At first glance it may seem that statistics and research ethics have nothing to do with each other. Not so! Consider why so many people volunteer for medical research studies. In many cases it is because there is an expected benefit. For example, in cancer clinical trials often the investigational drug is a last hope and may not be available outside of the trial. In many cardiovascular disease studies, participants appreciate the additional care and attention and are willing to try a new drug, for example, for hypertension. And in fact, it has been shown that often, clinical trial participants live longer and do better than the general population even if they are treated with a placebo. But what is perhaps not sufficiently appreciated is that many, many people participate in studies out of altruism to advance scientific knowledge. Scientific knowledge is not advanced when a study is poorly designed, or carried out without sufficient rigor, or not large enough to give an answer. Proper statistics are a determinant of the ethics of a study.

A prime example is the Women’s Health Initiative (WHI), described in Chapter 6. Postmenopausal women were asked to join a study of hormone replacement therapy; the study would continue for up to 12 years before the results were known and might not directly benefit the women themselves, but they would answer the important question of the effect of hormones on cancer, heart disease, and osteoporosis. Many of the WHI participants took part for their daughters and granddaughters, and they expressed pride and enthusiasm for answering the questions for future generations. And indeed they did achieve that goal—one part of WHI, the estrogen plus progestin trial versus placebo, has already answered these important questions, with a startling result: estrogen plus progestin increases risk of breast cancer and also increases heart attacks, stroke and blood clots, and dementia. So although the treatment does show benefit with regard to colorectal cancer and osteoporotic fractures, the overall risks outweigh the benefits. This trial has changed medical practice for generations to come.

Well that brings us back to statistics. This study was able to answer these questions because it had sufficient power to answer them. It required 16,608 women in that part of WHI to be able to detect these effects. Even if the result had been null (i.e., if it showed no difference between the treatment and placebo groups), we could have had faith in that result because the power was there to detect a true effect if there really was one. As it turned out, the results were clear-cut, though unexpected, in favor of placebo. So the point is that in order for a study to be “ethical,” it must be designed and powered well enough so that it can answer the questions it poses. Otherwise, people who consent to participate in the expectation that they will contribute to knowledge may actually not be contributing because the study is poorly designed, powered, or executed and may be needlessly exposed to risk.

Note that there are certain study designs for which power considerations are less relevant. Examples are pilot studies, which by definition are intended to test the feasibility of a research protocol or to gather preliminary data to plan a full study and are exempt from the power issue. Power considerations may also not apply to certain drug toxicity studies (Phase I trials) or certain types of cancer trials, but certainly in prevention trials, as well as Phase III treatment trials, power is a major consideration in the ethics of research.

Human subjects in medical research contribute greatly to improving the health of people. These volunteers must be protected from harm as much as possible. In the not-too-distant past, there were some egregious breaches of ethical principles in carrying out medical research. The world’s most appalling examples are the medical experiments carried out in the Nazi concentration camps—by doctors! It defies any kind of understanding how educated, presumably “civilized” professionals could so have distorted their profession and their own humanity. But these atrocities did occur and demonstrate the horrors people are capable of perpetrating. When these atrocities became known after World War II, the Nuremberg trials of Nazi war criminals (including the doctors who preformed such research) also resulted in the Nuremberg Code for conduct of medical research which established the basic requirement of voluntary informed consent. Subsequently, the Declaration of Helsinki, in 1964, expanded and refined the research guidelines, and became a world standard, which undergoes periodic revisions.

The most infamous example of unethical research in the United States was probably the Tuskegee Institute study of syphilis, which took place in the south in the United States from 1932 to 1972. The researchers wanted to study the natural course of syphilis. In the 1940s antibiotics became available which could treat this disease, but were withheld from the participants, who were poor Black men, because an intervention to treat the disease would interfere with this observational study. In 1972 the public became aware of this experiment and in 1974 the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was established. They developed a report known as The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. These guidelines are followed by all medical schools and other research institutions that conduct research involving human participants, and they are deemed to be universal principles, cutting across cultural lines. The guidelines are based on three basic principles: respect for persons, beneficence, and justice.