Mexico: more than 5,000 clinical experiments using human subjects

Doctor Susan M Reverby spent five years researching the Tuskegee study. This consisted of examining the effects of untreated syphilis in 400 poor black men who had been infected and who were denied any type of treatment for forty years. She found something totally unexpected: in the 1940s other experiments on syphilis had been carried out in Guatemala.

The Guatemalans subjects of these tests – prisoners, soldiers and the mentally challenged – did not know that they had been deliberately infected with syphilis. Just like those in the Tuskegee study, the Guatemalan subjects were not even informed that they were part of a clinical experiment.

Reverby’s findings not only prompted an investigation with respect to the United States; it also motivated the current president, Barack Obama, to offer an apology to his opposite number, Álvaro Colom, in October 2010.

The reason for this is that the National Institutes for Health (NIH), institutions that are part of the US health system and mandated carry out clinical tests throughout the world, financed the experiments in Guatemala.

In other countries, litigation has been commenced against transnational laboratories alleging irreparable damage to patients and violation of ethical principles during clinical experiments.

To date, the NIH has carried out 120,753 clinical trials in 178 countries, including Mexico. According to NIH statistics, they carried out 1,549 studies in Mexico; of these only 5% consisted of observation studies. In other words, 95% of the participants have been subject to interventions.

But the 1,500 clinical tests that the NIH performed, are not the only ones being carried out in Mexico. Data from public health institutions –obtained through Ley Federal de Transparencia y Acceso a la Información Pública Gubernamental– disclose the existence of 3,476 studies at the very least, that have been conducted which are similar to these.

There are 12 public health institutions in the country, whose mandate is to provide highly specialized medical services and to conduct scientific research in the health sector. Clinical tests were carried out at [nine of] these institutes [and they are]:
• Nacional de Cardiología Ignacio Chávez;
• Nacional de Ciencias Médicas y Nutrición Salvador Zubirán;
• Nacional de Enfermedades Respiratorias (INER);
• Nacional de Neurología y Neurocirugía Manuel Velasco Suárez;
• Nacional de Perinatología Isidro Espinosa de los Reyes;
• Nacional de Siquiatría Ramón de la Fuente Muñiz;
• Nacional de Rehabilitación;
• Nacional de Salud Pública; and
• Hospital Infantil de México Federico Gómez.

The [following] hospitals are also carrying out this type of study: General de México and Juárez de México.

Although all these public institutions admitted that they are carrying out clinical tests, the figure cited does not take into account all the studies carried out. This is because two institutions did not provide the relevant information. One of these was Instituto Nacional de Rehabilitación. It only gave details of two tests (the only ones concluded) and omitted to specify how many more are in progress. It argued that this information was confidential for 12 years.

Hospital Infantil de México neither provided information on the quantity and characteristics of the clinical tests already conducted. With respect to the tests in progress, it also responded that these are classified as confidential.

As for Instituto Nacional de Pediatría, while it provided Contralínea with information on the number of research plans registered and carried out in the period 2005 - June 2011, it did not specify which involved experimenting with humans.

Of the total of 3,476 clinical tests recorded in all the other institutes and hospitals, the following stand out:
• Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, that records 1,398 studies of this type in the period 1985 - 2011; and
• Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, with 1,353 investigations from 1996 through to 2010.

As for the number of people that participated in this type of test, not all the public institutions consulted provided accurate data. From the statistics provided, we deduce that there were at least 14,187 [participants].

But, the number of Mexicans that took part in a clinical test could be even higher; so too, the number of studies of this type carried out in the country. And it should include local public health institutions, academic research centres (both public and private), clinics and private hospitals and laboratories that carry out biomedical studies.

To find out the exact number of clinical tests taking place in Mexico, Contralínea requested Comisión Federal para la Protección contra Riesgos Sanitarios (Cofepris) [to give] the number of research protocols that it had authorized through a request for information, number 121500001412.

Ley General de Salud and Reglamento de la Ley General de Salud en Materia de Investigación para la Salud provides that in order to undertake a clinical test in Mexico, the health authority must authorize the research protocol that supports it. Within Cofepris, the Comisión de Autorización Sanitaria has been put in charge of reviewing research protocols on humans.

However, the reply given by the Secretary General and the Head of Unidad de Enlace de la Cofepris, José Rafael Fernández de Lara y Olivares, only handed over information relating to 2011. In the year before, 538 authorizations were granted to carry out investigations on human beings.

In relation to the protocol checked by Cofepris, we can see that most come from private research organizations such as:
• Instituto de Investigación Clínica de Occidente, SA de CV;
• Centro de Estudios Científicos y Clínicos Pharma, SA de CV; and
• Instituto de Investigación en Farmacología Clínica y Experimental, SA de CV.

Private health institutions also feature. These include:
• Centro Médico ABC – here a study by the pharmaceutical Baxter SA de CV was authorized;
• Hospital Ángeles de Puebla - here Eli Lilly y Compañía de México, SA de CV, has two protocols authorized; and
• Hospital Médica Sur - here Productos Roche, SA de CV, obtained consent to conduct a study.

As for information for previous years, Cofepris replied that prior to 2011, there were no statistics on authorizations of research protocols. Therefore, it was not possible to send this information.

It also stated that the Comisión de Autorización Sanitaria was established in December 2007, and began its activities in January 2008. This is why “after conducting an exhaustive search of all the files (in hard form and electronic) of the Commission’s technical area of research protocols using human subjects, the result was zero.

Pharmaceuticals behind the clinical tests

The information provided by Mexican health institutes, as well as the consultation on the basis of information provided by its US equals, reveals that most clinical trials taking place in the country are sponsored by the pharmaceutical industry.

With reference to Mexican public health institutions, twenty transnational pharmaceutical laboratories are behind almost half the studies that are being carried out. Leading [the pack], we find:
• Merck (German);
• Bristol-Myers Squibb and Pfizer (US);
• Glaxo Smithkline (English);
• Sanofi-Aventis (French/German); and
• Roche (Swiss).
These companies have sponsored 299 clinical tests.

Other laboratories that had more impact in carrying out this type of study in the country are: Eli Lilly and Company, Astrazeneca, Novartis, Schering-Plough, Bayer, Boehringer Ingelheim, Abbott, Pharmacia & Upjohn, Wyeth (from 2009, a subsidiary of Pfizer), Tibotec, Janssen, Kendle and Johnson & Johnson, all of foreign origin.

While pharmaceutical laboratories are not the only ones carrying out clinical tests in Mexico, this group of twenty pooled together 46% of the 1,152 studies where the name of the sponsor is known.

However the figure could vary, since it only takes account of INER information, information provided by the following institutions:
• Nacional de Perinatología Isidro Espinosa de los Reyes;
• Nacional de Salud Pública;
• Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, and
• Hospital General de México.
It did not include the 116 tests carried out in Instituto Nacional de Siquiatría (1983 – 2011) given that this institution claims it auto-financed these tests.

Neither did they take into account the tests of Instituto Nacional de Cardiología, that totalled 224 (2001 – 2011). Of these, 156 were internal studies and therefore had nothing to do with any financing. Although the Institute indicates that 65 plans were implemented through agreements with private entities, it does not give the names.

Hospital Juárez de México, that began 78 clinical tests (2003- 2011), classified information about the sponsors as confidential, on the basis of a confidentiality agreement and the non-use of information that it has with the sponsors. However its response to the request for information 1219000021011 was that the content of the research protocols that safeguard these tests “is to develop medicines that can be patented”.

Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez also referred to a confidentiality agreement to justify refusing to provide the names of those sponsoring the clinical tests in progress.

In the case of Instituto Nacional de Rehabilitación, the information on the two research protocols concluded, details that neither of them relied on external sponsorship.

The data of the US Health Institutes is more instructive regarding the impact of the pharmaceutical industry: of 1,549 clinical tests undertaken in Mexico, 60% are sponsored by one of the laboratories mentioned.

But in contrast to the statistics reported by the national public health institutions, the pharmaceutical that financed the most studies in the country –through the US health system – is Pfizer. It, and its subsidiary Wyeth, have sponsored 156. If we add the 61 tests that it financed through Mexican health institutes, the grand total is 217. This transforms it into the pharmaceutical company with greatest impact on studies using human subjects in the country.

Considered the most important pharmaceutical laboratory in the world, Pfizer was the first to produce penicillin industrially, and invented Viagra.

However, it is also responsible for carrying out clinical trials in 1996 in Nigeria. It tested a drug called Trovan on persons afflicted by an epidemic of meningitis without [however] informing them that the [drug] was still under trial.

This resulted in the death of 11 children and another 200 children with serious mental and physical deformities. Later on, we would find out from cables from the US embassy leaked by Wikileaks, that in April 2009, the US pharmaceutical had negotiated an agreement with the government of Nigeria to try to avoid the litigation Nigeria had initiated against it. Ultimately, the laboratory paid 75 million dollars to the families affected to avoid criminal proceedings going ahead.

NIH’s register [discloses that] the laboratories of Sanofi-Aventis have sponsored the second highest number of tests in the country. Here we have Europe’s most important pharmaceutical company, ranked number three in the world. It is present in Mexico not only on account of the drugs it is selling but also for the 167 clinical trials that it is carrying out (123 though US health institutes and 44 through Mexican institutes).

The US pharmaceuticals, Bristol-Myers Squibb and Eli Lilly and Company are also ranked among those that carry out the most clinical trials using human subjects in Mexico. The former financed 159 studies (98 through NIH, 61 through its Mexican equals), while the company established by the colonel and the pharmaceutical Eli Lilly has sponsored 136 clinical tests in the country.

Eli Lilly and Company, whose directors included the former US president George Bush, has been involved in various scandals that have raised ethical issues over its conduct. One of the best known is the case of Zyprexa, where it was held that the pharmaceutical had suppressed information that the drug might create a propensity to diabetes.

An article published in the US newspaper, The New York Times, on 17 December 2006 revealed that for a decade, the company had kept this information secret. This was because Zyprexa – used to treat schizophrenia – was the company’s best selling product.

Another scandal was the case of Fentress. Here a man, medicated with Prozac (an anti-depressant invented by the laboratory) fired an assault rifle at work, killing eight people and injuring another 12 before killing himself.

To avoid a judgement where a link might be established between the anti-depressant and suicidal tendencies, the company bribed the claimant’s lawyer so he would not present inculpatory evidence to the jury. Although the verdict was favourable to the pharmaceutical company, the judge referred the matter to the Supreme Court in Kentucky. This court set aside the ruling when it discovered the corruption in the judicial process.

In conformity with the Mexican report: the situation and perspectives of the ethical regulatory framework of the biomedical study and protection of subjects of the study, one of the biggest concerns over the practice of clinical tests is sponsorship by the pharmaceutical industry. This is due to the “reprehensible” conduct that has arisen.

The document refers, by way of example, to the laboratories approaching doctors directly to offer them money to recruit patients or to incorporate “virgin” patients (those who have never been subject to any prior medical treatment to treat their illness) in clinical tests or to carry out studies simply to promote products.

“This and other conduct has caused us to consider that the study sponsored by the pharmaceutical industry is, in general, the one which has the highest risk of flouting ethical standards”, rules the report issued by the Comisión Nacional de Bioética in 2006, and that forms part of the plan of the international network Eulabor.

Furthermore, they have detected problems in the research protocols used by the pharmaceutical industry, since multi-site studies cannot necessarily be adapted to the legislative framework of each country and it is difficult to conform them to local standards.

Targetting Mexico

For many years, US and European pharmaceutical companies conducted clinical tests in Asian countries, in particular, India. By outsourcing these clinical studies to India, pharmaceuticals have reduced their costs by as much as 60%.

But the companies have discovered new “markets” that offer even lower costs to conduct their trials. One of these new destinations is Latin America.
According to the article “Trials in Mexico: addressing the challenges”, published in Feb 2009 in Good Clinical Practice Journal (an English journal), most clinical tests are carried out in Argentina, Brazil and Mexico.

However the publication states:
“Mexico, in particular, has been transformed into a leader in the pharmaceutical market and a prominent location for clinical tests”.

Karen Politis Virk, the author of the text, sets out the reasons [for this as follows]:
• it is cheap to carry out clinical trials in Mexico (30% cheaper than in the US); and
• foreign pharmaceuticals have the opportunity to invest thanks to the North American Free Trade Treaty, signed between Mexico, the United States and Canada, which entered into force in 1994.
But these are not the only “advantages” that pharmaceuticals can find in Mexico that make it the destination of their studies. Mexico has:
• a higher recruitment rate than the United States;
• a high percentage of patients that have not been previously subject to treatments (the so called “virgin” patients);
• geographical proximity to the United States;
• ethnic diversity of patients; and
• high proportion of adult patients (favourable for carrying out research relation to diseases such as Alzheimers, Parkinson and osteoporosis).

• the prevalence of cardiovascular, pediatric or rheumatoid disease, diabetes and osteoporosis in the Mexican population.
All these factors make the country an attractive location for research using human subjects.

Politis Virk indicates that the following are disadvantages:
• the conditions of poverty in the population;
• illiteracy (8% in adults); and
• linguistic barriers.
The author suggests that anyone who is interested in undertaking clinical tests in Mexico should take these factors into account, particularly because, regulatory proceedings are invariably protracted.

This is because obtaining a patient’s informed consent is necessary to authorize a research protocol. [Obtaining consent] can be delayed because many health institutions request a second letter of consent, written in simple language and signed by two witnesses.

Although the author recognizes that this procedure is adopted to help eliminate ethical problems that can interfere with obtaining informed consent in the “less educated” population, she recognizes that several issues still need to be resolved.

In 2006, the Eulabor network that focuses on evaluating ethical regulatory systems in medical research involving human subjects, undertook a project for a comparative analysis of the profile of different countries carrying out clinical tests.

The assessment carried out by Comisión Nacional de Bioética (a decentralized organ of the Health Secretary) on Mexico addresses factors it considers problematic in conducting such studies in the country.

One of these is that the population is not highly educated. This is [a problem] because the ethical regulatory framework for biomedical research calls for letters of consent that are drafted in a way that is not readily comprehensible to participants. Thus, due to their length and complicated language, “it is difficult for a patient to really understand the extent of their involvement in the trial”.

The linguistic diversity in the country is another factor that must be taken into account to guarantee free and informed participation in clinical tests, particularly of the indigenous population that does not speak Spanish or speaks broken Spanish.

Another aspect to take into account, continues the Eulabor report, is access to social security in Mexico. Although there are both public and private health services, a large sector does not have access to either. Therefore this sector is unprotected when beset by adversity. At the same time, many people are unable to access to the medicines that they require since they are costly and beyond their means.

This situation complicates the ethical regulatory framework for clinical tests, warns Eulabor.
“On the one hand, patients do not objectively consider the extent of their participation in a study, if it represents “the difference between life and death” as they do not have access to a certain drug.

On the other hand, both doctors and members of the ethics committees in the study come into conflict. This is because they understand that their participation in a given project may be the only viable option for a patient to receive treatment”, rules the report.

The other factor that impacts development of biomedical studies in the country is the lack of funding to conduct research on health. This lack of funding translates into low wages and few opportunities for researchers, who could seek funding in any form.

With this, the protection of research subjects is compromised, since the overriding objective of researchers is to obtain funding. Furthermore, as performance is measured on the basis of quantitative indicators, the researchers are more concerned with how many publications they produce than the integrity of their research and the participants.

In order to understand the mechanisms of control and supervision that the health authorities implement with respect to clinical tests conducted in the country, Contralínea requested an interview with Mikel Arriola, the head of Cofepris. At the close of editing, the graduate, Rosalba Villanueva, responsible for the Commission’s Social Communication and through whom the request was made, had not responded.