Unethical Clinical Trials Still Being Conducted in Developing Countries

Health Letter, October 2014

Michael Carome, M.D.

In 1997, Public Citizen’s Health Research Group brought widespread international attention to unethical clinical trials. The trials were testing new methods for preventing the spread of HIV infection from pregnant women to their babies before or after giving birth in developing countries in Africa, Asia and the Caribbean.[1] In each of the trials — the majority of which were funded by the U.S. government — some women were randomly assigned to receive placebos or other treatments known to be ineffective, rather than a drug proven effective in preventing the spread of HIV infection from mother to baby and considered the standard of care at the time in the U.S. and other developed countries.

Unfortunately, nearly 20 years later, similarly unethical trials continue to be conducted. One recent such trial in India, reported in The Lancet in June, evaluated an experimental vaccine for preventing a very common, potentially life-threatening viral infection called rotavirus.[2] Despite the availability of two vaccines that have been proven to be highly effective in preventing serious rotavirus infections in infants and young children, more than 2,000 children in the India trial received placebo injections of salt water rather than one of the available effective vaccines. The continued conduct of such trials reflects a persistent, troubling disregard for international ethical principles for human subjects research, particularly research involving disadvantaged subjects in the developing world.

Rotavirus and available vaccines

Rotavirus infection is one of the leading causes of gastroenteritis and death in children worldwide. Symptoms of the infection develop suddenly one to three days after exposure to the virus and range from loose stools in mild cases to severe watery diarrhea, vomiting and fever in sicker infants.[3] In the most severe cases, infants can develop extreme dehydration and shock, which can result in death if they do not receive aggressive fluid replacement.[4] The illness usually lasts for three to seven days, but it can persist for as long as two to three weeks.[5]

Prior to the introduction of effective rotavirus vaccines, nearly every child in the world developed a rotavirus infection by ages 3 to 5, and 2 million children were hospitalized annually.[6] Even today, in developing countries, approximately 80 percent of infants suffer their first rotavirus infection before age 1.[7]

In 2013, the World Health Organization (WHO) issued a report estimating that in 2008, approximately 450,000 children died from rotavirus infection globally, accounting for about 5 percent of all child deaths.[8] Not surprisingly, 90 percent of these deaths occurred in low-income countries in Africa and Asia where adequate health care resources are lacking.[9]

Two rotavirus vaccines have been available for the past decade: RotaTeq, marketed by Merck & Co., and Rotarix, marketed by GlaxoSmithKline.[10] Large clinical trials of both vaccines demonstrated that they were highly effective in preventing rotavirus-induced gastroenteritis — including the most severe cases — and the need for hospitalization. These trials enrolled infants in both developed countries (including the U.S. and multiple European nations) and developing countries (including Costa Rica, Guatemala, South Africa, Malawi, Ghana, Kenya, Mali, Bangladesh and Vietnam).[11],[12],[13],[14],[15],[16]

Both are oral vaccines administered as a series of two or three doses in early infancy. Because of the demonstrated safety and effectiveness of these two vaccines, rotavirus vaccination is now part of the standard childhood vaccine schedule for infants in the U.S., administered at ages 2 to 6 months.[17] The WHO likewise recommends that rotavirus vaccines “be included in all national immunization programmes and considered a priority, particularly in countries with high [rotavirus infection]-associated fatality rates, such as in south and south-eastern Asia and sub-Saharan Africa.”[18]

The India vaccine trial[19]

The clinical trial in India — funded by multiple private and government sources, including the Bill & Melinda Gates Foundation and the National Institutes of Health — enrolled approximately 6,800 infants between March 11, 2011, and Nov. 5, 2012, in rural and urban areas of the country. The experimental vaccine was given by injection in three doses at 6-7 weeks, 10 weeks or older, and 14 weeks or older. Two-thirds of the infants received the vaccine, and one-third received saltwater placebo injections. Other standard childhood vaccines — for diphtheria, whooping cough, tetanus, Haemophilus influenzae type B, hepatitis B and polio — were given to all infants in the study.

The trial results showed that, as with the two available oral rotavirus vaccines, the new vaccine was effective in preventing severe rotavirus-induced gastroenteritis and hospitalizations due to such infections.

Given the availability of two highly effective rotavirus vaccines at the time the India study was initiated, the failure to provide infants with one of these two vaccines instead of a placebo violated international ethical standards for conducting human research.

At the time the study was conducted, the World Medical Association’s Declaration of Helsinki — Ethical Principles for Medical Research Involving Human Subjects stated:[20]

The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best current proven intervention, except in the following circumstances:

  • The use of placebo, or no treatment, is acceptable in studies where no current proven intervention exists; or

  • Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk or serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.

Saltwater placebo injections certainly did not represent the “best current proven intervention” available at the time the India trial began, given the proven efficacy of RotaTeq and Rotarix. Moreover, there were no compelling and scientifically sound reasons to use a placebo and thus expose subjects to risk of preventable, potentially fatal rotavirus infections. An ethically sound clinical trial designed to determine whether the new experimental vaccine had similar or greater effectiveness than either of the available oral vaccines was scientifically feasible and easily could have been conducted.

A persistent ethical double standard

A rotavirus vaccine study in which infants received a placebo would never have been permitted in the U.S., and it should not have been permitted in India. Allowing such research creates a double standard that allows research using unacceptable designs to proceed in developing countries. In 1997, Public Citizen’s Drs. Sidney Wolfe and Peter Lurie argued for the need to implement a single international standard of ethical research, noting the following:

Researchers assume greater ethical responsibilities when they enroll subjects in clinical studies. … Residents of impoverished, postcolonial countries, the majority of whom are people of color, must be protected from potential exploitation in research. Otherwise, the abominable state of health care in these countries can be used to justify studies that could never pass ethical muster in the sponsoring country.

With the increasing globalization of trade, government research dollars becoming scarce, and more attention being paid to the hazards posed by “emerging infections” to the residents of industrialized countries, it is likely that studies in developing countries will increase. It is time to develop standards of research that preclude the kinds of double standards evident in these trials.

As Wolfe and Lurie predicted, the number of clinical studies taking place in developing countries has increased dramatically. Unfortunately, the troubling rotavirus vaccine trial in India indicates that we still have a long way to go to achieve implementation of the single international ethical standard the Health Research Group called for nearly two decades ago.

References

[1] Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med. 1997;337(12):853-855.

[2] Bhandari N, Rongsen-Chandola T, Bavdekar A, et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: A randomized, double-blind, placebo-controlled trial. Lancet. 2014;383:2136-2143.

[3] World Health Organization. Rotavirus vaccines: WHO position paper – January 2013. Wkly Epidemiol Rec. 2013;88(5):49-64.

[4] Ibid.

[5] Ibid.

[6] Ibid.

[7] Ibid.

[8] Ibid.

[9] Ibid.

[10] Ibid.

[11] Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med. 2006;354(1):23-33.

[12] Armah G, Sow SO, Breimna RF, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: A randomised, double-blind, placebo-controlled trial. Lancet. August 21, 2010;376:606-614.

[13] Zaman K, Anh DD, Victor JC. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: A randomised, double-blind, placebo-controlled trial. Lancet. August 21, 2010;376:615-623.

[14] Madhi SA, Cunliffe NA, Steele D, et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med. 2010;362(4):289-298.

[15] Vesikari T, Karvonen A, Prymula R, et al. Efficacy of human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in European infants: Randomised, double-blind controlled study. Lancet. November 24, 2007;370:1757-1763.

[16] Linhares AC, Velazquez FR, Perez-Schael I, et al. Efficacy and safety of an oral live attenuated human rotavirus vaccine against rotavirus gastroenteritis during the first 2 years of life in Latin American infants: A randomised, double-blind, placebo-controlled phase III study. Lancet. April 5, 2008;371:1181-1189.

[17] Centers for Disease Control and Prevention. 2014 recommended immunizations for children from birth through 6 years old. http://www.cdc.gov/vaccines/parents/downloads/parent-ver-sch-0-6yrs.pdf. Accessed August 29, 2014.

[18] World Health Organization. Rotavirus vaccines: WHO position paper – January 2013. Wkly Epidemiol Rec. 2013;88(5):49-64.

[19] Bhandari N, Rongsen-Chandola T, Bavdekar A, et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: A randomized, double-blind, placebo-controlled trial. Lancet. 2014;383:2136-2143.

[20] World Medical Association. Declaration of Helsinki: Ethical principles for medical research involving human subjects. 2008.