The Synflorix trial on infants in Argentina: trading participation for access to healthcare?

Children pose a problem for participation in clinical trials because they cannot consent. A similar problem exists for participation of some elderly patients (as spelled out in a previous post on this blog), or for other categories of patients momentarily or permanently unable to understand the research nature of the trial, and therefore to give an informed consent.
While recently discovered unethical clinical trial on adults in Guatemala reached the first page of the newspapers, and Secretary of State Hillary Clinton had to present public excuses (also a post on this blog last October, you can access it here), other clinical trials performed in children echoed much less attention. Here’s a case in point. How many among you have actually heard about the Synflorix trial on infants, which took place in Argentina in 2008? (and on the contrary, how many of you have heard of the Tuskegee scandal or the Guatemalan scandal?)
The Argentinean province of Santiago del Estero, with a population of nearly a million, is one of the country’s poorest regions, and is severely affected by Streptococcus pneumoniae, that is the major cause of infant meningitis and pneumonia in Latin America. Data from UNICEF estimate that at least 50,000 children die each year of pneumonia in the region (updated as of 2006).
“COMPAS” is the name of the clinical trial designed to test the efficacy of Synflorix, experimental pediatric pneumonia vaccine. Developed by GlaxoSmithKline (GSK), the world’s fourth-largest pharmaceutical company in terms of global prescription-drug sales, the new vaccine was intended to compete against an existing vaccine being administer in the active comparator arm.
In all, at least 14 infants enrolled in clinical trials for the drug died during the testing. Eligibility criteria for study were age between 6 and 16 weeks, and “free of any known or suspected health problems”, therefore, healthy infants. It is estimated that more than 19,000 babies have received at least one dose of Synflorix (The COMPAS trial is still ongoing, but not recruiting anymore).

Sarah Alspach, US spokeswoman for GSK, said the company is not attributing the deaths to the experimental vaccine, which is being tested in three Latin American countries (Argentina, Panama, and Chile) and in other countries around the world. Notwithstanding Alspach, an independent board monitoring participants’ safety recommended that the Latin American trials be temporarily suspended -which they were -due to “received complaints about irregularities in the recruitment of patients“.
What did these irregularities in the recruitment of patients amount to? In practice, the parents – some illiterate- had their children signed up without understanding that they were taking part in an experimental research study. Local doctors who persuaded parents to enroll their babies in the trial reportedly received $ 350 per child. Dr. Ricardo Ruttiman, the regional medical affairs and research & development director of GlaxoSmithKline responsible for the COMPAS trial in Argentina, rebutted accusations and told ABCNews that participation was always voluntary and that parents were “informed, clearly and in a language they can understand, by experienced medical investigators” .
Synflorix received authorisation for EU marketing approval on March 31, 2009 and on November 6th of the same year received also WHO approval.

Synflorix vaccine

The vaccine will not be marketed in the US. As to the reasons underlying this decision and as reported CEO Andrew Witty for Reuters: “It’s clear that Synflorix versus Prevnar is a much more competitive innovation outside of the US because of the presence of different pneumococcal subtypes. […] My expectation, subject to some further analysis, is it probably won’t be Synflorix we take to the U.S”.

The Argentina’s National Medicine, Food and Medical Technology Administration started an independent investigation on whether the vaccine was responsible for the infants’ deaths. I could not retrieve information on how this independent investigation ended, but found this interesting piece of information here: one of the lead GSK investigators is Enrique Smith, who happens to be the brother of Juan Carlos Smith, the Argentine provincial health minister. As put by Jim Edwards (author of the story reference above), “So even if GSK has done nothing wrong, it just looks… weird“.

The scientific causes of the deaths in the COMPAS trial will probably never be brought to light, and so we are left with the doubt on whether they were due to pneumonia, other trial independent causes, or to the experimental Synflorix vaccine. The ethical concerns raised by the parental therapeutic misconception concerning the research nature of the study, though, remain.
But these are not the only ethical concerns raised by the study. As stated by Dr Ricardo Ruttiman to the ABC press, parents were informed not only about the benefits of the vaccine itself, but also about the collateral benefits derived from participation in the study, such as access to medical care and access to vaccinations against other diseases such as diphtheria, tetanus and hepatitis (in the active comparator arm). It seems therefore that, in a poor context like the one of Santiago del Estero, there has been a trade off between participation in the clinical trial and access to health care for disadvantaged families, that otherwise would not have had access to it. This trade-off is not limited to the study in point, but is a widespread concerns of the increasing trend of clinical trials moving offshore (meaning, away from the US and towards low and middle income countries) and, in my view, represents the most worrying aspect of this trial, and of many others on children that deserve all our attention. More soon on this topic on same blog by same author…

Further reading:

Edwards, J. Body Count Linked to GSK Vaccine Trial Rises, August 18, 2008.

Deaths of 14 children ‘could be linked to GlaxoSmithKline trial drug, Daily Mail Reporter, August 15, 2008.

Hunter A, Is GlaxoSmithKline Behaving Badly in Argentina? September 23, 2008

Petryna, A. When experiments travel: Clinical Trials and the Global Search for Human Subjects.Princeton University Press 2009.

Rey, D. Argentina investigates deaths of vaccinated kids, August 15, 2008

Reuters news, Glaxo may not launch Synflorix vaccine in U.S, February 5, 2009.

President Obama calls for a review of human subjects’ protection following the unraveling of the Guatemala STD study.

On October 5, 2010, I reported on this same blog on the recently discovered Tuskegee-like scandal, which took place in Guatemala in the ’40s and saw the purposeful infection of prisoners and other vulnerable populations with the syphilis bacterium (https://humanitiesandhealth.wordpress.com/2010/10/05/clinton-delivers-formal-apology-for-a-newly-discovered-tuskegee-like-study/). The study was only recently brought to light thanks to the studies of Wellesley College history professor Susan Reverby, which resulted in a formal apology delibered by Secretary of State Hillary Clinton on October 1, 2010, much on the footsteps of the apology given by former President Bill Clinton in 1997 to the Tuskegee victims.

More than two months have passed since Hillary Clinton’s public apology, and now President Obama has officially asked the Presidential Commission for the Study of Bioethical Issues to undertake an exhaustive review of human subjects’ protection guidelines. As we can read in the Presidential Memorandum, says Obama:

In light of this revelation [The Guatemalan study], I want to be assured that current rules for research participants protect people from harm or unethical treatment, domestically as well as internationally. I ask you, as the Chair of the Presidential Commission for the Study of Bioethical Issues, to convene a panel to conduct, beginning in January 2011, a thorough review of human subjects protection to determine if Federal regulations and international standards adequately guard the health and well-being of participants in scientific studies supported by the Federal Government. I also request that the Commission oversee a thorough fact-finding investigation into the specifics of the U.S. Public Health Service Sexually Transmitted Diseases Inoculation Study”.

The Presidential Commission for the Study of Bioethical Issues was appointed by Barack Obama one year ago to substitute the dismantled “President’s Council of Bioethics” and is chaired by political theorist Amy Gutmann, who symbolizes the greater emphasis put by the President on the policy implications of ethical positions taken by the Commission.

The past few years have witnessed an increasing number of clinical trials being moved offshore, i.e. to low and middle income countries, and as reported by Nellie Briston on the Lancet this week: “A thorough review of the safeguards in place to protect modern human trial participants is appropriate and timely” .

Also on a related topic, the Commission will need to explore the relationship between the FDA and Helsinki Declaration regulating internationally clinical research on human subjects. The Helsinki Declaration was controversially shelved by the FDA in October 2008, which favoured instead the adoption of Good Clinical Practice (GPC) Guidelines, which represent a weaker ethical standard as, for example, they are silent on the use of placebos in clinical trials when there exists an active treatment as an alternative.

The Presidential Commission will start its work on the issue in January and has 9 months to deliver the reports.

Further readings

Bristol, N. US reviews human trial participant protection, The Lancet 2010; 376(9757):1975-6, doi:10.1016/S0140-6736(10)62247-7; http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2962247-7/fulltext?rss=yes

Camporesi, S. The FDA decision to shelve the Helsinki Declaration: Ethical considerations, ecancermedicalscience, June 10, 2008; doi=10.3332/eCMS.2008.LTR76, http://www.ecancermedicalscience.com/comment-letters-to-the-editor.asp?doi=10.3332/eCMS.2008.LTR76#letter

McNeil, D. U.S. Apologizes for Syphilis Tests in Guatemala, The NewYorkTimes, October 1, 2010, http://www.nytimes.com/2010/10/02/health/research/02infect.html

Presidential Memorandum-Review of Human Subject Protection, November 24, 2010, http://www.whitehouse.gov/the-press-office/2010/11/24/presidential-memorandum-review-human-subjects-protection