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Health and Ethical Consequences of Outsourcing Pivotal Clinical Trials to Latin America: A Cross-Sectional, Descriptive Study

  • Núria Homedes ,

    nhomedes@gmail.com

    Affiliations Management Policy and Community Health, School of Public Health, University of Texas, El Paso, Texas, United States of America, Department of International Health, Georgetown University, Washington DC, United States of America

  • Antonio Ugalde

    Affiliation Department of Sociology, University of Texas, Austin, Texas, United States of America

Health and Ethical Consequences of Outsourcing Pivotal Clinical Trials to Latin America: A Cross-Sectional, Descriptive Study

  • Núria Homedes, 
  • Antonio Ugalde
PLOS
x

Abstract

Introduction

The implications of conducting clinical trials in low and middle income countries on the financial accessibility and safety of the pharmaceutical products available in those markets have not been studied. Regulatory practices and ethical declarations lead to the commercialization of the new products, referred to as New Molecular Entities (NMEs), in the countries where tested as soon as they are approved in high surveillance countries. Patients and patients’ associations use the Latin American courts to access new and expensive treatments, regardless of their safety profile and therapeutic value.

Design and Objectives

Cross-sectional, descriptive study. To determine the therapeutic value and safety profile of the NMEs approved by the Food and Drug Administration (FDA) in 2011 and 2012 that had been tested in Latin America, and the implications of their market approval for the pharmaceutical budgets in the countries where tested.

Setting

Latin America.

Measures

To assess the therapeutic value and safety of the NMEs commercialized in the different countries we used f independent drug bulletins. The prices of the NMEs for the consumers were obtained from the pharmaceutical price observatories of the countries were the medicines had been tested. If the price was not available in the observatories, it was obtained from pharmaceutical distributors. We used the countries’ minimum wage and per capita income to calculate the financial accessibility of a course of treatment with the NMEs.

Results

We found that 33 NMEs approved by the FDA in 2011 and 2012 have been tested in Latin America. Of these, 26 had been evaluated by independent drug bulletins and only five were found to add some value to a subset of patients and had significant side-effects. The pharmaceutical prices were very high, varied widely across countries and were unrelated to the countries’ income per capita or minimum wage.

Conclusion

The implementation of clinical trials in Latin America results in the commercialization of medicines with questionable safety profiles and limited therapeutic value, putting patients at risk and causing budgetary strains in pharmaceutical budgets.

Introduction

The trend in outsourcing clinical trials (CTs) to low and middle income countries (LMICs) has been well documented. Shortening the duration of the clinical trials has been identified as one of the major strategies to expand the duration of inventors’ monopoly-power. To that effect, an increasing number of clinical-trial participants are recruited in LMICs (or host countries) [1, 2], where patients are more easily recruited and retained, allowing the pharmaceutical industry to expedite the completion of the CTs and the attainment of marketing approval for the new molecular entities, thus maximizing the NMEs’ market-exclusivity period [3]. The inability to recruit enough research participants in high-income countries [4] and the few regulatory hurdles in LMICs reinforce this tendency.

There has been little scrutiny of the consequences that conducting CTs has on the availability, appropriate and safe use of the new pharmaceuticals, as well as on the health budgets of the host countries. International ethical declarations require that approved NMEs be made available to the populations in which they have been tested [5]. The Latin American regulatory agencies base their marketing decisions on the actions taken by their counterparts in “high sanitary surveillance countries” (United States, Japan, Australia, selected individual countries in Europe and the European Medicines Agency). In other words, once one of these agencies approves the commercialization of a NME, the drug should be made available in the countries where it had been tested.

Additionally, Latin American patients and patient groups are increasingly using the judiciary system to exercise their constitutional right to health, including access to new and expensive pharmaceuticals. Vargas-Pélaez et al [6] conducted a scoping study of the literature on lawsuits for access to medicines and health services. They identified 65 articles, and 80% of them involved a Latin American country (68% Brazil, 9% Colombia and 3% Argentina). The Latin American authors cited in this study mentioned that in some cases the courts decide without taking into consideration the evidence of drug efficacy and safety or the appropriateness of the treatment for a particular patient, possibly putting the plaintiff at risk of adverse effects and drug misuse. Moreover, some authors asserted that the pharmaceutical industry was interested in promoting access to medicines through the courts, because it resulted in the inclusion of medicines in the public formularies that might be useful for only a small group of patients rather than the needs of society.

The final result of this ethical principle and regulatory practice is that those countries where the NMEs have been tested have to cover the costs of the NMEs, regardless of their safety profile and whether they offer any advantage over cheaper existing treatments.

While the magnitude of the financial impact will differ across countries and will in part depend on the sales price of the NMEs in each country, public coverage of these new and expensive NMEs will strain the public pharmaceutical budgets.

The health consequences of outsourcing CTs have been off the radar of researchers, possibly because it is assumed that the regulatory agencies of “high sanitary surveillance countries” only allow the commercialization of products that are safe and effective, and what is available to the residents of high income countries ideally should also be offered to the residents of less prosperous countries, especially if they have contributed to their development.

This is the first study that questions the health benefits of the CTs implemented in Latin America not only for CT subjects but for the health systems and residents of those countries.

Using information on pricing and value of the NMEs approved by the FDA in 2011 and 2012 that were tested in Latin America, this article analyzes the health, financial and some ethical consequences of outsourcing CTs to the region.

Methods

This is a cross-sectional, descriptive study. The objectives were: (1) to determine the therapeutic value and safety of the NMEs approved by the FDA and tested in Latin America; and (2) to assess the financial accessibility of the NMEs in the countries where they had been tested. The list of NMEs approved by the FDA in 2011 and 2012 was obtained from FDA publications [7, 8]. The FDA’s medical reviews of the NMEs, included in the FDA’s drug approval history, provided the names of the countries where the CTs had been conducted. The drug approval histories can be found in the Drugs@FDA website [9]. If the medical reviews fail to mention the countries where the pivotal trials were conducted, we contacted the trial sponsors. It is possible that a few Latin American CTs included in our study were non-pivotal trials.

Data bases from two reputable independent drug bulletins, namely Prescrire (France) and the Health Research Group of Public Citizen (HRG) in the United States were consulted for evidence of the added therapeutic value of the NMEs to existing treatments. Prescrire often included information from other independent bulletins. The assessment of cancer treatments was supplemented with information from Fojo et al.[10].

The price of the unit dose of each product was obtained from the countries’ price observatories, which report the maximum price to consumers (Brazil, Mexico) or the observed consumer prices (Argentina, Chile, Colombia, Ecuador, Peru). In a few cases, when the information was not available in the observatories, local pharmaceutical experts obtained it from local distributors. The quantities needed to complete a course or a year of treatment, in the case of chronic conditions, were calculated by the authors using the recommendations included in the FDA-approved product label. We assessed the cost of a course of treatment with each NME in the countries where tested in absolute value, and as a proportion of the countries’ monthly minimum wage and monthly per capita income. The pricing information was gathered between August 25th and September 20th, 2014. (For additional information on pricing sources and the methodology to determine financial accessibility see Homedes and Ugalde [11]).

Findings

The 33 NMEs approved by the FDA in 2011 and 2012 and the Latin American countries where they were tested are listed in Table 1.

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Table 1. Products approved by the United States Food and Drug Administration in 2011 and 2012 that were tested in pivotal trials in Latin America.

https://doi.org/10.1371/journal.pone.0157756.t001

Therapeutic value and safety of the NMEs

Prescrire and/or HRG evaluated 26 of the 33 NMEs included in this study, and determined that 21 of the 26 (80%) offered no therapeutic advantage over existing treatments, had significant side effects and advised against the use of ten of them (See Table 2). According to these sources and the independent bulletins cited by Prescrire, the remaining five products (crizotinib, enzalutamide, ipilimumab, pasireotide, and telaprevir) could offer some advantage to a subset of patients, but the risk-benefit ratio was still uncertain. Only three of these five products were available in the countries where tested.

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Table 2. Clinical relevance of NMEs approved by the FDA in 2011 and 2012 according to independent drug bulletins.

https://doi.org/10.1371/journal.pone.0157756.t002

Of the 33 products included in our study, eight (25%) were included in Fojo et al’s evaluation [10]. Only one of them (enzalutamide) increased overall survival significantly: (by 4.8 months) in patients with castration-refractory prostate cancer); four increased the progression-free survival period (vandetanib, pertuzumab, carbozantinib, crizotinib), two NMEs did not fulfill the American Society of Clinical Oncology (ASCO) criteria to determine clinical relevance (ziv-aflibercept, regorafenib), and the authors were uncertain about ipilimumab (See Table 3).

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Table 3. Efficacy of oncological treatments approved by the FDA in 2011 and 2012 as evaluated by Fojo and collaborators (2014).

https://doi.org/10.1371/journal.pone.0157756.t003

In contrast with the methodology used by the independent drug bulletins mentioned above, Fojo et al. [10] assessed the value of each NME without comparing it with other treatment options. Two NMEs that qualified as useful in their publication (vandetanib and pertuzumab) were questioned by the independent drug bulletins. Vandetanib was considered more dangerous than beneficial, and the benefit-risk ratio of pertuzumab was judged to be insufficiently known. While Australian Prescriber and Medical Letter thought that it appeared to increase survival without worsening the condition of HER-2 positive women with metastasis of breast cancer, Medical Letter thought that the effect on overall survival had not been determined and others considered that it increased the side-effects, the benefits were uncertain, and there was insufficient information to recommend its commercialization. At a price of more than US$50,000 (pertuzumab) and US$100,000 (vandetanib) per treatment in Brazil and US$200,000 in Argentina (vandetanib) these NMEs are not affordable.

Price of the NMEs in the Latin American countries where tested

As reported in a previous article by Homedes and Ugalde [11], two years after receiving market authorization in the United States, 12 of the 33 NMEs had not been registered or marketed in the Latin American countries where they had been tested. We obtained the prices of 18 of the remaining 21 NMEs and they are displayed in Table 4.

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Table 4. Price of medicines by countries where tested, by number of months of income needed to pay for a course of treatment or a year of treatment for chronic conditions by monthly minimum wage (MMW), monthly income per capita (MIPC)) in US$.

(All MNW and MIPC figures above 3 months have been rounded)a.

https://doi.org/10.1371/journal.pone.0157756.t004

Prices varied widely by country, both in absolute and in relative terms. Argentina had the highest absolute price for many of the drugs included in this study (aflibercept, apixaban, belatacept, ipilimumab, pasireotide, telaprevir, ticaglecor, tofacitinib, vandetanib), on occasion even doubling the second highest price (aflibercept, belatacept, tofacitinib). Brazil had the lowest prices for apixaban, belatacept, pertuzumab, rivoraxavan and ticaglecor, but the price of belimumab was more than twice that in Chile. The price of belimumab, indacaterol and ipilimumab was lowest in Chile; Colombia had the lowest price for aflibercept and tofacitinib, and the highest for rivoraxavan.

We could not find any relationship between prices and the GDP per capita or the minimum wages in these countries. In Brazil aflibercept costs US$15,259 per course of treatment; in Argentina, which has a slightly lower GDP per capita than Brazil, the course of treatment of the same medication is US$30,410. Brazilians pay 46 times the monthly minimum wage and Argentineans 58, unaffordable in both countries but considerably more in Argentina. If we compare aflibercept in Colombia and Chile, which has a considerably higher GDP per capita than Colombia, the drug is slightly cheaper in Colombia, but in Colombia patients have to pay twice as many monthly minimum wages as Chileans. In the case of indacaterol, in Colombia the cost of the drug is twice that in Chile, and the same is true for rivaroxavan. Many other significant price and monthly minimum wages differences can be found in Table 4.

Discussion

The pharmaceutical industry had commercialized about two thirds of the NMEs approved by the FDA in the Latin American countries where they had been tested, within two years, but only a handful offered some advantage over existing treatments for specific groups of patients. Despite large price differentials across countries, all NMEs but one were being sold at highly unaffordable prices [11].

Fojo et al. [10], documented that the median gain in progression-free and overall survival offered by therapies for solid tumors approved by the FDA between 2002 and 2014 (N = 71) were 2.5 and 2.1 months, respectively. Subsequently, the authors used standards similar to those developed by four disease-specific groups of ASCO’s Research Committee to determine the clinical relevance, in terms of overall survival and/or quality of life, of the 71 NMEs approved by the FDA during the 12 year period. Although the standards were recognized as modest, the authors concluded that only 30 NMEs (or 42%) provided “clinically meaningful improvements.”

We have not found any explanation in the literature for the significant price differentials of the same NMEs across the Latin American countries. Exploring the reasons for the differences would require a detailed analysis of all the drug pricing components in each country, including the manufacturer’s sale price, transportation costs, importation tariffs, the margin of benefits for distributors and dispensers, sales taxes and others. This analysis could guide governmental decisions to make products more affordable, but it is unlikely to explain the wide price-differentials that we have observed in the region. Moreover, our data do not support the hypothesis that pharmaceutical manufacturers are abiding by WHO recommendations and setting prices according to the wealth of countries (differential pricing) [11]. Why the same drug requires a higher financial burden for Colombians than Brazilians, Mexicans or other Latin Americans needs to be clarified. More collaboration among pharmaceutical policy makers and procurement experts across countries could lead to improved pricing structures for the region.

In Latin America, patients and patient groups—often financially supported by the innovative pharmaceutical companies—are increasingly using their Constitutional right to health to sue the governments [4044] to gain access to the newest treatments that had not been included in the national formularies [4547]. It has been documented that judges base their decisions on individual needs instead of societal priorities; if this trend continues, health care systems will be severely strained and many could go bankrupt [4653]. This practice, known as judicialization, may have the undesirable health effect of exposing patients to NMEs that according to independent drug bulletins should not be used.

Given the approval process of the FDA and EMA [5462], which tend to approve all NMEs without ensuring that they are more effective and/or safer than existing treatments, the Latin American regulatory agencies could consider delinking their drug approval decisions from those agencies and instead use the advice of independent organizations that tend to provide more accurate assessments of the therapeutic value of the NMEs. Because of the dearth of true innovation, delaying the approval of NMEs until independent reports are available will not result in detrimental health effects for the residents in these countries. Exceptions could be made for true breakthrough NMEs. Given the relative importance of these pharmaceutical markets, such a change would not have a significant impact on the economic performance of the industry.

The fact that a large proportion of NMEs failed to add therapeutic value to existing treatments and had significant side effects leads us to conclude that the patients enrolled in the experimental arm of the clinical trial were in fact worst off than if they had received the standard treatment. Similarly, the patients included in the control arm, except those who received the best available treatment, were also incurring unnecessary risks, especially if they were enrolled in a placebo-controlled or non-inferiority trial. Some of these risks could potentially have been avoided if research sponsors had conducted a more in-depth analysis of the results of pre-clinical studies and of earlier phases of the CTs [63, 64] and if the NMEs were always tested against the best available treatment. To consciously expose research participants to unnecessary risks would translate into a violation of the ethical principle of beneficence.

According to article 20 of the Helsinki Declaration, vulnerable populations should not be subjects in clinical trials when the products can be tested in non-vulnerable populations. All products included in this study, except bedaquiline, which is used in the treatment of multidrug-resistant tuberculosis, could have been tested in non-vulnerable populations. In Latin America, most subjects who participate in clinical trials tend to be of low socioeconomic status, are often medically illiterate, and according to some authors should be considered vulnerable [6567].

If the 26 products included in our study, for which we obtained efficacy and safety information from independent sources, are a representative sample of the efficacy and safety of drugs that are tested in Latin America, there are several questions that need to be pondered: (1) Were all the clinical trials necessary? (2) Did the CTs have to be conducted in the vulnerable populations of Latin America? (3) Were the risks and benefits of participating in research being equally distributed in the population, as required by the ethical principle of justice?

Study Limitations. The FDA reviews included the clinical trials with the NMEs but did not always specify which clinical trials were used to approve the NME. As a result in a few cases we could have included countries where non-pivotal clinical trials were conducted. The information on medicine prices was collected in August-September 2014, and the information on GDP and Minimum wage dates from 2013 or 2014. Moreover, the countries included in our countries are highly inequitable; therefore the population in the lowest income deciles would have harder difficulties accessing the NMEs than we have reported in this study.

Conclusion

Three of the five products that the independent drug bulletins classified as offering some advantage over existing treatments for some patients were commercialized in the Latin American countries where tested (ipilimumab, pasireotide, telaprevir), but their cost, above US$44.000 per year or per treatment, made them unaffordable to the majority of the Latin American population.

The outsourcing of clinical trials to Latin America may have produced some financial benefits to the pharmaceutical corporations but may also financially strain public budgets while exposing test subjects and those who access the NMEs to health risks.

Latin American regulatory agencies should be very cautious in adopting the commercialization decisions of the FDA or of the regulatory agencies of other high sanitary surveillance countries, and include the advice of independent research groups in their regulatory decisions.

Since the large majority of CTs included in this review have failed to demonstrate new therapeutic value, and instead have largely resulted in the commercialization of drugs that independent drugs bulletins consider to be less safe than available therapies, Latin American governments, regulatory agencies and research ethics committees should be very vigilant when authorizing clinical trials, at least until the innovative pharmaceutical companies reverse the current research and development (R&D) model. It is unethical to expose subjects to high health risks, particularly in Latin America where most of the subjects are vulnerable, when the potential benefits for them or for their country are limited.

In addition, by approving the implementation of the CTs of NMEs, the countries risk having to purchase very expensive products, endangering the budget of the ministries of health without improving the health of the patients.

It will be useful to analyze the reasons for the differences in the price of the drugs across the different countries of the region. While the answer might be multifactorial, we hypothesize that a major contributor is that pharmaceutical firms charge whatever they consider the country is willing to pay.

Acknowledgments

Our task could not have been completed without the assistance of the experts who helped us gather the prices of some NMEs: Martín Cañas (Argentina), Corina Bontempo Duca de Freitas (Brasil), Andrea Carolina Reyes Rojas and Oscar Andía (Colombia). We would also like to acknowledge Paul Eisenbraun for his editorial assistance. Both authors contributed to the design of the study, NH carried out the data collection, and both authors contributed equally to the analysis of the data and the writing of this manuscript.

Author Contributions

Conceived and designed the experiments: NH AU. Performed the experiments: NH AU. Analyzed the data: NH AU. Contributed reagents/materials/analysis tools: NH AU. Wrote the paper: NH AU. Conceived the idea: NH AU. Collected the data: NH. Analyzed the results and conceptualized the presentation of results and discussion: NH AU. Equally contributed to this article: NH AU.

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