October 1996
WASHINGTON — What at first appeared to be a minor oversight in the wording of an informed consent form has exploded into claims of racial experimentation, resulting in significant changes in how CDC research programs are carried out.
At the center of the controversy is a measles vaccine study begun in 1990 in Los Angeles. It was conducted by Kaiser Permanente and overseen by the Centers for Disease Control and Prevention (CDC).
"Why was the study done?" asked Walter Orenstein, MD, at a recent meeting of the National Vaccine Advisory Committee (NVAC). "We suffered the largest measles outbreak in the United States in more than 12 years in 1989 to 1991. There were 55,000 cases and 130 deaths. Children younger than 5 years of age were disproportionately affected, as well as those younger than 12 months.
"Los Angeles actually was one of the most severely affected sites, with more than 10,000 cases reported in 1989 to 1991. Many of the cases occurred in children too young to be vaccinated with the available vaccine and have an acceptable immune response. That is because the available vaccine had substandard efficacy when used in children younger than 12 months of age." Orenstein is director of the National Immunization Program, CDC.
![[bar]](/art/gradred.gif){kind=small}
The purpose of the study was to determine whether a high-titer measles vaccine would be safe and effective for children younger than 1 year to protect them during an epidemic. The vaccine tested was made from the Edmonston-Zagreb (EZ) strain of measles virus, which was not licensed for use in the United States but which had been approved by the Food and Drug Administration (FDA) for investigation.
"The EZ vaccine had been used worldwide for many years," Orenstein said. "Studies of the EZ vaccine in the early 1980s showed a higher response than other vaccines in children who got vaccinated at younger than 9 months of age. In the late 1980s, multiple studies showed higher titer vaccine to be more effective at 6 months of age. In 1989, the World Health Organization (WHO) recommended that high-titer EZ vaccine be used for routine immunization at 6 months of age in countries and cities where measles mortality was high in children younger than 9 months of age. Therefore, given the problem we were seeing with measles in our inner cities and given the WHO recommendation, CDC sought to do similar studies in the United States."
The study population was heavily weighted with minority children.
"All [study participants] were members of Kaiser Permanente of Southern California," Orenstein said. "The study population consisted of 44% black, 44% Hispanic and 12% other children. They were chosen by Kaiser [from children] enrolled in three clinics in areas strongly affected by the measles outbreak. Overall, nationally, black and Hispanic children have a 700% to 900% increased risk of measles disease compared with the white population."
The informed consent form given to the parents of the children enrolled in the study, however, failed to make clear that EZ vaccine was under FDA review and was not licensed for use in the U.S.
The study was stopped in 1991, 18 months after the children were initially enrolled, because of reports of excess mortality in Senegal, Guinea Bissau and Haiti. Data showed that girls who received the higher titer vaccine had lower survival rates five years after vaccination.
Based on these findings, WHO recommended that use of the EZ vaccine be discontinued.
To date, one of the 1,200 children who were enrolled in the American study has died, but the death was unrelated to vaccination. No children have had any adverse effects related to the EZ vaccine, Orenstein said.
Although the CDC approved the study protocol, it did not see the actual consent form and brochure provided to parents.
"The study did include an initial consent form, which told parents about the study and about possible risks and benefits of having the children participate. All parents knew they were entering the study because they had to sign the consent form. A brochure for parents stated that more than 200 million children around the world had received EZ vaccine, and that Los Angeles county was the first place in the United States where the vaccine was being offered," Orenstein said. "The Office of Protection from Research Risk concluded that the study was both scientifically and ethically justified. In other words, the design was valid, the population chosen was appropriate and the intent of the study was good.
"However, we made a serious mistake by not telling parents that the vaccine was experimental and not licensed in the United States," he continued. "And we also did not accurately explain to parents the purposes at the time of entrance into the study. We have apologized publicly; we continue to apologize for jeopardizing trust in the research practices of not only the National Immunization Program but of CDC. Although no harm has been identified to date among the children who participated in the study, we did violate public trust, and we accept responsibility for that error."
The CDC has made changes. Dixie Snider, MD, assistant director for science at the CDC, outlined for NVAC the changes that have been made since 1993 in protecting human research subjects.
For example, the CDC's Policy Regarding Human Subjects Review has been revised since 1993, particularly in describing who is responsible for making and documenting certain decisions. The CDC has also developed a policy on the inclusion of women and minorities in research studies, and it now places an increased emphasis on training.
The staff of the Human Subjects Review Coordination has been increased from one person to three, and three Institutional Review Boards (IRBs) now meet every three weeks, rather than two IRBs meeting on an as-needed basis, Snider said.
These changes will help ensure that such an oversight does not occur in future studies, but they will do little to regain the trust of the minority community. A sense of distrust is especially prevalent among blacks, who continue to carry the legacy of the Tuskegee study, a 40-year project examining the effects of syphilis on black men.
From 1932 to 1972, the U.S. Public Health Service intentionally withheld treatment from 400 black men living in Macon County, Ala. Black community leaders were enlisted to encourage enrollment in the study, and free physical exams, food and transportation were provided to participants. The one thing that was not provided, however, was education, and researchers involved in the study took steps to ensure that the men did not seek treatment elsewhere. Many of the participants eventually died from the disease.
No children were harmed from participation in the EZ study, but minorities draw many similarities to the Tuskegee experiment. And the damage done to the credibility of the government will be difficult to repair.
"They [minorities] may not have the facts about what happened in the Tuskegee study straight, but they know something happened with the federal government using black people in an experiment," said NVAC member Robert Ross, MD. "That sense of distrust has never gone away. ... Every time parents are asked to make an informed decision about whether to use a new vaccine, they will ask, 'are you using my kid for an experiment?' It is for that reason that this hurts. ... We have to figure out a way to change the culture of sensitivity around studies that may happen to target communities of color.
"We can't get [vaccine] coverage unless we have trust, and the public's trust has been violated. It doesn't matter what the data say, it doesn't matter how many IRB reviews you have, if you violate the public's trust and you don't do something to make sure you are working with parents and communities and understanding their concerns, you are not going to get [vaccine] coverage," Ross said.
You can express your
views on this article, or other relevant themes, in the
Infectious Diseases in Children
Specialty Forums.
