Introduction
Low- and middle-income countries (LMCs) disproportionately bear the rising global cancer burden [
1],[
2]. Clinical research needs to address this high cancer burden in resource-limited settings, but only 10% of world’s expenditure on health research has focused on issues in lower resource settings [
1],[
3],[
4]. Simultaneously, clinical trials are becoming increasingly globalized. From 1995 to 2005, trial participation in sites outside of the United States more than doubled, including LMCs [
5],[
6]. A recent study found that 78% of clinical trials evaluating cancer therapies published between 2007 and 2011 were conducted in developed countries, while 22% of trials were conducted in developing countries [
7]. However, few studies have quantitatively addressed the role of LMC investigators in global clinical trials or ethical issues associated with their participation [
8].
To capture the level of involvement by investigators from different countries in randomized oncology trials, we systematically reviewed a cohort of published trials and describe trends in participation in these publications by LMCs investigators. Trial involvement includes tasks such as enrolling patients (participation) as well as more academic tasks such as participating in writing up study results (authorship). Our primary focus was on authorship trends but we also describe trends in other tasks where the information was available. We focused on oncology randomized control trials (RCTs) over a decade (1998–2008), specifically documenting the role of LMC investigators in clinical trials as reflected in the publication and the applicability of these trials to local resource settings when LMCs participated. We hypothesized that LMC authorship and participation in publications describing oncology RCTs increased over time, but that few LMC authors had leadership roles and few trial interventions were relevant to lower resource settings even when LMC investigators were involved.
Methods
Identification of studies
All phase III clinical trials from January 1, 1998 to December 31, 2008 evaluating treatment in five cancer cancers (lung, breast, colorectal, stomach, liver) were systematically identified from MEDLINE. We selected these cancers based on GLOBOCAN 2002 and American Cancer Society statistics which showed these cancers have the highest global mortality rates. Details of the search are listed in the Appendix. Articles retrieved from MEDLINE were then manually screened for inclusion in the study. Inclusion criteria were: 1) pertaining to one of 5 cancer sites (lung, breast, colorectal, liver or stomach), 2) published in English language, 3) evaluating a treatment intervention (chemotherapy, radiation therapy, surgery, palliative care, hormones or monoclonal antibodies/targeted agents), and 4) absence of exclusion criteria. Exclusion criteria were: 1) prevention, screening or diagnostic procedure trials, 2) articles presenting follow-up or updated data from previously published trials, or 3) sub-studies.
Data abstraction
From each article, information was extracted directly into a pre-designed electronic database, which underwent pilot testing to ensure face validity and inter-observer reliability. The following data were included: 1) year of publication, 2) country affiliations of first, corresponding and middle authors, 3) country affiliations of participating centers and additional investigators (where available), 4) trial characteristics, 5) types of treatment, 6) documentation of ethics, informed consent and funding sources, and 7) whether relevance of study to LMCs was discussed. Based on Gross National Income data available from World Bank statistics (2009), countries were stratified into high ($11,456 or more per capita), middle ($936-$11,455) and low ($935 or less) income groups. Corresponding author was defined as the primary contact author for the publication, while senior author was defined as the last author on the author list. First, corresponding or senior authorship positions were deemed as leadership roles. Participating centers were defined as institutions that were listed in the publication as having enrolled study participants. Interventions were divided into basic, limited, enhanced and maximal categories based on estimated cost and resources required for implementation as established previously for breast cancer and by one of the authors (MKK) for the other cancer sites applying general guiding principles set out by the Breast Health Global Initiative [
9]. Briefly, we considered basic resources to be core healthcare services (e.g. modified radical mastectomy); limited resources were key services that required limited finances and infrastructure (e.g. cyclophosphamide, methotrexate, 5-fluorouracil); enhanced resources were optional services that increased the number and quality of therapies (e.g. taxanes); and maximal resources were services that had lower priority in lower resource settings due to high cost or impracticality (e.g. growth factors) [
9]. Ethics were reported as documented if the publication explicitly stated that ethics approval was obtained for the study.
Statistical analysis
Summary statistics were used to present the data. We examined associations between whether studies had any authors from a low or middle income country (yes or no) and the following variables: year of publication, cancer site, funding type, multi- versus single-centre participation, use of placebo, type of treatment, treatment aim, type of randomized trial, ethics documentation, and whether the study mentioned informed consent. Adjusted analyses were performed using logistic regression, entering all variables into the model except for whether the study mentioned informed consent, due to small cell counts. No evidence of multi-collinearity was found (all variables had tolerances > 0.4). Assessment of the model’s calibration with the Hosmer-Lemeshow test (p-value = 0.67) and discrimination (C-statistic = 0.76) did not show lack of fit. Graphics were created in R v 2.13.1 (R Development Core Team, Vienna, Austria) and statistical analyses were conducted using SAS version 9.0 (SAS Institute Inc, Cary, NC).
Discussion
Through this systematic review, we found that the absolute number of publications describing oncology RCTs and the proportion of these publications that involved LMC investigators as authors increased over time. Most of the increased LMC authorship involved investigators from middle- rather than low-income countries and usually in non-leadership roles, ie. as middle authors. There were several publications that listed participating sites in LMCs but did not include investigators from those sites as authors. Since not all the publications listed all participating sites, while the absolute number of publications that included LMC authors has increased over time the proportion of studies that recruit in LMCs and include at least one LMC author may not be changing and may even be actually proportionally decreasing over time. A recent study found that, despite participation in global clinical trials, researchers from lower resource settings had proportionally lower rates of authorship per patient enrollment, compared to researchers from higher resource settings [
10]. Our study differs from this previous study by focusing specifically on publications in the area of oncology, and addressing additional issues such as relevance of interventions to LMC settings.
We found that publications describing industry funded RCTs were more likely to have authors from LMCs. This may be related to the spatial scope of the trial as industry funded trials are often larger and multinational thus there may be more opportunity for LMC investigators to participate in the trial. Unfortunately, we were unable to optimally control for spatial scope of the trial as information on participating countries was not available for approximately 40% of the manuscripts. Nevertheless, participation of LMC investigators in industry funded cancer trials can theoretically be mutually beneficial: LMC research centers may reap financial benefits from participating in industry trials, while the pharmaceutical industry may reduce costs in multinational trials by conducting them in LMCs [
6],[
11]. However, ethical concerns have been raised. LMCs centers traditionally have less regulation and transparency in the conduct of research [
6],[
12]. Compared to an average study participant from a higher resource setting, the average LMC study participant more likely perceives financial compensation for trial participation as substantial, or lacks understanding about the concept of clinical trials [
6]. The LMC investigators may also be more vulnerable in industry-funded trials: a recent study showed that the discrepancies in authorship between lower and higher resource settings in global clinical trials were exacerbated when the trials were industry-funded [
10].
Approximately two thirds of the publications in our cohort that included investigators from LMCs evaluated interventions that required at least enhanced resources for their delivery. This concerning finding resonates with the existing literature on the gap between research efforts and LMC needs. Although LMCs’ involvement in oncology trials may provide them with early access to interventions [
5], such interventions may not be feasible or even affordable in low resource health care systems in the real-world setting [
6],[
11]. Furthermore, most cancer drug development efforts do not focus on tumor types most relevant to LMCs: in a review of phase II and III cancer drug trials, treatments for cancers of the breast, lung, prostate and colorectal were most frequently studied [
13]. In higher income countries, there was a correlation between the incidence, prevalence and mortality of a type of cancer to the number of trials for that specific cancer [
13]. In LMCs, only prevalence correlated, suggesting that trials lacked emphasis on the actual cancers carrying higher mortality in LMCs [
13]. Similar disconnect between burden of disease and trials conducted in lower resource settings has been found in other medical conditions [
14]-[
16]. However, there are likely also inherent benefits for LMC centers that participate in clinical trials. These include gaining access to newer therapies, other healthcare provisions or improved quality of care during trials [
5],[
11],[
17], improving infrastructure including equipment or human capital [
17], improving global information exchange [
5], academic achievement or scientific progress [
11].
Global taskforces have discussed potential solutions for the high cancer burden in the lowest resource settings. The World Health Organization has developed global strategies and preventative measures [
18]. A number of cancer specific initiatives by oncology organizations have addressed breast cancer in LMCs [
19]. For example, the 2007 Breast Health Global Initiative has developed guidelines for radiation therapy [
20], pathology [
21], treatment resource allocation [
22], diagnosis resource allocation [
23] and early detection resource allocation [
24] in breast cancer. The 2010 Breast Health Global Initiative summit analyzed challenges in breast cancer management in LMCs [
25]. The U.S. Centers for Disease Control and Prevention, American Cancer Society and National Cancer Institute are leading other initiatives [
19].
How can we improve cancer treatment and outcomes in LMCs? Some authors have noted that improvement in breast cancer survival in the United States occurred before introduction of technological advances, raising the possibility that cancer survival in LMCs may be improved by focusing on increased awareness and early detection of cancers and by optimizing primary care and referral systems [
26]. Tele-oncology may also improve cancer survival in LMCs [
27]. A focus on primary prevention and screening, early diagnosis, low cost therapy and establishment of regional initiatives may improve care in LMCs [
28],[
29]. Finally, cancer treatment and outcomes are inextricably linked to research, and while improving access to existing treatments is important, we feel that investing in research that is relevant to LMCs will be key to ensure appropriate care relevant to local settings.
Our review has a number of limitations. First of all, given the lag between study design and publication, our review reflected trials that were predominantly designed in the 1990s. A review of trial registries – ideally multiple registries to ensure a comprehensive and international approach – could be helpful to provide a more current overview of LMC involvement in oncology trials. We also did not collect information on when studies were conducted, as studies may have been conducted several years prior to publication. Nevertheless, our review provides a baseline assessment for future comparisons and identifies a number of concerning trends to monitor. Secondly, a number of publications did not provide full listings of participating countries. Underreporting of participating countries probably leads to an underestimation of LMC participation more so than participation from higher resource settings, as higher resource settings were more likely to have been also listed in authorship affiliations. Acknowledgement of LMCs must be more consistent in published manuscripts. Lastly, we have limited our search to English language articles and there is the possibility that LMC relevant trials may have been published in local journals in other languages. We would encourage future studies to look at studies published in other languages.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
JC conducted the literature review and wrote the first draft of the manuscript. KF performed statistical analysis. SA participated in design of the study and literature review. ZL participated in the design of the study. MKK conceived of the study, and participated in its design and coordination. All authors read, edited and approved the final manuscript.