiority design [94, 98].

Patients, clinicians and ethics committee members may not know or well understand the status of “conditional marketing authorization” or “coverage with evidence development” [99, 100]. This can negatively impact trial feasibility [92, 99, 100]. It might make sense for regulators and payers to introduce an easy-to-understand concept like the “orange traffic light” status when a drug is made available to patients under conditions that require further clinical trials. This could facilitate recruitment in treatment-optimization trials. Limiting access to trial participants is an alternative option [99], e.g., for expensive new medicines in The Netherlands that have entered “de sluis” (the lock) [101]. Limiting payer coverage to participants in a pragmatic trial on intraarterial treatment for stroke had a positive effect on recruitment [102]. In Belgium, coverage of an app for rehabilitation after knee or hip arthroplasty was limited to participants to a trial [103].

A 2018 Cochrane review on strategies to improve recruitment identified only two interventions with high-level evidence for an effect [104]. A 6% absolute improvement was seen for patients who received a telephone call when not responding to a postal invitation. A 10% improvement was seen in an open trial compared with a blinded placebo trial [105, 106]. Retention also seemed to improve using an open trial design. The use of digital tools to improve recruitment and retention in trials is an active area of research [107–109].

Recruitment rates in practice can be low because of stringent eligibility criteria and/or eligible patients not willing to participate. In contrast to explanatory trials [110], pragmatic designs aim to include a more representative population. Input of patients in the trial design and the schedule of visits and examinations may result in a higher participation rate and a lower drop-out rate [111]. Overall, 72% of oncology patients stated they would accept to participate in a randomized trial, with a preference for trials comparing active treatments [112].

Non-teaching hospitals or GP practices may happen to treat the majority of the target patient population, so their participation in practice-oriented trials seems essential. Recruitment of patients outside of the hospital setting can be performed in a cost-effective way [113]. Simulations using budget tools show that the trial recruitment period and trial duration in general are more important drivers of the overall cost than the number of sites opened. A condition of course is that all opened sites or practices need to be able to cope with the trial workload.

Not only the classical trial newsletters, but also the KCE public dashboard showing the actual recruitment at each site is believed to lead to a healthy competition between recruiting sites.

Dissemination and implementation of results

The WHO best practices and the AllTrials campaign demands a summary of results is entered in the trials registry within 12 months after trial completion [14, 114]. Of relevance, medical journals do not consider this as dual publication [40]. While trial registration has become the norm, not all investigators perceive the need to publish the trial results on the registry, as reflected in the adherence to the WHO best practices on trial transparency for the KCE funded trials, available on the dashboard (https://trials.kce.be/dashboard) and in a report [115].

A plain language summary of the study results is posted on the KCE website in English, Dutch, and French (https://kce.fgov.be/en/kce-trials). All trial-related publications are shared using the dashboard. In addition, the KCE Trials symposia (https://kce.fgov.be/en/kce-trials/resources/presentations-from-kce-trials-symposia) offer a platform for investigators to present completed trials.

Implementation of the trial results in Belgium is enhanced by the position of KCE as an advisory body within the Belgian healthcare landscape. Based on the results, an additional HTA may be conducted to better inform the healthcare payer [63]. KCE is also well positioned to help adapt clinical practice guidelines where appropriate.

Collaboration between funders and multi-national clinical trials in the EU

KCE and ZonMw collaborate in the Belgium-Netherlands Funding of International Trials (BeNeFIT) calls for comparative effectiveness trials conducted jointly in both Belgium and The Netherlands. Investigators from both countries can apply to the joint trial selection and improvement process. Sponsor activities are often split between the main sponsor and the coordinating center in the other country. The payments made by KCE and ZonMw for the funded BeNeFIT trials will generally not cross the border.

Public funders of clinical trials reside under different ministries in different countries and typically act in isolation. However, there may be good reasons to collaborate. Sharing of good funding practices may improve the level of expertise of each participating funder. KCE Trials had a jump start using the processes of the NIHR HTA program. Best practices are also shared with ZonMw [116]. A platform of funders of comparative effectiveness trials could fit well in the existing Ensuring Value in Research (EViR) initiative [117].

For many trials recruiting in smaller patient populations, there is a need for international trials in Europe. Collaboration among funders could result in call synchronization across countries. Lack thereof hampers the start of recruitment in EU multi-national trials, for example, in trials coordinated by the European Clinical Research Infrastructure Network (ECRIN) [33, 84, 118, 119].

In Europe, about 40% of clinical trials with medicinal products are sponsored by non-commercial sponsors [33]. Most of these trials are small and nearly all are mono-national. The European Commission recognizes the issues with the funding of academic multi-national clinical trials but has not yet found efficient solutions [33]. The national–EU co-funded ERA4Health partnership uses a joint selection and (co-)funding mechanism for multi-national trials [120]. However, in common with most academic initiatives, it lacks the input from the national healthcare systems and may need additional efforts on the trial selection and improvement cycles, feasibility checks, use of data for HTA, trial budgeting, and the close monitoring of the trial progress. Further harmonization of the good practices among national funders, as was explored for the BeNeFIT collaboration, may be the next step forward.

Provided that standard care is similar across the countries, there may be an opportunity for a more centralized EU-wide approach to multi-national clinical trials. This could solve the issues related to call synchronization and national regulatory hurdles [33, 84, 119, 121]. The proposed EU Biotech Act is tackling some of these issues [34].

International rare disease registries funded by the EU should be designed with registry-based randomized trials in mind, which can then be run at low cost. HTA Joint Clinical Assessments (JCA) of novel drugs and medical devices at EU level are becoming a reality [122]. Based on the JCA, regulators and HTA bodies should together define the remaining research priorities that concern most if not all member states.

Member state clinical trial funders and public health insurance systems could contribute to an EU clinical trials fund and help set research priorities. Instead of the currently used national–EU co-funding approach and similar to the NIHR in England, a European Institute of Health and Care Research could be set up. It could use the EU trials fund to initiate without unnecessary delays the needed international non-commercial clinical trials. More efficiency in funding and conduct of a trial will allow patients to benefit more rapidly from the results. In case of an emergency situation, this fund together with a top-down management of the prioritized clinical trials in the EU might prove to be a fast route to start international publicly funded trials or re-orient the “ever warm” EU platform trials, coordinated by the Health Emergency Preparedness and Response Agency (HERA) [123]. In addition, a better collaboration between funders can improve response during an outbreak [124].

Discussion and conclusions

Publicly funded clinical trials can result in significant health benefits [2]. Funders of clinical trials have a set of tools and approaches available to improve the health impact of the funded clinical trials. Many of these practices have been tested over more than 30 years in the NIHR HTA program, resulting in significant health impact. Other practices have been developed and tested by commercial sponsors before being also taken up by public trial funding organizations, such as on-site feasibility checks and recruitment-based site payments. Experience to date at KCE Trials has shown such payment schedules are well accepted, replacing the traditional grant approach not linked to recruitment or milestones achieved. The use of a budget tool and milestone payments has been shown to work for two neighboring countries (BeNeFIT program), but it is yet to be tested in larger multi-national non-commercial trials.

The practices presented represent a burden for the funder. They require experienced personnel and the investment of time and resources, totaling about 10% of the overall trial funding budget. The study of the cost, the effectiveness, and the impact of individual clinical trial funding practices, instruments, and processes remains an under-studied area of research. Little is known about the relative cost of each practice in a funding program or its contribution to the overall impact. Nevertheless, the practices presented may inspire public or charity funders of non-commercial clinical trials to supplement their approach to the funding of clinical trials.

Participant recruitment remains a key hurdle for non-commercial trials, for example for treatment–optimization trials for drugs that entered the market using an accelerated pathway. Both national funders and regulators have a role to facilitate a rapid start of international trials in the EU. Collaborations among funders can synchronize calls and create common selection procedures. However, an earmarked EU trials fund and a more top-down management of EU trials may prove to be the more efficient way forward.

Abbreviations

BeNeFIT

Belgium–Netherlands Funding of International Trials

CTU

Clinical trial unit

ECRIN

European Clinical Research Infrastructure Network

EFFECTT

Empowering Funders For Enhanced Clinical Trial Transparency

EFPIA

European Federation of Pharmaceutical Industries and Associations

EMA

European Medicines Agency

EViR

Ensuring Value in Research

GCP

Good Clinical Practice

HERA

Health Emergency Preparedness and Response Agency

HTA

Health Technology Assessment

ICH

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use

ISO

International Organization for Standardization

JCA

Joint Clinical Assessment

JSC

Joint Scientific Consultation

KCE

Belgian Health Care Knowledge Centre

NIHR

National Institute of Health and Care Research

TwiCs

Trials within Cohorts

WHO

World Health Organization

QALYs

Quality-adjusted life years

QoL

Quality of life

Appendix 1

Literature search strategy

The funding of clinical trials does not have a specific Mesh term. PubMed was therefore searched on 24/9/2025 using (“Research support as topic”[MeSH Terms] and trials) for papers published from 2011 onwards. This yielded 754 hits, of which 15 publications were selected for citation by the first author.

The search “Clinical Trials as Topic/economics”[Mesh] and (“funding” or “funder” or “publicly funded”) and (“investigator-initiated” or “academic” or “non-commercial” or “non-industry sponsored”) yielded 64 hits, of which eight additional papers have been cited.

Five more references out of 58 hits were identified using a PubMed search for (“funding”[Title] or “funder”[Title] or “funders”[Title]) AND “trial”[Title].

Further relevant references were identified by the co-authors or using the snowballing technique.

Authors’ contributions

FH drafted the first outline for the manuscript, performed the literature search, and integrated the contributions from the co-authors. All co-authors provided additional concepts and references. All authors read and approved the final manuscript.

Funding

No funding was obtained.

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.