By Lorna Speid
Do the Horrors of the Guatemala Syphilis Study Indicate A Disregard for International Standards of Human Clinical Research In the USA?
The news that prisoners and the mentally ill were deliberately infected with syphilis and other sexually transmitted diseases in experiments conducted by the US in the late 1940s has sent shock waves around the world. What is most shocking is that this experiment occurred in the aftermath of the Nuremberg Trials which brought to light the Nazi experiments that were so abhorrent. The Nuremberg Code of 1948 set basic standards for studies to be conducted in humans. We are told that there may be 40 additional experiments yet to come to light which involved experimentation on people on US soil that were never told that they were taking part in experiments.
Why were these types of experiments conducted at all? The experiments conducted by the Nazis were so abhorrent that for the US to conduct these experiments after the Nuremberg Code was accepted suggests a disregard for this standard. Furthermore, the fact that the Tuskegee experiment started as early as 1932, and lasted long after the passage of the Nuremberg Code in 1948, the Geneva Code in 1948 and even the world accepted Declaration of Helsinki in 1964 appears to support this view.
Do these events suggest that there was the existence of an unacceptable culture amongst those involved with the conduct of government-sanctioned experiments? Did this culture encourage a blatant disregard and disrespect for the most basic standards of human experimentation? We must follow the evidence where it leads.
Could this happen today, or more to the point, is it happening in the US today? There is a greater awareness amongst the public about what is, and what is not acceptable research. Where violations of informed consent have occurred these have usually involved blatant disregards for accepted standards of bioethics or other good practices, such as the case of Jesse Gelsinger that involved his death during a gene therapy study at the University of Pennsylvania1.
Of concern today is the trend for US researchers to export studies to other countries in the interests of saving money or recruiting subjects faster. Some of these studies do not involve optimal study designs or obtaining proper informed consent. It is difficult to imagine rational research subjects giving their informed consent to enter some of the studies conducted in the developing world. US researchers appear to place studies without sufficient regard for the vulnerability of the population and the principles of informed consent.
Beyond the need companies have to conserve cash, is the temptation to conduct studies in developing countries that cannot be conducted for ethical reasons in the US or other developed countries. If a company wants to find out the true treatment effect for their drug, and they can’t conduct a placebo controlled study in the United States, because that would be ethically unacceptable, the attitude appears to be to find a country in which it can be done perhaps because of lack of regulatory scrutiny. Encouraging this approach is the fact that the FDA abandoned the Declaration of Helsinki in 2008 for studies not conducted under an Investigational New Drug Application2. This caused an outcry around the world[3, 4, 5, 6].
The abandonment of the Declaration of Helsinki allows sponsors to conduct studies to the principles of the International Conference of Harmonization’s Good Clinical Practice (GCP) Guideline, instead of the Declaration of Helsinki. However, there are differences between the Declaration of Helsinki and GCP, for instance the inclusion of placebos especially in developing world situations is not broadly sanctioned by the Declaration. Placebo controlled studies may be preferred by companies in some situations but are not always acceptable for ethical reasons. For instance, when appropriate treatment exists for serious illnesses. Sponsors may prefer placebo controlled studies because it is easier to demonstrate efficacy for a drug if it is compared against a placebo than if it is compared against another active drug. Placebo controlled studies may be smaller in size and therefore less expensive to conduct. Placebo studies can deny patients treatment that could be made available to them. The argument has been made that studies may be conducted in the developing world that cannot be conducted in the developed world because treatments may not be freely available in the developing world.
Those involved with the design of the Guatemalan experiment selected a country where they could perform studies that met their own personal scientific goals without sufficient regard for the human suffering resulting from the research. It is difficult to conceive of experiments involving the use of prostitutes to deliberately infect participants as was done in the Guatemala STD study, but is studying real life situations involving irresponsible human behavior very different? The CAPRISA 004 study is a case in point. It started on May 23, 2007 and continued for 30 months. It was reported in Science in 20107. It raised concerns in the minds of many, and yet the South African Health Authority and the local ethics committees approved the study for conduct. Those conducting the study claim that great care was taken to obtain informed consent from women aged 18-40.
The goal of CAPRISA 004 was to test the effectiveness of tenovir gel in protecting against the transmission HIV. At the outset of the study it was known that all women were sexually active and likely to engage in high risk sexual activity. There was no proof at the outset of the study that the gel would be effective in humans, and yet a placebo group was included in the study design. Women had a 50% chance of being randomized to the placebo or the tenovir groups. All women were HIV negative at the start of the study.
The authors indicate that the women were free to use condoms and that they were provided free of charge. One of the inherent flaws in the study concept is that success of the study has to be dependent on the non use of condoms which are known to be very effective in the prevention of the transmission of HIV8. The authors of the paper  admit that the women that were included in the study often cannot navigate the use of condoms during their sexual encounters. This raises concerns about their vulnerability and ability to give true informed consent. Would a reasonable person really consent to risk contracting the HIV virus? Although the authors appear to indicate that great care was taken to obtain their informed consent unlike in the Guatemala syphilis study, this study raises issues like the Guatemala study of the vulnerability of the population and whether such a study could be conducted in the United States, or indeed, in any developed country. By the end of the study, HIV incidence in the tenovir arm was 5.6 per 100 women years. HIV incidence in the placebo arm was 9.1 per 100 women years (p=0.017). The fact that all women were HIV negative at the outset of the study emphasizes the tragedy for the women that were HIV positive by the end of the study.
The physicians that took part in the Nazi experiments made the defense that the humans in the experiments entered the studies willingly, and gave their consent. However, the experiments conducted were so horrific that it was inconceivable that anyone could consent to take part in such experiments. Informed consent implies that consent cannot be given to undertake unreasonable risks. In 60 years will those reading about the CAPRISA 004 study and other similar studies cry shame on those who could conduct such studies? Should the US and the researchers from the US be held to international standards when they conduct studies abroad? I am hopeful that the FDA’s decision to abandon the Declaration of Helsinki will be revisited during the government review to be conducted in light of the Guatemala experiments.
Lorna Speid, Ph.D. is an expert on regulatory affairs, and drug development. She is President of Speid & Associates, Inc. and the author of Clinical Trials: What Patients and Healthy Volunteers Need to Know.
1. Extensive summary of documentation on the Jesse Gelsinger incident. http://www.circare.org/foia3/ihgtdocs.htm
2. DHHS FDA 21 CFR part 312 Human Subject Protection: Foreign clinical studies not conducted under an investigational new drug application. Final Rule April 28 2008, effective October 27 2008.
6. Rid, A & Schmidt, Harald (Spring 2010). “The 2008 Declaration of Helsinki — First among Equals in Research Ethics?”. The Journal of Law, Medicine & Ethics 38 (1): 143–8.
7. Karim QA, Karim SSA, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany ABM, et. al. Effectiveness and Safety of Tenofovir Gel, an Antiretroviral Microbicide, for the Prevention of HIV Infection in Women. Science, Science, 329 (5996):1168-74. PMID 20643915.
8. Centers for Disease Control Advice. http://www.cdc.gov/condomeffectiveness/latex.htm