Healthy Volunteers in Resource-Poor Settings

A variety of reasons may motivate participation of HVs in clinical trials, such as altruism, accessing ancillary healthcare benefits (e.g., a medical checkup), scientific interest, curiosity, meeting people, etc. However, financial gain is the primary reason why HVs participate in clinical trials. This has been well documented both in the U.S.^{Footnote 4} and in Europe^{Footnote 5} for “repeat volunteers,” i.e., those who have participated in several clinical trials, and also by researchers in India,^{Footnote 6} Brazil,^{Footnote 7} Romania,^{Footnote 8} and Portugal.^{Footnote 9} Motivations can vary based on demographic or socioeconomic characteristics, for instance, financial gains can be the main reason for participating for younger people,^{Footnote 10} but may be seen as of secondary importance by medical students.^{Footnote 11}

Resource-poor settings, i.e., difficult economic conditions, low literacy levels, limited access to healthcare, etc., can be found in low- and middle-income countries, but also in high-income countries, as was well documented by U.S. teams.^{Footnote 12} Some U.S. authors have described how economically disenfranchised people are systematically used in pharmaceutical development.^{Footnote 13} Others, describing the population of healthy people who volunteer for participation in clinical trials, have spoken of the “exploitation of a research underclass.”^{Footnote 14} Outside of the United States, little research seems to have been carried out to document the characteristics of HV populations who participate in clinical trials. There is little doubt that in many settings, HVs can be characterized as a specifically vulnerable population that is exposed to a risk of exploitation, because they may not be able to provide genuine informed consent for participating in a clinical trial.

The ability to provide informed consent rests on two pillars: the ability to properly understand the potential risks and benefits related to the proposed trial, and the ability to refuse participation. On both accounts, HVs in resource-poor settings are vulnerable: their literacy levels may not enable them to properly understand what risks they may expose themselves to, and the financial compensation provided for their participation can become an undue financial inducement if they are in no position to refuse it. Rabin et al.^{Footnote 15} have described how 58% of a panel of HVs in Israel did not even try to form a proper understanding of potential risks and benefits on which to base a “quality decision” to participate in a trial. Similar observations were made in India,^{Footnote 16} where a study found that most HVs had decided to participate before being offered any information during the informed consent process, or even before visiting the study centers. One of the few available papers on HVs in low- and middle-income countries shows how, in India, contract research organizations (CROs) resort to “middlemen” to recruit poor participants who have no understanding of what the studies are about and basically “chose to participate in the trials due to insufficient income and unstable jobs.”^{Footnote 17}

Several U.S. researchers have investigated “professional healthy volunteers,” who make a living out of their participation in multiple clinical trials. Payments of several thousand dollars for participation in a clinical trial are not unusual, which can lead in some cases to yearly incomes of over $30,000.^{Footnote 18} Several authors have described the tactics that some have developed to optimize their chances of being selected for the most appealing studies, most often those that offer the best financial benefits^{.Footnote 19,Footnote 20} For instance, Devine et al.^{Footnote 21} showed that in a sample of 100 subjects who had participated in at least two studies in the previous year, three-quarters reported concealing some health information from researchers in their lifetime to avoid exclusion from enrollment in a study. They had designed ways to hide their participation in concomitant studies, conceal underlying medical conditions, intake of concomitant medications, or substance abuse. Participation in multiple clinical trials, simultaneously or without respecting a sufficient “wash-out” interval between studies, exposes HVs to potential safety risks related to drug-drug interactions.^{Footnote 22} It may also compromise the validity of study results,^{Footnote 23} thereby exposing future patients to unforeseen safety and efficacy issues.

Results: Available Data on Studies with Healthy Volunteers

The TrialTrove database yielded a total of 28,716 Phase I studies, performed at 13,547 sites around the world. Focusing on planned or ongoing Phase 1 trials yielded a total of 1,435 trials. Table 1 shows the countries where these studies are reported to take place. North America, Western and Central Europe, and East Asia report the largest numbers of trials, but it is interesting to see that Phase 1 studies are carried out on all continents and in a large variety of countries.

Table 1. Planned and Ongoing Phase 1 Studies Reported in Two Web-Based Databases

Note: Numbers do not always add up; they are reported as they appear in the databases. Some adjustments in region allocation have been made to enable side-by-side comparisons between the two databases.

The U.S. clinicaltrials.gov database included a total of 250,494 studies, with no filter applied regarding study type or status (ongoing, completed, etc.). Out of these, 41,220 (16.5%) were reported as “Phase I studies,” and 11,832 were reported as planned or ongoing. Adding the term “healthy” as a “condition/disease” filter, 1,085 studies were identified. Overall, as shown in Table 1, the same distribution between continents and the same large variety of countries were found for both the TrialTrove and clinicaltrials.gov databases, with the notable exception of Mexico, for which the TrialTrove lists 367 trials while clinicaltrials.gov lists 2 trials.

We repeated the same exercise with the Clinical Trials Registry of India.^{Footnote 27} Out of a total of 9,114 studies registered, 312 (3.4%) were labeled as “Phase I” and 26 (0.3%) were reported when “Phase I” and “healthy volunteers” filters were combined. In both instances, many studies appeared to involve patients. As was observed with the U.S. database, when the term “healthy volunteer” was used as a key word, a sizeable number of studies (225) were found, with the same wide variations in the types of studies reported. The low number of “Phase I” studies is consistent with the requirement of Indian authorities that first administrations to “humans” of new chemical entities be carried out in the country of origin of the new compound. Therefore, the overwhelming majority of studies can be expected to be pharmacokinetic studies, reflecting the large number of generic companies present in India.^{Footnote 28}

Given the difficulties of interpreting data extracted from databases with large amounts of data entered by a wide variety of persons, we saw the database of one large multinational research-based pharmaceutical company as a way to help shed light on the situation. At the request of the Sanofi Bioethics Committee, we obtained data on studies sponsored by Sanofi, involving HVs and administration of medicines, performed during the years 2014, 2015 and 2016. As shown in Table 2, a total of 122 studies were performed over this 3-year period, involving approximately 4,800 HVs. Out of these 122 studies, 113 (93%) were pharmacokinetic studies (bioavailability, bioequivalence, drug-drug interaction), and only 9 (7%) were “first-in-human” studies (single or multiple ascending doses of new chemical entities). These studies were performed in 15 different countries, with Canada, Brazil, and Romania heading the list. The choice of countries differed depending on the type of studies. For “first-in-human” studies, study sites were largely chosen based on the previous experience of Sanofi scientists regarding the level of expertise of the investigators, the ease of the procurement process (meaning that formal agreements were more readily made with institutions with which Sanofi had already worked), and regulatory and logistical issues such as requirements for study drug labeling and shipment. For pharmacokinetic studies, countries were most often chosen based on regulatory requirements to have local data provided for registration (e.g., Indonesia, Malaysia, Russia, South Africa). Many pharmacokinetic studies were performed in Canada for reasons related to the quality, cost, and speed of data provided by CROs based in that country, and in Brazil since Sanofi has a large generic branch in that country.

Table 2. Sanofi-Sponsored Studies with Administration of Medicines Involving Healthy Volunteers, Performed During the Years 2014, 2015, and 2016

* Based on an average estimated number of 40 healthy volunteers per pharmacokinetic study.

Discussion: The Need for Better Informed Consent and National Registries

Even though assessing the actual number of studies involving HVs globally is a challenge, the data we have found from a variety of sources consistently supports some clear conclusions: tens of thousands of HVs are involved every year in clinical trials in a large variety of countries on all five continents, and the overwhelming majority of these studies appear to be pharmacokinetic rather than “first-in-human” studies. We believe that HVs would be better protected by improving the way their informed consent process is managed and by setting up national registries.

To ensure that HVs properly understand the information that is provided to them during the informed consent process and are able to determine the level of risk to which they expose themselves, it can be proposed that tests be performed to check that each HV has properly understood the most critical information provided. The results of these tests should be documented, and HVs who do not demonstrate a sufficient understanding, possibly after a second round of information, should be excluded from participation. Such an approach will exclude HVs that are not able to understand basic scientific concepts and would therefore help ensuring proper informed consent.

National compulsory registries, where each HV must be registered before being considered for participation, can prevent individual HVs from participating in several trials at the same time and thereby ensure that they respect the required “wash-out” periods between trials. Such registries can also be used to track payments made to each individual so as to ensure that they do not go above an acceptable level that could jeopardize their ability to refuse participation. To our knowledge, France and the U.K. are the only countries where national registries have been set up.

France’s national registry, the Volontaires Recherche Biomédicale,^{Footnote 29} is based on a law (loi Huriet-Serusclat), passed in late 1988, which established a legal framework for trials involving HVs.^{Footnote 30} It is administered by the Ministry of Health, and its operating mode was most recently revised by law in 2006.^{Footnote 31} Registration of HVs by investigators is mandatory, and HVs must be covered by the national “Sécurité Sociale” scheme. The information entered into the database includes the identity, date and place of birth of the HV, the dates of study participation, and, if appropriate, the poststudy exclusion period during which no other study participation is allowed. The amount of financial compensation received for each study is also entered, and a maximum level of earnings is set by law, currently 4,500 Euros over a 12-month period.

The U.K. national registry, the Over-Volunteering Prevention System “TOPS”,^{Footnote 32} was initially operated on a voluntary basis and administered by an independent charity. It was initiated following the findings by the Hammersmith Medical Research Phase I unit in London that from 1997 to 2001, 1 in 10 healthy volunteers they screened had completed a study of a potential new medicine within the previous 12 weeks, even though they had signed a statement to the contrary.^{Footnote 33} The same team has documented how the use of TOPS by an increasing number of U.K. Phase I units has resulted in decreasing the incidence of subjects attempting to volunteer within 3 months of completing another trial in another unit. Since 2013, TOPS has come within the remit of the National Health Service’s Health Research Authority, and registration of individual HVs has become a standard condition of ethical approval, as well as part of the Medicines & Healthcare Products Regulatory Agency accreditation scheme. HVs are identified by their National Insurance number (for U.K. citizens) or by their passport number and country of origin (for non-U.K. citizens). TOPS does not include information on post-study exclusion periods, only the date of the last dose of study medicine received. It does not include information on payments made to HVs.

The Swiss canton of Ticino also set up a mandatory registry for HVs in the early 2000s.^{Footnote 34} Voluntary, privately managed registries have been set up in the USA and Canada: the Clinical Research Subject Verification Program^{Footnote 35} and Verified Clinical Trials.^{Footnote 36} U.S. researchers have advocated that a national registry could play an important role in promoting research integrity and protecting subjects from harm.^{Footnote 37,Footnote 38,Footnote 39,Footnote 40} National mandatory registries require clear operating rules and multiple safeguards to ensure, in particular, HV data privacy. They can only be set up by law, and the examples of France and the U.K. could help other countries to design similar systems.