Over-volunteering in Phase I clinical trials: data from a healthy volunteers’ registry in Japan

Hiroyuki Fukase¹, François Bompart², François Hirsch², Yuji Kumagai³*

1. Clinical Research Hospital Tokyo, Tokyo, Japan
2. Inserm Ethics Committee, Paris, France.
3. Kitasato University Kitasato Institute Hospital, Tokyo, Japan

[email protected]

OPEN ACCESS

PUBLISHED 28 February 2026

CITATION Fukase, H., Bompart, F., et al., 2026. Over-volunteering in Phase I clinical trials: data from a healthy volunteers’ registry in Japan. Medical Research Archives, [online] 14(2). https://doi.org/10.18103/mra.v14i2.7231

COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI https://doi.org/10.18103/mra.v14i2.7231

ISSN 2375-1924

ABSTRACT

Background. Over-volunteering refers to situations where healthy human volunteers (HVs) participating to clinical trials do not respect exclusion periods between trials, usually to maximize financial gains. By doing so, HVs expose themselves to potential safety risks and may compromize the trials’ data integrity. The extent of this phenomenon is poorly documented in the scientific litterature.

Objectives. We sought to estimate the rate of over-volunteering based on trial enrollment data collected since 1995 by the Japan Association of Contract Institutes for clinical Pharmacology (JACiC). We also sought to review key issues related to over-volunteering and to reflect about effective systems that could address this phenomenon around the world.

Methods. Our study is based on yearly data on trial enrollment between 2004 and 2023 at participating Clinical Research Units (CRUs) published on the website of the JACiC. We focus on the number of over-volunteering attempts detected by JACiC’s Subject Matching System in healthy volunteers studies as data reflecting the reality of over-volunteering in Japan. We examine the Over-Volunteering Prevention Service (TOPS) in the UK as another example of functioning registries.

Results. Out of a total of more than 860,000 HVs screened for participation in approximately 20 Phase I research units for 20 years, we found rates of over-volunteering sustained at relatively constant levels around 2 to 3% every year, including during the COVID-19 pandemic 2019 to 2021 period. This stable rate of over-volunteering attempts contrasts with the data from a single research site in the UK where the TOPS system was implemented and progressively decreasing over-volunteering rates were observed over time.

Conclusions. The JACiC data published here are the first to provide objective evidence on its frequency through over 20 years of data collection in Japan and show the significant and stable occurrence of this phenomenon. To assess between-country differences in over-volunteering rates, collection and publication of similar data from other countries, including from privately-operated registries, would be very valuable. Finally, consideration should be given to the implementation of compulsory HV registries on a national or multinational basis as the best way to prevent over-volunteering and its detrimental effects on HVs safety and on scientific data integrity.

Keywords

Phase I clinical trials, healthy volunteers, over-volunteering, VOLRETHICS, national registries.

1. Introduction

The involvement of healthy human volunteers (HVs) in Phase I clinical trials, including first-in-human administrations of investigational drugs, is well known. However, HVs are also involved in many other types of clinical trials such as pharmacokinetic studies of approved pharmaceuticals such as bioavailability and bioequivalence studies for the development of generic formulations. They are also increasingly involved in the development of new drug modalities such as monoclonal antibodies and nucleic acid drugs, anti-cancer drugs such as immunomodulators and molecularly targeted drugs with better safety profiles than chemotherapy drugs. Protecting HVs from adverse events is of utmost importance as their benefit/risk balance differs markedly from that of patients involved in research. The term “over-volunteering” is used to describe situations where HVs do not respect exclusion (or “wash-out”) periods between trials to maximize financial gains. By over-volunteering, HVs may compromise their health and well-being but also the integrity of the study data. This phenomenon is very poorly documented in the scientific literature. We report here data from the Japan Association of Contract Institutes for clinical Pharmacology (JACiC)’s Subject Matching System: involving more than 860,000 HVs screened for participation in approximately 20 Phase I research units in Japan over 20 years. This article aims at reviewing key issues related to healthy volunteers’ over-participation in clinical trials and to reflect about effective systems that could address this phenomenon around the world. Although our focus is solely on JACiC’s data, implications of our findings extend beyond these borders, impacting future directions in mitigating risks surrounding participants and ensuring scientific data integrity in clinical trials.

2. Objectives of Clinical Trials involving Healthy Volunteers

The involvement of healthy volunteers (HVs) in first-in-human Phase I clinical trials of investigational drugs is well recognized. This strategy potentially allows for early clinical characterization of pharmacokinetic parameters and clinical safety profiles in the absence of confounding factors such as comorbidities and concomitant medications. In addition, it may be possible to eliminate site-to-site procedural variability since Phase I trials with HVs can often be completed at a single site. The primary objectives of Phase I clinical trials are to investigate the pharmacokinetics and pharmacodynamics of new drug candidates, determine appropriate dosing, and confirm safety and tolerability. However, healthy volunteers are involved in many clinical development steps beyond actual Phase I trials and the term “Phase I” has implicitly evolved to refer to all trials involving healthy research participants as opposed to patients. It is not possible to have a clear view of the number and types of studies involving HVs around the world, but is has been estimated that around 90% of trials involving HVs are not “first-in-man” administrations of novel compounds, but rather bioavailability, bioequivalence and other clinical pharmacology studies to evaluate pharmacokinetics, drug metabolism, food effects, potential drug-drug interactions, the effects of hepatic and renal dysfunction, and other pharmacological parameters essential for the development of pharmaceutical products and pharmacogenetic considerations.

In recent years, not only conventional small molecule drugs but also new drug modalities such as monoclonal antibodies and nucleic acid drugs have been studied in phase I clinical trials in healthy volunteers. Furthermore, recent scientific advances in cancer research have led to the development of immunomodulatory drugs and molecularly targeted drugs with superior safety profiles compared to chemotherapy drugs, making it possible to enroll healthy volunteers (HVs) in clinical trials. The safety risks to HVs in early-phase trials are now becoming increasingly diverse due to the diversity of drugs being tested and the resulting complexity of trial designs.

3. Healthy Volunteers as Participants in Clinical Trials

Healthy volunteers are, by definition, healthy people with no known medical conditions relevant to the purpose of the study. They are also defined as individuals who understand the study key features and can voluntarily consent to participate. Unlike patients with relevant diseases who participate in clinical trials, healthy volunteers in the majority of studies cannot expect to receive any direct medical benefit from the treatment being tested. HVs typically spend days to weeks at a residential research facility, allowing for extensive pharmacokinetic sampling plans and more in-depth safety monitoring and management of clinical pharmacology trials requiring crossover designs and long washout periods can be very challenging for patients, but are standard in HVs. Likewise, constraints are imposed on HVs during clinical trials, such as dietary and exercise limitations, isolation from friends and family, multiple safety checks, biological samples collections, site visits, etc. These constraints are implemented to ensure the safety of the HVs and the quality of the study data but it is important to realise that they may have consequences on the well-being of HVs, in ways that are very different from that of patients who participate to research. Overall, healthy volunteers who participate in biomedical research are exposed to a variety of risks different from those of patients, including risks to their rights, their own health and well-being, as well as risks of exploitation based on their economic status, education level, and motivations.

4. Over-volunteering

The term over-volunteering has been coined to describe situations where, to maximize payments, some volunteers participate in multiple studies simultaneously or without observing the required washout period between them. As a rule, information and informed consent documents specifically state washout periods among trial exclusion criteria. Some HVs deliberately ignore this issue when they attempt to over-volunteer, while other may misunderstand instructions about intervals between trials or overestimate the interval since their last trial. By doing so, they expose themselves to safety risks because of potential drug-drug interactions but also jeopardize the scientific integrity of the collected study data. Over-volunteering is a concealed phenomenon and therefore extremely difficult to assess. To our knowledge, only one scientific paper reports attempts at quantitatively documenting this issue. That is the 2012 paper by Boyce et al. which reports on the early days’ experience of the UK over-volunteering prevention system (TOPS) that is further described in this paper. Boyce at al report data from one of the participating sites on the number of detected over-volunteering attempts in the period 1997–2011. Every year, between 767 and 1811 HVs were screened for participation. In the first 2 years after TOPS started being used (2002), potential over-volunteering rates increased from about 1% to a peak of 4.6%. There was a progressive fall in the following years, and in the last few years the reported incidence was less than 1%, presumably as HVs became increasingly aware of the existence of TOPS. As the authors state “TOPS not only helps to prevent overvolunteering, but also deters subjects from trying to do so”. Overall, though, over-volunteering in HVs is a poorly documented issue in the scientific literature.

5. Over-volunteering data from the JACiC

In 1991 a “Subject Verification System” operated by the Japan Association of Contract Institutes for clinical Pharmacology (JACiC) was set up to detect potential over-participation of human research participants. It started being used by 13 clinical research units (CRUs) and is currently used on a voluntary basis by nearly 30 of the public and private CRUs that are members of JACiC. These represent a large majority of the CRUs in Japan, but do not include units dedicated to bioequivalence studies for generic drugs. Some medical institutions and clinical trial sponsors do not use the JACiC database, primarily because its usage requires payment of a yearly fee. The system collects only basic data on potential healthy research participants: name, date of birth, last administration date of the study drug, last observation date, and acceptable date of next participation. Data are not anonymized, but personal data are automatically erased after 2 years. The system can be used by accredited users only.

Year	Volunteers screened	Volunteers enrolled	Detected over-volunteering attempts (% of volunteers screened)
2004	34,460	8,322	1,354 (3.92%)
2005	35,946	7,389	1,107 (3.07%)
2006	41,567	9,466	1,350 (3.24%)
2007	42,283	8,955	1,326 (3.13%)
2008	39,564	9,035	1,038 (2.62%)
2009	38,543	9,237	989 (2.56%)
2010	46,124	12,544	1,030 (2.23%)
2011	48,775	12,436	840 (1.72%)
2012	54,847	14,897	1,380 (2.51%)
2013	58,095	15,972	1,123 (1.93%)
2014	48,858	13,917	1,096 (2.24%)
2015	59,178	17,113	1,369 (2.31%)
2016	47,058	11,943	1,754 (3.72%)
2017	42,094	11,916	743 (1.76%)
2018	40,738	11,538	933 (2.29%)
2019	36,653	9,037	928 (2.53%)
2020	43,034	11,035	1,180 (2.74%)
2021	38,441	11,284	1,042 (2.71%)
2022	30,462	8,107	909 (2.98%)
2023	39,814	10,928	894 (2.24%)
Total	866,534	225,071	22,385 (2.58%)

Data are available from JACiC’s homepage.

It is interesting to notice that over the 20 years reported here, including the COVID-19 pandemic 2019 to 2021 period, the number of screened subjects remained overall stable, as well as rates of over-volunteering, at around 2 to 3% every year. This stable rate of over-volunteering attempts contrasts with the experience of Boyle et al, where awareness of the registry seems to have played a role in progressively decreasing over-volunteering rates over time. This difference might be due to the fact that data from the UK concerned a single research site where potential HVs became increasingly aware of the implementation of the TOPS system, whereas the JACiC system is less widely known from Japanese HVs.

6. Risk Assessment in Clinical Trials

The ethical guidelines for clinical research established in the Declaration of Helsinki state that “Medical research involving human participants may only be conducted if the objective outweighs the risks and burdens to the research participants” (WMA, 2024). Research involving human subjects must be carried out in ways that minimize risks, or at least ensure that all adverse effects are known and predictable, with clear knowledge of how to manage them. Therefore, on a case-by-case basis, researchers must identify and minimize the risks posed by the trial and its research interventions, and determine whether they are justified by the potential benefits of the research. It goes without saying that safety of human participants is the first priority in all cases.

The risk identification process involves two axes of evaluation:

1. What is the likelihood that participation will pose a risk, and what measures are being taken to minimize such risks?
2. What is the magnitude of the anticipated risks of participation, and are they justifiable or avoidable?

Researchers must take all steps to address identified risks. Strictly defined exclusion criteria must be used to eliminate candidates who may be at increased risk. An important feature of actual Phase I clinical trials is that they are designed to detect early safety signals. As detailed by Jill Fisher, specific ethical issues arise from the fact that healthy study participants are deliberately exposed to increasing doses of pharmaceuticals to enable detection of safety issues that would be more complex, longer and more expensive to assess in patients.

7. Healthy Volunteers’ Understanding of Risk

Participants in Phase I healthy volunteer trials are financially compensated for their time and for the study constraints. As explained later, precautions must be taken for financial compensation not to become an undue inducement for trial participation. Nevertheless, there is no doubt that the perspective of financial gains may affect the HVs’ assessment of the risks they are exposed to in participating in a trial. These characteristics of Phase I HV trials create a research environment that is significantly different from clinical studies in patients who only get limited compensation for the expenses they may incur because of the research, exposing to the risk of enrollment of a disproportionate ratio of economically disadvantaged participants among HVs. It has been reported that HVs often perceive the overall risk of Phase I trials differently from their own personal risk of harm. Although the majority of participants view Phase I trials as carrying some level of risk, most hold contradictory views that they will not be personally harmed. A US study on the perception of risks by HVs concluded that the most structurally disadvantaged HVs can come to feel not exploited or endangered but grateful for the economic opportunity to participate in clinical trials.

8. Monetary Rewards As the Primary Motivator for Volunteers to Participate in Clinical Trials

Systematic studies examining volunteer motivation have revealed that monetary rewards are not the only, but consistently the primary motivator for HVs to participate in clinical trials. Monetary rewards as compensation for study constraints may undermine HVs’ ability to freely participate in research and may jeopardize the principle of autonomy, one of the fundamental principles of bioethics. In resource-limited settings, HVs are often poor and illiterate, do not understand the risks they may be taking, and are in no position to refuse financial incentives. For many of them, clinical trial participation is an important source of income. Economically disadvantaged groups tend to participate in more clinical trials and stay longer than more advantaged groups. This may lead them to secretly participate in multiple studies simultaneously to increase their income. Many repeat volunteers have become adept at manipulating screening tests for clinical trial participation by developing tactics to conceal their simultaneous participation in multiple studies, medical conditions, concomitant medications, or substance abuse. Such concealment not only exposes volunteers to medical risks (e.g., drug interactions), but also potentially biases study data, including the safety and pharmacokinetic profiles of the drugs being tested.

9. Risk of Undue Inducement

A delicate balance exists between fair financial compensation and undue financial inducement. Subjects, particularly those in Phase I trials whose health will not directly benefit from the study, routinely receive financial compensation for study-related constraints and dedicated time. However, if the amount paid is too high, it may induce potential subjects to participate in the study against their own judgment. All precautions must be taken to minimize safety risks and higher potential risks cannot equate higher rewards. Compensation amounts must only be based on the constraints that the study imposes on HVs. Researchers and research ethics committees should carefully consider regulatory guidelines regarding appropriate compensation for research participation without jeopardizing volunteers’ autonomy and ability to make the right choices. In some but not all countries, research ethics committees may refer to guidelines regarding appropriate payments for various studies and procedures and are asked to ensure that payments do not exert undue influence. In particular, excessive compensation that may encourage HVs in phase 1 trials to conceal information that would disqualify them from participating in the study.

10. Healthy Volunteers Registries

Two pillars of ethical and safe participation of HVs in clinical trials are the collection of a properly obtained informed consent and steps to minimize exposure to risks, including avoiding concealed participation in multiple trials. Obtaining valid consent is crucial to respecting HVs’ autonomy, as it gives them the opportunity to choose to participate in research and voluntarily accept the potential associated risks. It is the researcher’s responsibility to ensure that informed consent documents and procedures contain effective elements that ensure volunteers are making an informed choice about participating in the research. These elements must include information on the exclusion period to be respected between consecutive trials. However, as explained above, HVs may not always respect or understand this requirement and expose themselves to the risks related to over-volunteering. To address these risks, 3 countries to date have set up compulsory HVs registries: France since 1988, the UK since 2013 and Malaysia since 2021.

A recent article has reviewed the key features of each of these registries. As an example of functioning registries, the UK has set up a national participant database called The Over-Volunteering Prevention Service (TOPS). This system is managed and administered by the MHRA (Medicines & Healthcare products Regulatory Agency). Currently, to receive REC (UK Research Ethics Committees) approval, trials involving healthy participants must enroll participants in TOPS. Organisations must maintain a comprehensive list of all participants who have taken part in clinical trials, which will enable them to identify when any UK research center last dosed a participant. Procedures for managing databases comply with the latest data protection regulations. Any decision to use medical records or TOPS must be documented (e.g., as part of a risk assessment). TOPS is internet-based, simple, quick to use, and free to users. As mentioned earlier, an early version of TOPS used at a single facility was reported to have reduced the rate of subjects volunteering within three months of completing another study elsewhere to less than 1%. WHO officials in charge of the International Clinical Trials Registry Platform (ICTRP) have expressed willingness to provide assistance to countries for setting up their own HV registry.

Except for France, the UK, and Malaysia, other countries lack a central system to detect and prevent over-volunteering. Furthermore, no country limits the number of clinical trials allowed per HV or the amount of compensation participants can receive per year (except for France with a 12-months maximum of 6000 Euros). As a result, many countries have unknown numbers of “professional healthy volunteers” who, to optimize their financial gains may circumvent protections designed to minimize the risk of harm and ensure the integrity of research.

11. Over-volunteering and the VOLRETHICS initiative

Despite a few published empirical studies and ethical analyses of research involving HVs, there have been few concerted efforts to change the way research involving HVs is overseen and regulated. Because the risk-benefit balance is different in trials involving healthy people as compared to patients, specific guidelines are needed for trials involving HVs. Healthy volunteer trials are not always perceived as essential as patient trials, and some people consider them a necessary evil, which may be the reason why specific guidelines have not been put forward. In addition, unlike patients who are more and more considered as active participants in research, HVs are not organized in support groups to get their voices heard. A new collaborative effort to better protect and empower HVs globally is the VolREthics initiative, which has evolved in July 2025 into the non-profit VOLRETHICS Association. Launched in 2022, the initiative brings together the international community to address how to better protect HVs from risks of harm and exploitation and safeguarding the validity of clinical trials. Drawing on the experiences of stakeholders around the world, from those who conduct clinical trials to those who study and monitor how they are conducted, including HVs from several countries, a Global Ethical Charter for the Protection of Healthy Volunteers in Clinical Trials was published in 2024. It aims at supplementing existing global provisions on the protection of human research participants such as the ICH guidelines and Declaration of Helsinki ethical issues that are specific to HVs. The Charter defines 15 rights to which HVs are entitled. One of the key issues addressed in the Charter is the risk of over-volunteering, addressed through Article 10 which states “Preventing over-volunteering, i.e. not respecting exclusion (or “washout”) periods between trials, is crucial to protect participants and the integrity of clinical trials. Countries should develop and maintain mandatory systems across all clinical research settings to prevent over-volunteering. Consistent with national and international data privacy requirements, these systems should enable individual participant identification to ensure healthy volunteers adhere to the exclusion periods between trials. Wherever possible, these systems should operate across national borders.” In all its articles, the Global Ethics Charter highlights key issues and proposes ways to address them but relies on local stakeholders to decide on the level of importance and the practical implementation of its 15 recommendations.

12. Potential disadvantages of Introducing Volunteer Registries

The lack of data on the adverse events associated with over-volunteering and the lack of evidence on the cost-effectiveness of implementing nationwide HV registries may be considered as reasons for postponing decisions on their implementation. However, like all concealed phenomenons, over-volunteering cannot be accurately measured, only roughly assessed and partially prevented. Another argument against national registries could be that implementing stricter safeguards in some countries could incur additional costs for sponsors, leading them to conduct their studies in countries with less stringent regulatory protections. This could also encourage some HVs to travel to countries with less stringent regulatory protections in order to receive higher compensation through concealed repeated participations. These are the reasons why the Global Ethics Charter calls for systems that operate across national borders and avoid different protection standards between countries. A global, international system for protecting all human research participants, including HVs, would be highly desirable but it would be extremely complex to design and its implementation would require a level of international cooperation that is difficult to conceive in the foreseeable future because of differences in regulations between countries on issues such as the protection of personal data, the existence or not of national identification numbers, accreditation of research sites, etc.

13. Conclusion

Over-volunteering is a concealed phenomenon which consequences on participants’ safety and data integrity cannot be measured, but which can be prevented at least partly. The JACiC data published here are the first to provide objective evidence on its frequency through over 20 years of data collection in Japan and show the significant and stable occurrence of this phenomenon. Use of the JACiC registry protected hundreds of HVs from the risks of over-volunteering. A broader use of this registry across research sites in Japan should be encouraged to more comprehensively protect HVs across the country. To assess between-country differences in over-volunteering rates, collection and publication of similar data in other countries, including from privately-operated registries, would be very valuable. We also submit that consideration should be given to the implementation of compulsory HV registries on a national or multinational basis as the best way to prevent over-volunteering and its detrimental effects on HVs safety and on scientific data integrity. Given the globalization of clinical trials, it might be worth considering to incorporate this topic into ICH guidelines to encourage countries where no national registries are implemented to introduce mandatory systems to prevent over-volunteering.

Conflict of Interest Statement: The authors declare no conflicts of interest.

Funding Statement: The authors have nothing to report.

Acknowledgements: None.

Author Contributions: All authors conceptualized the manuscript and all provided significant inputs. H.F. wrote the manuscript, and all authors reviewed, edited and approved the manuscript.

 

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