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March 31, 2011

Symposium looks at human subject study abuse

Ethical research practices — particularly when human subjects are involved — are a perennial concern for researchers. Today, mandated training and review board approvals provide guidance, but a strong individual commitment to high standards is needed, agreed participants in a March 24 ethics symposium on campus.

Wellesley College faculty member Susan Reverby came to campus to discuss papers she found in Pitt’s archives documenting unpublished research overseen in Guatemala in the 1940s by U.S. Public Health Service (PHS) doctor John Cutler, who decades later became a regarded faculty member in Pitt’s Graduate School of Public Health (GSPH).

In the study, PHS doctors, without subjects’ consent, intentionally infected Guatemalan prisoners, mental hospital patients and soldiers with syphilis. Reverby, who studies the history of American health care, gender and race issues, uncovered evidence of the Guatemala research among papers Cutler donated to the University when he retired.

Her discovery, described in an article published in the Journal of Policy History, prompted a government apology, sparked a class action lawsuit on behalf of the former subjects and provided the impetus for the symposium sponsored by GSPH and the Pitt Center for Bioethics and Health Law.

Reverby talked about her discovery and participated in a panel discussion on ethics with  University of Wisconsin history of medicine and bioethics faculty member Susan E. Lederer and moderator Alan Meisel, director of Pitt’s Center for Bioethics and Health Law.

“Troubling issues remain,” said GSPH Dean Donald Burke in his opening remarks. “While there is no direct connection between Pitt and the studies, the discussion of Dr. Reverby’s article on those experiments here on our campus has more immediacy than elsewhere.

“Shortly after Dr. Reverby’s article was made public, my colleagues here at the Graduate School of Public Health — and indeed across the campus — began to wonder what our response, if any, should be to these revelations. We all agreed that we should seek to turn this into a teaching and learning opportunity for the University community.”

Meisel said he was a law student when he first was exposed to the topic of human-subject research. Early in the term, his class studied the Nuremburg trials, which followed the defeat of the Nazis in World War II. The medical research abuses brought to light during those tribunals seemed distant to him — both geographically and in terms of time. “It seemed like ancient history at the time,” he said. “And, fortunately, I thought, ‘we’ didn’t do those kinds of things.”

As the term progressed, he learned otherwise. “First I learned about Tuskegee, the CIA and the Army LSD experiments, the Jewish Chronic Disease Hospital case,” he said, citing publicized instances of research now considered to be unethical. More recent examples include the Henrietta Lacks case, Army radiation experiments and examples of research misconduct.

“Now we learned of another such event, the syphilis research conducted in Guatemala,” he said, raising the question: “Were these investigators responsible for conducting unethical research or should they be viewed in the ethical context of their time when, it might be said, if not everyone was doing it, lots of people were doing it?”

Reverby’s research in Pitt’s archives turned up documentation of Cutler’s 1946 study in which research subjects in Guatemala were infected with syphilis without their knowledge.

However, the Guatemala study was by no means unique. “It was not uncommon at this time to use vulnerable populations in the United States,” Reverby said. Infection studies had been done before with deception “seen as possibly normative in the interest of advancing science,” she said.

The Guatemala syphilis study was funded by a federal grant to the Pan American Sanitary Bureau (now the Pan American Health Organization) under the direction of the venereal disease research lab of the Public Health Service. Cutler was a PHS doctor in his late 20s when he began the research in Guatemala. He later was involved in the Tuskegee syphilis study and, in 1967, late in his career, he became a faculty member in Pitt’s GSPH.

In the Tuskegee study, although subjects were not intentionally infected, deception was a key element, Reverby said.

That 1932 study, formally titled as a “Study of Untreated Syphilis in the Negro Male,” involved 624 subjects who were told they were being treated — albeit with aspirin and iron tonics. Diagnostic spinal taps associated with the study were explained to them as “special treatments.” The research continued despite ethics questions that arose until it finally ended in 1972 amid  media outcry.

Reverby provided some historical context for the need for syphilis research in the early 20th century, citing statistics that equate mortality rates from syphilis in the 1920s to the number of AIDS deaths in the 1980s.

Cutler’s papers state that his study in Guatemala was designed in part to get information on prevention and the effects of treating the disease with penicillin, Reverby said.

“This is a period where a lot of syphilis researchers were feeling very rushed,” she said, noting that the growing recognition that penicillin was able to cure the disease — essentially in one shot — was creating worries among researchers that syphilis, which was not well understood, “would disappear with its secrets unexplained.”

There were several reasons for doing the research in Guatemala, she said. Among them was that it was legal to hire prostitutes to serve inmates in the penitentiary in Guatemala. “Infected prostitutes were allowed to continue to service men in the prisons — free, paid for by the U.S. tax money” that funded the research, she said.

In later parts of the study, Cutler’s team used mental hospital patients and soldiers as subjects. In those settings, prostitutes could not be used to deliver the disease, so researchers decided to make an inoculum that could be used to infect the subjects then treat them with penicillin.

Reverby pointed out that the work was done with the cooperation of the Guatemalan health ministry, its national army, its national mental health hospital and its ministry of justice.

Some of the incentives offered in exchange for their cooperation provide a glimpse into conditions in these Guatemalan institutions. The mental health hospital’s director was promised dilantin, a favored treatment for epilepsy, Reverby said, noting that many of the patients there were not mentally ill but suffered from epilepsy. Records show researchers gave the hospital a refrigerator, a movie projector and metal cups, plates and forks, in addition to cigarettes, which were a common giveaway for study participants.

The records also show that hospital officials weren’t informed that the inoculum being administered contained syphilis bacteria. By the mid-1940s, internal questions were being raised within the PHS; letters were sent to Cutler expressing concerns about using mental patients who could not give consent.

By 1948, Reverby said, penicillin was proving itself to be a one-shot cure, resulting in decreased interest in studying syphilis, so Cutler ended the study and returned to the United States.

Analysis of the documents showed that 86 percent of the subjects who were given syphilis by the United States government got adequate treatment. Records for the remaining 14 percent are incomplete and how they fared is not known, Reverby said. Some subjects got other diseases in the course of the research. Of them, 99.5 percent of those who were exposed to gonorrhea got adequate treatment, as did 97 percent of those who got chancroid, another sexually transmitted disease, the records showed.

Was this Guatemala research an aberration or an anomaly? Was Cutler a monster? Or was this research just business as usual? Susan E. Lederer, a professor at the University of Wisconsin, offered some historical context through which to view the Guatemala studies.

Although ethical concerns were raised, “the landscape of permissible human experimentation in the first half of the 20th century, I would argue, was very uneven,” she said.

“There are different ways that we might think about this. Whether it’s deliberately infecting someone with a disease to study it, the use of vulnerable populations — is there something about syphilis that makes it so problematic? Or finally, there’s this issue of racism,” Lederer said.

At that time, “There were clear rules when a disease was dangerous, but it becomes much less clear, I would argue, when you’re going to infect someone with a disease for which you have a readily available and apparently effective cure.”

Intentional infections

“The more dangerous the disease, the clearer the rules,” for deliberately infecting humans to study disease, Lederer said.

As an Army surgeon sent to Havana in 1900 to study the transmission of the deadly yellow fever, Walter Reed addressed the moral issues of exposing subjects to such a dangerous disease by limiting participation to men over 25 — the legal age of consent — and developed a permission document that was available in both English and Spanish.

“They also sweetened the pot by offering $100 in American gold; $200 to the family members if the person succumbed to the illness during the course of the experiment. Fortunately none of the research subjects died in the course of the study,” she said.

Reed and his colleagues, she said, were familiar with the critical reception and condemnation an Italian researcher received a few years earlier when he identified the virus and, without the subjects’ knowledge, injected several immigrants who were patients in a Uruguayan hospital with it, producing symptoms.

Use of vulnerable populations

Lederer cited several instances in which criticism arose over experiments with orphans and other institutionalized groups.

Among them:

• In the 1920s doctors deliberately induced scurvy and rickets in children at the Hebrew Orphan Asylum in New York City to study the etiology of the disease.

• Researchers attempted to induce stuttering in a group of orphans in Iowa in 1939. Although the research was not published, the so-called “monster study” came to light in a 2003 news article. Some of the children grew up to have speech impediments and psychosocial difficulties, Lederer said. Victims later sued, receiving $1 million each from the state of Iowa in an out-of-court settlement.

• An investigator submitted research to the Journal of Experimental Medicine in 1941 describing how he deliberately infected a 12-month-old infant “offered as a volunteer” with herpes. That journal’s editor refused to publish the research, condemning it as an abuse of power and infringement on the rights of the individual, “not excusable because the illness which followed had implications for science,” Lederer said. But the Journal of Pediatrics published the research in 1942, she said.

• Although French and British delegates to a meeting of the World Medical Association’s committee on ethics insisted on protections for institutionalized children and prisoners, those groups were excluded in the resulting policy document.

“These populations were important to American investigators and in the final Declaration of Helsinki, all those strictures about using institutionalized populations do not appear,” she said.

• In the 1950s and 1960s, children at the Willowbrook State School for mentally retarded children intentionally were infected with hepatitis. Although parents gave consent and researcher Saul Krugman defended his studies, Lederer said the quality of the consent has remained problematic. Parents were coerced to participate, she said, “because the only way to get your child into the institution was to enroll them in the study.”

The pathogens

The kind of pathogen involved seemed to impact ethical discussion, Lederer noted. Gonorrhea experiments conducted in the 1940s on patients in an Indiana federal prison produced an extended ethical discussion, but the deliberate infection of prisoners with malaria, a disease important to the war effort, did not.

American medical authorities also had concerns about other populations, she said. The Veterans Administration refused to participate in disease research that withheld treatment from a control group. It did allow a study in which all participants received streptomycin as a treatment for tuberculosis. However, the PHS had no such qualms, permitting a study in which a control group of patients was not treated and were not informed by doctors that they were not being given the drug, she said.

Racism

The American Institution for Cancer Research in 2003 removed the name of Cornelius P. Rhoads from its young investigators award after a controversy that arose over a letter he apparently wrote, but never mailed, while a researcher in Puerto Rico in the 1930s. In the letter, Rhoads, who later became director of Sloan-Kettering Institute for Cancer Research, reportedly denigrated Puerto Ricans as degenerate, thieving, dirty and lazy, going on to state that, “What the island needs is not public health work but a tidal wave or something to totally exterminate the population.” He added, “I have done my best to further the process of extermination by killing off eight and transplanting cancer into several more.”

Although the murderous claims were not confirmed, the controversy simmered for decades. “Those things have a long memory,” Lederer said.

In launching a question-and-answer session, Meisel said, “The road to hell is paved with good intentions. You do get the feeling that all of these people had good scientific intentions. I think that makes it so much more difficult to know just how to regulate this kind of enterprise. What can we do to make people more reflective and to attempt to prevent these kinds of abuses from taking place again, or at least … to minimize their occurrence?”

He noted that in addition to the known cases, such as those Lederer cited, “there’s the unpublished iceberg as well.”

Reverby responded, “If you’re calling for more regulation, I don’t think that’s the answer.”

Instead, she said, a departure from “cookbook ethics” is needed in educating researchers about ethical human experimentation.

Writing off past abuses as perpetrated by bad people or believing that such things couldn’t happen today because there is regulation and researchers today know much better, “The question becomes, how do we do that? … I think we are really struggling with what would that education look like,” Reverby said.

Video of the symposium will be posted on “GSPH lecture archives” at www.publichealth.pitt.edu.

—Kimberly K. Barlow


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