The Importance of Human Subject Databases in the US
Posted on: Friday 10 July 2026
Introduction
The reflections in this piece draw directly from careers in clinical trials across the United States where daily operational realities highlight the urgent need for stronger safeguards to protect research participants.
Protecting participants is the foundation of ethical pharmaceutical medicine. As clinical research expands in scale, complexity, and geographic reach, the risk of individuals enrolling in multiple concurrent studies or receiving overlapping investigational products unbeknownst to those running the trial has become a significant patient safety concern. The United States does not have a single, nationwide, government‑run/endorsed centralised human subject participation database to address over-volunteering (Fisher et al., 2024, Health Research Authority, 2024, National Pharmaceutical Regulatory Agency, 2021). There is no federal rule specifically governing healthy volunteers as a distinct class of research participant, and there is no mandatory national system that lets sites verify whether an individual is already in, or has already completed, another health-volunteer study (U.S. Food and Drug Administration, 2026b, U.S. Food and Drug Administration, 2026a). In contrast, several countries including the United Kingdom (TOPS), France (VRB), and Malaysia (NHRVR) (Fisher et al., 2024) have built centralised systems that look at over-volunteering as a system-level risk rather than a site-level inconvenience (Fisher et al., 2024, National Pharmaceutical Regulatory Agency, 2021, Health Research Authority, 2024, République Française, 2023, République Française, 2026). Instead, the U.S. relies on regulatory oversight from the Food and Drug Administration (FDA), and Institutional Review Bodies (IRBs), yet none of these bodies operate a unified system capable of tracking whether an individual is already enrolled in another clinical trial (U.S. Food and Drug Administration, 2026b, U.S. Food and Drug Administration, 2026a).
In the absence of a national registry, private, voluntary subject‑verification platforms have emerged. Systems such as Verified Clinical Trials (VCT) and CTSdatabase are increasingly used by sponsors and research sites to detect duplicate enrollment, ensure washout compliance, and prevent exposure to multiple investigational products. While valuable, these systems are not universal, not mandated, and do not replace the need for a coordinated national infrastructure. Indeed, while the case of over-volunteering may present as a compliance issue, there is a much deeper structural concern at the intersection of participant safety, data integrity, and social inequality (Kalbaugh et al., 2021, Kupetsky-Rincon and Kraft, 2012, Edelblute and Fisher, 2015, Fisher and Kalbaugh, 2011).
A statewide, citywide, or ideally nationwide centralised database would offer a transformative safeguard. It would strengthen eligibility verification, reduce protocol deviations, enhance data integrity, and protect participants from unnecessary risk.
Over-Volunteering in the US is Real, Harmful, and Difficult to Measure
Over-volunteering is related to, but not quite the same as serial participation. Whereas serial participation refers to repeated enrollment over time, over-volunteering refers to participation that is too frequent, overlapping, or inconsistent with required exclusion or washout periods (Kalbaugh et al., 2021, Kupetsky-Rincon and Kraft, 2012).
This distinction matters because serial participation is not necessarily prohibited and is quite common. Over-volunteering however, is difficult to detect without effective cross-site infrastructure. In a research market, relying on participants to self-disclose or relying on local records and exclusion criteria may be inadequate in an environment where participants may travel within and between regions in the knowledge that disclosing recent or current trial participation can make them ineligible for reimbursement in a paid study (Kalbaugh et al., 2021, Edelblute and Fisher, 2015, Fisher, 2009).
From a safety perspective, the rationale for a centralised approach to de-risking over-volunteering is straightforward. The UK Health Research Authority explains the need for TOPS in three domains (Health Research Authority, 2024):
- Medicines interactions risk: If studies are short, or overlap – medicines between trials may interact.
- Blood sampling: repeated and frequent blood sampling runs a risk of anaemia.
- Ethical considerations: exposing healthy people too often to medicines they do not need.
Concurrently, the scientific rationale for preventing over volunteering is of equal concern. Introducing noise into early-phase studies targeted to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics de-values and potentially invalidates the precise data these studies are meant to generate (Kalbaugh et al., 2021, Emanuel et al., 2015).
What is the Scale of the Problem in the US?
A lack of a national infrastructure limits the United States’ ability to measure over-volunteering. As such. The scale of the problem should not be assumed to be small and the strongest US data show that repeated Phase I participation is common, often economically motivated, and patterned by social inequality (Kalbaugh et al., 2021, Edelblute and Fisher, 2015, Fisher and Kalbaugh, 2011).
The Healthy VOICES project is a longitudinal study of 178 healthy volunteers recruited from seven US Phase I clinics. This study found that only 21% of participants were in their first clinical trial at recruitment, and participants had already enrolled in a median of five Phase I trials at baseline. Further, one quarter had previously enrolled in more than ten. Over the subsequent 3-year period, participants completed a median of 3 additional trials (Kalbaugh et al., 2021).
Interestingly, this same study identified a subgroup of participants who treated clinical trials as their full-time work. These “occupational” participants by consequence had a much more extensive history of participation and continued screening and enrolling at higher rates than other participants (Kalbaugh et al., 2021). This demonstrates a healthy-volunteer market which includes people who build strategies around repeated trial participation. While a registry wouldn’t eliminate the economic incentives driving this behaviour, it would make high-risk forms of overlapping or overly frequent participation harder to conceal.
Direct estimates of dual enrollment are even more limited. A review of healthy-volunteer registries reported that a German survey of healthy volunteers found a dual-enrollment rate of about 3%, while a US survey of 60 subjects found that 10% admitted to dual enrollment (Kupetsky-Rincon and Kraft, 2012). The same literature noted that local or private registry systems exist in North America, but partial coverage that be circumvented when participants move between clinics or regions (Kupetsky-Rincon and Kraft, 2012). The practical implication is that voluntary registry, or a local one, cannot solve a national problem.
Equality and Justice
One of the central arguments for a national registry is that over-volunteering is not only a safety problem but that of an equality one. Clinical trial diversity is often framed as a problem of underrepresentation; however, Fisher and colleagues argue that the common assumption that minority communities simply under-participate in clinical research is incomplete. Minorities may be underrepresented in later-stage therapeutic trials while being overrepresented in Phase I safety studies involving healthy volunteers (Fisher and Kalbaugh, 2011).
Again, the data from Healthy VOICES is striking. Participants were predominantly male, and two-thirds were classified as racial or ethnic minorities. At baseline, 41% were unemployed or retired, 34% worked part-time, and nearly half had household incomes below $25,000 (Kalbaugh et al., 2021). The study found that participants who were male, Black, Hispanic, unemployed, vocationally trained or lower-income tended to have completed more trials or to have participated over longer periods (Fisher and Kalbaugh, 2011). This is of course in the additional gender-specific context that exclusion practices around pregnancy potential and reproductive risk presents the issue of under-representation of women or people who can become pregnant, an issue in of itself (Cottingham and Fisher, 2022). In this study, the authors conclude that healthy volunteer participation in US Phase I trials is driven by social inequalities, with disadvantaged groups participating in more trials and for longer than more privileged groups. A US registry that tracks nationwide trial representation could in theory, therefore, be paired with more broader reforms to eligibility criteria, reproductive risk governance, and trial design (Cottingham and Fisher, 2022, US. Department of Health and Human Services, 2020).
In the absence of a nationalised database, tracking potential hot spots of over-volunteering means the US cannot reliably identify where participants are travelling long distances between clinics or how patterns vary between regions, commercial trial hubs, or underserved communities. The opportunity therefore exists for a national registry to make possible the analysis of aggregate data, and geographic burden for the first time.
International Models
United Kingdom: TOPS
The UK’s TOPS system is a strong proof of concept: a free database for UK organisations undertaking Phase I trials in healthy volunteers, now endorsed by the Health Research Authority (Health Research Authority, 2024). Volunteers are registered at screening and other units can see if a volunteer has attended a unit and may be intending to participate. Use of TOPS is indeed a standard condition of ethical approval for Phase I healthy-volunteer studies and established as part of the MHRA accreditation scheme. TOPS started as a charity initiative before being integrated into the HRA and is evidence that such a scheme has the potential to influence clinical decision making nationally.
The effectiveness of the TOPS scheme has been evidenced by a study reporting that TOPS had been used by 84 units since its creation in 2002, with 249,612 entries between 2002 and 2016. The authors reported very small numbers of potential over-volunteers identified in 2015 and 2016 and concluded that TOPS helps prevent and deter over-volunteering (Allen et al., 2017). This is the most valuable comparator for U.S. policy because it combines regulatory embedding with published system-level experience.
TOPS also demonstrates the limits of a registry. The HRA states that TOPS is designed to detect most accidental or deliberate over-volunteering, but not professional over-volunteering or fraud. Its FAQ shows that accurate identification, timely updating and communication between units remain essential. In other words, a registry is not a magic solution. It is an infrastructure tool that works best when backed by site accountability, identity verification and clear operating procedures.
France: national file and compensation cap
France provides a more legally formal model. French law requires a national file for healthy people who volunteer for certain research and for some patient-volunteers when the research is unrelated to their pathology. The system is linked to exclusion periods, prevention of simultaneous participation and monitoring of participation in covered research (République Française, 2026). France also caps the total annual indemnity a participant may receive. A 2023 order set the maximum compensation for participation in covered research over twelve consecutive months at €6,000 (République Française, 2023).
The French model is important because it recognises that over-volunteering is not only about scheduling but cumulative burden and financial incentives. A compensation cap directly targets the economic driver of professionalised participation. For the United States, this raises a policy question that should not be avoided: a registry could simply enforce washouts, or it could also monitor cumulative exposure and compensation. France shows that a broader model is possible.
The limitation is evidence transparency. Legal and administrative documentation confirms the framework, but publicly accessible, peer-reviewed evaluation of the French system appears much thinner than for TOPS. For U.S. advocacy, France is therefore best used as a regulatory design example rather than as a source of strong outcome-effectiveness data.
Malaysia: NHRVR
Malaysia’s National Healthy Research Volunteer Register (NHRVR) is a newer model with strong enforcement language. A 2021 National Pharmaceutical Regulatory Agency directive requires sponsors, applicants and investigators seeking clinical trial import licenses or manufacturing approvals for healthy-volunteer research to register such research with the NHRVR (National Pharmaceutical Regulatory Agency, 2021). The directive frames the system as a way to protect healthy-volunteer safety and trial integrity by preventing simultaneous enrolment within prohibited periods.
Malaysia’s model is notable because non-compliance can affect regulatory approvals and data acceptance. The directive links registry use to clinical-trial import licences, manufacturing approvals, Phase I units and bioequivalence centres (National Pharmaceutical Regulatory Agency, 2021). For US context, it shows how a registry can be embedded into the regulatory architecture rather than treated as a voluntary industry tool.
The limitation is maturity and scope: NHRVR is relatively new, and publicly available outcome evaluations are limited. Its scope is also tied to categories of healthy-volunteer research and regulatory approvals. As with France, the Malaysian system is a useful design comparator, but not yet an evidence base equivalent to TOPS.
What should a U.S. registry do?
A U.S. national registry should be designed around two functions: real-time participant protection and aggregate public accountability.
The first function is eligibility checking. Sites should be required to enter healthy volunteers at screening, not only after dosing. The registry should record a unique participant identifier, screening date, study status, dosing date, last-dose date, follow-up period, relevant blood-loss information and flags for biological products, radiolabelled products or long-term follow-up. Authorised sites should be able to query whether a participant is currently screened, enrolled, dosed, in follow-up, or within a required washout period. Records should also distinguish between screened-but-not-dosed and dosed participants, because the safety implications differ (Health Research Authority, 2024, Allen et al., 2017, Kupetsky-Rincon and Kraft, 2012).
The second function is equity reporting. The registry should generate de-identified aggregate reports on participant burden by sex, race, ethnicity, age, region and socioeconomic indicators where ethically and legally appropriate. The FDA’s guidance on enhancing clinical-trial participation emphasises consideration of sex, race, ethnicity, age and location of residency in clinical-trial populations (US. Department of Health and Human Services, 2020). A healthy-volunteer registry could extend that representativeness logic to the burden side of research: not just who gets access to studies, but who repeatedly bears risk in studies with no prospect of direct medical benefit (Kalbaugh et al., 2021, Fisher and Kalbaugh, 2011, US. Department of Health and Human Services, 2020).
A U.S. registry should be mandatory for Phase I healthy-volunteer drug studies and bioequivalence studies, with consideration of expansion to other non-therapeutic healthy-volunteer research involving investigational products, substantial blood draws or confinement. It should be administered by, or under authority delegated from, a federal body such as FDA, NIH or HHS, with clear privacy protections, limited access, audit trails and penalties for non-compliance (U.S. Food and Drug Administration, 2026b, U.S. Food and Drug Administration, 2026a, US. Department of Health and Human Services, 2020). Commercial registry vendors may provide technical lessons, but a national system should not depend on voluntary sponsor participation or fragmented market adoption (Kupetsky-Rincon and Kraft, 2012).
The system should also avoid overreach by not stigmatising healthy volunteers, creating a blacklist, or preventing adults from making informed decisions about research participation. Its purpose should be to enforce protocol-defined safety intervals, prevent overlapping participation and enable oversight. Participants should be told clearly what data are collected, who can access them, how long data are retained and how disputes or errors can be corrected (Kupetsky-Rincon and Kraft, 2012, US. Department of Health and Human Services, 2020).
Addressing likely objections
One objection is that a national registry would be paternalistic. But the ethical case for a registry is not that healthy volunteers are incapable of decision-making. It is that no individual participant can manage risks that are invisible to sites, sponsors and regulators. If one clinic cannot see that a person was dosed elsewhere last week, the problem is informational, not merely individual. A registry supports informed, accountable research participation rather than replacing participant autonomy (Resnik, 2011).
A second objection is that the evidence base is incomplete. That is true, but it strengthens rather than weakens the case for infrastructure. The U.S. cannot accurately measure over-volunteering because it lacks a centralised system. Existing studies show extensive serial participation, evidence of dual enrollment, and clear social-patterning of repeated participation (Kalbaugh et al., 2021, Edelblute and Fisher, 2015, Fisher and Kalbaugh, 2011).
A third objection is cost and burden. TOPS suggests that a relatively targeted registry can be integrated into existing research workflows (Allen et al., 2017, Health Research Authority, 2024). The costs of a registry should be compared with the costs of compromised safety data, avoidable adverse events, failed studies and preventable ethical controversy. A national registry would be a modest infrastructure intervention in a high-value research sector.
Conclusion
A centralised human subject database is a patient‑safety imperative. Beyond the United States, any country or region lacking such infrastructure would benefit from adopting similar systems to prevent over‑participation, reinforce ethical conduct, and strengthen public trust in clinical research (Fisher et al., 2024). The United States has a mature clinical-trials enterprise but an underdeveloped system for protecting healthy volunteers who participate repeatedly in early-phase studies. Over-volunteering is a foreseeable consequence of paid, fragmented, multi-site research. It creates risks to participants, threatens data integrity and raises justice concerns because repeated participation is concentrated among socially disadvantaged groups (Fisher and Kalbaugh, 2011, Kalbaugh et al., 2021).
International experience shows that centralised registries are feasible. The UK’s TOPS system provides the strongest published evidence of effectiveness (Allen et al., 2017). France shows how a registry can be paired with compensation limits (République Française, 2023, République Française, 2026). Malaysia shows how registry use can be tied to regulatory approval and accreditation (National Pharmaceutical Regulatory Agency, 2021). The U.S. should learn from all three.
A national healthy-volunteer registry would not solve every ethical problem in Phase I research. It would not, by itself, correct gender exclusion, eliminate socioeconomic coercion, or prevent all fraud. But it would close a major gap in participant protection and make visible the distribution of early-phase research burdens. In a system that depends on healthy people accepting risk for the advancement of medicine, that is a minimal and overdue safeguard.
References
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