Based on the literature review, four potential mechanisms for funding clinical research with off-patent or generic repurposed medicines were identified and are summarized in (Figure 1). Next, fourteen interviews were conducted with sixteen participants (two interviews involved two study participants simultaneously) to learn more about the application potential of such models in Europe. Interviewees represent various stakeholder groups, including not-for-profit organisations (N = 5), academia (N = 3), university hospitals (N = 2), pharmaceutical industry (N = 2), a health research funding organisation (N = 1), a private bank (N = 1), a consultancy company (N = 1) and a health technology assessment body (N = 1) (Table 1. Characteristics of interview participants).
TABLE 1. CHARACTERISTICS OF INTERVIEW PARTICIPANTS
INTERVIEW
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STAKEHOLDER GROUP
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COUNTRY
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A
|
Academia
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Ireland
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B
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University hospital
|
Belgium
|
C
|
Not-for-profit research organisation
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The Netherlands
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D1
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Consultancy
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Belgium
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D2
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Private bank
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Belgium
|
E
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Not-for-profit organisation
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UK
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F
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Not-for-profit organisation
|
Belgium
|
G
|
Health technology assessment body
|
Belgium
|
H
|
Not-for-profit research organisation
|
Belgium
|
I
|
University hospital
|
Belgium
|
J
|
Health research funding organisation
|
The Netherlands
|
K
|
Academia
|
Belgium
|
L
|
Not-for-profit research organisation
|
Belgium
|
M
|
Academia
|
Belgium
|
N1
|
Pharmaceutical industry
|
Belgium
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N2
|
Pharmaceutical industry
|
Belgium
|
Grant or donation-based funding mechanisms
Traditional grant funding
The best-known mechanism to fund independent clinical trials is through grant funding programs, which typically involve a funding body and numerous applicants (i.e., academia and research institutes). Funding can come from different sources, such as government agencies, not-for-profit and philanthropic organisations, universities, research foundations and pharmaceutical companies. In most cases, the research project should meet specific criteria to be eligible for the grant, and a project proposal has to be submitted for review by a committee of scientific experts and, sometimes, patients.
Even though grant funding is well established in all types of research, it has several limitations. Most importantly, grant funding programs are highly competitive and the available funds are limited (34). Funding applications for clinical trials with off-patent or generic medicines in new therapeutic indications are often at a disadvantage because drug repurposing is not considered sufficiently innovative. “Innovation in science and medicine is often measured by creation of something new, not by repurposing something old and available” (9). However, Dr Richard Thompson from Findacure defended the innovative nature of drug repurposing in his paper for Medical News (35): “Innovation is also equally about innovative ideas – finding new ways to deliver a service or improved ways to use current resources. Drug repurposing is an excellent example of this form of innovation: using a scientific approach to identify new uses for existing drugs”.
Not-for-profit organisations, government agencies and pharmaceutical companies are increasingly awarding grants specifically focused on clinical drug repurposing research in all disease areas (36–40) (Table 2). For example, the Anticancer Fund, a Belgian-based not-for-profit organisation scientifically and financially supports independent clinical trials with off-patent or generic repurposed medicines in cancer patients, and recently launched a call for research proposals together with the Swiss Rising Tide Foundation for Clinical Cancer Research (41). CuresWithinReach and the Michael J. Fox Foundation, two US-based not-for-profit organisations, have also awarded multiple grants for investigating new therapeutic uses of existing medicines in various disease areas (42,43). Moreover, several government organisations, such as the Belgian Healthcare Knowledge Center (KCE), the Dutch ZonMw and the UK National Institute for Health Research (NIHR), have included drug repurposing as a focus area in their calls for funding of independent clinical research (44–46). Some pharmaceutical companies also provide grants to support investigator-initiated clinical research with their approved medicines (47–51). Bayer even ran a specific ‘Grants4Indications’ program that provided grants and further financial support to explore new therapeutic indications for their own compounds (52).
Interviewees highlighted the need for additional government funding to support independent research in all areas where there is market failure due to a lack of incentives and ROI. Besides for the repurposing of off-patent or generic medicines, funding is needed for the research into new treatment options for rare, paediatric and neglected diseases, psychotherapy research, research on surgical techniques, clinical trials with diet and life-style interventions, development of new antibiotics, and post-marketing trials to optimize existing treatments.
“The trick is of course to think of areas where things are not going well. […] Only if there were a real market failure, you would have to look for other ways to finance this, through government funding in my case.” (Interview J)
Several interviewees also mentioned the increased need for a top-down or demand-oriented approach in which governments identify the most important unmet needs in healthcare, and allocate research funding accordingly. A more active role of patient organisations in raising and allocating funds for independent research into treatment options addressing the highest patients’ needs was also mentioned several times during the interviews. However, interviewees argued that not every patient organisation is equally well organised, and that not every disease is well represented, which is especially a problem for (ultra-)rare diseases.
Finally, some interviewees were concerned that a clinical research project that was funded with public money, once de-risked, may be taken over by a pharmaceutical company and end up in for-profit development.
“Traditional grant funding can work. […] You have to rebuild a strong case based on the science for that and that can also deliver, but tends to end up reeling down to pharmaceutical pathway ultimately, so ends up generating the pharma profits.” (Interview E)
TABLE 2. FUNDING OPPORTUNITIES FOR INDEPENDENT CLINICAL REPURPOSING RESEARCH
Funding source
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Organisation
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Name of funding opportunity*
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Available funds
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Duration of research
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Geographic area
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Disease area
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Government organisations
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Belgian Healthcare knowledge center (KCE) (BE)
|
KCE investigator-led trials
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€10,000,000 per year, no defined max. amount per project
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Results preferably within 5 years
|
International study possible under certain conditions
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All
|
ZonMw (NL)
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Goed Gebruik Geneesmiddelen – Drug Rediscovery
|
Max. €1,000,000 per call
|
Not specified
|
International study possible if chief investigator and lead institution are NL-based
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All
|
National Institute for Health Research (NIHR) and Medical Research Council (MRC) (UK)
|
19/136 Call for Evaluating interventions for the diagnosis and treatment of autoimmune diseases
|
Case by case negotiations
|
Not specified
|
International study possible if chief investigator and lead institution are UK-based
|
Autoimmune diseases
|
Companies
|
Bayer
|
Grants4Indications
|
Case by case negotiations
|
Max. 2 years
|
International
|
All
|
Not-for-profit organisations
|
CuresWithinReach
|
ReGRoW Pilot
|
US$ 25,000 - 50,000 per project
|
12 – 36 months
|
Low and lower-middle income countries (LMICs)
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Any unsolved disease in
LMICs
|
Michael J. Fox Foundation
|
Therapeutic Pipeline Program
|
US$2,000,000 per project
|
2 - 3 years
|
International
|
Parkinson's disease
|
The Anticancer Fund (ACF) and Rising Tide Foundation for Clinical Cancer Research (RTFCCR)
|
The RTFCCR/ACF Multi-arm Clinical Trial Award
|
US$ 3,000,000
in total
|
Not specified
|
International
|
Cancer
|
* Non-exhaustive list of research calls with a focus on drug repurposing between January 2017 and January 2020
|
|
Crowdfunding
An alternative model to fund independent clinical research is by raising small donations from a large number of people via online platforms or portals, which is called crowdfunding (Box 1, Figure 1). One of the major benefits of crowdfunding for clinical research is the opportunity to raise funds for innovative projects with a potentially high societal or patient impact but low commercial return, as is the case for repurposing off-patent or generic medicines. The NeoART study, a phase II RCT investigating the efficacy of the anti-malarial agent artesunate in colorectal cancer, is an example of a drug repurposing project that collected funds (£54,247) through a crowdfunding campaign on FutSci.com (53). Additionally, crowdfunding enables patient and public engagement in prioritizing clinical research goals and increases public awareness of research needs (54,55). Crowdfunding can be particularly interesting for early-career investigators, who generally have a lower chance of success in competitive grant programs (56,57).
BOX 1 | CROWDFUNDING: BASIC PRINCIPLES
Crowdfunding can be either reward-based, equity-based or donation-based depending on the return that is offered to the funders (62). Donation-based crowdfunding is most relevant to fund independent clinical research where financial ROI and other rewards are lacking. A donation-based crowdfunding model typically involves three types of stakeholders: the project initiator (in this case a research organisation seeking funding to conduct a clinical trial), the donors, and the online platform provider. Campaigns to fund clinical research can either be hosted on general-purpose (e.g., Indiegogo.com, Kickstarter.com) or research-focused crowdfunding platforms (e.g., Experiment.com, Consano.org). Each campaign features a description of the research project in lay language, a monetary goal, and an indication of how close the campaign is to meeting this goal. Most campaigns specify a limited period to accept contributions. Some campaigns adhere to an “all-or-nothing” or “fixed-funding” model, meaning that donations are kept only if the monetary goal is met or exceeded.
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However, some practical limitations and ethical concerns regarding crowdfunding for clinical research have been raised. First, setting up a successful crowdfunding campaign can be time-consuming and challenging as it requires a lot of strategic planning and a multidisciplinary support team (56). High overhead and administrative costs, including transaction costs of platforms, can make crowdfunding efforts less efficient (58). One interviewee, having had experience with setting up crowdfunding campaigns, confirmed this challenge.
“We’ve run a few crowdfunding campaigns ourselves […] they are lots of hard work for limited success.” (Interview E).
The success of a crowdfunding campaign is not guaranteed. For example, in 2015, Sharma et al. identified twenty campaigns for clinical research, of which seven were still ongoing. Of the thirteen completed campaigns, only eight (62%) reached their financial goal. The funds raised in these campaigns ranged from US$3600 to about US$3 million, with an average of US$540,000, and a median of US$167,000 (59,60). An inconclusive or negative trial outcome, which is relatively common in clinical research, could also erode public trust (61).
Previous research suggests that crowdfunding could be a viable model to support small proof-of-concept trials, but would not be sufficient to fund larger RCTs (57,62). All interviewees agreed that large clinical trials are too expensive to fund via a crowdfunding approach. Still, it could be used to de-risk early-stage projects and thus increase their chance of success in obtaining traditional research grants (59,60,62).
“Clinical trials are expensive, so getting that amount in a crowdfunding effort is close to impossible.” (Interview H)
Furthermore, research that receives the most funds via crowdfunding may not always address the highest unmet medical needs. A US-based survey showed that researchers working on therapies for rare and/or age-related diseases will have more difficulty to reach their financial goal in crowdfunding campaigns than others (63). Two interviewees pointed out that research into rare diseases is at a disadvantage in crowdfunding campaigns because fewer people have an emotional connection to such diseases.
“Because conditions are rare, there isn’t a huge public understanding of many of the conditions and probably not a huge public understanding of what is needed to deliver research either, so I think that makes it a challenging route and certainly not sustainable route.” (Interview E)
Additional ethical concerns of crowdfunded research, which were not mentioned by the interviewees, include a lack of control over the quality, scientific integrity and feasibility of crowdfunded research (54,56,58,61).
Mechanisms with a direct financial return
Public-Private partnerships
A public-private partnership (PPP) is a collaboration between at least one public partner and one private partner with a common goal, for example improving health outcomes. PPPs are no longer a new concept in the healthcare sector and have been established to serve many different purposes (64,65). Some PPPs tackle specific precompetitive issues, while others focus more on development or access to medicines. The structure of each PPP may vary depending on the involved stakeholders, such as the pharmaceutical industry, academia, government, not-for-profit organisations, hospitals, research and patient organisations (Figure 1). Multi-stakeholder PPPs allow synergies and sharing of knowledge, expertise and resources between all partners. A PPP can be seen as a win-win model that aims to reduce development costs, to increase the scale and scope of the research, and to share the financial risks of drug development between all partners (30). Consequently, PPPs have been proposed as a potential model to facilitate and fund drug repurposing research (66,67).
Indeed, various PPPs have been established between academic researchers, public funders and the pharmaceutical industry to support drug repurposing research, but most are situated in the precompetitive space and focus on the repurposing of shelved compounds. Examples include the UK Medical Research Council (MRC) Mechanisms for Human Diseases Initiative, the US National Center for Advancing Translational Sciences (NCATS) Discovering New Therapeutic Uses for Existing Molecules initiative, the US Clinical and Translational Science Awards (CTSA) Pharmaceutical assets Portal and the EU Innovative Medicines Initiative (IMI) pilot programme on a clinical compound bank for repurposing (4,68). In the product development area, there is one US-based PPP between the Therapeutics for Rare and Neglected Diseases program of the US National Institutes of Health (US NIH) Chemical Genomics Center, The Leukemia & Lymphoma Society, and University of Kansas Cancer Center, which is called The Learning Collaborative. This partnership repurposed auranofin, an off-patent medicine initially approved to treat rheumatoid arthritis in the mid-1980s, for the treatment for relapsed chronic lymphocytic leukaemia (69). Moreover, the UK-based aPODD foundation is open to supporting partnerships in drug repurposing projects for paediatric oncology indications (70) and the Dutch Fair Medicine foundation proposes a coalition model between patient associations, hospitals, researchers, health insurers, large and small investors and pharmaceutical developers to develop sustainable and affordable medicines, including repurposed medicines (39).
Despite the many potential benefits of PPPs, interviewees argued that they do not offer a sustainable solution for off-patent drug repurposing due to the lack of incentives for the private partners. Social corporate responsibility was mentioned as a potential reason for companies to participate in such a PPP but this was not deemed as sufficiently motivating, unless in areas where the competitive pressure is low, for example for finding new treatment options for neglected diseases in low- and middle income countries (LMICs) (11). The Drugs for Neglected Diseases initiative (DNDi) and the Medicines for Malaria Venture (MMV), both well-established global PPPs, already included several rescued and repurposed medicines in their research portfolios (30,71,72).
Social Impact Bonds or pay-for-success models
A social impact bond (SIB) is an innovative model that leverages private investments to develop public health services or interventions. A SIB, also referred to as pay-for-success financing, is a formal agreement between an outcome payer (typically a government, payer or private insurance company) and a service provider (in this case a not-for-profit or research organisation seeking funding to conduct one or more clinical trial), where the outcome payer specifies a desired outcome and guarantees to pay back the investors their upfront investments plus a return if this outcome is reached (Box 2, Figure 1). So far, SIBs have predominantly been applied to fund preventive health measures that could result in significant long-term health care savings (73,74). The UK-based organisation Findacure started exploring a SIB model to incentivize investment into drug repurposing clinical trials in rare diseases, in collaboration with various organisations including CuresWithinReach, Mission:Cure, Numbers4Good and Costello Medical (37,39,74–76). More specifically, the goal of this Rare Disease Drug Repurposing SIB is to create a portfolio of up to ten phase II efficacy clinical trials that, if successful, could lead to off-label prescription of affordable repurposed medicines for patients with rare diseases who currently have no treatment. The improved outcomes and reduced care needs of those patients would then result in significant savings for healthcare systems and a proportion of these savings would subsequently be paid back by the outcome payer (in this example, the UK National Health Service) to the investors as a success payment (16). Recently, the US-based think tank Helena and its partners proposed a similar financial model to fund generic drug repurposing for Alzheimer’s disease (77).
A SIB concept is a win-win-win model that, if successful, improves health outcomes, reduces healthcare spending and realizes economic return (78). Additionally, SIBs enable a shift in financial risk from governments to investors compared to the grant funding model, attract new sources of capital to scale up health programs and research, and stimulate not-for-profit organisations and researchers to focus on productivity and outcomes (73). SIBs could also be scaled-up to an international level to share the risks among more investors and distribute the pay-outs between outcome payers (75). SIBs are a relatively new way to fund health programs, so evidence with regard to their efficacy to support clinical research with off-patent and generic medicines is limited. Accordingly, only few interviewees had experience with SIBs, although everyone was open to the idea and recognized their potential value for off-patent drug repurposing.
Still, several difficulties and potential drawbacks of SIBs have been reported in literature (79), some of which were confirmed by interviewees in this study. First, not every not-for-profit program is fit for a SIB. SIBs need easily quantifiable outcomes that can be achieved in a limited time period and lead to clear government savings (79). Interviewees voiced some concerns about the identification of robust clinical outcome measures to demonstrate social impact and cost savings of a new treatment, and about the long duration and low success rates of most clinical trials.
“There is actually a big risk to those organisations [service providers] in getting involved if they haven’t set up the measure of success well or they’ve been over ambitious in what they’re saying they can achieve and don’t deliver. They won’t receive the returns they need to pay their costs.” (Interview E)
Besides, establishing a SIB requires a long-term vision and the political will of governments, payers and/or insurance companies to guarantee success payments for projects that will only pay off in a couple of years (16,80). Interviewees who had experience with SIBs confirmed the difficulty of securing commitment and resources from governments, especially in multi-level governance and multi-payer systems.
“It will not be a problem to find private investments. […] I think the bottleneck is in the public funds.” (Interview D)
BOX 2 | IMPACT INVESTING: BASIC PRINCIPLES
Currently, about 441 million dollars have been raised for 138 Social Impact Bonds (SIBs) worldwide (108). The use of the term “bond”, which refers to a fixed income instrument in finance circles, is somewhat misleading because the investors’ return in a SIB is dependent on the success of achieving predefined outcomes (109). In fact, a SIB is more similar to a public-private partnership between private or impact investors, a service provider and an outcome payer (Figure 1) (110). Most SIBs include an intermediary to convene all stakeholders and provide legal, financial and structural support. An independent evaluator typically measures the outcomes, which are key to determine the cost savings, success payments and social impact of a project. For a SIB to be successful, outcomes should be quantifiable and should lead to clear societal and government savings.
The SIB model should not be confused with another upcoming finance model, which is called “venture philanthropy”. The venture philanthropy model is based on a partnership between a charity and a drug company and provides a mechanism for not-for-profit organisations to help finance the development of a treatment in return for a share in profits, which can later be reinvested in other new treatments (39). For example, the Cystic Fibrosis Foundation invested US$150 million in Vertex Pharmaceuticals for the development of ivacaftor, and had a return of US$3.3 billion in exchange for its royalty interests (111). Even though this model may lead to promising new treatments, ethical questions have been raised about the sustainability of a model that maximizes profits using philanthropic funds (112).
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Finally, statistical, legal and contracting expertise is required for establishing a SIB, and the transaction costs and organisational burden are high. Therefore, sufficient start-up funding is needed. One interviewee was of the opinion that governments should provide administrative, legal and financial support for setting up SIBs that aim to achieve better social and health outcomes. If SIBs were to become more common, transaction costs would automatically decrease as a result of the standardization of legal forms and contracts.
“I think given that charities and third sector organisations are generally those organisations that are going to deliver these interventions, they don’t have a huge amount of disposable income to put all of that work and infrastructure in place.” (Interview E)
Overall, interviewees believed that the potential benefits of SIBs outweigh their costs and risks, and that their application potential at a national and international level warrants further exploration.
FIGURE 1. OVERVIEW OF MECHANISMS TO FUND CLINICAL DRUG REPURPOSING RESEARCH
Abbreviations: Social Impact Bond (SIB); Return-On-Investment (ROI)
Improving efficiency of independent clinical research
Interviewees highlighted that, in addition to exploring new funding mechanisms, independent clinical research should become more efficient. Even though parallelism in research may increase productivity to some extent, there is a lot of fragmentation and duplication of research efforts. Moreover, independent clinical trials are often not sufficiently powered to show evidence of clinical efficacy, probably also due to the limited funds and less organisational support compared to industry-sponsored trials.
“I am not saying that it’s always the case, but it is a personal opinion that there is probably too much fragmentation to be very efficient.” (Interview N)
Increased national and international cooperation and consortium-building between research groups and foundations could be key to address this problem (38,81). Furthermore, interviewees mentioned that funding efforts to support clinical research, such as grant-funding programs and SIBs, should be organised at a European or international level to become more feasible and efficient.
“You have to organise [research funding] on an international level to reach critical mass, that is just a given.” (Interview K)
Yet, harmonisation and centralisation of independent clinical research on a European level would require the establishment of one or more coordinating centres or, as suggested by one of the interviewees, a multi-stakeholder review board or steering committee overviewing independent clinical trials in Europe. The European Organisation for Research and Treatment of Cancer (EORTC) was put forward several times as an ideal candidate to fulfil such a role within cancer research.
“We see a third partner to guide the process and to make sure that it is useful, that it is done in a correct way and that you can also make connections with European funds or with other research institutes in other countries.” (Interview N)
RCTs are still the golden standard for determining the efficacy of a medicine in a new therapeutic indication but they entail high costs, a long duration and a substantial administrative burden (82). Interviewees mentioned the potential of optimizing clinical trial designs and methodology for drug repurposing research. Various cost-effective and robust study designs have been proposed in scientific literature to replace or at least complement traditional RCTs, such as multi-arm/multi-stage or platform trials (83–85), registry-based RCTs (86,87), N-of-1 trials for rare diseases (88), and crowdsourcing studies of real-world patient data (15,89).
“What is important to us to consider first, is an optimization of the methodology of the trial to be able to use other designs, other methodology, other technology that can limit the need for financing or the costs, if I may say, for the trial.” (Interview N)