Oct 04 2010
Several of the bloggers here at SBM have repeatedly criticized various clinical trials for so-called “complementary and alternative medicine” interventions for various conditions and diseases (or should I say dis-eases?) for being completely unethical. Examples include the misbegotten clinical trial for the Gonzalez protocol for pancreatic cancer, which — surprise, surprise! — ended up showing that patients undergoing Dr. Gonzalez’s combination of 150 supplements a day, dietary manipulations, and coffee enemas, actually did much worse than those undergoing standard of care, despite how depressingly poor the results of standard of care are; clinical trials of homeopathy in Honduras and other Third World countries, which both Wally Sampson and I lambasted; and ongoing clinical trial of chelation therapy for cardiovascular disease. I’ve also criticized the “autism biomed” movement, that amalgamation of parents who believe that vaccines cause autism and yet are willing to subject their children to all sorts of quackery to “cure” the “vaccine injury” of uncontrolled and unethical experimentation on autistic children. As valid as all these criticisms are, it is important to recognize that science-based medicine is not free of its own abuse of ethics.
A couple of weeks ago, I wrote about the concept of clinical equipoise. Clinical equipoise is a critical concept in any clinical trial. Basically, a state of clinical equipoise exists when there is genuine scientific uncertainty over which of the options being tested in/on living, breathing human beings is better, and any clinical trial in which a state of clinical equipoise does not exist is at the very least ethically dodgy and probably downright unethical. For example, when the occasional anti-vaccine activist argues for a randomized controlled clinical trial comparing vaccinated children and unvaccinated children, it’s easy to shoot that idea down as unethical because there is no clinical equipoise. The children receiving placebo vaccines would be put at a much higher risk of suffering harm compared to the vaccinated children because they would be left unprotected against life-threatening diseases. In the realm of conventional medicine, the reason that few cancer clinical trials involve a placebo control group anymore but instead test a new therapy either against the standard of care or with the standard of care is because in many, if not nearly all, cases placebo use in a cancer patient is unethical when there exists effective therapy, even if the therapy is not all that effective. What all this boils down to is that science is only part of the basis of science-based medicine. Medical ethics must take precedence. After all, arguably the most efficacious way to test a new antibiotic would be to infect people with the bacteria the antibiotic treats and then divide these people up into a placebo control group and a group receiving the antibiotics to see how each group does. After all, this is the sort of thing that the Nazis and Japanese did during World War II, and the same sort of dehumanization and abuse of research subjects that every ethical precept regarding human subjects research that has been developed since then, such as the Helsinki Declaration of 1964, has been designed to prevent.
Unfortunately, medical scientists in the U.S. have not always lived up to these precepts. The most famous example is arguably the Tuskegee syphilis experiment, in which poor black men with syphilis were studied and the control group denied effective therapy for syphilis even after it was known that penicillin was an effective treatment for syphilis. This study spanned 40 years, from 1932 to 1972, and is justifiably held up as one of the worst examples of research misconduct in American history, if not the history of the world. The shock the revelation of this study to the American public in 1972, when it learned of men dying of syphilis, women contracting syphilis, and babies being born with congenital syphilis, all unnecessarily, led to Belmont Report and the establishment of the Office for Human Research Protections (OHRP).
It turns out that there was an even worse atrocity against medical science perpetrated by U.S. investigators in Guatemala over 60 years ago that only now has come to light in stories in the New York Times, MSNBC, and elsewhere. So bad was the offense that Secretary of State Hillary Clinton and Secretary of Health and Human Services Kathleen Sebelius have issued a formal apology to the Guatemalan government for the experiments in which Guatemalan prisoners were intentionally infected with syphilis and then treated with antibiotics, an apology that President Obama reiterated in a personal telephone call to Guatemalan President Alvaro Colom on Friday.
Experimenting on Guatemalans
The Guatemala syphilis experiment might have remained lost in the depths of history, unknown, records of its having taken place buried in archives at the University of Pittsburgh, were it not for the efforts of Wellesley College Professor of Women’s Studies Susan Reverby and medical historian, who unearthed the notes of John C. Cutler, who, ironically enough, later spent some time as an important member of the team carrying out the Tuskegee experiment and continued to defend the study 20 years after it was closed. What she found was horrifying, and she has recently published a manuscript describing her findings. Because I always like to go to the primary source wherever possible, I will refer you to the manuscript, available on Dr. Reverby’s faculty web page and entitled “Normal Exposure” and Inoculation Syphilis: A PHS “Tuskegee” Doctor in Guatemala, 1946-48 (synopsis here). The HHS response can be found here, including the statement issued on Friday by Clinton and Sebelius in both English and Spanish.
The background behind Professor Reverby’s revelations is important. As she states in the advanced synopsis:
Perhaps the most infamous of American research studies is the “Tuskegee” Syphilis Study in which the U.S. Public Health Service (PHS) watched, but did not treat, hundreds of African American men with late stage syphilis for forty years (1932-1972).1 Much of the folklore surrounding this study assumes that the doctors actually infected African American men in Macon County, Alabama with syphilis by inoculating them with the disease. Historians of the Study, the author included, have spent years now explaining why this was not true and why this myth persists. Part of the explanation is that the spirochete-shaped bacteria that cause syphilis cannot be cultured and grown in a laboratory, easily put into a syringe, or transferred from the blood of one infected person to another.
The inoculation story that is part of the Tuskegee myths did, however, go on elsewhere. In 1946-48, Dr. John C. Cutler, a PHS physician who would later be part of the Syphilis Study in Alabama in the 1960s and continue to defend it two decades after it ended in the 1990s, was running a syphilis inoculation project in Guatemala, co-sponsored by the PHS, the National Institutes of Health, the Pan American Health Sanitary Bureau (now the Pan American Health Organization), and the Guatemalan government.
It was the early days of penicillin and the PHS was deeply interested in whether penicillin could be used to prevent, not just cure, early syphilis infection, whether better blood tests for the disease could be established, what dosages of penicillin actually cured infection, and to understand the process of re-infection after cures. Many scientific questions remained to be answered.
Now you see why the Guatemala syphilis experiment is arguably worse than the Tuskegee experiment, although the Guatemalan experiment only lasted two years and every man infected with syphilis was given penicillin. On the other hand, as the full manuscript describes, although researchers did obtain permission for their studies from the prisons and other institutions with which they worked, they did not receive permission from the inmates or their families. Indeed, deception was part and parcel of the entire process. In return for cooperation, researchers offered supplies to the institution, such as anti-seizure medications like Dilantin, refrigerators to store medications, and a “motion picture projector that supplied the sole recreation for the inmates, metal cups, plates and forks to supplement the completely inadequate supply available.” Individual subjects were plied with cigarettes, “an entire packet for inoculation, blood draws or spinal taps and a single cigarette for ‘clinical observation.’”
Researchers also went to ludicrous extremes to infect the men with syphilis. First, they took advantage of legalized prostitution in Guatemala and the fact that Guatemala allowed prostitutes to pay regular visits to men in penal institutions by locating prostitutes with syphilis:
With the cooperation of officials at the Ministry of Justice and the warden of Guatemala City’s Central Penitentiary, which housed nearly 1500 inmates, prostitutes who tested positive for either syphilis or gonorrhea were allowed to offer their services to prison inmates, paid for by U.S. taxpayers through the funds of the PHS. In yet another set of experiments, uninfected prostitutes had inoculum of the diseases placed on their cervixes before the sexual visits began. Serological tests were done on the inmates before the prostitutes were invited to the prison and then afterwards to see if infection had occurred. The men were divided into groups and various chemical and biological prophylaxis techniques were tested after presumed infection. If positive, the men were then provided with enough penicillin to produce a cure.
Your tax dollars at work in 1946. This method soon ran into problems:
Not enough of the sexually well-serviced men (the researchers actually timed how long they spent with the prostitutes and thought they acted “like rabbits”), even when plied with alcohol, seemed to getting syphilis. The prostitutes were not easily controlled either, and one researcher lamented, “unfortunately our female donor is leaving her profession for marriage and is no longer available.”
Due to the unreliability of the serological tests used to diagnose syphilis in the 1940s, the researchers soon went beyond these methods. It turned out that there were too many positive blood tests even before the men were exposed to syphilis, which posed a huge problem given that the research protocol required men who had never had syphilis or who’d had it and been cured. This led to a trial examining the serum of children in an orphanage, where they found that indeed the false positive rate of the serological test for syphilis was quite high. This problem also meant that the researchers couldn’t yet answer whether penicillin could prevent syphilis.
So Cutler and his team went beyond using prostitutes and isolated syphilis to directly inoculate inmates with. Their sources were the gumma (syphilitic growths) on the testicles of infected rabbits or scraping the penile chancres of infected men, from which they had to isolate the spirochete that causes syphilis. This was difficult, because the spirochete could not survive more than 45 to 90 minutes outside the body, during which time it had to be isolated, centrifuged with fresh home-made beef heart broth, and then delivered to the subjects:
With the men, the inoculation was often much more direct after what soldiers for generations had called the “short arm” inspection. They chose men with “at least moderately long foreskins [to keep the mucus membranes moist]” and who could “sit or stand calmly in one spot for several hours.” In the experiments, a doctor held the subject’s penis, pulled back the foreskin, abraded the penis slightly just short of drawing blood by scraping the skin with a hypodermic needle, introduced a cotton pledget (or small dressing) and dripped drops of the syphilitic emulsion onto the pad and through it to the roughed skin on the man’s penis for at least an hour, sometimes two.
This was also compared with other methods of introducing the spirochete, including scraping of the forearm, ingestion of syphilitic tissue mixed with distilled water, introduction into the spinal fluid, and direct injection into the bloodstream.
It turns out that even back in 1946 many of the officials who knew of or participated in the experiment knew it was unethical. Even Cutler was reported to have said, “As you can imagine, we are holding our breath, and we are explaining to the patients and others concerned with but a few key exceptions, that the treatment is a new one utilizing serum followed by penicillin. This double talk keeps me hopping at times.” Even more disturbing is the general attitude among several researchers seemed to view law breaking as sometimes necessary for the advancement of medical science, as Thomas Rivers, who led the Rockefeller Institute for Medical Research Hospital in New York, made clear in his memoir in 1967:
Well, all I can say is, it’s against the law to do many things, but the law winks when a reputable man wants to do a scientific experiment. For example, the criminal code of the City of New York holds that is a felony to inject a person with infectious material. Well, I tested out live yellow fever vaccine right on my ward in the Rockefeller Hospital. It was no secret, and I assure you that the people in the New York City Department of Health knew it was being done….Unless the law winks occasionally, you have no progress in medicine.
It is against this attitude that ethical standards and laws have evolved. It is also as a result of these abuses that many minorities and underprivileged groups of people are mistrustful of physicians and science. Supporters of SBM can’t deny that there have been serious ethical violations committed by overzealous scientists who came to value the study of their scientific question more than they did for the rights and dignity of their human subjects, because the evidence of such violations of human rights are incontrovertible. The questions remain: What to do about them and how to prevent them?
The Belmont Report, The Common Rule, and CAM
After the horrors of Nazi medical experimentation and the abuses during the Tuskegee syphilis study (remember, the Guatemala syphilis experiment was not widely known until now), it was clear that rules were needed to protect human research subjects from such abuses. First came the Nuremberg Code in 1947. This code, drafted in the wake of the infamous Doctors’ Trial at Nuremberg set forth ten principles to govern human subjects experimentation, many of which regular readers of SBM will be familiar with. Examples include the requirement for informed consent; that unnecessary pain and suffering be avoided; that the experiment should be designed based on the results of animal experimentation and knowledge of the natural history of the disease that justifies the performance of the experiment (prior plausibility, anyone?); the requirement that subjects can refuse to continue at any time; and that no experiment should be conducted where injury, disability, or death can reasonably be expected (clinical equipoise). The Declaration of Helsinki, introduced in 1964 by the World Medical Assembly, is based on the same principles as the Nuremberg Code but takes them even further, for example, stating that “the interest of science and society should never take precedence over considerations related to the well-being of the subject.” The Helsinki Declaration was last updated in 2008. It is ironic that at the time the Nuremberg Code was being written and approved that the U.S. government was engaging in the same sort of abuse of human research subjects that the Nuremberg Code was designed to combat.
In the U.S., the Nuremberg Code and the Helsinki Declaration notwithstanding, the Tuskegee debacle was the impetus that led to the Belmont Report on Ethical Principles and Guidelines for the Protection of Human Subjects of Research finalized on April 18, 1979. This report identifies three essential and fundamental ethical principles for human subject research (respect for persons, beneficence, and justice) that form the basis of all Department of Health and Human Services human subject protection regulations to this day. It is essential reading for anyone doing human subject research in this country. In 1991, these regulations were — finally! — codified into what is now known as The Common Rule. All institutions doing federally funded research are required to adhere to The Common Rule.
A key aspect of The Common Rule is the Institutional Review Board (IRB). The IRB is in essence a committee that oversees all human subject research for an institution and makes sure that the studies are ethical in design and that they conform to all federal regulations. Basically, IRBs are charged with weighing the risks and benefits of proposed human subject research and making sure that (1) the risks are minimized and that the risk:benefit ratio is very favorable; (2) to minimize any pain or suffering that might come about because of the experimental therapy; and (3) to make sure that researchers obtain truly informed consent. I’ve written extensively about The Common Rule before in the context of how certain CAM trials violate the Common Rule and how, for example, Mark and David Geier created a sham IRB packed with their cronies (as so ably documented by Kathleen Seidel) to rubber-stamp their unethical studies of using Lupron to treat the “vaccine injury” they believe to be the cause of autism. What is important (and embarrassing for proponents of SBM) to note is that The Common Rule only first went into effect in 1981 and reached its current form in the 1991 revision to the U.S. Department of Health and Human Services Title 45 CFR 46 (Public Welfare) Subparts A, B, C and D. Subpart A. What that means is that, in the United States at least, the current government regulations mandating a baseline standard of ethics have only been in effect less than 30 years and only in their current form for less than 20 years.
Ethics: The difference between CAM and SBM
Not surprisingly, CAM proponents have jumped all over these revelations. For example, even quackery promoter Mike Adams has a grain of a valid point when he writes hysterical headlines like Guatemalan STD medical experiments were just one crime in a long history of medical-government collusion to use humans as guinea pigs. Unfortunately for him, he can’t resist taking a valid criticism and running right off the rails with it. Most of the examples he mentions date back at least 50 years and are now commonly known. Few of them are more recent than the 1970s. Most of these are either problems that couldn’t reasonably been foreseen (for instance, the observation that 30% of the participants of a trial for a vaccine against hepatitis B were found to be HIV-positive in 1983) or that are questionable pseudoscience at best, such as ranting against the clinical trials of Gardasil or labeling vaccine mandates as being the equivalent to the Tuskegee or Guatemala syphilis experiments. This is a point that Anne Dachel, Media Editor for the anti-vaccine propaganda blog Age of Autism, predictably parroted yesterday in a post entitled Valid Concern for 60 Year Old Medical Travesty: What About Today’s?, in which she attacks bioethicist Art Caplan for alleged hypocrisy in his refutations of anti-vaccine misinformation in “contrast” to his justifiable outrage over the revelation of the Guatemala syphilis experiment, even going so far as to write:
Increasing exposure to mercury is having a dramatic impact on our lives. “Nonetheless, officials knew it was wrong” also means that there’s a great incentive to cover up the damage at all costs. There is a real lesson from the Guatemala and Tuskegee experiments. Let’s hope it doesn’t take 60 years before officials admit what mercury exposure in vaccine has done to our children.
Never mind that the concept that mercury in vaccines causes autism is a long-discredited hypothesis, a failed hypothesis even more discredited (if that were possible) than the hypothesis that vaccines cause autism. The difference is important; in the case of vaccines science is on the side of those defending the clinical trials studying vaccines and their efficacy, not on the side of anti-vaccine activists like Anne Dachel. Odd, too, that she failed to mention Mark and David Geier’s and Andrew Wakefield’s completely unethical experiments.
Not really, actually.
Yes, charges of hypocrisy go both ways, which is why one of the reasons I wanted to write about the Guatemala syphilis experiment is that it is a stark reminder to proponents of SBM (like myself) that SBM does have a history of not always being as ethically pure as we should be. Indeed, the U.S. Government was right, albeit late, to apologize to the Guatemalan government:
The sexually transmitted disease inoculation study conducted from 1946-1948 in Guatemala was clearly unethical. Although these events occurred more than 64 years ago, we are outraged that such reprehensible research could have occurred under the guise of public health. We deeply regret that it happened, and we apologize to all the individuals who were affected by such abhorrent research practices. The conduct exhibited during the study does not represent the values of the United States, or our commitment to human dignity and great respect for the people of Guatemala. The study is a sad reminder that adequate human subject safeguards did not exist a half-century ago.
Today, the regulations that govern U.S.-funded human medical research prohibit these kinds of appalling violations. The United States is unwavering in our commitment to ensure that all human medical studies conducted today meet exacting U.S. and international legal and ethical standards. In the spirit of this commitment to ethical research, we are launching a thorough investigation into the specifics of this case from 1946. In addition, through the Presidential Commission for the Study of Bioethical Issues, we are also convening a body of international experts to review and report on the most effective methods to ensure that all human medical research conducted around the globe today meets rigorous ethical standards.
Reparations to survivors and families would be entirely appropriate in a case like this, as is the investigation ordered by the U.S. government into what happened. It is also entirely appropriate to point out, as Robert Herriman does, that at the time Dr. Cutler’s experiments were being carried out, the U.S. government was passing judgment on the Nazi doctors who carried out the same sorts of experiments, such as purposely infecting prisoners with tetanus and other agents to test the effectiveness of the antibiotic, sulfonamide? What was done in Guatemala in the name of public health was, at its core, different only in that the U.S. didn’t actually round up prisoners and throw them in concentration camps to do its experiments. In other words, little different.
The difference, however, is that proponents of SBM must be (and, for the most part, are) advocates for ethics in all medical experimentation, be it animal or human research. SBM depends upon science and rigorous clinical trials, but never at the expense of violating clinical equipoise, subjecting subjects to risks without true informed consent, or violating patient autonomy. All too many CAM advocates and anti-vaccine advocates use ethical misadventures and abuses as nothing more than a tu quoque argument; they delight in pointing out the gross ethical violations that are committed from time to time by science-based investigators while ignoring those committed by “their side,” such as Nicholas Gonzalez and the investigators performing the Gonzalez trial, Mark and David Geier, Andrew Wakefield, and the investigators performing the TACT trial. (Ironically, except for the Geiers’ trial, all of these trials were funded by our tax dollars — every bit as much as the Guatemalan or Tuskegee syphilis trials.)
I have long argued that there should be no such thing as “alternative” medicine. Rather, there should be one scientific standard for medicine regardless of where it comes from, and that includes all of what is commonly referred to as “CAM.” Similarly, there should be one ethical standard for all research involving human subjects. Unlike Adams and Dachel, when I condemn ethical atrocities in CAM trials that does not mean I will turn a blind eye when such lapses occur in trials of ostensibly science-based medicine and nor should anyone else. The Guatemalan syphilis experiment was indeed a gross failure on the part of SBM to live up to ethical precepts and police its own, but, as shocking as this incident is, it does not validate Mike Adam’s quackery and conspiracy theories or Anne Dachel’s anti-vaccine pseudoscience any more than it invalidates science-based medicine. What it should do is to strengthen the resolve of anyone involved in SBM never to let something like this happen again, regardless of the kind of medical study.
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