Research Ethics

Overview

Marcia Angell

Marcia Angell, the executive editor of the New England Journal of Public Health, shocked the research community when she published an editorial comparing the AZT clinical trials in the developing world and the infamous Tuskegee Study. Your job in this module is to determine whether this comparison is apt.

The FDA approved AZT in 1987. AZT was the first antiviral drug approved in the U.S. to treat HIV/AIDS. The safety and effectiveness of AZT was established by a placebo controlled double blind study. HIV+ subjects were divided into two groups: the control group and the experimental group. Participants in the control group were given a placebo. Participants in the experimental group were given 1500 mg of AZT daily. The study was planned to last 24 weeks. Researchers ended the study after 16 weeks—19 members of the control group had died while only one member of the experimental group had died. The researchers then gave AZT to members of the control group.

Later studies showed that AZT was effective in reducing perinatal transmission (Links to an external site.)Links to an external site.. In the U.S. and other developed countries, AZT is routine. This was indeed a groundbreaking development—HIV+ mothers did not have to pass on the virus to their children. However, most HIV+ mothers in the world today live in countries where the health ministry cannot afford the $1000 price tag. So although there is a way to prevent infants being born HIV+, many still are because the drug is simply out of their price range.

Medical professions and researchers in the developing world sought to do what they could, given their financial constraints. In the Thailand, Ivory Coast and Uganda, scientists developed clinical studies to see if a shorter (and hence more affordable) dose of AZT would be effective. Of course, the full dose would still be the preferential treatment. But the full dose was not an option. So scientists wanted to see how much bang for their buck they could get from a $50 dose.

The controversy surrounds the design of the study. Researchers again ran a placebo-controlled study. They gave the control group a placebo and they gave the experimental group the short course of AZT. Note that it had already been established that the $800 longer course of AZT was the most effective. Ethicists argue that once an effective dose has been established, it is wrong to use a placebo. Scientists in these countries should have tested the $50 dose against the $800 dose, and not against a placebo.

As we learned in the last module, for a study to be sound it must promise results. A condition known as “clinical equipoise” must exist. When scientists are testing a new drug they are hoping the new drug will be more effective than standard treatment. If there is reason to believe, say based on animal studies, that the new drug will be less effective than standard treatment, then the study is redundant.

The Nuremburg Code says human subjects can only be used if the study promises fruitful results. Clinical equipoise is the state of not knowing whether the new drug is better than existing treatment. Critics argue that because we know the longer course is effective, use of placebo is morally wrong. Angell explains.

Only when there is no known effective treatment is it ethical to compare a potential new treatment with a placebo. When effective treatment exists, a placebo may not be used. Instead, subjects in the control group of the study must receive the best-known treatment. Investigators are responsible for all subjects enrolled in a trial, not just some of them, and the goals of the research are always secondary to the wellbeing of the participants. Those requirements are made clear in the Declaration of Helsinki of the World Health Organization (WHO), which is widely regarded as providing the fundamental guiding principles of research involving human subjects. (Angell, p. 1)

The improper use of placebo shows, Angell argues, that the researchers in these cases place their research above the wellbeing of the participants.

It states, “In research on man, the interest of science and society should never take precedence over considerations related to the wellbeing of the subject,” and “In any medical study, every patient — including those of a control group, if any — should be assured of the best proven diagnostic and therapeutic method.” The subjects in these studies are being used as a means to an end.

Angel then draws the comparison of these AZT trials and the infamous Tuskegree Study. Let me quote Angell at length.

A textbook example of unethical research is the Tuskegee Study of Untreated Syphilis.

In that study, which was sponsored by the U.S. Public Health Service and lasted from 1932 to 1972, 412 poor African-American men with untreated syphilis were followed and compared with 204 men free of the disease to determine the natural history of syphilis. Although there was no very good treatment available at the time the study began (heavy metals were the standard treatment), the research continued even after penicillin became widely available and was known to be highly effective against syphilis. The study was not terminated until it came to the attention of a reporter and the outrage provoked by front-page stories in the Washington Star and New York Times embarrassed the Nixon administration into calling a halt to it.

The ethical violations were multiple: Subjects did not provide informed consent (indeed, they were deliberately deceived); they were denied the best known treatment; and the study was continued even after highly effective treatment became available. And what were the arguments in favor of the Tuskegee study? That these poor African-American men probably would not have been treated anyway, so the investigators were merely observing what would have happened if there were no study; and that the study was important (a “never-to-be-repeated opportunity,” said one physician after penicillin became available).

Ethical concern was even stood on its head when it was suggested that not only was the information valuable, but it was especially so for people like the subjects — an impoverished rural population with a very high rate of untreated syphilis. The only lament seemed to be that many of the subjects inadvertently received treatment by other doctors. (Angell, p. 3)

One point is absolutely clear—researchers would never get approval in the United States to conduct a placebo-controlled study comparing the shorter course of AZT and placebo. To say that such studies are permissible in third-world countries but not the United States is unethical. It’s like saying that research subjects in the U.S. have rights under the Nuremburg Code but that subjects in third-world countries do not.

I want to pause here and evaluate Angell’s line of thought. Intuitively, something does not feel right about the AZT trials. Research scientists are not just scientists; they are doctors. And doctors have an obligation to provide the very best care they can for their patients. Use of placebo is not the very best care; it is no care at all. Even the short course is not the best care; it is substandard care. So why do the study? Why make use of pregnant HIV+ African women?

Don Marquis

Marquis begins his article by highlighting the conflict, mentioned above, between doctor-as-researcher and doctor-as-physician. The physician has a duty to promote the wellbeing of his or her patients. When placing subjects in the control group, the researcher is not promoting the wellbeing of the subjects. One way to resolve this conflict is by appealing to the notion of clinical equipoise—if researchers don’t know which protocol is more effective, they can’t be said to be treating the control group unfairly. Marquis rejects this standard. Scientists always have hunches. They are always inclined to think the new intervention will be more successful than existing protocol—otherwise they would be wasting their time.

Does this mean that placebo-controlled clinical trials are immoral? Let me note that medicine (and science in general) depends on placebo-controlled clinical trials. Without such trials, doctors would still be bloodletting. How then can placebo-controlled studies be justified? Marquis’s answer here is informed consent. Researchers must be completely upfront with prospective participants. They must inform potential participants that they have a 50 percent chance of being placed in the control group, where they will receive no intervention.

Bagenda and Musoke-Mudido

Let us take up this standard and evaluate the morality of the AZT perinatal studies in Uganda. Bagenda and Mudido are the Ugandan doctors who designed the AZT perinatal studies. In their article “We’re Trying to Help Our Sickest People: Not Exploit Them” they set out the motivation for the study.

At the Mulago Hospital [where they work], where more than 20,000 women deliver each year, we are trying to find effective therapies to stop transmission of HIV from pregnant women to their babies. About one in five babies becomes infected with HIV during pregnancy and delivery. If he mother breast-feeds her baby, there is an additional 15- to 25-percent chance that the baby will later become infected. There is no available treatment for the disease in Uganda. After careful consideration among researchers from developing and developed countries, the World Health Organization (WHO) recommended in 1994 that the best way to find safe and effective treatment for sufferers in countries in the developing world is to conduct studies in which new treatments, better tailored to the local population, are compared with placebos (inactive pills).

Bagenda and Mudido note that they go to great lengths to educate prospective participants and to secure informed consent.

Women who enroll in our studies undergo intensive education and individual counseling. They are given a comprehensive consent form, written in the local language, which they are encouraged to take home and discuss with their families. It describes the potential risks of participating in the study and their chances of receiving a placebo. Only when they and their counselors are satisfied that all questions have been answered are they asked to sign the form. Our careful attention to these measures has consistently met the standards of national and international ethical review committees.

They further note that they hire only female counselors. (In Ugandan society males tend to dominate females. The female-to-female counseling helps ensure a level playing field.) They also hire counselors who speak the woman’s native language. Uganda has 40 native languages. The counselors explain to the women that they may be placed in the control group or the experimental group. None of the subjects were harmed. In fact, all benefited from participating in the study—all received doctor’s visits, clean water and prenatal vitamins. Angell’s qualm can be flipped around—it’s not that the doctors failed to give women in the control group the very best care. It’s that women in the control group were not helped as much as the women in the experimental group.

This is a key point raised in the reading by Brody (p. 303). In the Tuskegee Study the men were denied treatment that should have been made available to them. The doctors actively withheld treatment. They chose to withhold treatment. And that is clearly wrong. But the same criticism cannot be leveled against the AZT trials. Doctors in developing countries do not have access to expensive medications.

But still is it okay to use pregnant HIV+ women who are scientifically illiterate in a clinical trial? Your answer to this question depends largely on whether you think pregnant HIV+ women who are scientifically illiterate are capable of giving informedconsent. (Note that to say they can’t, smacks of paternalism.) I am inclined to say these women are capable of deciding what is in the best interests for their child.

I want to return to Angell’s comparison of this experiment with Tuskegee. I think there are two key differences. In Tuskegee, the men did not know they were a part of a study. There is no question that researches failed to obtain informed consent. In the AZT trials it seems that Bagenda and Mudido went to great lengths to secure informed consent.

Second, Angell’s claim that the women were used as a means to an end rests on a mistaken reading of Kant. Recall that Kant says we ought to treat people as ends in themselves and never merely as a means to an end. The key word here is “merely”. Yes, Bagenda and Mudido were using them to obtain results. But they are not coercing the women to participate in the study. It would seem the key difference between Tuskegee and the AZT study is one of coercion.

I want to touch on one further question: Does affordability impact clinical equipoise? In the Tuskegee Study the doctors had access to penicillin and yet they chose not to treat the men. In the AZT study, Bagenda and Mudido did not have access to the $800 per person protocol. Here’s a math problem for you. Suppose you only have $800 to run your study. You can either treat one pregnant HIV+ woman. The results here would be one newborn with a 96 percent chance of being born HIV-. Or you can treat 16 women with the $50 dose and have 16 newborns with a 92 percent chance of being born HIV-. (The shorter course of AZT reduces perinatal transmission from 26-34 percent, depending on whether the mother breastfeeds down to 8 percent.) If you are working at an underfunded hospital in a third-world country, you have to ration medication based on rationing schemes that are going to treat the most people as inexpensively as possible.

There is yet another factor that must be taken into account. The overwhelming majority of women in the United States seek prenatal care. HIV tests are standard procedure. To be effective, AZT must be started in the first trimester of pregnancy. Women in Uganda cannot afford prenatal care. But Ugandan women rarely get prenatal treatment in the first trimester. Many do not show up until after 30 weeks of pregnancy. After this time, AZT is not effective. The longer course of AZT is simply not culturally feasible.

Moreover, Bagenda and Mudido point out that Ugandan women often suffer from Malaria and iron deficiency. The placebo-controlled study was necessary to see how existing health conditions prevalent in Ugandan society impact the effectiveness of AZT.