Medical research in humans has come a long way from the dissection of corpses and animals in the day of William Harvey. Two separate disciplines, ethics and statistics have informed modern practice and are necessary to understand for an appreciation of some of the research challenges posed by amniotic fluid embolism.
Human Research Ethics in Practice
First and foremost in enrolling patients in research study is the necessity of obtaining informed consent. The first published, generally accepted, guidelines concerning ethical human research came out of war crimes trials in Nuremburg, Germany at the end of World War II. The Nuremberg Code emphasized the rights of the individual to choose to participate—or not—and to end study participation at any time. Furthermore, individual risk and suffering had to be minimized and a specific scientific benefit has to be derived from the study. The ten principals that emerged were further codified by the Declaration of Helsinki, first published by the World Medical Association in 1964, and revised periodically.
The potential ethical problems in human research (outside of the atrocities of World War II) are perhaps no where better exemplified than in the Tuskegee syphilis experiment conducted by the US Public Health Service in Tuskegee Alabama from 1932 to 1972. Black men with syphilis were studied to learn about natural disease progression. At the start of the study, the slightly effective treatment that was available was offered. However, when penicillin was developed as a treatment for syphilis by 1947, study participants were not offered the cure. In fact, diagnostic testing for neurosyphylis, in the form of a spinal tap, was presented to study participants as a “treatment.” The study came to an abrupt end in 1972 when a Public Health Service employee, Peter Buxton, went to the press after complaining with PHS for six years about the study. 128 men of the original 400 had died of syphilis, 40 of their wives had been infected and 19 of their children had been born with congenital syphilis.
As a result of the Tuskegee study scandal, the US Department of Health, Education, and Welfare commissioned a study known as the Belmont Report to inform future legislation and oversight of medical research in the United States. Issued in 1976, the report emphasized basic ethical principles which are now taught in medical schools. “Respect for persons” reflects the believe that people are autonomous and that those with diminished autonomy should be protected. “Beneficence” describes the ethical duty that goes beyond respecting autonomy of people to secure their well-being. (For instance, a patient may request a procedure or treatment but if a physician does not believe it will be helpful, is ethically obligated to decline.) Finally, “justice” refers to the relationship between a study’s benefits and its risks—not just to individuals but as these risks and benefits affect different populations differently.
Although little recognized, the Tuskegee study reentered American consciousness in the 2008 presidential campaign between Barak Obama and John McCain. Mr. Obama’s minister, Reverend Jeremiah Wright, had been widely televised as stating during one of his sermons that, “The United States Government had developed the AIDS virus to commit genocide on black people.” While many commentators were outraged at this outlandish claim, it was apparent from their remarks that they were unfamiliar with the reality of the Tuskegee study in which the government did withhold treatment from black men for a sexually transmitted infection. Of course, Reverend Wright failed to mention that the United States Government has established a huge oversight mechanism to be sure that another Tuskegee study never happens.
As a result of the Belmont Report and decades of legislation, human research in the United States has to be approved at the outset and then monitored by Institutional Review Boards. Comprised of both lay people and physicians, the IRB’s are responsible for assuring that all studies that receive federal funding provide adequate protection and supervision of study participants. IRB approval is required before any patient can be enrolled in a study and study review is required at least annually.
Obtaining Institutional Review Board approval for a study is a highly specialized, formal process. For example, the principal investigator who submits the protocol has to provide documentation that he or she has reviewed the National Institutes of Health course on medical research—which includes a discussion of the Nuremberg Code, the Helsinki Declaration, the Belmont Report, and the. In general, IRB submissions are created with the help of a clinical research nurse who has specialized training in the rules and regulations surrounding clinical research at that institution (i.e. hospital or university). Once approved, the researcher has to submit annual reports concerning patient enrollment, outcomes, data, and adverse events as well as statements regarding potential financial conflicts of interest. In general, even studies funded by foundations and not by federal grants try to adhere to federal guidelines—both for ethical reasons. Obviously, research subjects in privately funded studies should not have less protection than those in federal studies.
These ethical considerations make research more difficult and more expensive. This is not an argument that research regulations should be relaxed. Rather, this discussion is intended to help the reader appreciate the complexity of medical research and give insight as to why it is so expensive (and of course as to why donations are needed.)
Although current research on AFE does not involve treatment (with potentially dangerous side effects) obtaining ANY blood or tissue samples from hospitalized patients requires informed consent. As AFE patients are often too ill to given consent, research consent can be obtained from family members. Since AFE is entirely unpredictable, and can occur at any time, an effective consent program requires the availability of specifically designated, highly trained individual 7 days a week. Typically, a group clinical research nurses at a tertiary care center who participate in a variety of research studies, the University or Hospital requires substantial funding to support these nurses.
To give but one example of the practical considerations in AFE research, even the simple collection of placentas is a significant undertaking. Placentas (the afterbirth) are normally discarded after delivery, without any specific discussion or consent by the patient. Although federal guidelines do not specifically call for obtaining consent for the use of tissues that are normally discarded, the IRB at Dr. Benson’s hospital has decided that informed consent is required. Dr. Benson thought this was wise since adherence to the highest ethical standard is only prudent, and since any medical journal in which the work is published will want to know about research participant consent. The point is that even obtaining tissue that would be normally discarded is a highly regulated process (that requires effort, time and money).
To given another example, even though much speculation about AFE is published, physicians at institutions which do not already have an AFE research protocol in place cannot simply obtain research specimens and send them for analysis. Failure to get informed consent from the patient in the context of an already existing human research protocol approved by that institution’s IRB could potentially place the hospital or university in violation of federal law and jeopardize all of the facility’s other research. In short, to efficiently study a disease which occurs every one in 8 to 20,000 pregnancies, research protocols are needed at institutions in which tens of thousands of deliveries are taking place.
Another aspect of modern medical research is the use of statistics to inform study design and data reporting. Both statistics itself and its interface with medicine is evolving. One frequently cited statistic in news reporting is “significance.” This is a reference to a calculated statistic that the difference seen between two groups is due to chance. If the probability (“p-value”) is less than 5% that the results are due to random sampling error, the difference is said to be statistically significant. However over the past two decades, the power of a study to detect differences between two groups has become more important. Given certain assumptions about likely differences between two study populations and their intended enrollment size, how likely is it that the study will actually find a difference if one exists?
As can be seen, medical research encompasses far more than enrolling patients and obtaining lab results. A specialized statistician is usually needed to be sure that the study results are reported in the proper perspective. In many of the AFE studies reported here, Jennifer Beaumont, was the biostatistician and is cited as a coauthor. Of course, research biostatisticians are not directly involved in patient care and need funding from outside the institution. In turn researchers who use them have their research accounts billed. Statistical analysis is an important improvement in medical research but adds further expense to study publication.