What is ethics principle

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This chapter describes ethical problems of medical research on vulnerable humans, starting with an historical review of medical experimentation by Nazi physicians and secret American medical research. Its major topics are the Tuskegee Study of untreated syphilis in Alabama and later studies in Africa to prevent mother-to-child transmis- sion of HIV. The chapter also discusses financial conflicts in research, especially with research sponsored by pharmaceutical companies. It also discusses medical research in vulnerable populations in developing countries, including a controversial experi- ment in neuroscience on Romanian orphans, the Bucharest Early Intervention Pro- ject. It also discusses the Krieger Lead Paint Study and the Jesse Gelsinger case.

INFAMOUS MEDICAL EXPERIMENTS

William Beaumont

In 1822, physician William Beaumont, the father of gastric physiology, treated patient St. Martin for a bullet wound in the stomach; St. Martin survived, but the wound healed strangely, leaving a hole. Beaumont then employed St. Martin as a servant and proved the previously unknown fact that stomach juices digest food. St. Martin ran away and Beaumont had him caught to continue to exhibit him. Hospitals today in Texas and Michigan bear Beaumont’s name.

Nazi Medical Research

Besides participating in the Holocaust, physicians during the Nazi regime conducted heinous experiments. They reasoned that if victims in concentration camps were going to die anyway, why not use them to benefit medical science?

From 1943 to 1945, gay men, convicted criminals, Russian officers, Polish dis- sidents, Jews, and gypsies on Ward 46 at Buchenwald in Germany got experimental

C H A P T E R 9

Medical Research on Vulnerable Populations

Tuskegee, Krieger lead-paint, HIV Vertical Transmission in Africa, Bucharest Early Intervention Studies

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vaccines against typhus. Physicians injected blood infected with typhus into 40 invol- untary subjects, who served as a treatment group. Overall, they infected 1,000 pris- oners, 158 of whom died.

In experiments at Buchenwald, physicians tried to cure gay men of being homo- sexual with hormone shots, had inmates shot to study gunshot wounds, starved inmates to study the physiology of nutrition, and amputated women’s bones and limbs to study regeneration. To study malaria, physicians used Anopheles mosquitoes to infect subjects. Physician Ernst Grawitz infected legs of women with staphylococci, gas, and tetanus bacilli. In testing sulfa drugs, he rubbed into wounds particles of glass and stone.

In experiments at Ravensbrück, physician Sigmund Rascher devised his “sky ride wagon” to simulate rapid changes in altitude. Victims were locked inside an enclosed box on wheels with monitoring equipment inside.1 Rascher froze 100 nude Jewish and Russian prisoners in icy waters to study techniques to revive downed pilots in similar waters. He also forced nude Jewish women to revive the subjects sexually, degrading the subjects and women for the amusement of the guards.

Josef Mengele

Josef Mengele, known as the Angel of Death, participated in the deaths of 400,000 victims in concentration camps. Ambitious, young Mengele sought fame and stud- ied medical anthropology and genetics between 1930 and 1936, when eugenics movements swept Germany and America.

Contrary to some accounts, German medical schools did not resist, but led, Nazi eugenics and the killing of undesirables. To advance, Mengele joined the Brownshirts, a fanatical Nazi movement that promoted Aryan racial purity.

Mengele needed groundbreaking research to become a full professor. In 1943 at the Auschwitz concentration camp, he experimented to overcome the effects of genetics by modifying environments. He wanted to produce blue eyes, blonde hair, and healthy bodies free of genetic disease.

As subjects, he needed identical twins, natural controls. So he examined incom- ing trains of boxcars filled with Jews, looking for twins and other usable subjects, signaling his choices with a flick of his wrist.

He injected blue dye into children’s eyes to see if he could create blue eyes. To see if twins could be produced, he forced female twins to engage in coitus with male twins. He interchanged blood of identical twins to observe results; he inter- changed blood between pairs of twins.

One pair of fraternal twins consisted of a hunchback and a normal child; Mengele surgically grafted the hunchback to the normal child’s back, creating the effect of conjoined twins. He accentuated this effect by sewing their wrists back to back. A witness reported that when these conjoined children returned to the bar- racks, “there was a terrible smell of gangrene. The cuts were dirty and the children cried every night.”2

Mengele obtained between 150 and 200 twins, most of whom died. Mengele also tested endurance by subjecting 75 prisoners to electric shock; 25 of them died imme- diately. He subjected Polish nuns to high dosages of radiation to produce sterility.

He once found a hunchback and the hunchback’s son; he had both of them killed, their bodies boiled, their flesh stripped, and their skeletons dipped in

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gasoline for preservation for his anthropological studies of body types. Coming upon seven dwarfs from a circus family, he exhibited them to visiting physicians.

When 300 Jewish children escaped a gas chamber, Mengele—cool, impersonal, and detached—had them recaptured, lit a gasoline fire set in a large pit, and had the children thrown in.

When the Russian army approached Auschwitz in 1945, Mengele escaped to Paraguay. He lived there for 40 years, eluding Israelis who tried to capture him as a war criminal. In later conversations with his grown son Rolf, he expressed no regret for his actions: It was not his fault that Jews had to die at Auschwitz, he said, so why not use them to advance medical knowledge and his own chances for a professorship? Never captured or tried as a war criminal, Mengele died in Brazil in 1985.3

The Nuremberg Code

After World War II, at the Nuremberg trials in 1946, German physicians defended themselves against charges of war crimes by saying that they had merely been fol- lowing orders, that their experiments had been properly related to solving medical problems of war, and that what they had done did not differ from similar research done on captives by American physicians.

The judges at Nuremberg lacked a code of ethics for experimentation on captive populations, so they created 10 principles for ethical experimentation, known as the Nuremberg Code. Its most important principle was that people, even prisoners or inmates of institutions, should freely consent to participation in any experiment.

Questionable American Research

In 1941, American researchers experimented on orphans at the Ohio Soldiers and Sailors Orphan’s Home, on inmates at New Jersey State Colony for the Fee- ble-Minded, and on patients at a mental institution in Dixon, Illinois.4 To develop a vaccine against shigella, they injected deadened forms of the bacteria into subjects. None died, but many got sick.

Some questionable research used military personnel as subjects. Cornelius Rhoads, Director of Memorial Sloan Kettering Cancer Hospital in New York City, led the military’s secret chemical warfare service. He exposed thousands of Amer- ican troops to mustard gas, accidentally learning that the gas killed white blood cells and cancerous cells. After the war, he experimented with mustard gas as an anticancer drug.5 About 4,000 to 5,000 subjects inhaled mustard gas in gas cham- bers. Altogether, in research conducted by the armed forces on poisonous agents, 60,000 subjects did not know what they were undergoing.6

During World War II, Franklin Roosevelt established the Committee on Medical Research, which approached its work with a wartime mentality that carried over after the war: Disease was the enemy, researchers battled it, and victory could be won—with enough resources and enough will. As bioethicist David Rothman wrote, during the war, ethical concerns about experiments carried little weight:

A wartime environment also undercut the protection of human subjects, because of the power of the example of the draft. Every day thousands of men were com- pelled to risk death, however limited their understanding of the aims of the war or

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the immediate campaign might be. By extension, researchers doing laboratory work were also engaged in a military activity, and they did not need to seek the permis- sion of their subjects any more than the selective service or field commanders did of draftees. … In a society mobilized for war, these arguments carried great weight. Some people were ordered to face bullets and storm a hill; others were told to take an injection and test a vaccine. In philosophical terms, wartime inevitably promoted utilitarian over absolutistic positions.7

When subjects of secret chemical research later applied for treatment at veterans’ hospitals, the Veterans Administration (VA) denied that they had been exposed to these agents. This scenario recurred after the war in Vietnam and after Operation Desert Storm.

During the 1940s, radiation enthralled some physicians. Joseph Hamilton of the University of California at Berkeley injected plutonium into 18 unsuspecting patients diagnosed with cancer. According to Kenneth Scott, a scientist who later investi- gated these abuses, two patients were mistakenly diagnosed with cancer but nev- ertheless given “many times the lethal dose of plutonium.”8

Physicians also studied radioactive isotopes used in diagnosis and research. In the late 1940s at Vanderbilt University, physicians injected 819 pregnant women with radioactive iron in a nutritional study. A study in 1960 found that three of their children died of rare forms of cancer.9 In 1945, Eda Charlton entered Strong Memorial Hospital in Rochester, New York, with a mild case of hepatitis and was secretly injected with plutonium-239 to study how her body eliminated radiation. Physicians then secretly followed her for years to observe the effects (she died of a heart attack in 1983).

From World War II to the mid-1970s, physician-researchers subjected over 16,000 American patients to radiation experiments.10 The Department of Energy or its prede- cessors conducted at least 435 experiments in 21 states. From the 1940s to the 1960s, physicians exposed 1,500 military aviators and submarine crewmen to encapsulated radium on the end of wires inserted high into their nostrils for several minutes.11

In another experiment, physician-researchers paid 130 male prisoners $200 to undergo X-ray radiation of their testicles; afterward, these men got vasectomies. In another, physicians injected plutonium into an indigent 36-year-old Texan’s injured leg, which surgeons then amputated. In 1995, the President’s Committee on Human Radiation Experiments investigated these experiments and concluded that the gov- ernment should apologize to involuntary subjects and should compensate people who had been injured.12

In 1966, Harvard medical professor Henry Beecher criticized 22 specific medical experiments published in medical journals that had not obtained consent of sub- jects; he pointed out that this was the norm and criticized this fact.13 About the same time, physician Henry Pappworth similarly criticized 500 medical experi- ments.14 That year, the U.S. Public Health Service began to require informed con- sent of subjects, an important fact in judging the Tuskegee Study.

In 1991 in Operation Desert Storm, officers forced soldiers to take experimental vaccines against biological agents. Federal law stated that, under operational condi- tions, soldiers could not refuse such vaccinations. Subsequently, many soldiers became sick. For years afterward, the Pentagon and Department of Defense denied that their sickness was service-related. Yet the military’s own records showed many

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causes of such sickness, especially acting in combination, with sand storms, biolog- ical weapons, oil fires, contaminated water, rare microorganisms, the vaccines dis- cussed earlier, chemical vapors from bombed Iraqi storage areas, unspent rocket fuel, and high levels of stress.15

THE TUSKEGEE STUDY (OR “STUDY”)

Nature and History of Syphilis

Past victims of untreated syphilis included Cleopatra, King Herod of Judea, Char- lemagne, Henry VIII, Napoleon Bonaparte, Frederick the Great, Catherine the Great, Christopher Columbus, Paul Gauguin, Franz Schubert, Albrecht Dürer, Johann Wolfgang von Goethe, Friedrich Nietzsche, John Keats, and James Joyce.16

Between 1900 and 1948, and especially during the two world wars, American reformers mounted the Syphilophobia Campaign. Reformers emphasized that prosti- tutes spread syphilis and that it rapidly killed. As an alternative for men to visiting prostitutes, they advocated clean, active sports, or “Muscular Christianity.”

Anti-syphilis crusaders split twice over methods to prevent spread of syphilis: once during World War I over giving out condoms and again during World War II over giving out penicillin. In each conflict, reformers who wanted to reduce the harm of syphilis battled those who wanted to reduce illicit behavior.17

This conflict repeated over the next century in battles about venereal diseases, prostitution, alcoholism, drug addiction, gambling, and sex education. The Harm Reduction Movement (HRM) focuses on reducing the associated harms of these behaviors, not on moral censure or eliminating the behaviors. Moralists who oppose HRM attack the illicit behavior and view HRM as enabling it, for example, by teaching men how to use condoms.

During the world wars, the armed services adopted HRM. Commanders who needed healthy troops ordered the release of condoms in the first war and penicillin in the second. After the wars, returning troops continued to use both, normalizing these practices.

Physicians today treat syphilis with penicillin. Such treatment has been possible only since 1948, when penicillin became available to everyone.

Schaudinn discovered in 1906 the spirochete that causes syphilis. It is a chronic, contagious bacterial disease, often venereal and sometimes congenital. It has three stages. In the first stage, primary syphilis, spirochetes mass and produce a primary lesion, a chancre (pronounced “SHANK-er”). During this stage, syphilis is highly infectious. After the chancre subsides, the disease spreads silently for a time, but then produces an outbreak of secondary symptoms such as fever, rash, and swollen lymph glands.

In the second stage of latent syphilis, spirochetes disseminate from the primary lesion throughout the body, producing systemic and widespread lesions, usually in internal organs. Syphilis may then spread silently from 1 to 30 years. During this stage, symptoms vary so widely that syphilis was once known as the Great Pretender.

In the last stage of tertiary syphilis, chronic destructive lesions damage the car- diac and neurological systems. Syphilis then may produce paresis (slight or

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incomplete paralysis), gummas (gummy or rubbery tumors), altered gait, blindness, or lethal narrowing of the aorta.

Beginning in the sixteenth century, to treat syphilis physicians applied the heavy metal mercury as a paste on the back. During the nineteenth century, they similarly administered another heavy metal, bismuth. Neither mercury nor bismuth killed the spirochetes, though they ameliorated symptoms.

In 1909, after the spirochete causing syphilis had been identified, two researchers—a German, Paul Erlich, and a Japanese, S. Hata—tried 605 forms of arsenic and discovered a “magic bullet” against it in combination of 606 heavy metals (which included arsenic). Erlich humbly called this Salvarsan (implying salvation from syphilis); its generic name is arsphenamine.18 After finding that it cured syphilis in rabbits, Erlich injected it intra- muscularly into men with syphilis.

At first, Salvarsan seemed to work wonders, and during 1910, physicians greeted Erlich with standing ovations. Later, syphilis recurred in some patients treated with Salvarsan, and some died, either from syphilis or from Salvarsan. Erlich maintained that the drug had been given incorrectly, but he still developed a less toxic form, Neosalvarsan.

Physicians injected Neosalvarsan intramuscularly in 20 to 40 dosages over a year, charging patients a dollar per visit. For full treatment, patients needed both time and money. Neosalvarsan was no one-time treatment for syphilis, as penicillin later was.

Between 1890 and 1910, Norwegian Caesar Boeck studied the natural course of untreated syphilis in 1,978 subjects. He correctly believed that heavy metals removed only the symptoms of syphilis. Because they killed some syphilitics, he studied whether subjects might fare better if left untreated.

In 1929, Boeck’s successor, J. E. Bruusgaard, selected 473 of Boeck’s subjects for further evaluation.19 Bruusgaard learned that of subjects who had had syphilis for more than 20 years, 73 percent were asymptomatic. Because this discovery dra- matically contradicted the Syphilophobia Campaign, the leaders of this movement resisted the fact that syphilis did not universally kill, much less did not do so rapidly (foreshadowing similar battles later about AIDS). Even more disturbing to the Syph- ilophobia Campaign, Bruusgaard confirmed that some latent syphilitics might never develop symptoms at all.

So when the Tuskegee Study began in 1932, Boeck’s and Bruusgaard’s studies had caused physicians to question the received views about the natural course and treatment of syphilis.

The Racial Environment

In the 1930s, American-medicine was racist. Most physicians held stereotypes about African-American patients, as in this example from a 1914 Journal of the American Medical Association:

The negro springs from a southern race, and as such his sexual appetite is strong; all of his environments stimulate this appetite, and as a general rule his emotional type of religion certainly does not decrease it.20

Physicians saw African-Americans as dirty, shiftless, promiscuous, and incapa- ble of personal hygiene. In 1900, a Georgia physician wrote, “Virtue in the negro

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race is like ‘angels’ visits’—few and far between. In a practice of 16 years in the South, I have never examined a virgin over 14 years of age.”21 In 1919, a medical professor in Chicago wrote that African-American men were like bulls in furor sex- ualis, unable to resist copulation around females.22

Given such racism, white physicians around 1929 saw syphilis as a natural consequence of low character in African-Americans, described by one white physi- cian as a “notoriously syphilis-soaked race.”23 Such physicians also assumed that African-American men would not seek treatment for venereal disease.

Development of the Tuskegee Study

A Study in Nature Begins.!Physiologist Claude Bernard in 1865 distinguished stud- ies in nature from normal experiments: In the former, someone merely observes what would have happened without any interventions; in the latter, scientists manipulate a variable. The Tuskegee Study was a study in nature.

The great physician William Osler once said, “Know syphilis in all its manifes- tations and relations, and all other things clinical will be added unto you.”24 Yet as of 1932, syphilis’s natural history had not been documented, and because of Boeck/ Bruussgaard’s results, physicians doubted the inexorability of its course.

This explains why the U.S. Public Health Service (USPHS) believed it needed a study in nature. Around 1929, six counties in America had high rates of syphi- lis—above 20 percent—and a charity, the Julius Rosenwald Foundation of Philadel- phia, treated all syphilitics in those counties with Neosalvarsan. In 1930, this foundation surveyed African-American men in Macon County, Alabama, where Tuskegee is the chief town. Its citizens were 82 percent black, and its rate of syphilis was then the highest in the nation, 36 percent. The foundation treated or partially treated some of these 3,694 syphilitics with Neosalvarsan.

Then something unforeseen happened: In 1929 the Great Depression began. Soon, funds for charity plummeted, and the Rosenwald Foundation left, hoping that USPHS would continue its program. Funds for public health also plummeted, and in 1935, the USPHS budget fell from $1 million to less than $60,000.

In 1931, USPHS repeated the Rosenwald Foundation’s survey of syphilis in Macon County, testing 4,400 African-American residents, and found that 22 percent of men had syphilis, as well as a dangerous 62 percent rate of congenital syphilis. Of great importance for the Tuskegee Study, this survey identified 399 African - American men who had had syphilis of several years’ duration, but who had never been treated.

The Surgeon General himself, Raymond Vonderlehr, wrote in 1936 in the Journal of the American Medical Association that the Tuskegee Study was “an unusual oppor- tunity to study the untreated syphilitic patient from the beginning of the disease to the death of the infected person.”25 His decision began the Tuskegee Study.

Three points deserve emphasis. First, the 399 subjects had latent syphilis, not infectious syphilis. During this stage, syphilis is largely noninfectious during sexual intercourse. Second, researchers did not divide the 399 subjects into the typical experimental and control groups: They were all simply observed. There was, how- ever, another group of natural controls, 200 age-matched African-American men living in Macon County who had never had syphilis.

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Third, the 399 men with syphilis and the 200 men without it were perfect for a study in nature because they were so vulnerable: They were poor, illiterate, and tied to the land as tenant farmers. As such, unlike other people with syphilis over the next four decades, they were unlikely to ever leave Macon County. Partly because of this vulnerability, Vonderlehr implied, they presented an “unusual opportunity.”

Vonderlehr had no sense that it might be wrong to use such vulnerable subjects in a lifelong experiment. Like many of his time, he may have assumed that people with syphilis got what they deserved and that these poor black men would never have had the means, will, or opportunity to get treatment, even though the Public Health Service could have one day provided it.

The Middle Phase: Poor Design.!No one physician oversaw this study. It lacked written protocols, and later investigators often mixed up the subjects in the no-treat- ment group of 399 syphilitics with the 200 “controls” without syphilis. Nurse Eunice Rivers, an African-American nurse assigned to stay in Tuskegee and keep track of the study, kept poor records, lost them, and because many of the men had the same last names, later researchers often confused one patient for another.

Researchers assumed that controls would remain uninfected, but in a county where one in three people had syphilis, many controls eventually contracted syph- ilis. Unfortunately, when they happened, some were switched to the no-treatment group of syphilitics.

The study had gaps. Federal doctors visited in 1939 and then not until 1948; seven years passed between visits in 1963 and 1970. Only Nurse Rivers held the shaky study together.

During the course of the research, many of the 399 syphilitic subjects, who were supposed to remain untreated, obtained Neosalvarsan or penicillin outside Macon County. James Lucas, a CDC physician, said, “Effective and undocumented treat- ment had been given to the vast majority of patients in the syphilitic group.”26 So researchers would never know whether any observed subject really represented the consequences of untreated syphilis or when the subject had contracted it.

Ultimately, the study proved nothing. Before it began, physicians knew that syphilitics had greater morbidity and mortality than nonsyphilitics, and from Bruus- gaard’s discovery, that not all men in the latent phase died of syphilis. The Tuskegee Study added nothing new.

Spinal Taps and Deception.!When physicians returned, they wanted to know, first, if they had a subject in the study group, and second, if so, how far his syphilis had progressed. To determine progression, they did spinal punctures on 271 of the 399 syphilitic subjects.

In doing spinal taps, they inserted a 10-inch needle between two vertebrae into the cerebrospinal fluid to withdraw a small amount of fluid. Because this is a deli- cate and uncomfortable process, physicians warned subjects to stay still, lest the needle swerve and puncture their spinal cord or spinal nerves, causing infection and possible paralysis.

Some physicians then and now regard spinal taps as insignificant, justified to prove a diagnosis. On the other hand, professionals who describe spinal taps this way may be thinking more about administering one rather than receiving one.

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Unlike taking blood, a spinal tap is not a minor procedure. Some patients experience effects such as being unable to stand for a week without a severe head- ache. One person in 1 million will become paralyzed or permanently comatose.27

Tapping someone involuntarily, without obtaining informed consent, is legally a form of battery. Researchers who need healthy volunteers for spinal taps offer subjects as much as $1,000.

To induce subjects to travel to town and undergo these painful taps, physicians in this study offered a series of incentives: free transportation, free hot lunches, free medicine for any disease other than syphilis, and free burials.

But these freebies and the persuasion of Nurse Rivers failed to get all men to come to town for the “round-ups,” so researchers resorted to deception. Infamously, they told the black men that they had “bad blood” and that the spinal taps were treatment for their bad blood. Researchers sent the subjects the following letter, under the imposing letterhead “Macon County Health Department,” with the subheading “Alabama State Board of Health and U.S. Public Health Service Cooperating with Tuskegee Institute”:

Dear Sir: Some time ago you were given a thorough examination and since that time we hope you have gotten a great deal of treatment for bad blood. You will now be given your last chance to get a second examination. This examination is a very special one and after it is finished you will be given a special treatment if it is believed you are in a condition to stand it.28

The “special treatment” mentioned was the spinal tap to culture for neurosyph- ilis. The subjects were instructed to meet Nurse Rivers for transportation to “Tus- kegee Institute Hospital for this free treatment.” The letter closed, in capitals:

REMEMBER THIS IS YOUR LAST CHANCE FOR SPECIAL FREE TREATMENT. BE SURE TO MEET THE NURSE.

To repeat, the researchers never treated the subjects for syphilis. Although pen- icillin was developed around 1941–1943 and was widely available by 1948, the subjects in the Tuskegee Study never received it, even during the 1960s or up to 1972. During World War II, researchers contacted the local draft board, which prevented eligible subjects from being drafted, and hence from being treated for syphilis with penicil- lin by the armed services.

Revelation of the Study to the World.!In 1966, USPHS venereal disease investiga- tor Peter Buxtun learned about the study. By this time, supervision of the study (and Buxtun) had moved to the newly created Centers for Disease Control (CDC) in Atlanta. When Buxtun asked about the study, the CDC threatened to fire him.

By 1969, Buxtun’s protests led to a meeting of a small group of physicians at CDC to consider stopping the Tuskegee Study or revealing it. Ultimately, they voted to continue the study and to keep it secret.

In 1970, the American Public Health Association published a monograph on syphilis. It stated that treatment for late benign syphilis should consist of “6.0 to 9.0 million units of benzathine penicillin G given 3.0 million units at sessions seven days apart.”29 The first author was William J. Brown, head of CDC’s Tuskegee

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section from 1957 to 1971. Brown, on the CDC committee in 1969, had argued for continuing the study and not giving penicillin to any subjects.

Buxtun eventually contacted Jean Heller, who worked for the Associated Press. On July 26, 1972, her story appeared on front pages of newspapers nationwide.30 She described a study run by the federal government in Tuskegee, Alabama, where poor, uneducated African-American men had been used as guinea pigs. After noting the terrible effects of tertiary syphilis, she stated that in 1969, a CDC study of 276 of the untreated subjects had proved that at least seven subjects died “as a direct result of syphilis.”

Heller’s story stunned congressmen. Senator William Proxmire called it a “moral and ethical nightmare.” In reply, J. D. Millar, chief of Venereal Disease Con- trol at CDC, said that the study “was never clandestine,” correctly pointing to 15 published articles in medical journals over 30 years.

After Heller’s story appeared, the Secretary of Health, Education, and Welfare terminated the study. The CDC estimated that 28 syphilitics had died of syphilis during the study; it then gave penicillin to the remaining subjects.

In 1973, on behalf of the Tuskegee subjects, lawyer Fred Gray filed a class-action suit against the federal government. In 1974, the U.S. government settled out of court. According to the settlement, living syphilitics received $37,500 each; heirs of deceased syphilitics, $15,000 (since children might have had congenital syphilis); heirs of living controls, $16,000; heirs of deceased controls, $5,000. Controls and their descendants received compensation, because they and their families had been deprived of antibiotics during the decades of the study. The government provided free lifetime medical care for the subjects, their wives, and their children.

In 1972, as a direct revelation of the study, the federal government required all institutions that conduct human medical experimentation and receive federal funds to have Institutional Review Boards (IRBs). Today, IRBs must scrutinize written proposals and defend against abuses in medical research.

In 1988, 21 of the original 399 syphilitic subjects were still alive, each of whom had had syphilis for at least 62 years.31 In addition, 41 wives and 19 children had evidence of syphilis and had received free medical care.

In 1997, President Clinton met four of the eight living survivors to apologize for the Tuskegee Study, “What the United States did was shameful, and I am sorry.”32 The youngest survivor then was 87, the oldest between 100 and 109.33 By then, the government had paid $10 million to the study’s original 600 members or to their families or heirs, who numbered more than 6,000. Because of lack of treatment for syphilis of men in the study, any of these other people might have contracted syphilis.34

Perhaps the worst effect of revelation of the study was distrust by African-Americans of medical experiments, a legacy that researchers today must overcome.

ETHICAL ISSUES IN THE TUSKEGEE STUDY

Informed Consent and Deception

In the Tuskegee Study, the subjects did not know they were part of a government study lasting throughout their lives, did not even know what syphilis was, and did

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not know that they weren’t being treated with available drugs. In other words, they had no informed consent, which many critics considered to be ethically outrageous.

R. H. Kampmeier, an emeritus professor of medicine at Vanderbilt Medical School, worked as a syphilologist during the decades of the study.35 He argued that a study undertaken in the 1930s could not be faulted for lack of informed consent, which began only after 1966. Would it make sense, he argued, to judge Pasteur unethical because he, too, did not get consent?

Kampmeier cited another landmark study by USPHS in 1943 that studied giving penicillin to 35,000 syphilitics; it did not get consent from subjects. Medical histo- rian and physician Thomas Benedek dismissed informed consent in the Tuskegee Study as “anachronistic,” emphasizing that USPHS did not require informed con- sent until 1966.36

While it is true that informed consent in medical experiments was not mandated by court decisions until 1966, the presumption had always been that physicians would “First, do no harm” to their patients. Not obtaining consent for procedures that might benefit subjects differs from procedures that might harm subjects.

Finally, and granted that telling patients the truth was not legally required before 1966, was it ethical for the Tuskegee researchers to lie to their subjects for all those decades? Isn’t the truth what one person owes another, especially as doctor and patient?

Racism

The Tuskegee Study took place in Alabama and all its subjects were African-American. Under such circumstances, was it only a coincidence that no subjects were white? Would white subjects have been deceived and left untreated the same way?

In his classic work, Bad Blood, medical historian James Jones saw the Tuskegee Study as a result of pervasive racism in American medicine during the 1930s.

It is true that some physicians then believed that syphilis ran a different course in different races, and this implied the need for a parallel study of untreated white syphilitics. That the USPHS did no parallel study of white subjects shows that it saw black subjects as expendable but not white subjects.

Media Coverage

In defending the Tuskegee Study, Kampmeier objected to the “great hue and cry” in the media in 1972 and to journalists’ claims that “treatment was purposefully withheld to evaluate the course of untreated disease.” He said about Time and American Medical News, “In complete disregard of their abysmal ignorance, members of the fourth estate bang out anything on their typewriters that will make headlines.”37

With regard to the first objection, Kampmeier exaggerated the “hue and cry” of the media. Indeed, the media botched the story. Coverage shrank within days, and the story moved to the back pages, where only short paragraphs followed it.

To begin with the second objection, Kampmeier attacked the media for report- ing the damaging aspects of the study, such as the withholding of treatment. In

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defense of the media, researchers did intend to withhold treatment. That was pre- cisely the intention of the study.

The Tuskegee Study deserved far more attention. True, it had complex issues that involved racism at a time when racial turmoil upset Americans, but today such a story would receive weeks of nationwide scrutiny and probably get a congressional hearing on television.

The relation then between medicine and the media can also be questioned. Before Heller’s story broke, the Tuskegee Study had been reported repeatedly in at least 17 articles in medical journals between 1936 and 1972. Researchers did not conceal the study within medicine. Despite this, no professional publication, phy- sician, or editor alerted the nation to the story.

Between 1966 and 1971, one African-American professional at the CDC mailed boxes of documents about the study to several national newspapers and maga- zines.38 Nothing happened. Why is that?

The answer is important to understanding many issues in medical ethics and to whistleblowing about corruption. Print and television reporters need an expert to help them understand such complex stories and, equally important, to take responsibility for claims about wrongdoing. Virtually no reporters then or now have the medical background to understand such complicated stories and, without that, cannot risk charging physicians with possible crimes.

A natural tendency also exists to want someone else to be the whistleblower and to bear the brunt of retaliation. As a result, merely mailing information or passing it along conversationally is not enough for reporters to publicize wrongdoing.

Harm to Subjects

Kampmeier argued that if the Tuskegee Study had never occurred, its subjects would have received no treatment and would have been no worse off. Such a claim can never be proved. If the Tuskegee Study had not occurred, many things might have happened. Another charity might have provided Neosalvarsan. A writer like John Steinbeck might have soon written a novel about syphilis in Macon County, arousing national concern and getting penicillin to people there infected with syphilis.

So what harm, if any, resulted to subjects with syphilis from nontreatment? This question might seem even absurd: If subjects were left untreated, of course they must have been harmed! However, the issue is not that simple.

In 1931, penicillin was unavailable, so physicians withheld Neosalvarsan from subjects. Because Neosalvarsan was expensive and cumbersome to administer, even if this study had not occurred, subjects might not have received it. Boeck and Bruusgaard had also undermined claims about the benefits of heavy metals, so harm is difficult to prove. In a review of medical evidence available in 1940, medical historian Benedek concluded that in 1937, untreated syphilitics actually lived longer and better than those partially treated with heavy metals.39

Not everyone agrees. UAB professor of internal medicine Benjamin Friedman, whose career spanned the decades of this study, countered:

In the 1940s it was known that patients receiving as few as 20 injections of arsen- icals rarely developed symptomatic aortic disease. Since we could not determine in advance which of the latent syphilitics would, after 20 or 30 years, develop

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symptomatic aortic disease, it was necessary to treat all of them. One cannot main- tain that some small number of syphilitics deprived of treatment did not therefore suffer injury.40

By 1934, the major professional organization of physicians treating syphilis in America, the Cooperating Clinical Group, proved that use of heavy metals improved Bruusgaard’s statistics and recommended that all syphilitics get Neosalvarsan, mer- cury, and bismuth.41 Even if many patients could not afford such therapy, they should have been told about it.

Later during the study, penicillin became available. Although Alexander Flem- ing discovered penicillin in 1929, the world did not appreciate his discovery until 1941, and only around 1946, as a result of wartime production to treat soldiers, did penicillin become available to most Americans. By 1948, anyone could get it.42

Kampmeier argued that withholding penicillin in 1946 did not harm subjects with latent syphilis, which he said was a “chronic, granulomatous, self-limiting dis- ease” and not fatal. He argued next that proof of penicillin’s effectiveness did not come until 1948 and then only for primary syphilis. So the study’s subjects by 1948 could no longer have been helped by penicillin; the damage to them had already been done.43

Benedek disagreed. He concluded that giving penicillin to latent syphilitics in 1948 “might have exerted a definitely beneficial effect on the prognosis of only 12.5 percent of the subjects.”44 Still, that would have helped 50 subjects.

Effects on Subjects’ Families

“Virtually all subjects were or had been married” and had an average of 5.2 chil- dren.45 Recall that Macon County had a rate of congenital syphilis of 62 percent.

When we consider the subjects’ families, wouldn’t the men in the study want to know they had syphilis? Even in latency, wouldn’t they want to know they could become infectious again? Did the researchers withhold the truth because they thought these men couldn’t refrain from sex?

These researchers subjected women and children in Macon County to harm. Either the researchers discounted this harm or thought it didn’t matter.

Kant and Motives of Researchers

When physicians at CDC and USPHS debated the Tuskegee Study in 1969, many assumed that if no harm could be proved, nothing unethical had been done. This is also Kampmeier’s unstated assumption.

Focusing on consequences, however, is only one way to judge morality. We can also adopt, not a consequentialism or utilitarianism, but a Kantian ethics focused on motives or a virtue ethics focused on the character of researchers.

Although we cannot prove that being left untreated harmed the study’s sub- jects, it may have been only good luck that the study caused no more harm than it did. Why is that?

Historical evidence cuts both ways. We cannot use differing historical standards at differing times to excuse lack of informed consent but not pay attention to what else researchers believed at the time. Let us put ourselves in the minds of

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researchers in the late 1940s. The crucial fact is that when penicillin became available, most physicians believed it would help latent syphilitics.

So they believed that subjects would be harmed by not getting penicillin. For all anyone knew in 1948, penicillin could have helped patients with aortic heart disease or at least would have ameliorated it.

For Kantian ethics, researchers deliberately willed harm on these subjects. They used them as “mere means,” as guinea pigs, and could not universalize such behav- ior as a maxim for all physicians to act on. Not only did they lack what Kant calls a “good will,” they had an ill will toward vulnerable subjects.

It is no good appealing to sophisticated knowledge that came later about how the damage from syphilis had already occurred. Researchers then believed they were depriving syphilitics of something likely to help them, or depriving them of something that could help them not pass syphilis on to their female partners. But out of a desire by researchers to prove the final ravages of syphilis, or lack thereof, researchers deceived subjects and believed they were allowing them to be harmed.

OTHER STUDIES LIKE THE TUSKEGEE STUDY

HIV Prevention in Africa: Another Tuskegee Study?

Unfortunately, research by physicians in wartime and the Tuskegee Study are not the only examples in the history of modern medical ethics of questionable research on vulnerable subjects. We now discuss a famous study in Africa that involved not syphilis but AIDS, and readers can see how the issues of the Tuskegee Study frame some of the criticisms of the African study.

In 1994, researchers had proved that giving the drug AZT (zidovudine) during pregnancy cut by two-thirds transmission of HIV from mother to child in North America.46 In 1995, CDC, NIH, and the World Health Organization (WHO) began to study whether doing a similar study in Africa could prevent HIV in the 800 infected babies born there every day and started a randomized control trial (RCT).

One might well ask, “As the ability of AZT to block vertical HIV transmission had already been proven, why conduct such a study at all in Africa?” One answer: the strain of HIV in Africa differs from that common in North America. A second answer: in Africa, researchers felt that they needed a quick proof that AZT could block mother-to-child transmission of HIV.

In 1997, Marcia Angell, executive editor of the New England Journal of Medicine, claimed that this research mimicked the Tuskegee Study because researchers gave pregnant, HIV-infected black women placebos (harmless sugar pills), and thus babies were born with preventable HIV infections.47 Because giving AZT to all HIV+ pregnant women was the American standard of care, not giving AZT in a placebo group was unethical: “If it is unethical to do placebo-controlled trials in America, it should also be unethical to do them in third-world countries.”48

This study had subjects who were highly vulnerable because they were (1) black, (2) female, (3) poor, (4) illiterate, (5) victims of sexually transmitted diseases, and (6) without other available treatment. Like the Tuskegee Study, magisterial but dis- tant governmental agencies conducted the research. Like the Tuskegee Study,

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vulnerability and powerlessness characterized the subjects. Columnist Ellen Good- man noted that the Tuskegee Study had not ended but had been merely exported.49

Apologists passionately retorted that, had their research not been done, infected mothers would not have gotten AZT and their babies would have been infected anyway.

African officials replied that Angell and Goodman were ethical imperialists, imposing American ethical standards on African countries.50 Such officials were also black and had lost children to HIV unlike the white USPHS physicians of the Tuskegee Study.51

They also replied that if they could prove—via a placebo-controlled trial—that a shorter regimen of AZT could reduce HIV transmission by half, they could save 150,000 children a year. If skeptics such as Angell caused delays of proof, more children would die.

Officials also claimed that a placebo-controlled trial of HIV-transmission could be done faster and with fewer subjects than a AZT-controlled study, and that once they had good results, African governments would give all pregnant, HIV+ women the new, smaller dosage of AZT.

Researchers also argued procedurally that review committees in both countries had approved the studies and that, unlike the Alabama men, the women themselves had consented. Subsequent interviews by the New York Times cast doubt on how much the women understood.

Angell argued that researchers didn’t need placebo-controlled studies; compar- ing dosages of AZT to other anti-HIV drugs could prove the same thing. Given the poverty of such countries, she denied that a proven, reduced dosage would later be given to all pregnant women because—even at $80—AZT costs 11 times more per year than that normally spent on such African women.

Both sides invoked justice.52 One philosophical side invoked Bentham, utilitar- ianism, and public health ethics. The other hailed Kant, his axiom that people can never be used as a “mere means,” and his belief that ethical principles are not local but universal.

For researchers, the risk/benefit ratio had to be different for poor, illiterate women in impoverished countries who otherwise would not have gotten treatment. For critics, the same reasoning had led to the Tuskegee Study and to Nazi experi- ments: “They’re going to get die anyway, so we might as well study them to learn something.”53 As Angell retorted, “People can’t be used as a means to a noble end.”54

In 1998, CDC proved that $80 worth of AZT in the last four weeks of pregnancy cut transmission in half, and they suspended the study.55 At this early cessation, both sides claimed victory.

The Krieger Lead Paint Study

In 2001, after Ellen Roche died in a study of a drug to prevent asthma, the federal Office of Protection from Research Risks (OPRR) halted all federally funded research at Johns Hopkins Medical School. When she volunteered for the study, Ellen was healthy; soon, she was dead.

After its research stopped, a physician from Hopkins on television denounced suspension of Hopkins’s research monies, claiming Hopkins had only killed one

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person in many decades of medical research and that lives would be lost from such a suspension because of delayed cures.

The Krieger case was a study by a branch of Johns Hopkins Medical School that studied mental handicaps in children from lead paint—which six of seven judges on Maryland’s highest court likened it to the Tuskegee Study.56 The study, conducted in the mid-1990s by Hopkins’s Kennedy Krieger Institute, recruited 108 poor, vulnerable, black families to live in East Baltimore in houses with lead paint.

Ingesting lead-based paint is a known cause of cognitive disability in small children. According to the Krieger Institute, the study sought cheaper ways to reduce lead contamination in houses so landlords in East Baltimore would not aban- don them.

Did the parents understand the nature of the study? Did they understand the risk to their children by living in these houses? “It can be argued that the research- ers intended that the children be the canaries in the mines but never clearly told the parents,” one critic said.57 Moreover:

Maryland Court of Appeals Judge Dale R. Cathell, who wrote last week’s scathing opinion, said the board [had] instructed Kennedy Krieger researchers to write con- sent forms for study participants that skirted federal regulations requiring disclosure about risks.

The Court of Appeals ruling ordered trials to be held in lawsuits filed against Kennedy Krieger by two women, Viola Hughes and Catina Higgins, whose children were involved in the study. Hughes’s daughter now suffers from learning disabilities and cognitive impairments, both of which are often associated with lead poisoning. … Higgins says researchers withheld tests results that showed high levels of lead contamination from her. …

Kennedy Krieger is a major institution in the study of lead paint abatement. Marc Farfel, who conducted the study, said today that it identified more effective ways to remove lead hazards and prompted legislation forcing landlords to remove those hazards.58

Amazingly, an investigation by OPRR revealed that the IRB at Johns Hopkins, which supposedly had reviewed and discussed the ethics of the Krieger Study and all other research at the medical school, had rarely met face-to-face.

The Krieger Study resembled the Tuskegee Study in that vulnerable, poor black people were deliberately recruited to a study where physicians foresaw harm to subjects. Researchers rationalized the harm by saying that if the study had not occurred, the subjects would have lived in such housing anyway. Revelation of the Krieger Study further damaged already bad relations between Baltimore’s African- Americans and Hopkins.

1946–1948: The Guatemalan Syphilis Study

In 2011, Wellesley historian Susan Reverby, while researching the Tuskegee Study, chanced upon documents at the National Archives revealing that the USPHS between 1946 and 1948 paid syphilis-infected prostitutes in Guatemala to visit pris- oners and inmates of mental institutions to study how easily syphilis could be trans- mitted and if penicillin could prevent transmission.59 When men failed to become infected, researchers scraped penises and faces and injected infected pus, causing

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about 1,300 of the 5,500 enrolled men to catch syphilis or gonorrhea. Following this revelation, Secretary of State Hillary Clinton apologized to the Guatemalan people for the actions of the United States in this shameful episode of research on people even more vulnerable than those in the Tuskegee Study.

Financial Conflicts and Twenty-First-Century Research

The Bayh-Dole Act of 1980 erased an ethical bright line between academic and corporate medicine and allowed universities and their researchers to patent and reap royalties together. Since then, scandals about money keep recurring in medical research.

Thirty-five years later, pharmaceutical companies fund most research into drugs and devices at universities. They do not fund independent peer review of their new drugs and do not publicize bad results. By indirectly paying physicians to test new drugs and by financially encouraging physicians to recruit patients for experiments, drug companies cause physicians to choose their drug and not the best drug for their patients.

In 1998, a study by the Department of Health and Human Services concluded that IRBs could no longer handle the job of protecting subjects from abuses in medical experimentation.60 It found that IRBs were underfunded and overworked and that the volume of work expected of volunteers could not be accurately and conscientiously performed. Another study in 2002 by the Institute of Medicine reached similar conclusions.61 Since then, several medical research centers improved their structures for reviewing research, although financial conflicts continue.

In 1991, the federal government adopted the Common Rule, under which uni- versities’ IRBs must review all protocols the same way, regardless of funding. This rule subjects all protocols to the same standards as those required by NIH and the U.S. Federal Drug Administration (FDA).

Several scandals erupted in the 1990s, wherein a few physicians appeared to have taken millions of dollars from drug companies for dubious research.62 Some doctors in Georgia allegedly made $4 million over seven years from aggressively soliciting people with schizophrenia for drug trials; they made another $6 million over the same period from testing other drugs.63

In 1996, Apotex Inc. tried to suppress adverse findings by Nancy Olivieri, a Canadian hematologist.64 When using its experimental iron chelating drug (deferiprone) on patients with thalassemia, a heritable blood disorder, in a clinical trial paid for by Apotex, she discovered serious risks and attempted to publish them, but Apotex threatened to sue her for doing so. Because of its financial ties to Apo- tex, her employer, the University of Toronto (UT), failed to support her. In 1998, she published her findings and UT terminated her employment. The case exposed the limits of academic freedom in Canadian medicine and the ties between medical universities and drug companies. An investigation in 2001 by the Canadian Asso- ciation of University Teachers vindicated Olivieri.65

Physicians who work for drug companies can make half-million dollars a year flying around the country giving talks to physicians to promote a pharmaceutical company’s new drug.

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Medical journals run expensive ads from drug companies, and almost all med- ical practices allow drug representatives to buy them and their staff expensive daily lunches or dinners. Drug companies give these gifts because they work. Learning to take free stuff from drug companies begins in medical school, when students learn to expect free food at lunch paid for by drug companies. The organization No Free Lunch tries to counter these gifts on medical students and physicians (look at their website for more information).

Toward International Standards of Research Ethics

Over the last 50 years, Big Pharma has exported lots of research to people in devel- oping countries, although less than 10 percent of that research is intended to benefit such people.66 In North America and Europe, despite some famous exceptions, consensus has developed about standards of ethical research.

During the past 50 years, many thousands of people in third-world countries were subjects of studies, many of them placebo-controlled. One occurred in 1996 by Pfizer in Kano, Nigeria, during an epidemic there of deadly meningitis in chil- dren. Pfizer researchers flew there and gave half of 200 infected children either the low dosage of the standard antibiotic ceftriaxone or Pfizer’s experimental drug Tro- van. Pfizer had never tested this drug in oral form on children.67

Researchers commonly create conditions most favorable to proving efficacy of their own drugs, such as giving low dosages of standard drugs or “washing out” all traces of previous drugs in subjects, making them worse off.68 In this study, five children died who took Trovan, six died who took the lower dose of ceftriaxone, and “many others [were] blind, deaf, paralyzed, or brain-damaged.”

Work over the past decade in bioethics has focused on four questions about such medical research in developing countries: (1) How can we prevent vulnerable patients from being exploited by research? (2) How can such patients give informed consent? (3) Is it right to apply standards of research of developed countries to research in developing countries, or can there be a double standard? (4) Are there special problems of context in doing research on poor, illiterate people in developing countries?

The first problem, of exploitation, can be illustrated by the fact that the 10 biggest pharmaceutical companies in 2002 had more combined profits than the combined profits of the other 490 companies on the Fortune 500 list.69 Given such profits isn’t any drug testing by Big Pharma on vulnerable patients likely to exploit them? The 2005 film The Constant Gardener chronicles one such case in Africa. Is there any way to adequately compensate poor Africans for being the guinea pigs for new drugs that will mainly benefit children in North America?

The second problem, of informed consent, has been contested by people who say it upholds an individualistic model of autonomous, educated patients not applicable to members of illiterate tribes in South America and Africa. In the vertical-HIV-transmission trial, consent of tribal leaders was the best that could be achieved.

Perhaps that is so, but it also resembles excuses of the USPHS in not telling the men of the Tuskegee Study about “bringing them to autopsy” because the men were too ignorant to understand.

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The third problem, a double standard, vexes many people. In America, IRBs and the FDA monitor research, but nothing like these institutions exist in most developing countries. Who then monitors, say, Merck Pharmaceutical’s research in Guatemala?

A problem here is where placebos can be used in developing countries. In developed countries, a new drug or device is generally tested against the traditional drug or device, not a placebo. Even where researchers did not originally do placebo- controlled studies, new drugs are usually only tested against currently used drugs, not placebos. Yet the vertical-HIV-transmission study on vulnerable African mothers did use a placebo before it was stopped.

One solution is to have domestic IRBs of researchers monitor overseas research and apply the same standards. In that case, the vertical-HIV-transmission research could not have been done because, as said, giving AZT to all HIV+ babies was the standard of care at the time.

The final dilemma concerns contextual problems of doing research overseas in poor countries. In America but not in the middle of the savannah or jungle, should a problem arise in a Phase I study of a drug, emergency rooms, EMT personnel, and local hospitals are available to treat allergic reactions. Does that mean such research can never be done in the wild?

The Collaborative Model

One widely discussed solution to most of these problems is for the institution spon- soring the research and the area of the developing country to develop a long-term partnership. Rather than an international company swooping down for a one-time research trial, both sides should think of an arrangement lasting for decades. In this way, both sides can potentially benefit.

First, research on vulnerable populations should not be done if such people cannot benefit from the research at all. Second, if the research is successful, the people on whom it has been tested should receive adequate supplies of the drugs as partial recompense for their participation.

Third, it might be necessary to help a developing country build infrastructure to facilitate a long-term partnership in research. When UAB built an AIDS hospital in Zambia, it was necessary to fund small refrigerators running on small generators to keep medicine cool in remote areas.70 Similarly, it might be necessary to train and fund medical technicians, midwives, or local physicians to draw blood over a decade in order to study the long-term effectiveness of interventions. More radically, traditional tests for diseases depend on high-tech, faraway, diagnostic labs not avail- able in developing countries. Lack of such labs and their results may affect the health of many people in poor countries. To overcome this gap, point-of-care testing with wireless transmission back-and-forth via satellites may be necessary to help indigent populations.71

The reverse of this seems obvious: If no partnership exists, researchers will be perceived as exploitive and countries will refuse to grant rights to investigate, to take samples, or to apply for patents. If something like Severe acute respiratory syndrome or SARS breaks out, this could be dangerous for the world.

Such collaboration is called the Fair Benefits Model and emphasizes sharing the benefits of successful medical research.72 One good start is the third edition in 2002

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of the International Ethical Guidelines for Biomedical Research Involving Human Subjects by the Council for International Organizations of Medical Sciences (CIOMS).73 These are good guidelines for researchers in North American countries funded by multinational pharmaceutical companies, using vulnerable subjects in low-resource countries for the subjects, and include guidelines for compensating such subjects who are injured in research.

The Death of Jesse Gelsinger

The death of teenager Jesse Gelsinger from gene therapy changed American medical research. In 1999 in Tucson, Arizona, 17-year-old Jesse worked as a clerk and rode a motorcycle on weekends. He volunteered for experimental gene therapy at the University of Pennsylvania for his inherited disorder, ornithine transcarbamylase (OTC) deficiency.

In OTC, the liver doesn’t properly cleanse blood of ammonia, produced in normal metabolism, resulting in toxic levels. Many OTC newborns die around birth; half don’t live to age 5. A new regimen of drugs and diet enabled Jesse to live to be a teenager, but without a cure, he would eventually die.

Jesse entered the study as a healthy research volunteer. A friend said he “wanted to prove he was a man.”74 Penn researchers claim they told Jesse that the experiment wouldn’t help him, but that it might help OTC babies. Jesse wanted “to help save lives,” his father said.

Penn researcher James Wilson injected an adenovirus into Jesse that contained copies of the gene lacking in OTC patients. Four days later, Jesse’s liver had been destroyed, his blood thickened to jelly, and all his organs shut down.75

A subsequent wrongful death lawsuit claimed that Wilson both knew that the virus had injured other OTC adults and that he failed to explain this to the Gelsing- ers. Penn bioethicist Arthur Caplan claimed Wilson’s study was never even possibly therapeutic for Jesse, merely a Phase I safety-toxicity study, going so far as to say, “If you cured anybody, you’d publish it in a religious journal. It would be a miracle. All you’re doing is you’re saying, I’ve got this vector. I want to see if it can deliver the gene where I want it to go without killing or hurting or having any side effects.”76

Wilson also had a financial conflict of interest. His company, Genovo, owned patents on the adenovirus, and Biogen, Inc. had already paid Genovo $37 million for rights to genetic therapies developed by Wilson and Genovo. Wilson denied that money influenced his decisions, claiming that he was only motivated to be the first to cure a genetic disease.77

Yet Wilson reported to the FDA only 39 of 700 problems about the virus, although the law required reporting all 700. In 2000, researchers concluded that adenoviruses should be used only as a last resort, not on healthy volunteers, and NIH halted gene therapy.

The Gelsinger family settled out of court with Penn for undisclosed monies. After an investigation of Wilson’s research, the NIH in 2000 suspended medical research at Penn. After a congressional hearing into Jesse’s death, the NIH vowed to better monitor medical research. As a result, it suspended medical research at the University of Colorado Medical Center, at the University of North Carolina, at Johns Hopkins Hospitals, and at the University of Alabama at Birmingham.

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THE BUCHAREST EARLY INTERVENTION PROJECT (BEIP)

Nicolae Ceau"escu ruled Romania as a dictator as part of the Union of Soviet Social- ist Republics from 1967 until he was killed in 1989. Desiring to increase his popu- lation, he made use of contraception and abortions a crime, resulting in many unwanted children, whose parents often dumped them in state-run orphanages. In 1990, over 170,000 children resided in Romanian orphanages.

In 2001, researchers Charles Nelson of Harvard Medical School, Charles H. Zeanah of Tulane Medical School, and psychologist Nathan Fox of the University of Maryland saw a study in nature, hence an opportunity to follow these children to study how neglect damaged the developing brain. They screened 187 orphans under the age of 31 months and divided them into two groups: a control group of 33 boys and 35 girls to remain in orphanages and an intervention group of 34 boys and 34 girls, who were placed in foster homes.

The study continued until 2013, when the authors published their Romania’s Abandoned Children, which became a landmark study in neuroscience proving that lack of stimulation severely damages the brain.78 Hearing about BEIP, bioethicist Joseph Fins likened it to the Tuskegee Study because a control group existed that could have been helped by intervention.79

Nelson, Fox, and Zeanah replied that Romanian officials suspected agents of foster care with selling babies and also saw nothing wrong with their orphanages. These officials needed hard proof that life in their orphanages harmed children. The researchers also replied that no children were worse-off because of BEIP, that IRBs at their three institutions approved the study, that the hard evidence proved by BEIP helped millions of orphans worldwide to leave institutions, and that after the study finished, Romania banned institutionalization of children under age 2.

Nevertheless, parallels with the Tuskegee Study were striking: Both studies had a non-treatment group over many years for a comparison, both used vulnerable, poor subjects who could not leave; both were run by prestigious organizations, and both were not secret. Moreover, in both studies, researchers claimed the subjects would not have gotten treatment anyway and that local officials cooperated with them. Finally, visiting evaluators in BEIP were ordered not to touch the subjects and, if they started crying, to leave the room, so as to not influence the children.

Critics claimed that in 2001 when BEIP began, substantial evidence already existed that extreme deprivation harmed the developing human brain. Also, was it really necessary to leave children in the control group for 12 years? Shouldn’t a stop rule have been invoked, once it became obvious that deprivation was harming kids who were controlled? Were children in the control group, in Kant’s terms, treated as a mere means to scientific knowledge?

Even if it is true that without BEIP, no orphans might have been adopted, once the researchers included the orphans in their research, didn’t they have any obli- gations to them? Did Romania get enough benefits from the research? Did Harvard, and the MacArthur Foundation (which helped fund BEIP), have any obligations to use their vast endowments to help children in the control group?

Fins believes that some of the greatest abuses occur because no one speaks truth to power. Is this one of those cases?

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