Trends in clinical trials performed in Chile

Background: An increasingly large proportion of clinical trials is being conducted at non-traditional geographic regions such as Latin America. However, concerns have been raised that hosting countries may lack adequate research regulations and that clinical trials may not address local health needs. In this context, Chile has been hosting a relatively large proportion of clinical trials and has introduced new regulatory protections. Aim : To study trends and characteristics of clinical trials in Chile, including the effects of regulatory protections and whether clinical trials are aligned with the local burden of diseases. Material and Methods: Data from clinical trials on pharmaceutical products registered over the last decade in Chile’s Institute of Public Health was reviewed. Clinical trials were analyzed according to sponsorship, phase, disease studied, and whether distribution of trials according to diseases was aligned with the local burden of diseases measured in disability-adjusted life years. Results: Most of the 876 clinical trials analyzed were funded by external pharmaceutical companies and corresponded to late-phase trials. The most commonly studied disease groups were neoplasms, musculoskeletal disorders, other noncommunicable diseases, chronic respiratory diseases, diabetes and kidney diseases, neurological disorders, and circulatory diseases. The distribution of clinical trials was partially aligned with the distribution of major causes of disease burden. The introduction of new regulatory protections was followed by changes in the number of trials studying certain disease groups associated with a high burden. Conclusions : Clinical trials conducted in Chile over the last decade are largely funded by external pharmaceutical companies. Their distribution is partially aligned with local disease burden. The introduction of regulatory protections was followed by changes in the distribution of diseases studied. (Rev Med Chile 2021; 149: 110-118)

T he global landscape of clinical research has changed in the last two decades, with increasing numbers of clinical trials (CTs) shifting to non-traditional geographic regions, especially towards so-called "emerging economies" in Latin America, Eastern Europe, and Asia [1][2][3] . In this context, Chile stands out as the country with the highest number of CTs per million population in Latin America 4 .
The globalization of CTs is often seen as an opportunity to shift research investment towards developing countries and bridge the global gap in research that has traditionally focused on the health priorities of high-income, developed countries 5 . However, externally sponsored CTs have also been accused of taking unfair advantage of inadequate research regulations and oversight in developing countries 6 . As a result, many countries in the region have introduced new regulatory protections 7,8 . Again, Chile is a good example: In 2012 Law 20.584 9 prohibited research with subjects who are unable to provide informed consent due to cognitive impairment, and in 2015, Law 20.850 10 introduced stringent regulatory protections concerning compensation for research injuries and post-trial access to research treatments.
However, even well-intended regulatory protections can have unwanted consequences for the countries that promulgate them. Requirements that are more strict than the provisions of international ethical guidelines, or contain vague formulations and leave procedures unclear, can lead sponsors to conduct their CTs in countries with more convenient regulations 11 . In Chile, the introduction of Law 20.850 has indeed been followed by a 20% decline in the number of CTs registered in the country 12 . However, little is known about the characteristics of CTs conducted in Chile.
To investigate this issue, this article reviews data from registered CTs on pharmaceutical products in Chile over the last decade and characterizes them with respect to phase, sponsorship and diseases studied. To evaluate the extent to which CTs address local health needs, the proportion of CTs targeting each disease group is compared with the burden of disease attributable to that group in Chile. This investigation can shed light on how international research is being conducted in Chile, the effects of new regulatory protections, and how responsive the research is to local health needs and priorities.

Material and Methods
In this study, I examined data on 876 CTs registered in Chile from 2010-2019, obtained through a freedom of information request to the Chilean Institute of Public Health (Instituto de Salud Pública or ISP). Sponsors are legally required to register all CTs on pharmaceutical products that have not been previously approved, or approved for a different application, by this regulatory agency 13  To assess whether the conditions studied by CTs were aligned with the burden of disease in Chile, the local burden was measured in disability-adjusted life years (DALYs), a measure that represents the number of years lost due to illness, disability, or premature death. The estimate of DALYs for Chile was based on the Global Burden of Diseases 2017 Study 14 . Following Atal et al. 15 , I considered that there was a research gap for a disease group when the proportion of CTs corresponding to that group (registered over the observed period) was less than 50% of the proportional burden of disease attributable to that group. For example, if in Chile 14% of the burden of disease corresponds to neoplasms and the proportion of trials corresponding to that disease group is less than 7%, then there is a research gap. A partial research gap was identified when the proportion of CTs relative to the local disease burden fell between 50% and 75%. When that proportion was higher than 75%, research was considered to be aligned with the local disease burden.
The classification of disease groups was also based on the Global Burden of Diseases 2017 Study, which classified diseases into 22 groups at Level 2 of aggregation 16 . When more specificity was needed, disease groups were also broken down into more specific disease categories at Level 3 of aggregation. For example, the Level 2 group neoplasms maps onto 46 different cancer categories at Level 3. Finally, the classification of each trial was performed based on the study title as provided by the ISP. When the title suggested the study of more than one condition, the trial was classified based on the primary disease under study.

Trends in trial sponsorship 2010-2019
Over the studied period, 96.5% of CTs on drugs in Chile have been sponsored by external pharmaceutical companies or research organizations. Local pharmaceutical companies sponsored 1.1% of CTs, whereas 2.4% of CTs were funded by non-profit institutions: local universities (0.5%), external universities (0.6%), local non-profit institutions (0.5%), and external non-profit institutions (0.9%). This overall distribution has remained stable throughout the studied time frame.
Among external pharmaceutical companies sponsoring CTs in Chile, 10 companies have sponsored 50% of CTs. Bristol-Myers, Sanofi-Aventis, GlaxoSmithKline, and AstraZeneca are among the top 5 sponsors, with Merck SD taking the lead with 9% of all CTs (Table 1). Sponsorship for the remaining 50% of CTs is diverse and includes the participation of 170 pharmaceutical companies and two Contract Research Organizations (CROs), which provide research services for large pharmaceutical companies.

Clinical trials by phase and disease groups
Over the studied period, 4% of CTs were phase 1, 23% phase 2, 68% phase 3, and 5% phase 4 ( Figure 1). Across time, the proportion of CTs has remained almost constant for phase 2 and phase 3; however, after 2015, there has been an overall increase in the propotion of phase 1 trials (3% to 7%) and a decrease in the proportion of phase 4 trials (6% to 3%).
With respect to the distribution of CTs by disease group (at Level 2 of aggregation), the most studied diseases correspond to neoplasms (26%), musculoskeletal disorders (12%), other nonconmmunicable diseases (11%), chronic respiratory diseases (10%), diabetes and kidney diseases (6%), neurological disorders (6%), and cardiovascular and circulatory diseases (6%). Seven disease groups were each studied in a proportion between 1% and 4% of CTs. Of the remaining nine disease groups, each of them was studied by less than 1% of CTs (Table 2).

Clinical trials by disease groups after the enactment of Laws 20.584 and 20.850
In the three years following the enactment of Law 20.584 in 2012 there was a decrease in the proportion of CTs studying other noncommunicable diseases (15% to 10%), neurological disorders (9% to 6%) and mental disorders (4% to 1%). On the other hand, during the same time period there was an increase in the proportion of CTs studying five disease groups, notably chronic respiratory diseases (10% to 13%), respiratory infections and tuberculosis (2% to 5%) and neoplasms (19% to 21%). The remaining disease groups stayed constant or their proportion varied less than 2% between pre-and post-law periods (Figure 2).
With respect to Law 20.850, after it was enacted in 2015 there was a increase in the proportion of CTs studying neoplasms (20% to 38%), digestive diseases (2% to 7%), respiratory infections and tuberculosis (3% to 4%), sense organ diseases (1% to 2%), and maternal and neonatal disorders (1% to 2%). By contrast, the proportion of CTs studying seven disease groups has decreased, notably other noncommunicable diseases (12% to 9%) and chronic respiratory diseases (12% to 7%). The remaining disease groups have stayed constant between pre-and post-law periods (Figure 2).

Alignment between CTs and the burden of disease in Chile
When viewed at Level 2 of aggregation, 11 of the 22 disease groups' local burden of disease is aligned with the research effort (measured as the respective number of CTs registered between 2010 and 2019). They include the two disease groups with the highest burden of disease in Chile (neoplasms and musculoskeletal disorders). In contrast,  in 9 disease groups the local burden of disease is misaligned with the research effort (i.e. there is a research gap). They include the third and fourth main causes of disease burden in Chile (cardiovascular and circulatory diseases and mental disorders). Finally, there is a partial alignment between research effort and disease burden for two disease groups (digestive diseases and sense organ diseases) ( Table 2).
To examine how much research effort is placed on more specific diseases associated with a high disease burden in Chile, a similar analysis was carried based on the ten most common causes of DALYs in Chile considered at Level 3 of aggregation. These are low back pain, ischemic heart disease, stroke, diabetes, cirrhosis, neonatal disorders, depressive disorders, headache disorders, road injuries, and anxiety disorders. Altogether, these disease categories correspond to 37% of the Chilean burden of disease. However, just 16% of CTs registered between 2010 and 2019 address one of them.

Discussion
The globalization of clinical research over the last two decades has seen a migration of CTs to emerging economies with a high proportion of industry-sponsored research. Chile provides a good example of this phenomenon, as well as of attemps to protect research participants through legal requirements. The present study provides the first analysis of trends in CTs over an extended period in a Latin American country, including trial sponsorship, diseases studied, and the effects of new legal protections.
The vast majority of CTs in Chile are sponsored by external pharmaceutical companies or CROs and 70% correspond to late-phase or post marketing studies. This is consistent with data about CTs conducted in other emerging regions 17,18,19 . In contrast, a marginal amount of CTs in Chile are sponsored by local pharmaceutical companies, universities, or other non-profit institutions. This may be due to several factors, including the high costs of conducting CTs, and insufficient research training and infrastructure 20,21 . Even though progress has been made in the development of funding instruments for basic and applied research in Chile, public support for the long and costly clinical trial process remains limited 22,23 . These factors can also help explain the low proportion of phase 1 and 2 CTs conducted in Chile, since these early-phase CTs are more demanding in terms of the research capacity and infrastructure required.
For private sponsors, the ten largest global pharmaceutical companies (by market share) 24 have a share in the sponsorship of CTs conducted in Chile. Five of those companies figure among the top ten sponsors in the country (Table 1). However, there is a strikingly high number of different private for-profit entities (n = 182), resulting in most of them (n = 143) being sponsors of less than three CTs in Chile over the studied period. These are mostly small and medium-sized pharmaceutical companies, which have been described as "the growth engine of the pharmaceutical industry" 25 .
The overall distribution of disease groups studied since 2010 shows that the majority of CTs registered in Chile (59%) are concentrated on four groups: neoplasms, musculoskeletal disorders, other noncommunicable diseases and chronic respiratory diseases ( Figure 2). In contrast, the nine disease groups that are less studied by CTs comprise less than 5% of CTs registered in the country. The overall research effort appears to be partially aligned with the burden of disease in Chile. Even though half of the 22 Level 2 disease groups show a good alignment between CTs studying them and the disease burden, some diseases with a high local burden appear to be understudied (e.g. cardiovascular and circulatory diseases and mental disorders). This idea is confirmed by the more specific analysis of disease groups at Level 3 of aggregation, which shows a research gap for the ten most common causes of DALYs in Chile. Therefore, the partial alignment between research effort and disease burden in Chile may be less than what was suggested by the analysis of diseases at Level 2 of aggregation.
Law 20.584 has been followed by a sharp decline in CTs targeting neurological disorders and mental disorders. Since there has been no global downward trend in CTs studying those disease groups 26 , this decline may be explained by the fact that law 20.584 prohibited research with subjects who are unable to provide informed consent due to cognitive impairment. This is cause of concern since neurological and mental disorders are among those with the highest burden in Chile. As for Law 20.850, the reduction in the overall number of CTs after its enactment has been accompanied by an increase in the proportion of CTs dealing with certain disease groups, notably CTs studying neoplasms which have more than doubled after 2015. This may be explained by the fact that oncology is the area with the largest proportion of clinical development spending worldwide 27 . Research on neoplasms in Chile is worthwhile since this disease group causes important social and economic burdens, which can be expected to increase given the country's rapidly aging population 28 . Meanwhile, the proportion of CTs studying certain disease groups has declined after Law 20.850. The most significant reductions (to half or less of their prelaw percentage) have been in cardiovascular and circulatory diseases, mental disorders, and neurological disorders. This is concerning since these disease groups are among the top five groups with the highest disease burden in Chile.
There are some limitations to the present research. CTs included in this study are just those registered in the ISP and therefore focus on testing pharmaceutical products. Unfortunately, registration of non-pharmaceutical CTs is not mandatory in Chile and there is no reliable registry of them. This omission may lead to an underestimation of the local research effort, in particular concerning disease groups which are less likely to be studied through pharmacological interventions (e.g. transport injuries). In addition, given that the absolute number of CTs conducted in Chile is relatively low, the variations observed after the enactment of Laws 20.584 and 20.850 may not justify categorical statements.

Conclusions
Clinical trials conducted in Chile over the last decade are largely funded by external pharmaceutical companies, with marginal participation of local private or public sponsors. The majority of CTs correspond to late-phase studies focusing on four disease groups. The introduction of new regulatory protections has been followed by a decline in CTs studying certain disease groups associated Trends in clinical research in Chile -B. Aguilera with a high disease burden in Chile, which is cause of concern. At the same time, CTs studying other disease groups associated with high local buden (especially neoplasms) have increased in recent years, which may be explained by global trends in industry reseearch. But since the absolute number of trials per year has decreased after the regulatory protections, it is plausible to hypothesize that the regulations have had a disincentivizing effect on at least some areas of research.
Overall, CTs in Chile are partially aligned with the local burden of disease. When disease groups are broken down into more specific categories, diseases carrying the highest local disease burden appear to be associated with a relatively low research effort. This suggests that the decision of which diseases are targeted by CTs in Chile is based on commercial interests and not on what are the most pressing health needs of the population (Cf. 29). Regulations and policies that promote collaborative partnerships between external sponsors and local authorities, as well as provide more funding and support for local researchers, may pave the way towards making CTs more responsive to the local health priorities and more likely to yield benefits such as improving local healthcare and research capabilities.