Over-volunteering in Phase I clinical trials: data from a healthy volunteers’ registry in Japan Healthy participant safety in early phase clinical trials
Article Sidebar
Downloads
Submit your own article
Register as an author to reserve your spot in the next issue of the Medical Research Archives.
Author RegistrationJoin the Society
The European Society of Medicine is more than a professional association. We are a community. Our members work in countries across the globe, yet are united by a common goal: to promote health and health equity, around the world.
Join Europe’s leading medical society and discover the many advantages of membership, including free article publication.
MembershipMain Article Content
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.
Article Details
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
2. Cherian JJ, Poomali A, Mukherjee A. Increasing early phase clinical trials capacity in India. Communications Medicine. 2025;5:255. doi:10.10 38/s43856-025-00970-z
3. Bende B, Németh A. EARLY PHASE TRIALS. Curriculum Development of Human Clinical Trials for the Next Generation of PhD Students and Early Career Researchers in the Medical, Science, Pharmacy and Health Professions. 2024.
4. Bompart F. Healthy volunteers for clinical trials in resource-poor settings: national registries can address ethical and safety concerns. Camb Q Healthc Ethics 2019; 28(1): 134–143.
5. Tranter E, Peters G, Boyce M et al. Giving monoclonal antibodies to healthy volunteers in phase 1 trials is it safe? Br J Clin Pharmacol. 2013;76:164–172. doi: 10.1111/bcp.12096
6. Willmann S, Marostica E, Snelder N, Solms A, Jensen M, Lobmeyer M, Lensing AWA, Bethune C, Morgan E, Yu RZ, Wang Y, Jung SW, Geary R, Bhanot S. PK/PD modeling of FXI antisense oligonucleotides to bridge the dose-FXI activity relation from healthy volunteers to end-stage renal disease patients. CPT Pharmacometrics Syst Pharmacol. 2021 Aug;10(8):890-901. doi: 10.1002/ psp4.12663. Epub 2021 Jun 23. PMID: 34085768; PMCID: PMC8376138.
7.Geretti AM, Sostelly A, Buatois S, Lu S, Lemenuel A, Attley G, Bopst M, Alvarez-Sánchez R, Mueller H, Gane E.2025.Safety, pharmacokinetics, and pharmacodynamics of the antisense oligonucleotide RO7239958 in healthy volunteers and adults with chronic hepatitis B infection. Antimicrob Agents Chemother69:e00679-25. https://doi.org/10.1128/aac.00679-25
8.Han K, Theodore D, McMullen G, Swayze E, McCaleb M, Billioud G, Wieland S, Hood S, Paff M, Bennett CF, Kwoh TJ. Preclinical and Phase 1 Assessment of Antisense Oligonucleotide Bepirovirsen in Hepatitis B Virus-Transgenic Mice and Healthy Human Volunteers: Support for Clinical Dose Selection and Evaluation of Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses. Clin Pharmacol Drug Dev. 2022 Oct;11(10):1191-1202. doi: 10.1002/cpdd.1154. Epub 2022 Aug 16. Erratum in: Clin Pharmacol Drug Dev. 2025 Oct 27. doi: 10.1002/cpdd.1620. PMID: 35971951; PMCID: PMC9804925.
9. Omes-Smit G, Garsen M, Zwiers A. Healthy Volunteer Studies in the Development of Anticancer Drugs with Genotoxic Findings. Ther Innov Regul Sci. 2022;56:76-84. doi: 10.1007/s 43441-021-00330-8. Epub 2021 Aug 11. PMID: 34379306; PMCID: PMC8688384.
10. Radanovic I, Klarenbeek N, Rissmann R et al. Integration of healthy volunteers in early phase clinical trials with immuno-oncological compounds. Front. Oncol. 2022; 12: 1-18. doi: 10.3389/ fonc.2022.954806
11. de Las Heras B, Bouyoucef-Cherchalli D, Reeve L, Reichl A, Mandarino D, Flach S, Vidal L, van Brummelen EMJ, Steeghs N. Healthy volunteers in first-in-human oncology drug development for small molecules. Br J Clin Pharmacol. 2022;88: 1773-1784. doi: 10.1111/bcp.15092. Epub 2021 Oct 19. PMID: 34558113; PMCID: PMC10234445.
12. Drezner N. Regulatory Challenges In the Use of Healthy Volunteers. 2018. https://www.ascpt.org/Portals/28/docs/Annual%20Meetings/2018%20Annual%20Meeting/Presentations/March%2023%202018/Drezner_%20Nicole%20Healthy%20Volunteers%20ASCPT.pdf?ver=2018-04-12-195032-280
13. Courville J, Barber A, Fura A. Navigating First-in-Human and Early-Phase Patient Studies Study Designs, Risk Mitigation, and Population Selection Challenges J Clin Pharmacol. 2025;65:835-849. doi: 10.1002/jcph.70002.
14. Lorch U, Vincent C. The safety of early phase clinical trials Bridging the gap between governance and practice. Br J Clin Pharmacol. 2024;90:1538–1540. doi: 10.1111/bcp.16141
15. Bompart F, Fisher JA, Allen E et al. The VolREthics initiative to protect the well-being of healthy volunteers in biomedical research. Nat Med. 2023; 29: 2393–2394. doi.org/10.1038/s415 91-023-02490-6
16. Karkar M, Lemaitre C, Bompart F et al. Healthy volunteers' protection around the world. Med Sci (Paris). 2023; 39: 769-775. doi: 10.1051/medsci/ 2023118
17. Fisher JA, McManus L, Wood MM et al. Healthy Volunteers’ Perceptions of the Benefits of Their Participation in Phase I Clinical Trials. J Empir Res Hum Res Ethics. 2018; 13: 494–510. doi:10.1 177/1556264618804962
18. Abadie R, Fisher JA, Mwale S, Bompart F, Hirsch F. Policy recommendations for implementing registries to minimize over-volunteering in Phase I clinical trials. Clin Trials. 2025;22:757-760. doi: 10.1177/17407745251360649. Epub 2025 Jul 29. PMID: 40727967.
19. Boyce M, Walther M, Nentwich H et al. TOPS: an internet-based system to prevent healthy subjects from over-volunteering for clinical trials. Eur J Clin Pharmacol. 2012;68: 1019-1024. doi: 10.1007/s00228-012-1231-8
20. Number of double registration prevented cases. https://jacicp.jp/subject-verification-system/double-medication-prevention-count-1.html
21. Emmanuel OA. ETHICS OF TRIALS IN HEALTHY VOLUNTEERS. South American Journal of Clinical Research. 2025; 2.
22. Fisher JA. Adverse events: race, inequality, and the testing of new pharmaceuticals. New York University Press. 2020.
23. Yu H, Fang Y,Qi X et al. Sociodemographic characteristics of healthy volunteers along with their experience, attitude and concerns of clinical trials in Wuhan, China. Sci Rep. 2023;13:19550. doi: 10.1038/s41598-023-46979-z
24. Walker RL, MacKay D, Waltz M, Lyerly AD, Fisher JA. Ethical Criteria for Improved Human Subject Protections in Phase I Healthy Volunteer Trials. Ethics Hum Res. 2022;44:2-20. doi: 10.1002/eahr.500139. PMID: 36047278; PMCID: PMC9931499.
25. Seo JH, Kim OJ, Yoo SH. A Study on the Characteristics of Healthy Volunteers who Participate in Phase I Clinical Trials in Korea. J Empir Res Hum Res Ethics. 2022;17:193-212. doi: 10.1177/15562646211034275
26. Ranjan R, Agarwal NB, Kapur P et al. Factors Influencing Participation Of Healthy Volunteers In Clinical Trials: Findings From A Cross-Sectional Study In Delhi, North India. Patient Preference and Adherence. 2019;13:2007–2015. doi: 10.2147/PPA .S206728
27. Cottingham MD, Fisher JA. Risk and Emotion Among Healthy Volunteers in Clinical Trials. Soc Psychol Q. 2016 Sep;79(3):222-242. doi: 10.1177/ 0190272516657655. Epub 2016 Jul 29. PMID: 28867852; PMCID: PMC5580945.
28. Ji-Hye S, Ock-Joo K, Eun KC et al. Comparison of the characteristics of healthy volunteers participating in Phase 1 clinical trials in Korea and Japan. Transl Clin Pharmacol. 2025;33: 183-196. doi: 10.12793/tcp.2025.33.e16
29. Stunkel L, Grady C. More than the money: a review of the literature examining healthy volunteer motivations. Contemp Clin Trials. 2010; 32: 342-352.
30. Tishler CL, Bartholomae S. The recruitment of normal healthy volunteers: a review of the literature on the use of financial incentives. J Clin Pharmacol. 2002; 42: 365-375,
31. Grady C, Bedarida G, Sinaii N et al. Motivations, enrollment decisions, and socio-demographic characteristics of healthy volunteers in phase 1 research. Clin Trials. 2017; 14:526-536.
32. Ji-Hye S, Ock-Joo K, Eun KC et al. Comparison of the characteristics of healthy volunteers participating in Phase 1 clinical trials in Korea and Japan. Transl Clin Pharmacol. 2025; 33: 183-196. doi: 10.12793/tcp.2025.33.e16
33. Kalbaugh CA, Kalbaugh JM, McManus L et al. Healthy volunteers in US phase I clinical trials: Sociodemographic characteristics and participation over time. PLoS One. 2021; 16:e0256994. doi: 10.1371/journal.pone.0256994.
34. Leisinger KM, Schmitt KM, Bompart F. Healthy Volunteers in Clinical Studies. Ethics Dumping. 2018; 67-70. doi: 10.1007/978-3-319-64731-9_8
35. Edelblute HB, Fisher JA. Using "clinical trial diaries" to track patterns of participation for serial healthy volunteers in U.S. phase I studies. J Empir Res Hum Res Ethics. 2015; 10:65-doi: 10.1177/ 1556264614568280. Epub 2015 Jan 20. PMID: 25742668; PMCID: PMC4408988.
36. Emmanuel OA. ETHICS OF TRIALS IN HEALTHY VOLUNTEERS. South American Journal of Clinical Research. 2025; 2.
37. Walker RL, Cottingham MD, Fisher JA. Serial Participation and the Ethics of Phase 1 Healthy Volunteer Research Open Access. The Journal of Medicine and Philosophy. 2018;43: 83–114, doi.org: 10.1093/jmp/jhx033
38. Erik R, Mårten S, Folke S et al. Characteristics, Motivations, and Preferences of Healthy Volunteers in Phase I Clinical Trials in Sweden. Journal of Empirical Research on Human Research Ethics. 2025;20:59-70. doi: 10.1177/15562646241309142
39.https://www.legifrance.gouv.fr/codes/section_lc/LEGITEXT000006072665/LEGISCTA000006190202/2003-05-27
40. Smith RN. Safeguards for healthy volunteers in drug studies.Lancet. 1975 Sep 6;2(7932):449-50. doi: 10.1016/s0140-6736(75)90856-9. PMID: 51249
41. McManus L, Davis A, Forcier RL et al. Appraising Harm in Phase I Trials: Healthy Volunteers’ Accounts of Adverse Events. J Law Med Ethics. J Law Med Ethics. 2019;47:323–333. doi: 10.1177/1073110519857289
42. Emmanuel OA. ETHICS OF TRIALS IN HEALTHY VOLUNTEERS. South American Journal of Clinical Research. 2025; 2.
43. Over-Volunteering (Appendix 1, point 16). MHRA Phase I Accreditation Scheme Guidance FINAL v5 01 April 2025
44. Makadi A. Protection of Healthy Volunteers in Clinical Trials: A Crucial Ethical Commitment. Available from https://pace-cr.com/news/protection-of-healthy-volunteers-in-clinical-trials-a-crucial-ethical-commitment/
45. Fisher JA, Abadie R, Hirsch F. Implementing a Global Ethics Charter to Protect US Healthy Volunteers. American Journal of Medicine. 2025;138: 601-603.
46. Jonnalagadda VG. The Global Ethics Health Charter to Protect Healthy Volunteers: Is the Problem Local or International?. American Journal of Medicine. 2025; 138: E112.
47. The Multi-Regional Clinical Trials Center of Brigham and Women's Hospital and Harvard. Public Comments submitted: VolREthics initiative – Global Ethics Charter for the Protection of Healthy Volunteers in Clinical Trials March 30, 2024. Available from https://mrctcenter.org/resource/public-comments-submitted-volrethics-initiative-draft-global-ethics-charter-for-the-protection-of-healthy-volunteers-in-clinical-trials/
48. Edelblute HB, Fisher JA. Using ‘‘clinical trial diaries’’to track patterns of participation for serial healthy volunteers in US phase I studies. J Empir Res Hum Res Ethics. 2015; 10(1): 65–75.
49. Walker RL, MacKay D, Waltz M et al. Ethical Criteria for Improved Human Subject Protections in Phase I Healthy Volunteer Trials. Ethics Hum Res. 2022; 44:2-21. doi:10.1002/eahr.500139
50. Naseer S. Safety Considerations in Phase 1 Trials. 2024 https://www.fda.gov/media/185120/download
51. Naseer S. Safety Considerations in Clinical Drug Development https://www.fda.gov/media/175394/download. 2023.
52. Fisher JA. Global Efforts to Protect Healthy Volunteers. Hastings Cent Rep. 2023; 53: 2. doi: 10.1002/hast.1494
53. https://volrethics.org/
54. VolREthics A Global Ethics Charter for the Protection of Healthy Volunteers in Clinical Trials June 2024. Available from https://www.inserm.fr/wp-content/uploads/Inserm_VolREthics_EthicsCharterFinalVersion_July24.pdf
55. Aguilera B, DeGrazia D, Rid A. Regulating international clinical research: an ethical framework for policy-makers. BMJ Glob Health. 2020 May;5(5) :e002287. doi: 10.1136/bmjgh-2020-002287. PMI D: 32461225; PMCID: PMC7259867.
56. Deiteren A, Coenen E, Lenders S et al. Data driven evaluation of healthy volunteer characteristics at screening for phase I clinical trials to inform on study design and optimize screening processes. Clinical Trial Clin Transl Sci. 2021;14:2450-2460. doi: 10.1111/cts.13113. Epub 2021 Aug 11.