Self-funding of clinical trials by participants started in the 1980s in the United States (Table 1). Another quite relevant problem is that participant-funded trials are included in registers such as ClinicalTrials.gov (a public register of the National Institutes of Health of the United States), providing potential patients free access to information about studies that may not always be of good quality.10

Stem cell therapies are particularly “appealing” for performance of self-funded trials, as there are countries (such as the United States) where regulation of this type of trial is less stringent compared to trials of other forms of treatment that are more tightly regulated. This, however, is not the case in Spain (or the European Union), where clinical trials using advanced therapies (such as stem cell therapies) are subject to the same regulation as trials of any other drug with additional safeguards.11,12

Although self-funding of clinical trials has existed for a while, the use of crowdfunding for this purpose is a relatively recent phenomenon.13 As we will discuss at a later point, funding of clinical trials through crowdfunding can take different forms, including fundraising based exclusively on altruistic donations by many different people or a mixed system in which altruistic donations are combined with significant contributions from patients interested in participating.

There are 3 recognised types of patient-funded access to experimental drugs: pay to try, pay to play/participate, and the plutocratic proposal. An important aspect to consider is that these models are feasible in the early phases of drug development (phases 1 and 2a—the latter known as the proof of concept phase), when donors are guaranteed treatment with the experimental drug. It is very unlikely that patients would pay to participate in trials where they may be assigned to placebo. The 3 models are based on the individual freedom, based on the autonomy of the patient, to engage in free trade, assuming that this exchange is voluntary and the patient is well informed: the patient gains access to the experimental drug and the researcher to funding that makes research possible.14 All of this is particularly relevant to patients with ultra-rare diseases (defined in Europe as those with a prevalence < 1 per 50 000 inhabitants11) in which the development of treatments is often hindered by lack of funding.

In this modality, the patient pays for access to the experimental drug under compassionate use conditions. Thus, this does not fit the customary definition of clinical trial, although in the case of Mila, the girl with a variant of Batten disease, the researchers defined it from a methodological perspective as a trial with n = 1.3 In this modality, the treatment is usually given to a single or very few patients, so that participants have to pay considerable sums.14 Since these are not considered clinical trials in the United States, the treatment protocol does not need to be approved by a research ethics committee, as occurred in Mila’s case, in which approval was given by the president of the ethics committee of the particular hospital.3

In this modality, each participant in the trial pays a certain amount of money, usually large. Table 2 summarises the positive and negative aspects of this model. There are some that consider that pay-to-play clinical trials are of little scientific quality, with some of the drawbacks including selection bias and the challenge of interpreting the results in the absence of a control group, and also ethically questionable, mainly as regards their value to society and fair selection of participants.7,15 In fact, there are those that call for banning this model of patient-funded clinical trial.15 One factor that promotes this attitude is that clinical trials are carried out in the United States that would not be allowed in the European Union. Thus, for example, stem cell trials in private clinics without public funding or the intent to obtain authorization to market the drug from the FDA do not require approval by a research ethics committee9 (a scenario that would not be allowed in Europe). In the United States, there are corporate research ethics committees (which do not exist in Europe) that have approved trials of variable rigour.10 That said, if all scientific and ethical standards are met, as would be the case if the study protocol adhered to European regulations on clinical trials, there is no reason to ban pay-to-play patient-funded trials.14,16,17

The plutocratic proposal model21 can resolve most of the problems of the payment for participation model. However, it has had minimal reach, possibly because only a short time has passed since the model was first proposed in 2017 and because its implementation is very complex.

In the plutocratic proposal, the donor is offered the possibility—although not a guarantee—of participating in a clinical trial, a possibility that can be transferred to a third party (a relative, friend or total stranger); furthermore, eventual participation would take place 2 or 3 years after donation of funds, or possibly even later, for instance, if vectors for gene therapy need to be developed. These two characteristics differentiate the plutocratic proposal from the two previous models, which guaranteed access to the experimental drug within a short time frame to the donor. Correct implementation of this model requires the cooperation of an external “matching agency” serving as the intermediary between the patient/donor and the researchers and ensuring that the trial process that follows is ethical, scientifically useful and financially secure.21Table 3 presents the main characteristics of this model. In addition to repurposing or repositioning of known drugs, it can be used for development of gene replacement, molecular or gene editing therapies that presumably would require administration of a single or few doses.

Table 4 presents the 3 basic ethical principles that must be fulfilled in research in humans22 and the extent to which the pay to play and plutocratic proposal models adhere to these principles.

To this point, we have addressed the first 3 questions we formulated at the beginning of the article. We now have to answer the fourth: is crowdfunding a valid alternative that does not interfere with the system currently established for the development of new medicines?

Crowdfunding for medical research projects has mainly focused on cancer and rare diseases, including basic research and genomic, preclinical and clinical trials, using online platforms for fundraising.23,24 These platforms are usually from the United States, but some now have an international scope, such as GoFundMe (the largest in the world), which operates in 20 countries, including Spain since 2017, in which health care-related campaigns are most common and bring in the most money in every country.25 Most of these platforms are run by for-profit organizations, which usually charge a 5% commission and a little over 3% in additional transaction fees per donation. As these platforms have no control over who runs the campaigns or their objectives, they raise a variety of concerns. The biggest (and sometimes most striking) problem with medical campaigns is fraud: raising funds for inefficacious treatments that are potentially harmful.26,27

A recent study identified the 16 platforms in the United States, 5 in Europe (one of them in Spain: Funds4Research) and 1 in Australia exclusively dedicated to health care crowdfunding.28 In addition, as concerns Spain, when it comes to general scientific crowdfunding, we ought to mention Precipita, the public platform of the Fundación Española para la Ciencia y la Tecnología (Spanish Foundation for Science and Technology, FECYT). For example, the researchers of the Lagenbio group of the Universidad de Zaragoza are using Precipita to raise funds to research the potential effect of 5-fluorouracil for treatment of amyotrophic lateral sclerosis.29 There are also several initiatives of national scope (such as Stop-FA, for research of Friedreich ataxia30) or integrated in international frameworks (such as Apoyodravet, which operates within the International Research Network on Dravet Syndrome and Refractory Epilepsy31) that make possible a variety of scientific projects. The success of raising funds through donations received through crowdfunding campaigns depends to a great extent on the researchers having extensive personal or professional contacts and participation in social media: each tweet or retweet increases the success of the campaign by 1 percentage point.32

An analysis of 13 crowdfunding campaigns for clinical trials found that 8 raised the target amounts, 5 of the 8 were for pilot studies or phase 1 trials; most successful campaigns had mixed funding, that is, funding from sources in addition to crowdfunding.33Table 5 summarises the benefits and risks of crowdfunding in health care research. Table 6 presents some interesting data on crowdfunding campaigns in biomedicine.

It must be taken into account that crowdfunding introduces new market norms in countries with well-established public health systems that may alter the traditional perception of healthcare of the population.34 However, it is highly unlikely that crowdfunding for clinical trials will ever unsettle the existing system of drug development. The reason is that the number of trials for treatments of ultra-rare diseases that could be launched through this funding model is very small. Such trials would amount to a negligible percentage of the nearly 4000 clinical trials that are authorised each year in Europe, of which 61% (about 2450 a year) are sponsored by the pharmaceutical industry and the remaining 39% (about 1550 a year) by non-industry sponsors, mainly academia.39 In Spain, the Agencia Española de Medicamentos y Productos Sanitarios (Spanish Agency of Medicines and Medical Devices, AEMPS) authorises approximately 800 clinical trials each year, of which 78% (about 625 a year) are sponsored by industry and the other 22% (about 165 a year) by researchers and not-for-profit organziations.40 From a different perspective, in February 2020, based on the Spanish Register of Clinical Trials of the AEMPS, there were 379 clinical trials of treatments for rare diseases in the patient recruitment period, while 110 had received approval and had yet to start. The addition in Spain of 1 or 2 trials per year funded by patients through crowdfunding would not create a disturbance in this system.

It is well known that the mass media (press, radio, television) play a key role in the success of some crowdfunding campaigns, especially if a famous figure or celebrity is involved. Furthermore, the use of social media (such as Twitter or Facebook) is very important for the purpose of attracting an audience with an interest in the project and to sustain this interest.32

Murdoch et al. analysed how these crowdfunding campaigns are represented in the press (Table 7).41 A striking aspect that is consistent with the coverage of other subjects related to science is that the press, unlike academic publications, rarely brings up the potential drawbacks of crowdfunding. This may generate a favourable perception of crowdfunding in society and legitimise it as a source of funding for health care,41 as reflected by the nearly 7.5 million dollars raised by campaigns to fund therapies against cancer of highly questionable nature through 2 platforms in 16 countries and 4 continents.26

Self-funding of clinical trials by participants suffering from specific ultra-rare diseases is an avenue that opened years ago and that is likely to grow in the near future. Nothing is ethically questionable in patients themselves—or their parents, relatives or friends—funding their participation in trials, and therefore there is no reason to ban trials funded by this method as long as they meet the requisite standards that apply to any clinical trial.14,16,17 Most of the problems that have been identified, especially those concerning a lack of scientific and social value, can be avoided by applying current Spanish regulation on clinical trials: all patient-funded trials must be approved by the competent research ethics committee and the AEMPS.12 Patient funding of clinical trials may be particularly useful for repositioning of already known treatments or even repurposing of drugs already marketed for other indications.42

Of the 3 models of patient funding (pay to try, pay to play and the plutocratic proposal), the plutocratic proposal seems to be most appropriate for early investigation of new orphan drugs. Although this new option is perceived positively,43 to our knowledge it has not been introduced in any country. The need for a “matching agency” (which has the most significant role in this model and is the main innovation in it) may be the most complicated aspect that is hindering its implementation. This matching agency should be a not-for-profit organization run by a committee including, at minimum, basic scientists, clinicians, patients, lawyers and financial experts. In Spain, the Federación Española de Enfermedades Raras (Spanish Federation of Rare Diseases, FEDER) could become the matching agency or integrate within its structure an organization that could fit this role, although this would require amending the statutes of said organization. The CIBERER, or networking centres for research of rare diseases of the Instituto de Salud Carlos III, could offer scientific consultation, and the AEMPS should be involved in the evaluation of projects from an early stage in a regulatory role. Thus, FEDER is ideally positioned to be the key intermediary in projects concerning orphan drugs requiring self-funding by participants and to collaborate with associations of patients with rare diseases or their families that seek to start clinical trials with funding to be raised by them through different means.

Self-funding of clinical trials by participants—stemming from a lack of public or private funding—may in most cases require resorting to crowdfunding. The use of crowdfunding in biomedical research is controversial,33,44 although in and of itself this approach does not entail ethical conflicts and provides a way for society to support those affected by a rare disease. There are those that consider that this is not the best way to address the deficiencies of health care systems.32 However, this does not mean that crowdfunding could not play a role in the early phases of development of certain orphan drugs, as crowdfunding campaigns are frequently successful33 and, in principle, would have a negligible impact on the currently established system for drug development.

As our knowledge of the genetic basis of many ultra-rare diseases is advancing at an unstoppable pace, Spain (and the European Union) should have an administrative procedure in place to allow the AEMPS to streamline authorization of trials of new experimental drugs under the condition of compassionate use. For this to be possible, the two provisions that we mentioned at the beginning of the article (for the drug to be currently in clinical trials or an application for marketing authorization to have been filed) in current regulation5 should be expanded with a third provision allowing the initial administration of an experimental drug to a first patient, and possibly a few others, exempting researchers from having to file all the documentation normally required for performance of a clinical trial. The clinical situation of patients affected by ultra-rare diseases, which, by definition, are chronic or severely disabling and possibly even life-threatening, requires that regulations adapt to scientific advances so that delivery of potentially beneficial treatments is not delayed. This is even more so in the case of the adaptation proposed here, which would apply to the development of orphan drugs indicated for treatment of the very few patients affected by diseases with extremely low prevalence that, due to lack of public or private funding, would have to be financed through crowdfunding, a factor adding to the delay in their development and subsequent administration.

This work did not require any funding.

The authors have no conflicts of interest to declare.